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The Research Behind It — Free Papers on What Drives Chronic Disease and Why These Resources Can Help

Chapter 17 of 18 in Notbroken's Free Metabolic & Mental Health Help Directory: 280 listings in 20 categories, each carefully checked. Open the full directory of 2299 listings.
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Last Updated: November 1, 2026 • For Educational Purposes Only • Not Medical Advice • Created by Nathan Leary
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The Research Behind It — Free Papers on What Drives Chronic Disease and Why These Resources Can Help
280 listings · 20 categories
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The Research Behind It — Free Papers on What Drives Chronic Disease and Why These Resources Can Help
THE EVIDENCE
THE EVIDENCE

The Research Behind It — Free Papers on What Drives Chronic Disease and Why These Resources Can Help

Why would a support group, a walking club, a low-carb book or an online CBT course help — and what drives chronic illness in the first place? This chapter gathers the research behind each part of the directory, and the research on causes: metabolic therapies, the nutrients in food, plastics and pollution, stress and trauma, the microbiome, and damp and mould. That is 280 studies, reviews and clinical guidelines, every one free to read and download in full, permanently and without a login. Most are kept in PubMed Central, the US National Library of Medicine's public archive; the rest are open access at the publisher, or free guidance from the World Health Organization and NICE. Each entry says what was found, why it matters here — which listings it backs up, or what it explains about chronic disease — and how strong the evidence is: strong (systematic reviews and guidelines with consistent findings), moderate (smaller or lower-certainty reviews, single large trials and large cohort studies) or early (pilot, cross-sectional and laboratory studies — promising, not proof). Studies that follow people over time show links, not proof of cause, and the entries say so. Where a study was funded by a company, or its authors run a listed programme, the note says so; where a listed book or service was not itself tested, the entry says it backs the approach rather than the product. Research moves on, so read these as good reasons to try something, not guarantees — and talk to your own clinician before changing a treatment or a medicine. Every paper was checked at least twice: by the researcher who chose it and again, independently, against its abstract and full text (the first 186 a third time); its public record was checked for corrections, retractions and expressions of concern (none is retracted), every number was looked up in the full text, and every link was opened in a browser.

Metabolic Health — Low-Carb, Ketogenic & Remission Diets for Diabetes, Weight & Insulin Resistance

Diets for weight management in adults with type 2 diabetes: an umbrella review of published meta-analyses and systematic review of trials of diets for diabetes remission — Churuangsuk et al., Diabetologia 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC8660762/
Umbrella review of 21 systematic reviews (19 meta-analyses) of randomised trials, plus a systematic review of 14 remission studies. Strong evidence. Diabetologia 2022;65(1):14–36. DOI 10.1007/s00125-021-05577-2. Free full text in PubMed Central (PMC8660762) — open access, CC BY 4.0. Note: Most of the evidence covers 1 year or less; it does not show low-carb beats other diets for weight, and remission evidence for ketogenic diets is very low certainty.
What It Found
Brought together 19 published meta-analyses of weight-loss diets for type 2 diabetes. Low-carbohydrate diets were no better for weight loss than higher-carbohydrate, low-fat diets (high certainty), and no nutrient mix came out ahead, though very-low-energy and formula meal-replacement diets gave the most weight loss. Programmes starting with formula total diet replacement gave the highest 1-year remission: a median 54%, against 4–12% with usual care (high certainty).
Why It Matters Here
Backs up Roy Taylor's Life Without Diabetes (chapter 10), whose plan starts with a formula low-calorie phase, and the low-carb guides in chapter 10 and low-carb clinicians in chapter 01 as one option among several: no single diet style wins for weight.
Umbrella review of 21 systematic reviews (19 meta-analyses) of randomised trials, plus a systematic review of 14 remission studies. Strong evidence. Diabetologia 2022;65(1):14–36. DOI 10.1007/s00125-021-05577-2. Free full text in PubMed Central (PMC8660762) — open access, CC BY 4.0. Note: Most of the evidence covers 1 year or less; it does not show low-carb beats other diets for weight, and remission evidence for ketogenic diets is very low certainty.
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Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: systematic review and meta-analysis of published and unpublished randomized trial data — Goldenberg et al., BMJ 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC7804828/
Systematic review and meta-analysis — 23 randomised trials, 1,357 adults with type 2 diabetes. Moderate evidence. BMJ 2021;372:m4743. DOI 10.1136/bmj.m4743. Free full text in PubMed Central (PMC7804828) — open access, CC BY-NC 4.0. Note: Remission here allowed diabetes medicines; counting only people off medication, the benefit was small and uncertain (low certainty). Remission data at 12 months were sparse.
What It Found
Pooled 23 randomised trials of low-carbohydrate diets (under 130 g a day) lasting at least 12 weeks. At 6 months, 57% on low-carb diets reached remission (HbA1c below 6.5%) versus 31% on control diets (risk difference 32%, moderate certainty), with more weight loss and better triglycerides and insulin sensitivity. Most of these benefits shrank by 12 months, and no clear increase in adverse events was seen.
Why It Matters Here
Backs up the low-carb approach of the practitioner directories in chapter 01, the LCHF and keto communities in chapters 13 and 14, and the guides in chapter 10 (Diet Doctor, Freshwell, Phinney & Volek, Westman), mainly for adults with type 2 diabetes.
Systematic review and meta-analysis — 23 randomised trials, 1,357 adults with type 2 diabetes. Moderate evidence. BMJ 2021;372:m4743. DOI 10.1136/bmj.m4743. Free full text in PubMed Central (PMC7804828) — open access, CC BY-NC 4.0. Note: Remission here allowed diabetes medicines; counting only people off medication, the benefit was small and uncertain (low certainty). Remission data at 12 months were sparse.
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5-year follow-up of the randomised Diabetes Remission Clinical Trial (DiRECT) of continued support for weight loss maintenance in the UK: an extension study — Lean et al., Lancet Diabetes Endocrinol 2024

https://doi.org/10.1016/S2213-8587(23)00385-6
Extension study of a cluster-randomised trial (DiRECT, 49 UK general practices) — 5-year follow-up. Moderate evidence. Lancet Diabetes Endocrinol 2024;12(4):233–246. Free full text at the publisher — open access, CC BY 4.0. Note: Only 95 of 149 intervention participants joined the non-randomised extension, and remission fell over time as average weight loss shrank; lasting remission needs weight kept off.
What It Found
DiRECT tested a GP-practice programme of low-calorie formula diet (total diet replacement), food reintroduction and ongoing support. At 2 years, 36% of the intervention group were in remission (mean loss 7.6 kg). Of 95 who took up 3 more years of light support, 85 were seen at 5 years: 13% were in remission (mean loss 6.1 kg), and 26% of those in remission at 2 years still were. Over 5 years the intervention group was in remission at 27% of visits, controls at 4%.
Why It Matters Here
Backs up Roy Taylor's Life Without Diabetes (chapter 10), which sets out the DiRECT/Newcastle plan, and GP-supported remission programmes, while showing that keeping weight off long term is the hard part.
Extension study of a cluster-randomised trial (DiRECT, 49 UK general practices) — 5-year follow-up. Moderate evidence. Lancet Diabetes Endocrinol 2024;12(4):233–246. Free full text at the publisher — open access, CC BY 4.0. Note: Only 95 of 149 intervention participants joined the non-randomised extension, and remission fell over time as average weight loss shrank; lasting remission needs weight kept off.
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Comparison of dietary macronutrient patterns of 14 popular named dietary programmes for weight and cardiovascular risk factor reduction in adults: systematic review and network meta-analysis of randomised trials — Ge et al., BMJ 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7190064/
Systematic review and network meta-analysis — 121 randomised trials, 21,942 adults with overweight or obesity. Strong evidence. BMJ 2020;369:m696. DOI 10.1136/bmj.m696. Free full text in PubMed Central (PMC7190064) — open access, CC BY-NC 4.0. Note: Differences between diets were small, and benefits of every diet, low-carb included, largely faded by 12 months.
What It Found
Compared 14 named diets, including Atkins and other low-carbohydrate plans, and broad diet types. At 6 months, low-carbohydrate and low-fat diets cut weight by 4.63 kg and 4.40 kg more than usual diet (moderate certainty; low-fat figure from a 2020 correction), with similar falls in blood pressure; Atkins gave about 5.5 kg. By 12 months weight loss had shrunk for every diet, and improvements in heart-risk factors had largely gone, except with the Mediterranean diet.
Why It Matters Here
Backs up the low-carb approach taught by the books, guides and apps in chapters 10 and 16 and followed in the LCHF and keto communities in chapters 13 and 14, as one reasonable choice among several for weight loss rather than a superior one.
Systematic review and network meta-analysis — 121 randomised trials, 21,942 adults with overweight or obesity. Strong evidence. BMJ 2020;369:m696. DOI 10.1136/bmj.m696. Free full text in PubMed Central (PMC7190064) — open access, CC BY-NC 4.0. Note: Differences between diets were small, and benefits of every diet, low-carb included, largely faded by 12 months.
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Intermittent fasting strategies and their effects on body weight and other cardiometabolic risk factors: systematic review and network meta-analysis of randomised clinical trials — Semnani-Azad et al., BMJ 2025

https://pmc.ncbi.nlm.nih.gov/articles/PMC12175170/
Systematic review and network meta-analysis — 99 randomised trials, 6,582 adults. Strong evidence. BMJ 2025;389:e082007. DOI 10.1136/bmj-2024-082007. Free full text in PubMed Central (PMC12175170) — open access, CC BY-NC 4.0. Note: Most trials were short (median 12 weeks); in trials of 24 weeks or more, fasting was no better than ordinary calorie cutting.
What It Found
Compared alternate-day fasting, time-restricted eating and whole-day fasting (such as 5:2) with everyday calorie cutting and with no diet. Every fasting approach and continuous calorie restriction reduced weight compared with no diet. Alternate-day fasting gave slightly more loss than continuous restriction (1.29 kg, moderate certainty); otherwise fasting and calorie cutting had similar effects on weight and cardiometabolic risk factors.
Why It Matters Here
Backs up the intermittent fasting approach in Jason Fung's books (chapter 10), The Fasting Method community, the Zero app and Mayo Clinic's LCHF and fasting group (chapter 13): fasting is a workable way to eat less, not a superior one.
Systematic review and network meta-analysis — 99 randomised trials, 6,582 adults. Strong evidence. BMJ 2025;389:e082007. DOI 10.1136/bmj-2024-082007. Free full text in PubMed Central (PMC12175170) — open access, CC BY-NC 4.0. Note: Most trials were short (median 12 weeks); in trials of 24 weeks or more, fasting was no better than ordinary calorie cutting.
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Nutrition therapy for adults with diabetes or prediabetes: a consensus report — Evert et al., Diabetes Care 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC7011201/
Consensus report of the American Diabetes Association: expert recommendations based on a PubMed review of studies published 2014–2018. Strong evidence. Diabetes Care 2019;42(5):731–754. DOI 10.2337/dci19-0014. Free full text in PubMed Central (PMC7011201). Note: Very-low-carb plans can lower blood glucose quickly, so insulin and similar medicines may need reducing from the start; more research is needed in pregnancy, kidney disease and disordered eating.
What It Found
The American Diabetes Association's guidance on eating for diabetes and prediabetes. It concludes that reducing overall carbohydrate intake has the most evidence for improving blood glucose, and that low- or very-low-carbohydrate eating plans are a viable approach for selected adults with type 2 diabetes not meeting targets or wanting to reduce medicines. It also says no single eating pattern is best for everyone and that remission rises with the amount of weight lost.
Why It Matters Here
Backs up the clinician-supported low-carb care in chapter 01 and the low-carb approach of the programmes and guides in chapters 10 and 16, and gives readers a mainstream statement to take to their own doctor or dietitian.
Consensus report of the American Diabetes Association: expert recommendations based on a PubMed review of studies published 2014–2018. Strong evidence. Diabetes Care 2019;42(5):731–754. DOI 10.2337/dci19-0014. Free full text in PubMed Central (PMC7011201). Note: Very-low-carb plans can lower blood glucose quickly, so insulin and similar medicines may need reducing from the start; more research is needed in pregnancy, kidney disease and disordered eating.
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Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin — Knowler et al., N Engl J Med 2002

https://pmc.ncbi.nlm.nih.gov/articles/PMC1370926/
Randomised controlled trial — 3,234 adults with raised blood glucose, average follow-up 2.8 years. Moderate evidence. N Engl J Med 2002;346(6):393–403. DOI 10.1056/NEJMoa012512. Free full text in PubMed Central (PMC1370926). Note: The lifestyle programme was intensive and not a low-carb diet; later follow-up found the prevention effect narrowed over time.
What It Found
The landmark US Diabetes Prevention Program randomised adults with prediabetes to an intensive lifestyle programme (goals: 7% weight loss and 150 minutes of activity a week), metformin or placebo. The lifestyle programme cut new cases of type 2 diabetes by 58% (95% CI 48–66%) compared with placebo, and metformin by 31%; about 7 people needed the lifestyle programme for 3 years to prevent one case.
Why It Matters Here
Backs up the CDC National Diabetes Prevention Program in chapter 16, which is built on this trial, and lifestyle support for anyone told they have prediabetes.
Randomised controlled trial — 3,234 adults with raised blood glucose, average follow-up 2.8 years. Moderate evidence. N Engl J Med 2002;346(6):393–403. DOI 10.1056/NEJMoa012512. Free full text in PubMed Central (PMC1370926). Note: The lifestyle programme was intensive and not a low-carb diet; later follow-up found the prevention effect narrowed over time.
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Effects of a low-carbohydrate dietary intervention on hemoglobin A1c: a randomized clinical trial — Dorans et al., JAMA Netw Open 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9606840/
Randomised controlled trial — 150 adults with untreated HbA1c 6.0–6.9%, 6 months. Moderate evidence. JAMA Netw Open 2022;5(10):e2238645. DOI 10.1001/jamanetworkopen.2022.38645. Free full text in PubMed Central (PMC9606840) — open access, CC BY 4.0. Note: A single 6-month trial; the authors could not separate the effect of carbohydrate cutting from weight loss, and long-term results are unknown.
What It Found
Adults with raised blood glucose (HbA1c 6.0–6.9%, prediabetes or early untreated diabetes) not taking diabetes medicines were randomised to a low-carbohydrate diet (under 40 g net carbohydrate a day for 3 months, then under 60 g) or their usual diet. After 6 months the low-carb group's HbA1c was 0.23 percentage points lower, fasting glucose 10.3 mg/dL lower and weight 5.9 kg lower than the usual-diet group.
Why It Matters Here
Backs up low-carb eating for people with raised blood glucose not yet on diabetes medicines — the approach in the low-carb guides and Ben Bikman's book in chapter 10 and used by the low-carb practitioners in chapter 01.
Randomised controlled trial — 150 adults with untreated HbA1c 6.0–6.9%, 6 months. Moderate evidence. JAMA Netw Open 2022;5(10):e2238645. DOI 10.1001/jamanetworkopen.2022.38645. Free full text in PubMed Central (PMC9606840) — open access, CC BY 4.0. Note: A single 6-month trial; the authors could not separate the effect of carbohydrate cutting from weight loss, and long-term results are unknown.
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Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet – a randomised controlled trial — Holmer et al., JHEP Rep 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8059083/
Randomised controlled trial — 74 adults with non-alcoholic fatty liver disease, 12 weeks. Moderate evidence. JHEP Rep 2021;3(3):100256. DOI 10.1016/j.jhepr.2021.100256. Free full text in PubMed Central (PMC8059083) — open access, CC BY 4.0. Note: A small 12-week trial; 20% dropped out of the LCHF arm (mainly stomach upsets), and long-term liver outcomes are unknown.
What It Found
People with fatty liver were randomised to a low-carbohydrate high-fat (LCHF) diet, the 5:2 intermittent fasting diet or standard advice from a liver specialist. Liver fat fell by 7.2 percentage points with LCHF and 6.1 with 5:2, versus 3.6 with standard care, and weight by 7.3 kg and 7.4 kg versus 2.5 kg. The two diets worked about equally well; 5:2 was better tolerated and was linked to lower LDL cholesterol.
Why It Matters Here
Backs up the fatty-liver focus of Ben Bikman's and Jason Fung's books (chapter 10), low-carb clinicians in chapter 01 and the LCHF and fasting groups in chapter 13: either approach can reduce liver fat.
Randomised controlled trial — 74 adults with non-alcoholic fatty liver disease, 12 weeks. Moderate evidence. JHEP Rep 2021;3(3):100256. DOI 10.1016/j.jhepr.2021.100256. Free full text in PubMed Central (PMC8059083) — open access, CC BY 4.0. Note: A small 12-week trial; 20% dropped out of the LCHF arm (mainly stomach upsets), and long-term liver outcomes are unknown.
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Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake — Hall et al., Cell Metab 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC7946062/
Randomised crossover trial — 20 adults living on a research ward, 2 weeks on each diet. Moderate evidence. Cell Metab 2019;30(1):67–77.e3. DOI 10.1016/j.cmet.2019.05.008. Free full text in PubMed Central (PMC7946062). Note: Only 20 people for 4 weeks on a research ward; it shows short-term overeating, not long-term weight or disease outcomes.
What It Found
A tightly controlled US National Institutes of Health trial in which 20 adults ate an ultra-processed or an unprocessed diet for two weeks each, in random order, eating as much as they wanted. On the ultra-processed diet they ate about 508 kcal more per day and gained about 0.9 kg; on the unprocessed diet they lost about 0.9 kg.
Why It Matters Here
Backs up the books on ultra-processed food in chapter 10 — Chris van Tulleken's Ultra-Processed People and Robert Lustig's Metabolical — and the real-food cooking resources in chapter 14.
Randomised crossover trial — 20 adults living on a research ward, 2 weeks on each diet. Moderate evidence. Cell Metab 2019;30(1):67–77.e3. DOI 10.1016/j.cmet.2019.05.008. Free full text in PubMed Central (PMC7946062). Note: Only 20 people for 4 weeks on a research ward; it shows short-term overeating, not long-term weight or disease outcomes.
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Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: a 2-year non-randomized clinical trial — Athinarayanan et al., Front Endocrinol 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6561315/
Non-randomised controlled trial — 262 adults on the intervention, 87 on usual care, 2 years. Early evidence. Front Endocrinol 2019;10:348. DOI 10.3389/fendo.2019.00348. Free full text in PubMed Central (PMC6561315) — open access, CC BY 4.0. Note: Not randomised (people chose their group), run and mostly written by the company, and about a quarter of participants lacked 2-year data.
What It Found
Adults with type 2 diabetes chose remote, app-based coaching with doctor-supervised nutritional ketosis (Virta Health) or usual care. After 2 years the ketosis group's HbA1c had fallen 12% (from 7.7%) and weight 10%; use of diabetes medicines other than metformin fell from 55.7% to 26.8%, insulin use by 62% and sulfonylurea use stopped entirely. 53.5% met the study's definition of diabetes 'reversal' and 17.6% 'remission'; usual care showed no such changes.
Why It Matters Here
Backs up clinician-supervised ketogenic care for type 2 diabetes — the low-carb doctors and coaches in chapter 01 and Dr Sarah Hallberg's talk and Dr Eric Westman's courses in chapter 10 — especially where medicines need adjusting.
Non-randomised controlled trial — 262 adults on the intervention, 87 on usual care, 2 years. Early evidence. Front Endocrinol 2019;10:348. DOI 10.3389/fendo.2019.00348. Free full text in PubMed Central (PMC6561315) — open access, CC BY 4.0. Note: Not randomised (people chose their group), run and mostly written by the company, and about a quarter of participants lacked 2-year data.
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What predicts drug-free type 2 diabetes remission? Insights from an 8-year general practice service evaluation of a lower carbohydrate diet with weight loss — Unwin et al., BMJ Nutr Prev Health 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10407412/
Service evaluation (uncontrolled cohort) — 186 people with type 2 diabetes in one UK general practice, 2013–2021. Early evidence. BMJ Nutr Prev Health 2023;6(1):46–55. DOI 10.1136/bmjnph-2022-000544. Free full text in PubMed Central (PMC10407412) — open access, CC BY-NC 4.0. Note: An uncontrolled audit of volunteers in one practice, with no comparison group; results may not apply to everyone offered the diet.
What It Found
A UK GP practice offered a lower-carbohydrate diet to people with type 2 diabetes; 186 took it up and were followed for an average of 33 months. Median weight fell from 97 to 86 kg and HbA1c from 63 to 46 mmol/mol, and 51% achieved drug-free remission — 77% of those diagnosed under a year earlier but 20% of those diagnosed over 15 years. LDL cholesterol, triglycerides and blood pressure also fell, and the practice spent less on diabetes drugs.
Why It Matters Here
Backs up GP-led low-carb care — the approach behind Dr David Unwin's sugar infographics (Public Health Collaboration) and the similar Freshwell project in chapter 10, and used by low-carb practitioners in chapter 01 — especially soon after diagnosis.
Service evaluation (uncontrolled cohort) — 186 people with type 2 diabetes in one UK general practice, 2013–2021. Early evidence. BMJ Nutr Prev Health 2023;6(1):46–55. DOI 10.1136/bmjnph-2022-000544. Free full text in PubMed Central (PMC10407412) — open access, CC BY-NC 4.0. Note: An uncontrolled audit of volunteers in one practice, with no comparison group; results may not apply to everyone offered the diet.
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Effects of ketogenic diet on reproductive hormones in women with polycystic ovary syndrome — Khalid et al., J Endocr Soc 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10484165/
Systematic review and meta-analysis — 7 small clinical trials (4 single-arm), 170 women. Early evidence. J Endocr Soc 2023;7(10):bvad112. DOI 10.1210/jendso/bvad112. Free full text in PubMed Central (PMC10484165) — open access, CC BY-NC-ND 4.0. Note: Few, small and mostly uncontrolled studies; the authors say results must be interpreted carefully. PCOS guidelines do not yet favour any one diet.
What It Found
Combined 7 small trials of ketogenic diets lasting 45 days to 24 weeks in women with polycystic ovary syndrome (PCOS). Pooled results suggested a lower LH/FSH ratio and lower free testosterone, higher sex-hormone-binding globulin, and weight loss in every study — changes in the hormone pattern behind many PCOS symptoms. The authors describe a possible link that needs confirming.
Why It Matters Here
Backs up the PCOS advice in Ben Bikman's Why We Get Sick (chapter 10) and low-carb clinicians in chapter 01, as an early option for women with PCOS to discuss with their doctor; most relevant to women with PCOS, including members of PCOS Challenge (chapter 06).
Systematic review and meta-analysis — 7 small clinical trials (4 single-arm), 170 women. Early evidence. J Endocr Soc 2023;7(10):bvad112. DOI 10.1210/jendso/bvad112. Free full text in PubMed Central (PMC10484165) — open access, CC BY-NC-ND 4.0. Note: Few, small and mostly uncontrolled studies; the authors say results must be interpreted carefully. PCOS guidelines do not yet favour any one diet.
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Metabolic Psychiatry & Brain Health — Ketogenic Therapy for Mental Illness, Epilepsy & Neurological Conditions

Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group — Kossoff et al., Epilepsia Open 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC5983110/
International expert consensus guideline — 31 clinicians and dietitians (55% outside the USA), with a survey of their centres. Moderate evidence. Epilepsia Open 2018;3(2):175-192. DOI 10.1002/epi4.12225. Free full text in PubMed Central (PMC5983110) — open access, CC BY-NC-ND 4.0. Note: An expert consensus for children: many recommendations rest on clinical experience rather than trials, and it does not cover adults.
What It Found
The international guideline for ketogenic diet therapy in children, updated by 31 specialists. It says the diet should be strongly considered once two anti-seizure medicines have failed, and used first for Glut1 deficiency and pyruvate dehydrogenase deficiency. It sets out the four main diets (classic, MCT, modified Atkins, low glycaemic index), advises a trial of at least 3 months, and covers monitoring (blood tests every 3 months in the first year) and supplements.
Why It Matters Here
Backs up the epilepsy diet services and societies — the Charlie Foundation and the Global Symposium on Ketogenic Therapies in chapter 16, the International Neurological Ketogenic Society in chapter 01 and Ketogenic Diet India in chapter 14. Most relevant to parents and clinicians.
International expert consensus guideline — 31 clinicians and dietitians (55% outside the USA), with a survey of their centres. Moderate evidence. Epilepsia Open 2018;3(2):175-192. DOI 10.1002/epi4.12225. Free full text in PubMed Central (PMC5983110) — open access, CC BY-NC-ND 4.0. Note: An expert consensus for children: many recommendations rest on clinical experience rather than trials, and it does not cover adults.
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Ketogenic diets for drug-resistant epilepsy — Martin-McGill et al., Cochrane Database Syst Rev 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7387249/
Cochrane systematic review — 13 randomised or quasi-randomised trials, 932 people (711 children, 221 adults). Moderate evidence. Cochrane Database Syst Rev 2020;6:CD001903. DOI 10.1002/14651858.CD001903.pub5. Free full text in PubMed Central (PMC7387249). Note: None of the trials was blinded and certainty was rated low to very low; the benefit is clearer in children than in adults.
What It Found
Pooled trials of ketogenic diets for epilepsy that medicines had not controlled. In children (4 trials, 385 children), the diet made a 50% or greater fall in seizures nearly six times as likely as usual care (RR 5.80, 95% CI 3.48 to 9.65; low certainty) and seizure freedom about three times as likely (RR 3.16; very low certainty). In adults (modified Atkins diet, 2 trials) the effect was uncertain. Vomiting, constipation and diarrhoea were common.
Why It Matters Here
Backs up the ketogenic-therapy services for epilepsy — the Charlie Foundation and the Global Symposium on Ketogenic Therapies in chapter 16, the International Neurological Ketogenic Society in chapter 01 and Ketogenic Diet India in chapter 14. Most relevant to families of children with hard-to-treat epilepsy.
Cochrane systematic review — 13 randomised or quasi-randomised trials, 932 people (711 children, 221 adults). Moderate evidence. Cochrane Database Syst Rev 2020;6:CD001903. DOI 10.1002/14651858.CD001903.pub5. Free full text in PubMed Central (PMC7387249). Note: None of the trials was blinded and certainty was rated low to very low; the benefit is clearer in children than in adults.
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Efficacy of low carbohydrate and ketogenic diets in treating mood and anxiety disorders: systematic review and implications for clinical practice — Dietch et al., BJPsych Open 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10134254/
Systematic review — 12 studies, 389 people (9 case reports, 2 cohort studies, 1 analysis of online posts; no randomised trials). Early evidence. BJPsych Open 2023;9(3):e70. DOI 10.1192/bjo.2023.36. Free full text in PubMed Central (PMC10134254) — open access, CC BY 4.0. Note: Mostly case reports with no control groups, and ketosis was not confirmed in 5 of the 12 studies; it maps early signals, not evidence that the diet works.
What It Found
Searched for every study of low-carbohydrate or ketogenic diets in depression, anxiety, bipolar and schizoaffective disorder and found 12 (389 people), none randomised. Most reported fewer symptoms or steadier mood, mainly in bipolar and schizoaffective disorder, but two case reports found no benefit (one with worse anxiety). The authors conclude there is no high-quality evidence yet and call for robust trials.
Why It Matters Here
Backs up, with honest limits, the metabolic psychiatry listings — the books, free programme and clinician letter in chapter 10 (Brain Energy, Change Your Diet Change Your Mind, THINK+SMART), Metabolic Mind in chapter 16 and the clinician directories in chapter 01 — by setting out what is and is not yet known.
Systematic review — 12 studies, 389 people (9 case reports, 2 cohort studies, 1 analysis of online posts; no randomised trials). Early evidence. BJPsych Open 2023;9(3):e70. DOI 10.1192/bjo.2023.36. Free full text in PubMed Central (PMC10134254) — open access, CC BY 4.0. Note: Mostly case reports with no control groups, and ketosis was not confirmed in 5 of the 12 studies; it maps early signals, not evidence that the diet works.
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The Ketogenic Diet for Refractory Mental Illness: A Retrospective Analysis of 31 Inpatients — Danan et al., Front Psychiatry 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9299263/
Retrospective case series, no control group — 31 psychiatric inpatients, 28 analysed. Early evidence. Front Psychiatry 2022;13:951376. DOI 10.3389/fpsyt.2022.951376. Free full text in PubMed Central (PMC9299263) — open access, CC BY 4.0. Note: No control group or blinding, and patients were also in hospital with medicine changes; two authors had ties to low-carbohydrate companies. Randomised trials are still needed.
What It Found
Looked back at 31 adults in a French psychiatric hospital with hard-to-treat depression, bipolar II or schizoaffective disorder who were offered a ketogenic diet alongside usual care. In the 28 who kept to it for over two weeks, average depression scores (HAM-D, 23 people) fell from 25.4 to 7.7, psychosis scores (PANSS, 10 people) from 91.4 to 49.3, 43% reached clinical remission and 27 lost weight.
Why It Matters Here
Backs up the supervised approach used by Accord Metabolic Psychiatry (chapter 16) and the clinicians in the Metabolic Mind and Diagnosis Diet directories (chapter 01), as a record of ketogenic therapy in a hospital. Co-author Georgia Ede wrote the chapter 10 book and clinician letter.
Retrospective case series, no control group — 31 psychiatric inpatients, 28 analysed. Early evidence. Front Psychiatry 2022;13:951376. DOI 10.3389/fpsyt.2022.951376. Free full text in PubMed Central (PMC9299263) — open access, CC BY 4.0. Note: No control group or blinding, and patients were also in hospital with medicine changes; two authors had ties to low-carbohydrate companies. Randomised trials are still needed.
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A pilot study of a ketogenic diet in bipolar disorder: clinical, metabolic and magnetic resonance spectroscopy findings — Campbell et al., BJPsych Open 2025

https://pmc.ncbi.nlm.nih.gov/articles/PMC12001942/
Single-group open pilot study — 27 adults with bipolar disorder recruited, 20 completed 6–8 weeks. Early evidence. BJPsych Open 2025;11(2):e34. DOI 10.1192/bjo.2024.841. Free full text in PubMed Central (PMC12001942) — open access, CC BY 4.0. Note: Small, uncontrolled 6–8-week study in people who were already well; the mood findings are only correlations, and the authors call for randomised trials.
What It Found
Adults with bipolar disorder who were well at the start followed a modified ketogenic diet for 6–8 weeks with weekly dietitian support; 20 of 26 who started finished. Mood scores stayed in the healthy range. On days with higher blood ketones, people rated mood and energy higher and anxiety and impulsivity lower (small correlations, 14 people). Weight fell by 4.2 kg on average and brain scans showed about 12–14% less glutamate plus glutamine in two regions.
Why It Matters Here
Backs up the bipolar listings in chapter 10 — Bipolarcast (co-host Iain Campbell was first author) and the approach in THINK+SMART, which was not itself tested — plus Metabolic Mind in chapter 16 and the metabolic psychiatry clinicians in chapter 01. For people with bipolar disorder.
Single-group open pilot study — 27 adults with bipolar disorder recruited, 20 completed 6–8 weeks. Early evidence. BJPsych Open 2025;11(2):e34. DOI 10.1192/bjo.2024.841. Free full text in PubMed Central (PMC12001942) — open access, CC BY 4.0. Note: Small, uncontrolled 6–8-week study in people who were already well; the mood findings are only correlations, and the authors call for randomised trials.
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Impaired Glucose Homeostasis in First-Episode Schizophrenia: A Systematic Review and Meta-analysis — Pillinger et al., JAMA Psychiatry 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC6352957/
Systematic review and meta-analysis of case-control studies — 16 studies, 731 patients and 614 healthy controls. Moderate evidence. JAMA Psychiatry 2017;74(3):261-269. DOI 10.1001/jamapsychiatry.2016.3803. Free full text in PubMed Central (PMC6352957). Note: Shows a link, not that diet treats schizophrenia; lifestyle factors such as diet, activity and smoking could not be fully ruled out.
What It Found
Compared people at their first episode of schizophrenia, with no or at most 2 weeks of antipsychotic treatment, with healthy people. Patients already had higher fasting glucose (g 0.20), fasting insulin (g 0.41) and insulin resistance (HOMA-IR g 0.35, 95% CI 0.14 to 0.55), and these differences held in those who had never taken antipsychotics. The authors conclude that glucose regulation is altered from illness onset, not only as a side effect of medicines.
Why It Matters Here
Backs up one idea behind metabolic psychiatry — that blood-sugar regulation and insulin resistance matter in psychosis — as explained in Brain Energy and Change Your Diet, Change Your Mind (chapter 10) and by Metabolic Mind (chapter 16). Relevant to anyone weighing why metabolic health matters in psychosis.
Systematic review and meta-analysis of case-control studies — 16 studies, 731 patients and 614 healthy controls. Moderate evidence. JAMA Psychiatry 2017;74(3):261-269. DOI 10.1001/jamapsychiatry.2016.3803. Free full text in PubMed Central (PMC6352957). Note: Shows a link, not that diet treats schizophrenia; lifestyle factors such as diet, activity and smoking could not be fully ruled out.
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Randomized crossover trial of a modified ketogenic diet in Alzheimer's disease — Phillips et al., Alzheimers Res Ther 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC7901512/
Randomised crossover trial (assessor-blinded) — 26 people with Alzheimer's disease, two 12-week diet periods. Early evidence. Alzheimers Res Ther 2021;13:51. DOI 10.1186/s13195-021-00783-x. Free full text in PubMed Central (PMC7901512) — open access, CC BY 4.0. Note: Small, short trial in which patients and carers knew which diet they were on; memory scores did not change significantly and LDL cholesterol rose modestly.
What It Found
26 people with Alzheimer's disease in New Zealand spent 12 weeks on a modified ketogenic diet and 12 weeks on their usual diet with low-fat healthy-eating advice, in random order; 21 completed the ketogenic phase and most reached mild ketosis. Daily function (ADCS-ADL, +3.13 points) and quality of life (QOL-AD, +3.37) were better on the ketogenic diet; the change in a memory and thinking test (ACE-III) was not significant. No serious side effects occurred.
Why It Matters Here
Backs up the ketogenic-therapy practitioners in chapter 01 for people with Alzheimer's disease; it tested a modified ketogenic diet, not the Bredesen ReCODE programme also listed there. Relevant to people with dementia and their carers (chapter 06: Alzheimer's Disease International, Dementia Alliance International).
Randomised crossover trial (assessor-blinded) — 26 people with Alzheimer's disease, two 12-week diet periods. Early evidence. Alzheimers Res Ther 2021;13:51. DOI 10.1186/s13195-021-00783-x. Free full text in PubMed Central (PMC7901512) — open access, CC BY 4.0. Note: Small, short trial in which patients and carers knew which diet they were on; memory scores did not change significantly and LDL cholesterol rose modestly.
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A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT — Fortier et al., Alzheimers Dement 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8048678/
Randomised placebo-controlled trial (BENEFIC) — 122 people with mild cognitive impairment, 83 completed 6 months and were analysed. Early evidence. Alzheimers Dement 2021;17(3):543-552. DOI 10.1002/alz.12206. Free full text in PubMed Central (PMC8048678) — open access, CC BY-NC-ND 4.0. Note: About a third dropped out (mostly stomach upsets) and only a few of many test scores improved; part-funded by Nestlé Health Science, and three authors worked for Nestlé.
What It Found
Older adults with mild cognitive impairment in Canada drank 30 g a day of a ketogenic medium-chain triglyceride (MCT) drink or a matched placebo oil for 6 months. Compared with placebo, the MCT drink raised blood ketones and improved four of many test scores (one memory measure, category fluency, naming, and errors on a mental-flexibility test); on some tests bigger ketone rises went with bigger gains. No serious side effects occurred, but stomach upsets were common.
Why It Matters Here
Backs up the idea behind ketogenic approaches to brain health offered by practitioners in chapter 01 — it tested an MCT drink, not a diet or the Bredesen ReCODE programme listed there. Relevant to people with early memory problems and the dementia organisations in chapter 06.
Randomised placebo-controlled trial (BENEFIC) — 122 people with mild cognitive impairment, 83 completed 6 months and were analysed. Early evidence. Alzheimers Dement 2021;17(3):543-552. DOI 10.1002/alz.12206. Free full text in PubMed Central (PMC8048678) — open access, CC BY-NC-ND 4.0. Note: About a third dropped out (mostly stomach upsets) and only a few of many test scores improved; part-funded by Nestlé Health Science, and three authors worked for Nestlé.
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Low-fat versus ketogenic diet in Parkinson's disease: A pilot randomized controlled trial — Phillips et al., Mov Disord 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6175383/
Pilot randomised controlled trial (assessor-blinded) — 47 people with Parkinson's disease, 38 completed 8 weeks. Early evidence. Mov Disord 2018;33(8):1306-1314. DOI 10.1002/mds.27390. Free full text in PubMed Central (PMC6175383) — open access, CC BY-NC-ND 4.0. Note: Small 8-week pilot in which patients knew their diet; 12 on the ketogenic diet had worse tremor or stiffness early on, and LDL cholesterol rose. Erratum published 2019.
What It Found
47 people with Parkinson's in New Zealand were randomised to a low-fat or a ketogenic diet for 8 weeks; 38 finished. Both groups improved. Non-motor symptoms (MDS-UPDRS Part 1) fell 41% on the ketogenic diet against 11% on the low-fat diet (between-group P<0.001), led by urinary problems, pain, fatigue, daytime sleepiness and thinking; motor scores improved on both diets, with no significant difference between them.
Why It Matters Here
Backs up the International Neurological Ketogenic Society and the ketogenic-therapy practitioners in chapter 01 for Parkinson's. Relevant to people with Parkinson's in touch with the chapter 06 organisations (Parkinson's Europe, the Michael J. Fox Foundation).
Pilot randomised controlled trial (assessor-blinded) — 47 people with Parkinson's disease, 38 completed 8 weeks. Early evidence. Mov Disord 2018;33(8):1306-1314. DOI 10.1002/mds.27390. Free full text in PubMed Central (PMC6175383) — open access, CC BY-NC-ND 4.0. Note: Small 8-week pilot in which patients knew their diet; 12 on the ketogenic diet had worse tremor or stiffness early on, and LDL cholesterol rose. Erratum published 2019.
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Phase II study of ketogenic diets in relapsing multiple sclerosis: safety, tolerability and potential clinical benefits — Brenton et al., J Neurol Neurosurg Psychiatry 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9350909/
Single-arm phase II trial — 65 adults with relapsing MS on a modified Atkins ketogenic diet for 6 months. Early evidence. J Neurol Neurosurg Psychiatry 2022;93(6):637-644. DOI 10.1136/jnnp-2022-329074. Free full text in PubMed Central (PMC9350909). Note: No control group and mostly self-reported outcomes; the authors say it was not designed to show the diet works, which needs a randomised trial.
What It Found
65 adults with stable relapsing MS followed a modified Atkins ketogenic diet for 6 months; 83% kept to it, checked with daily urine ketone strips. Fatigue (MFIS) fell by about 14 points and depression (BDI) by about 4, quality-of-life scores rose by 11–12 points, the 6-minute walk improved by 78 feet and fat mass fell by 7.7 kg. Constipation and diarrhoea were the commonest side effects; no relapses were reported.
Why It Matters Here
Backs up the ketogenic-therapy practitioners and societies in chapter 01 and Ketogenic Diet India in chapter 14, which covers MS. It tested a modified Atkins ketogenic diet, not the Wahls Protocol or Overcoming MS (a low-saturated-fat diet). For people with relapsing MS.
Single-arm phase II trial — 65 adults with relapsing MS on a modified Atkins ketogenic diet for 6 months. Early evidence. J Neurol Neurosurg Psychiatry 2022;93(6):637-644. DOI 10.1136/jnnp-2022-329074. Free full text in PubMed Central (PMC9350909). Note: No control group and mostly self-reported outcomes; the authors say it was not designed to show the diet works, which needs a randomised trial.
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Impact of the Swank and Wahls elimination dietary interventions on fatigue and quality of life in relapsing-remitting multiple sclerosis: The WAVES randomized parallel-arm clinical trial — Wahls et al., Mult Scler J Exp Transl Clin 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8326636/
Randomised parallel-group trial (assessor-blinded) — 87 adults with relapsing-remitting MS and fatigue, Wahls vs Swank diet for 24 weeks. Early evidence. Mult Scler J Exp Transl Clin 2021;7(3):20552173211035399. DOI 10.1177/20552173211035399. Free full text in PubMed Central (PMC8326636) — open access, CC BY-NC 4.0. Note: No usual-diet comparison group, participants knew their diet, and the lead author created the Wahls diet and has financial interests in it.
What It Found
87 people with relapsing-remitting MS and fatigue were randomised to the Wahls elimination diet or the low-saturated-fat Swank diet for 24 weeks, after a 12-week usual-diet run-in. Fatigue (FSS) fell on both diets, with no significant difference between them. The Wahls group had larger gains in quality of life, and only the Wahls group's 6-minute walk improved significantly at 24 weeks (+36.6 m).
Why It Matters Here
Backs up the Wahls Protocol listings — the practitioner directory in chapter 01 and the book in chapter 10 — as a randomised test of one version of the Wahls diet, and Overcoming MS in chapter 16, whose diet, like the Swank diet tested here, is low in saturated fat.
Randomised parallel-group trial (assessor-blinded) — 87 adults with relapsing-remitting MS and fatigue, Wahls vs Swank diet for 24 weeks. Early evidence. Mult Scler J Exp Transl Clin 2021;7(3):20552173211035399. DOI 10.1177/20552173211035399. Free full text in PubMed Central (PMC8326636) — open access, CC BY-NC 4.0. Note: No usual-diet comparison group, participants knew their diet, and the lead author created the Wahls diet and has financial interests in it.
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Ketosis and migraine: a systematic review of the literature and meta-analysis — Neri et al., Front Nutr 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10292926/
Systematic review and meta-analysis — 10 studies (3 small randomised crossover trials, 7 non-randomised). Early evidence. Front Nutr 2023;10:1204700. DOI 10.3389/fnut.2023.1204700. Free full text in PubMed Central (PMC10292926) — open access, CC BY 4.0. Note: Few, small, mostly non-randomised studies, most from one Italian research group, with high heterogeneity and inconsistent checks of ketosis.
What It Found
Reviewed 10 studies of ketogenic diets or ketone supplements for migraine (one on cluster headache), mostly in Italian adults (16–96 people each). In the studies that reported it, 58–83% of people had at least 50% fewer attacks, but of the three randomised crossover trials only one (a very-low-calorie ketogenic diet) found fewer attacks; the other two found no clear benefit.
Why It Matters Here
Backs up, cautiously, the ketogenic-therapy practitioners and the International Neurological Ketogenic Society in chapter 01 for migraine. Relevant to people with migraine, including those using the National Headache Foundation in chapter 06, but the evidence is still thin.
Systematic review and meta-analysis — 10 studies (3 small randomised crossover trials, 7 non-randomised). Early evidence. Front Nutr 2023;10:1204700. DOI 10.3389/fnut.2023.1204700. Free full text in PubMed Central (PMC10292926) — open access, CC BY 4.0. Note: Few, small, mostly non-randomised studies, most from one Italian research group, with high heterogeneity and inconsistent checks of ketosis.
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International recommendations for the management of adults treated with ketogenic diet therapies — Cervenka et al., Neurol Clin Pract 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8610544/
International expert recommendations — survey of 20 centres treating more than 2,000 adults, plus the medical literature. Early evidence. Neurol Clin Pract 2021;11(5):385–397. DOI 10.1212/CPJ.0000000000001007. Free full text in PubMed Central (PMC8610544). Note: Preliminary recommendations from a survey and expert opinion, not from randomised trials; centres differed on monitoring and long-term safety checks.
What It Found
Neurologists and dietitians from 20 centres that had treated more than 2,000 adults with ketogenic diet therapies compared their practice and the literature to set preliminary recommendations for adults: who may benefit, how to start, what side effects to expect and how to monitor them. They conclude these diets may be safe and effective for adults with drug-resistant epilepsy, with emerging evidence in other neurological conditions.
Why It Matters Here
Backs up the metabolic and ketogenic practitioners in chapter 01: it shows why medically supervised ketogenic therapy, with monitoring, matters for adults with epilepsy or other neurological conditions.
International expert recommendations — survey of 20 centres treating more than 2,000 adults, plus the medical literature. Early evidence. Neurol Clin Pract 2021;11(5):385–397. DOI 10.1212/CPJ.0000000000001007. Free full text in PubMed Central (PMC8610544). Note: Preliminary recommendations from a survey and expert opinion, not from randomised trials; centres differed on monitoring and long-term safety checks.
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Food & Mood — Nutritional Psychiatry, Ultra-Processed Food & Cooking Skills

The Effects of Dietary Improvement on Symptoms of Depression and Anxiety: A Meta-Analysis of Randomized Controlled Trials — Firth et al., Psychosom Med 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6455094/
Systematic review and meta-analysis — 16 randomised trials, 45,826 people. Moderate evidence. Psychosom Med 2019;81(3):265–280. DOI 10.1097/PSY.0000000000000673. Free full text in PubMed Central (PMC6455094) — open access, CC BY-NC-ND 4.0. Note: Effects were small and varied between trials; all but one trial was in people without diagnosed depression, no benefit was found for anxiety, and corrected results are smaller than first published.
What It Found
Pooled 16 randomised trials (45,826 people) that changed what people ate; all but one were in people without a depression diagnosis. In the corrected figures (errata 2020–21), diet improvement reduced depressive symptoms by a small amount (g = 0.162, 95% CI 0.055–0.269), with a similar effect in higher-quality trials (g = 0.171). There was no clear effect on anxiety (11 trials, g = 0.085, not significant). Benefits were larger in studies of women.
Why It Matters Here
Backs up the nutritional psychiatry books and the Food & Mood course in the Cooking & Eating Well section of chapter 10: pooled trial evidence that improving diet can modestly ease low mood. Most relevant to people with milder symptoms, alongside usual care.
Systematic review and meta-analysis — 16 randomised trials, 45,826 people. Moderate evidence. Psychosom Med 2019;81(3):265–280. DOI 10.1097/PSY.0000000000000673. Free full text in PubMed Central (PMC6455094) — open access, CC BY-NC-ND 4.0. Note: Effects were small and varied between trials; all but one trial was in people without diagnosed depression, no benefit was found for anxiety, and corrected results are smaller than first published.
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Clinical guidelines for the use of lifestyle-based mental health care in major depressive disorder: World Federation of Societies for Biological Psychiatry (WFSBP) and Australasian Society of Lifestyle Medicine (ASLM) taskforce — Marx et al., World J Biol Psychiatry 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10972571/
International clinical guideline — systematic literature searches and graded recommendations from an expert taskforce of two professional societies. Moderate evidence. World J Biol Psychiatry 2023;24(5):333–386. DOI 10.1080/15622975.2022.2112074. Free full text in PubMed Central (PMC10972571) — open access, CC BY-NC-ND 4.0. Note: The diet recommendation rests on four small trials at high risk of bias and is graded lower than exercise or sleep; it is advised alongside, not instead of, standard treatment.
What It Found
An international taskforce from two professional societies made nine graded recommendations on lifestyle care for adults with major depression. Dietary counselling towards healthy eating 'may be used' (Grade 3: low strength of evidence, from four small trials with 395 people at high risk of bias), a weaker grade than exercise, relaxation, sleep, mindfulness and work-directed interventions (Grade 2). Lifestyle care is advised as a foundation alongside other treatments.
Why It Matters Here
Backs up the nutritional psychiatry resources in chapter 10 (Food & Mood course, Brain Changer, This Is Your Brain on Food) and the dietitian finders in chapter 15: a professional guideline that names diet as a recommended part of depression care.
International clinical guideline — systematic literature searches and graded recommendations from an expert taskforce of two professional societies. Moderate evidence. World J Biol Psychiatry 2023;24(5):333–386. DOI 10.1080/15622975.2022.2112074. Free full text in PubMed Central (PMC10972571) — open access, CC BY-NC-ND 4.0. Note: The diet recommendation rests on four small trials at high risk of bias and is graded lower than exercise or sleep; it is advised alongside, not instead of, standard treatment.
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A randomised controlled trial of dietary improvement for adults with major depression (the 'SMILES' trial) — Jacka et al., BMC Med 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5282719/
Randomised controlled trial — 67 adults with major depression, 12 weeks. Early evidence. BMC Med 2017;15:23. DOI 10.1186/s12916-017-0791-y. Free full text in PubMed Central (PMC5282719) — open access, CC BY 4.0. Note: Small, short trial; participants knew their group, and a published critique (answered by the authors) questioned whether diet-focused recruitment inflated the effect. Results need replication.
What It Found
Adults with major depression who were eating poorly had one-to-one support from a clinical dietitian to move towards a Mediterranean-style whole-food diet, or a social-support (befriending) control, on top of their usual care. After 12 weeks the diet group improved more on the MADRS depression scale (Cohen's d = −1.16), and 32.3% were in remission versus 8.0% of controls (number needed to treat 4.1, 95% CI 2.3–27.8).
Why It Matters Here
Backs up the dietitian-led, Mediterranean-style approach behind the Deakin Food & Mood course and Felice Jacka's Brain Changer in chapter 10 (the course and book were not themselves tested), Oldways' guides, and the dietitian finders in chapter 15. Most relevant to adults with depression and a poor diet.
Randomised controlled trial — 67 adults with major depression, 12 weeks. Early evidence. BMC Med 2017;15:23. DOI 10.1186/s12916-017-0791-y. Free full text in PubMed Central (PMC5282719) — open access, CC BY 4.0. Note: Small, short trial; participants knew their group, and a published critique (answered by the authors) questioned whether diet-focused recruitment inflated the effect. Results need replication.
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A brief diet intervention can reduce symptoms of depression in young adults – A randomised controlled trial — Francis et al., PLoS One 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6784975/
Randomised controlled trial — 101 young adults with elevated depressive symptoms and a poor diet, 3 weeks. Early evidence. PLoS One 2019;14(10):e0222768. DOI 10.1371/journal.pone.0222768. Free full text in PubMed Central (PMC6784975) — open access, CC BY 4.0. Note: Small three-week trial in university students (76 analysed); participants knew their group, the control group got no food or contact, and only the diet group was followed up.
What It Found
Young adults with raised depression symptoms and a poor, highly processed diet were either given brief guidance and support (a short dietitian video, a food hamper and two check-in calls) to switch to a healthier whole-food diet for three weeks, or kept their usual diet. The diet group ended with lower depression scores (CESD-R, Cohen's d = 0.65; DASS-21 depression, d = 0.75), and diet-group members reached by phone three months later still scored lower than at the start.
Why It Matters Here
Backs up the simple, low-cost route into healthier eating in chapter 10 (the Food & Mood course, budget cookbooks such as Good and Cheap, Mediterranean guides) and the meal-prep communities in chapter 14: even a brief change in diet may help mood.
Randomised controlled trial — 101 young adults with elevated depressive symptoms and a poor diet, 3 weeks. Early evidence. PLoS One 2019;14(10):e0222768. DOI 10.1371/journal.pone.0222768. Free full text in PubMed Central (PMC6784975) — open access, CC BY 4.0. Note: Small three-week trial in university students (76 analysed); participants knew their group, the control group got no food or contact, and only the diet group was followed up.
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Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies — Lassale et al., Mol Psychiatry 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6755986/
Systematic review and meta-analysis of observational studies — 20 longitudinal and 21 cross-sectional studies. Moderate evidence. Mol Psychiatry 2019;24(7):965–986. DOI 10.1038/s41380-018-0237-8. Free full text in PubMed Central (PMC6755986) — open access, CC BY 4.0. Note: Observational studies show association, not cause: people who are less depressed may also eat better, and confounding by income and lifestyle is hard to remove.
What It Found
Brought together 41 observational studies (20 that followed people over time, 21 one-off surveys) linking overall diet quality scores with depression. The strongest finding was for a traditional Mediterranean diet: people with the highest adherence had a lower risk of developing depression than those with the lowest (relative risk 0.67, 95% CI 0.55–0.82, four cohort studies). A less inflammatory diet was also linked to lower risk (relative risk 0.76, 0.63–0.92).
Why It Matters Here
Backs up the whole-food, Mediterranean-style eating guides (Oldways) and the nutritional psychiatry books in chapter 10; most relevant to people wanting to lower their risk of depression.
Systematic review and meta-analysis of observational studies — 20 longitudinal and 21 cross-sectional studies. Moderate evidence. Mol Psychiatry 2019;24(7):965–986. DOI 10.1038/s41380-018-0237-8. Free full text in PubMed Central (PMC6755986) — open access, CC BY 4.0. Note: Observational studies show association, not cause: people who are less depressed may also eat better, and confounding by income and lifestyle is hard to remove.
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Ultra-processed food exposure and adverse health outcomes: umbrella review of epidemiological meta-analyses — Lane et al., BMJ 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC10899807/
Umbrella review of 45 pooled analyses from 14 meta-analyses of observational studies — 9,888,373 people. Moderate evidence. BMJ 2024;384:e077310. DOI 10.1136/bmj-2023-077310. Free full text in PubMed Central (PMC10899807) — open access, CC BY-NC 4.0. Note: All studies were observational (the anxiety results from one-off surveys) and certainty for mental health was low; the definition of ultra-processed food is debated, so cause is not shown.
What It Found
Graded 45 pooled analyses from published meta-analyses linking ultra-processed food to health. Convincing (class I) evidence linked higher intake with more anxiety (odds ratio 1.48, 1.37–1.59) and common mental disorders (odds ratio 1.53, 1.43–1.63), plus cardiovascular death and type 2 diabetes; highly suggestive evidence linked it with depression (1.22, 1.16–1.28). GRADE certainty for the mental health results was low.
Why It Matters Here
Backs up the ultra-processed food books in chapter 10 (Ultra-Processed People, Metabolical) and the reasoning behind its cook-from-scratch and budget-cooking resources: the broadest summary of the links between ultra-processed food and poorer physical and mental health.
Umbrella review of 45 pooled analyses from 14 meta-analyses of observational studies — 9,888,373 people. Moderate evidence. BMJ 2024;384:e077310. DOI 10.1136/bmj-2023-077310. Free full text in PubMed Central (PMC10899807) — open access, CC BY-NC 4.0. Note: All studies were observational (the anxiety results from one-off surveys) and certainty for mental health was low; the definition of ultra-processed food is debated, so cause is not shown.
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Food and mood: how do diet and nutrition affect mental wellbeing? — Firth et al., BMJ 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7322666/
Peer-reviewed analysis (narrative review), BMJ Food for Thought series. Moderate evidence. BMJ 2020;369:m2382. DOI 10.1136/bmj.m2382. Free full text in PubMed Central (PMC7322666) — open access, CC BY-NC 4.0. Note: A narrative rather than systematic review; the authors stress that causal effects of diet on mood are not yet established.
What It Found
A balanced overview of what is and is not known about diet and mental health. Mediterranean-style eating is linked with lower depression risk, smaller trials in people with depression report benefits, but a large prevention trial in people with mild symptoms found none, and reverse causation and participant expectations may explain part of the link. The authors suggest cutting highly processed and refined foods for body and mind.
Why It Matters Here
Backs up the nutritional psychiatry books (Naidoo, Jacka) and the Food & Mood course in chapter 10 with a sober, clinician-friendly summary; useful for readers who want to know how much weight to put on diet-and-mood claims.
Peer-reviewed analysis (narrative review), BMJ Food for Thought series. Moderate evidence. BMJ 2020;369:m2382. DOI 10.1136/bmj.m2382. Free full text in PubMed Central (PMC7322666) — open access, CC BY-NC 4.0. Note: A narrative rather than systematic review; the authors stress that causal effects of diet on mood are not yet established.
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The effect of culinary interventions (cooking classes) on dietary intake and behavioral change: a systematic review and evidence map — Hasan et al., BMC Nutr 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC7050805/
Systematic review and evidence map — 30 studies (6 randomised), 7,381 people. Moderate evidence. BMC Nutr 2019;5:29. DOI 10.1186/s40795-019-0293-8. Free full text in PubMed Central (PMC7050805) — open access, CC BY 4.0. Note: Only 6 of the 30 studies were randomised (all at high risk of bias); outcomes were mostly self-reported, and mental health was not assessed beyond two small quality-of-life studies.
What It Found
Reviewed 30 studies of cooking classes (hands-on or demonstration) for children and adults, followed for about 25 weeks on average. Cooking classes were linked with better attitudes to healthy food, more confidence in the kitchen (self-efficacy) and healthier eating, particularly when combined with nutrition education, gardening or physical activity. They were not linked with any significant change in weight, blood pressure or LDL cholesterol.
Why It Matters Here
Backs up cooking classes such as those in chapter 14 (Food for Life, Cook To Heal; the named programmes were not tested) and the learn-to-cook books in chapter 10: classes build kitchen confidence and healthier eating.
Systematic review and evidence map — 30 studies (6 randomised), 7,381 people. Moderate evidence. BMC Nutr 2019;5:29. DOI 10.1186/s40795-019-0293-8. Free full text in PubMed Central (PMC7050805) — open access, CC BY 4.0. Note: Only 6 of the 30 studies were randomised (all at high risk of bias); outcomes were mostly self-reported, and mental health was not assessed beyond two small quality-of-life studies.
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Psychosocial Benefits of Cooking Interventions: A Systematic Review — Farmer et al., Health Educ Behav 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC5862744/
Systematic review — 11 studies (from 377 screened) of cooking programmes in hospital and community settings. Early evidence. Health Educ Behav 2018;45(2):167–180. DOI 10.1177/1090198117736352. Free full text in PubMed Central (PMC5862744). Note: Small, mostly non-randomised studies using different, often unvalidated measures; benefits are promising but unconfirmed.
What It Found
Looked at whether cooking programmes help people's wellbeing, not just their diet. Across 11 studies, from baking groups on mental health wards to community kitchens, a community cooking course and cooking classes for people with cancer, participants reported better socialising, self-esteem, quality of life and mood (affect). The authors judged the research weak, mostly non-randomised, and the evidence preliminary.
Why It Matters Here
Backs up group cooking classes in chapter 14 (such as Food for Life and Cook To Heal; the named programmes were not tested) and cooking with others as a social activity. Most relevant to people who are isolated or in recovery.
Systematic review — 11 studies (from 377 screened) of cooking programmes in hospital and community settings. Early evidence. Health Educ Behav 2018;45(2):167–180. DOI 10.1177/1090198117736352. Free full text in PubMed Central (PMC5862744). Note: Small, mostly non-randomised studies using different, often unvalidated measures; benefits are promising but unconfirmed.
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How a 7-Week Food Literacy Cooking Program Affects Cooking Confidence and Mental Health: Findings of a Quasi-Experimental Controlled Intervention Trial — Rees et al., Front Nutr 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC8970183/
Quasi-experimental controlled trial (non-randomised, wait-list control) — 657 adults, 7 weeks, 6-month follow-up. Early evidence. Front Nutr 2022;9:802940. DOI 10.3389/fnut.2022.802940. Free full text in PubMed Central (PMC8970183) — open access, CC BY 4.0. Note: Not randomised and most did not complete follow-up (176 of 493 analysed; controls not followed to six months); mental health gains were small and self-reported.
What It Found
Tested Jamie's Ministry of Food, a community cooking programme of seven weekly 90-minute hands-on classes in Western Australia, against a wait-list group. Participants gained cooking confidence and satisfaction (p < 0.001), felt more able to change eating habits, and reported small improvements in mental and general health (p < 0.05, small effect sizes), which held at six months in those followed up. Fruit, vegetable and takeaway intake did not change.
Why It Matters Here
Backs up hands-on community cooking classes like those in chapter 14 (Food for Life, Cook To Heal) and the learn-to-cook books in chapter 10: one of few studies to measure mental wellbeing after a community cooking course.
Quasi-experimental controlled trial (non-randomised, wait-list control) — 657 adults, 7 weeks, 6-month follow-up. Early evidence. Front Nutr 2022;9:802940. DOI 10.3389/fnut.2022.802940. Free full text in PubMed Central (PMC8970183) — open access, CC BY 4.0. Note: Not randomised and most did not complete follow-up (176 of 493 analysed; controls not followed to six months); mental health gains were small and self-reported.
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Food insecurity and mental health: a systematic review and meta-analysis — Pourmotabbed et al., Public Health Nutr 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC10200655/
Systematic review and meta-analysis of observational studies — 19 studies, 372,143 people in ten countries. Moderate evidence. Public Health Nutr 2020;23(10):1778–1790. DOI 10.1017/S136898001900435X. Free full text in PubMed Central (PMC10200655). Note: 18 of the 19 studies were one-off surveys, so it shows a link, not that food insecurity causes depression; poverty and other hardships overlap with both.
What It Found
Pooled 19 studies on not having reliable access to enough food (food insecurity) and mental health. Food-insecure adults had higher odds of depression (odds ratio 1.40, 95% CI 1.30–1.58) and stress (1.34, 1.24–1.44); the link with anxiety was not significant. The association with depression was strongest in people aged 65 and over (odds ratio 1.75). The authors conclude that reducing food insecurity could support wellbeing.
Why It Matters Here
Backs up the case for food support and budget cooking: the meal service in chapter 14 (Project Angel Food) and the budget cookbooks and recipe sites in chapter 10 (Good and Cheap, Budget Bytes), though it did not test them. Most relevant to people on low incomes.
Systematic review and meta-analysis of observational studies — 19 studies, 372,143 people in ten countries. Moderate evidence. Public Health Nutr 2020;23(10):1778–1790. DOI 10.1017/S136898001900435X. Free full text in PubMed Central (PMC10200655). Note: 18 of the 19 studies were one-off surveys, so it shows a link, not that food insecurity causes depression; poverty and other hardships overlap with both.
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Let them eat fruit! The effect of fruit and vegetable consumption on psychological well-being in young adults: A randomized controlled trial — Conner et al., PLoS One 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5291486/
Randomised controlled trial — 171 young adults who ate little fruit and vegetables, 14 days, three groups. Early evidence. PLoS One 2017;12(2):e0171206. DOI 10.1371/journal.pone.0171206. Free full text in PubMed Central (PMC5291486) — open access, CC BY 4.0. Note: Two-week trial in healthy students; benefits were for wellbeing and motivation only, not depression, anxiety or mood.
What It Found
Young adults were randomised to their usual diet, text reminders plus a voucher to buy produce, or being given fresh fruit and vegetables to eat two extra servings a day. Only those given the produce itself reported more vitality, flourishing and motivation over two weeks; reminders and vouchers did not change wellbeing. Neither approach improved depressive symptoms, anxiety or mood compared with usual diet.
Why It Matters Here
Backs up the idea behind food support that puts fresh food in people's hands, such as the meal service in chapter 14 (Project Angel Food; not itself tested), and the whole-food cooking resources in chapter 10: making fresh food easy to eat may matter more than advice alone.
Randomised controlled trial — 171 young adults who ate little fruit and vegetables, 14 days, three groups. Early evidence. PLoS One 2017;12(2):e0171206. DOI 10.1371/journal.pone.0171206. Free full text in PubMed Central (PMC5291486) — open access, CC BY 4.0. Note: Two-week trial in healthy students; benefits were for wellbeing and motivation only, not depression, anxiety or mood.
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Talking Therapies — Psychotherapy, Counselling, Trauma Therapy & Telehealth

Psychotherapies for depression: a network meta-analysis covering efficacy, acceptability and long-term outcomes of all main treatment types — Cuijpers et al., World Psychiatry 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8129869/
Network meta-analysis — 331 randomised trials, 34,285 adults with depression. Moderate evidence. World Psychiatry 2021;20(2):283-293. DOI 10.1002/wps.20860. Free full text in PubMed Central (PMC8129869). Note: The authors rated certainty low to very low for most comparisons; only 31% of trials were at low risk of bias, and long-term data were more limited.
What It Found
Compared the main talking therapies for adult depression: CBT, behavioural activation, problem-solving, interpersonal, psychodynamic, third-wave (such as ACT), life-review and non-directive supportive counselling. All did better than usual care (standardised effects about 0.3 to 0.8; CBT 0.67) and waiting lists, and they did not differ from each other except supportive counselling, which was weaker. Most still beat usual care at 12 months.
Why It Matters Here
Backs up the general therapist directories in chapter 05 (Psychology Today, GoodTherapy, It's Complicated, International Therapist Directory) and the ACT practitioner directory: for depression several therapy types work about equally, so preference, fit and access can guide the choice.
Network meta-analysis — 331 randomised trials, 34,285 adults with depression. Moderate evidence. World Psychiatry 2021;20(2):283-293. DOI 10.1002/wps.20860. Free full text in PubMed Central (PMC8129869). Note: The authors rated certainty low to very low for most comparisons; only 31% of trials were at low risk of bias, and long-term data were more limited.
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A network meta-analysis of the effects of psychotherapies, pharmacotherapies and their combination in the treatment of adult depression — Cuijpers et al., World Psychiatry 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC6953550/
Network meta-analysis — 101 randomised trials, 11,910 patients with depression. Moderate evidence. World Psychiatry 2020;19(1):92-107. DOI 10.1002/wps.20701. Free full text in PubMed Central (PMC6953550). Note: Most trials were in adults with moderate to severe depression and measured short-term response; the authors say more research is needed on long-term effects.
What It Found
Pooled 101 trials comparing talking therapy, antidepressants and the two combined. Psychotherapy alone and medication alone worked about equally well (response RR 0.99, 95% CI 0.92–1.08), while combining them did better than either alone (RR 1.27 vs psychotherapy, 1.25 vs medication). People were more likely to stay in combined treatment or psychotherapy than in medication alone.
Why It Matters Here
Backs up the therapist directories in chapter 05: talking therapy worked about as well as antidepressants and combining the two worked best, which matters for people who prefer not to take medication or want more than medication alone.
Network meta-analysis — 101 randomised trials, 11,910 patients with depression. Moderate evidence. World Psychiatry 2020;19(1):92-107. DOI 10.1002/wps.20701. Free full text in PubMed Central (PMC6953550). Note: Most trials were in adults with moderate to severe depression and measured short-term response; the authors say more research is needed on long-term effects.
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The efficacy of psychotherapies and pharmacotherapies for mental disorders in adults: an umbrella review and meta-analytic evaluation of recent meta-analyses — Leichsenring et al., World Psychiatry 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC8751557/
Umbrella review — 102 meta-analyses covering 3,782 randomised trials and 650,514 patients across 11 adult mental disorders. Strong evidence. World Psychiatry 2022;21(1):133-145. DOI 10.1002/wps.20941. Free full text in PubMed Central (PMC8751557). Note: Average effects are small and risk of bias in the underlying trials was often high; the authors call for better treatments and better trials.
What It Found
Pulled together the largest recent meta-analyses for depression, anxiety, trauma, OCD, eating, insomnia, substance use and other disorders. Talking therapies beat placebo or usual care by an average standardised effect of 0.34 (95% CI 0.26–0.42), close to medication (0.36); the two did not differ head-to-head (0.11, −0.05 to 0.26), and combining them added 0.31. Most effects were small.
Why It Matters Here
Backs up every therapist listing in chapter 05 with a realistic message: across many conditions psychotherapy helps about as much as medication, but gains are usually modest, so it is one useful tool rather than a guaranteed fix.
Umbrella review — 102 meta-analyses covering 3,782 randomised trials and 650,514 patients across 11 adult mental disorders. Strong evidence. World Psychiatry 2022;21(1):133-145. DOI 10.1002/wps.20941. Free full text in PubMed Central (PMC8751557). Note: Average effects are small and risk of bias in the underlying trials was often high; the authors call for better treatments and better trials.
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The Efficacy of Cognitive Behavioral Therapy: A Review of Meta-analyses — Hofmann et al., Cognit Ther Res 2012

https://pmc.ncbi.nlm.nih.gov/articles/PMC3584580/
Review of meta-analyses — 269 meta-analyses identified, 106 reviewed. Moderate evidence. Cognit Ther Res 2012;36(5):427-440. DOI 10.1007/s10608-012-9476-1. Free full text in PubMed Central (PMC3584580). Note: A 2012 narrative synthesis: many underlying studies were small or lacked adequate control groups, and no meta-analysis had looked separately at minority or low-income groups.
What It Found
Reviewed 106 meta-analyses of cognitive behavioural therapy (CBT) across many problems. Support was strongest for anxiety disorders, somatoform (body-symptom) disorders, bulimia, anger problems and general stress; for depression, CBT had medium effects against waiting list or no treatment, while comparisons with other therapies were mixed. In 11 studies comparing response rates, CBT did better in 7 and worse in 1.
Why It Matters Here
Backs up the CBT-trained therapists found through the chapter 05 directories, and is most relevant to people with anxiety, stress, health anxiety or bulimia who want a structured, skills-based therapy.
Review of meta-analyses — 269 meta-analyses identified, 106 reviewed. Moderate evidence. Cognit Ther Res 2012;36(5):427-440. DOI 10.1007/s10608-012-9476-1. Free full text in PubMed Central (PMC3584580). Note: A 2012 narrative synthesis: many underlying studies were small or lacked adequate control groups, and no meta-analysis had looked separately at minority or low-income groups.
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Cognitive behavioral therapy for anxiety and related disorders: A meta-analysis of randomized placebo-controlled trials — Carpenter et al., Depress Anxiety 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC5992015/
Meta-analysis — 41 placebo-controlled randomised trials, 2,835 adults with anxiety-related disorders. Strong evidence. Depress Anxiety 2018;35(6):502-514. DOI 10.1002/da.22728. Free full text in PubMed Central (PMC5992015). Note: Signs of publication bias: adjusting for likely missing studies cut the effect to g = 0.33; some disorders had very few trials and most non-PTSD samples were white.
What It Found
Compared CBT with a psychological or pill placebo, a tougher test than a waiting list, for PTSD, social anxiety, panic, OCD, acute stress and generalised anxiety. CBT reduced the main symptoms more than placebo (g = 0.56, 95% CI 0.44–0.69), with large effects for OCD, generalised anxiety and acute stress and smaller ones for PTSD, social anxiety and panic. The odds of responding were about three times higher (OR 2.97), and benefits were still present at follow-up (g = 0.47).
Why It Matters Here
Backs up the CBT therapists and trauma specialists in the chapter 05 directories (ISTSS, Psychology Today, GoodTherapy), and is most relevant to people with anxiety, panic, OCD or trauma symptoms.
Meta-analysis — 41 placebo-controlled randomised trials, 2,835 adults with anxiety-related disorders. Strong evidence. Depress Anxiety 2018;35(6):502-514. DOI 10.1002/da.22728. Free full text in PubMed Central (PMC5992015). Note: Signs of publication bias: adjusting for likely missing studies cut the effect to g = 0.33; some disorders had very few trials and most non-PTSD samples were white.
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Psychological therapies for post-traumatic stress disorder in adults: systematic review and meta-analysis — Lewis et al., Eur J Psychotraumatol 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7144187/
Systematic review and meta-analysis — 114 randomised trials, 8,171 adults with PTSD. Moderate evidence. Eur J Psychotraumatol 2020;11(1):1729633. DOI 10.1080/20008198.2020.1729633. Free full text in PubMed Central (PMC7144187) — open access, CC BY-NC 4.0. Note: The authors rated the evidence moderate quality for trauma-focused CBT overall but low for EMDR and each named therapy; publication bias was possible and complex cases were mostly excluded.
What It Found
Reviewed 114 trials of talking therapies for adult PTSD to inform the ISTSS treatment guidelines. There was robust evidence of a clinically important benefit for trauma-focused CBT and for EMDR, judged against a demanding pre-set bar (an effect above 0.8 versus waiting list). Cognitive Processing Therapy, Cognitive Therapy and Prolonged Exposure had the strongest evidence; CBT without a trauma focus, group or guided internet versions and present-centred therapy had some.
Why It Matters Here
Backs up the trauma listings in chapter 05 (the ISTSS trauma-specialist directory and the EMDRAA therapist finder): trauma-focused CBT and EMDR are the best-supported talking therapies for adults with PTSD.
Systematic review and meta-analysis — 114 randomised trials, 8,171 adults with PTSD. Moderate evidence. Eur J Psychotraumatol 2020;11(1):1729633. DOI 10.1080/20008198.2020.1729633. Free full text in PubMed Central (PMC7144187) — open access, CC BY-NC 4.0. Note: The authors rated the evidence moderate quality for trauma-focused CBT overall but low for EMDR and each named therapy; publication bias was possible and complex cases were mostly excluded.
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Guidelines for the management of conditions specifically related to stress — WHO 2013

https://www.who.int/publications/i/item/9789241505406
WHO guideline from an independent Guidelines Development Group — 21 graded recommendations on stress after recent trauma, PTSD and bereavement. Moderate evidence. Geneva: WHO; 2013. ISBN 978-92-4-150540-6. Free from the World Health Organization. Note: Dates from 2013, and WHO rated much of the evidence low or very low quality, especially for children and adolescents.
What It Found
WHO guidance for non-specialist health workers on stress after trauma, PTSD and bereavement. For adults with PTSD, individual or group trauma-focused CBT, EMDR or stress management should be considered (moderate-quality evidence for individual trauma-focused CBT and EMDR); antidepressants should not be first-line. It advises against benzodiazepines in the first month after trauma and against routine structured psychological help for bereaved people without a mental disorder.
Why It Matters Here
Backs up the trauma listings in chapter 05 (EMDRAA therapist finder, ISTSS trauma-specialist directory): WHO recommends trauma-focused CBT and EMDR for PTSD in adults and young people, including in non-specialist care worldwide.
WHO guideline from an independent Guidelines Development Group — 21 graded recommendations on stress after recent trauma, PTSD and bereavement. Moderate evidence. Geneva: WHO; 2013. ISBN 978-92-4-150540-6. Free from the World Health Organization. Note: Dates from 2013, and WHO rated much of the evidence low or very low quality, especially for children and adolescents.
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Somatic experiencing – effectiveness and key factors of a body-oriented trauma therapy: a scoping literature review — Kuhfuß et al., Eur J Psychotraumatol 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8276649/
Scoping review — 16 studies, including 2 small randomised trials (63 and 91 participants). Early evidence. Eur J Psychotraumatol 2021;12(1):1929023. DOI 10.1080/20008198.2021.1929023. Free full text in PubMed Central (PMC8276649) — open access, CC BY-NC 4.0. Note: Early evidence: only two small randomised trials, both with high-risk-of-bias domains, and mixed study quality; the authors say unbiased trials are needed.
What It Found
Mapped the research on Somatic Experiencing (SE), a body-focused trauma therapy that works with physical sensations. Of 16 studies, only two were randomised trials (63 and 91 people). The authors found preliminary evidence of benefit for PTSD symptoms and possible benefits for mood, physical symptoms and well-being; clients and practitioners named touch and a focus on personal resources as key ingredients.
Why It Matters Here
Backs up the Somatic Experiencing International practitioner finder in chapter 05, honestly: SE is promising but far less tested than trauma-focused CBT or EMDR, so it is best seen as a less-proven, body-based option.
Scoping review — 16 studies, including 2 small randomised trials (63 and 91 participants). Early evidence. Eur J Psychotraumatol 2021;12(1):1929023. DOI 10.1080/20008198.2021.1929023. Free full text in PubMed Central (PMC8276649) — open access, CC BY-NC 4.0. Note: Early evidence: only two small randomised trials, both with high-risk-of-bias domains, and mixed study quality; the authors say unbiased trials are needed.
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Telehealth v. face-to-face provision of care to patients with depression: a systematic review and meta-analysis — Scott et al., Psychol Med 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9693715/
Systematic review and meta-analysis — 9 randomised trials, 1,268 patients. Moderate evidence. Psychol Med 2022;52(14):2852-2860. DOI 10.1017/S0033291722002331. Free full text in PubMed Central (PMC9693715) — open access, CC BY 4.0. Note: Only 9 trials, all in the US; blinding was impossible, attrition was often high, and few trials followed people up for long.
What It Found
Compared the same therapy (mostly CBT-based) delivered by video (5 trials) or telephone (4) with face-to-face care for depression. Depression severity did not differ at the end of treatment (SMD −0.04, 95% CI −0.21 to 0.13) or at 3 months (0.10, −0.08 to 0.28), and satisfaction and working alliance did not differ in the few trials that measured them.
Why It Matters Here
Backs up the online and telehealth therapy offered through chapter 05 directories (Psychology Today, It's Complicated, Open Path) and EAP platforms such as Intellect: for depression, therapy by video or phone appears to work about as well as in person.
Systematic review and meta-analysis — 9 randomised trials, 1,268 patients. Moderate evidence. Psychol Med 2022;52(14):2852-2860. DOI 10.1017/S0033291722002331. Free full text in PubMed Central (PMC9693715) — open access, CC BY 4.0. Note: Only 9 trials, all in the US; blinding was impossible, attrition was often high, and few trials followed people up for long.
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Telehealth Versus Face-to-face Psychotherapy for Less Common Mental Health Conditions: Systematic Review and Meta-analysis of Randomized Controlled Trials — Greenwood et al., JMIR Ment Health 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC8956990/
Systematic review and meta-analysis — 12 randomised trials, 931 patients. Moderate evidence. JMIR Ment Health 2022;9(3):e31780. DOI 10.2196/31780. Free full text in PubMed Central (PMC8956990) — open access, CC BY 4.0. Note: Few, small trials; participants could not be blinded and many reports lacked detail; confidence intervals were too wide to confirm equivalence, and no trials covered psychosis or bipolar disorder.
What It Found
Looked at therapy by video (7 trials) or telephone for addictions, eating disorders, children's mental health and the psychological side of chronic conditions such as type 1 diabetes, chronic fatigue and cancer. Symptom severity did not differ from face-to-face therapy (SMD 0.05, 95% CI −0.17 to 0.27), nor did satisfaction or working alliance; the authors call this insufficient evidence of a difference, not proven equivalence.
Why It Matters Here
Backs up the online and phone therapy offered through chapter 05 directories, including the Chronic Illness Therapist directory, for people whose health, energy or location makes travelling to sessions hard.
Systematic review and meta-analysis — 12 randomised trials, 931 patients. Moderate evidence. JMIR Ment Health 2022;9(3):e31780. DOI 10.2196/31780. Free full text in PubMed Central (PMC8956990) — open access, CC BY 4.0. Note: Few, small trials; participants could not be blinded and many reports lacked detail; confidence intervals were too wide to confirm equivalence, and no trials covered psychosis or bipolar disorder.
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Effectiveness of a brief behavioural intervention on psychological distress among women with a history of gender-based violence in urban Kenya: A randomised clinical trial — Bryant et al., PLoS Med 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5557357/
Randomised controlled trial — 421 women with a history of gender-based violence in Nairobi, Kenya. Moderate evidence. PLoS Med 2017;14(8):e1002371. DOI 10.1371/journal.pmed.1002371. Free full text in PubMed Central (PMC5557357) — open access, CC BY 4.0. Note: A single trial with only 3-month follow-up, self-report measures, women only and no attention-control group.
What It Found
Tested WHO's Problem Management Plus (PM+), a five-session programme delivered by lay community health workers after 8 days' training, against enhanced usual care from community nurses, in women who had experienced gender-based violence. Three months after treatment PM+ gave a moderate extra fall in psychological distress (effect size 0.57, 95% CI 0.32–0.83) and smaller gains in PTSD symptoms (0.21) and daily functioning (0.26).
Why It Matters Here
Backs up the community programmes of the Canadian Mental Health Association in chapter 05 and the violence-survivor services in chapter 06 in principle: brief, structured help from trained non-specialists reduced distress in women who had experienced violence. Those services were not themselves tested.
Randomised controlled trial — 421 women with a history of gender-based violence in Nairobi, Kenya. Moderate evidence. PLoS Med 2017;14(8):e1002371. DOI 10.1371/journal.pmed.1002371. Free full text in PubMed Central (PMC5557357) — open access, CC BY 4.0. Note: A single trial with only 3-month follow-up, self-report measures, women only and no attention-control group.
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Psychotherapies for depression in low- and middle-income countries: a meta-analysis — Cuijpers et al., World Psychiatry 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC5775122/
Meta-analysis — 253 randomised trials, 32 of them in non-Western countries. Moderate evidence. World Psychiatry 2018;17(1):90-101. DOI 10.1002/wps.20493. Free full text in PubMed Central (PMC5775122). Note: Results varied widely between trials (I² = 90%), and the larger effects may partly reflect weak comparison care or lower trial quality in some settings.
What It Found
Asked whether talking therapies developed in Western countries work elsewhere. In the 32 trials from non-Western countries the pooled effect was large (g = 1.10, 95% CI 0.91–1.30), falling to 0.73 after adjusting for publication bias. Effects were larger, not smaller, than in Western trials, and whether a therapy had been adapted to local conditions made no clear difference in this analysis.
Why It Matters Here
Backs up the international and multilingual directories in chapter 05 (It's Complicated, International Therapist Directory, Psychology Today Hong Kong & Singapore, Singapore Association for Counselling): therapies developed in Western countries appear to work in other cultures too.
Meta-analysis — 253 randomised trials, 32 of them in non-Western countries. Moderate evidence. World Psychiatry 2018;17(1):90-101. DOI 10.1002/wps.20493. Free full text in PubMed Central (PMC5775122). Note: Results varied widely between trials (I² = 90%), and the larger effects may partly reflect weak comparison care or lower trial quality in some settings.
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The current status of culturally adapted mental health interventions: a practice-focused review of meta-analyses — Rathod et al., Neuropsychiatr Dis Treat 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC5757988/
Umbrella review — 12 meta-analyses and reviews of culturally adapted psychological interventions. Moderate evidence. Neuropsychiatr Dis Treat 2018;14:165-178. DOI 10.2147/NDT.S138430. Free full text in PubMed Central (PMC5757988) — open access, CC BY-NC 3.0. Note: Most trials compared adapted therapy with usual care rather than the unadapted version; the authors say most reviews lacked rigour, and the reviews overlapped.
What It Found
Brought together 12 reviews of therapies adapted to clients' culture, language and values, mostly for Latino, African American, Asian American and Native American groups with depression, schizophrenia or youth problems. Most found moderate to large benefits (effects about 0.23–0.75), and one review found adapted versions beat unadapted versions of the same therapy (g = 0.52). Common adaptations covered language, therapist, content, family and cultural norms.
Why It Matters Here
Backs up Inclusive Therapists and the multilingual directories in chapter 05: therapy adapted to a person's culture, language and values generally helped, which supports seeking a culturally responsive therapist. It does not cover LGBTQ+-affirmative therapy.
Umbrella review — 12 meta-analyses and reviews of culturally adapted psychological interventions. Moderate evidence. Neuropsychiatr Dis Treat 2018;14:165-178. DOI 10.2147/NDT.S138430. Free full text in PubMed Central (PMC5757988) — open access, CC BY-NC 3.0. Note: Most trials compared adapted therapy with usual care rather than the unadapted version; the authors say most reviews lacked rigour, and the reviews overlapped.
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The alliance in mental health care: conceptualization, evidence and clinical applications — Wampold & Flückiger, World Psychiatry 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC9840508/
Narrative review of meta-analytic and trial evidence on the therapeutic alliance. Moderate evidence. World Psychiatry 2023;22(1):25-41. DOI 10.1002/wps.21035. Free full text in PubMed Central (PMC9840508). Note: A narrative review by leading alliance researchers; the alliance-outcome link is mainly correlational, so it shows association rather than proof of cause.
What It Found
Summarises the research on the working alliance: agreement on goals and tasks plus a personal bond. Across many forms of therapy, the alliance measured early in treatment reliably predicts outcome, even after allowing for early symptom change. Most of its benefit appears to come from the therapist's interpersonal skills, such as warmth, empathy, hope and repairing ruptures; evidence for online alliances is still preliminary.
Why It Matters Here
Backs up the core idea behind every therapist directory in chapter 05: who you see matters, so it is worth taking time to find a therapist you trust and agree with on goals, whatever their method.
Narrative review of meta-analytic and trial evidence on the therapeutic alliance. Moderate evidence. World Psychiatry 2023;22(1):25-41. DOI 10.1002/wps.21035. Free full text in PubMed Central (PMC9840508). Note: A narrative review by leading alliance researchers; the alliance-outcome link is mainly correlational, so it shows association rather than proof of cause.
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Peer Support, Mutual Help & Recovery Communities

Alcoholics Anonymous and other 12-step programs for alcohol use disorder — Kelly et al., Cochrane Database Syst Rev 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7065341/
Cochrane systematic review and meta-analysis — 27 studies (21 randomised or quasi-randomised), 10,565 people. Strong evidence. Cochrane Database Syst Rev 2020;3:CD012880. DOI 10.1002/14651858.CD012880.pub2. Free full text in PubMed Central (PMC7065341). Note: The high-certainty abstinence result comes from 2 studies of structured programmes that link people into AA; most other outcomes were rated lower certainty.
What It Found
Reviewed 27 studies (10,565 people) comparing Alcoholics Anonymous, or clinical programmes that link people into AA ('Twelve-Step Facilitation'), with other treatments such as CBT. Manualised AA/TSF led to more people staying continuously abstinent at 12 months (risk ratio 1.21, 95% CI 1.03 to 1.42; 2 studies, 1,936 people; high-certainty evidence), probably lowers healthcare costs, and appeared at least as good on other drinking outcomes.
Why It Matters Here
Backs up the Alcoholics Anonymous 'Big Book' listing in chapter 10: the review tested AA and clinical programmes that link people into AA, not reading the book on its own. Most relevant to people with alcohol problems, their families, and peer workers deciding whether to suggest a meeting.
Cochrane systematic review and meta-analysis — 27 studies (21 randomised or quasi-randomised), 10,565 people. Strong evidence. Cochrane Database Syst Rev 2020;3:CD012880. DOI 10.1002/14651858.CD012880.pub2. Free full text in PubMed Central (PMC7065341). Note: The high-certainty abstinence result comes from 2 studies of structured programmes that link people into AA; most other outcomes were rated lower certainty.
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A longitudinal study of the comparative efficacy of Women for Sobriety, LifeRing, SMART Recovery, and 12-step groups for those with AUD — Zemore et al., J Subst Abuse Treat 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC5884451/
Prospective cohort study — 647 mutual-help group members followed for 12 months. Early evidence. J Subst Abuse Treat 2018;88:18–26. DOI 10.1016/j.jsat.2018.02.004. Free full text in PubMed Central (PMC5884451). Note: Self-selected online sample, likely weighted towards long-standing members, with no randomisation, so it shows association, not cause; the authors call the analyses exploratory.
What It Found
Followed 647 adults with a lifetime alcohol use disorder who attended Women for Sobriety, LifeRing, SMART Recovery or 12-step groups for a year. Once people's own recovery goals were allowed for, members of the secular alternatives did as well as 12-step members. In all groups, greater involvement at 6 months went with much higher odds of not drinking across the 6- and 12-month follow-ups (odds ratio 3.97, 95% CI 1.96 to 8.04).
Why It Matters Here
Backs up the SMART Recovery and LifeRing Secular Recovery listings in chapter 06 as alternatives to AA that may work as well, and is the closest evidence for other non-12-step groups such as Recovery Dharma (not studied); most relevant to people who do not connect with the 12-step approach.
Prospective cohort study — 647 mutual-help group members followed for 12 months. Early evidence. J Subst Abuse Treat 2018;88:18–26. DOI 10.1016/j.jsat.2018.02.004. Free full text in PubMed Central (PMC5884451). Note: Self-selected online sample, likely weighted towards long-standing members, with no randomisation, so it shows association, not cause; the authors call the analyses exploratory.
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The effectiveness of one-to-one peer support in mental health services: a systematic review and meta-analysis — White et al., BMC Psychiatry 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7657356/
Systematic review and meta-analysis — 19 randomised trials, 3,329 people. Moderate evidence. BMC Psychiatry 2020;20:534. DOI 10.1186/s12888-020-02923-3. Free full text in PubMed Central (PMC7657356) — open access, CC BY 4.0. Note: Several trials were small pilots and outcome reporting was often incomplete; the authors judge clinical benefits unlikely.
What It Found
Reviewed 19 randomised trials (3,329 adults) of one-to-one support from trained peer workers — staff who draw on their own lived experience of mental distress — in mental health services. Peer support may have a modest positive effect on people's own sense of recovery and empowerment, and might improve social support (less certain), but it did not change clinical symptoms or use of services.
Why It Matters Here
Backs up peer workers in mental health services, such as the peer support offered by community mental health organisations in chapter 05, and is the closest evidence for peer-led programmes such as NAMI Peer-to-Peer in chapter 06 (a group course, not tested here); relevant to peer workers and people offered one.
Systematic review and meta-analysis — 19 randomised trials, 3,329 people. Moderate evidence. BMC Psychiatry 2020;20:534. DOI 10.1186/s12888-020-02923-3. Free full text in PubMed Central (PMC7657356) — open access, CC BY 4.0. Note: Several trials were small pilots and outcome reporting was often incomplete; the authors judge clinical benefits unlikely.
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Lived Experience in New Models of Care for Substance Use Disorder: A Systematic Review of Peer Recovery Support Services and Recovery Coaching — Eddie et al., Front Psychol 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6585590/
Systematic review — 24 reports of 23 studies (7 randomised trials), 6,544 people. Moderate evidence. Front Psychol 2019;10:1052. DOI 10.3389/fpsyg.2019.01052. Free full text in PubMed Central (PMC6585590) — open access, CC BY 4.0. Note: The authors call the findings tentative: peer effects were hard to separate from other services and many studies lacked a proper comparison group.
What It Found
Reviewed 23 studies (6,544 people, including 7 randomised trials) of peer recovery coaches — people in recovery who support others with alcohol or drug problems. Peer recovery support was linked with less substance use and relapse, better relationships with providers and supporters, staying in treatment longer and greater satisfaction, although many studies found no difference.
Why It Matters Here
Backs up the lived-experience principle behind the peer-led recovery communities in chapter 06 (SMART Recovery, LifeRing, Recovery Dharma, The Phoenix), though it studied peer recovery coaches and support workers in clinical settings, not these groups; especially relevant to people training as peer or recovery workers.
Systematic review — 24 reports of 23 studies (7 randomised trials), 6,544 people. Moderate evidence. Front Psychol 2019;10:1052. DOI 10.3389/fpsyg.2019.01052. Free full text in PubMed Central (PMC6585590) — open access, CC BY 4.0. Note: The authors call the findings tentative: peer effects were hard to separate from other services and many studies lacked a proper comparison group.
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Peer Support Interventions for Adults With Diabetes: A Meta-Analysis of Hemoglobin A1c Outcomes — Patil et al., Ann Fam Med 2016

https://pmc.ncbi.nlm.nih.gov/articles/PMC5389404/
Meta-analysis — 17 randomised trials (14 individual, 3 cluster), 4,715 adults with diabetes. Moderate evidence. Ann Fam Med 2016;14(6):540–551. DOI 10.1370/afm.1982. Free full text in PubMed Central (PMC5389404). Note: The overall effect was small and varied between trials; the differences by ethnic group come from comparing whole studies, and the authors call these comparisons post hoc.
What It Found
Pooled 17 randomised trials (4,715 adults with diabetes) of support from peers rather than health professionals. Peer support improved long-term blood glucose (HbA1c) by 0.24 percentage points on average (95% CI 0.05 to 0.43), a small effect. Benefits were larger in studies of mainly minority-ethnic groups (0.53 points) and absent in mainly non-Hispanic white groups.
Why It Matters Here
Backs up the idea behind peer support for metabolic conditions, such as the fasting and low-carb support groups in chapter 13 (not tested here; the trials used trained peer supporters, often by phone): support from people with the same condition can lower HbA1c, if only slightly. Most relevant to people with diabetes.
Meta-analysis — 17 randomised trials (14 individual, 3 cluster), 4,715 adults with diabetes. Moderate evidence. Ann Fam Med 2016;14(6):540–551. DOI 10.1370/afm.1982. Free full text in PubMed Central (PMC5389404). Note: The overall effect was small and varied between trials; the differences by ethnic group come from comparing whole studies, and the authors call these comparisons post hoc.
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The effectiveness, implementation, and experiences of peer support approaches for mental health: a systematic umbrella review — Cooper et al., BMC Med 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC10902990/
Umbrella review — 35 systematic and scoping reviews covering 426 primary studies. Moderate evidence. BMC Med 2024;22:72. DOI 10.1186/s12916-024-03260-y. Free full text in PubMed Central (PMC10902990) — open access, CC BY 4.0. Note: 97% of the included reviews were rated low or critically low quality, so the findings are suggestive rather than firm.
What It Found
Brought together 35 reviews (426 studies) of paid peer support for mental health. Effectiveness results were mixed, but pooled analyses suggested improvements in depression (especially around pregnancy and after birth), self-efficacy and recovery. Peer roles were more likely to succeed with proper training, supervision, clear roles and supportive leadership; role confusion and low pay were common problems.
Why It Matters Here
Backs up paid peer support workers in mental health services, such as those at the Canadian Mental Health Association (chapter 05), and is indirect support for peer-led programmes in chapter 06 such as NAMI Peer-to-Peer (not studied); its implementation findings help peer workers and services.
Umbrella review — 35 systematic and scoping reviews covering 426 primary studies. Moderate evidence. BMC Med 2024;22:72. DOI 10.1186/s12916-024-03260-y. Free full text in PubMed Central (PMC10902990) — open access, CC BY 4.0. Note: 97% of the included reviews were rated low or critically low quality, so the findings are suggestive rather than firm.
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Peer support for people with chronic conditions: a systematic review of reviews — Thompson et al., BMC Health Serv Res 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC8973527/
Systematic review of reviews — 31 reviews (cancer, diabetes and heart disease most common). Moderate evidence. BMC Health Serv Res 2022;22:427. DOI 10.1186/s12913-022-07816-7. Free full text in PubMed Central (PMC8973527) — open access, CC BY 4.0. Note: 24 of the 31 reviews were rated critically low confidence, and peer support was defined and measured in many different ways.
What It Found
Summarised 31 reviews of various kinds (systematic, literature, scoping and qualitative) of peer support for people with long-term physical conditions, most often cancer, diabetes and heart disease. Quality of life and self-efficacy were the outcomes most often measured. Most reviews reported positive but not statistically significant effects, and the authors conclude that how well peer support works, and which form suits whom, is still unclear.
Why It Matters Here
Backs up the chronic-illness and condition-specific communities in chapter 06 (e.g. HealthUnlocked, Crohn's & Colitis Foundation groups) while setting realistic expectations; it is only indirect evidence for the sleep peer groups in chapter 11 and gut-condition groups in chapter 15.
Systematic review of reviews — 31 reviews (cancer, diabetes and heart disease most common). Moderate evidence. BMC Health Serv Res 2022;22:427. DOI 10.1186/s12913-022-07816-7. Free full text in PubMed Central (PMC8973527) — open access, CC BY 4.0. Note: 24 of the 31 reviews were rated critically low confidence, and peer support was defined and measured in many different ways.
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Digital Peer Support Mental Health Interventions for People With a Lived Experience of a Serious Mental Illness: Systematic Review — Fortuna et al., JMIR Ment Health 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7165313/
Systematic review — 30 studies of 24 interventions (11 randomised trials). Early evidence. JMIR Ment Health 2020;7(4):e16460. DOI 10.2196/16460. Free full text in PubMed Central (PMC7165313) — open access, CC BY 4.0. Note: Half the studies were simple before-and-after designs, most were small single-site studies, and there is no pooled effect size; which parts of digital peer support help is unknown.
What It Found
Reviewed 30 studies (11 randomised trials) of peer support delivered through technology for people with schizophrenia-spectrum or bipolar disorder: online peer-to-peer networks, peer workers using technology to deliver support, and live or message-based online sessions. Most studies found these services feasible and acceptable, with early signs of benefit, but the authors stress the field is young and needs larger, longer trials.
Why It Matters Here
Backs up the approach of the online forums and virtual peer groups for mental health in chapter 06 (e.g. Out of the Storm, The Mighty), which were not themselves tested; the review covered only people with schizophrenia-spectrum or bipolar disorder. Most relevant to people who can only reach support online.
Systematic review — 30 studies of 24 interventions (11 randomised trials). Early evidence. JMIR Ment Health 2020;7(4):e16460. DOI 10.2196/16460. Free full text in PubMed Central (PMC7165313) — open access, CC BY 4.0. Note: Half the studies were simple before-and-after designs, most were small single-site studies, and there is no pooled effect size; which parts of digital peer support help is unknown.
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A systematic review and meta-analysis of randomised controlled trials of peer support for people with severe mental illness — Lloyd-Evans et al., BMC Psychiatry 2014

https://pmc.ncbi.nlm.nih.gov/articles/PMC3933205/
Systematic review and meta-analysis — 18 randomised trials, 5,597 people. Moderate evidence. BMC Psychiatry 2014;14:39. DOI 10.1186/1471-244X-14-39. Free full text in PubMed Central (PMC3933205) — open access, CC BY 2.0. Note: Nearly all trials had some serious risk of bias and the evidence was low or very low quality for every outcome; the authors say it does not support making peer support mandatory.
What It Found
Pooled 18 randomised trials (5,597 people with severe mental illness) of three kinds of peer support: mutual support groups (4 trials), peer support services (11) and services delivered by peers (3). There was little or no evidence of effects on hospital admission, symptoms or satisfaction, but some evidence of gains in hope, recovery and empowerment, not consistent across trials (e.g. a small effect on recovery for peer support services, SMD -0.24, 95% CI -0.39 to -0.09).
Why It Matters Here
Backs up the peer-run groups for mental health in chapter 06 and gives an honest picture of what they can and cannot do; useful for peer workers explaining that the main gains are in hope and recovery rather than symptom relief.
Systematic review and meta-analysis — 18 randomised trials, 5,597 people. Moderate evidence. BMC Psychiatry 2014;14:39. DOI 10.1186/1471-244X-14-39. Free full text in PubMed Central (PMC3933205) — open access, CC BY 2.0. Note: Nearly all trials had some serious risk of bias and the evidence was low or very low quality for every outcome; the authors say it does not support making peer support mandatory.
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Interventions to improve the experience of caring for people with severe mental illness: systematic review and meta-analysis — Yesufu-Udechuku et al., Br J Psychiatry 2015

https://doi.org/10.1192/bjp.bp.114.147561
Systematic review and meta-analysis — 21 randomised trials, 1,589 carers. Moderate evidence. Br J Psychiatry 2015;206(4):268–274. Free full text at the publisher — open access, CC BY-NC-ND 4.0. Note: Evidence for support groups was rated very low quality, came only from 4 small trials in Chinese populations, and results varied widely.
What It Found
Pooled 21 randomised trials (1,589 carers) of help for family and friends caring for someone with a severe mental illness such as psychosis. There was evidence, mostly of low or very low quality, that carer support groups (SMD -1.16, 95% CI -1.96 to -0.36) and psychoeducation (SMD -1.03, 95% CI -1.69 to -0.36) improved the experience of caring by the end of the programme; carer-focused help also appeared to improve quality of life and reduce distress.
Why It Matters Here
Backs up the family and carer support groups in chapter 06 (e.g. SMART Recovery Family & Friends) and chapter 09 (e.g. CADDAC's parent and caregiver groups), though it studied only carers of people with severe mental illness; most relevant to those carers.
Systematic review and meta-analysis — 21 randomised trials, 1,589 carers. Moderate evidence. Br J Psychiatry 2015;206(4):268–274. Free full text at the publisher — open access, CC BY-NC-ND 4.0. Note: Evidence for support groups was rated very low quality, came only from 4 small trials in Chinese populations, and results varied widely.
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State-of-the-art literature review of Recovery College evaluative studies between 2013-2024 — Briand et al., Front Psychiatry 2025

https://pmc.ncbi.nlm.nih.gov/articles/PMC12358375/
State-of-the-art literature review with a systematic search — 64 evaluative studies of Recovery Colleges, 2013–2024. Early evidence. Front Psychiatry 2025;16:1584110. DOI 10.3389/fpsyt.2025.1584110. Free full text in PubMed Central (PMC12358375) — open access, CC BY 4.0. Note: No randomised trials yet; most studies lacked a control group, and the authors say efficacy cannot be concluded.
What It Found
Reviewed 64 evaluations of Recovery Colleges, where people with lived experience and professionals co-design and co-teach adult-education courses on mental health and recovery. Mostly before-and-after studies reported gains in wellbeing and empowerment, and learners described renewed hope; some found fewer emergency visits and admissions, and one Australian study estimated net savings of AUD 269 per student per year.
Why It Matters Here
Backs up the recovery colleges run by community mental health organisations in chapter 05 (e.g. Canadian Mental Health Association), and is the closest evidence for peer-led courses such as NAMI Peer-to-Peer in chapter 06 (not itself studied); relevant to anyone considering a course.
State-of-the-art literature review with a systematic search — 64 evaluative studies of Recovery Colleges, 2013–2024. Early evidence. Front Psychiatry 2025;16:1584110. DOI 10.3389/fpsyt.2025.1584110. Free full text in PubMed Central (PMC12358375) — open access, CC BY 4.0. Note: No randomised trials yet; most studies lacked a control group, and the authors say efficacy cannot be concluded.
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Peer-supported self-management for people discharged from a mental health crisis team: a randomised controlled trial — Johnson et al., Lancet 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6083437/
Randomised controlled trial — 441 people discharged from six crisis teams in England. Moderate evidence. Lancet 2018;392(10145):409–418. DOI 10.1016/S0140-6736(18)31470-3. Free full text in PubMed Central (PMC6083437) — open access, CC BY 4.0. Note: A single trial in England; admission rates were lower than expected and the confidence interval was wide, so the size of the benefit is uncertain.
What It Found
Randomised 441 people leaving six crisis resolution teams in England to up to ten sessions with a peer support worker built around a recovery workbook, or the workbook alone by post. Within a year, 29% of the peer-supported group (64 of 218) were readmitted to acute care compared with 38% (83 of 216) of the comparison group (odds ratio 0.66, 95% CI 0.43 to 0.99).
Why It Matters Here
Backs up peer support workers in community mental health services (chapter 05) and is the closest trial evidence for peer-led self-management courses such as NAMI Peer-to-Peer in chapter 06 (a group format, not tested here); most relevant to people leaving crisis care and the peer workers who support them.
Randomised controlled trial — 441 people discharged from six crisis teams in England. Moderate evidence. Lancet 2018;392(10145):409–418. DOI 10.1016/S0140-6736(18)31470-3. Free full text in PubMed Central (PMC6083437) — open access, CC BY 4.0. Note: A single trial in England; admission rates were lower than expected and the confidence interval was wide, so the size of the benefit is uncertain.
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Determining the relative importance of the mechanisms of behavior change within Alcoholics Anonymous: a multiple mediator analysis — Kelly et al., Addiction 2012

https://pmc.ncbi.nlm.nih.gov/articles/PMC3242865/
Mediation analysis of a multisite randomised trial (Project MATCH) — 1,726 adults with alcohol use disorder. Early evidence. Addiction 2012;107(2):289–299. DOI 10.1111/j.1360-0443.2011.03593.x. Free full text in PubMed Central (PMC3242865). Note: Observational analysis within a 1990s trial: people chose whether to go to AA, so it points to likely pathways but cannot show cause and effect.
What It Found
Used data from 1,726 adults in a large US alcohol treatment trial to ask why going to AA helps. The main routes were social: positive changes in people's social networks and more confidence about staying sober in social situations. For people in aftercare after inpatient or day-hospital treatment, spirituality and less negative mood also played a part. Together these accounted for 43% to 67% of the link between AA attendance and better drinking outcomes.
Why It Matters Here
Backs up the AA 'Big Book' listing in chapter 10 by showing how AA attendance seems to work — through new sober relationships and confidence — and suggests why other mutual-help groups in chapter 06 may help; useful for peer workers explaining why 'the fellowship' matters.
Mediation analysis of a multisite randomised trial (Project MATCH) — 1,726 adults with alcohol use disorder. Early evidence. Addiction 2012;107(2):289–299. DOI 10.1111/j.1360-0443.2011.03593.x. Free full text in PubMed Central (PMC3242865). Note: Observational analysis within a 1990s trial: people chose whether to go to AA, so it points to likely pathways but cannot show cause and effect.
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Developing a change model for peer worker interventions in mental health services: a qualitative research study — Gillard et al., Epidemiol Psychiatr Sci 2015

https://pmc.ncbi.nlm.nih.gov/articles/PMC8367355/
Qualitative comparative case study — 10 peer worker programmes, 71 interviews. Early evidence. Epidemiol Psychiatr Sci 2015;24(5):435–445. DOI 10.1017/S2045796014000407. Free full text in PubMed Central (PMC8367355). Note: A qualitative study: it explains how peer work may help but does not measure outcomes.
What It Found
Interviewed 71 peer workers, service users, staff and managers across 10 peer worker programmes in statutory (NHS) and voluntary-sector mental health services in England. It identified three ways peer workers bring about change: trusting relationships built on shared lived experience, role-modelling that recovery is possible, and helping people engage with services and their community.
Why It Matters Here
Backs up the lived-experience principle behind the peer-led mental health groups in chapter 06 and the peer roles in community mental health organisations in chapter 05; especially useful for people training as peer workers to understand what makes the role work.
Qualitative comparative case study — 10 peer worker programmes, 71 interviews. Early evidence. Epidemiol Psychiatr Sci 2015;24(5):435–445. DOI 10.1017/S2045796014000407. Free full text in PubMed Central (PMC8367355). Note: A qualitative study: it explains how peer work may help but does not measure outcomes.
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Living With Chronic Illness & Pain — Self-Management, Education & Integrative Care

A Meta-Analysis of Health Status, Health Behaviors, and Health Care Utilization Outcomes of the Chronic Disease Self-Management Program — Brady et al., Prev Chronic Dis 2013

https://pmc.ncbi.nlm.nih.gov/articles/PMC3547675/
Meta-analysis — 23 studies (25 study arms; randomised trials and longitudinal studies), 8,688 participants. Moderate evidence. Prev Chronic Dis 2013;10:120112. DOI 10.5888/pcd10.120112. Free full text in PubMed Central (PMC3547675) — public domain. Note: Effects were small, much of the data came from before-and-after studies rather than randomised trials, and pain and fatigue improved only slightly.
What It Found
Pooled 23 studies (8,688 people) of the six-week Stanford Chronic Disease Self-Management Program, taught by trained leaders. In English-language small groups, at 4–6 months people had small-to-moderate gains in self-efficacy (effect size 0.35), health distress (−0.28), depression (−0.22), symptom-management skills, exercise and talking with doctors, plus slightly fewer hospital days; mood, distress and self-efficacy gains remained at 9–12 months.
Why It Matters Here
Backs up Living a Healthy Life with Chronic Conditions in chapter 10, the handbook of the group course tested here (the book on its own was not tested); relevant to anyone living with one or more long-term conditions.
Meta-analysis — 23 studies (25 study arms; randomised trials and longitudinal studies), 8,688 participants. Moderate evidence. Prev Chronic Dis 2013;10:120112. DOI 10.5888/pcd10.120112. Free full text in PubMed Central (PMC3547675) — public domain. Note: Effects were small, much of the data came from before-and-after studies rather than randomised trials, and pain and fatigue improved only slightly.
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Psychological therapies for the management of chronic pain (excluding headache) in adults — Williams et al., Cochrane Database Syst Rev 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7437545/
Cochrane systematic review and meta-analysis — 75 randomised trials, 9,401 adults. Strong evidence. Cochrane Database Syst Rev 2020;8:CD007407. DOI 10.1002/14651858.CD007407.pub4. Free full text in PubMed Central (PMC7437545). Note: Average benefits of CBT are small, and the trials reported little about possible harms.
What It Found
Pooled 75 randomised trials (9,401 adults) of psychological therapies for chronic non-cancer pain other than headache. Cognitive behavioural therapy (CBT) had small benefits over usual care for pain (SMD −0.22), disability (−0.32) and distress (−0.34) at the end of treatment, largely kept at follow-up, and very small benefits over other active treatments. Evidence for behavioural therapy and ACT was very uncertain.
Why It Matters Here
Backs up the CBT approach taught in the pain workbooks in chapter 10 (such as The Pain Management Workbook; the books themselves were not tested) and the chronic-illness therapists in chapter 05; most relevant to adults with long-lasting pain wondering whether psychological help is worth trying.
Cochrane systematic review and meta-analysis — 75 randomised trials, 9,401 adults. Strong evidence. Cochrane Database Syst Rev 2020;8:CD007407. DOI 10.1002/14651858.CD007407.pub4. Free full text in PubMed Central (PMC7437545). Note: Average benefits of CBT are small, and the trials reported little about possible harms.
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Acceptance and commitment therapy for patients with chronic pain: A systematic review and meta-analysis on psychological outcomes and quality of life — Ye et al., PLoS One 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11178235/
Systematic review and meta-analysis — 21 randomised trials, 1,298 participants (ACT vs usual care or waiting list). Moderate evidence. PLoS One 2024;19(6):e0301226. DOI 10.1371/journal.pone.0301226. Free full text in PubMed Central (PMC11178235) — open access, CC BY 4.0. Note: Compared only with usual care or waiting lists, no GRADE rating and follow-up only to three months; the 2020 Cochrane review judged ACT evidence very uncertain.
What It Found
Pooled 21 randomised trials (1,298 people) comparing acceptance and commitment therapy (ACT) for chronic pain with usual care or a waiting list. Straight after treatment ACT improved pain interference (SMD −0.50), day-to-day functioning (−0.74), depression (−0.59), anxiety (−0.47), pain acceptance (0.68) and quality of life (0.43), with a smaller effect on pain intensity (−0.37); effects on most outcomes were still present at three months.
Why It Matters Here
Backs up finding an ACT-trained therapist through the ACBS directory or the chronic-illness therapists in chapter 05; relevant to people who want to live more fully alongside pain that has not gone away.
Systematic review and meta-analysis — 21 randomised trials, 1,298 participants (ACT vs usual care or waiting list). Moderate evidence. PLoS One 2024;19(6):e0301226. DOI 10.1371/journal.pone.0301226. Free full text in PubMed Central (PMC11178235) — open access, CC BY 4.0. Note: Compared only with usual care or waiting lists, no GRADE rating and follow-up only to three months; the 2020 Cochrane review judged ACT evidence very uncertain.
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Pain neuroscience education in patients with chronic musculoskeletal pain: an umbrella review — Cuenca-Martínez et al., Front Neurosci 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10704151/
Umbrella review — 16 systematic reviews (11 with meta-analysis) of randomised or controlled clinical trials (quality rated with AMSTAR-2). Moderate evidence. Front Neurosci 2023;17:1272068. DOI 10.3389/fnins.2023.1272068. Free full text in PubMed Central (PMC10704151) — open access, CC BY 4.0. Note: All 16 reviews were rated critically low quality, results and teaching methods varied widely, and the authors say better studies are needed before clinical use.
What It Found
Brought together 16 systematic reviews of pain neuroscience education (PNE) — teaching how pain works, as in Explain Pain — for chronic musculoskeletal pain such as back pain, fibromyalgia and osteoarthritis. Adding PNE to other treatments, mostly exercise, seemed to give bigger improvements than those treatments alone, especially on psychological measures; PNE on its own did not clearly improve pain, disability or psychological measures.
Why It Matters Here
Backs up the pain-science education approach behind Explain Pain, Tame the Beast and Retrain Pain in chapter 10 and apps such as Curable in chapter 13 (none tested themselves); suggests they work best alongside exercise or physiotherapy (chapter 12).
Umbrella review — 16 systematic reviews (11 with meta-analysis) of randomised or controlled clinical trials (quality rated with AMSTAR-2). Moderate evidence. Front Neurosci 2023;17:1272068. DOI 10.3389/fnins.2023.1272068. Free full text in PubMed Central (PMC10704151) — open access, CC BY 4.0. Note: All 16 reviews were rated critically low quality, results and teaching methods varied widely, and the authors say better studies are needed before clinical use.
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Effect of Graded Sensorimotor Retraining on Pain Intensity in Patients With Chronic Low Back Pain: A Randomized Clinical Trial — Bagg et al., JAMA 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9346551/
Randomised clinical trial — 276 adults, intervention versus sham-procedure control, 1-year follow-up. Moderate evidence. JAMA 2022;328(5):430–439. DOI 10.1001/jama.2022.9930. Free full text in PubMed Central (PMC9346551). Note: A single trial; the pain benefit was small and faded by one year, and the programme was delivered by trained physiotherapists, not self-guided reading.
What It Found
Trial in 276 adults with chronic low back pain of graded sensorimotor retraining, a 12-session programme that starts with pain education and then retrains body sense and movement step by step, compared with sham treatments. At 18 weeks pain was 1 point lower on a 0–10 scale (−1.0, 95% CI −1.5 to −0.4) and disability was also better; at one year disability was still better but the pain difference was no longer significant.
Why It Matters Here
Backs up the approach of the Explain Pain handbook in chapter 10 (its co-author Lorimer Moseley was a trial author; the book itself was not tested) and the physiotherapists in chapter 12 who combine pain education with graded movement; most relevant to people with long-lasting low back pain.
Randomised clinical trial — 276 adults, intervention versus sham-procedure control, 1-year follow-up. Moderate evidence. JAMA 2022;328(5):430–439. DOI 10.1001/jama.2022.9930. Free full text in PubMed Central (PMC9346551). Note: A single trial; the pain benefit was small and faded by one year, and the programme was delivered by trained physiotherapists, not self-guided reading.
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Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain: A Randomized Clinical Trial — Ashar et al., JAMA Psychiatry 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC8482298/
Randomised clinical trial — 151 adults, three arms (pain reprocessing therapy, open-label placebo, usual care), 1-year follow-up. Moderate evidence. JAMA Psychiatry 2022;79(1):13–23. DOI 10.1001/jamapsychiatry.2021.2669. Free full text in PubMed Central (PMC8482298) — open access, CC BY 4.0. Note: One trial in a well-educated, active group with low-to-moderate pain, with sessions given by the method's developers; it was not tested against other leading treatments.
What It Found
Trial of pain reprocessing therapy (PRT), the method in The Way Out, in 151 adults with chronic back pain. After treatment 66% of the PRT group were pain-free or nearly pain-free, against 20% given an open-label placebo and 10% with usual care (Hedges g −1.14 versus placebo, −1.74 versus usual care); a smaller benefit remained at one year (g −0.70 versus placebo).
Why It Matters Here
Backs up the therapy taught in The Way Out in chapter 10 (the trial tested therapist-delivered sessions, not the book); most relevant to people with chronic back pain where no ongoing injury or disease explains the pain.
Randomised clinical trial — 151 adults, three arms (pain reprocessing therapy, open-label placebo, usual care), 1-year follow-up. Moderate evidence. JAMA Psychiatry 2022;79(1):13–23. DOI 10.1001/jamapsychiatry.2021.2669. Free full text in PubMed Central (PMC8482298) — open access, CC BY 4.0. Note: One trial in a well-educated, active group with low-to-moderate pain, with sessions given by the method's developers; it was not tested against other leading treatments.
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WHO guideline for non-surgical management of chronic primary low back pain in adults in primary and community care settings — WHO 2023

https://www.who.int/publications/i/item/9789240081789
WHO guideline — GRADE-based evidence reviews of 37 non-surgical interventions. Moderate evidence. Geneva: World Health Organization; 2023. ISBN 978-92-4-008178-9. Free from the World Health Organization — open access, CC BY-NC-SA 3.0 IGO. Note: All recommendations are conditional and most rest on low or very low certainty evidence (very low for education and CBT); it covers adults with chronic primary low back pain only.
What It Found
WHO guideline on chronic primary low back pain in adults that weighed 37 non-surgical treatments. As part of care it conditionally recommends options including structured education and advice, exercise programmes, CBT, operant (behavioural) therapy, multicomponent biopsychosocial care, acupuncture, spinal manipulation, massage and NSAIDs, and advises against routine use of opioids, TENS, traction, back braces and several other medicines.
Why It Matters Here
Backs up the pain education, CBT and self-management resources in chapter 10 and the physiotherapy and exercise services in chapter 12 for long-lasting low back pain; useful for anyone deciding which treatments are worth their time.
WHO guideline — GRADE-based evidence reviews of 37 non-surgical interventions. Moderate evidence. Geneva: World Health Organization; 2023. ISBN 978-92-4-008178-9. Free from the World Health Organization — open access, CC BY-NC-SA 3.0 IGO. Note: All recommendations are conditional and most rest on low or very low certainty evidence (very low for education and CBT); it covers adults with chronic primary low back pain only.
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Decision aids for people facing health treatment or screening decisions — Stacey et al., Cochrane Database Syst Rev 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC10823577/
Cochrane systematic review and meta-analysis — 209 randomised trials, 107,698 people. Strong evidence. Cochrane Database Syst Rev 2024;1:CD001431. DOI 10.1002/14651858.CD001431.pub6. Free full text in PubMed Central (PMC10823577). Note: It tested structured decision aids against usual care, which ranged from general health information to nothing; effects on adherence, health outcomes and costs are unclear.
What It Found
Cochrane review of 209 randomised trials (107,698 people) of patient decision aids — leaflets, videos or online tools that lay out options, benefits and harms. Compared with usual care, people knew more (11.9 points out of 100), judged risks more accurately (RR 1.94), felt better informed and clearer about what mattered to them, took a less passive role (RR 0.72) and probably more often made choices that matched their values (RR 1.75).
Why It Matters Here
Backs up resources that set out treatment options, benefits and harms to weigh with a clinician, such as Deprescribing.org in chapter 06; the review tested structured decision aids, not this site.
Cochrane systematic review and meta-analysis — 209 randomised trials, 107,698 people. Strong evidence. Cochrane Database Syst Rev 2024;1:CD001431. DOI 10.1002/14651858.CD001431.pub6. Free full text in PubMed Central (PMC10823577). Note: It tested structured decision aids against usual care, which ranged from general health information to nothing; effects on adherence, health outcomes and costs are unclear.
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Association of the Functional Medicine Model of Care With Patient-Reported Health-Related Quality-of-Life Outcomes — Beidelschies et al., JAMA Netw Open 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6822085/
Retrospective cohort study — 7,252 patients; 398 propensity-matched pairs (functional medicine centre vs primary care), Cleveland Clinic. Early evidence. JAMA Netw Open 2019;2(10):e1914017. DOI 10.1001/jamanetworkopen.2019.14017. Free full text in PubMed Central (PMC6822085) — open access, CC BY. Note: Retrospective, single-centre and not randomised (the authors call it hypothesis-generating); people choosing functional medicine may be more motivated, and the gap was not significant at 12 months.
What It Found
Compared 1,595 patients at the Cleveland Clinic's functional medicine centre (longer visits, dietitian and health coach) with 5,657 primary-care patients (398 matched pairs). At six months the functional medicine group improved more on a standard physical-health score (1.59 vs 0.33 points), and more reached a meaningful gain (30.9% vs 22.1%); at 12 months the difference from primary care was no longer significant.
Why It Matters Here
Backs up, cautiously, the functional and integrative medicine directories in chapter 01 (such as the Institute for Functional Medicine); it tested one hospital clinic's team model, which many listed practitioners do not offer.
Retrospective cohort study — 7,252 patients; 398 propensity-matched pairs (functional medicine centre vs primary care), Cleveland Clinic. Early evidence. JAMA Netw Open 2019;2(10):e1914017. DOI 10.1001/jamanetworkopen.2019.14017. Free full text in PubMed Central (PMC6822085) — open access, CC BY. Note: Retrospective, single-centre and not randomised (the authors call it hypothesis-generating); people choosing functional medicine may be more motivated, and the gap was not significant at 12 months.
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Patient navigators for people with chronic disease: A systematic review — McBrien et al., PLoS One 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC5819768/
Systematic review (narrative synthesis, no meta-analysis) — 67 randomised trials (cancer, diabetes, HIV, heart and kidney disease, dementia). Moderate evidence. PLoS One 2018;13(2):e0191980. DOI 10.1371/journal.pone.0191980. Free full text in PubMed Central (PMC5819768) — open access, CC BY 4.0. Note: Two-thirds of trials were in cancer care; navigation mostly improved steps in care such as screening and follow-up, but evidence on health, experience and costs is thin.
What It Found
Reviewed 67 randomised trials of patient navigators — people who guide patients through appointments, tests and services — for chronic diseases. Two-thirds of trials (45 of 67) found a significant improvement in their main outcome, mostly 'processes of care', that is, whether recommended care actually happened; few trials measured patient experience, health outcomes or costs.
Why It Matters Here
Backs up the approach behind the case-management and patient-advocacy services in chapter 16 (such as the Patient Advocate Foundation) that help people find their way through care; the programmes tested were mostly clinic- or hospital-based navigators.
Systematic review (narrative synthesis, no meta-analysis) — 67 randomised trials (cancer, diabetes, HIV, heart and kidney disease, dementia). Moderate evidence. PLoS One 2018;13(2):e0191980. DOI 10.1371/journal.pone.0191980. Free full text in PubMed Central (PMC5819768) — open access, CC BY 4.0. Note: Two-thirds of trials were in cancer care; navigation mostly improved steps in care such as screening and follow-up, but evidence on health, experience and costs is thin.
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Efficacy of Diet on Fatigue and Quality of Life in Multiple Sclerosis: A Systematic Review and Network Meta-analysis of Randomized Trials — Snetselaar et al., Neurology 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC12326367/
Systematic review and network meta-analysis — 12 randomised trials, 608 people with MS, 7 diets. Moderate evidence. Neurology 2023;100(4):e357–e366. DOI 10.1212/WNL.0000000000201371. Free full text in PubMed Central (PMC12326367). Note: Credibility of every direct comparison was rated very low (few, small trials, mostly at moderate or high risk of bias); the authors say results need confirming in better trials.
What It Found
Network meta-analysis of 12 randomised trials (608 people with multiple sclerosis) comparing seven diets with usual eating. Paleolithic-style (the basis of the Wahls Protocol), low-fat and Mediterranean diets were linked with less fatigue (SMD −1.27, −0.90 and −0.89), and Paleolithic and Mediterranean diets with better physical and mental quality of life.
Why It Matters Here
Backs up, with caution, the diets behind The Wahls Protocol (chapter 10) and its practitioner directory (chapter 01), and Overcoming MS's low-saturated-fat diet (chapter 16); relevant to people with MS interested in diet alongside their medical care.
Systematic review and network meta-analysis — 12 randomised trials, 608 people with MS, 7 diets. Moderate evidence. Neurology 2023;100(4):e357–e366. DOI 10.1212/WNL.0000000000201371. Free full text in PubMed Central (PMC12326367). Note: Credibility of every direct comparison was rated very low (few, small trials, mostly at moderate or high risk of bias); the authors say results need confirming in better trials.
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Outcomes of patients who participate in randomized controlled trials compared to similar patients receiving similar interventions who do not participate — Vist et al., Cochrane Database Syst Rev 2008

https://pmc.ncbi.nlm.nih.gov/articles/PMC8276557/
Cochrane methodology review — 85 studies (5 randomised, 80 cohort) comparing 86,640 trial participants with 57,205 non-participants. Moderate evidence. Cochrane Database Syst Rev 2008;(3):MR000009. DOI 10.1002/14651858.MR000009.pub4. Free full text in PubMed Central (PMC8276557). Note: It compared the same treatments inside and outside trials, mostly in non-randomised studies published before 2008; it says nothing about the risks of new experimental treatments.
What It Found
Cochrane review of whether people fare better or worse by joining a randomised trial. Across 85 studies comparing 86,640 trial participants with 57,205 similar patients given the same treatment outside a trial, most comparisons found no difference (85 of 98 yes/no outcomes), with a few favouring each side; the authors conclude that taking part is associated with similar outcomes.
Why It Matters Here
Backs up the trial-finding services in chapter 16 (ClinicalTrials.gov, ResearchMatch, TrialMatch) and the trial registries in chapter 15: people treated within trials did about as well as similar patients treated outside them, so joining should not, by itself, be expected to improve or worsen outcomes.
Cochrane methodology review — 85 studies (5 randomised, 80 cohort) comparing 86,640 trial participants with 57,205 non-participants. Moderate evidence. Cochrane Database Syst Rev 2008;(3):MR000009. DOI 10.1002/14651858.MR000009.pub4. Free full text in PubMed Central (PMC8276557). Note: It compared the same treatments inside and outside trials, mostly in non-randomised studies published before 2008; it says nothing about the risks of new experimental treatments.
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Chronic pain (primary and secondary) in over 16s: assessment of all chronic pain and management of chronic primary pain (NICE guideline NG193) — NICE 2021

https://www.nice.org.uk/guidance/ng193
National clinical guideline based on systematic evidence reviews and committee consensus. Moderate evidence. NICE NG193, published 7 April 2021. Free to read on the NICE website. Note: Covers people aged 16 and over in England; benefits of the recommended treatments were often modest, and for pain caused by another condition other NICE guidance applies.
What It Found
England's national guideline for chronic pain. For chronic primary pain (pain with no condition that adequately explains it) it recommends a supervised group exercise programme, staying active, and considering ACT or CBT for pain, a single course of acupuncture in set conditions, or certain antidepressants. It advises against starting opioids, gabapentinoids, benzodiazepines, NSAIDs or paracetamol for this kind of pain, and against TENS, ultrasound or biofeedback.
Why It Matters Here
Backs up the exercise professionals and programmes in chapter 12, the therapists in chapter 05 who offer ACT or CBT for pain, and the CBT and ACT skills in pain workbooks in chapter 10 (NICE recommends therapist-led therapy and made no recommendation on pain education or pain programmes).
National clinical guideline based on systematic evidence reviews and committee consensus. Moderate evidence. NICE NG193, published 7 April 2021. Free to read on the NICE website. Note: Covers people aged 16 and over in England; benefits of the recommended treatments were often modest, and for pain caused by another condition other NICE guidance applies.
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Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management (NICE guideline NG206) — NICE 2021

https://www.nice.org.uk/guidance/ng206
National clinical guideline based on systematic evidence reviews and committee consensus. Moderate evidence. NICE NG206, published 29 October 2021. Free to read on the NICE website. Note: Much of the evidence was low or very low quality, and its advice on graded exercise and CBT was contested before publication (NICE held a roundtable on the concerns in October 2021).
What It Found
England's guideline for ME/CFS says there is currently no curative treatment, and recommends energy management (pacing): a self-led plan, supported by a specialist team, that keeps activity within each person's fluctuating energy limits to reduce the risk of post-exertional malaise. It says not to offer graded exercise therapy or any fixed, incremental exercise programme, and to offer CBT only as support for living with the illness, not as a treatment that ends it.
Why It Matters Here
Backs up the approach of the #MEAction pacing guide in chapter 10 and the ME/CFS organisations in chapter 06, and is an important caution for anyone in chapters 12 and 13 offering exercise to people with ME/CFS.
National clinical guideline based on systematic evidence reviews and committee consensus. Moderate evidence. NICE NG206, published 29 October 2021. Free to read on the NICE website. Note: Much of the evidence was low or very low quality, and its advice on graded exercise and CBT was contested before publication (NICE held a roundtable on the concerns in October 2021).
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Coming Off Medication Safely — Tapering & Deprescribing

Medicines associated with dependence or withdrawal symptoms: safe prescribing and withdrawal management for adults — NICE 2022

https://www.nice.org.uk/guidance/ng215
National clinical guideline (England) based on evidence reviews by the National Guideline Centre; covers opioids, benzodiazepines, gabapentinoids, Z-drugs and antidepressants. Moderate evidence. NICE guideline NG215, 20 April 2022. Free to read on the NICE website. Note: NICE found the evidence comparing tapering speeds inconclusive, so much of the advice on how to withdraw rests on committee experience; written for adults in England.
What It Found
NICE's guideline on withdrawing opioids, benzodiazepines, gabapentinoids, Z-drugs and antidepressants. Prescribers should not stop them abruptly except in exceptional circumstances such as serious side effects, should reach agreement by shared decision-making, make sure the planned rate of reduction is acceptable to the person and reviewed regularly, and explain that withdrawal can be difficult and may take several months or more. It suggests offering details of peer support.
Why It Matters Here
Backs up the tapering and deprescribing resources in chapter 06, especially UK ones such as Mind's coming-off-medication guide, LEAP for Prescribed Drug Dependence and the Beyond Pills Alliance, by setting out agreed, gradual withdrawal with access to peer support as recommended practice. Most relevant in the UK.
National clinical guideline (England) based on evidence reviews by the National Guideline Centre; covers opioids, benzodiazepines, gabapentinoids, Z-drugs and antidepressants. Moderate evidence. NICE guideline NG215, 20 April 2022. Free to read on the NICE website. Note: NICE found the evidence comparing tapering speeds inconclusive, so much of the advice on how to withdraw rests on committee experience; written for adults in England.
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A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence-based? — Davies & Read, Addict Behav 2019

https://doi.org/10.1016/j.addbeh.2018.08.027
Systematic review — 24 studies of mixed design and size (including online surveys, observational studies and trials); weighted averages, no formal meta-analysis. Moderate evidence. Addict Behav 2019;97:111–121. Free full text at the publisher — open access, CC BY-NC-ND 4.0. Note: Relied heavily on self-selected online surveys and drew published critiques; a 2024 meta-analysis (Henssler et al.) estimated a lower rate: 31%, or about 15% allowing for placebo effects.
What It Found
Reviewed 24 studies to test UK and US guideline statements that antidepressant withdrawal is 'self-limiting', typically resolving within one to two weeks. In 14 studies, 27% to 86% of people had withdrawal effects (weighted average 56%); in four large studies a weighted average of 46% of those affected chose the most severe rating offered; seven of ten studies on duration found a significant proportion affected for more than two weeks, and several months was not uncommon.
Why It Matters Here
Backs up the antidepressant withdrawal resources in chapter 06 (the Tapering Strip, Outro Health, Inner Compass Initiative, Surviving Antidepressants, LEAP and Mind's guide) by showing withdrawal can be common and sometimes severe or long-lasting; it did not test any tapering method.
Systematic review — 24 studies of mixed design and size (including online surveys, observational studies and trials); weighted averages, no formal meta-analysis. Moderate evidence. Addict Behav 2019;97:111–121. Free full text at the publisher — open access, CC BY-NC-ND 4.0. Note: Relied heavily on self-selected online surveys and drew published critiques; a 2024 meta-analysis (Henssler et al.) estimated a lower rate: 31%, or about 15% allowing for placebo effects.
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Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis — Henssler et al., Lancet Psychiatry 2024

https://doi.org/10.1016/S2215-0366(24)00133-0
Systematic review and meta-analysis — 79 studies (44 randomised trials, 35 observational), 21,002 people. Moderate evidence. Lancet Psychiatry 2024;11(7):526–535. Free full text at the publisher — open access, CC BY 4.0. Note: Heterogeneity was substantial, studies defined and measured symptoms differently and many were small; it drew critical letters, including from Read and Davies, and an erratum in 2024.
What It Found
Pooled 79 studies (21,002 people) in which an antidepressant or placebo was stopped. At least one discontinuation symptom followed stopping an antidepressant in 31% (95% CI 27–35%) versus 17% after placebo; severe symptoms in 2.8% versus 0.6%. Allowing for non-specific effects seen with placebo, the authors estimate about 15% (one in six to seven). Desvenlafaxine, venlafaxine, imipramine, escitalopram and paroxetine were linked to more frequent or severe symptoms.
Why It Matters Here
Backs up the antidepressant tapering listings in chapter 06 with a large, recent estimate of how often discontinuation symptoms occur, and helps readers weigh it against higher survey-based figures such as Davies and Read's.
Systematic review and meta-analysis — 79 studies (44 randomised trials, 35 observational), 21,002 people. Moderate evidence. Lancet Psychiatry 2024;11(7):526–535. Free full text at the publisher — open access, CC BY 4.0. Note: Heterogeneity was substantial, studies defined and measured symptoms differently and many were small; it drew critical letters, including from Read and Davies, and an erratum in 2024.
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Internet and Telephone Support for Discontinuing Long-Term Antidepressants: The REDUCE Cluster Randomized Trial — Kendrick et al., JAMA Netw Open 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11197448/
Cluster randomised trial — 131 UK general practices, 330 long-term antidepressant users. Moderate evidence. JAMA Netw Open 2024;7(6):e2418383. DOI 10.1001/jamanetworkopen.2024.18383. Free full text in PubMed Central (PMC11197448) — open access, CC BY. Note: Only 4.9% of patients invited took part (a selected, low-risk group), and the extra support did not increase the number who stopped.
What It Found
In 131 UK general practices, 330 adults on long-term antidepressants who were well, at low risk of relapse and wanted to try stopping had a GP review; practices randomised to the intervention also offered online self-management and telephone support. With the extra support, depression scores at six months were no worse (PHQ-9 difference −1.1, 95% CI −2.1 to −0.1) and withdrawal symptoms slightly less severe; similar proportions stopped (45.5% vs 41.9%).
Why It Matters Here
Backs up the clinician-guided approach to reviewing long-term antidepressants offered by services such as Outro Health in chapter 06 (Outro itself was not tested); most relevant to people who are well and want to discuss stopping with their GP.
Cluster randomised trial — 131 UK general practices, 330 long-term antidepressant users. Moderate evidence. JAMA Netw Open 2024;7(6):e2418383. DOI 10.1001/jamanetworkopen.2024.18383. Free full text in PubMed Central (PMC11197448) — open access, CC BY. Note: Only 4.9% of patients invited took part (a selected, low-risk group), and the extra support did not increase the number who stopped.
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Successful use of tapering strips for hyperbolic reduction of antidepressant dose: a cohort study — Groot & van Os, Ther Adv Psychopharmacol 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8404667/
Retrospective questionnaire cohort — 824 people who used tapering strips to try to stop an antidepressant. Early evidence. Ther Adv Psychopharmacol 2021;11:20451253211039327. DOI 10.1177/20451253211039327. Free full text in PubMed Central (PMC8404667) — open access, CC BY 4.0. Note: No comparison group, a 59% response rate and self-reported results; one author helped develop the strips, and the declared conflicts include a grant from the pharmacy that makes them.
What It Found
Surveyed people whose doctors had prescribed tapering strips (rolls of daily pouches, each the same as or slightly lower than the one before). Of 824 who wanted to stop an antidepressant (71% had tried to stop without strips at least once; 66% were on venlafaxine or paroxetine), 72% reported stopping, over a median of 56 days. Median recalled withdrawal severity was 3 with the strips versus 6 in attempts without them.
Why It Matters Here
Backs up the Tapering Strip listing in chapter 06 directly, and the gradual, hyperbolic approach described by Inner Compass Initiative and Surviving Antidepressants; most relevant to people who have struggled to stop before.
Retrospective questionnaire cohort — 824 people who used tapering strips to try to stop an antidepressant. Early evidence. Ther Adv Psychopharmacol 2021;11:20451253211039327. DOI 10.1177/20451253211039327. Free full text in PubMed Central (PMC8404667) — open access, CC BY 4.0. Note: No comparison group, a 59% response rate and self-reported results; one author helped develop the strips, and the declared conflicts include a grant from the pharmacy that makes them.
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Deprescribing benzodiazepine receptor agonists: Evidence-based clinical practice guideline — Pottie et al., Can Fam Physician 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC5951648/
Evidence-based clinical practice guideline (GRADE) with a systematic review of benzodiazepine and Z-drug deprescribing trials for insomnia. Moderate evidence. Can Fam Physician 2018;64(5):339–351. Free full text in PubMed Central (PMC5951648). Note: The evidence was rated low quality, and it covers insomnia only, not benzodiazepines taken for anxiety or other conditions.
What It Found
This deprescribing.org guideline recommends offering a slow taper to adults aged 65 or over who take benzodiazepines or Z-drugs for insomnia, whatever the duration of use (strong recommendation, low-quality evidence), and suggests the same for adults aged 18 to 64 who have used them for over four weeks (weak recommendation). Its review found tapering improved stopping rates over usual care without serious harms; it advises involving patients in the tapering plan.
Why It Matters Here
Backs up deprescribing.org and the Canadian Deprescribing Network in chapter 06, the slow-tapering approach the Benzodiazepine Information Coalition promotes, and the CBT-I programmes and sleep books in chapters 10 and 11, as the guideline pairs tapering with behavioural sleep advice.
Evidence-based clinical practice guideline (GRADE) with a systematic review of benzodiazepine and Z-drug deprescribing trials for insomnia. Moderate evidence. Can Fam Physician 2018;64(5):339–351. Free full text in PubMed Central (PMC5951648). Note: The evidence was rated low quality, and it covers insomnia only, not benzodiazepines taken for anxiety or other conditions.
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Brief interventions targeting long-term benzodiazepine and Z-drug use in primary care: a systematic review and meta-analysis — Lynch et al., Addiction 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7891570/
Systematic review and meta-analysis — 8 randomised trials, 2,071 patients. Moderate evidence. Addiction 2020;115(9):1618–1639. DOI 10.1111/add.14981. Free full text in PubMed Central (PMC7891570) — open access, CC BY-NC 4.0. Note: Only two of the eight trials were at low risk of bias in most areas, results varied between trials (I² 55%) and few included Z-drug users.
What It Found
Pooled 8 randomised trials (2,071 patients) of brief primary-care interventions for people taking benzodiazepines or Z-drugs for three months or more, mostly letters signed by the prescriber or a pharmacist, sometimes with a booklet, or a short consultation with a GP, pharmacist or nurse. Stopping was about 2.7 times as likely as with usual care at six months (RR 2.73, 95% CI 1.84–4.06) and about 3.4 times as likely at 12 months (2 trials).
Why It Matters Here
Backs up deprescribing.org, the Canadian Deprescribing Network and the Benzodiazepine Information Coalition in chapter 06: clear information and a prompt from a trusted clinician can help people come off sleeping pills and tranquillisers.
Systematic review and meta-analysis — 8 randomised trials, 2,071 patients. Moderate evidence. Addiction 2020;115(9):1618–1639. DOI 10.1111/add.14981. Free full text in PubMed Central (PMC7891570) — open access, CC BY-NC 4.0. Note: Only two of the eight trials were at low risk of bias in most areas, results varied between trials (I² 55%) and few included Z-drug users.
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Effect of a Pharmacist-Led Educational Intervention on Inappropriate Medication Prescriptions in Older Adults: The D-PRESCRIBE Randomized Clinical Trial — Martin et al., JAMA 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6248132/
Cluster randomised trial — 69 community pharmacies, 489 adults aged 65 or over. Moderate evidence. JAMA 2018;320(18):1889–1898. DOI 10.1001/jama.2018.16131. Free full text in PubMed Central (PMC6248132). Note: One Canadian province and six months' follow-up; too few people on antihistamines to analyse.
What It Found
489 Quebec adults aged 65+ on a potentially inappropriate medicine (sedative-hypnotics, glyburide, NSAIDs or older antihistamines) took part; in intervention pharmacies they got a deprescribing brochure and their doctor a pharmacist's advice. At six months 43% had stopped filling it vs 12% with usual care (risk difference 31%, 95% CI 23–38%); sedative-hypnotics 43% vs 9%. No adverse events needed hospital care; 38% of those tapering a sedative reported withdrawal symptoms.
Why It Matters Here
Backs up the Canadian Deprescribing Network and deprescribing.org in chapter 06, which offer patient deprescribing brochures of the kind tested here; most relevant to older adults on several medicines and to their carers.
Cluster randomised trial — 69 community pharmacies, 489 adults aged 65 or over. Moderate evidence. JAMA 2018;320(18):1889–1898. DOI 10.1001/jama.2018.16131. Free full text in PubMed Central (PMC6248132). Note: One Canadian province and six months' follow-up; too few people on antihistamines to analyse.
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Deprescribing proton pump inhibitors: Evidence-based clinical practice guideline — Farrell et al., Can Fam Physician 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5429051/
Evidence-based clinical practice guideline (GRADE) with a systematic review of PPI deprescribing trials. Moderate evidence. Can Fam Physician 2017;63(5):354–364. Free full text in PubMed Central (PMC5429051). Note: Does not apply to people with Barrett's oesophagus, severe oesophagitis or a history of bleeding ulcers; the evidence dates from 2017.
What It Found
Guideline from the deprescribing.org team, built with GRADE methods, a systematic review of trials of reducing or stopping proton pump inhibitors and reviews of harms of long-term use. It recommends that adults who have taken a PPI for at least four weeks for heartburn, mild-to-moderate reflux or oesophagitis, and whose symptoms have settled, be offered a lower dose, use only when needed, or stopping.
Why It Matters Here
Backs up deprescribing.org and the Canadian Deprescribing Network in chapter 06, and gives useful background to readers of chapter 15's gastroenterology listings who take long-term reflux medicine.
Evidence-based clinical practice guideline (GRADE) with a systematic review of PPI deprescribing trials. Moderate evidence. Can Fam Physician 2017;63(5):354–364. Free full text in PubMed Central (PMC5429051). Note: Does not apply to people with Barrett's oesophagus, severe oesophagitis or a history of bleeding ulcers; the evidence dates from 2017.
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Deprescribing antipsychotics for behavioural and psychological symptoms of dementia and insomnia: Evidence-based clinical practice guideline — Bjerre et al., Can Fam Physician 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC5962971/
Evidence-based clinical practice guideline (GRADE) drawing on a Cochrane review of withdrawal trials in dementia and a systematic review for insomnia. Moderate evidence. Can Fam Physician 2018;64(1):17–27. Free full text in PubMed Central (PMC5962971). Note: Covers dementia-related behaviour and insomnia only, not schizophrenia or bipolar disorder, where stopping carries different risks.
What It Found
Guideline from the deprescribing.org team, built with GRADE methods, a Cochrane review of antipsychotic withdrawal trials in dementia and a systematic review for insomnia. It recommends tapering and stopping antipsychotics in adults treated for at least three months for behavioural and psychological symptoms of dementia whose symptoms have settled or not responded, and in adults taking them for insomnia, with patients and carers involved in planning the taper.
Why It Matters Here
Backs up deprescribing.org and the Canadian Deprescribing Network in chapter 06, and the dementia support organisations in chapter 06 whose members and carers often face questions about antipsychotics.
Evidence-based clinical practice guideline (GRADE) drawing on a Cochrane review of withdrawal trials in dementia and a systematic review for insomnia. Moderate evidence. Can Fam Physician 2018;64(1):17–27. Free full text in PubMed Central (PMC5962971). Note: Covers dementia-related behaviour and insomnia only, not schizophrenia or bipolar disorder, where stopping carries different risks.
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CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022 — Dowell et al., MMWR Recomm Rep 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9639433/
National clinical practice guideline (12 recommendations) informed by systematic reviews. Moderate evidence. MMWR Recomm Rep 2022;71(No. RR-3):1–95. DOI 10.15585/mmwr.rr7103a1. Free full text in PubMed Central (PMC9639433) — public domain. Note: Written for US clinicians; its tapering advice rests mainly on lower-certainty evidence and clinical experience.
What It Found
The US national guideline on opioids for pain (not for sickle cell disease, cancer or end-of-life care). It notes that rigid use of dose thresholds, and rapid tapers or abrupt stops without working with patients, have contributed to harms including serious withdrawal, worse pain, psychological distress, overdose and suicidal thoughts and behaviour. Unless there is a life-threatening issue, it advises against stopping opioids abruptly or rapidly reducing higher doses.
Why It Matters Here
Backs up the case made by chapter 06's deprescribing groups for slow, agreed and supported reductions, and the non-drug pain approaches in chapters 10 and 13 that the guideline encourages.
National clinical practice guideline (12 recommendations) informed by systematic reviews. Moderate evidence. MMWR Recomm Rep 2022;71(No. RR-3):1–95. DOI 10.15585/mmwr.rr7103a1. Free full text in PubMed Central (PMC9639433) — public domain. Note: Written for US clinicians; its tapering advice rests mainly on lower-certainty evidence and clinical experience.
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Efficacy of interventions to reduce long term opioid treatment for chronic non-cancer pain: systematic review and meta-analysis — Avery et al., BMJ 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC8977989/
Systematic review and meta-analysis — 36 studies (27 randomised trials) kept after 130 were excluded for critical risk of bias. Moderate evidence. BMJ 2022;377:e066375. DOI 10.1136/bmj-2021-066375. Free full text in PubMed Central (PMC8977989) — open access, CC BY-NC 4.0. Note: Little evidence on possible harms such as overdose, which the authors call a particular concern; certainty was low or very low for 41 of 44 outcomes.
What It Found
Reviewed ways to help people on long-term opioids for chronic non-cancer pain reduce their use; 130 of 166 eligible studies were excluded for critical risk of bias. Pain self-management programmes probably lowered daily opioid dose (by about 14 mg oral morphine equivalent; 5 studies, 428 people; moderate certainty) and might moderately ease pain (low certainty); prescriber-focused interventions gave smaller dose reductions but made stopping somewhat more likely.
Why It Matters Here
Backs up the opioid side of chapter 06's deprescribing networks, and the pain self-management approach behind the courses, books and psychological therapies in chapters 05, 10 and 13 (those named listings were not tested themselves).
Systematic review and meta-analysis — 36 studies (27 randomised trials) kept after 130 were excluded for critical risk of bias. Moderate evidence. BMJ 2022;377:e066375. DOI 10.1136/bmj-2021-066375. Free full text in PubMed Central (PMC8977989) — open access, CC BY-NC 4.0. Note: Little evidence on possible harms such as overdose, which the authors call a particular concern; certainty was low or very low for 41 of 44 outcomes.
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Association of Dose Tapering With Overdose or Mental Health Crisis Among Patients Prescribed Long-term Opioids — Agnoli et al., JAMA 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8335575/
Retrospective cohort study — 113,618 US patients on stable, higher-dose long-term opioids (insurance claims, 2008–2019). Moderate evidence. JAMA 2021;326(5):411–419. DOI 10.1001/jama.2021.11013. Free full text in PubMed Central (PMC8335575). Note: Observational, so association not cause. Corrected in 2022 for coding errors (smaller but still significant effects); the PMC copy shows the original figures with the correction linked.
What It Found
Followed 113,618 US patients on stable, higher-dose long-term opioids. After a 2022 correction for coding errors, periods after a dose taper were still linked to more overdose or withdrawal events (adjusted incidence rate ratio 1.28, 95% CI 1.15–1.43) and more mental health crises (1.74, 1.50–2.01) than periods without tapering; the errors had inflated the original figures (1.68 and 2.28).
Why It Matters Here
Backs up chapter 06's message that reducing long-term opioids can carry real risks and should be done with care, monitoring and support; most relevant to people on long-term pain medicines and their families.
Retrospective cohort study — 113,618 US patients on stable, higher-dose long-term opioids (insurance claims, 2008–2019). Moderate evidence. JAMA 2021;326(5):411–419. DOI 10.1001/jama.2021.11013. Free full text in PubMed Central (PMC8335575). Note: Observational, so association not cause. Corrected in 2022 for coding errors (smaller but still significant effects); the PMC copy shows the original figures with the correction linked.
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Exercise & Movement as Treatment

Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials — Noetel et al., BMJ 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC10870815/
Systematic review and network meta-analysis — 218 randomised trials, 14,170 people with depression. Moderate evidence. BMJ 2024;384:e075847. DOI 10.1136/bmj-2023-075847. Free full text in PubMed Central (PMC10870815) — open access, CC BY-NC 4.0. Note: The authors rated confidence in the results as low for walking or jogging and very low for other exercise types, because only one trial met the criteria for a low risk of bias.
What It Found
Compared exercise types for people with depression across 218 trials. Against active control conditions, walking or jogging (Hedges g −0.62), yoga (−0.55), strength training (−0.49), mixed aerobic exercise (−0.43) and tai chi or qigong (−0.42) all reduced depressive symptoms, roughly a moderate effect. Benefits were larger at higher prescribed intensity, and strength training and yoga were the best tolerated.
Why It Matters Here
Backs up the exercise-for-mood books and free home workouts in chapter 10, the walking and running groups in chapter 13, and the exercise physiologists and Mind's getting-started guide in chapter 12. Most relevant to people living with depression.
Systematic review and network meta-analysis — 218 randomised trials, 14,170 people with depression. Moderate evidence. BMJ 2024;384:e075847. DOI 10.1136/bmj-2023-075847. Free full text in PubMed Central (PMC10870815) — open access, CC BY-NC 4.0. Note: The authors rated confidence in the results as low for walking or jogging and very low for other exercise types, because only one trial met the criteria for a low risk of bias.
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Effectiveness of physical activity interventions for improving depression, anxiety and distress: an overview of systematic reviews — Singh et al., Br J Sports Med 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10579187/
Umbrella review (overview of systematic reviews) — 97 reviews of 1,039 randomised trials, 128,119 people. Moderate evidence. Br J Sports Med 2023;57(18):1203–1209. DOI 10.1136/bjsports-2022-106195. Free full text in PubMed Central (PMC10579187) — open access, CC BY-NC 4.0. Note: 77 of the 97 included reviews were rated critically low quality (AMSTAR), and many trials were in people without a diagnosed mental illness.
What It Found
Brought together 97 systematic reviews covering 1,039 trials and 128,119 adults. Compared with usual care, physical activity reduced symptoms of depression (median effect size −0.43) and anxiety (median −0.42) by what the authors call a medium amount, across healthy people and those with mental or physical illness. Higher-intensity activity gave larger improvements, and shorter programmes tended to show bigger effects than longer ones.
Why It Matters Here
Backs up the movement books, free workouts and NHS Active 10 in chapter 10, the walking and activity groups in chapter 13 and the exercise professionals in chapter 12. Relevant to anyone using activity to help with low mood, worry or stress.
Umbrella review (overview of systematic reviews) — 97 reviews of 1,039 randomised trials, 128,119 people. Moderate evidence. Br J Sports Med 2023;57(18):1203–1209. DOI 10.1136/bjsports-2022-106195. Free full text in PubMed Central (PMC10579187) — open access, CC BY-NC 4.0. Note: 77 of the 97 included reviews were rated critically low quality (AMSTAR), and many trials were in people without a diagnosed mental illness.
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World Health Organization 2020 guidelines on physical activity and sedentary behaviour — Bull et al., Br J Sports Med 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7719906/
International guideline (WHO) built on updated systematic reviews, graded with GRADE. Strong evidence. Br J Sports Med 2020;54(24):1451–1462. DOI 10.1136/bjsports-2020-102955. Free full text in PubMed Central (PMC7719906) — open access, CC BY 4.0. Note: Many of the links to disease and death come from observational studies, and the evidence was too thin to set a specific limit on sitting time.
What It Found
Sets out WHO's evidence-based activity guidelines for all ages, including pregnancy, chronic conditions and disability. In adults, regular activity is linked to lower all-cause and cardiovascular death, less high blood pressure, type 2 diabetes and some cancers, fewer anxiety and depression symptoms, and better thinking and sleep. Adults are advised at least 150–300 minutes of moderate (or 75–150 of vigorous) activity a week, and 'some physical activity is better than none'.
Why It Matters Here
Backs up the WHO and Australian guideline listings and the condition guides in chapter 12, the beginner and walking programmes in chapters 10 and 13, and the adaptive-sport finders in chapter 12 (the advice explicitly includes people living with disability).
International guideline (WHO) built on updated systematic reviews, graded with GRADE. Strong evidence. Br J Sports Med 2020;54(24):1451–1462. DOI 10.1136/bjsports-2020-102955. Free full text in PubMed Central (PMC7719906) — open access, CC BY 4.0. Note: Many of the links to disease and death come from observational studies, and the evidence was too thin to set a specific limit on sitting time.
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Is there evidence that walking groups have health benefits? A systematic review and meta-analysis — Hanson & Jones, Br J Sports Med 2015

https://pmc.ncbi.nlm.nih.gov/articles/PMC4453623/
Systematic review and meta-analysis — 42 studies of outdoor walking groups, 1,843 people. Moderate evidence. Br J Sports Med 2015;49(11):710–715. DOI 10.1136/bjsports-2014-094157. Free full text in PubMed Central (PMC4453623) — open access, CC BY 4.0. Note: Results are before-and-after changes in walkers, not comparisons with a control group; only 22 of 42 studies were randomised, many were small, and most walkers were women.
What It Found
Pooled 42 studies of outdoor walking groups (1,843 people). Between the start and end of the programmes, walkers' blood pressure fell (systolic −3.7 mmHg, diastolic −3.1 mmHg), as did resting heart rate, body fat, BMI and total cholesterol, while fitness (VO2max +2.7 mL/kg/min; six-minute walk +80 m), physical functioning and depression scores (SMD −0.67) improved. No notable side effects were reported, and adherence was good (about 75% where reported).
Why It Matters Here
Backs up the group-walking approach of chapter 13's walking groups, such as Walk With A Doc, Ramblers Wellbeing Walks, Heart Foundation Walking and Walk With Ease (one included study evaluated Walk With Ease's group format; the others were not tested). Most relevant to inactive adults and older people starting out.
Systematic review and meta-analysis — 42 studies of outdoor walking groups, 1,843 people. Moderate evidence. Br J Sports Med 2015;49(11):710–715. DOI 10.1136/bjsports-2014-094157. Free full text in PubMed Central (PMC4453623) — open access, CC BY 4.0. Note: Results are before-and-after changes in walkers, not comparisons with a control group; only 22 of 42 studies were randomised, many were small, and most walkers were women.
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Exercise-based cardiac rehabilitation for coronary heart disease: a meta-analysis — Dibben et al., Eur Heart J 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC9902155/
Systematic review and meta-analysis — 85 randomised trials, 23,430 people with coronary heart disease. Strong evidence. Eur Heart J 2023;44(6):452–469. DOI 10.1093/eurheartj/ehac747. Free full text in PubMed Central (PMC9902155) — open access, CC BY. Note: No clear effect on deaths from all causes; the fall in cardiovascular deaths was not significant at 6–12 months, and quality-of-life gains were small and inconsistent.
What It Found
Pooled 85 trials of exercise-based cardiac rehabilitation for people with coronary heart disease, such as after a heart attack, stent or bypass. Over a median 12 months, rehabilitation cut cardiovascular deaths (RR 0.74), heart attacks (RR 0.82) and all-cause hospital admissions (RR 0.77), with some evidence of better quality of life. It made no clear difference to deaths from all causes (RR 0.96).
Why It Matters Here
Backs up the cardiac rehabilitation finders in chapter 12 (AACVPR, Heart Foundation Australia) and the exercise physiologists who run these programmes. Most relevant to people recovering from a heart attack, stent or bypass surgery, and their carers.
Systematic review and meta-analysis — 85 randomised trials, 23,430 people with coronary heart disease. Strong evidence. Eur Heart J 2023;44(6):452–469. DOI 10.1093/eurheartj/ehac747. Free full text in PubMed Central (PMC9902155) — open access, CC BY. Note: No clear effect on deaths from all causes; the fall in cardiovascular deaths was not significant at 6–12 months, and quality-of-life gains were small and inconsistent.
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Exercise therapy for chronic low back pain — Hayden et al., Cochrane Database Syst Rev 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8477273/
Cochrane systematic review and meta-analysis — 249 randomised trials, 24,486 people. Strong evidence. Cochrane Database Syst Rev 2021;9:CD009790. DOI 10.1002/14651858.CD009790.pub2. Free full text in PubMed Central (PMC8477273). Note: The improvement in function fell short of the clinically important threshold, and gains over other conservative treatments were small.
What It Found
Cochrane review of 249 trials of exercise therapy for chronic low back pain (pain lasting more than 12 weeks). Compared with no treatment, usual care or placebo, exercise reduced pain by about 15 points on a 0–100 scale (MD −15.2) and functional limitation by about 7 points (MD −6.8), with moderate-certainty evidence. The average pain change just reached the review's 15-point threshold for a clinically important difference.
Why It Matters Here
Backs up the physiotherapist and exercise physiologist finders in chapter 12 and the exercise-for-your-condition guides there. Most relevant to adults with long-lasting low back pain.
Cochrane systematic review and meta-analysis — 249 randomised trials, 24,486 people. Strong evidence. Cochrane Database Syst Rev 2021;9:CD009790. DOI 10.1002/14651858.CD009790.pub2. Free full text in PubMed Central (PMC8477273). Note: The improvement in function fell short of the clinically important threshold, and gains over other conservative treatments were small.
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Exercise for preventing falls in older people living in the community — Sherrington et al., Cochrane Database Syst Rev 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6360922/
Cochrane systematic review and meta-analysis — 108 randomised trials, 23,407 people in 25 countries. Strong evidence. Cochrane Database Syst Rev 2019;1:CD012424. DOI 10.1002/14651858.CD012424.pub2. Free full text in PubMed Central (PMC6360922). Note: Applies to people aged 60+ living at home; benefits for fall-related fractures and falls needing medical care were low certainty, and side effects were poorly monitored.
What It Found
Cochrane review of exercise programmes for people aged 60 and over living at home. Exercise reduced the rate of falls by 23% (rate ratio 0.77) and the number of people who fell by 15% (risk ratio 0.85), both high-certainty evidence. Balance and functional exercises worked (rate ratio 0.76), and programmes combining several exercise types probably worked too (0.66).
Why It Matters Here
Backs up the physiotherapy finders, exercise physiologists and older-adult guidance in chapter 12, the balance and strength work in senior and low-impact workouts (chapter 10) and tai chi classes in chapter 13 (the review assessed exercise types, not named providers). Most relevant to older people and families.
Cochrane systematic review and meta-analysis — 108 randomised trials, 23,407 people in 25 countries. Strong evidence. Cochrane Database Syst Rev 2019;1:CD012424. DOI 10.1002/14651858.CD012424.pub2. Free full text in PubMed Central (PMC6360922). Note: Applies to people aged 60+ living at home; benefits for fall-related fractures and falls needing medical care were low certainty, and side effects were poorly monitored.
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Good Life with osteoArthritis in Denmark (GLA:D™): evidence-based education and supervised neuromuscular exercise delivered by certified physiotherapists nationwide — Skou & Roos, BMC Musculoskelet Disord 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5297181/
National registry study (before-and-after, no control group) — 9,825 people with knee or hip osteoarthritis. Early evidence. BMC Musculoskelet Disord 2017;18:72. DOI 10.1186/s12891-017-1439-y. Free full text in PubMed Central (PMC5297181) — open access, CC BY 4.0. Note: No control group, so the authors note effects are probably overestimated; about a third of people had no 12-month data.
What It Found
Reports national outcomes from GLA:D, a programme of patient education plus supervised neuromuscular exercise run by certified physiotherapists in Denmark. Pain fell by 12.4 mm on a 100 mm scale at 3 months and 13.7 mm at 12 months; painkiller use dropped (knee: 56% to 37% at 3 months), sick leave fell from 24% to 15% at 12 months, and walking speed, chair stands and quality of life improved.
Why It Matters Here
Backs up the GLA:D International and GLA:D Australia clinic finders in chapter 12 and the physiotherapists who deliver it. Most relevant to people with hip or knee osteoarthritis weighing up options before or instead of surgery.
National registry study (before-and-after, no control group) — 9,825 people with knee or hip osteoarthritis. Early evidence. BMC Musculoskelet Disord 2017;18:72. DOI 10.1186/s12891-017-1439-y. Free full text in PubMed Central (PMC5297181) — open access, CC BY 4.0. Note: No control group, so the authors note effects are probably overestimated; about a third of people had no 12-month data.
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Exercise for osteoarthritis of the knee — Lawford et al., Cochrane Database Syst Rev 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11613324/
Cochrane systematic review and meta-analysis — 139 randomised trials, 12,468 people with knee osteoarthritis. Moderate evidence. Cochrane Database Syst Rev 2024;12:CD004376. DOI 10.1002/14651858.CD004376.pub4. Free full text in PubMed Central (PMC11613324). Note: Pain evidence was low certainty, benefits did not clearly reach patient-important thresholds, most trials were unblinded, and adverse events may be more common with exercise.
What It Found
Cochrane update of 139 trials of exercise for knee osteoarthritis. Compared with no treatment or usual care, exercise reduced pain by about 13 points and improved physical function by about 12.5 points on 0–100 scales (low and moderate certainty), and quality of life by about 5 points, in the short term. The authors conclude exercise probably helps, but the clinical importance of these benefits is uncertain.
Why It Matters Here
Backs up the GLA:D finders, physiotherapists and exercise physiologists in chapter 12 and Walk With Ease in chapter 13. Most relevant to people with knee osteoarthritis, and useful for setting realistic expectations of the size of benefit.
Cochrane systematic review and meta-analysis — 139 randomised trials, 12,468 people with knee osteoarthritis. Moderate evidence. Cochrane Database Syst Rev 2024;12:CD004376. DOI 10.1002/14651858.CD004376.pub4. Free full text in PubMed Central (PMC11613324). Note: Pain evidence was low certainty, benefits did not clearly reach patient-important thresholds, most trials were unblinded, and adverse events may be more common with exercise.
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Pulmonary rehabilitation for chronic obstructive pulmonary disease — McCarthy et al., Cochrane Database Syst Rev 2015

https://pmc.ncbi.nlm.nih.gov/articles/PMC10008021/
Cochrane systematic review and meta-analysis — 65 randomised trials, 3,822 people with COPD. Strong evidence. Cochrane Database Syst Rev 2015;(2):CD003793. DOI 10.1002/14651858.CD003793.pub3. Free full text in PubMed Central (PMC10008021). Note: Certainty was moderate at best and low or very low for several outcomes, such as fatigue, sense of control and six-minute walking distance; participants could not be blinded.
What It Found
Cochrane review comparing pulmonary rehabilitation (exercise training, with or without education) with usual care in COPD. Rehabilitation improved breathlessness, fatigue, emotional function and sense of control by more than the minimum change that matters to patients (e.g. breathlessness MD 0.79 on the CRQ), improved overall quality of life (SGRQ −6.9 points) and added about 44 metres to six-minute walking distance.
Why It Matters Here
Backs up the pulmonary rehabilitation finders in chapter 12 (Lung Foundation Australia, AACVPR) and the physiotherapists and exercise physiologists who run these programmes. Most relevant to people living with COPD and their carers.
Cochrane systematic review and meta-analysis — 65 randomised trials, 3,822 people with COPD. Strong evidence. Cochrane Database Syst Rev 2015;(2):CD003793. DOI 10.1002/14651858.CD003793.pub3. Free full text in PubMed Central (PMC10008021). Note: Certainty was moderate at best and low or very low for several outcomes, such as fatigue, sense of control and six-minute walking distance; participants could not be blinded.
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Physical exercise for people with Parkinson's disease: a systematic review and network meta-analysis — Ernst et al., Cochrane Database Syst Rev 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11001292/
Cochrane systematic review and network meta-analysis — 154 randomised trials, 7,837 people with Parkinson's disease. Moderate evidence. Cochrane Database Syst Rev 2024;4:CD013856. DOI 10.1002/14651858.CD013856.pub3. Free full text in PubMed Central (PMC11001292). Note: Most trials were small; quality-of-life findings were mostly low certainty, and evidence for LSVT BIG specifically was very low certainty.
What It Found
Compared kinds of exercise for Parkinson's across 154 trials. Against a no-exercise control group, most types improved movement symptoms (UPDRS motor scale), e.g. dance −10.2 points, gait/balance/functional training −7.5 and multi-domain training −5.9 (moderate certainty), with little evidence that one type beats another. Several types also improved quality of life, and the programmes were described as relatively safe.
Why It Matters Here
Backs up the approach of the Parkinson's exercise programmes in chapter 13 (Dance for PD, Rock Steady Boxing, PWR!; the review tested exercise types, not these brands), the Every Victory Counts manual in chapter 10 and physiotherapists in chapter 12. For people with Parkinson's and care partners.
Cochrane systematic review and network meta-analysis — 154 randomised trials, 7,837 people with Parkinson's disease. Moderate evidence. Cochrane Database Syst Rev 2024;4:CD013856. DOI 10.1002/14651858.CD013856.pub3. Free full text in PubMed Central (PMC11001292). Note: Most trials were small; quality-of-life findings were mostly low certainty, and evidence for LSVT BIG specifically was very low certainty.
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Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable — Campbell et al., Med Sci Sports Exerc 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC8576825/
International consensus statement (ACSM-convened roundtable) based on systematic reviews and randomised trials to mid-2018. Strong evidence. Med Sci Sports Exerc 2019;51(11):2375–2390. DOI 10.1249/MSS.0000000000002116. Free full text in PubMed Central (PMC8576825). Note: Evidence was insufficient for pain, nausea, chemotherapy nerve damage, cognition, falls and treatment tolerance; searches ended in 2018.
What It Found
An international roundtable convened by the American College of Sports Medicine graded the research on exercise during and after cancer treatment. It found strong evidence that exercise improves anxiety, depressive symptoms, fatigue, health-related quality of life and physical function, and that supervised resistance training is safe with breast cancer-related lymphoedema; moderate evidence for bone health and sleep. Supervised programmes generally appeared more effective.
Why It Matters Here
Backs up ACSM's Moving Through Cancer programme directory and the exercise physiologists in chapter 12, and the cancer pages of condition guides such as Exercise Right and Moving Medicine. Most relevant to people during and after cancer treatment.
International consensus statement (ACSM-convened roundtable) based on systematic reviews and randomised trials to mid-2018. Strong evidence. Med Sci Sports Exerc 2019;51(11):2375–2390. DOI 10.1249/MSS.0000000000002116. Free full text in PubMed Central (PMC8576825). Note: Evidence was insufficient for pain, nausea, chemotherapy nerve damage, cognition, falls and treatment tolerance; searches ended in 2018.
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Exercise/Physical Activity in Individuals with Type 2 Diabetes: A Consensus Statement from the American College of Sports Medicine — Kanaley et al., Med Sci Sports Exerc 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC8802999/
Consensus statement (American College of Sports Medicine) summarising randomised trials and meta-analyses. Moderate evidence. Med Sci Sports Exerc 2022;54(2):353–368. DOI 10.1249/MSS.0000000000002800. Free full text in PubMed Central (PMC8802999). Note: A consensus statement: the panel summarised earlier trials and meta-analyses without a new systematic review or formal grading of the evidence.
What It Found
ACSM's expert panel summarised the research on activity in type 2 diabetes. Regular aerobic training is linked to HbA1c reductions of about 0.5–0.7% and better insulin sensitivity, blood fats and blood pressure even without weight loss, and resistance training adds strength and metabolic benefits. In the Diabetes Prevention Program, people at high risk who met the activity goal had 44% lower diabetes incidence even if they missed the weight-loss target.
Why It Matters Here
Backs up the exercise physiologists, Exercise is Medicine network and condition guides (Exercise Right, Moving Medicine) in chapter 12, and walking groups in chapter 13. Most relevant to people with or at risk of type 2 diabetes.
Consensus statement (American College of Sports Medicine) summarising randomised trials and meta-analyses. Moderate evidence. Med Sci Sports Exerc 2022;54(2):353–368. DOI 10.1249/MSS.0000000000002800. Free full text in PubMed Central (PMC8802999). Note: A consensus statement: the panel summarised earlier trials and meta-analyses without a new systematic review or formal grading of the evidence.
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Physical Activity, Cognition, and Brain Outcomes: A Review of the 2018 Physical Activity Guidelines — Erickson et al., Med Sci Sports Exerc 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6527141/
Review of systematic reviews and meta-analyses for the 2018 US Physical Activity Guidelines Advisory Committee. Moderate evidence. Med Sci Sports Exerc 2019;51(6):1242–1251. DOI 10.1249/MSS.0000000000001936. Free full text in PubMed Central (PMC6527141). Note: The lower dementia risk comes from observational studies; in trials, effects of exercise on thinking were small to moderate and varied.
What It Found
The US guidelines committee's review of activity and the brain. It found strong evidence that more active people have a lower risk of cognitive decline and dementia (one meta-analysis of 15 cohort studies, over 33,000 people: 38% lower risk of decline), moderate evidence that exercise programmes improve thinking in adults over 50, and moderate evidence of benefit for people already living with dementia.
Why It Matters Here
Backs up the walking groups and adaptive programmes in chapter 13, the exercise professionals in chapter 12 and books such as Spark in chapter 10. Most relevant to middle-aged and older adults concerned about memory and thinking.
Review of systematic reviews and meta-analyses for the 2018 US Physical Activity Guidelines Advisory Committee. Moderate evidence. Med Sci Sports Exerc 2019;51(6):1242–1251. DOI 10.1249/MSS.0000000000001936. Free full text in PubMed Central (PMC6527141). Note: The lower dementia risk comes from observational studies; in trials, effects of exercise on thinking were small to moderate and varied.
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Mindfulness, Meditation, Yoga, Tai Chi & Breathing

Meditation programs for psychological stress and well-being: a systematic review and meta-analysis — Goyal et al., JAMA Intern Med 2014

https://pmc.ncbi.nlm.nih.gov/articles/PMC4142584/
Systematic review and meta-analysis — 47 randomised trials with active control groups, 3,515 participants (3,320 in the free manuscript's abstract). Strong evidence. JAMA Intern Med 2014;174(3):357-368. DOI 10.1001/jamainternmed.2013.13018. Free full text in PubMed Central (PMC4142584). Note: Effects were small, evidence for most other outcomes was low or insufficient, and meditation was not shown to be better than medicines, exercise or other active treatments.
What It Found
Reviewed 47 trials of meditation programmes for adults with a range of health problems, against active control activities. Mindfulness programmes gave small improvements in anxiety (effect size 0.38 at 8 weeks, 0.22 at 3–6 months), depression (0.30 and 0.23) and pain (0.33), with moderate-strength evidence; evidence for stress and quality of life was low. Meditation was not shown to be better than active treatments such as medicines, exercise or other behavioural therapies.
Why It Matters Here
Backs up the approach behind the meditation and mindfulness listings in chapter 13 (such as Palouse Mindfulness and meditation groups) and the mindfulness books and apps in chapter 10; the trials tested taught programmes, not these listings. Relevant to adults wanting a non-drug way to ease anxiety, low mood or pain.
Systematic review and meta-analysis — 47 randomised trials with active control groups, 3,515 participants (3,320 in the free manuscript's abstract). Strong evidence. JAMA Intern Med 2014;174(3):357-368. DOI 10.1001/jamainternmed.2013.13018. Free full text in PubMed Central (PMC4142584). Note: Effects were small, evidence for most other outcomes was low or insufficient, and meditation was not shown to be better than medicines, exercise or other active treatments.
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The empirical status of mindfulness-based interventions: a systematic review of 44 meta-analyses of randomized controlled trials — Goldberg et al., Perspect Psychol Sci 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC8364929/
Umbrella review — 44 meta-analyses covering 336 randomised trials and 30,483 people. Strong evidence. Perspect Psychol Sci 2022;17(1):108-130. DOI 10.1177/1745691620968771. Free full text in PubMed Central (PMC8364929). Note: Risk of bias was rarely low across the pooled trials, comparisons with active treatments were often underpowered, and side effects were reported inconsistently.
What It Found
Brought together 44 meta-analyses of mindfulness-based programmes. Compared with no treatment they helped across most groups and problems (effect sizes 0.10 to 0.89). Against other active activities they still helped for depression, smoking, substance use and psychiatric disorders (0.13 to 0.42) but not for pain, physical illness or anxiety. Against proven treatments such as CBT or antidepressants they generally did about as well.
Why It Matters Here
Backs up the general approach behind the mindfulness courses, apps and groups in chapter 13 and the mindfulness books and apps in chapter 10; it pools trials of mindfulness programmes, not those products. Useful for readers and clinicians who want the big picture in one paper.
Umbrella review — 44 meta-analyses covering 336 randomised trials and 30,483 people. Strong evidence. Perspect Psychol Sci 2022;17(1):108-130. DOI 10.1177/1745691620968771. Free full text in PubMed Central (PMC8364929). Note: Risk of bias was rarely low across the pooled trials, comparisons with active treatments were often underpowered, and side effects were reported inconsistently.
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Mindfulness meditation for chronic pain: systematic review and meta-analysis — Hilton et al., Ann Behav Med 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5368208/
Systematic review and meta-analysis — 38 randomised trials. Moderate evidence. Ann Behav Med 2017;51(2):199-213. DOI 10.1007/s12160-016-9844-2. Free full text in PubMed Central (PMC5368208) — open access, CC BY. Note: The pain benefit was small and rated low-quality evidence, and only 7 of 38 trials reported on safety.
What It Found
Reviewed 38 randomised trials of mindfulness meditation (mostly MBSR or MBCT courses) for chronic pain conditions such as back pain, fibromyalgia, migraine and arthritis. Across 30 trials, mindfulness was linked to a small decrease in pain compared with control groups (SMD 0.32, 95% CI 0.09 to 0.54), but the authors rated this evidence low quality. Depression and quality of life also improved. Only 7 trials reported on safety.
Why It Matters Here
Backs up the approach behind the mindfulness-for-pain listings in chapter 13 (such as Headspace Pain Management and Palouse Mindfulness) and Full Catastrophe Living, the MBSR book, in chapter 10; the trials mostly tested taught courses, not these products.
Systematic review and meta-analysis — 38 randomised trials. Moderate evidence. Ann Behav Med 2017;51(2):199-213. DOI 10.1007/s12160-016-9844-2. Free full text in PubMed Central (PMC5368208) — open access, CC BY. Note: The pain benefit was small and rated low-quality evidence, and only 7 of 38 trials reported on safety.
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Testing the efficacy of a multicomponent, self-guided, smartphone-based meditation app: three-armed randomized controlled trial — Goldberg et al., JMIR Ment Health 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7732708/
Randomised controlled trial — 343 adults, 8 weeks, two app versions vs waiting list. Moderate evidence. JMIR Ment Health 2020;7(11):e23825. DOI 10.2196/23825. Free full text in PubMed Central (PMC7732708) — open access, CC BY. Note: Compared only with a waiting list, in mostly female, highly educated volunteers recruited through a US university; effects were small and nearly half did not complete a follow-up survey.
What It Found
Tested two versions of the free Healthy Minds Program meditation app against a waiting list in 343 adults (mostly women, recruited through a US university) over 8 weeks. People given the app had a small fall in psychological distress compared with the waiting list (d = -0.28) and small gains in mindfulness and social connection, with less repetitive negative thinking. The two app versions worked about equally well.
Why It Matters Here
Backs up the Healthy Minds Program app in chapter 10, which this trial tested directly. Relevant to adults wanting a structured, free way to start meditating.
Randomised controlled trial — 343 adults, 8 weeks, two app versions vs waiting list. Moderate evidence. JMIR Ment Health 2020;7(11):e23825. DOI 10.2196/23825. Free full text in PubMed Central (PMC7732708) — open access, CC BY. Note: Compared only with a waiting list, in mostly female, highly educated volunteers recruited through a US university; effects were small and nearly half did not complete a follow-up survey.
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Efficacy of mindfulness-based cognitive therapy in prevention of depressive relapse: an individual patient data meta-analysis from randomized trials — Kuyken et al., JAMA Psychiatry 2016

https://pmc.ncbi.nlm.nih.gov/articles/PMC6640038/
Individual patient data meta-analysis — 9 randomised trials, 1,258 people with recurrent depression. Strong evidence. JAMA Psychiatry 2016;73(6):565-574. DOI 10.1001/jamapsychiatry.2016.0076. Free full text in PubMed Central (PMC6640038). Note: Trials were of a taught 8-week group course for people in recovery; it does not show that a book or app alone works as well, or that MBCT treats a current episode.
What It Found
Pooled the raw data from 9 trials of the 8-week Mindfulness-Based Cognitive Therapy (MBCT) course for people with recurrent depression in full or partial remission. Over 60 weeks, people who did MBCT were less likely to relapse than those who did not (hazard ratio 0.69, 95% CI 0.58 to 0.82); comparisons with active treatments, including antidepressants, also suggested a lower risk (0.79, 0.64 to 0.97). Benefit may be greater when symptoms are worse before treatment.
Why It Matters Here
Backs up the method in The Mindful Way through Depression, the self-help version of MBCT, in chapter 10; the trials tested the taught course, not the book. Most relevant to people who have had several episodes of depression and want to stay well.
Individual patient data meta-analysis — 9 randomised trials, 1,258 people with recurrent depression. Strong evidence. JAMA Psychiatry 2016;73(6):565-574. DOI 10.1001/jamapsychiatry.2016.0076. Free full text in PubMed Central (PMC6640038). Note: Trials were of a taught 8-week group course for people in recovery; it does not show that a book or app alone works as well, or that MBCT treats a current episode.
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Mindfulness-based stress reduction vs escitalopram for the treatment of adults with anxiety disorders: a randomized clinical trial — Hoge et al., JAMA Psychiatry 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC9647561/
Randomised non-inferiority trial — 276 adults with anxiety disorders at 3 US centres (208 completed). Moderate evidence. JAMA Psychiatry 2023;80(1):13-21. DOI 10.1001/jamapsychiatry.2022.3679. Free full text in PubMed Central (PMC9647561). Note: One trial, cut short by COVID-19 (276 of 368 planned), with no placebo group; it used instructor-led classes plus daily home practice, so does not show a free online course works as well.
What It Found
Compared the 8-week Mindfulness-Based Stress Reduction (MBSR) course with the antidepressant escitalopram in adults with generalised anxiety, social anxiety, panic disorder or agoraphobia. Both groups improved by a similar amount on a blinded clinician rating (difference -0.07 points, 95% CI -0.38 to 0.23), which met the trial's test for MBSR being no worse. Side effects linked to the study were reported by 15.4% in the MBSR group and 78.6% in the medicine group.
Why It Matters Here
Backs up the approach behind Palouse Mindfulness (a free online course based on MBSR) in chapter 13 and Full Catastrophe Living, the book behind MBSR, in chapter 10; the trial tested instructor-led classes. Relevant to adults with anxiety weighing up options with their doctor.
Randomised non-inferiority trial — 276 adults with anxiety disorders at 3 US centres (208 completed). Moderate evidence. JAMA Psychiatry 2023;80(1):13-21. DOI 10.1001/jamapsychiatry.2022.3679. Free full text in PubMed Central (PMC9647561). Note: One trial, cut short by COVID-19 (276 of 368 planned), with no placebo group; it used instructor-led classes plus daily home practice, so does not show a free online course works as well.
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Mindfulness-based programmes for mental health promotion in adults in nonclinical settings: a systematic review and meta-analysis of randomised controlled trials — Galante et al., PLoS Med 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC7799763/
Systematic review and meta-analysis — 136 randomised trials, 11,605 adults in 29 countries. Moderate evidence. PLoS Med 2021;18(1):e1003481. DOI 10.1371/journal.pmed.1003481. Free full text in PubMed Central (PMC7799763) — open access, CC BY 4.0. Note: Every trial was at high risk of bias; only the effect on distress survived removing the weakest trials, and mindfulness did not outperform other well-being programmes.
What It Found
Looked at in-person mindfulness courses offered to adults in everyday settings such as workplaces, universities and communities. Compared with doing nothing, courses reduced anxiety (SMD -0.56), depression (-0.53) and distress (-0.45) and improved well-being (0.33). Against comparison activities not designed to help, only depression still improved, and mindfulness was not shown to be better than other well-being programmes. Certainty ranged from moderate to very low.
Why It Matters Here
Backs up the approach behind the mindfulness courses and groups in chapter 13, such as Palouse Mindfulness; the trials tested in-person courses, not these listings. Most relevant to people without a diagnosis who want to manage stress.
Systematic review and meta-analysis — 136 randomised trials, 11,605 adults in 29 countries. Moderate evidence. PLoS Med 2021;18(1):e1003481. DOI 10.1371/journal.pmed.1003481. Free full text in PubMed Central (PMC7799763) — open access, CC BY 4.0. Note: Every trial was at high risk of bias; only the effect on distress survived removing the weakest trials, and mindfulness did not outperform other well-being programmes.
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Yoga for chronic non-specific low back pain — Wieland et al., Cochrane Database Syst Rev 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9673466/
Cochrane systematic review — 21 randomised trials, 2,223 people. Moderate evidence. Cochrane Database Syst Rev 2022;11:CD010671. DOI 10.1002/14651858.CD010671.pub3. Free full text in PubMed Central (PMC9673466). Note: Benefits were small and no greater than other back exercise; all trials were at high risk of bias because participants knew their group and rated their own symptoms.
What It Found
Compared with no exercise, yoga gave small improvements at 3 months in back-related function (1.69 points on a 0–24 scale, low certainty) and pain (4.5 points on a 0–100 scale, moderate certainty), both smaller than the change people usually notice. Yoga probably works about as well as other back exercise for function (moderate certainty). Yoga was linked to more side effects than no exercise, mainly increased back pain (43 vs 9 per 1,000, low certainty).
Why It Matters Here
Backs up yoga as one reasonable way to stay active with long-term back pain, as offered through the yoga teacher and yoga therapist finders in chapter 12 and Yoga With Adriene in chapter 13 (none was itself tested). Relevant to people choosing an exercise they will keep doing.
Cochrane systematic review — 21 randomised trials, 2,223 people. Moderate evidence. Cochrane Database Syst Rev 2022;11:CD010671. DOI 10.1002/14651858.CD010671.pub3. Free full text in PubMed Central (PMC9673466). Note: Benefits were small and no greater than other back exercise; all trials were at high risk of bias because participants knew their group and rated their own symptoms.
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Systematic review and meta-analysis: Tai Chi for preventing falls in older adults — Huang et al., BMJ Open 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5293999/
Systematic review and meta-analysis — 18 randomised trials, 3,824 older adults. Moderate evidence. BMJ Open 2017;7(2):e013661. DOI 10.1136/bmjopen-2016-013661. Free full text in PubMed Central (PMC5293999) — open access, CC BY-NC 4.0. Note: The authors found signs of publication bias, so the benefit may be overestimated; tai chi styles, doses and participants varied.
What It Found
Pooled 18 randomised trials of tai chi in older adults. Compared with control groups, tai chi reduced the number of people who fell by about a fifth (risk ratio 0.80, 95% CI 0.72 to 0.88; 16 trials) and the overall rate of falls by about 30% (rate ratio 0.69, 95% CI 0.60 to 0.80; 15 trials). The benefit appeared larger with more frequent practice.
Why It Matters Here
Backs up tai chi for preventing falls, the approach taught through the tai chi listings in chapter 13 (Tai Chi For Health Institute) and chapter 12 (Taoist Tai Chi Society); the trials did not test these organisations' classes. Most relevant to older adults worried about falling.
Systematic review and meta-analysis — 18 randomised trials, 3,824 older adults. Moderate evidence. BMJ Open 2017;7(2):e013661. DOI 10.1136/bmjopen-2016-013661. Free full text in PubMed Central (PMC5293999) — open access, CC BY-NC 4.0. Note: The authors found signs of publication bias, so the benefit may be overestimated; tai chi styles, doses and participants varied.
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Effect of tai chi versus aerobic exercise for fibromyalgia: comparative effectiveness randomized controlled trial — Wang et al., BMJ 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC5861462/
Randomised controlled trial — 226 adults with fibromyalgia, 52 weeks. Moderate evidence. BMJ 2018;360:k851. DOI 10.1136/bmj.k851. Free full text in PubMed Central (PMC5861462) — open access, CC BY-NC. Note: A single trial at one US hospital in which participants knew their programme; the advantage over aerobic exercise was modest.
What It Found
Compared classic Yang-style tai chi classes (once or twice a week for 12 or 24 weeks) with supervised aerobic exercise in 226 adults with fibromyalgia. At 24 weeks the tai chi groups together improved more on a fibromyalgia symptom score than aerobic exercise (5.5 points, 95% CI 0.6 to 10.4), and 24 weeks of tai chi helped more than 12 weeks; twice a week was no better than once. No serious side effects were linked to either programme.
Why It Matters Here
Backs up tai chi classes of the kind found through the tai chi listings in chapter 13 (Tai Chi For Health Institute) and chapter 12 (Taoist Tai Chi Society), particularly for people living with fibromyalgia; the trial did not test these organisations' classes.
Randomised controlled trial — 226 adults with fibromyalgia, 52 weeks. Moderate evidence. BMJ 2018;360:k851. DOI 10.1136/bmj.k851. Free full text in PubMed Central (PMC5861462) — open access, CC BY-NC. Note: A single trial at one US hospital in which participants knew their programme; the advantage over aerobic exercise was modest.
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Effect of breathwork on stress and mental health: a meta-analysis of randomised-controlled trials — Fincham et al., Sci Rep 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC9828383/
Meta-analysis of randomised controlled trials — 12 trials (785 adults) for stress; 18–20 for anxiety and depression. Moderate evidence. Sci Rep 2023;13:432. DOI 10.1038/s41598-022-27247-y. Free full text in PubMed Central (PMC9828383) — open access, CC BY. Note: No trial was at low risk of bias and outcomes were self-reported; stress fell clearly only in people without a health condition, and one fast-breathing trial reported hot flushes and breathlessness.
What It Found
Pooled randomised trials of deliberate breathing practices (breathwork) in adults. Compared with control conditions, breathwork lowered self-reported stress by a small-to-moderate amount (g = -0.35, 95% CI -0.55 to -0.14; 12 trials, 785 adults). It also lowered anxiety (g = -0.32, 20 studies) and depression (g = -0.40, 18 studies). Most of the stress trials used slow-paced breathing.
Why It Matters Here
Backs up the general case for breathing practice in the chapter 10 breathing books (Breath; The Healing Power of the Breath) and behind the site's Breathe tool; it pooled many different practices, not the books or the tool's patterns. Relevant to anyone wanting a simple, free way to manage stress.
Meta-analysis of randomised controlled trials — 12 trials (785 adults) for stress; 18–20 for anxiety and depression. Moderate evidence. Sci Rep 2023;13:432. DOI 10.1038/s41598-022-27247-y. Free full text in PubMed Central (PMC9828383) — open access, CC BY. Note: No trial was at low risk of bias and outcomes were self-reported; stress fell clearly only in people without a health condition, and one fast-breathing trial reported hot flushes and breathlessness.
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How breath-control can change your life: a systematic review on psycho-physiological correlates of slow breathing — Zaccaro et al., Front Hum Neurosci 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6137615/
Systematic review — 15 experimental studies of slow breathing (no randomised trials). Early evidence. Front Hum Neurosci 2018;12:353. DOI 10.3389/fnhum.2018.00353. Free full text in PubMed Central (PMC6137615) — open access, CC BY. Note: None of the studies were randomised trials, most were small and methods varied; it describes short-term changes, not lasting health benefits.
What It Found
Reviewed 15 studies of what happens in body and mind during slow breathing (fewer than 10 breaths a minute) in healthy adults. Slow breathing was linked to higher heart rate variability, usually read as a sign of the calming parasympathetic nervous system, and to changes in brain-wave patterns, alongside feeling more relaxed, comfortable and alert and less anxious or angry.
Why It Matters Here
Backs up the idea behind slow paced breathing, such as the 5-5 pattern in the site's Breathe tool and the Coherent Breathing taught in The Healing Power of the Breath (chapter 10). It explains a likely mechanism; it did not test the tool, the book or any treatment.
Systematic review — 15 experimental studies of slow breathing (no randomised trials). Early evidence. Front Hum Neurosci 2018;12:353. DOI 10.3389/fnhum.2018.00353. Free full text in PubMed Central (PMC6137615) — open access, CC BY. Note: None of the studies were randomised trials, most were small and methods varied; it describes short-term changes, not lasting health benefits.
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How does eye movement desensitization and reprocessing therapy work? A systematic review on suggested mechanisms of action — Landin-Romero et al., Front Psychol 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6106867/
Systematic review — 87 studies of proposed mechanisms (psychological, physiological and brain imaging). Early evidence. Front Psychol 2018;9:1395. DOI 10.3389/fpsyg.2018.01395. Free full text in PubMed Central (PMC6106867) — open access, CC BY 4.0. Note: The authors call this research 'in its infancy': studies were small and varied, results were mixed, and no meta-analysis was possible.
What It Found
Reviewed 87 studies on how the eye movements and other side-to-side (bilateral) stimulation used in EMDR therapy might work. There was reasonable support for the working-memory explanation: doing a distracting task while recalling a memory makes it feel less vivid and less upsetting. There was also support for physical calming during successful therapy. Tones and taps also reduced vividness, though several lab studies found eye movements worked better than tones.
Why It Matters Here
Backs up the reasoning behind EMDR therapy, offered by the EMDR therapists in chapter 05, and explains the idea behind the side-to-side stimulation in the site's Calm tool. It studied therapy and lab tasks; it does not show that self-help bilateral stimulation, or the Calm tool, works.
Systematic review — 87 studies of proposed mechanisms (psychological, physiological and brain imaging). Early evidence. Front Psychol 2018;9:1395. DOI 10.3389/fpsyg.2018.01395. Free full text in PubMed Central (PMC6106867) — open access, CC BY 4.0. Note: The authors call this research 'in its infancy': studies were small and varied, results were mixed, and no meta-analysis was possible.
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Brief structured respiration practices enhance mood and reduce physiological arousal — Balban et al., Cell Rep Med 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC9873947/
Randomised controlled trial — 108 adults, 5 minutes a day for one month. Early evidence. Cell Rep Med 2023;4(1):100895. DOI 10.1016/j.xcrm.2022.100895. Free full text in PubMed Central (PMC9873947) — open access, CC BY-NC-ND 4.0. Note: A small exploratory remote trial, mostly in Stanford students and registered after it began; mood was self-rated and only cyclic sighing clearly beat meditation.
What It Found
Compared three 5-minute daily breathing exercises — cyclic sighing (double inhale, long exhale), box breathing, and cyclic hyperventilation with breath holds — with 5 minutes of mindfulness meditation for a month. All groups felt less anxious after each session, equally so; their usual anxiety did not change. Breathing raised positive mood more than meditation (clearly only for cyclic sighing) and slowed resting breathing. Heart rate, its variability and sleep did not change.
Why It Matters Here
Backs up the idea behind the cyclic-sigh (physiological sigh) and box-breathing patterns in the site's Breathe tool and the chapter 10 breathing books; it tested these exercises as a 5-minute daily practice, not the tool or the books. Relevant to anyone wanting a short daily practice for stress.
Randomised controlled trial — 108 adults, 5 minutes a day for one month. Early evidence. Cell Rep Med 2023;4(1):100895. DOI 10.1016/j.xcrm.2022.100895. Free full text in PubMed Central (PMC9873947) — open access, CC BY-NC-ND 4.0. Note: A small exploratory remote trial, mostly in Stanford students and registered after it began; mood was self-rated and only cyclic sighing clearly beat meditation.
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Nature, Social Connection & Community

Social relationships and mortality risk: a meta-analytic review — Holt-Lunstad et al., PLoS Med 2010

https://pmc.ncbi.nlm.nih.gov/articles/PMC2910600/
Meta-analysis of 148 prospective studies — 308,849 people followed for an average of 7.5 years. Moderate evidence. PLoS Med 2010;7(7):e1000316. DOI 10.1371/journal.pmed.1000316. Free full text in PubMed Central (PMC2910600) — open access, CC BY 4.0. Note: Observational studies: a strong link, not proof that adding social contact extends life; how relationships were measured varied widely.
What It Found
Pooled 148 studies that followed 308,849 people for an average of 7.5 years. People with stronger social relationships had 50% greater odds of survival (odds ratio 1.50, 95% CI 1.42 to 1.59). The link was strongest for measures combining several aspects of social life (complex measures of social integration) and weakest for simply living alone versus with others. The authors judged the effect comparable with well-established risk factors for death.
Why It Matters Here
Backs up the reason for the support-group, community and walking-group listings in chapters 06 and 13: regular contact and belonging are linked with longer life. Most relevant to people cut off by chronic illness, carers and anyone with few close ties.
Meta-analysis of 148 prospective studies — 308,849 people followed for an average of 7.5 years. Moderate evidence. PLoS Med 2010;7(7):e1000316. DOI 10.1371/journal.pmed.1000316. Free full text in PubMed Central (PMC2910600) — open access, CC BY 4.0. Note: Observational studies: a strong link, not proof that adding social contact extends life; how relationships were measured varied widely.
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Loneliness and social isolation as risk factors for coronary heart disease and stroke: systematic review and meta-analysis of longitudinal observational studies — Valtorta et al., Heart 2016

https://pmc.ncbi.nlm.nih.gov/articles/PMC4941172/
Systematic review and meta-analysis of longitudinal studies — 23 papers from 16 datasets; 4,628 heart disease and 3,002 stroke events. Moderate evidence. Heart 2016;102(13):1009–1016. DOI 10.1136/heartjnl-2015-308790. Free full text in PubMed Central (PMC4941172) — open access, CC BY 4.0. Note: Observational studies: an association, not evidence of cause; results varied between studies and some small studies may be missing (possible publication bias).
What It Found
Reviewed 23 papers reporting 16 long-term studies in high-income countries (4,628 heart disease and 3,002 stroke events; 3 to 21 years of follow-up) and pooled 11 for coronary heart disease and 8 for stroke. Poor social relationships (loneliness or social isolation) were linked with a 29% higher risk of new coronary heart disease (relative risk 1.29, 95% CI 1.04 to 1.59) and a 32% higher risk of stroke (1.32, 1.04 to 1.68).
Why It Matters Here
Backs up the community, walking and group-activity listings in chapters 06 and 13 for readers focused on metabolic and heart health: poor social connection is linked with heart disease and stroke, alongside the better-known risk factors.
Systematic review and meta-analysis of longitudinal studies — 23 papers from 16 datasets; 4,628 heart disease and 3,002 stroke events. Moderate evidence. Heart 2016;102(13):1009–1016. DOI 10.1136/heartjnl-2015-308790. Free full text in PubMed Central (PMC4941172) — open access, CC BY 4.0. Note: Observational studies: an association, not evidence of cause; results varied between studies and some small studies may be missing (possible publication bias).
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From loneliness to social connection: charting a path to healthier societies. Report of the WHO Commission on Social Connection — WHO 2025

https://iris.who.int/handle/10665/381746
Global WHO commission report (213 pages) drawing on systematic reviews and worldwide survey data. Moderate evidence. Geneva: World Health Organization; 2025. ISBN 978-92-4-011236-0. Free from the World Health Organization — open access, CC BY-NC-SA 3.0 IGO. Note: Evidence on harms is mostly observational; the report says high-quality studies of community programmes are limited, and psychological approaches show the most promise so far.
What It Found
WHO's flagship report estimates that loneliness affects about one in six people worldwide (2014–2023) and accounts for about 871,000 deaths a year (2014–2019). It describes harms to physical health (such as heart disease, stroke and type 2 diabetes), to mental health (depression and anxiety) and early death, and concludes that effective ways to build social connection exist and should be scaled up.
Why It Matters Here
Backs up treating the support-group, community and group-activity listings in chapters 06 and 13 as part of health, not an optional extra. Most relevant to people living alone, carers, older adults and anyone isolated by illness.
Global WHO commission report (213 pages) drawing on systematic reviews and worldwide survey data. Moderate evidence. Geneva: World Health Organization; 2025. ISBN 978-92-4-011236-0. Free from the World Health Organization — open access, CC BY-NC-SA 3.0 IGO. Note: Evidence on harms is mostly observational; the report says high-quality studies of community programmes are limited, and psychological approaches show the most promise so far.
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Interventions associated with reduced loneliness and social isolation in older adults: a systematic review and meta-analysis — Hoang et al., JAMA Netw Open 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9577679/
Systematic review and meta-analysis of randomised trials — 70 trials, 8,259 older adults. Moderate evidence. JAMA Netw Open 2022;5(10):e2236676. DOI 10.1001/jamanetworkopen.2022.36676. Free full text in PubMed Central (PMC9577679) — open access, CC BY. Note: The authors rated the overall quality of evidence as very low (GRADE), with few trials per type of intervention and wide variation between them.
What It Found
Reviewed 70 randomised trials in 8,259 older adults, 44 of them pooled for loneliness. Animal therapy, multicomponent programmes, exercise, technology such as video calls, and psychological therapies were associated with less loneliness, but most effects were small. The largest, each from a few small trials in long-term care, were animal therapy (standardised mean difference −1.86, 95% CI −3.14 to −0.59, excluding one trial) and video-conferencing (−1.40, −2.37 to −0.44).
Why It Matters Here
Backs up the group activities, community programmes and connection-focused services in chapters 06 and 13: some approaches may reduce loneliness in later life. Most relevant to older adults, carers and families of people in residential care.
Systematic review and meta-analysis of randomised trials — 70 trials, 8,259 older adults. Moderate evidence. JAMA Netw Open 2022;5(10):e2236676. DOI 10.1001/jamanetworkopen.2022.36676. Free full text in PubMed Central (PMC9577679) — open access, CC BY. Note: The authors rated the overall quality of evidence as very low (GRADE), with few trials per type of intervention and wide variation between them.
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What is the evidence on the role of the arts in improving health and well-being? A scoping review — Fancourt & Finn, WHO 2019

https://iris.who.int/handle/10665/329834
Scoping review of over 3,000 studies, from small pilots to large cohort studies and randomised trials. Moderate evidence. Copenhagen: WHO Regional Office for Europe; 2019. HEN synthesis report 67. ISBN 978-92-890-5455-3. Free from the World Health Organization — open access, CC BY-NC-SA 3.0 IGO. Note: A scoping review maps the evidence rather than grading it; much of the underlying research is small or uncontrolled.
What It Found
WHO Europe's review drew on over 3,000 studies of arts such as music, singing, dance, theatre, visual arts and reading. It concluded that the arts can play a major role in preventing ill health, promoting health, and managing and treating illness across the lifespan; for example, dance has repeatedly improved movement in Parkinson's disease. Evidence ranged from small uncontrolled pilots and case studies to large cohort studies and randomised trials.
Why It Matters Here
Backs up arts-based activities in chapter 13, such as the dance classes run by Dance for PD (the review describes the programme as a case study but did not test it), and the wider idea that shared creative activities support health. Relevant to people with long-term conditions, older adults and carers.
Scoping review of over 3,000 studies, from small pilots to large cohort studies and randomised trials. Moderate evidence. Copenhagen: WHO Regional Office for Europe; 2019. HEN synthesis report 67. ISBN 978-92-890-5455-3. Free from the World Health Organization — open access, CC BY-NC-SA 3.0 IGO. Note: A scoping review maps the evidence rather than grading it; much of the underlying research is small or uncontrolled.
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Is volunteering a public health intervention? A systematic review and meta-analysis of the health and survival of volunteers — Jenkinson et al., BMC Public Health 2013

https://pmc.ncbi.nlm.nih.gov/articles/PMC3766013/
Systematic review and meta-analysis — 40 papers: 5 randomised trials, 4 non-randomised trials, 17 cohort studies. Moderate evidence. BMC Public Health 2013;13:773. DOI 10.1186/1471-2458-13-773. Free full text in PubMed Central (PMC3766013) — open access, CC BY 2.0. Note: Mostly observational: healthier people may be more likely to volunteer, and the few small randomised trials did not confirm the benefits.
What It Found
Reviewed 40 papers on volunteers' health. Cohort studies linked volunteering with less depression and better life satisfaction and wellbeing, but not better physical health, and a pooled analysis of five cohorts found a lower risk of death (risk ratio 0.78, 95% CI 0.66 to 0.90). These findings were not confirmed by the small number of experimental studies.
Why It Matters Here
Backs up the volunteering approach behind GoodGym and Cycling Without Age in chapter 13 (neither scheme was itself studied): giving time to others is linked with better mental wellbeing. Relevant to people looking for purpose and contact as part of recovery.
Systematic review and meta-analysis — 40 papers: 5 randomised trials, 4 non-randomised trials, 17 cohort studies. Moderate evidence. BMC Public Health 2013;13:773. DOI 10.1186/1471-2458-13-773. Free full text in PubMed Central (PMC3766013) — open access, CC BY 2.0. Note: Mostly observational: healthier people may be more likely to volunteer, and the few small randomised trials did not confirm the benefits.
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Spending at least 120 minutes a week in nature is associated with good health and wellbeing — White et al., Sci Rep 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6565732/
Cross-sectional national survey — 19,806 adults in England. Early evidence. Sci Rep 2019;9:7730. DOI 10.1038/s41598-019-44097-3. Free full text in PubMed Central (PMC6565732) — open access, CC BY 4.0. Note: A snapshot survey: healthier, happier people may simply visit nature more, and the authors call the 120-minute threshold a tentative starting point.
What It Found
In an English national survey of 19,806 adults, people who spent at least 120 minutes in nature in the past week were more likely to report good health (odds ratio 1.59, 95% CI 1.31 to 1.92, for 120–179 minutes) and high wellbeing (1.23, 1.08 to 1.40) than people with no nature contact. Benefits levelled off at 200–300 minutes, and it did not matter whether the time came in one visit or several.
Why It Matters Here
Backs up the walking, hiking and nature-therapy listings in chapter 13 and gives readers a rough weekly figure to aim for, which the authors call tentative. The pattern held for older adults and people with long-term health conditions.
Cross-sectional national survey — 19,806 adults in England. Early evidence. Sci Rep 2019;9:7730. DOI 10.1038/s41598-019-44097-3. Free full text in PubMed Central (PMC6565732) — open access, CC BY 4.0. Note: A snapshot survey: healthier, happier people may simply visit nature more, and the authors call the 120-minute threshold a tentative starting point.
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The health benefits of the great outdoors: a systematic review and meta-analysis of greenspace exposure and health outcomes — Twohig-Bennett & Jones, Environ Res 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6562165/
Systematic review and meta-analysis — 143 studies (103 observational, 40 interventional). Moderate evidence. Environ Res 2018;166:628–637. DOI 10.1016/j.envres.2018.06.030. Free full text in PubMed Central (PMC6562165) — open access, CC BY 4.0. Note: Mostly observational with high heterogeneity: greener neighbourhoods may differ in other ways (such as income) that also affect health.
What It Found
Reviewed 143 studies on green space and health. In pooled analyses, more exposure to green space was linked with lower salivary cortisol, heart rate and diastolic blood pressure, and lower risk of type 2 diabetes (odds ratio 0.72, 95% CI 0.61 to 0.85), cardiovascular death (0.84, 0.76 to 0.93) and death from any cause (0.69, 0.55 to 0.87), as well as better self-reported health (1.12, 1.05 to 1.19).
Why It Matters Here
Backs up the general case for time in green places behind the nature-therapy and outdoor listings in chapter 13, such as Green Gym, forest bathing (27 of its 40 intervention studies were forest-bathing studies) and outdoor walking groups; the named schemes were not themselves tested.
Systematic review and meta-analysis — 143 studies (103 observational, 40 interventional). Moderate evidence. Environ Res 2018;166:628–637. DOI 10.1016/j.envres.2018.06.030. Free full text in PubMed Central (PMC6562165) — open access, CC BY 4.0. Note: Mostly observational with high heterogeneity: greener neighbourhoods may differ in other ways (such as income) that also affect health.
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Nature-based outdoor activities for mental and physical health: systematic review and meta-analysis — Coventry et al., SSM Popul Health 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8498096/
Systematic review and meta-analysis — 50 studies, including 16 randomised trials. Moderate evidence. SSM Popul Health 2021;16:100934. DOI 10.1016/j.ssmph.2021.100934. Free full text in PubMed Central (PMC8498096) — open access, CC BY 4.0. Note: Only 16 of the 50 studies were randomised trials and each pooled result rests on a handful of them; the non-randomised studies had moderate to high risk of bias.
What It Found
Reviewed 50 studies (16 randomised trials) of nature-based activities for adults, such as gardening, green exercise and nature-based therapy. Pooled trials showed better depressive mood (standardised mean difference −0.64, 95% CI −1.05 to −0.23), positive affect (0.95, 0.59 to 1.31) and negative affect (−0.52, −0.77 to −0.26), and a less certain effect on anxiety. Physical-health gains were less clear; 8–12 week programmes with 20–90 minute sessions looked best.
Why It Matters Here
Backs up the kinds of activity offered by Green Gym, Trellis (horticultural therapy), forest-bathing guides and outdoor walking groups in chapter 13, though these schemes were not tested themselves. Some studies included people living with a mental health condition.
Systematic review and meta-analysis — 50 studies, including 16 randomised trials. Moderate evidence. SSM Popul Health 2021;16:100934. DOI 10.1016/j.ssmph.2021.100934. Free full text in PubMed Central (PMC8498096) — open access, CC BY 4.0. Note: Only 16 of the 50 studies were randomised trials and each pooled result rests on a handful of them; the non-randomised studies had moderate to high risk of bias.
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Effect of nature prescriptions on cardiometabolic and mental health, and physical activity: a systematic review — Nguyen et al., Lancet Planet Health 2023

https://doi.org/10.1016/S2542-5196(23)00025-6
Systematic review and meta-analysis — 92 studies (28 in meta-analyses) of randomised and non-randomised controlled designs. Moderate evidence. Lancet Planet Health 2023;7(4):e313–e328. Free full text at the publisher — open access, CC BY-NC-ND 4.0. Note: Most included studies had moderate to high risk of bias, so the size of the benefits is uncertain.
What It Found
Reviewed 92 studies of nature prescriptions — referrals or organised programmes from health or social professionals to encourage time in nature — and pooled 28 controlled studies. Compared with controls, nature prescriptions lowered systolic blood pressure (−4.82 mmHg, 95% CI −8.92 to −0.72) and diastolic blood pressure (−3.82 mmHg), reduced depression and anxiety scores, and added about 900 daily steps; weekly physical activity did not clearly change.
Why It Matters Here
Backs up referral-based nature programmes in chapter 13, such as Green Gym (available via GP referral), and the nature side of the social-prescribing approach promoted by Beyond Pills Alliance in chapter 06. The named schemes were not themselves tested.
Systematic review and meta-analysis — 92 studies (28 in meta-analyses) of randomised and non-randomised controlled designs. Moderate evidence. Lancet Planet Health 2023;7(4):e313–e328. Free full text at the publisher — open access, CC BY-NC-ND 4.0. Note: Most included studies had moderate to high risk of bias, so the size of the benefits is uncertain.
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Effects of Shinrin-Yoku (forest bathing) and nature therapy on mental health: a systematic review and meta-analysis — Kotera et al., Int J Ment Health Addict 2022

https://doi.org/10.1007/s11469-020-00363-4
Systematic review and meta-analysis — 20 studies (12 randomised trials, 8 pre-post studies), 2,257 adults. Early evidence. Int J Ment Health Addict 2022;20(1):337–361 (online 2020). Free full text at the publisher — open access, CC BY 4.0. Note: Trials had medium-to-high risk of bias with no blinding, results varied hugely between studies, and there was no follow-up, so how long any benefit lasts is unknown.
What It Found
Reviewed 20 studies of forest bathing and nature therapy in Asia and Europe (2,257 adults; 12 randomised trials). Pooled results suggested short-term reductions in depression, anxiety and anger, but effect sizes varied enormously between studies and the pooled randomised-trial result for anxiety was not statistically significant. The authors call for more rigorous trials with longer follow-up.
Why It Matters Here
Backs up the practice taught by the forest-bathing listings in chapter 13 (The Forest Bathing Institute, Association of Nature and Forest Therapy) as a promising but still early-stage approach for anxiety and low mood; neither organisation's programme was tested.
Systematic review and meta-analysis — 20 studies (12 randomised trials, 8 pre-post studies), 2,257 adults. Early evidence. Int J Ment Health Addict 2022;20(1):337–361 (online 2020). Free full text at the publisher — open access, CC BY 4.0. Note: Trials had medium-to-high risk of bias with no blinding, results varied hugely between studies, and there was no follow-up, so how long any benefit lasts is unknown.
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Gardening is beneficial for health: a meta-analysis — Soga et al., Prev Med Rep 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5153451/
Meta-analysis — 22 studies (76 comparisons) of gardening or horticultural therapy versus controls. Early evidence. Prev Med Rep 2017;5:92–99. DOI 10.1016/j.pmedr.2016.11.007. Free full text in PubMed Central (PMC5153451) — open access, CC BY-NC-ND 4.0. Note: Mostly small before-and-after or gardener-versus-non-gardener comparisons, not randomised trials; study quality was not assessed, results varied widely and there were signs of publication bias.
What It Found
Pooled 22 studies (76 comparisons) of gardening, including horticultural therapy, against controls (before versus after gardening, or gardeners versus non-gardeners). Gardening was linked with a small-to-moderate overall benefit for health (effect size 0.42, 95% CI 0.36 to 0.48), including less depression and anxiety, lower body mass index, and more life satisfaction, quality of life and sense of community. After adjusting for publication bias the effect was 0.35.
Why It Matters Here
Backs up the gardening and horticultural-therapy approach used by Trellis and Green Gym in chapter 13 (neither was itself studied). Relevant to people wanting a gentle, regular outdoor activity with others.
Meta-analysis — 22 studies (76 comparisons) of gardening or horticultural therapy versus controls. Early evidence. Prev Med Rep 2017;5:92–99. DOI 10.1016/j.pmedr.2016.11.007. Free full text in PubMed Central (PMC5153451) — open access, CC BY-NC-ND 4.0. Note: Mostly small before-and-after or gardener-versus-non-gardener comparisons, not randomised trials; study quality was not assessed, results varied widely and there were signs of publication bias.
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Blue care: a systematic review of blue space interventions for health and wellbeing — Britton et al., Health Promot Int 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7245048/
Systematic review — 33 studies of blue-space interventions, none randomised (mostly qualitative or mixed-method). Early evidence. Health Promot Int 2020;35(1):50–69 (online 2018). DOI 10.1093/heapro/day103. Free full text in PubMed Central (PMC7245048) — open access, CC BY 4.0. Note: No randomised trials; most studies were small, qualitative or mixed-method, and the reviewers did not formally assess study quality.
What It Found
Reviewed 33 studies of 'blue care' — structured, mostly physical activities in and around water, such as surfing, dragon-boat racing, sailing and fishing — for people with a health need. Most reported positive or weak associations with health and wellbeing, particularly mental health and psycho-social wellbeing. Findings on social connectedness were inconsistent and there was very little evidence on physical health.
Why It Matters Here
Backs up, in part, the water-based activity listings in chapter 13 such as the Outdoor Swimming Society: structured water activities (mostly surfing, boating and fishing, rarely swimming) were linked with better mental wellbeing, but the evidence is early.
Systematic review — 33 studies of blue-space interventions, none randomised (mostly qualitative or mixed-method). Early evidence. Health Promot Int 2020;35(1):50–69 (online 2018). DOI 10.1093/heapro/day103. Free full text in PubMed Central (PMC7245048) — open access, CC BY 4.0. Note: No randomised trials; most studies were small, qualitative or mixed-method, and the reviewers did not formally assess study quality.
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Sleep — Insomnia Treatment, Sleep Apnoea & Sleep Health

Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline — Edinger et al., J Clin Sleep Med 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC7853203/
Clinical practice guideline (GRADE) built on a systematic review and meta-analyses — 66 randomised trials of CBT-I identified, 49 pooled. Strong evidence. J Clin Sleep Med 2021;17(2):255–262. DOI 10.5664/jcsm.8986. Free full text in PubMed Central (PMC7853203). Note: The CBT-I recommendation rests mainly on trials of therapist-delivered CBT-I; the panel found too little evidence to recommend particular formats such as online programmes or self-help books.
What It Found
The American Academy of Sleep Medicine graded the randomised-trial evidence for non-drug insomnia treatments. It strongly recommends multicomponent cognitive behavioural therapy for insomnia (CBT-I) for adults with chronic insomnia; gives conditional recommendations for brief behavioural therapy, stimulus control, sleep restriction and relaxation; and suggests not using sleep-hygiene advice on its own.
Why It Matters Here
Backs up the CBT-I therapist directories in chapter 11, since the strong recommendation rests mainly on CBT-I given by trained professionals. It found too little evidence to recommend particular formats, so the online programmes and apps in chapter 11 and the books and guides in chapter 10 are supported less directly.
Clinical practice guideline (GRADE) built on a systematic review and meta-analyses — 66 randomised trials of CBT-I identified, 49 pooled. Strong evidence. J Clin Sleep Med 2021;17(2):255–262. DOI 10.5664/jcsm.8986. Free full text in PubMed Central (PMC7853203). Note: The CBT-I recommendation rests mainly on trials of therapist-delivered CBT-I; the panel found too little evidence to recommend particular formats such as online programmes or self-help books.
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The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023 — Riemann et al., J Sleep Res 2023

https://doi.org/10.1111/jsr.14035
Clinical practice guideline by a European expert group, based on systematic and meta-analytic reviews, with graded (A–C) recommendations. Strong evidence. J Sleep Res 2023;32(6):e14035. Free full text at the publisher — open access, CC BY 4.0.
What It Found
European insomnia experts updated the European insomnia guideline. Its first-line recommendation (grade A) is CBT-I for adults of any age with chronic insomnia, including people with other physical or mental illnesses, delivered face to face or digitally. Medicines are for when CBT-I is not effective enough; it advises against antihistamines, antipsychotics, fast-release melatonin and herbal remedies for insomnia.
Why It Matters Here
Backs up the CBT-I therapists, digital CBT-I programmes and sleep clinics in chapter 11 and the CBT-I books and NHS inform guide in chapter 10; also tells readers of the natural-therapy listings in chapter 11 that herbal sleep remedies are not recommended.
Clinical practice guideline by a European expert group, based on systematic and meta-analytic reviews, with graded (A–C) recommendations. Strong evidence. J Sleep Res 2023;32(6):e14035. Free full text at the publisher — open access, CC BY 4.0.
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Components and Delivery Formats of Cognitive Behavioral Therapy for Chronic Insomnia in Adults: A Systematic Review and Component Network Meta-Analysis — Furukawa et al., JAMA Psychiatry 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC10794978/
Systematic review and component network meta-analysis — 241 randomised trials, 31,452 adults. Moderate evidence. JAMA Psychiatry 2024;81(4):357–365. DOI 10.1001/jamapsychiatry.2023.5060. Free full text in PubMed Central (PMC10794978) — open access, CC BY. Note: The authors call the component results hypothesis-generating: they rest on indirect comparisons, assume the parts simply add up, and certainty was moderate to low.
What It Found
Pooled 241 trials to see which parts of CBT-I matter. Cognitive restructuring (incremental odds ratio for remission 1.68), mindfulness/acceptance (1.49), sleep restriction (1.49) and stimulus control (1.43) helped; sleep-hygiene education (1.01) added nothing and relaxation (0.81) may be counterproductive. In-person therapist delivery helped most (1.83). Versus in-person sleep education, the four helpful parts given in person meant one extra remission per three treated.
Why It Matters Here
Backs up the CBT-I therapists and programmes in chapter 11 and the CBT-I books in chapter 10. Its finding that mindfulness and acceptance parts added to CBT-I helped is relevant to The Sleep Book's approach, though that book was not tested. Useful for checking a programme includes the techniques that carry the effect.
Systematic review and component network meta-analysis — 241 randomised trials, 31,452 adults. Moderate evidence. JAMA Psychiatry 2024;81(4):357–365. DOI 10.1001/jamapsychiatry.2023.5060. Free full text in PubMed Central (PMC10794978) — open access, CC BY. Note: The authors call the component results hypothesis-generating: they rest on indirect comparisons, assume the parts simply add up, and certainty was moderate to low.
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Clinical and cost-effectiveness of nurse-delivered sleep restriction therapy for insomnia in primary care (HABIT): a pragmatic, superiority, open-label, randomised controlled trial — Kyle et al., Lancet 2023

https://doi.org/10.1016/S0140-6736(23)00683-9
Pragmatic randomised controlled trial — 642 adults with insomnia disorder in 35 English general practices. Moderate evidence. Lancet 2023;402(10406):975–987. Free full text at the publisher — open access, CC BY 4.0. Note: Open-label trial with self-reported outcomes; the comparison was a booklet rather than another active therapy.
What It Found
Practice nurses gave four brief sessions of sleep restriction therapy (a core part of CBT-I) plus a sleep-hygiene booklet, compared with the booklet alone. At 6 months insomnia severity was clearly lower with sleep restriction (Insomnia Severity Index 10.9 vs 13.9; difference −3.05, 95% CI −3.83 to −2.28; d = −0.74), and it was likely cost-effective for the NHS (£2,076 per quality-adjusted life year).
Why It Matters Here
Backs up brief behavioural treatment for insomnia through ordinary health services, the sleep-restriction step taught in the CBT-I books and NHS inform guide in chapter 10, and the CBT-I programmes in chapter 11; relevant to people who cannot get full CBT-I.
Pragmatic randomised controlled trial — 642 adults with insomnia disorder in 35 English general practices. Moderate evidence. Lancet 2023;402(10406):975–987. Free full text at the publisher — open access, CC BY 4.0. Note: Open-label trial with self-reported outcomes; the comparison was a booklet rather than another active therapy.
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Effect of Digital Cognitive Behavioral Therapy for Insomnia on Health, Psychological Well-being, and Sleep-Related Quality of Life: A Randomized Clinical Trial — Espie et al., JAMA Psychiatry 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6583463/
Randomised controlled trial (DIALS) — 1,711 adults with insomnia, run online. Moderate evidence. JAMA Psychiatry 2019;76(1):21–30. DOI 10.1001/jamapsychiatry.2018.2745. Free full text in PubMed Central (PMC6583463). Note: Funded by Big Health, which makes Sleepio and helped design and run the trial; the lead author co-founded the company. Participants were mostly white (91%) and female (78%).
What It Found
Adults with insomnia were randomised to Sleepio, a fully automated six-session digital CBT-I course, or online sleep-hygiene education, both on top of usual care. At 24 weeks the Sleepio group had small gains in day-to-day functional health (d = 0.31) and psychological well-being (d = 0.38), a large gain in sleep-related quality of life (d = 1.46) and much less insomnia (d = 1.51); better sleep accounted for 46–84% of these gains.
Why It Matters Here
Backs up Sleepio in chapter 11 directly. For the other digital CBT-I courses and apps there (Sleepstation, THIS WAY UP, VA Insomnia Coach) and the CBT-I books in chapter 10 it supports the approach, not those products. Relevant to people who cannot reach a CBT-I therapist.
Randomised controlled trial (DIALS) — 1,711 adults with insomnia, run online. Moderate evidence. JAMA Psychiatry 2019;76(1):21–30. DOI 10.1001/jamapsychiatry.2018.2745. Free full text in PubMed Central (PMC6583463). Note: Funded by Big Health, which makes Sleepio and helped design and run the trial; the lead author co-founded the company. Participants were mostly white (91%) and female (78%).
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The effects of improving sleep on mental health (OASIS): a randomised controlled trial with mediation analysis — Freeman et al., Lancet Psychiatry 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5614772/
Randomised controlled trial — 3,755 university students with insomnia at 26 UK universities. Moderate evidence. Lancet Psychiatry 2017;4(10):749–758. DOI 10.1016/S2215-0366(17)30328-0. Free full text in PubMed Central (PMC5614772) — open access, CC BY 4.0. Note: About half dropped out (more with Sleepio), outcomes were self-reported, and manic symptoms rose slightly with treatment. Two authors worked for Big Health, which makes Sleepio.
What It Found
Students with insomnia were randomised to Sleepio, a six-session digital CBT-I course, or usual care. At 10 weeks insomnia had improved markedly (d = 1.11), with small falls in paranoia (d = 0.19) and hallucinatory experiences (d = 0.24) and less depression (d = 0.48) and anxiety (d = 0.33). Better sleep accounted for about 58% of the fall in paranoia and 39% of that in hallucinations, which the authors take as evidence that poor sleep contributes to mental-health problems.
Why It Matters Here
Backs up Sleepio and the approach of the other online CBT-I programmes in chapter 11 and the CBT-I books in chapter 10 as a low-cost first step that can also ease low mood and anxiety; most relevant to students and young adults.
Randomised controlled trial — 3,755 university students with insomnia at 26 UK universities. Moderate evidence. Lancet Psychiatry 2017;4(10):749–758. DOI 10.1016/S2215-0366(17)30328-0. Free full text in PubMed Central (PMC5614772) — open access, CC BY 4.0. Note: About half dropped out (more with Sleepio), outcomes were self-reported, and manic symptoms rose slightly with treatment. Two authors worked for Big Health, which makes Sleepio.
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Improving sleep quality leads to better mental health: A meta-analysis of randomised controlled trials — Scott et al., Sleep Med Rev 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8651630/
Systematic review and meta-analysis — 65 randomised trials (72 interventions), 8,608 participants. Moderate evidence. Sleep Med Rev 2021;60:101556. DOI 10.1016/j.smrv.2021.101556. Free full text in PubMed Central (PMC8651630) — open access, CC BY. Note: Only trials that had already improved sleep were included; results varied widely (I² = 76%), and the mental-health gain was much smaller at 6 months or more (g = −0.18).
What It Found
Pooled 65 randomised trials in which a sleep treatment, mostly CBT-I, measurably improved sleep, then looked at mental health. Better sleep led to medium-sized gains in overall mental health (g = −0.53), depression (−0.63), anxiety (−0.51) and rumination (−0.49), and smaller gains for stress (−0.42) and positive psychotic symptoms (−0.26). The bigger the sleep improvement, the bigger the mental-health gain.
Why It Matters Here
Backs up the CBT-I programmes, therapists and books in chapters 10 and 11 as a route to better mental health as well as better sleep; especially relevant to people with depression or anxiety whose sleep is poor.
Systematic review and meta-analysis — 65 randomised trials (72 interventions), 8,608 participants. Moderate evidence. Sleep Med Rev 2021;60:101556. DOI 10.1016/j.smrv.2021.101556. Free full text in PubMed Central (PMC8651630) — open access, CC BY. Note: Only trials that had already improved sleep were included; results varied widely (I² = 76%), and the mental-health gain was much smaller at 6 months or more (g = −0.18).
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Cognitive behavioral therapy for insomnia in patients with mental disorders and comorbid insomnia: A systematic review and meta-analysis — Hertenstein et al., Sleep Med Rev 2022

https://doi.org/10.1016/j.smrv.2022.101597
Systematic review and meta-analysis — 22 randomised trials in adults with a mental disorder and insomnia. Moderate evidence. Sleep Med Rev 2022;62:101597. Free full text at the publisher — open access, CC BY-NC-ND 4.0. Note: Few, small trials for bipolar disorder and psychosis; benefits for the mental disorder itself were not significant at later follow-up.
What It Found
Pooled 22 randomised trials of CBT-I for people whose insomnia sits alongside depression, PTSD, alcohol dependence, bipolar disorder, psychosis or mixed diagnoses. Insomnia improved with medium-to-large effects (effect size 0.5 in depression, 1.5 in PTSD, 1.4 in alcohol dependence), and depression (0.5) and PTSD (1.3) symptoms also eased after treatment. The authors suggest CBT-I as a first-line insomnia treatment in this group.
Why It Matters Here
Backs up the CBT-I providers in chapter 11 and the approach of the Carney & Manber workbook (insomnia with depression, anxiety or pain) in chapter 10; most relevant to people whose insomnia comes with a mental-health condition, and to therapists in chapter 05 who offer CBT-I.
Systematic review and meta-analysis — 22 randomised trials in adults with a mental disorder and insomnia. Moderate evidence. Sleep Med Rev 2022;62:101597. Free full text at the publisher — open access, CC BY-NC-ND 4.0. Note: Few, small trials for bipolar disorder and psychosis; benefits for the mental disorder itself were not significant at later follow-up.
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Prevention of Incident and Recurrent Major Depression in Older Adults With Insomnia: A Randomized Clinical Trial — Irwin et al., JAMA Psychiatry 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC8733847/
Randomised controlled trial — 291 adults aged 60 or over with insomnia and no current depression, followed for 3 years. Moderate evidence. JAMA Psychiatry 2022;79(1):33–41. DOI 10.1001/jamapsychiatry.2021.3422. Free full text in PubMed Central (PMC8733847) — open access, CC BY 4.0. Note: A single US site with a mostly white sample; only about half had 3-year data, and more people dropped out of the CBT-I group in the first two years.
What It Found
Older adults with insomnia but no current depression had two months of weekly group CBT-I or group sleep education. Over three years, 12.2% of the CBT-I group developed major depression versus 25.9% of the education group (hazard ratio 0.51, 95% CI 0.29–0.88); about seven people needed CBT-I to prevent one case. Those whose insomnia stayed in remission had the lowest risk.
Why It Matters Here
Backs up the CBT-I therapists in chapter 11 (the trial used psychologist-led group CBT-I) as a way to protect mood, not only sleep, and the CBT-I books in chapter 10 less directly; most relevant to older adults, and to therapists in chapter 05 who offer CBT-I.
Randomised controlled trial — 291 adults aged 60 or over with insomnia and no current depression, followed for 3 years. Moderate evidence. JAMA Psychiatry 2022;79(1):33–41. DOI 10.1001/jamapsychiatry.2021.3422. Free full text in PubMed Central (PMC8733847) — open access, CC BY 4.0. Note: A single US site with a mostly white sample; only about half had 3-year data, and more people dropped out of the CBT-I group in the first two years.
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The Consensus Sleep Diary: Standardizing Prospective Sleep Self-Monitoring — Carney et al., Sleep 2012

https://pmc.ncbi.nlm.nih.gov/articles/PMC3250369/
Expert consensus and patient focus-group development study. Moderate evidence. Sleep 2012;35(2):287–302. DOI 10.5665/sleep.1642. Free full text in PubMed Central (PMC3250369). Note: Describes how the diary was designed; it is a measuring tool, not a treatment, and this paper did not test whether keeping it improves sleep.
What It Found
Explains how the standard sleep diary used in insomnia research and CBT-I was built. Diaries from 25 experts at a sleep assessment conference were collected and an expert committee condensed them into a core diary; six focus groups of good sleepers, people with insomnia and people with sleep apnoea refined the wording, and another group checked the draft. The core diary needs only a US third-grade reading level. The authors call it a living document still needing validation.
Why It Matters Here
Backs up the Consensus Sleep Diary listing in chapter 10 (this paper describes the diary behind the free app and PDF) and the sleep-diary step built into the CBT-I programmes and apps in chapter 11; useful for anyone starting CBT-I or preparing for a sleep-clinic appointment.
Expert consensus and patient focus-group development study. Moderate evidence. Sleep 2012;35(2):287–302. DOI 10.5665/sleep.1642. Free full text in PubMed Central (PMC3250369). Note: Describes how the diary was designed; it is a measuring tool, not a treatment, and this paper did not test whether keeping it improves sleep.
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Treatment of Adult Obstructive Sleep Apnea with Positive Airway Pressure: An American Academy of Sleep Medicine Clinical Practice Guideline — Patil et al., J Clin Sleep Med 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6374094/
Clinical practice guideline (GRADE) built on a systematic review and meta-analyses of randomised trials. Strong evidence. J Clin Sleep Med 2019;15(2):335–343. DOI 10.5664/jcsm.7640. Free full text in PubMed Central (PMC6374094).
What It Found
The American Academy of Sleep Medicine reviewed the trials of CPAP and other positive airway pressure (PAP) machines. It strongly recommends PAP for adults with obstructive sleep apnoea who are excessively sleepy (38 trials), suggests it for poor sleep-related quality of life and high blood pressure, and strongly recommends education when starting PAP, with behavioural, troubleshooting and telemonitoring support suggested to help people keep using it.
Why It Matters Here
Backs up the sleep-clinic finders in chapter 11, where sleep apnoea is diagnosed and PAP is started, and the CPAP education offered by the patient organisations there. Its education and support advice is about clinic care; it did not test peer support. Most relevant to people newly diagnosed with sleep apnoea.
Clinical practice guideline (GRADE) built on a systematic review and meta-analyses of randomised trials. Strong evidence. J Clin Sleep Med 2019;15(2):335–343. DOI 10.5664/jcsm.7640. Free full text in PubMed Central (PMC6374094).
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Educational, supportive and behavioural interventions to improve usage of continuous positive airway pressure machines in adults with obstructive sleep apnoea — Askland et al., Cochrane Database Syst Rev 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7137251/
Cochrane systematic review and meta-analysis — 41 randomised trials, 9,005 adults. Strong evidence. Cochrane Database Syst Rev 2020;4:CD007736. DOI 10.1002/14651858.CD007736.pub3. Free full text in PubMed Central (PMC7137251). Note: Over half the trials had a high risk of bias, peer-led support was not assessed as a separate category, and effects on sleepiness and quality of life were uncertain.
What It Found
Reviewed 41 trials of ways to help people with sleep apnoea keep using CPAP. Behavioural approaches such as motivational support raised use by about 1.3 hours a night (95% CI 0.95 to 1.66; high-certainty evidence) and helped more people reach 4+ hours a night; ongoing supportive help such as follow-up contact added about 0.7 hours (moderate certainty). Evidence for education alone was very low certainty.
Why It Matters Here
Backs up the idea behind the CPAP support listings in chapter 11 (the AWAKE peer-mentor programme, Hope2Sleep, Apnea Board): ongoing support and motivation help people keep using CPAP, although these services themselves were not tested. Relevant to anyone struggling to get used to CPAP.
Cochrane systematic review and meta-analysis — 41 randomised trials, 9,005 adults. Strong evidence. Cochrane Database Syst Rev 2020;4:CD007736. DOI 10.1002/14651858.CD007736.pub3. Free full text in PubMed Central (PMC7137251). Note: Over half the trials had a high risk of bias, peer-led support was not assessed as a separate category, and effects on sleepiness and quality of life were uncertain.
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A Pilot Study of CPAP Adherence Promotion by Peer Buddies with Sleep Apnea — Parthasarathy et al., J Clin Sleep Med 2013

https://pmc.ncbi.nlm.nih.gov/articles/PMC3659373/
Randomised controlled pilot trial — 39 newly diagnosed patients, with 13 experienced CPAP users as peer buddies. Early evidence. J Clin Sleep Med 2013;9(6):543–550. DOI 10.5664/jcsm.2744. Free full text in PubMed Central (PMC3659373). Note: A small single-centre pilot; a larger trial is needed before peer buddies can be said to improve CPAP use.
What It Found
Newly diagnosed people with obstructive sleep apnoea were randomised to be paired with an experienced CPAP user (a 'peer buddy') or to usual care. Over the first 90 days, weekly CPAP use was higher in the peer-buddy group (p = 0.04), and 91% rated the buddy system satisfactory or very satisfactory. There were no differences in daytime functioning, vigilance or self-efficacy.
Why It Matters Here
Backs up, as early evidence, the one-to-one CPAP peer mentoring in chapter 11 (the AWAKE peer-mentor programme), and more loosely the patient-led apnoea support there (Hope2Sleep, Apnea Board, Project Sleep's Sleep Apnea Squad); most relevant to people starting CPAP.
Randomised controlled pilot trial — 39 newly diagnosed patients, with 13 experienced CPAP users as peer buddies. Early evidence. J Clin Sleep Med 2013;9(6):543–550. DOI 10.5664/jcsm.2744. Free full text in PubMed Central (PMC3659373). Note: A small single-centre pilot; a larger trial is needed before peer buddies can be said to improve CPAP use.
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Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline — Winkelman et al., J Clin Sleep Med 2025

https://pmc.ncbi.nlm.nih.gov/articles/PMC11701286/
Clinical practice guideline (GRADE) based on a systematic review of treatment trials. Strong evidence. J Clin Sleep Med 2025;21(1):137–152. DOI 10.5664/jcsm.11390. Free full text in PubMed Central (PMC11701286). Note: Over half the recommendations are conditional and rest on low- or very-low-certainty evidence; it comes from a US professional body.
What It Found
The American Academy of Sleep Medicine's updated guideline for restless legs syndrome. It advises regular iron checks and dealing first with triggers such as alcohol, caffeine, some medicines and untreated sleep apnoea. It strongly recommends gabapentinoid medicines, and intravenous ferric carboxymaltose when iron is below RLS-specific levels. It suggests against standard use of dopamine-type medicines, because of worsening over time (augmentation), and against valerian.
Why It Matters Here
Backs up the treatment information from the Restless Legs Syndrome Foundation (and its Quality Care Centers) and the RLS-UK/EARLS community in chapter 11, and the sleep-clinic finders there; it does not test these services. Most relevant to people with RLS reviewing a long-standing treatment.
Clinical practice guideline (GRADE) based on a systematic review of treatment trials. Strong evidence. J Clin Sleep Med 2025;21(1):137–152. DOI 10.5664/jcsm.11390. Free full text in PubMed Central (PMC11701286). Note: Over half the recommendations are conditional and rest on low- or very-low-certainty evidence; it comes from a US professional body.
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Self-Help Books, Online Programs & Apps

Therapist-supported Internet-based cognitive behaviour therapy yields similar effects as face-to-face therapy for psychiatric and somatic disorders: an updated systematic review and meta-analysis — Hedman-Lagerlöf et al., World Psychiatry 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10168168/
Systematic review and meta-analysis — 31 randomised trials (3,053 people) directly comparing therapist-guided internet CBT with face-to-face CBT across 16 conditions. Strong evidence. World Psychiatry 2023;22(2):305–314. DOI 10.1002/wps.21088. Free full text in PubMed Central (PMC10168168). Note: Applies to courses with regular therapist support, not to self-guided apps or books; 31 trials spread over 16 conditions means few trials per condition.
What It Found
Pooled 31 randomised trials that compared CBT delivered as an online course with a therapist checking in against the same therapy delivered face to face, across 16 mental and physical health conditions (about half were depression or anxiety). The two formats gave practically the same results (pooled effect size g=0.02, 95% CI −0.09 to 0.14).
Why It Matters Here
Backs up the therapist-supported online CBT courses in chapter 10, such as MindSpot's guided courses and THIS WAY UP when prescribed by a clinician, and is useful for anyone choosing between online CBT and the in-person therapists listed in chapter 05.
Systematic review and meta-analysis — 31 randomised trials (3,053 people) directly comparing therapist-guided internet CBT with face-to-face CBT across 16 conditions. Strong evidence. World Psychiatry 2023;22(2):305–314. DOI 10.1002/wps.21088. Free full text in PubMed Central (PMC10168168). Note: Applies to courses with regular therapist support, not to self-guided apps or books; 31 trials spread over 16 conditions means few trials per condition.
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Internet-Based Cognitive Behavioral Therapy for Depression: A Systematic Review and Individual Patient Data Network Meta-analysis — Karyotaki et al., JAMA Psychiatry 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8027916/
Systematic review and individual patient data network meta-analysis — 39 randomised trials, 9,751 people with depression. Strong evidence. JAMA Psychiatry 2021;78(4):361–371. DOI 10.1001/jamapsychiatry.2020.4364. Free full text in PubMed Central (PMC8027916). Note: The extra benefit of guidance was small on average and not seen at 6–12 months; results depend on people staying with the course.
What It Found
Re-analysed raw data from 9,751 people in 39 trials of internet CBT for depression. Both guided courses (a coach or therapist checks in) and self-guided courses did better than control conditions in the short and longer term. Guided courses were better at the end of treatment (PHQ-9 mean difference −0.8, 95% CI −1.4 to −0.2), mainly for moderate-to-severe depression; for mild symptoms self-guided courses did about as well, and no difference was found at 6 or 12 months.
Why It Matters Here
Backs up the online CBT courses in chapter 10 (the approach used by moodgym, THIS WAY UP and MindSpot) and helps readers choose: a self-guided course is a reasonable start for mild low mood, while people with moderate or severe depression tend to do better with a guided one.
Systematic review and individual patient data network meta-analysis — 39 randomised trials, 9,751 people with depression. Strong evidence. JAMA Psychiatry 2021;78(4):361–371. DOI 10.1001/jamapsychiatry.2020.4364. Free full text in PubMed Central (PMC8027916). Note: The extra benefit of guidance was small on average and not seen at 6–12 months; results depend on people staying with the course.
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Current evidence on the efficacy of mental health smartphone apps for symptoms of depression and anxiety. A meta-analysis of 176 randomized controlled trials — Linardon et al., World Psychiatry 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC10785982/
Meta-analysis — 176 randomised controlled trials of smartphone apps for depression and anxiety. Moderate evidence. World Psychiatry 2024;23(1):139–149. DOI 10.1002/wps.21183. Free full text in PubMed Central (PMC10785982). Note: Average effects are small and were measured at the end of use (mostly 1–12 weeks); they were smaller against placebo apps, and the social anxiety, OCD and PTSD results rest on small, weaker trials.
What It Found
Pooled 176 randomised trials of smartphone apps for depression or anxiety. Apps had small but significant effects on depressive symptoms (g=0.28; about one extra person helped for every 11–12 users) and generalised anxiety (g=0.26), larger for apps using CBT or chatbots. Effects were moderate for social anxiety (g=0.52) and obsessive-compulsive symptoms (g=0.51), mostly from small, high-risk trials; small for post-traumatic stress (g=0.12) and not significant for panic.
Why It Matters Here
Backs up the mental-health apps in chapter 10 as a modest, low-cost first step for low mood or worry: apps built on CBT did best, while mindfulness apps such as the Healthy Minds Program did less well in some analyses. Effects on PTSD symptoms were small, worth knowing for PTSD Coach users.
Meta-analysis — 176 randomised controlled trials of smartphone apps for depression and anxiety. Moderate evidence. World Psychiatry 2024;23(1):139–149. DOI 10.1002/wps.21183. Free full text in PubMed Central (PMC10785982). Note: Average effects are small and were measured at the end of use (mostly 1–12 weeks); they were smaller against placebo apps, and the social anxiety, OCD and PTSD results rest on small, weaker trials.
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User characteristics and outcomes from a national digital mental health service: an observational study of registrants of the Australian MindSpot Clinic — Titov et al., Lancet Digit Health 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7571905/
Observational study of a national service — 96,018 completed assessments and 21,745 people starting a therapist-guided course, 2013–2019. Early evidence. Lancet Digit Health 2020;2(11):e582–e593. DOI 10.1016/S2589-7500(20)30224-7. Free full text in PubMed Central (PMC7571905) — open access, CC BY. Note: No control group, so it shows what users achieved, not what the course caused (some would have improved anyway); the authors run the clinic.
What It Found
Seven years of routine data from MindSpot, Australia's free, government-funded online clinic. Of 21,745 adults who started a therapist-guided online CBT course, 66.7% completed it; depression (PHQ-9) and anxiety (GAD-7) scores fell substantially (pre-post d=1.40 and 1.45), gains held at 3 months, 1.4–2.2% reliably worsened, and about 97% would recommend the course. A third of those assessed had never talked to a health professional about their symptoms.
Why It Matters Here
Backs up the MindSpot Clinic listed in chapter 10 directly, and more broadly the free online CBT clinics and courses there. Most relevant to Australian adults with anxiety or low mood, including people who have never sought help before.
Observational study of a national service — 96,018 completed assessments and 21,745 people starting a therapist-guided course, 2013–2019. Early evidence. Lancet Digit Health 2020;2(11):e582–e593. DOI 10.1016/S2589-7500(20)30224-7. Free full text in PubMed Central (PMC7571905) — open access, CC BY. Note: No control group, so it shows what users achieved, not what the course caused (some would have improved anyway); the authors run the clinic.
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Delivering interventions for depression by using the internet: randomised controlled trial — Christensen et al., BMJ 2004

https://pmc.ncbi.nlm.nih.gov/articles/PMC324455/
Randomised controlled trial — 525 community adults with raised depressive symptoms (Canberra, Australia). Moderate evidence. BMJ 2004;328(7434):265. DOI 10.1136/bmj.37945.566632.EE. Free full text in PubMed Central (PMC324455). Note: One short-term trial in people recruited from the community; a later UK GP trial (REEACT, BMJ 2015) found MoodGYM added nothing to usual care, and few used it despite weekly phone support.
What It Found
525 adults with elevated depressive symptoms were randomised to MoodGYM (an online CBT course), BluePages (a depression information website) or an attention-placebo control. Both websites reduced depression scores more than control: MoodGYM by 3.2 points (95% CI 0.9 to 5.4) and BluePages by 3.0 (0.6 to 5.2). MoodGYM also reduced dysfunctional thinking, and BluePages improved understanding of effective treatments.
Why It Matters Here
Backs up moodgym in chapter 10 directly: the founding trial of one of the most-studied online CBT programmes. Also relevant to readers using plain-language information sites as a first step.
Randomised controlled trial — 525 community adults with raised depressive symptoms (Canberra, Australia). Moderate evidence. BMJ 2004;328(7434):265. DOI 10.1136/bmj.37945.566632.EE. Free full text in PubMed Central (PMC324455). Note: One short-term trial in people recruited from the community; a later UK GP trial (REEACT, BMJ 2015) found MoodGYM added nothing to usual care, and few used it despite weekly phone support.
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Influence of initial severity of depression on effectiveness of low intensity interventions: meta-analysis of individual patient data — Bower et al., BMJ 2013

https://pmc.ncbi.nlm.nih.gov/articles/PMC3582703/
Individual patient data meta-analysis — 16 randomised trial datasets, 2,470 people with depression. Moderate evidence. BMJ 2013;346:f540. DOI 10.1136/bmj.f540. Free full text in PubMed Central (PMC3582703) — open access, CC BY-NC 2.0. Note: Data were available for only about half of eligible trials, few participants had a formal diagnosis, there were signs of publication bias, and the comparison was usual care, not therapy.
What It Found
Combined patient-level data from 16 trials in primary care and community settings comparing low-intensity help (mainly guided self-help with written materials and internet programmes, with limited professional support) against usual care. These interventions reduced depression (standardised effect −0.42, 95% CI −0.55 to −0.29), and people with more severe depression at the start benefited at least as much as those with milder symptoms.
Why It Matters Here
Backs up the guided use of CBT self-help books, workbooks and online programmes in chapter 10 (the approach behind Reading Well, CCI workbooks, Getselfhelp and moodgym), and reassures readers that self-help is not only for mild problems when some support is available.
Individual patient data meta-analysis — 16 randomised trial datasets, 2,470 people with depression. Moderate evidence. BMJ 2013;346:f540. DOI 10.1136/bmj.f540. Free full text in PubMed Central (PMC3582703) — open access, CC BY-NC 2.0. Note: Data were available for only about half of eligible trials, few participants had a formal diagnosis, there were signs of publication bias, and the comparison was usual care, not therapy.
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Guided Self-Help Cognitive Behavioural Therapy for Depression in Primary Care: A Randomised Controlled Trial — Williams et al., PLoS One 2013

https://pmc.ncbi.nlm.nih.gov/articles/PMC3543408/
Randomised controlled trial — 281 adults with depression in seven Glasgow general practices. Moderate evidence. PLoS One 2013;8(1):e52735. DOI 10.1371/journal.pone.0052735. Free full text in PubMed Central (PMC3543408) — open access, CC BY. Note: Only 41.6% were followed up at 12 months, and the lead author wrote the book tested and has a financial stake in the company that sells it.
What It Found
281 adults with depression in Glasgow general practices were randomised to a CBT self-help book (Overcoming Depression: A Five Areas Approach) with three or four short support sessions, or to usual GP care. At 4 months the book group's depression scores were 5.3 points lower on the BDI-II (95% CI 2.6 to 7.9), and 42.6% v 24.5% had halved their score. At 12 months the gap was similar (5.4 points, 95% CI 1.3 to 9.6) but only 41.6% were followed up.
Why It Matters Here
Backs up the guided use of CBT self-help books and workbooks in chapter 10 (the approach behind Reading Well books on prescription, Mind Over Mood and the CCI workbooks): a CBT book used with brief support from a non-clinical helper helped GP patients with depression.
Randomised controlled trial — 281 adults with depression in seven Glasgow general practices. Moderate evidence. PLoS One 2013;8(1):e52735. DOI 10.1371/journal.pone.0052735. Free full text in PubMed Central (PMC3543408) — open access, CC BY. Note: Only 41.6% were followed up at 12 months, and the lead author wrote the book tested and has a financial stake in the company that sells it.
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Effectiveness and treatment moderators of internet interventions for adult problem drinking: An individual patient data meta-analysis of 19 randomised controlled trials — Riper et al., PLoS Med 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6298657/
Individual patient data meta-analysis — 19 randomised trials, 14,198 adults. Moderate evidence. PLoS Med 2018;15(12):e1002714. DOI 10.1371/journal.pmed.1002714. Free full text in PubMed Central (PMC6298657) — open access, CC BY 4.0. Note: Follow-up was mostly only 1–3 months, 43% of participants had no follow-up data, drinking was self-reported, and trials with waiting-list controls showed bigger effects.
What It Found
Pooled the raw data of 14,198 adults (averaging 38 standard units of alcohol a week) from 19 trials of online programmes to cut down drinking. Users drank 5.02 standard units a week less than controls (95% CI 2.48 to 7.57) and had higher odds of ending up within low-risk limits (OR 2.20). Programmes with human support did better than fully automated ones (a further 6.78 units a week less), and people over 55 responded better.
Why It Matters Here
Backs up the online cut-down-drinking self-help in chapter 10, such as Rethinking Drinking (the listed programmes were not tested). Programmes built on therapy techniques kept more people within low-risk limits than feedback alone, and human support, such as a coach or therapist, improved results.
Individual patient data meta-analysis — 19 randomised trials, 14,198 adults. Moderate evidence. PLoS Med 2018;15(12):e1002714. DOI 10.1371/journal.pmed.1002714. Free full text in PubMed Central (PMC6298657) — open access, CC BY 4.0. Note: Follow-up was mostly only 1–3 months, 43% of participants had no follow-up data, drinking was self-reported, and trials with waiting-list controls showed bigger effects.
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Internet-based cognitive and behavioural therapies for post-traumatic stress disorder (PTSD) in adults — Simon et al., Cochrane Database Syst Rev 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8136365/
Cochrane systematic review — 13 randomised trials, 808 adults. Moderate evidence. Cochrane Database Syst Rev 2021;5:CD011710. DOI 10.1002/14651858.CD011710.pub3. Free full text in PubMed Central (PMC8136365). Note: Very low certainty from few, small trials, all with therapist guidance; it says nothing about self-guided apps or books, and face-to-face trauma therapy remains better studied.
What It Found
Reviewed 13 trials (808 adults with PTSD) of internet-delivered CBT, all with therapist guidance. Compared with a waiting list, it reduced PTSD symptoms after treatment (SMD −0.61, 95% CI −0.93 to −0.29; 10 trials, 608 people), but the certainty of evidence was very low. It showed no clear advantage over other internet programmes (2 small trials), and too few trials compared it with face-to-face therapy.
Why It Matters Here
Backs up therapist-guided online trauma courses in chapter 10, such as the THIS WAY UP PTSD course used with a clinician, as a possible start for people who cannot yet reach a trauma therapist. It did not test self-guided tools such as PTSD Coach Online or trauma workbooks.
Cochrane systematic review — 13 randomised trials, 808 adults. Moderate evidence. Cochrane Database Syst Rev 2021;5:CD011710. DOI 10.1002/14651858.CD011710.pub3. Free full text in PubMed Central (PMC8136365). Note: Very low certainty from few, small trials, all with therapist guidance; it says nothing about self-guided apps or books, and face-to-face trauma therapy remains better studied.
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Print-based self-help interventions for smoking cessation — Livingstone-Banks et al., Cochrane Database Syst Rev 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC7112723/
Cochrane systematic review — 75 randomised trials. Strong evidence. Cochrane Database Syst Rev 2019;1:CD001118. DOI 10.1002/14651858.CD001118.pub4. Free full text in PubMed Central (PMC7112723). Note: Gains are modest in absolute terms; the trials tested leaflets and manuals rather than any particular popular book, and all came from high-income countries.
What It Found
Reviewed 75 trials of printed self-help for quitting smoking. Used on their own, standard booklets or manuals increased quitting compared with nothing (RR 1.19, 95% CI 1.03 to 1.37; 11 trials, 13,241 people; moderate certainty), and personalised materials also helped (RR 1.34, 1.20 to 1.49; 12 trials, 19,190 people), though not clearly more than standard materials sent as often. They added no clear benefit on top of a health professional's advice or nicotine replacement.
Why It Matters Here
Backs up written stop-smoking self-help in chapter 10, the format of Allen Carr's Easy Way to Stop Smoking (the book itself was not tested). Most relevant to smokers quitting on their own, without a stop-smoking service or nicotine replacement.
Cochrane systematic review — 75 randomised trials. Strong evidence. Cochrane Database Syst Rev 2019;1:CD001118. DOI 10.1002/14651858.CD001118.pub4. Free full text in PubMed Central (PMC7112723). Note: Gains are modest in absolute terms; the trials tested leaflets and manuals rather than any particular popular book, and all came from high-income countries.
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Effectiveness, reach, uptake, and feasibility of digital health interventions for adults with type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials — Moschonis et al., Lancet Digit Health 2023

https://doi.org/10.1016/S2589-7500(22)00233-3
Systematic review and meta-analysis — 56 randomised trials (11,486 adults); 26 trials (4,546 adults) pooled for HbA1c. Strong evidence. Lancet Digit Health 2023;5(3):e125–e143. Free full text at the publisher — open access, CC BY. Note: Results varied widely between trials (considerable heterogeneity), 46% of trials were at high risk of bias, and the average HbA1c gain is modest; the listed apps were not tested.
What It Found
Reviewed 56 randomised trials of digital programmes for adults with type 2 diabetes. In the 26 trials pooled for blood-glucose control, digital interventions lowered HbA1c by 0.30 percentage points more than control (95% CI 0.19 to 0.42; moderate certainty). Smartphone apps (−0.42) and text messages (−0.37) helped; websites showed no clear benefit.
Why It Matters Here
Backs up the digital programmes for type 2 diabetes in chapter 16, such as the Low Carb Program app (digital programmes in general were tested, not the named apps). Most relevant to adults with type 2 diabetes using an app or text-message programme alongside usual care.
Systematic review and meta-analysis — 56 randomised trials (11,486 adults); 26 trials (4,546 adults) pooled for HbA1c. Strong evidence. Lancet Digit Health 2023;5(3):e125–e143. Free full text at the publisher — open access, CC BY. Note: Results varied widely between trials (considerable heterogeneity), 46% of trials were at high risk of bias, and the average HbA1c gain is modest; the listed apps were not tested.
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Outcomes of a Digitally Delivered Low-Carbohydrate Type 2 Diabetes Self-Management Program: 1-Year Results of a Single-Arm Longitudinal Study — Saslow et al., JMIR Diabetes 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6238840/
Single-arm longitudinal study — 1,000 programme users with type 2 diabetes followed for 1 year. Early evidence. JMIR Diabetes 2018;3(3):e12. DOI 10.2196/diabetes.9333. Free full text in PubMed Central (PMC6238840) — open access, CC BY 4.0. Note: No control group and 12-month results were self-reported, so it shows what users reported, not what the programme caused; one author works for the company that runs it.
What It Found
Followed 1,000 randomly selected UK users of the Low Carb Program for a year; 708 reported 12-month outcomes (non-responders were counted as unchanged). Of those starting with HbA1c of 6.5% or more, 26.2% got below 6.5% while on metformin alone or no glucose-lowering drugs; 40.4% of those on diabetes drugs reduced or stopped at least one; and 46.4% lost at least 5% of body weight. Benefits were largest in people who completed the programme.
Why It Matters Here
Backs up the Low Carb Program app in chapter 16 directly and, more loosely, the free self-guided low-carb programmes in chapter 10 (Freshwell, Public Health Collaboration). For people with type 2 diabetes, ideally with their GP monitoring medicines.
Single-arm longitudinal study — 1,000 programme users with type 2 diabetes followed for 1 year. Early evidence. JMIR Diabetes 2018;3(3):e12. DOI 10.2196/diabetes.9333. Free full text in PubMed Central (PMC6238840) — open access, CC BY 4.0. Note: No control group and 12-month results were self-reported, so it shows what users reported, not what the programme caused; one author works for the company that runs it.
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Depression in adults: treatment and management (NICE guideline NG222) — NICE 2022

https://www.nice.org.uk/guidance/ng222
National clinical guideline based on systematic evidence reviews and network meta-analyses. Strong evidence. NICE guideline NG222, 2022. Free to read on the NICE website. Note: Recommends self-help with practitioner support for less severe depression; it does not endorse reading or apps alone, or self-help as the only treatment for severe depression.
What It Found
England's national guideline for treating depression in adults. For a new episode of less severe depression, its table of treatment options lists guided self-help first: printed or digital materials based on CBT, behavioural activation, problem-solving or psychoeducation, supported by a trained practitioner, usually over 6 to 8 structured sessions in person, by phone or online.
Why It Matters Here
Backs up the kind of CBT self-help books, workbooks and online courses in chapter 10 (Reading Well, CCI workbooks, Mind Over Mood, THIS WAY UP, MindSpot): used with a trained practitioner's support, guided self-help is a first-line option for less severe depression.
National clinical guideline based on systematic evidence reviews and network meta-analyses. Strong evidence. NICE guideline NG222, 2022. Free to read on the NICE website. Note: Recommends self-help with practitioner support for less severe depression; it does not endorse reading or apps alone, or self-help as the only treatment for severe depression.
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Neurodiversity — ADHD, Autism, Dyslexia, Dyspraxia, Dyscalculia & Tics

Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis — Cortese et al., Lancet Psychiatry 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6109107/
Systematic review and network meta-analysis — 133 double-blind randomised trials (10,068 children and adolescents, 8,131 adults in the main analysis). Strong evidence. Lancet Psychiatry 2018;5(9):727–738. DOI 10.1016/S2215-0366(18)30269-4. Free full text in PubMed Central (PMC6109107) — open access, CC BY 4.0. Note: Trials were short (about 12 weeks), with too few data to judge effects at 6–12 months, and the authors rated certainty low or very low for many comparisons.
What It Found
Pooled 133 double-blind trials of seven ADHD medicines. Over about 12 weeks, all seven reduced clinician-rated ADHD symptoms in children and adolescents compared with placebo (methylphenidate SMD −0.78, 95% CI −0.93 to −0.62), and four of the five tested in adults did (amphetamines SMD −0.79, −0.99 to −0.58). Weighing benefit against side-effects, the authors favoured methylphenidate for children and amphetamines for adults as first choices for short-term treatment.
Why It Matters Here
Backs up the ADHD practitioner directories and organisations in chapter 09 (CHADD, ADDA, AADPA, ADHD UK) and the ADHD books and webinars in chapter 10 that explain medication choices: a specialist assessment opens the door to medicines with well-tested short-term benefit.
Systematic review and network meta-analysis — 133 double-blind randomised trials (10,068 children and adolescents, 8,131 adults in the main analysis). Strong evidence. Lancet Psychiatry 2018;5(9):727–738. DOI 10.1016/S2215-0366(18)30269-4. Free full text in PubMed Central (PMC6109107) — open access, CC BY 4.0. Note: Trials were short (about 12 weeks), with too few data to judge effects at 6–12 months, and the authors rated certainty low or very low for many comparisons.
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Cognitive Behavioral Therapy vs Relaxation With Educational Support for Medication-Treated Adults With ADHD and Persistent Symptoms: A Randomized Controlled Trial — Safren et al., JAMA 2010

https://pmc.ncbi.nlm.nih.gov/articles/PMC3641654/
Randomised controlled trial — 86 adults with ADHD already taking medication; 12 individual sessions; follow-up to 12 months. Moderate evidence. JAMA 2010;304(8):875–880. DOI 10.1001/jama.2010.1192. Free full text in PubMed Central (PMC3641654). Note: A single-site trial of 86 adults who were already on medication; results may not carry over to unmedicated adults or routine services.
What It Found
Tested the 12-session CBT programme set out in the authors' 'Mastering Your Adult ADHD' manuals in 86 adults whose symptoms persisted despite medication, against relaxation training with education. More people responded to CBT (53% vs 23% on clinician global ratings; 67% vs 33% on an ADHD rating scale), self-reported symptoms also fell more, and those who responded or partly responded to CBT kept their gains at 6 and 12 months.
Why It Matters Here
Backs up 'Mastering Your Adult ADHD' in chapter 10 directly (the trial used the first-edition programme), the ADHD psychologists and therapists found through the chapter 09 directories (ADDA, AADPA, CHADD) and the therapist directories in chapter 05: structured CBT skills can add to medication for adults.
Randomised controlled trial — 86 adults with ADHD already taking medication; 12 individual sessions; follow-up to 12 months. Moderate evidence. JAMA 2010;304(8):875–880. DOI 10.1001/jama.2010.1192. Free full text in PubMed Central (PMC3641654). Note: A single-site trial of 86 adults who were already on medication; results may not carry over to unmedicated adults or routine services.
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Autism intervention meta-analysis of early childhood studies (Project AIM): updated systematic review and secondary analysis — Sandbank et al., BMJ 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10644209/
Systematic review and meta-analysis — 252 studies (173 randomised; 289 reports) of young autistic children (average age under 8), 13,304 participants. Moderate evidence. BMJ 2023;383:e076733. DOI 10.1136/bmj-2023-076733. Free full text in PubMed Central (PMC10644209) — open access, CC BY-NC 4.0. Note: Most outcomes were at risk of bias (unblinded raters, caregiver reports); only one effect survived every bias check, and adverse events were seldom reported.
What It Found
Reviewed 252 studies of non-drug early support for young autistic children. In randomised trials, naturalistic developmental behavioural interventions (child-led, play-based) improved social communication (g 0.35, 95% CI 0.23 to 0.47), as did developmental approaches (g 0.28). Most effects lost significance in stricter analyses (no caregiver ratings, blinded assessors); harms were rarely monitored, so the authors say families should watch for distress or negative effects.
Why It Matters Here
Backs up the autism service directories and organisations in chapter 09 that families use to find early support (National Autistic Society directory, Autism Society, Autism-Europe): it shows which early supports have some trial evidence, how modest it is, and why to watch for harms.
Systematic review and meta-analysis — 252 studies (173 randomised; 289 reports) of young autistic children (average age under 8), 13,304 participants. Moderate evidence. BMJ 2023;383:e076733. DOI 10.1136/bmj-2023-076733. Free full text in PubMed Central (PMC10644209) — open access, CC BY-NC 4.0. Note: Most outcomes were at risk of bias (unblinded raters, caregiver reports); only one effect survived every bias check, and adverse events were seldom reported.
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Risk markers for suicidality in autistic adults — Cassidy et al., Mol Autism 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6069847/
Cross-sectional survey — 164 autistic adults and 169 general-population adults. Early evidence. Mol Autism 2018;9:42. DOI 10.1186/s13229-018-0226-4. Free full text in PubMed Central (PMC6069847) — open access, CC BY 4.0. Note: A one-off survey of volunteers (self-reported diagnoses, no intellectual disability): it shows associations, not cause and effect.
What It Found
Surveyed 164 autistic and 169 general-population adults. 72% of autistic adults scored at or above the clinical cut-off on a questionnaire about suicidal thoughts and behaviour, against 34% of the comparison group. Among autistic adults, camouflaging (hiding autistic traits to fit in), non-suicidal self-injury and unmet support needs each predicted higher scores after allowing for depression, anxiety and other factors, but each explained only a small extra share (3–4%).
Why It Matters Here
Backs up the autistic-led organisations and communities in chapter 09 (ASAN, Reframing Autism, Wrong Planet) and 'Unmasking Autism' and the AASPIRE toolkit in chapter 10: lowering the pressure to mask and meeting support needs are plausible protective targets.
Cross-sectional survey — 164 autistic adults and 169 general-population adults. Early evidence. Mol Autism 2018;9:42. DOI 10.1186/s13229-018-0226-4. Free full text in PubMed Central (PMC6069847) — open access, CC BY 4.0. Note: A one-off survey of volunteers (self-reported diagnoses, no intellectual disability): it shows associations, not cause and effect.
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Experiences of Autism Acceptance and Mental Health in Autistic Adults — Cage et al., J Autism Dev Disord 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC5807490/
Cross-sectional online survey — 111 autistic adults (UK). Early evidence. J Autism Dev Disord 2018;48(2):473–484. DOI 10.1007/s10803-017-3342-7. Free full text in PubMed Central (PMC5807490) — open access, CC BY 4.0. Note: A small, self-selected, mostly female online survey using new single-item acceptance ratings; it shows associations, not cause and effect.
What It Found
Surveyed 111 autistic adults in the UK about how far they felt accepted by society, by family and friends, and by themselves. Feeling accepted by others and accepting oneself both predicted lower depression; adding acceptance raised the explained variation in depression from 34.6% to 52.1%. Acceptance by others was also linked to lower stress, but acceptance did not predict anxiety. The 27 people who mentioned camouflaging reported more depression and felt less accepted.
Why It Matters Here
Backs up the autistic-led and neurodiversity-affirming organisations, communities and practitioner directories in chapter 09 (ASAN, Reframing Autism, Neurodivergent Practitioners) and 'Unmasking Autism' in chapter 10: feeling accepted, and accepting oneself, go with better mental health.
Cross-sectional online survey — 111 autistic adults (UK). Early evidence. J Autism Dev Disord 2018;48(2):473–484. DOI 10.1007/s10803-017-3342-7. Free full text in PubMed Central (PMC5807490) — open access, CC BY 4.0. Note: A small, self-selected, mostly female online survey using new single-item acceptance ratings; it shows associations, not cause and effect.
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The Development and Evaluation of an Online Healthcare Toolkit for Autistic Adults and their Primary Care Providers — Nicolaidis et al., J Gen Intern Med 2016

https://pmc.ncbi.nlm.nih.gov/articles/PMC5023610/
Community-based participatory development and single-group pre/post evaluation — 259 autistic adults and 51 primary care providers in all (evaluation: 170 adults, 41 providers). Early evidence. J Gen Intern Med 2016;31(10):1180–1189. DOI 10.1007/s11606-016-3763-6. Free full text in PubMed Central (PMC5023610). Note: No control group, a one-month follow-up and a self-selected US sample, so the improvements cannot be firmly credited to the toolkit.
What It Found
Autistic adults and researchers built the AASPIRE Healthcare Toolkit as equal partners; 259 autistic adults and 51 primary care providers helped develop and test it. Over 94% of autistic users found it easy to use, important and useful; 82% of responding providers rated its accommodations report useful. A month later, average barriers to care fell from 4.07 to 2.82, with small gains in healthcare self-efficacy and, for those who saw their provider, communication satisfaction.
Why It Matters Here
Backs up the AASPIRE Healthcare Toolkit in chapter 10 directly, and the autistic-led organisations and neurodiversity-affirming practitioner directories in chapter 09 that help people ask for healthcare adjustments.
Community-based participatory development and single-group pre/post evaluation — 259 autistic adults and 51 primary care providers in all (evaluation: 170 adults, 41 providers). Early evidence. J Gen Intern Med 2016;31(10):1180–1189. DOI 10.1007/s11606-016-3763-6. Free full text in PubMed Central (PMC5023610). Note: No control group, a one-month follow-up and a self-selected US sample, so the improvements cannot be firmly credited to the toolkit.
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Effectiveness of Treatment Approaches for Children and Adolescents with Reading Disabilities: A Meta-Analysis of Randomized Controlled Trials — Galuschka et al., PLoS ONE 2014

https://pmc.ncbi.nlm.nih.gov/articles/PMC3935956/
Meta-analysis of 22 randomised controlled trials (49 comparisons; 1,138 children in intervention and 764 in control groups). Moderate evidence. PLoS ONE 2014;9(2):e89900. DOI 10.1371/journal.pone.0089900. Free full text in PubMed Central (PMC3935956) — open access, CC BY. Note: The phonics effect was small, shrank further after allowing for likely publication bias, and few trials blinded their assessors.
What It Found
Pooled 22 randomised trials of help for children and teenagers with reading disabilities (dyslexia). Systematic phonics instruction, explicitly teaching letter–sound links and how to blend them, was the only approach with a statistically confirmed benefit for reading and spelling (reading g′ 0.32, 95% CI 0.18 to 0.47). Other approaches tested, such as reading-fluency training, auditory training and coloured overlays, did not show significant effects.
Why It Matters Here
Backs up the dyslexia tutor and assessor directories in chapter 09 (British Dyslexia Association, PATOSS, International Dyslexia Association) and 'Overcoming Dyslexia' in chapter 10, which explains dyslexia as a difficulty with the sounds of words: structured, phonics-based teaching is the approach with trial evidence.
Meta-analysis of 22 randomised controlled trials (49 comparisons; 1,138 children in intervention and 764 in control groups). Moderate evidence. PLoS ONE 2014;9(2):e89900. DOI 10.1371/journal.pone.0089900. Free full text in PubMed Central (PMC3935956) — open access, CC BY. Note: The phonics effect was small, shrank further after allowing for likely publication bias, and few trials blinded their assessors.
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International clinical practice recommendations on the definition, diagnosis, assessment, intervention, and psychosocial aspects of developmental coordination disorder — Blank et al., Dev Med Child Neurol 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6850610/
International clinical practice recommendations (European Academy of Childhood Disability) — literature reviews plus formal expert consensus (Delphi). Moderate evidence. Dev Med Child Neurol 2019;61(3):242–285. DOI 10.1111/dmcn.14132. Free full text in PubMed Central (PMC6850610) — open access, CC BY-NC-ND 4.0. Note: Only 8 of the 35 recommendations rest directly on research evidence (the rest are expert consensus), and the authors set them to be revised by the end of 2022.
What It Found
An international panel convened by the European Academy of Childhood Disability agreed 35 recommendations on defining, diagnosing, assessing and treating developmental coordination disorder (dyspraxia), including the first international advice for adolescents and adults. Its top grade (level A) goes to activity- and participation-oriented therapy such as task-specific training or the CO-OP approach; sensory integration therapy is not recommended (evidence inconclusive).
Why It Matters Here
Backs up the dyspraxia/DCD organisations and support groups in chapter 09 (Dyspraxia Foundation, CanChild, DCD Australia, EACD) and 'Caged in Chaos' in chapter 10: DCD is a recognised condition, in adults as well as children, with agreed assessment and therapy pathways.
International clinical practice recommendations (European Academy of Childhood Disability) — literature reviews plus formal expert consensus (Delphi). Moderate evidence. Dev Med Child Neurol 2019;61(3):242–285. DOI 10.1111/dmcn.14132. Free full text in PubMed Central (PMC6850610) — open access, CC BY-NC-ND 4.0. Note: Only 8 of the 35 recommendations rest directly on research evidence (the rest are expert consensus), and the authors set them to be revised by the end of 2022.
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The Diagnosis and Treatment of Dyscalculia — Haberstroh & Schulte-Körne, Dtsch Arztebl Int 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6440373/
Systematic review and meta-analysis underpinning the German S3 clinical practice guideline (20 professional societies). Moderate evidence. Dtsch Arztebl Int 2019;116(7):107–114. DOI 10.3238/arztebl.2019.0107. Free full text in PubMed Central (PMC6440373). Note: High-quality trials are few, and there is little evidence or suitable programmes for older teenagers and adults.
What It Found
Summarises the German evidence-based (S3) guideline on dyscalculia, agreed by 20 professional societies and built on a systematic review and meta-analysis. Across intervention studies, maths support had a moderate average effect (g 0.52, 95% CI 0.42 to 0.62). Training aimed at the specific maths content a child finds hard worked best; group sessions were less effective than one-to-one, and the authors advise starting early in primary school with trained specialists.
Why It Matters Here
Backs up the dyscalculia assessor and tutor directories in chapter 09 (Dyscalculia Network, BDA dyscalculia accreditation) and the content-focused teaching approach of 'The Dyscalculia Toolkit' in chapter 10: specialist, individual, content-focused teaching has the best evidence.
Systematic review and meta-analysis underpinning the German S3 clinical practice guideline (20 professional societies). Moderate evidence. Dtsch Arztebl Int 2019;116(7):107–114. DOI 10.3238/arztebl.2019.0107. Free full text in PubMed Central (PMC6440373). Note: High-quality trials are few, and there is little evidence or suitable programmes for older teenagers and adults.
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European clinical guidelines for Tourette syndrome and other tic disorders—version 2.0. Part II: psychological interventions — Andrén et al., Eur Child Adolesc Psychiatry 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC8314030/
Clinical practice guideline (European Society for the Study of Tourette Syndrome) — systematic literature search to May 2021, narrative review and expert consensus. Strong evidence. Eur Child Adolesc Psychiatry 2022;31(3):403–423. DOI 10.1007/s00787-021-01845-z. Free full text in PubMed Central (PMC8314030) — open access, CC BY 4.0. Note: Exposure and response prevention rests on one randomised trial and group or internet formats on a few small studies; even for HRT/CBIT, effects were medium-sized.
What It Found
The European Society for the Study of Tourette Syndrome's updated guideline on psychological treatment. It advises psychoeducation for everyone first, then behavioural therapy as first-line treatment for children and adults whose tics need it: habit reversal training (HRT, the core of CBIT) or exposure and response prevention. HRT/CBIT has the strongest evidence; cognitive and third-wave therapies are not advised on their own.
Why It Matters Here
Backs up the Tourette organisations and provider directories in chapter 09 (Tourette Association of America, Tourettes Action, Tourette Canada), which offer psychoeducation and routes to behavioural therapy, and the CBIT workbook 'Managing Tourette Syndrome' in chapter 10.
Clinical practice guideline (European Society for the Study of Tourette Syndrome) — systematic literature search to May 2021, narrative review and expert consensus. Strong evidence. Eur Child Adolesc Psychiatry 2022;31(3):403–423. DOI 10.1007/s00787-021-01845-z. Free full text in PubMed Central (PMC8314030) — open access, CC BY 4.0. Note: Exposure and response prevention rests on one randomised trial and group or internet formats on a few small studies; even for HRT/CBIT, effects were medium-sized.
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Autistic peer-to-peer information transfer is highly effective — Crompton et al., Autism 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7545656/
Experimental study (diffusion-chain design) — 72 adults in autistic, non-autistic and mixed chains. Early evidence. Autism 2020;24(7):1704–1712. DOI 10.1177/1362361320919286. Free full text in PubMed Central (PMC7545656) — open access, CC BY-NC 4.0. Note: A small laboratory experiment with one storytelling task, in which participants knew each other's diagnosis; it does not measure therapy or support outcomes.
What It Found
72 adults passed a story along chains of eight people that were all autistic, all non-autistic, or mixed. Autistic chains passed on details as well as non-autistic chains did; detail was lost faster only in mixed chains, where people also rated rapport lower. The authors read this as a mismatch between autistic and non-autistic communication styles (the 'double empathy' idea) rather than an autistic deficit.
Why It Matters Here
Backs up the neurodivergent-led practitioner directories in chapter 09 (Neurodivergent Practitioners, Neurodivergent Therapists) and autistic peer communities such as Wrong Planet: autistic people can share information and build rapport with each other as well as non-autistic people do.
Experimental study (diffusion-chain design) — 72 adults in autistic, non-autistic and mixed chains. Early evidence. Autism 2020;24(7):1704–1712. DOI 10.1177/1362361320919286. Free full text in PubMed Central (PMC7545656) — open access, CC BY-NC 4.0. Note: A small laboratory experiment with one storytelling task, in which participants knew each other's diagnosis; it does not measure therapy or support outcomes.
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Attention deficit hyperactivity disorder: diagnosis and management (NICE guideline NG87) — NICE 2018

https://www.nice.org.uk/guidance/ng87
National clinical guideline based on systematic evidence reviews and committee consensus. Strong evidence. NICE NG87, published 14 March 2018, last updated 13 September 2019. Free to read on the NICE website. Note: Written for the NHS in England; services, waiting times and medicine approvals differ in other countries.
What It Found
England's guideline on recognising, diagnosing and supporting ADHD in children, young people and adults. Diagnosis should be made by a specialist with ADHD training. It recommends adjustments to the person's surroundings first, ADHD-focused group parent training for children under 5, medication when symptoms still cause significant problems, and psychological support for adults who prefer not to take medication or still struggle on it.
Why It Matters Here
Backs up the ADHD practitioner directories in chapter 09 (diagnosis by a clinician with ADHD expertise), the ADHD organisations and support groups there (NICE advises telling people about them) and the ADHD information and CBT books in chapter 10. Relevant to people seeking an ADHD assessment and to families.
National clinical guideline based on systematic evidence reviews and committee consensus. Strong evidence. NICE NG87, published 14 March 2018, last updated 13 September 2019. Free to read on the NICE website. Note: Written for the NHS in England; services, waiting times and medicine approvals differ in other countries.
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The World Federation of ADHD International Consensus Statement: 208 Evidence-based Conclusions about the Disorder — Faraone et al., Neurosci Biobehav Rev 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8328933/
International consensus statement built only from meta-analyses or studies of 2,000+ people. Strong evidence. Neurosci Biobehav Rev 2021;128:789–818. DOI 10.1016/j.neubiorev.2021.01.022. Free full text in PubMed Central (PMC8328933) — open access, CC BY. Note: A summary of existing evidence rather than new research or a treatment guideline; several authors report links with ADHD medicine makers, as disclosed in the paper.
What It Found
To counter misconceptions that stigmatise ADHD and delay treatment, the authors kept only strong evidence (large studies and meta-analyses that checked for publication bias) and turned it into 208 statements about how common ADHD is, its causes, course, outcomes and treatments. The statements were approved by 80 authors from 27 countries and endorsed by 403 more readers.
Why It Matters Here
Backs up the ADHD organisations and advocacy groups in chapter 09 and the ADHD books in chapter 10: it is a well-sourced reference for explaining that ADHD is a real, treatable condition across the lifespan.
International consensus statement built only from meta-analyses or studies of 2,000+ people. Strong evidence. Neurosci Biobehav Rev 2021;128:789–818. DOI 10.1016/j.neubiorev.2021.01.022. Free full text in PubMed Central (PMC8328933) — open access, CC BY. Note: A summary of existing evidence rather than new research or a treatment guideline; several authors report links with ADHD medicine makers, as disclosed in the paper.
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Gut Health & the Gut–Brain Axis

Efficacy of a low-FODMAP diet in adult irritable bowel syndrome: a systematic review and meta-analysis — van Lanen et al., Eur J Nutr 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8354978/
Systematic review and meta-analysis — 12 controlled intervention studies (9 parallel, 3 crossover), 772 adults with IBS. Moderate evidence. Eur J Nutr 2021;60(6):3505–3522. DOI 10.1007/s00394-020-02473-0. Free full text in PubMed Central (PMC8354978) — open access, CC BY 4.0. Note: Trials were small, lasted 3 months at most and were hard to blind, with signs of publication bias; the review was funded by Unilever, where the authors worked.
What It Found
Pooled 12 controlled studies (772 adults with IBS) comparing a low-FODMAP diet with other diets. The low-FODMAP diet reduced overall IBS symptom severity (standardised mean difference −0.66, 95% CI −0.88 to −0.44), lowered the IBS Symptom Severity Score by about 45 points in the studies that used it, and improved IBS-specific quality of life (mean difference 4.93 points, 95% CI 1.77 to 8.08).
Why It Matters Here
Backs up the low-FODMAP diet taught by the FODMAP-trained dietitians in chapter 15 (Monash University and King's College London directories) and the national dietitian finders there; most relevant to adults with IBS thinking about a supervised low-FODMAP diet.
Systematic review and meta-analysis — 12 controlled intervention studies (9 parallel, 3 crossover), 772 adults with IBS. Moderate evidence. Eur J Nutr 2021;60(6):3505–3522. DOI 10.1007/s00394-020-02473-0. Free full text in PubMed Central (PMC8354978) — open access, CC BY 4.0. Note: Trials were small, lasted 3 months at most and were hard to blind, with signs of publication bias; the review was funded by Unilever, where the authors worked.
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Functional bowel disorders with diarrhoea: Clinical guidelines of the United European Gastroenterology and European Society for Neurogastroenterology and Motility — Savarino et al., United European Gastroenterol J 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9278595/
European clinical guideline — GRADE-assessed evidence review and Delphi consensus of 30 experts from 10 countries (31 statements). Moderate evidence. United European Gastroenterol J 2022;10(6):556–584. DOI 10.1002/ueg2.12259. Free full text in PubMed Central (PMC9278595) — open access, CC BY-NC-ND 4.0. Note: Covers diarrhoea-predominant IBS only; the diet, psychological-therapy, probiotic and FMT recommendations all rest on low-quality evidence.
What It Found
Europe's gastroenterology societies graded the evidence for diarrhoea-predominant IBS. They strongly recommend gut-directed psychological therapies (low-quality evidence, 89% agreement) and short-term use of a low-FODMAP diet when other measures fail (strong, low quality, 100%), conditionally support some probiotics (93%), and recommend against a gluten-free diet and against faecal microbiota transplant for IBS.
Why It Matters Here
Backs up the gastroenterologist finders, FODMAP-trained dietitians and GI psychologist directory in chapter 15, and supports the directory's message that FMT is for recurrent C. difficile, not IBS; most relevant to people with IBS-D and their clinicians.
European clinical guideline — GRADE-assessed evidence review and Delphi consensus of 30 experts from 10 countries (31 statements). Moderate evidence. United European Gastroenterol J 2022;10(6):556–584. DOI 10.1002/ueg2.12259. Free full text in PubMed Central (PMC9278595) — open access, CC BY-NC-ND 4.0. Note: Covers diarrhoea-predominant IBS only; the diet, psychological-therapy, probiotic and FMT recommendations all rest on low-quality evidence.
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Assessing telephone-delivered cognitive–behavioural therapy (CBT) and web-delivered CBT versus treatment as usual in irritable bowel syndrome (ACTIB): a multicentre randomised trial — Everitt et al., Gut 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6709776/
Multicentre randomised controlled trial — 558 adults with refractory IBS, three arms, 12-month follow-up. Moderate evidence. Gut 2019;68(9):1613–1623. DOI 10.1136/gutjnl-2018-317805. Free full text in PubMed Central (PMC6709776) — open access, CC BY-NC 4.0. Note: A single trial in which participants and therapists could not be blinded; 30% did not complete 12-month follow-up.
What It Found
558 UK adults whose IBS had not improved with first-line treatment were randomised to telephone CBT, web-based CBT with minimal therapist support, or usual care. At 12 months symptom scores (IBS-SSS) were 61.6 points lower with telephone CBT (95% CI 33.8 to 89.5) and 35.2 points lower with web CBT (95% CI 12.6 to 57.8) than with usual care; work and social functioning also improved, with no serious adverse reactions.
Why It Matters Here
Backs up the GI psychologists in chapter 15 (Rome Foundation GastroPsych directory) and CBT therapists found through chapter 05, and shows IBS-specific CBT can work by phone or online; most relevant to adults with long-standing IBS who cannot easily attend face-to-face therapy.
Multicentre randomised controlled trial — 558 adults with refractory IBS, three arms, 12-month follow-up. Moderate evidence. Gut 2019;68(9):1613–1623. DOI 10.1136/gutjnl-2018-317805. Free full text in PubMed Central (PMC6709776) — open access, CC BY-NC 4.0. Note: A single trial in which participants and therapists could not be blinded; 30% did not complete 12-month follow-up.
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Improvement in Gastrointestinal Symptoms After Cognitive Behavior Therapy for Refractory Irritable Bowel Syndrome — Lackner et al., Gastroenterology 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6035059/
Randomised controlled trial (IBSOS) — 436 adults with refractory IBS at two US centres, three arms, 6-month follow-up. Moderate evidence. Gastroenterology 2018;155(1):47–57. DOI 10.1053/j.gastro.2018.03.063. Free full text in PubMed Central (PMC6035059). Note: All three groups, education included, improved similarly on the IBS symptom severity score; CBT's advantage was in global improvement ratings. Mostly white women at two US centres.
What It Found
436 adults with IBS were randomised to 10 sessions of standard CBT, 4 sessions of mostly home-based CBT, or 4 sessions of IBS education. Two weeks after treatment 61.0% of the home-based CBT group rated their gut symptoms moderately or substantially improved versus 43.5% with education; at 6 months gastroenterologists rated 58.4% versus 44.8% as improved. Home-based CBT was at least as effective as the longer clinic-based course.
Why It Matters Here
Backs up the GI psychologists in chapter 15 (Rome Foundation GastroPsych directory) and CBT therapists found through chapter 05; most relevant to people with IBS who want a shorter, mainly home-based course of CBT using a workbook.
Randomised controlled trial (IBSOS) — 436 adults with refractory IBS at two US centres, three arms, 6-month follow-up. Moderate evidence. Gastroenterology 2018;155(1):47–57. DOI 10.1053/j.gastro.2018.03.063. Free full text in PubMed Central (PMC6035059). Note: All three groups, education included, improved similarly on the IBS symptom severity score; CBT's advantage was in global improvement ratings. Mostly white women at two US centres.
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The Efficacy of Hypnotherapy in the Treatment of Irritable Bowel Syndrome: A Systematic Review and Meta-analysis — Lee et al., J Neurogastroenterol Motil 2014

https://pmc.ncbi.nlm.nih.gov/articles/PMC4015203/
Systematic review and meta-analysis — 7 randomised trials, 374 people with IBS. Moderate evidence. J Neurogastroenterol Motil 2014;20(2):152–162. DOI 10.5056/jnm.2014.20.2.152. Free full text in PubMed Central (PMC4015203) — open access, CC BY-NC 3.0. Note: Few, small trials (all before 2014) that could not be blinded, with large differences between them; long-term benefit is uncertain.
What It Found
Pooled 7 randomised trials (374 people whose IBS had not responded to usual care) comparing hypnotherapy with conventional treatment or no treatment. At 3 months hypnotherapy reduced abdominal pain more than control (standardised mean difference −0.83, 95% CI −1.65 to −0.01), and 3 of 4 trials found greater improvement in overall gut symptoms; the effect at one year was not statistically clear.
Why It Matters Here
Backs up the psychogastroenterology clinicians in chapter 15 (Rome Foundation GastroPsych directory) and therapists found through the chapter 05 directories who offer gut-directed hypnotherapy; most relevant to people with persistent IBS interested in it.
Systematic review and meta-analysis — 7 randomised trials, 374 people with IBS. Moderate evidence. J Neurogastroenterol Motil 2014;20(2):152–162. DOI 10.5056/jnm.2014.20.2.152. Free full text in PubMed Central (PMC4015203) — open access, CC BY-NC 3.0. Note: Few, small trials (all before 2014) that could not be blinded, with large differences between them; long-term benefit is uncertain.
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Fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile (Clostridium difficile) — Minkoff et al., Cochrane Database Syst Rev 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10125800/
Cochrane systematic review and meta-analysis — 6 randomised trials, 320 adults. Strong evidence. Cochrane Database Syst Rev 2023;(4):CD013871. DOI 10.1002/14651858.CD013871.pub2. Free full text in PubMed Central (PMC10125800). Note: Only six trials; findings apply to adults with healthy immune systems, and the authors say registry data are needed on longer-term safety.
What It Found
Six randomised trials (320 adults) compared faecal microbiota transplant (FMT) with other treatments, mostly antibiotics, for recurrent C. difficile infection. FMT likely leads to a large increase in resolution of the infection (risk ratio 1.92, 95% CI 1.36 to 2.71; number needed to treat 3; moderate-certainty evidence). Serious adverse events and deaths were too few to judge safety with confidence.
Why It Matters Here
Backs up the regulated FMT services and guidance in chapter 15 (Birmingham Microbiome Treatment Centre, NICE, TGA), the AGA FMT registry in chapter 01 and the C. diff advocacy and FMT research charities in chapter 16; most relevant to people with recurring C. difficile.
Cochrane systematic review and meta-analysis — 6 randomised trials, 320 adults. Strong evidence. Cochrane Database Syst Rev 2023;(4):CD013871. DOI 10.1002/14651858.CD013871.pub2. Free full text in PubMed Central (PMC10125800). Note: Only six trials; findings apply to adults with healthy immune systems, and the authors say registry data are needed on longer-term safety.
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International consensus conference on stool banking for faecal microbiota transplantation in clinical practice — Cammarota et al., Gut 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6872442/
International consensus statement — 29 experts from Europe, North America and Australia; Delphi process, 40 statements (17 GRADE-assessed). Moderate evidence. Gut 2019;68(12):2111–2121. DOI 10.1136/gutjnl-2019-319548. Free full text in PubMed Central (PMC6872442) — open access, CC BY-NC 4.0. Note: About safety and organisation rather than effectiveness; 23 of the 40 statements rest on expert opinion, and regulation differs by country.
What It Found
Experts agreed how stool banks should run so that FMT is safe, traceable and widely available: healthy donors not chosen by the patient, who pass a health questionnaire plus blood and stool tests (repeated every 8–12 weeks), approval by national regulators, supply through doctors rather than direct to patients, donor and recipient records kept for at least 10 years, and registries to track side effects.
Why It Matters Here
Backs up the regulated FMT programmes and regulator pages in chapter 15 (Birmingham Microbiome Treatment Centre, TGA) and gives a checklist for judging clinics found through the FMT directory in chapter 01; relevant to patients and clinicians.
International consensus statement — 29 experts from Europe, North America and Australia; Delphi process, 40 statements (17 GRADE-assessed). Moderate evidence. Gut 2019;68(12):2111–2121. DOI 10.1136/gutjnl-2019-319548. Free full text in PubMed Central (PMC6872442) — open access, CC BY-NC 4.0. Note: About safety and organisation rather than effectiveness; 23 of the 40 statements rest on expert opinion, and regulation differs by country.
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Fecal Microbiota Transplantation Is Highly Effective in Real-World Practice: Initial Results From the FMT National Registry — Kelly et al., Gastroenterology 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8034505/
Prospective observational registry — 259 people treated with FMT for C. difficile at 20 North American sites. Early evidence. Gastroenterology 2021;160(1):183–192.e3. DOI 10.1053/j.gastro.2020.09.038. Free full text in PubMed Central (PMC8034505). Note: Observational with no comparison group; many people were lost to follow-up and the sites were larger centres with an interest in FMT.
What It Found
First results from the AGA-led FMT National Registry: of 259 people given FMT for C. difficile at 20 sites, 90% of those followed for one month had resolution, 98% of them after a single FMT, and 4% of those initially resolved who were followed to six months had a recurrence. Hospital admission possibly related to FMT occurred in 1%, and new IBS or IBD was diagnosed in 1% each by six months.
Why It Matters Here
Backs up the AGA FMT National Registry listed in chapter 01 and the regulated FMT services in chapter 15; most relevant to people weighing FMT for recurrent C. difficile who want real-world results alongside trial data.
Prospective observational registry — 259 people treated with FMT for C. difficile at 20 North American sites. Early evidence. Gastroenterology 2021;160(1):183–192.e3. DOI 10.1053/j.gastro.2020.09.038. Free full text in PubMed Central (PMC8034505). Note: Observational with no comparison group; many people were lost to follow-up and the sites were larger centres with an interest in FMT.
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Probiotics for the prevention of pediatric antibiotic-associated diarrhea — Guo et al., Cochrane Database Syst Rev 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6490796/
Cochrane systematic review and meta-analysis — 33 randomised trials, 6,352 children. Strong evidence. Cochrane Database Syst Rev 2019;(4):CD004827. DOI 10.1002/14651858.CD004827.pub5. Free full text in PubMed Central (PMC6490796). Note: 20 of 33 trials had high risk of bias; serious harms have been reported outside trials in very ill or immunocompromised children.
What It Found
Across 33 trials (6,352 children taking antibiotics), probiotics reduced antibiotic-associated diarrhoea from 19% to 8% (risk ratio 0.45, 95% CI 0.36 to 0.56; number needed to treat 9; moderate-certainty evidence). Benefit looked larger with higher-dose products such as Lactobacillus rhamnosus or Saccharomyces boulardii, which the authors say needs confirming; no serious adverse events were attributed to probiotics.
Why It Matters Here
Backs up the evidence-graded probiotic guides in chapter 15 (ISAPP, Clinical Guide to Probiotic Products, NIH fact sheet, WGO guideline), which stress that benefit depends on the specific product and situation; most relevant to parents and clinicians.
Cochrane systematic review and meta-analysis — 33 randomised trials, 6,352 children. Strong evidence. Cochrane Database Syst Rev 2019;(4):CD004827. DOI 10.1002/14651858.CD004827.pub5. Free full text in PubMed Central (PMC6490796). Note: 20 of 33 trials had high risk of bias; serious harms have been reported outside trials in very ill or immunocompromised children.
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The 2026 British Society of Gastroenterology guidelines on the diagnosis and management of adult coeliac disease — Penny et al., Gut 2026

https://doi.org/10.1136/gutjnl-2025-337747
National clinical guideline — multidisciplinary panel from the UK, Sweden, Italy and Australia; 15 GRADE-assessed recommendations, 19 good-practice statements and 6 expert opinions, each voted on by a consensus group. Moderate evidence. Gut 2026 (published online 9 July 2026). Free full text at the publisher — open access, CC BY-NC 4.0. Note: Several key recommendations, including the life-long gluten-free diet, rest on low-certainty evidence; it covers adults only, and the no-biopsy route is optional.
What It Found
The British Society of Gastroenterology's updated guideline for adults with coeliac disease recommends a life-long gluten-free diet to improve symptoms and quality of life and reduce complications (strong recommendation, low-certainty evidence), signposting people at diagnosis to an established advocacy group such as Coeliac UK, and regular follow-up for up to 2 years. Adults with very high tTG antibody levels may be diagnosed without a biopsy after shared decision-making.
Why It Matters Here
Backs up the coeliac charities and local groups in chapter 15 (Coeliac UK, Coeliac Australia, AOECS societies), which it advises pointing people to at diagnosis, and the coeliac practitioner finder; most relevant to adults newly diagnosed with coeliac disease.
National clinical guideline — multidisciplinary panel from the UK, Sweden, Italy and Australia; 15 GRADE-assessed recommendations, 19 good-practice statements and 6 expert opinions, each voted on by a consensus group. Moderate evidence. Gut 2026 (published online 9 July 2026). Free full text at the publisher — open access, CC BY-NC 4.0. Note: Several key recommendations, including the life-long gluten-free diet, rest on low-certainty evidence; it covers adults only, and the no-biopsy route is optional.
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Consensus standards of healthcare for adults and children with inflammatory bowel disease in the UK — Kapasi et al., Frontline Gastroenterol 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7223296/
National consensus standards — modified Delphi (3 rounds, 28 voters) informed by a survey of 151 professionals and 689 patients; 59 statements. Moderate evidence. Frontline Gastroenterol 2020;11(3):178–187 (online 2019). DOI 10.1136/flgastro-2019-101260. Free full text in PubMed Central (PMC7223296) — open access, CC BY-NC 4.0. Note: Expert and patient consensus, not trial evidence; led and funded by Crohn's & Colitis UK, which is listed in the directory.
What It Found
IBD UK, an alliance of patient and professional organisations, agreed 59 standards of care through a Delphi process informed by 689 patients and 151 professionals. They include that newly diagnosed people be signposted to patient organisations and be able to see a psychologist and specialist dietitian when needed, and that patients get clear information for self-managing flares and a telephone/email advice line.
Why It Matters Here
Backs up the IBD charities' information hubs, local networks and support groups in chapter 15 and the IBD support groups in chapter 06; most relevant to people with Crohn's or colitis, and families, checking what good care should include.
National consensus standards — modified Delphi (3 rounds, 28 voters) informed by a survey of 151 professionals and 689 patients; 59 statements. Moderate evidence. Frontline Gastroenterol 2020;11(3):178–187 (online 2019). DOI 10.1136/flgastro-2019-101260. Free full text in PubMed Central (PMC7223296) — open access, CC BY-NC 4.0. Note: Expert and patient consensus, not trial evidence; led and funded by Crohn's & Colitis UK, which is listed in the directory.
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The Microbiota-Gut-Brain Axis: From Motility to Mood — Margolis et al., Gastroenterology 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8634751/
Narrative review of mechanistic, animal and human studies. Early evidence. Gastroenterology 2021;160(5):1486–1501. DOI 10.1053/j.gastro.2020.10.066. Free full text in PubMed Central (PMC8634751). Note: Narrative review of mostly animal and early human research; it explains possible mechanisms but does not show that any gut–brain treatment works.
What It Found
Three gut–brain researchers explain how the gut, its microbes and the brain signal to each other (vagus nerve, immune system, microbial metabolites, serotonin) and how this may relate to IBS and depression. They stress that the best-studied pathways come largely from animal models, that a causal role for the microbiome 'remains to be determined', and that clinically significant effects of probiotics for psychiatric disorders have not been shown.
Why It Matters Here
Backs up the gut–brain science listings in chapter 15 (Rome Foundation, APC Microbiome Ireland, Gut Microbiota for Health) and gives context for food-and-mood resources in chapter 10; useful for anyone wanting an honest picture of what is and is not yet known.
Narrative review of mechanistic, animal and human studies. Early evidence. Gastroenterology 2021;160(5):1486–1501. DOI 10.1053/j.gastro.2020.10.066. Free full text in PubMed Central (PMC8634751). Note: Narrative review of mostly animal and early human research; it explains possible mechanisms but does not show that any gut–brain treatment works.
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Metabolic Therapies — Fasting, Formula Diets, Ketogenic Therapy, Exercise, Surgery & Medicines

Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials — Patikorn et al., BMC Med 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10210275/
Umbrella review — 17 meta-analyses covering 68 randomised trials, re-analysed and graded with GRADE. Moderate evidence. BMC Med 2023;21:196. DOI 10.1186/s12916-023-02874-y. Free full text in PubMed Central (PMC10210275) — open access, CC BY 4.0. Note: Most trials were small and short (median 42 people, 13 weeks); whether these changes mean fewer heart attacks or longer life is unknown.
What It Found
Re-analysed and graded 17 published meta-analyses of randomised trials of ketogenic diets. High-quality evidence showed about five times as many children with drug-resistant epilepsy cutting their seizures by at least half, and, in adults with type 2 diabetes, lower triglycerides but higher LDL cholesterol. Moderate-quality evidence showed lower body weight and HbA1c. Most of the 115 effects examined rested on low or very low quality evidence.
Why It Matters Here
Backs up the ketogenic and low-carb practitioners in chapter 01, the keto communities in chapter 14 and keto books and guides in chapter 10, while showing the trade-off: weight, blood sugar and triglycerides improved, but LDL cholesterol rose by an amount the authors judged clinically meaningful.
Umbrella review — 17 meta-analyses covering 68 randomised trials, re-analysed and graded with GRADE. Moderate evidence. BMC Med 2023;21:196. DOI 10.1186/s12916-023-02874-y. Free full text in PubMed Central (PMC10210275) — open access, CC BY 4.0. Note: Most trials were small and short (median 42 people, 13 weeks); whether these changes mean fewer heart attacks or longer life is unknown.
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The use of ketogenic diets in cancer patients: a systematic review — Römer et al., Clin Exp Med 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8505380/
Systematic review — 39 studies, 770 people with cancer (3 randomised trials, 2 controlled studies, the rest single-arm studies and case reports). Early evidence. Clin Exp Med 2021;21(4):501–536. DOI 10.1007/s10238-021-00710-2. Free full text in PubMed Central (PMC8505380) — open access, CC BY 4.0. Note: Search ended in 2019; most studies were small, uncontrolled and at high risk of bias, so neither benefits nor harms are well measured.
What It Found
Gathered the clinical studies of ketogenic diets in people with cancer published up to April 2019. There was no conclusive evidence that the diet slows tumours or lengthens survival. Most patients lost a significant amount of weight and had mild to moderate side effects, and in the uncontrolled studies that measured it only 60% kept to the diet. The authors conclude that clinical evidence of benefit is still lacking.
Why It Matters Here
Explains the state of evidence on ketogenic diets for cancer, relevant to keto communities that mention cancer (Ketogenic Diet India, chapter 14) and keto practitioners in chapter 01: it is a research question, not an established cancer treatment.
Systematic review — 39 studies, 770 people with cancer (3 randomised trials, 2 controlled studies, the rest single-arm studies and case reports). Early evidence. Clin Exp Med 2021;21(4):501–536. DOI 10.1007/s10238-021-00710-2. Free full text in PubMed Central (PMC8505380) — open access, CC BY 4.0. Note: Search ended in 2019; most studies were small, uncontrolled and at high risk of bias, so neither benefits nor harms are well measured.
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Comparison of seven popular structured dietary programmes and risk of mortality and major cardiovascular events in patients at increased cardiovascular risk: systematic review and network meta-analysis — Karam et al., BMJ 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10053756/
Systematic review and network meta-analysis — 40 randomised trials, 35,548 people at increased cardiovascular risk. Strong evidence. BMJ 2023;380:e072003. DOI 10.1136/bmj-2022-072003. Free full text in PubMed Central (PMC10053756) — open access, CC BY-NC 4.0. Note: Benefits rested on moderate-certainty evidence, partly from trials that also added exercise, medicines or quit-smoking help; no low-carbohydrate programme trials qualified.
What It Found
Compared named diet programmes in people at raised risk of heart disease. With moderate certainty, Mediterranean programmes reduced death from any cause (odds ratio 0.72; about 17 fewer deaths per 1,000 people at intermediate risk over five years), cardiovascular death, stroke and non-fatal heart attack compared with minimal advice. Low-fat programmes also reduced deaths and heart attacks. Ornish, Pritikin and the other programmes generally showed little or no benefit.
Why It Matters Here
Backs up the Mediterranean-style eating resources in chapter 10 (the Oldways guides): of the named diet programmes tested over the long term, Mediterranean and low-fat programmes were the ones with moderate-certainty evidence of fewer heart attacks and deaths.
Systematic review and network meta-analysis — 40 randomised trials, 35,548 people at increased cardiovascular risk. Strong evidence. BMJ 2023;380:e072003. DOI 10.1136/bmj-2022-072003. Free full text in PubMed Central (PMC10053756) — open access, CC BY-NC 4.0. Note: Benefits rested on moderate-certainty evidence, partly from trials that also added exercise, medicines or quit-smoking help; no low-carbohydrate programme trials qualified.
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A journey into a Mediterranean diet and type 2 diabetes: a systematic review with meta-analyses — Esposito et al., BMJ Open 2015

https://pmc.ncbi.nlm.nih.gov/articles/PMC4538272/
Systematic review of 8 meta-analyses and 5 randomised trials, with new meta-analyses of trials lasting 6 months or more. Moderate evidence. BMJ Open 2015;5(8):e008222. DOI 10.1136/bmjopen-2015-008222. Free full text in PubMed Central (PMC4538272) — open access, CC BY-NC 4.0. Note: The diabetes-control result rests on only three trials, and the lower diabetes risk comes mainly from observational studies.
What It Found
Pulled together the evidence on Mediterranean eating in type 2 diabetes and prediabetes. In three long-term trials, a Mediterranean diet lowered HbA1c by 0.47 percentage points more than usual care or low-fat diets, and two trials found a 49% higher chance of the metabolic syndrome resolving. Earlier meta-analyses also favoured it for weight and cholesterol, and closer adherence was linked with a 19–23% lower risk of developing diabetes.
Why It Matters Here
Backs up the Mediterranean-style eating guides in chapter 10 (Oldways) as an option for people with type 2 diabetes or prediabetes, alongside low-carb approaches.
Systematic review of 8 meta-analyses and 5 randomised trials, with new meta-analyses of trials lasting 6 months or more. Moderate evidence. BMJ Open 2015;5(8):e008222. DOI 10.1136/bmjopen-2015-008222. Free full text in PubMed Central (PMC4538272) — open access, CC BY-NC 4.0. Note: The diabetes-control result rests on only three trials, and the lower diabetes risk comes mainly from observational studies.
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Vegetarian and Vegan Dietary Patterns to Treat Adult Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials — Guest et al., Adv Nutr 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11540868/
Systematic review and meta-analysis with GRADE ratings — 7 randomised trials, 770 adults with type 2 diabetes. Moderate evidence. Adv Nutr 2024;15(10):100294. DOI 10.1016/j.advnut.2024.100294. Free full text in PubMed Central (PMC11540868) — open access, CC BY 4.0. Note: Only seven mostly small trials lasting 12–74 weeks, with varied comparison diets; HbA1c was pooled from just five of them.
What It Found
Reviewed randomised trials of vegetarian and vegan eating for adults with type 2 diabetes. Compared with non-vegetarian diets, vegetarian diets likely lowered HbA1c by 0.40 percentage points and BMI by 0.96 (moderate-certainty evidence) and may allow less diabetes medication (low certainty). They showed no clear effect on fasting glucose, fasting insulin or LDL cholesterol.
Why It Matters Here
Backs up the plant-based cooking classes (PCRM’s Food for Life) and the plant-based meal-prep community in chapter 14: vegetarian or vegan eating is a reasonable option for type 2 diabetes, not only low-carb. Four of the seven trials were led by PCRM’s president, Neal Barnard.
Systematic review and meta-analysis with GRADE ratings — 7 randomised trials, 770 adults with type 2 diabetes. Moderate evidence. Adv Nutr 2024;15(10):100294. DOI 10.1016/j.advnut.2024.100294. Free full text in PubMed Central (PMC11540868) — open access, CC BY 4.0. Note: Only seven mostly small trials lasting 12–74 weeks, with varied comparison diets; HbA1c was pooled from just five of them.
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Doctor Referral of Overweight People to Low Energy total diet replacement Treatment (DROPLET): pragmatic randomised controlled trial — Astbury et al., BMJ 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6156558/
Pragmatic randomised controlled trial — 278 adults with obesity in 10 UK general practices, 1 year. Moderate evidence. BMJ 2018;362:k3760. DOI 10.1136/bmj.k3760. Free full text in PubMed Central (PMC6156558) — open access, CC BY 4.0. Note: Only 73% were re-measured at 12 months, follow-up stopped at one year, and the trial was part-funded by the formula maker.
What It Found
GP patients with obesity were randomised to a total diet replacement programme (formula foods of 810 kcal a day as the only food for 8 weeks, then food reintroduction, with weekly support) or usual practice-nurse support. At 12 months the programme group had lost 10.7 kg versus 3.1 kg (difference 7.2 kg); 45% versus 15% lost at least 10% of their weight. Mild side effects such as constipation were more common, but moderate or worse adverse events were similar (11% v 12%).
Why It Matters Here
Backs up the low-calorie, formula-first approach in Roy Taylor's Life Without Diabetes (chapter 10), showing that this kind of programme can work for people with obesity, with or without diabetes, when offered through ordinary general practice.
Pragmatic randomised controlled trial — 278 adults with obesity in 10 UK general practices, 1 year. Moderate evidence. BMJ 2018;362:k3760. DOI 10.1136/bmj.k3760. Free full text in PubMed Central (PMC6156558) — open access, CC BY 4.0. Note: Only 73% were re-measured at 12 months, follow-up stopped at one year, and the trial was part-funded by the formula maker.
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Effect of Time-Restricted Eating on Weight Loss in Adults With Type 2 Diabetes: A Randomized Clinical Trial — Pavlou et al., JAMA Netw Open 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10611992/
Randomised controlled trial — 75 adults with type 2 diabetes and obesity, 6 months. Moderate evidence. JAMA Netw Open 2023;6(10):e2339337. DOI 10.1001/jamanetworkopen.2023.39337. Free full text in PubMed Central (PMC10611992) — open access, CC BY-NC-ND 4.0. Note: Small (75 people), 6 months and not blinded; more people in the time-restricted group were already on weight-lowering diabetes drugs.
What It Found
Compared eating only between noon and 8 pm (no calorie counting), cutting calories by 25% a day, and no change. After 6 months the time-restricted group had lost 3.56% more body weight than controls; calorie cutting's 1.78% was not statistically significant, and the two diets did not differ significantly from each other. HbA1c fell by about 0.9 percentage points in both diet groups versus controls, with no serious adverse events, and low blood sugar was no more common.
Why It Matters Here
Backs up time-restricted eating, as used by the fasting communities and the Zero app in chapter 13 and the fasting books in chapter 10, as one option for people with type 2 diabetes; in the trial, glucose-lowering medicines were adjusted under a set protocol.
Randomised controlled trial — 75 adults with type 2 diabetes and obesity, 6 months. Moderate evidence. JAMA Netw Open 2023;6(10):e2339337. DOI 10.1001/jamanetworkopen.2023.39337. Free full text in PubMed Central (PMC10611992) — open access, CC BY-NC-ND 4.0. Note: Small (75 people), 6 months and not blinded; more people in the time-restricted group were already on weight-lowering diabetes drugs.
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Effects of Time-Restricted Eating on Nonalcoholic Fatty Liver Disease: The TREATY-FLD Randomized Clinical Trial — Wei et al., JAMA Netw Open 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10024204/
Randomised controlled trial — 88 adults with obesity and fatty liver, 12 months, liver fat measured by MRI. Moderate evidence. JAMA Netw Open 2023;6(3):e233513. DOI 10.1001/jamanetworkopen.2023.3513. Free full text in PubMed Central (PMC10024204) — open access, CC BY 4.0. Note: One centre in China with young adults (average age 32); liver fat was measured by MRI, not biopsy, so effects on liver scarring are uncertain.
What It Found
Everyone followed the same calorie-reduced diet; half also ate only between 8 am and 4 pm. Liver fat (MRI) fell by 8.3 percentage points with time-restricted eating and 8.1 with calorie cutting alone at 6 months (6.9 v 7.9 at 12 months), and weight by 8.4 kg v 7.8 kg at 12 months, with no significant differences. Liver stiffness, blood pressure and blood fats improved equally; only insulin resistance improved more with time restriction, at 12 months.
Why It Matters Here
Backs up the fasting communities in chapter 13 and fasting books in chapter 10 only in part: for fatty liver, eating within an 8-hour window worked as well as ordinary calorie cutting but no better, and the authors conclude that cutting calories explains most of the benefit.
Randomised controlled trial — 88 adults with obesity and fatty liver, 12 months, liver fat measured by MRI. Moderate evidence. JAMA Netw Open 2023;6(3):e233513. DOI 10.1001/jamanetworkopen.2023.3513. Free full text in PubMed Central (PMC10024204) — open access, CC BY 4.0. Note: One centre in China with young adults (average age 32); liver fat was measured by MRI, not biopsy, so effects on liver scarring are uncertain.
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EASL-EASD-EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) — European Association for the Study of the Liver (EASL) et al., Obes Facts 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11299976/
Joint clinical practice guideline of the European liver, diabetes and obesity societies — graded recommendations with Delphi consensus. Strong evidence. Obes Facts 2024;17(4):374–444 (also published in J Hepatol 2024;81(3):492–542). DOI 10.1159/000539371. Free full text in PubMed Central (PMC11299976) — open access, CC BY-NC 4.0. Note: Evidence that lifestyle weight loss helps advanced scarring or cirrhosis is insufficient, and diet trials lasted only 2–24 months, so long-term liver outcomes are unknown.
What It Found
For adults with fatty liver linked to metabolic risk, recommends lasting weight loss of at least 5% to reduce liver fat, 7–10% to improve inflammation and 10% or more to improve scarring, Mediterranean-style eating with fewer ultra-processed foods and sugary drinks, and regular exercise; incretin medicines and bariatric surgery are options where indicated. Evidence was insufficient for very-low-carb ketogenic diets, and thin that time-restricted eating beats calorie cutting.
Why It Matters Here
Backs up calorie-reduced eating plans for fatty liver, Mediterranean-style (the Oldways guides, chapter 10) or lower-carb (chapters 01 and 10), and the exercise professionals in chapter 12, while flagging thin evidence for ketogenic diets and time-restricted eating.
Joint clinical practice guideline of the European liver, diabetes and obesity societies — graded recommendations with Delphi consensus. Strong evidence. Obes Facts 2024;17(4):374–444 (also published in J Hepatol 2024;81(3):492–542). DOI 10.1159/000539371. Free full text in PubMed Central (PMC11299976) — open access, CC BY-NC 4.0. Note: Evidence that lifestyle weight loss helps advanced scarring or cirrhosis is insufficient, and diet trials lasted only 2–24 months, so long-term liver outcomes are unknown.
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Exercise in the Management of Metabolic-Associated Fatty Liver Disease (MAFLD) in Adults: A Position Statement from Exercise and Sport Science Australia — Keating et al., Sports Med 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10687186/
Position statement of Exercise & Sports Science Australia — evidence-graded recommendations based on systematic reviews and meta-analyses. Strong evidence. Sports Med 2023;53(12):2347–2371. DOI 10.1007/s40279-023-01918-w. Free full text in PubMed Central (PMC10687186) — open access, CC BY 4.0. Note: The fall in liver fat is modest, and there is little evidence yet that exercise alone improves liver inflammation or scarring.
What It Found
Graded the evidence for exercise in fatty liver disease. High-certainty evidence shows that regular aerobic exercise (most studies used 150–240 minutes a week of at least moderate intensity) lowers liver fat by about 2–4% in absolute terms, even without weight loss, and improves fitness. High-intensity interval training appears comparable; the effect of resistance training on liver fat is uncertain; and there is little evidence on liver inflammation or scarring.
Why It Matters Here
Backs up the accredited exercise physiologists and other clinical exercise professionals in chapter 12, and the exercise programmes in chapter 10, as part of care for fatty liver alongside diet.
Position statement of Exercise & Sports Science Australia — evidence-graded recommendations based on systematic reviews and meta-analyses. Strong evidence. Sports Med 2023;53(12):2347–2371. DOI 10.1007/s40279-023-01918-w. Free full text in PubMed Central (PMC10687186) — open access, CC BY 4.0. Note: The fall in liver fat is modest, and there is little evidence yet that exercise alone improves liver inflammation or scarring.
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Effect of exercise on cardiometabolic health of adults with overweight or obesity: Focus on blood pressure, insulin resistance, and intrahepatic fat—A systematic review and meta-analysis — Battista et al., Obes Rev 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8365642/
Systematic review and meta-analysis — 54 randomised trials in adults with overweight or obesity. Moderate evidence. Obes Rev 2021;22(Suppl 4):e13269. DOI 10.1111/obr.13269. Free full text in PubMed Central (PMC8365642) — open access, CC BY 4.0. Note: Trials were mostly small (median 38 people) and 43% were rated poor quality; results varied between studies.
What It Found
Pooled trials of exercise training programmes. Exercise lowered systolic blood pressure by about 3 mmHg and diastolic by about 2 mmHg, gave a small reduction in insulin resistance (standardised mean difference −0.34; −0.50 in people with type 2 diabetes) and a moderate reduction in liver fat measured by MRI (−0.59, 13 studies), with high-intensity interval training showing a larger effect on liver fat.
Why It Matters Here
Backs up the exercise professionals in chapter 12 and the home-workout programmes in chapter 10 as a way to improve insulin resistance, blood pressure and liver fat in people living with overweight or obesity.
Systematic review and meta-analysis — 54 randomised trials in adults with overweight or obesity. Moderate evidence. Obes Rev 2021;22(Suppl 4):e13269. DOI 10.1111/obr.13269. Free full text in PubMed Central (PMC8365642) — open access, CC BY 4.0. Note: Trials were mostly small (median 38 people) and 43% were rated poor quality; results varied between studies.
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Long-Term Outcomes of Medical Management vs Bariatric Surgery in Type 2 Diabetes — Courcoulas et al., JAMA 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC10900968/
Pooled long-term follow-up of 4 US randomised trials (ARMMS-T2D) — 262 adults with type 2 diabetes, median 11 years. Moderate evidence. JAMA 2024;331(8):654–664. DOI 10.1001/jama.2024.0318. Free full text in PubMed Central (PMC10900968). Note: Small open-label trials were pooled and 25% of the medical group later had surgery; a 2026 Cochrane review rated long-term remission evidence very uncertain.
What It Found
Adults with type 2 diabetes and obesity had been randomised to bariatric surgery (gastric bypass, sleeve or band) or medical and lifestyle care. At 7 years HbA1c had fallen by 1.6 percentage points after surgery versus 0.2 with medical care; diabetes remission was 18.2% v 6.2% at 7 years and 12.7% v 0% at 12 years, with fewer diabetes medicines. Anaemia, fractures and gut problems were more common after surgery.
Why It Matters Here
Explains the long-term benefits and trade-offs of metabolic surgery for type 2 diabetes, useful context for readers comparing it with the diet-based remission approaches described in chapter 10.
Pooled long-term follow-up of 4 US randomised trials (ARMMS-T2D) — 262 adults with type 2 diabetes, median 11 years. Moderate evidence. JAMA 2024;331(8):654–664. DOI 10.1001/jama.2024.0318. Free full text in PubMed Central (PMC10900968). Note: Small open-label trials were pooled and 25% of the medical group later had surgery; a 2026 Cochrane review rated long-term remission evidence very uncertain.
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Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis — Nong et al., BMJ 2026

https://doi.org/10.1136/bmj-2026-372161
Systematic review and network meta-analysis — 262 randomised trials, 99,791 adults, 19 drugs, GRADE. Strong evidence. BMJ 2026;394:e372161. Free full text at the publisher — open access, CC BY-NC 4.0. Note: Follow-up ranged from 12 to 172 weeks, so long-term benefits and harms, especially of the newest drugs, remain uncertain.
What It Found
At one year, compared with lifestyle change alone, tirzepatide gave the most extra weight loss (14.9%), then cagrilintide-semaglutide (14.8%), oral semaglutide (10.9%), orforglipron (9.9%) and injected semaglutide (9.8%) (moderate to high certainty). Larger losses generally came with more side effects and stopping. Only injected semaglutide reduced deaths and heart attacks (mostly in trials of high-risk people), and no drug meaningfully improved quality of life.
Why It Matters Here
Explains what modern weight-loss medicines can and cannot do, so readers can weigh them against the diet, fasting and exercise approaches in this directory (chapters 01, 10, 12 and 13) with their clinician.
Systematic review and network meta-analysis — 262 randomised trials, 99,791 adults, 19 drugs, GRADE. Strong evidence. BMJ 2026;394:e372161. Free full text at the publisher — open access, CC BY-NC 4.0. Note: Follow-up ranged from 12 to 172 weeks, so long-term benefits and harms, especially of the newest drugs, remain uncertain.
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Weight regain after cessation of medication for weight management: systematic review and meta-analysis — West et al., BMJ 2026

https://pmc.ncbi.nlm.nih.gov/articles/PMC12776922/
Systematic review and meta-analysis — 37 studies (63 treatment arms), 9,341 adults with overweight or obesity. Moderate evidence. BMJ 2026;392:e085304. DOI 10.1136/bmj-2025-085304. Free full text in PubMed Central (PMC12776922) — open access, CC BY 4.0. Note: Only one study followed people for two years after stopping; for the newest drugs, regain beyond 12 months was projected rather than observed.
What It Found
After stopping weight-loss medicines, people regained on average 0.4 kg a month, with weight projected to return to its starting point about 1.7 years later and gains in blood sugar, cholesterol and blood pressure projected to reverse within about 1.4 years. Regain was faster after the newer incretin drugs (0.8 kg a month) and faster than after behavioural weight-loss programmes, whatever the initial weight loss.
Why It Matters Here
Explains that the benefits of weight-loss medicines fade quickly once they stop, faster than after behavioural programmes: useful context for readers weighing medicines against, or alongside, the lifestyle resources in chapters 10, 12, 13 and 14.
Systematic review and meta-analysis — 37 studies (63 treatment arms), 9,341 adults with overweight or obesity. Moderate evidence. BMJ 2026;392:e085304. DOI 10.1136/bmj-2025-085304. Free full text in PubMed Central (PMC12776922) — open access, CC BY 4.0. Note: Only one study followed people for two years after stopping; for the newest drugs, regain beyond 12 months was projected rather than observed.
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Early findings from the NHS Type 2 Diabetes Path to Remission Programme: a prospective evaluation of real-world implementation — Valabhji et al., Lancet Diabetes Endocrinol 2024

https://doi.org/10.1016/S2213-8587(24)00194-3
National prospective service evaluation — 7,540 people referred in England; 1,740 started the 12-month programme in time to be assessed. Moderate evidence. Lancet Diabetes Endocrinol 2024;12(9):653–663. Free full text at the publisher — open access, CC BY. Note: An uncontrolled service evaluation: only 55% completed the programme and many lacked HbA1c results, so the true remission rate is uncertain and lower than in the trials.
What It Found
The NHS offered adults aged 18–65 diagnosed with type 2 diabetes in the last 6 years a 12-month programme starting with 12 weeks of total diet replacement (soups and shakes, about 800–900 kcal a day) plus coaching. Among 1,710 starters with weight data, mean weight loss at a year was 9.4 kg (10.3 kg among completers). Of those with two HbA1c results recorded, 27% were in remission (32% of completers).
Why It Matters Here
Backs up the diet-led remission approach in Professor Roy Taylor's book Life Without Diabetes in chapter 10 (he is a co-author) and shows the approach can work in an ordinary health service, not only in trials.
National prospective service evaluation — 7,540 people referred in England; 1,740 started the 12-month programme in time to be assessed. Moderate evidence. Lancet Diabetes Endocrinol 2024;12(9):653–663. Free full text at the publisher — open access, CC BY. Note: An uncontrolled service evaluation: only 55% completed the programme and many lacked HbA1c results, so the true remission rate is uncertain and lower than in the trials.
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Nutrients — Vitamins, Minerals, Protein, Fats, Sugars & Fibre: Benefits, Deficiencies & Harms

Health effects of dietary risks in 195 countries, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 — GBD 2017 Diet Collaborators, Lancet 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6899507/
Global modelling study (comparative risk assessment) — 15 dietary factors in adults aged 25+ across 195 countries, using risk estimates from meta-analyses of cohort studies. Moderate evidence. Lancet 2019;393(10184):1958–1972. DOI 10.1016/S0140-6736(19)30041-8. Free full text in PubMed Central (PMC6899507) — open access, CC BY 4.0. Note: Modelled from observational studies, so these are links, not proof of cause; the later GBD 2019 analysis, using updated methods, put diet-linked deaths lower, at about 8 million in 2019.
What It Found
Estimated how much chronic disease worldwide is linked to 15 dietary factors. In 2017, 11 million adult deaths (22% of all adult deaths) and 255 million disability-adjusted life-years were attributed to dietary risks, mainly through cardiovascular disease (10 million deaths), then cancers and type 2 diabetes. The leading risks were a diet high in sodium (3 million deaths), low in whole grains (3 million) and low in fruit (2 million).
Why It Matters Here
Explains why everyday diet quality matters for chronic disease: too much salt and too few whole grains and fruit carried the largest diet-linked toll. The cooking classes and food communities in chapter 14, the eating-well resources in chapter 10 and the dietitian finders in chapter 15 can help.
Global modelling study (comparative risk assessment) — 15 dietary factors in adults aged 25+ across 195 countries, using risk estimates from meta-analyses of cohort studies. Moderate evidence. Lancet 2019;393(10184):1958–1972. DOI 10.1016/S0140-6736(19)30041-8. Free full text in PubMed Central (PMC6899507) — open access, CC BY 4.0. Note: Modelled from observational studies, so these are links, not proof of cause; the later GBD 2019 analysis, using updated methods, put diet-linked deaths lower, at about 8 million in 2019.
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Carbohydrate intake for adults and children: WHO guideline — WHO 2023

https://iris.who.int/handle/10665/370420
WHO guideline — GRADE-rated systematic reviews of trials and cohort studies (fibre: 100 cohort studies and 49 trials in adults). Strong evidence. Geneva: World Health Organization; 2023. ISBN 978-92-4-007359-3. Free from the World Health Organization — open access, CC BY-NC-SA 3.0 IGO. Note: The disease links come from observational studies (moderate certainty); trials mainly measured risk factors such as weight and cholesterol.
What It Found
In cohort studies pooled for this WHO guideline, adults eating the most fibre had lower risks than those eating the least: death from any cause 15% lower (RR 0.85), coronary heart disease 24% lower (RR 0.76), type 2 diabetes and colorectal cancer each 16% lower (RR 0.84), all moderate certainty. WHO strongly recommends carbohydrate mainly from whole grains, vegetables, fruit and pulses, and at least 25 g of fibre a day for adults; it sets no total-carbohydrate target.
Why It Matters Here
Backs up the cooking classes and food programmes in chapter 14, the cooking and eating-well resources in chapter 10 and the dietitian finders in chapter 15: it sets out why fibre-rich whole foods matter for heart disease, diabetes and bowel cancer.
WHO guideline — GRADE-rated systematic reviews of trials and cohort studies (fibre: 100 cohort studies and 49 trials in adults). Strong evidence. Geneva: World Health Organization; 2023. ISBN 978-92-4-007359-3. Free from the World Health Organization — open access, CC BY-NC-SA 3.0 IGO. Note: The disease links come from observational studies (moderate certainty); trials mainly measured risk factors such as weight and cholesterol.
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Guideline: sugars intake for adults and children — WHO 2015

https://iris.who.int/handle/10665/149782
WHO guideline — GRADE-rated systematic reviews of trials and cohort studies on body weight and dental caries. Moderate evidence. Geneva: World Health Organization; 2015. ISBN 978-92-4-154902-8. Free from the World Health Organization. Note: The guideline only weighed body weight and tooth decay; the stricter 5% suggestion rests on very low-quality evidence.
What It Found
WHO strongly recommends keeping free sugars (sugars added to food and drink, plus those in honey, syrups and fruit juice) below 10% of daily energy, and suggests below 5%. In trials, adults who cut free sugars lost a little weight (−0.80 kg) and those who added them gained (+0.75 kg), because of the extra energy rather than sugar as such. In cohort studies of children, more free sugars was linked with more tooth decay. The 10% advice rests on moderate-quality evidence.
Why It Matters Here
Backs up the advice to cut added sugar in metabolic-health books in chapter 10, such as The Obesity Code, and the recipe sites there that avoid refined sugar: cutting free sugars is a WHO recommendation for people of all ages.
WHO guideline — GRADE-rated systematic reviews of trials and cohort studies on body weight and dental caries. Moderate evidence. Geneva: World Health Organization; 2015. ISBN 978-92-4-154902-8. Free from the World Health Organization. Note: The guideline only weighed body weight and tooth decay; the stricter 5% suggestion rests on very low-quality evidence.
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Reduction in saturated fat intake for cardiovascular disease — Hooper et al., Cochrane Database Syst Rev 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC8092457/
Cochrane systematic review and meta-analysis — 15 randomised trials, 56,675 people. Strong evidence. Cochrane Database Syst Rev 2020;8:CD011737. DOI 10.1002/14651858.CD011737.pub3. Free full text in PubMed Central (PMC8092457). Note: Saturated fat remains debated: the benefit was fewer combined heart and stroke events, with little or no effect on deaths, and trials varied widely.
What It Found
Pooled 15 randomised trials (56,675 people) that reduced saturated fat for at least two years. Cutting saturated fat lowered combined cardiovascular events by 17% (RR 0.83, 95% CI 0.70–0.98; moderate-quality evidence), with bigger cuts giving bigger benefit; replacing it with polyunsaturated fat or carbohydrate both looked useful. It made little or no difference to deaths from any cause (RR 0.96) or cardiovascular deaths (RR 0.95).
Why It Matters Here
Explains what randomised trials show about saturated fat and heart disease — useful context for readers of the high-fat keto, carnivore and low-carb communities. The dietitian finders in chapter 15 can help people change the fats they eat.
Cochrane systematic review and meta-analysis — 15 randomised trials, 56,675 people. Strong evidence. Cochrane Database Syst Rev 2020;8:CD011737. DOI 10.1002/14651858.CD011737.pub3. Free full text in PubMed Central (PMC8092457). Note: Saturated fat remains debated: the benefit was fewer combined heart and stroke events, with little or no effect on deaths, and trials varied widely.
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Replacing salt with low-sodium salt substitutes (LSSS) for cardiovascular health in adults, children and pregnant women — Brand et al., Cochrane Database Syst Rev 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9363242/
Cochrane systematic review and meta-analysis — 26 randomised trials, 34,961 adults and 92 children. Strong evidence. Cochrane Database Syst Rev 2022;8:CD015207. DOI 10.1002/14651858.CD015207. Free full text in PubMed Central (PMC9363242) — open access, CC BY. Note: Effects were small; trials left out people at risk of high potassium (e.g. kidney disease or some medicines), so safety for them is not established.
What It Found
Pooled 26 randomised trials in which people or households swapped regular salt for low-sodium salt substitutes, mostly potassium-enriched. In adults, substitutes probably lowered blood pressure slightly (systolic −4.76 mmHg, diastolic −2.43 mmHg) and probably slightly reduced non-fatal stroke, acute coronary syndrome and cardiovascular deaths (moderate certainty), while slightly raising blood potassium. Evidence in children was very uncertain.
Why It Matters Here
Explains one simple, tested way to eat less sodium and more potassium at home, relevant to the cooking communities in chapter 14 and the cooking and eating-well resources in chapter 10. All trials excluded people for whom extra potassium could be harmful, such as some with kidney disease.
Cochrane systematic review and meta-analysis — 26 randomised trials, 34,961 adults and 92 children. Strong evidence. Cochrane Database Syst Rev 2022;8:CD015207. DOI 10.1002/14651858.CD015207. Free full text in PubMed Central (PMC9363242) — open access, CC BY. Note: Effects were small; trials left out people at risk of high potassium (e.g. kidney disease or some medicines), so safety for them is not established.
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Dietary intake of total, animal, and plant proteins and risk of all cause, cardiovascular, and cancer mortality: systematic review and dose-response meta-analysis of prospective cohort studies — Naghshi et al., BMJ 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7374797/
Systematic review and dose–response meta-analysis — 32 prospective cohort studies, 715,128 people. Moderate evidence. BMJ 2020;370:m2412. DOI 10.1136/bmj.m2412. Free full text in PubMed Central (PMC7374797) — open access, CC BY 4.0. Note: Observational studies only, so these are links rather than proof of cause; results varied between studies and diet was mostly self-reported.
What It Found
Pooled 32 cohort studies (715,128 people, 113,039 deaths). Higher total protein intake was linked with a 6% lower risk of death from any cause (0.94, 95% CI 0.89–0.99), and higher plant protein with lower all-cause (0.92) and cardiovascular (0.88) death. Animal protein showed no significant link either way with death from any cause, cardiovascular disease or cancer. Each extra 3% of daily energy from plant protein was linked with 5% lower all-cause mortality.
Why It Matters Here
Explains how protein sources relate to long-term health — relevant to the carnivore, keto and plant-based communities in chapter 14 and to people using the protein-tracking apps in chapters 13 and 16.
Systematic review and dose–response meta-analysis — 32 prospective cohort studies, 715,128 people. Moderate evidence. BMJ 2020;370:m2412. DOI 10.1136/bmj.m2412. Free full text in PubMed Central (PMC7374797) — open access, CC BY 4.0. Note: Observational studies only, so these are links rather than proof of cause; results varied between studies and diet was mostly self-reported.
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Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease — Abdelhamid et al., Cochrane Database Syst Rev 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7049091/
Cochrane systematic review and meta-analysis — 86 randomised trials, 162,796 people. Strong evidence. Cochrane Database Syst Rev 2020;3:CD003177. DOI 10.1002/14651858.CD003177.pub5. Free full text in PubMed Central (PMC7049091). Note: Most trials tested capsules; there was little trial evidence on eating oily fish itself.
What It Found
Pooled 86 randomised trials (162,796 people), mostly of fish-oil (long-chain omega-3) capsules, lasting 1–7 years. More long-chain omega-3 made little or no difference to death from any cause (RR 0.97; high certainty), cardiovascular events (RR 0.96; high certainty) or stroke, and may slightly reduce coronary heart disease events (RR 0.91; low certainty). More plant omega-3 (ALA) probably makes little or no difference to deaths.
Why It Matters Here
Explains that omega-3 capsules made little or no difference to deaths or overall cardiovascular events in trials — useful context when weighing supplements suggested by practitioners, clinics or retreats. The dietitian finders in chapter 15 can advise on omega-3 from food.
Cochrane systematic review and meta-analysis — 86 randomised trials, 162,796 people. Strong evidence. Cochrane Database Syst Rev 2020;3:CD003177. DOI 10.1002/14651858.CD003177.pub5. Free full text in PubMed Central (PMC7049091). Note: Most trials tested capsules; there was little trial evidence on eating oily fish itself.
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Dietary magnesium intake and the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality: a dose–response meta-analysis of prospective cohort studies — Fang et al., BMC Med 2016

https://pmc.ncbi.nlm.nih.gov/articles/PMC5143460/
Dose–response meta-analysis — 40 prospective cohort studies, more than 1 million people. Moderate evidence. BMC Med 2016;14:210. DOI 10.1186/s12916-016-0742-z. Free full text in PubMed Central (PMC5143460) — open access, CC BY 4.0. Note: Observational studies of diet, not supplement trials, so other features of magnesium-rich diets may explain part of the links.
What It Found
Pooled 40 cohort studies of more than 1 million people followed for 4–30 years. Each extra 100 mg a day of dietary magnesium was linked with a 19% lower risk of type 2 diabetes (RR 0.81), 22% lower heart failure (RR 0.78), 7% lower stroke (RR 0.93) and 10% lower death from any cause (RR 0.90), but not with total cardiovascular disease or coronary heart disease.
Why It Matters Here
Explains links between magnesium-rich eating (whole grains, green leafy vegetables and nuts) and chronic disease. The nutrient-tracking apps in chapter 16, such as Cronometer, and the dietitian finders in chapter 15 can help people check their intake.
Dose–response meta-analysis — 40 prospective cohort studies, more than 1 million people. Moderate evidence. BMC Med 2016;14:210. DOI 10.1186/s12916-016-0742-z. Free full text in PubMed Central (PMC5143460) — open access, CC BY 4.0. Note: Observational studies of diet, not supplement trials, so other features of magnesium-rich diets may explain part of the links.
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Daily iron supplementation for improving anaemia, iron status and health in menstruating women — Low et al., Cochrane Database Syst Rev 2016

https://pmc.ncbi.nlm.nih.gov/articles/PMC10182438/
Cochrane systematic review and meta-analysis — 67 trials (randomised or quasi-randomised), 8,506 women. Strong evidence. Cochrane Database Syst Rev 2016;4:CD009747. DOI 10.1002/14651858.CD009747.pub2. Free full text in PubMed Central (PMC10182438). Note: Most trials were small with unclear methods; the fatigue findings came from separate trials with mixed results that were not pooled.
What It Found
Pooled 67 trials (8,506 menstruating women) of daily iron supplements. Iron cut the chance of being anaemic at the end of treatment by 61% (RR 0.39; moderate quality), raised haemoglobin (high quality) and reduced iron deficiency (RR 0.62). It improved exercise performance and appeared to reduce symptomatic fatigue, though fatigue data could not be pooled. Constipation and loose stools were about twice as common with iron.
Why It Matters Here
Explains what daily iron supplements do for women who menstruate, a group in which iron deficiency and anaemia are common worldwide — useful background for readers with ongoing tiredness, which has many possible causes. Testing and treatment belong with a doctor.
Cochrane systematic review and meta-analysis — 67 trials (randomised or quasi-randomised), 8,506 women. Strong evidence. Cochrane Database Syst Rev 2016;4:CD009747. DOI 10.1002/14651858.CD009747.pub2. Free full text in PubMed Central (PMC10182438). Note: Most trials were small with unclear methods; the fatigue findings came from separate trials with mixed results that were not pooled.
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What Endocrinologists Should Know About Iodine: Population Deficiency, Individual Excess and Misinformation in the United Kingdom — Taylor et al., Clin Endocrinol (Oxf) 2026

https://pmc.ncbi.nlm.nih.gov/articles/PMC13629602/
Narrative expert review by UK thyroid and nutrition specialists. Moderate evidence. Clin Endocrinol (Oxf) 2026;105(5):523–530. DOI 10.1111/cen.70162. Free full text in PubMed Central (PMC13629602) — open access, CC BY 4.0. Note: A narrative review focused on the UK, where salt is not iodised; iodine status differs by country.
What It Found
UK thyroid and nutrition experts review the return of mild-to-moderate iodine deficiency: the 2019–2023 national survey found a median urinary iodine of 82 µg/L in women aged 16–49, below the WHO adequacy level. Risks include avoiding dairy, eating little fish, unfortified plant milks (only 28% are fortified) and sea or Himalayan salt, which has negligible iodine. They warn that kelp supplements and 'iodine resets' can deliver far too much iodine and trigger thyroid problems.
Why It Matters Here
Explains why vegans, people avoiding dairy and people with very restricted eating (including some neurodivergent people) can run short of iodine — relevant to the plant-based communities in chapter 14, the neurodiversity resources in chapter 09, the thyroid foundation in chapter 06 and dietitians in chapter 15.
Narrative expert review by UK thyroid and nutrition specialists. Moderate evidence. Clin Endocrinol (Oxf) 2026;105(5):523–530. DOI 10.1111/cen.70162. Free full text in PubMed Central (PMC13629602) — open access, CC BY 4.0. Note: A narrative review focused on the UK, where salt is not iodised; iodine status differs by country.
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Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study — Aroda et al., J Clin Endocrinol Metab 2016

https://pmc.ncbi.nlm.nih.gov/articles/PMC4880159/
Secondary analysis of a randomised trial (Diabetes Prevention Program) and its open-label follow-up — 2,155 people; vitamin B12 measured at 5 and 13 years. Moderate evidence. J Clin Endocrinol Metab 2016;101(4):1754–1761. DOI 10.1210/jc.2015-3754. Free full text in PubMed Central (PMC4880159). Note: B12 was measured only in people with stored blood samples; anaemia was more common with metformin but was not related to B12 status.
What It Found
Adults at high risk of type 2 diabetes were randomised to metformin or placebo, and the metformin group kept taking it for about 9 more years. Low or borderline-low vitamin B12 was more common with metformin at 5 years (19.1% vs 9.5%) and 13 years (20.3% vs 15.6%), and each year of metformin use was linked with 13% higher odds of B12 deficiency. Anaemia was more common with metformin, and nerve damage (neuropathy) was more common in metformin users with low B12.
Why It Matters Here
Explains that long-term metformin, widely used for prediabetes and type 2 diabetes, can lower vitamin B12 — worth knowing for readers of the metabolic-health resources in chapters 01 and 16 (the CDC National Diabetes Prevention Program in chapter 16 grew out of this trial).
Secondary analysis of a randomised trial (Diabetes Prevention Program) and its open-label follow-up — 2,155 people; vitamin B12 measured at 5 and 13 years. Moderate evidence. J Clin Endocrinol Metab 2016;101(4):1754–1761. DOI 10.1210/jc.2015-3754. Free full text in PubMed Central (PMC4880159). Note: B12 was measured only in people with stored blood samples; anaemia was more common with metformin but was not related to B12 status.
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Effects and safety of periconceptional oral folate supplementation for preventing birth defects — De-Regil et al., Cochrane Database Syst Rev 2015

https://pmc.ncbi.nlm.nih.gov/articles/PMC8783750/
Cochrane systematic review and meta-analysis — 5 randomised trials, 7,391 women. Strong evidence. Cochrane Database Syst Rev 2015;(12):CD007950. DOI 10.1002/14651858.CD007950.pub3. Free full text in PubMed Central (PMC8783750). Note: The benefit is specific to neural tube defects; the trials are older and most reported their methods unclearly.
What It Found
Pooled 5 randomised trials (7,391 women) of folic acid taken around conception and in early pregnancy. Folic acid, alone or with other vitamins and minerals, cut neural tube defects such as spina bifida by about two-thirds (RR 0.31, 95% CI 0.17–0.58; 6,708 births; high-quality evidence), including repeat cases in women with a previously affected pregnancy. There was no clear effect on other birth defects or on miscarriage.
Why It Matters Here
Explains one of the clearest nutrient benefits shown in trials, relevant to anyone who could become pregnant. The trials tested folic acid supplements, not diet alone; a doctor, pharmacist or the dietitian finders in chapter 15 can advise.
Cochrane systematic review and meta-analysis — 5 randomised trials, 7,391 women. Strong evidence. Cochrane Database Syst Rev 2015;(12):CD007950. DOI 10.1002/14651858.CD007950.pub3. Free full text in PubMed Central (PMC8783750). Note: The benefit is specific to neural tube defects; the trials are older and most reported their methods unclearly.
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Homocysteine-lowering interventions for preventing cardiovascular events — Martí-Carvajal et al., Cochrane Database Syst Rev 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC6483699/
Cochrane systematic review and meta-analysis — 15 randomised trials, 71,422 people. Strong evidence. Cochrane Database Syst Rev 2017;8:CD006612. DOI 10.1002/14651858.CD006612.pub5. Free full text in PubMed Central (PMC6483699). Note: The stroke benefit was small (4.3% vs 5.1%), and trials differed in participants, vitamin doses and access to folic-acid-fortified foods.
What It Found
Pooled 15 randomised trials (71,422 people) of vitamin B6, B9 (folic acid) and/or B12 supplements given to lower blood homocysteine, a marker linked with heart disease. Compared with placebo they made no difference to heart attacks (RR 1.02) or death from any cause (RR 1.01), both high-quality evidence, but stroke was slightly less common (4.3% vs 5.1%; RR 0.90). Serious adverse events did not differ.
Why It Matters Here
Explains that lowering homocysteine with B-vitamin pills did not prevent heart attacks or deaths — useful context when a practitioner or wellness programme suggests B-vitamin pills to lower homocysteine for heart health.
Cochrane systematic review and meta-analysis — 15 randomised trials, 71,422 people. Strong evidence. Cochrane Database Syst Rev 2017;8:CD006612. DOI 10.1002/14651858.CD006612.pub5. Free full text in PubMed Central (PMC6483699). Note: The stroke benefit was small (4.3% vs 5.1%), and trials differed in participants, vitamin doses and access to folic-acid-fortified foods.
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Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease — Manson et al., N Engl J Med 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6425757/
Randomised placebo-controlled trial (VITAL) — 25,871 US adults (men 50+, women 55+), median 5.3 years. Moderate evidence. N Engl J Med 2019;380(1):33–44. DOI 10.1056/NEJMoa1809944. Free full text in PubMed Central (PMC6425757). Note: Most participants were not deficient (mean 25(OH)D 30.8 ng/mL; 12.7% below 20 ng/mL), so results may differ for people with low vitamin D.
What It Found
A large randomised trial gave daily vitamin D3 or placebo to 25,871 US adults not selected for deficiency, for a median of 5.3 years. Vitamin D did not reduce invasive cancer (HR 0.96, 95% CI 0.88–1.06) or major cardiovascular events (HR 0.97, 0.85–1.12), and deaths from any cause were similar (HR 0.99). An analysis not planned in advance hinted at fewer cancer deaths after the first one to two years. No excess of high calcium or kidney stones was seen.
Why It Matters Here
Explains that vitamin D pills did not prevent cancer or heart disease in generally healthy older adults — useful context when weighing supplements suggested by practitioners or wellness programmes. It does not test treatment of diagnosed deficiency.
Randomised placebo-controlled trial (VITAL) — 25,871 US adults (men 50+, women 55+), median 5.3 years. Moderate evidence. N Engl J Med 2019;380(1):33–44. DOI 10.1056/NEJMoa1809944. Free full text in PubMed Central (PMC6425757). Note: Most participants were not deficient (mean 25(OH)D 30.8 ng/mL; 12.7% below 20 ng/mL), so results may differ for people with low vitamin D.
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Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases — Bjelakovic et al., Cochrane Database Syst Rev 2012

https://pmc.ncbi.nlm.nih.gov/articles/PMC8407395/
Cochrane systematic review and meta-analysis — 78 randomised trials, 296,707 people. Strong evidence. Cochrane Database Syst Rev 2012;(3):CD007176. DOI 10.1002/14651858.CD007176.pub2. Free full text in PubMed Central (PMC8407395). Note: The excess deaths were small and showed up only in some analyses; the review dates from 2012 and studied supplements, not antioxidant-rich foods.
What It Found
Pooled 78 randomised trials (296,707 people) of beta-carotene, vitamin A, vitamin C, vitamin E and selenium supplements, in healthy people and people with stable disease. Overall they did not lower deaths (RR 1.02, 95% CI 0.98–1.05). In the 56 trials at low risk of bias, deaths were slightly higher with supplements (RR 1.04), driven by beta-carotene (RR 1.05) and vitamin E (RR 1.03); vitamin A, vitamin C and selenium had no significant effect.
Why It Matters Here
Explains why more is not always better with supplements: antioxidant pills did not lengthen life in trials, and some were linked with slightly more deaths — useful context when weighing supplement protocols offered by clinics, retreats or online programmes.
Cochrane systematic review and meta-analysis — 78 randomised trials, 296,707 people. Strong evidence. Cochrane Database Syst Rev 2012;(3):CD007176. DOI 10.1002/14651858.CD007176.pub2. Free full text in PubMed Central (PMC8407395). Note: The excess deaths were small and showed up only in some analyses; the review dates from 2012 and studied supplements, not antioxidant-rich foods.
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Calcium intake and risk of fracture: systematic review — Bolland et al., BMJ 2015

https://pmc.ncbi.nlm.nih.gov/articles/PMC4784799/
Systematic review and meta-analysis — 26 randomised trials of calcium supplements, plus 2 trials and 44 cohort studies of dietary calcium, in people over 50. Moderate evidence. BMJ 2015;351:h4580. DOI 10.1136/bmj.h4580. Free full text in PubMed Central (PMC4784799) — open access, CC BY-NC 4.0. Note: Evidence on dietary calcium is observational; the supplement benefit shrank to nothing in the best-designed trials and the authors found signs of publication bias.
What It Found
Reviewed studies of calcium and fractures in people over 50. Most of the 44 cohort studies found no link between dietary calcium, milk or dairy intake and fracture risk, and no trial showed that more dietary calcium prevents fractures. In 26 trials, calcium supplements reduced total fractures by 11% (RR 0.89) and vertebral fractures slightly, but not hip or forearm fractures; in the four trials at lowest risk of bias there was no effect at any site.
Why It Matters Here
Explains that eating more calcium was not linked with fewer fractures and that calcium pills gave weak, inconsistent protection — useful context when bone-health supplements are suggested by practitioners or wellness programmes.
Systematic review and meta-analysis — 26 randomised trials of calcium supplements, plus 2 trials and 44 cohort studies of dietary calcium, in people over 50. Moderate evidence. BMJ 2015;351:h4580. DOI 10.1136/bmj.h4580. Free full text in PubMed Central (PMC4784799) — open access, CC BY-NC 4.0. Note: Evidence on dietary calcium is observational; the supplement benefit shrank to nothing in the best-designed trials and the authors found signs of publication bias.
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Plastics, Chemicals & Pollution — How the Environment Is Linked to Chronic Disease

Pollution and health: a progress update — Fuller et al., Lancet Planet Health 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC11995256/
Update of the Lancet Commission on pollution and health — global estimates from Global Burden of Disease 2019 data (modelling, not a trial). Moderate evidence. Lancet Planet Health 2022;6(6):e535–e547. DOI 10.1016/S2542-5196(22)00090-0. Free full text in PubMed Central (PMC11995256) — open access, CC BY-NC-ND 4.0. Note: Deaths are modelled estimates that rely on exposure–risk links from observational studies; the authors say chemical pollution is probably undercounted.
What It Found
Updating the Lancet Commission on pollution and health with 2019 data, the authors estimate pollution caused about 9 million premature deaths that year — one in six deaths worldwide. Air pollution accounted for 6.7 million, water pollution 1.4 million, lead 0.9 million and toxic workplace exposures 0.87 million. Deaths from 'modern' pollution, such as outdoor air pollution and lead, have risen by over 66% since 2000, while deaths from household air and water pollution fell.
Why It Matters Here
Explains that pollution sits alongside unhealthy diet, smoking, alcohol and inactivity as a major driver of chronic disease (WHO lists air pollution among five major risk factors), and that lead's toll is better measured than that of newer chemicals such as PFAS.
Update of the Lancet Commission on pollution and health — global estimates from Global Burden of Disease 2019 data (modelling, not a trial). Moderate evidence. Lancet Planet Health 2022;6(6):e535–e547. DOI 10.1016/S2542-5196(22)00090-0. Free full text in PubMed Central (PMC11995256) — open access, CC BY-NC-ND 4.0. Note: Deaths are modelled estimates that rely on exposure–risk links from observational studies; the authors say chemical pollution is probably undercounted.
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WHO global air quality guidelines: particulate matter (PM2.5 and PM10), ozone, nitrogen dioxide, sulfur dioxide and carbon monoxide — WHO 2021

https://iris.who.int/handle/10665/345329
WHO guideline — recommendations based on WHO-commissioned systematic reviews, rated with an adapted GRADE approach. Strong evidence. Geneva: World Health Organization, 2021. ISBN 9789240034228. Free from the World Health Organization — open access, CC BY-NC-SA 3.0 IGO. Note: The evidence comes mainly from long-term observational studies; guideline levels are targets for governments, not advice for individuals.
What It Found
WHO's 2021 update halved its yearly guideline level for fine particles (PM2.5) from 10 to 5 µg/m³ and lowered most others (the 24-hour sulfur dioxide level rose); all its recommendations are rated strong. It says strong evidence shows PM2.5 is a cause of death overall and of heart disease, stroke, COPD, lung cancer and chest infections, with growing evidence for type 2 diabetes. About 7 million deaths a year are attributed to outdoor and household air pollution combined.
Why It Matters Here
Explains why the air people breathe every day is a risk factor for heart, lung and metabolic disease, and sets the clean-air benchmarks that governments use; useful context for anyone living with heart or lung disease or diabetes.
WHO guideline — recommendations based on WHO-commissioned systematic reviews, rated with an adapted GRADE approach. Strong evidence. Geneva: World Health Organization, 2021. ISBN 9789240034228. Free from the World Health Organization — open access, CC BY-NC-SA 3.0 IGO. Note: The evidence comes mainly from long-term observational studies; guideline levels are targets for governments, not advice for individuals.
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Estimates, trends, and drivers of the global burden of type 2 diabetes attributable to PM2·5 air pollution, 1990–2019: an analysis of data from the Global Burden of Disease Study 2019 — GBD 2019 Diabetes and Air Pollution Collaborators, Lancet Planet Health 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9278144/
Global burden analysis — exposure–response curve from cohort and case–control studies applied to Global Burden of Disease 2019 data for 204 countries. Moderate evidence. Lancet Planet Health 2022;6(7):e586–e600. DOI 10.1016/S2542-5196(22)00122-X. Free full text in PubMed Central (PMC9278144) — open access, CC BY 4.0. Note: Modelled estimates that treat links found in observational studies as causal; the figures carry considerable uncertainty.
What It Found
Combining cohort and case–control studies into an exposure–response curve and applying it to 2019 global data, the authors estimate that about a fifth of the worldwide burden of type 2 diabetes was attributable to fine-particle (PM2.5) air pollution: 13.4% of type 2 diabetes deaths were linked to outdoor PM2.5 and 6.5% to household air pollution. The attributable burden rose by 50% since 1990, driven largely by population growth and ageing.
Why It Matters Here
Explains that polluted air is now counted as a risk factor for type 2 diabetes, not only for heart and lung disease; relevant to anyone at risk of, or living with, diabetes, and a reminder that clean-air policy is also part of diabetes prevention.
Global burden analysis — exposure–response curve from cohort and case–control studies applied to Global Burden of Disease 2019 data for 204 countries. Moderate evidence. Lancet Planet Health 2022;6(7):e586–e600. DOI 10.1016/S2542-5196(22)00122-X. Free full text in PubMed Central (PMC9278144) — open access, CC BY 4.0. Note: Modelled estimates that treat links found in observational studies as causal; the figures carry considerable uncertainty.
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Air Pollution (Particulate Matter) Exposure and Associations with Depression, Anxiety, Bipolar, Psychosis and Suicide Risk: A Systematic Review and Meta-Analysis — Braithwaite et al., Environ Health Perspect 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6957283/
Systematic review and meta-analysis — 22 observational studies (9 in the main meta-analyses). Moderate evidence. Environ Health Perspect 2019;127(12):126002. DOI 10.1289/EHP4595. Free full text in PubMed Central (PMC6957283) — public domain. Note: Few studies, with varied methods and possible residual confounding; the authors call for better studies before cause can be judged.
What It Found
Reviewing 22 observational studies, the authors found long-term exposure to fine particles (PM2.5) was linked with a higher chance of depression: pooled odds ratio 1.10 per 10 µg/m³ increase (95% CI 1.02 to 1.19; five studies). Two studies also linked long-term PM2.5 with anxiety, and short-term rises in PM10 (all particles up to 10 µm across) were linked with suicide over the following 0–2 days.
Why It Matters Here
Explains that air quality may be one of many influences on mental health as well as physical health; relevant to people living with depression or anxiety and to the clinicians and peer workers who support them.
Systematic review and meta-analysis — 22 observational studies (9 in the main meta-analyses). Moderate evidence. Environ Health Perspect 2019;127(12):126002. DOI 10.1289/EHP4595. Free full text in PubMed Central (PMC6957283) — public domain. Note: Few studies, with varied methods and possible residual confounding; the authors call for better studies before cause can be judged.
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Ambient air pollution and clinical dementia: systematic review and meta-analysis — Wilker et al., BMJ 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10498344/
Systematic review and meta-analysis — 51 longitudinal studies (14 pooled for PM2.5). Moderate evidence. BMJ 2023;381:e071620. DOI 10.1136/bmj-2022-071620. Free full text in PubMed Central (PMC10498344) — open access, CC BY-NC 4.0. Note: Most studies were at high risk of bias and the overall estimate was not statistically clear; the authors urge caution in interpreting the pooled figures.
What It Found
Of 51 studies, 14 could be pooled for fine particles (PM2.5): the overall hazard ratio for dementia was 1.04 per 2 µg/m³ (95% CI 0.99 to 1.09), a small rise that was not statistically clear. In seven studies that actively checked every participant for dementia it was 1.42 (1.00 to 2.02). Links with nitrogen dioxide and nitrogen oxides were uncertain, and ozone showed no clear link. The authors conclude PM2.5 might be a risk factor for dementia.
Why It Matters Here
Explains that outdoor air pollution is a possible, still uncertain, risk factor for dementia that can be reduced at population level; relevant to readers concerned about brain health in later life.
Systematic review and meta-analysis — 51 longitudinal studies (14 pooled for PM2.5). Moderate evidence. BMJ 2023;381:e071620. DOI 10.1136/bmj-2022-071620. Free full text in PubMed Central (PMC10498344) — open access, CC BY-NC 4.0. Note: Most studies were at high risk of bias and the overall estimate was not statistically clear; the authors urge caution in interpreting the pooled figures.
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Does ambient PM2.5 reduce the protective association of leisure-time physical activity with mortality? A systematic review, meta-analysis, and individual-level pooled analysis of cohort studies involving 1.5 million adults — Ku et al., BMC Med 2025

https://pmc.ncbi.nlm.nih.gov/articles/PMC12661664/
Systematic review and meta-analysis of 7 cohort studies (1,515,094 adults) plus pooled individual data from 3 cohorts (869,038 adults). Moderate evidence. BMC Med 2025;23:647. DOI 10.1186/s12916-025-04496-y. Free full text in PubMed Central (PMC12661664) — open access, CC BY 4.0. Note: Observational cohorts with self-reported activity, mostly in high-income countries; it is uncertain whether results apply where PM2.5 exceeds 50 µg/m³.
What It Found
Across seven cohorts of 1.5 million adults, meeting recommended leisure-time activity levels was linked with about a 30% lower risk of death where yearly fine-particle (PM2.5) levels were below 25 µg/m³, but only 12–15% lower at 25 µg/m³ or more. Pooled individual data from three cohorts confirmed the pattern: activity stayed beneficial even at high PM2.5, with the greatest benefit in cleaner air, though for cancer deaths it was no longer clear at 35–50 µg/m³.
Why It Matters Here
Backs up the walking and activity groups in chapter 13 and the exercise professionals in chapter 12: being active is still linked with longer life where air is polluted, although the benefit is smaller in very polluted air; relevant to readers in cities with poor air quality.
Systematic review and meta-analysis of 7 cohort studies (1,515,094 adults) plus pooled individual data from 3 cohorts (869,038 adults). Moderate evidence. BMC Med 2025;23:647. DOI 10.1186/s12916-025-04496-y. Free full text in PubMed Central (PMC12661664) — open access, CC BY 4.0. Note: Observational cohorts with self-reported activity, mostly in high-income countries; it is uncertain whether results apply where PM2.5 exceeds 50 µg/m³.
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The Minderoo-Monaco Commission on Plastics and Human Health — Landrigan et al., Ann Glob Health 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10038118/
International commission report — narrative review of evidence across the plastic life cycle (production, use and disposal). Moderate evidence. Ann Glob Health 2023;89(1):23. DOI 10.5334/aogh.4056. Free full text in PubMed Central (PMC10038118) — open access, CC BY 4.0. Note: A narrative (not systematic) review that also argues for a global plastics treaty; much of the human evidence is associational and micro/nanoplastic data are early.
What It Found
Plastics contain thousands of chemicals, including carcinogens, neurotoxicants and hormone disruptors (phthalates, bisphenols, PFAS) that leach into people. The commission links these additives with premature birth, neurodevelopmental disorders, male reproductive birth defects, infertility, obesity, heart and kidney disease, and cancers; evidence on micro- and nanoplastics is emerging but incomplete. Yearly production rose from under 2 to 460 million tonnes (1950–2019).
Why It Matters Here
Explains the main ways everyday plastics may affect long-term health, and why babies in the womb and young children are thought to be most vulnerable; useful background for readers wanting to reduce plastic exposure at home.
International commission report — narrative review of evidence across the plastic life cycle (production, use and disposal). Moderate evidence. Ann Glob Health 2023;89(1):23. DOI 10.5334/aogh.4056. Free full text in PubMed Central (PMC10038118) — open access, CC BY 4.0. Note: A narrative (not systematic) review that also argues for a global plastics treaty; much of the human evidence is associational and micro/nanoplastic data are early.
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Effects of Microplastic Exposure on Human Digestive, Reproductive, and Respiratory Health: A Rapid Systematic Review — Chartres et al., Environ Sci Technol 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11697325/
Rapid systematic review (Navigation Guide method) — 3 human observational studies and 28 animal studies. Early evidence. Environ Sci Technol 2024;58(52):22843–22864. DOI 10.1021/acs.est.3c09524. Free full text in PubMed Central (PMC11697325) — open access, CC BY 4.0. Note: Mostly animal studies, with only three small human studies; 'suspected' harm is not proof of harm in people.
What It Found
Using a formal review method, the authors found three human and 28 animal studies on microplastics and digestive, reproductive or respiratory health. Rating the mainly animal evidence as high or moderate quality for several outcomes, they concluded microplastics are 'suspected' to harm reproductive health (sperm quality), digestive health and respiratory health, with a suggested link to colon and lung cancer. Human evidence on birth outcomes was too weak to classify.
Why It Matters Here
Explains what is, and is not yet, known about microplastics and human health — the current concern is suspected harm rather than proof — which helps readers weigh alarming headlines.
Rapid systematic review (Navigation Guide method) — 3 human observational studies and 28 animal studies. Early evidence. Environ Sci Technol 2024;58(52):22843–22864. DOI 10.1021/acs.est.3c09524. Free full text in PubMed Central (PMC11697325) — open access, CC BY 4.0. Note: Mostly animal studies, with only three small human studies; 'suspected' harm is not proof of harm in people.
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Microplastics and Nanoplastics in Atheromas and Cardiovascular Events — Marfella et al., N Engl J Med 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11009876/
Prospective multicentre observational study — 257 patients having carotid artery surgery, followed for about 34 months. Early evidence. N Engl J Med 2024;390(10):900–910. DOI 10.1056/NEJMoa2309822. Free full text in PubMed Central (PMC11009876). Note: A single small observational study that cannot show cause; the authors note that laboratory contamination could not be firmly ruled out.
What It Found
In 257 people who had fatty plaque surgically removed from a neck (carotid) artery, polyethylene was found in the plaque of 150 (58.4%) and polyvinyl chloride in 31 (12.1%). Over about 34 months, those with micro- or nanoplastics in their plaque had a higher risk of heart attack, stroke or death from any cause than those without (hazard ratio 4.53; 95% CI 2.00 to 10.27).
Why It Matters Here
Explains why scientists are now studying plastic particles as a possible risk for heart attack and stroke; relevant to readers with heart or artery disease, though it shows a link in one group of surgical patients, not that plastics cause heart attacks.
Prospective multicentre observational study — 257 patients having carotid artery surgery, followed for about 34 months. Early evidence. N Engl J Med 2024;390(10):900–910. DOI 10.1056/NEJMoa2309822. Free full text in PubMed Central (PMC11009876). Note: A single small observational study that cannot show cause; the authors note that laboratory contamination could not be firmly ruled out.
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EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals — Gore et al., Endocr Rev 2015

https://pmc.ncbi.nlm.nih.gov/articles/PMC4702494/
Scientific statement of the Endocrine Society — expert review of human and animal studies, mainly from 2010–2015. Moderate evidence. Endocr Rev 2015;36(6):E1–E150. DOI 10.1210/er.2015-1010. Free full text in PubMed Central (PMC4702494). Note: Much of the evidence comes from animal studies, and the Society itself cautions against inferring cause in humans; published in 2015.
What It Found
The Endocrine Society reviewed evidence on endocrine-disrupting chemicals (EDCs) such as BPA, phthalates, pesticides and PCBs in seven areas: obesity and diabetes, female and male reproduction, hormone-sensitive cancers in women, prostate, thyroid, and brain development. It concluded the evidence had strengthened since 2009, with causal links shown in animals that are consistent with human correlational data, especially for exposures in early development.
Why It Matters Here
Explains how everyday chemicals that mimic or block hormones may contribute to obesity, diabetes, fertility problems and thyroid disease, and why pregnancy and early childhood are sensitive windows.
Scientific statement of the Endocrine Society — expert review of human and animal studies, mainly from 2010–2015. Moderate evidence. Endocr Rev 2015;36(6):E1–E150. DOI 10.1210/er.2015-1010. Free full text in PubMed Central (PMC4702494). Note: Much of the evidence comes from animal studies, and the Society itself cautions against inferring cause in humans; published in 2015.
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Exposure to endocrine-disrupting chemicals and anthropometric measures of obesity: a systematic review and meta-analysis — Ribeiro et al., BMJ Open 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7311014/
Systematic review and meta-analysis — 73 observational studies, mostly cross-sectional. Moderate evidence. BMJ Open 2020;10(6):e033509. DOI 10.1136/bmjopen-2019-033509. Free full text in PubMed Central (PMC7311014) — open access, CC BY-NC 4.0. Note: Mostly cross-sectional studies that measured chemicals once, so they cannot show whether exposure led to weight gain or the reverse.
What It Found
Across 73 studies (over 32,000 people for BPA and over 21,000 for phthalates), bisphenol A and phthalates were consistently associated with general and abdominal obesity in children and adults. In adults, higher BPA exposure was linked with obesity (odds ratio 1.50; 95% CI 1.27 to 1.77) and a larger waist (1.50; 1.27 to 1.78). The authors state that causality cannot be determined from these data.
Why It Matters Here
Explains a possible extra contributor to weight gain beyond food and activity — chemicals found in plastics, packaging and personal-care products — for readers working on weight and metabolic health.
Systematic review and meta-analysis — 73 observational studies, mostly cross-sectional. Moderate evidence. BMJ Open 2020;10(6):e033509. DOI 10.1136/bmjopen-2019-033509. Free full text in PubMed Central (PMC7311014) — open access, CC BY-NC 4.0. Note: Mostly cross-sectional studies that measured chemicals once, so they cannot show whether exposure led to weight gain or the reverse.
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Risk to human health related to the presence of perfluoroalkyl substances in food — EFSA Panel on Contaminants in the Food Chain (CONTAM) et al., EFSA J 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7507523/
Scientific opinion (risk assessment) of the European Food Safety Authority's expert panel — human, animal and exposure data. Moderate evidence. EFSA J 2020;18(9):e06223. DOI 10.2903/j.efsa.2020.6223. Free full text in PubMed Central (PMC7507523) — open access, CC BY-ND 4.0. Note: EFSA judged the overall uncertainty of its assessment to be high, and the safe-intake figure was derived from a single study of 1-year-old children.
What It Found
EFSA set a tolerable weekly intake of 4.4 ng per kg of body weight for four PFAS combined (PFOA, PFNA, PFHxS and PFOS), based on weaker antibody responses to vaccines in children. It found clear evidence linking PFAS with higher blood cholesterol and a possible causal link with lower birth weight, but insufficient evidence for diabetes, obesity or metabolic syndrome. Parts of the European population exceed the safe intake; fish, fruit and eggs contributed most.
Why It Matters Here
Explains which health effects of PFAS ('forever chemicals') a major food-safety regulator considers well supported and which remain unproven; relevant to parents and PFAS-affected communities. In 2023 the WHO cancer agency (IARC) classed PFOA as carcinogenic to humans, mainly on animal and mechanistic evidence.
Scientific opinion (risk assessment) of the European Food Safety Authority's expert panel — human, animal and exposure data. Moderate evidence. EFSA J 2020;18(9):e06223. DOI 10.2903/j.efsa.2020.6223. Free full text in PubMed Central (PMC7507523) — open access, CC BY-ND 4.0. Note: EFSA judged the overall uncertainty of its assessment to be high, and the safe-intake figure was derived from a single study of 1-year-old children.
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Human health implications of organic food and organic agriculture: a comprehensive review — Mie et al., Environ Health 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5658984/
Comprehensive (narrative) review, written after a European Parliament (STOA) workshop. Moderate evidence. Environ Health 2017;16:111. DOI 10.1186/s12940-017-0315-4. Free full text in PubMed Central (PMC5658984) — open access, CC BY 4.0. Note: A narrative review; most health links are from observational studies, and it is unclear how far farm-exposure findings apply to residues in food.
What It Found
Residues on conventional fruit and vegetables are most people's main source of pesticide exposure; in EU testing about 1.5% of food samples were estimated to exceed short-term safety limits, but none of the organic samples did. Farm and spray exposure has been linked with Parkinson's disease, type 2 diabetes and some cancers, and prenatal organophosphate exposure with poorer child cognition. Organic eating may lower allergy and overweight risk, but confounding is likely.
Why It Matters Here
Explains how food choices change pesticide exposure and what organic food can and cannot be expected to do, stressing that residues are no reason to eat less fruit and vegetables; relevant to readers weighing up organic produce.
Comprehensive (narrative) review, written after a European Parliament (STOA) workshop. Moderate evidence. Environ Health 2017;16:111. DOI 10.1186/s12940-017-0315-4. Free full text in PubMed Central (PMC5658984) — open access, CC BY 4.0. Note: A narrative review; most health links are from observational studies, and it is unclear how far farm-exposure findings apply to residues in food.
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Environmental toxic metal contaminants and risk of cardiovascular disease: systematic review and meta-analysis — Chowdhury et al., BMJ 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6113772/
Systematic review and meta-analysis — 37 observational studies, 348,259 participants. Moderate evidence. BMJ 2018;362:k3310. DOI 10.1136/bmj.k3310. Free full text in PubMed Central (PMC6113772) — open access, CC BY-NC 4.0. Note: Based only on observational studies that may be affected by unmeasured confounding, so the authors say cause is hard to establish.
What It Found
Pooling 37 studies of 348,259 people, those in the top third of exposure had a higher risk of cardiovascular disease than those in the bottom third for arsenic (relative risk 1.30), lead (1.43), cadmium (1.33) and copper (1.81); lead was also linked with an 85% higher risk of coronary heart disease. Mercury showed no clear link. Risk rose steadily with exposure for arsenic, lead and cadmium.
Why It Matters Here
Explains that everyday exposure to toxic metals is linked with heart disease beyond the usual lifestyle risk factors; relevant to readers with, or at risk of, heart disease.
Systematic review and meta-analysis — 37 observational studies, 348,259 participants. Moderate evidence. BMJ 2018;362:k3310. DOI 10.1136/bmj.k3310. Free full text in PubMed Central (PMC6113772) — open access, CC BY-NC 4.0. Note: Based only on observational studies that may be affected by unmeasured confounding, so the authors say cause is hard to establish.
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Low-Level Environmental Lead Exposure and Children's Intellectual Function: An International Pooled Analysis — Lanphear et al., Environ Health Perspect 2005

https://pmc.ncbi.nlm.nih.gov/articles/PMC1257652/
Pooled analysis of 7 prospective cohorts in 4 countries — 1,333 children, IQ tested at ages 5–10. Moderate evidence. Environ Health Perspect 2005;113(7):894–899 (erratum: Environ Health Perspect 2019;127(9):099001). DOI 10.1289/ehp.7688. Free full text in PubMed Central (PMC1257652) — public domain. Note: Observational cohorts begun before 1995; a 2019 erratum corrected some figures (the PMC page shows the originals) without changing the conclusions.
What It Found
Pooling seven cohorts from four countries (including Port Pirie, South Australia), the study found that higher blood lead in children went with lower IQ, with no safe threshold seen. In the corrected (2019) figures, a rise in blood lead from 2.4 to 30 µg/dL was linked with 6.7 fewer IQ points, and the loss was steepest at low levels: 3.8 points from 2.4 to 10 µg/dL, against 1.8 points from 10 to 20 µg/dL.
Why It Matters Here
Explains why even low lead exposure in early childhood matters for brain development and why no safe level is known; relevant to parents and carers of young children and to communities with known lead contamination.
Pooled analysis of 7 prospective cohorts in 4 countries — 1,333 children, IQ tested at ages 5–10. Moderate evidence. Environ Health Perspect 2005;113(7):894–899 (erratum: Environ Health Perspect 2019;127(9):099001). DOI 10.1289/ehp.7688. Free full text in PubMed Central (PMC1257652) — public domain. Note: Observational cohorts begun before 1995; a 2019 erratum corrected some figures (the PMC page shows the originals) without changing the conclusions.
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Lifestyle interventions to reduce endocrine-disrupting phthalate and phenol exposures among reproductive age men and women: A review and future steps — Martin et al., Environ Int 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9890927/
Review of 21 intervention studies (dietary, behavioural and household) aiming to lower phthalate and phenol levels such as BPA and parabens. Early evidence. Environ Int 2022;170:107576. DOI 10.1016/j.envint.2022.107576. Free full text in PubMed Central (PMC9890927) — open access, CC BY-NC-ND 4.0. Note: Mostly small, short studies measuring urine levels, not health outcomes; results varied and some interventions did not lower exposure.
What It Found
Of 21 studies that tried to cut exposure to phthalates and phenols such as BPA and parabens, the most successful provided replacement products or diets and targeted several exposure routes, often with personalised education and regular support such as meetings or support groups. Results were mixed: in one fresh-food study chemical levels rose, likely from contaminated foods. Few studies checked whether lower levels improve health.
Why It Matters Here
Explains which practical steps have lowered everyday exposure to hormone-disrupting chemicals from food packaging and personal-care products, and that studies offering ongoing personal support tended to do better.
Review of 21 intervention studies (dietary, behavioural and household) aiming to lower phthalate and phenol levels such as BPA and parabens. Early evidence. Environ Int 2022;170:107576. DOI 10.1016/j.envint.2022.107576. Free full text in PubMed Central (PMC9890927) — open access, CC BY-NC-ND 4.0. Note: Mostly small, short studies measuring urine levels, not health outcomes; results varied and some interventions did not lower exposure.
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Stress, Trauma & Adversity — How They Are Linked to Chronic Disease

The effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis — Hughes et al., Lancet Public Health 2017

https://doi.org/10.1016/S2468-2667(17)30118-4
Systematic review and meta-analysis — 37 studies, 253,719 adults, 23 health outcomes. Moderate evidence. Lancet Public Health 2017;2(8):e356–e366. Free full text at the publisher — open access, CC BY-NC-ND. Note: The studies were observational and mostly relied on adults recalling childhood events, so they show links, not proof of cause; results varied widely between studies for about half the outcomes.
What It Found
Adults who had at least four adverse childhood experiences (such as abuse, neglect or domestic violence) were at higher risk of every outcome studied than those with none. The links were weaker for physical inactivity, overweight and diabetes (odds ratios under 2), moderate for smoking, heavy drinking, cancer, heart disease and respiratory disease (2–3), and strongest for problem drug use and violence (over 7).
Why It Matters Here
Explains why childhood adversity matters for long-term physical as well as mental health, and why the trauma therapists in chapter 05 and the trauma survivor support in chapter 06 are relevant to people living with chronic illness.
Systematic review and meta-analysis — 37 studies, 253,719 adults, 23 health outcomes. Moderate evidence. Lancet Public Health 2017;2(8):e356–e366. Free full text at the publisher — open access, CC BY-NC-ND. Note: The studies were observational and mostly relied on adults recalling childhood events, so they show links, not proof of cause; results varied widely between studies for about half the outcomes.
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Life course health consequences and associated annual costs of adverse childhood experiences across Europe and North America: a systematic review and meta-analysis — Bellis et al., Lancet Public Health 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC7098477/
Systematic review and meta-analysis — 23 studies (11 in Europe, 12 in North America), with attributable-fraction and cost modelling. Moderate evidence. Lancet Public Health 2019;4(10):e517–e528. DOI 10.1016/S2468-2667(19)30145-8. Free full text in PubMed Central (PMC7098477) — open access, CC BY 4.0. Note: Observational studies, many retrospective and self-reported; the attributable shares and costs assume the links are causal.
What It Found
Pooled 23 studies comparing adults with and without adverse childhood experiences (ACEs: abuse, neglect, household dysfunction). Two or more ACEs were reported by 18.7% in Europe and 35.0% in North America. The authors estimated ACEs could account for about 40% of depression and 30% of anxiety in North America (over a quarter in Europe) and smaller shares of heart disease, cancer and diabetes, costing US$581 billion a year in Europe and $748 billion in North America.
Why It Matters Here
Explains how much adult ill health — especially depression, anxiety, drug use, heavy drinking and smoking — is linked with a hard childhood, which is why the trauma-focused therapists in chapter 05 and the survivor communities in chapter 06 belong alongside the metabolic and medical listings.
Systematic review and meta-analysis — 23 studies (11 in Europe, 12 in North America), with attributable-fraction and cost modelling. Moderate evidence. Lancet Public Health 2019;4(10):e517–e528. DOI 10.1016/S2468-2667(19)30145-8. Free full text in PubMed Central (PMC7098477) — open access, CC BY 4.0. Note: Observational studies, many retrospective and self-reported; the attributable shares and costs assume the links are causal.
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The impact of adverse childhood experiences on multimorbidity: a systematic review and meta-analysis — Senaratne et al., BMC Med 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11325707/
Systematic review and meta-analysis — 25 observational studies, 372,162 people (dose–response analysis in 8 studies, 197,981 people). Moderate evidence. BMC Med 2024;22:315. DOI 10.1186/s12916-024-03505-w. Free full text in PubMed Central (PMC11325707) — open access, CC BY 4.0. Note: Observational studies with recalled ACEs; most were rated at high risk of bias from confounding, and childhood socio-economic status could not be separated out.
What It Found
Brought together 25 studies (372,162 adults) on childhood adversity and multimorbidity, meaning living with two or more long-term conditions. Pooled, 48.1% had at least one ACE and 34.5% had multimorbidity. In the eight studies with enough data, each additional ACE was linked with 12.9% higher odds of multimorbidity (95% CI 7.9% to 17.9%), a dose–response pattern, although results varied a lot between studies (I² 76.9%).
Why It Matters Here
Explains that childhood adversity is linked with a higher chance of living with several long-term conditions, which supports trauma-aware care from the chronic-illness and trauma therapists in chapter 05 and the multi-condition communities in chapter 06.
Systematic review and meta-analysis — 25 observational studies, 372,162 people (dose–response analysis in 8 studies, 197,981 people). Moderate evidence. BMC Med 2024;22:315. DOI 10.1186/s12916-024-03505-w. Free full text in PubMed Central (PMC11325707) — open access, CC BY 4.0. Note: Observational studies with recalled ACEs; most were rated at high risk of bias from confounding, and childhood socio-economic status could not be separated out.
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Adverse childhood experience is associated with an increased risk of reporting chronic pain in adulthood: a stystematic review and meta-analysis — Bussières et al., Eur J Psychotraumatol 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10993817/
Systematic review and meta-analysis — 85 observational studies, 826,452 adults (57 studies pooled). Moderate evidence. Eur J Psychotraumatol 2023;14(2):2284025. DOI 10.1080/20008066.2023.2284025. Free full text in PubMed Central (PMC10993817) — open access, CC BY-NC 4.0. Note: Observational studies relying mostly on adults' recall; an association, not proof that adversity causes pain, and results varied between studies.
What It Found
Reviewed 85 studies of 826,452 adults. People who reported direct childhood adversity (sexual, physical or emotional abuse, or neglect) had higher odds of chronic pain as adults (adjusted odds ratio 1.45, 95% CI 1.38 to 1.53), and childhood physical abuse was also linked with pain-related disability (1.46, 1.03 to 2.08). Risk rose with the number of ACEs, from 1.29 for one ACE to 1.95 for four or more.
Why It Matters Here
Explains why childhood adversity comes up so often in chronic pain: it is linked with a higher chance of pain and pain-related disability later in life. Relevant to the pain books in chapter 10, the trauma therapists in chapter 05 and the chronic-pain and fibromyalgia communities in chapter 06.
Systematic review and meta-analysis — 85 observational studies, 826,452 adults (57 studies pooled). Moderate evidence. Eur J Psychotraumatol 2023;14(2):2284025. DOI 10.1080/20008066.2023.2284025. Free full text in PubMed Central (PMC10993817) — open access, CC BY-NC 4.0. Note: Observational studies relying mostly on adults' recall; an association, not proof that adversity causes pain, and results varied between studies.
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Childhood and Adolescent Adversity and Cardiometabolic Outcomes: A Scientific Statement From the American Heart Association — Suglia et al., Circulation 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC7792566/
American Heart Association scientific statement — expert review of the published evidence (16 authors). Moderate evidence. Circulation 2018;137(5):e15–e28. DOI 10.1161/CIR.0000000000000536. Free full text in PubMed Central (PMC7792566). Note: A narrative statement, not a meta-analysis; most underlying studies were cross-sectional and relied on adults' recall of childhood.
What It Found
The American Heart Association reviewed how adversity in childhood and adolescence relates to obesity, high blood pressure, type 2 diabetes and heart disease. It found substantial evidence of an association across the life course, often rising with more adversity and most consistent for physical and sexual abuse. It outlined likely pathways through behaviour (such as smoking and overeating), mental health and stress biology, and noted most studies were cross-sectional.
Why It Matters Here
Explains why heart and metabolic risk can have roots in childhood stress, linking the metabolic-health books in chapter 10 with the trauma therapists in chapter 05. Most relevant to readers with diabetes, weight or heart concerns and a difficult childhood.
American Heart Association scientific statement — expert review of the published evidence (16 authors). Moderate evidence. Circulation 2018;137(5):e15–e28. DOI 10.1161/CIR.0000000000000536. Free full text in PubMed Central (PMC7792566). Note: A narrative statement, not a meta-analysis; most underlying studies were cross-sectional and relied on adults' recall of childhood.
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Childhood Adversities Increase the Risk of Psychosis: A Meta-analysis of Patient-Control, Prospective- and Cross-sectional Cohort Studies — Varese et al., Schizophr Bull 2012

https://pmc.ncbi.nlm.nih.gov/articles/PMC3406538/
Meta-analysis — 36 studies: 18 patient–control, 10 prospective and 8 population-based cross-sectional (about 81,000 people). Moderate evidence. Schizophr Bull 2012;38(4):661–671. DOI 10.1093/schbul/sbs050. Free full text in PubMed Central (PMC3406538) — open access, CC BY-NC 3.0. Note: Mostly patient–control and cross-sectional studies that differed widely in how adversity was measured; observational, so cause is not shown.
What It Found
Pooled 36 studies on childhood adversity (sexual, physical and emotional abuse, neglect, parental death and bullying) and psychosis. Adversity was linked with almost three times the odds of psychosis (odds ratio 2.78, 95% CI 2.34 to 3.31), with similar results in prospective studies (2.75). The estimated population attributable risk was 33% (16% to 47%), a figure that assumes the link is causal.
Why It Matters Here
Explains why trauma history matters in serious mental illness, backing trauma-informed help from the therapists in chapter 05 and the survivor and mental-health communities in chapter 06 for people living with psychosis.
Meta-analysis — 36 studies: 18 patient–control, 10 prospective and 8 population-based cross-sectional (about 81,000 people). Moderate evidence. Schizophr Bull 2012;38(4):661–671. DOI 10.1093/schbul/sbs050. Free full text in PubMed Central (PMC3406538) — open access, CC BY-NC 3.0. Note: Mostly patient–control and cross-sectional studies that differed widely in how adversity was measured; observational, so cause is not shown.
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Population vs Individual Prediction of Poor Health From Results of Adverse Childhood Experiences Screening — Baldwin et al., JAMA Pediatr 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC7835926/
Two prospective birth cohorts — E-Risk (UK; 2,009 followed to age 18) and Dunedin (New Zealand; 918 followed to age 45). Moderate evidence. JAMA Pediatr 2021;175(4):385–393. DOI 10.1001/jamapediatrics.2020.5602. Free full text in PubMed Central (PMC7835926) — open access, CC BY 4.0. Note: Two cohorts from high-income countries, with health measured at 18 and 45 years, so later-life disease was not covered.
What It Found
Tested whether ACE scores can tell who will become unwell. In the UK cohort each extra ACE was linked with a 14% higher risk of a mental health problem and 9% of a physical one, yet scores sorted individuals barely better than chance (AUC 0.58 and 0.60; 0.50 is chance). Of children with four or more ACEs, 56% had a mental health problem at 18, against 33% of those with none. The New Zealand cohort gave the same picture.
Why It Matters Here
Explains how to read ACE research: a high score signals higher risk across a group, not a fixed future for any one person, and screening by ACE score alone is unlikely to target help well. Useful for anyone who has done an online ACE quiz.
Two prospective birth cohorts — E-Risk (UK; 2,009 followed to age 18) and Dunedin (New Zealand; 918 followed to age 45). Moderate evidence. JAMA Pediatr 2021;175(4):385–393. DOI 10.1001/jamapediatrics.2020.5602. Free full text in PubMed Central (PMC7835926) — open access, CC BY 4.0. Note: Two cohorts from high-income countries, with health measured at 18 and 45 years, so later-life disease was not covered.
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Trauma and PTSD in the WHO World Mental Health Surveys — Kessler et al., Eur J Psychotraumatol 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5632781/
Cross-national population surveys — WHO World Mental Health surveys in 24 countries, 68,894 adults. Early evidence. Eur J Psychotraumatol 2017;8(sup5):1353383. DOI 10.1080/20008198.2017.1353383. Free full text in PubMed Central (PMC5632781) — open access, CC BY 4.0. Note: Traumas were recalled in lay interviews and PTSD was assessed with a structured survey interview using DSM-IV criteria, not by clinicians.
What It Found
Representative surveys of 68,894 adults in 24 countries found 70.4% had lived through at least one traumatic event, with an average of 3.2 traumas per person across the population. About 4% of traumas led to PTSD, but risk varied greatly by type and was highest after interpersonal violence, reaching 19% after rape. Rape, other sexual assault, being stalked and the unexpected death of a loved one together made up about half of all years lived with PTSD.
Why It Matters Here
Backs up the sexual-violence and trauma-survivor services in chapter 06 (such as RAINN, After Silence and 1800RESPECT) and the trauma specialists in chapter 05: trauma is common, and violence, above all sexual violence, carries the highest risk of PTSD.
Cross-national population surveys — WHO World Mental Health surveys in 24 countries, 68,894 adults. Early evidence. Eur J Psychotraumatol 2017;8(sup5):1353383. DOI 10.1080/20008198.2017.1353383. Free full text in PubMed Central (PMC5632781) — open access, CC BY 4.0. Note: Traumas were recalled in lay interviews and PTSD was assessed with a structured survey interview using DSM-IV criteria, not by clinicians.
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Stress related disorders and risk of cardiovascular disease: population based, sibling controlled cohort study — Song et al., BMJ 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6457109/
Population-based, sibling-controlled cohort study (Sweden) — 136,637 people with stress-related disorders, 171,314 siblings and 1,366,370 matched people. Moderate evidence. BMJ 2019;365:l1255. DOI 10.1136/bmj.l1255. Free full text in PubMed Central (PMC6457109) — open access, CC BY-NC 4.0. Note: Observational: the sibling design controls for shared family background, but other differences, such as lifestyle, may explain part of the link.
What It Found
Followed Swedish people diagnosed with PTSD or other stress-related disorders for up to 27 years. Compared with their own unaffected brothers and sisters, they had a 64% higher risk of cardiovascular disease in the first year after diagnosis (hazard ratio 1.64, 95% CI 1.45 to 1.84) and a 29% higher risk after that (1.29, 1.24 to 1.34). The link was stronger for cardiovascular disease starting before age 50.
Why It Matters Here
Explains that severe stress reactions such as PTSD are linked with heart and blood-vessel disease, not only with mood; the authors call for closer clinical attention after diagnosis. Relevant to people using the trauma therapists in chapter 05 and the trauma communities in chapter 06.
Population-based, sibling-controlled cohort study (Sweden) — 136,637 people with stress-related disorders, 171,314 siblings and 1,366,370 matched people. Moderate evidence. BMJ 2019;365:l1255. DOI 10.1136/bmj.l1255. Free full text in PubMed Central (PMC6457109) — open access, CC BY-NC 4.0. Note: Observational: the sibling design controls for shared family background, but other differences, such as lifestyle, may explain part of the link.
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Association of Stress-Related Disorders With Subsequent Autoimmune Disease — Song et al., JAMA 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6583688/
Population- and sibling-matched cohort study (Sweden) — 106,464 people with stress-related disorders, 1,064,640 matched people and 126,652 siblings. Moderate evidence. JAMA 2018;319(23):2388–2400. DOI 10.1001/jama.2018.7028. Free full text in PubMed Central (PMC6583688). Note: Observational registry study of diagnosed stress disorders, so everyday stress is not covered and cause is not shown.
What It Found
Over a mean of 10 years, people diagnosed with stress-related disorders (PTSD, acute stress reaction, adjustment disorder) developed autoimmune disease at 9.1 per 1,000 person-years, against 6.0 in matched people and 6.5 in their siblings. Their risk was 36% higher (hazard ratio 1.36, 95% CI 1.33 to 1.40); for PTSD it was 1.46 for any and 2.29 for three or more autoimmune diseases. Results held in the sibling comparison.
Why It Matters Here
Explains a link between severe stress reactions and later autoimmune disease. Relevant to the autoimmune communities in chapter 06 and to anyone living with both trauma and an autoimmune condition, alongside the trauma therapists in chapter 05.
Population- and sibling-matched cohort study (Sweden) — 106,464 people with stress-related disorders, 1,064,640 matched people and 126,652 siblings. Moderate evidence. JAMA 2018;319(23):2388–2400. DOI 10.1001/jama.2018.7028. Free full text in PubMed Central (PMC6583688). Note: Observational registry study of diagnosed stress disorders, so everyday stress is not covered and cause is not shown.
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Global and regional estimates of violence against women: prevalence and health effects of intimate partner violence and non-partner sexual violence — WHO 2013

https://iris.who.int/handle/10665/85239
WHO systematic reviews and global estimates — prevalence data from 155 studies in 81 countries, plus reviews of health effects. Moderate evidence. Geneva: World Health Organization; 2013. ISBN 978 92 4 156462 5. Free from the World Health Organization. Note: Health-effect estimates come from observational studies; prevalence data are from before 2013 (WHO published updated 2018 estimates in 2021).
What It Found
WHO's first global review found 35% of women worldwide had experienced physical or sexual violence by a partner or sexual violence by someone else, and up to 38% of murders of women were committed by partners. Women abused by a partner were almost twice as likely to experience depression (pooled odds ratio 1.97 in longitudinal studies); non-partner sexual violence was linked with 2.3 times the odds of alcohol use disorders and 2.6 times depression or anxiety.
Why It Matters Here
Backs up the domestic, family and sexual violence services in chapter 06 (1800RESPECT, Women's Aid, the US National Domestic Violence Hotline, RAINN) and the trauma therapists in chapter 05: violence is common and leaves lasting harm to mental and physical health.
WHO systematic reviews and global estimates — prevalence data from 155 studies in 81 countries, plus reviews of health effects. Moderate evidence. Geneva: World Health Organization; 2013. ISBN 978 92 4 156462 5. Free from the World Health Organization. Note: Health-effect estimates come from observational studies; prevalence data are from before 2013 (WHO published updated 2018 estimates in 2021).
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Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data — Kivimäki et al., Lancet 2012

https://pmc.ncbi.nlm.nih.gov/articles/PMC3486012/
Individual-participant meta-analysis — 13 European cohort studies, 197,473 employees, 2,358 coronary events. Moderate evidence. Lancet 2012;380(9852):1491–1497. DOI 10.1016/S0140-6736(12)60994-5. Free full text in PubMed Central (PMC3486012). Note: Observational: job strain was self-reported once; the link is modest and was smaller in unpublished than in published studies.
What It Found
Pooled original records from 13 European cohorts (197,473 working people followed for a mean of 7.5 years). The 15% who reported job strain (high demands with little control) had a 23% higher risk of a first heart attack or coronary death (hazard ratio 1.23, 95% CI 1.10 to 1.37), still seen after excluding early events. The authors estimated job strain accounts for 3.4% of coronary events, a much smaller share than smoking.
Why It Matters Here
Explains that job strain is linked with a modestly higher risk of heart disease; the authors suggest easing workplace stress might lower risk, though far less than tackling smoking. Relevant to the workplace mental-health support in chapter 05 and the stress-reduction resources in chapters 10 and 13.
Individual-participant meta-analysis — 13 European cohort studies, 197,473 employees, 2,358 coronary events. Moderate evidence. Lancet 2012;380(9852):1491–1497. DOI 10.1016/S0140-6736(12)60994-5. Free full text in PubMed Central (PMC3486012). Note: Observational: job strain was self-reported once; the link is modest and was smaller in unpublished than in published studies.
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WHO guidelines on mental health at work — WHO 2022

https://iris.who.int/handle/10665/363177
WHO guideline developed with GRADE systematic reviews — recommendations on organisational, manager, worker and individual interventions. Moderate evidence. Geneva: World Health Organization; 2022. ISBN 978-92-4-005305-2. Free from the World Health Organization — open access, CC BY-NC-SA 3.0 IGO. Note: Most recommendations are conditional and rest on low or very low certainty evidence; WHO made no recommendation on workplace screening.
What It Found
WHO's first global guidelines on mental health at work. They recommend training managers to support workers' mental health (strong recommendation, moderate-certainty evidence) and reasonable adjustments for workers with mental health conditions. Stress-management programmes based on mindfulness or CBT, and leisure-time exercise, may be considered (conditional; low or very low certainty). WHO estimates 15% of working-age adults have a mental disorder at any time.
Why It Matters Here
Backs up the workplace mental-health service in chapter 05 and the CBT, mindfulness and exercise resources in chapters 10 and 13 for people whose stress comes from work. Also useful for managers and employers.
WHO guideline developed with GRADE systematic reviews — recommendations on organisational, manager, worker and individual interventions. Moderate evidence. Geneva: World Health Organization; 2022. ISBN 978-92-4-005305-2. Free from the World Health Organization — open access, CC BY-NC-SA 3.0 IGO. Note: Most recommendations are conditional and rest on low or very low certainty evidence; WHO made no recommendation on workplace screening.
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Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α — Baumeister et al., Mol Psychiatry 2016

https://pmc.ncbi.nlm.nih.gov/articles/PMC4564950/
Meta-analysis — 25 studies; C-reactive protein in 16,870 people, interleukin-6 in 3,751 and TNF-α in 881. Moderate evidence. Mol Psychiatry 2016;21(5):642–649. DOI 10.1038/mp.2015.67. Free full text in PubMed Central (PMC4564950) — open access, CC BY 4.0. Note: Effects were small and studies mostly measured inflammation once in people recalling past trauma, so cause and long-term consequences are not shown.
What It Found
Pooled 25 studies comparing adults with and without childhood trauma. Those exposed had higher blood levels of three markers of inflammation: C-reactive protein (Fisher's z 0.10, 95% CI 0.05 to 0.14), interleukin-6 (0.08) and TNF-α (0.23), all small effects. Different kinds of abuse were linked with different markers, and age, body mass index and sex did not explain the results.
Why It Matters Here
Explains one way early trauma may 'get under the skin': low-grade inflammation, which the authors propose as a biological link between childhood adversity and later physical and mental illness. Background for the trauma books in chapter 10.
Meta-analysis — 25 studies; C-reactive protein in 16,870 people, interleukin-6 in 3,751 and TNF-α in 881. Moderate evidence. Mol Psychiatry 2016;21(5):642–649. DOI 10.1038/mp.2015.67. Free full text in PubMed Central (PMC4564950) — open access, CC BY 4.0. Note: Effects were small and studies mostly measured inflammation once in people recalling past trauma, so cause and long-term consequences are not shown.
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Neurobiological and Systemic Effects of Chronic Stress — McEwen, Chronic Stress (Thousand Oaks) 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5573220/
Narrative review by the scientist who developed the concept of allostatic load. Early evidence. Chronic Stress (Thousand Oaks) 2017;1:2470547017692328. DOI 10.1177/2470547017692328. Free full text in PubMed Central (PMC5573220) — open access, CC BY-NC 3.0. Note: Expert narrative review drawing heavily on animal and laboratory studies; it is not a systematic review and does not measure risks in people.
What It Found
Explains 'allostasis': the body's stress systems (the HPA axis and cortisol, the autonomic nervous system, immune and metabolic signals) help us adapt, but when overused or out of balance they cause wear and tear, called 'allostatic load'. It describes how chronic stress reshapes brain circuits and affects immune and metabolic health, how early adversity has lasting effects, and urges better sleep, social support, healthy diet and moderate activity.
Why It Matters Here
Explains the biology linking chronic stress with illness, and why the sleep, movement, social-connection and stress-reduction resources in chapters 06, 10 and 13 all bear on it.
Narrative review by the scientist who developed the concept of allostatic load. Early evidence. Chronic Stress (Thousand Oaks) 2017;1:2470547017692328. DOI 10.1177/2470547017692328. Free full text in PubMed Central (PMC5573220) — open access, CC BY-NC 3.0. Note: Expert narrative review drawing heavily on animal and laboratory studies; it is not a systematic review and does not measure risks in people.
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Quantity and Quality of Sleep and Incidence of Type 2 Diabetes: A systematic review and meta-analysis — Cappuccio et al., Diabetes Care 2010

https://pmc.ncbi.nlm.nih.gov/articles/PMC2809295/
Systematic review and meta-analysis — 10 prospective studies (13 cohorts), 107,756 people, 3,586 new cases of type 2 diabetes. Moderate evidence. Diabetes Care 2010;33(2):414–420. DOI 10.2337/dc09-1124. Free full text in PubMed Central (PMC2809295) — open access, CC BY-NC-ND 3.0. Note: Observational, with self-reported sleep; it does not show that improving sleep lowers diabetes risk.
What It Found
Pooled 10 prospective studies of 107,756 adults followed for 4 to 32 years. Short sleep (5–6 hours or less a night) was linked with a 28% higher risk of developing type 2 diabetes (relative risk 1.28, 95% CI 1.03 to 1.60) and long sleep (over 8–9 hours) with a 48% higher risk. Difficulty falling asleep (1.57) and difficulty staying asleep (1.84) were also linked with higher risk.
Why It Matters Here
Explains that short, long and broken sleep are all linked with a higher risk of type 2 diabetes. Background for the sleep clinics and insomnia programmes in chapter 11 and the sleep books in chapter 10, though it did not test whether better sleep lowers that risk.
Systematic review and meta-analysis — 10 prospective studies (13 cohorts), 107,756 people, 3,586 new cases of type 2 diabetes. Moderate evidence. Diabetes Care 2010;33(2):414–420. DOI 10.2337/dc09-1124. Free full text in PubMed Central (PMC2809295) — open access, CC BY-NC-ND 3.0. Note: Observational, with self-reported sleep; it does not show that improving sleep lowers diabetes risk.
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Psychological interventions for coronary heart disease — Richards et al., Cochrane Database Syst Rev 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC6478177/
Cochrane systematic review and meta-analysis — 35 randomised trials, 10,703 people with coronary heart disease. Moderate evidence. Cochrane Database Syst Rev 2017;4:CD002902. DOI 10.1002/14651858.CD002902.pub4. Free full text in PubMed Central (PMC6478177). Note: Considerable uncertainty: trial reporting was often poor, evidence for heart deaths and symptoms was low quality, and there were signs of small-study bias.
What It Found
Reviewed 35 trials of psychological treatments, mostly combining several approaches, for people with coronary heart disease. They did not reduce deaths from all causes (risk ratio 0.90, 95% CI 0.77 to 1.05; moderate-quality evidence), but deaths from heart causes fell by 21% (0.79, 0.63 to 0.98; low quality). Depression, anxiety and stress symptoms improved modestly (low or very low quality).
Why It Matters Here
Backs up the therapists in chapter 05 for people living with heart disease: psychological care may ease distress and may lower deaths from heart causes, though it was not shown to lengthen life overall.
Cochrane systematic review and meta-analysis — 35 randomised trials, 10,703 people with coronary heart disease. Moderate evidence. Cochrane Database Syst Rev 2017;4:CD002902. DOI 10.1002/14651858.CD002902.pub4. Free full text in PubMed Central (PMC6478177). Note: Considerable uncertainty: trial reporting was often poor, evidence for heart deaths and symptoms was low quality, and there were signs of small-study bias.
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The Microbiome & Chronic Disease

Role of the gut microbiota in nutrition and health — Valdes et al., BMJ 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6000740/
Narrative review, including a summary table of 22 systematic reviews of probiotic trials (313 trials, 46,826 participants). Early evidence. BMJ 2018;361:k2179. DOI 10.1136/bmj.k2179. Free full text in PubMed Central (PMC6000740) — open access, CC BY-NC 4.0. Note: Narrative rather than systematic review; much of the evidence it covers is observational or from animals, and authors declare links to nutrition, prebiotic and synbiotic companies.
What It Found
The authors explain how gut microbes ferment fibre into short-chain fatty acids and how diet, medicines and antibiotics shape the microbiome. Lower microbial diversity has been found in obesity, cardiometabolic and autoimmune conditions, but they stress that observational studies cannot show cause. Their summary of 22 systematic reviews (313 trials, 46,826 people) found good evidence that probiotics help prevent some conditions, such as diarrhoea and, in children, eczema.
Why It Matters Here
Explains how food, fibre and medicines shape the gut microbiome and what probiotics can and cannot do; backs up the microbiome-science and probiotic guides in chapter 15 and the home-cooking and food-and-mood resources in chapter 10.
Narrative review, including a summary table of 22 systematic reviews of probiotic trials (313 trials, 46,826 participants). Early evidence. BMJ 2018;361:k2179. DOI 10.1136/bmj.k2179. Free full text in PubMed Central (PMC6000740) — open access, CC BY-NC 4.0. Note: Narrative rather than systematic review; much of the evidence it covers is observational or from animals, and authors declare links to nutrition, prebiotic and synbiotic companies.
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Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases — Sanna et al., Nat Genet 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6441384/
Mendelian randomisation study — genotypes, gut metagenomes and stool short-chain fatty acids in 952 Dutch adults without diabetes, tested against 17 metabolic traits; propionate result replicated in UK Biobank. Early evidence. Nat Genet 2019;51(4):600–605. DOI 10.1038/s41588-019-0350-x. Free full text in PubMed Central (PMC6441384). Note: Effects were small and rest on Mendelian randomisation assumptions; the propionate result missed the authors' main significance threshold until replicated in UK Biobank.
What It Found
Most microbiome–disease links are associations. This study used people's genes as a natural experiment (Mendelian randomisation) in 952 adults. Genetically higher gut production of butyrate, made when bacteria ferment fibre, was linked with a better insulin response after a glucose drink (P = 9.8×10⁻⁵), and higher stool propionate with higher type 2 diabetes risk (odds ratio 1.15 per standard deviation; P = 0.004). The authors read this as evidence of a causal effect.
Why It Matters Here
Explains why fibre-fermenting gut bacteria may matter for blood-sugar control, using genetics to test cause rather than simple association; background for the gut-health and metabolic resources elsewhere in the directory rather than support for any one listing.
Mendelian randomisation study — genotypes, gut metagenomes and stool short-chain fatty acids in 952 Dutch adults without diabetes, tested against 17 metabolic traits; propionate result replicated in UK Biobank. Early evidence. Nat Genet 2019;51(4):600–605. DOI 10.1038/s41588-019-0350-x. Free full text in PubMed Central (PMC6441384). Note: Effects were small and rest on Mendelian randomisation assumptions; the propionate result missed the authors' main significance threshold until replicated in UK Biobank.
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Gut microbiota–derived metabolite trimethylamine-N-oxide and multiple health outcomes: an umbrella review and updated meta-analysis — Li et al., Am J Clin Nutr 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9257469/
Umbrella review and updated meta-analyses of observational studies — 24 meta-analyses, 82 studies, 18 health outcomes. Moderate evidence. Am J Clin Nutr 2022;116(1):230–243. DOI 10.1093/ajcn/nqac074. Free full text in PubMed Central (PMC9257469) — open access, CC BY 4.0. Note: All included studies were observational, so cause cannot be inferred; TMAO is closely tied to kidney function, and a Mendelian randomisation study found no causal link with heart disease.
What It Found
TMAO forms when gut bacteria break down choline and carnitine (found in meat, eggs, dairy and seafood) and the liver converts the product. People with the highest blood TMAO had a higher risk of major cardiovascular events (hazard ratio 1.74, 95% CI 1.55 to 1.95; 36 studies) and of death from any cause (1.60, 1.43 to 1.79; 37 studies) than those with the lowest. Six links, including diabetes and high blood pressure, were rated 'highly suggestive'; none 'convincing'.
Why It Matters Here
Explains one way gut bacteria may connect diet with heart, kidney and metabolic disease; the authors call TMAO a possible risk marker and say it is not yet known whether lowering it would prevent disease.
Umbrella review and updated meta-analyses of observational studies — 24 meta-analyses, 82 studies, 18 health outcomes. Moderate evidence. Am J Clin Nutr 2022;116(1):230–243. DOI 10.1093/ajcn/nqac074. Free full text in PubMed Central (PMC9257469) — open access, CC BY 4.0. Note: All included studies were observational, so cause cannot be inferred; TMAO is closely tied to kidney function, and a Mendelian randomisation study found no causal link with heart disease.
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Gut microbiome–targeted therapies in nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression — Sharpton et al., Am J Clin Nutr 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6599739/
Systematic review and meta-analysis — 21 randomised trials, 1,252 people with non-alcoholic fatty liver disease. Moderate evidence. Am J Clin Nutr 2019;110(1):139–149. DOI 10.1093/ajcn/nqz042. Free full text in PubMed Central (PMC6599739). Note: Results varied widely between trials (I² over 90% for ALT and liver stiffness), trials were short, and none used liver biopsy, so long-term benefit is unknown.
What It Found
Twenty-one randomised trials (1,252 people with non-alcoholic fatty liver disease, now called MASLD) tested probiotics or synbiotics (probiotics plus prebiotic fibre) for 8–28 weeks. They lowered the liver enzyme ALT (by 11.2 IU/L; 16 trials) and liver stiffness (by 0.70 kPa; 4 trials), and raised the odds of less fat on ultrasound (odds ratio 2.40, 95% CI 1.50 to 3.84; 6 trials). No trials of antibiotics or faecal transplant were found; none measured liver biopsy changes.
Why It Matters Here
Backs up the probiotic guides in chapter 15 (WGO probiotics guideline, Clinical Guide to Probiotic Products, ISAPP) for people with fatty liver; most relevant to anyone told they have fatty liver disease who is asking about probiotics.
Systematic review and meta-analysis — 21 randomised trials, 1,252 people with non-alcoholic fatty liver disease. Moderate evidence. Am J Clin Nutr 2019;110(1):139–149. DOI 10.1093/ajcn/nqz042. Free full text in PubMed Central (PMC6599739). Note: Results varied widely between trials (I² over 90% for ALT and liver stiffness), trials were short, and none used liver biopsy, so long-term benefit is unknown.
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Effects of fecal microbiota transplantation on glycemic and lipid profiles in overweight or obese patients with metabolic disorders: a systematic review and meta-analysis — Zhang et al., Front Endocrinol (Lausanne) 2025

https://pmc.ncbi.nlm.nih.gov/articles/PMC12745229/
Systematic review and meta-analysis — 11 randomised trials, 320 adults with overweight or obesity and metabolic disease (PROSPERO-registered). Moderate evidence. Front Endocrinol (Lausanne) 2025;16:1737543. DOI 10.3389/fendo.2025.1737543. Free full text in PubMed Central (PMC12745229) — open access, CC BY 4.0. Note: Low-certainty evidence from small trials with different donors and methods; an earlier meta-analysis found small short-term HbA1c and insulin improvements but no weight loss.
What It Found
Eleven randomised trials (320 adults with overweight or obesity plus metabolic syndrome, type 2 diabetes or related problems) tested faecal microbiota transplant (FMT) from healthy lean donors. Pooled, FMT did not significantly change body mass index (−0.65; P = 0.07), insulin resistance (HOMA-IR −0.64; P = 0.06) or HbA1c (P = 0.74), on low-certainty evidence. The authors conclude its true metabolic benefit remains uncertain.
Why It Matters Here
Explains that faecal transplant is not an established treatment for weight or blood sugar; context for the FMT clinic directory in chapter 01 and the regulated FMT services in chapter 15, whose proven use is recurrent C. difficile infection.
Systematic review and meta-analysis — 11 randomised trials, 320 adults with overweight or obesity and metabolic disease (PROSPERO-registered). Moderate evidence. Front Endocrinol (Lausanne) 2025;16:1737543. DOI 10.3389/fendo.2025.1737543. Free full text in PubMed Central (PMC12745229) — open access, CC BY 4.0. Note: Low-certainty evidence from small trials with different donors and methods; an earlier meta-analysis found small short-term HbA1c and insulin improvements but no weight loss.
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Fecal transplantation for treatment of inflammatory bowel disease — Imdad et al., Cochrane Database Syst Rev 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10133790/
Cochrane systematic review and meta-analysis — 12 randomised trials, 550 adults and children with ulcerative colitis or Crohn's disease. Moderate evidence. Cochrane Database Syst Rev 2023;(4):CD012774. DOI 10.1002/14651858.CD012774.pub3. Free full text in PubMed Central (PMC10133790). Note: Low-certainty evidence from small, short trials using different donors and routes; no trial tested FMT for bringing Crohn's disease into remission.
What It Found
Twelve randomised trials (550 people) tested faecal microbiota transplant (FMT) for inflammatory bowel disease. In active ulcerative colitis, FMT may increase the chance of clinical remission (10 trials, 468 people; risk ratio 1.79, 95% CI 1.13 to 2.84; low-certainty evidence), with little or no difference in overall side effects. Evidence on serious harms, on keeping remission and on Crohn's disease was very uncertain.
Why It Matters Here
Explains where faecal transplant stands for Crohn's and colitis: it may help bring active ulcerative colitis into remission (low-certainty evidence) but is unproven for Crohn's; context for the FMT listings in chapter 01, the FMT programmes and trial registries in chapter 15 and the IBD groups in chapters 06 and 15.
Cochrane systematic review and meta-analysis — 12 randomised trials, 550 adults and children with ulcerative colitis or Crohn's disease. Moderate evidence. Cochrane Database Syst Rev 2023;(4):CD012774. DOI 10.1002/14651858.CD012774.pub3. Free full text in PubMed Central (PMC10133790). Note: Low-certainty evidence from small, short trials using different donors and routes; no trial tested FMT for bringing Crohn's disease into remission.
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Antibiotic use as a risk factor for inflammatory bowel disease across the ages: a population-based cohort study — Faye et al., Gut 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC9998355/
Nationwide registry cohort — 6,104,245 Danish residents aged 10 and over, 2000–2018, 52,898 new cases of IBD. Moderate evidence. Gut 2023;72(4):663–670. DOI 10.1136/gutjnl-2022-327845. Free full text in PubMed Central (PMC9998355). Note: Observational: the infections being treated, rather than the antibiotics, may explain part of the link, and early undiagnosed IBD could prompt prescriptions.
What It Found
Following everyone in Denmark aged 10 or over from 2000 to 2018 (6.1 million people; 52,898 new cases of inflammatory bowel disease), antibiotic use was linked with a higher rate of IBD at every age: 28% higher at 10–40 years, 48% at 40–60 and 47% at 60 and over (incidence rate ratios 1.28, 1.48, 1.47). Risk rose with more courses, peaked 1–2 years after use, and was highest after antibiotics often used for gut infections.
Why It Matters Here
Explains how disturbing the gut microbiome may contribute to Crohn's disease and colitis, and why the authors see antibiotic stewardship as important; context for the IBD organisations and support groups in chapters 06 and 15.
Nationwide registry cohort — 6,104,245 Danish residents aged 10 and over, 2000–2018, 52,898 new cases of IBD. Moderate evidence. Gut 2023;72(4):663–670. DOI 10.1136/gutjnl-2022-327845. Free full text in PubMed Central (PMC9998355). Note: Observational: the infections being treated, rather than the antibiotics, may explain part of the link, and early undiagnosed IBD could prompt prescriptions.
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Association of Infant Antibiotic Exposure With Childhood Health Outcomes — Aversa et al., Mayo Clin Proc 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC7796951/
Population-based birth cohort — 14,572 children born 2003–2011 in Olmsted County, Minnesota, followed to 2017. Moderate evidence. Mayo Clin Proc 2021;96(1):66–77. DOI 10.1016/j.mayocp.2020.07.019. Free full text in PubMed Central (PMC7796951). Note: Observational, from one US county; the infections antibiotics were given for may explain some links (confounding by indication), and reverse causation is possible.
What It Found
Of 14,572 children born in one US county, 70% had at least one antibiotic prescription before age 2. Early antibiotics were linked with higher risk of childhood asthma, allergic rhinitis, eczema (atopic dermatitis), coeliac disease, overweight, obesity and ADHD (hazard ratios 1.20 to 2.89). Links depended on the number, type and timing of courses. The authors stress their findings 'reflect associations, not causation'.
Why It Matters Here
Explains how antibiotics in the first two years, which disturb the developing gut microbiome, may be linked with later allergies, coeliac disease and weight; context for the coeliac organisations in chapter 15.
Population-based birth cohort — 14,572 children born 2003–2011 in Olmsted County, Minnesota, followed to 2017. Moderate evidence. Mayo Clin Proc 2021;96(1):66–77. DOI 10.1016/j.mayocp.2020.07.019. Free full text in PubMed Central (PMC7796951). Note: Observational, from one US county; the infections antibiotics were given for may explain some links (confounding by indication), and reverse causation is possible.
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Gut microbiome of multiple sclerosis patients and paired household healthy controls reveal associations with disease risk and course — iMSMS Consortium, Cell 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC10143502/
Case–control study — 576 people with multiple sclerosis and 576 healthy household partners at seven sites in the USA, Argentina, Scotland and Spain. Early evidence. Cell 2022;185(19):3467–3486.e16. DOI 10.1016/j.cell.2022.08.021. Free full text in PubMed Central (PMC10143502). Note: A one-off comparison, so it cannot show whether microbes help cause MS or whether MS and its treatments change the microbes.
What It Found
Each of 576 people with multiple sclerosis was compared with a genetically unrelated healthy person from the same household (mostly spouses, sharing diet and surroundings). The MS group had more of some bacteria, such as Akkermansia muciniphila, and less of others, such as Faecalibacterium prausnitzii, a major butyrate producer; microbiome function also differed with MS treatments. The authors say the results 'strongly support' links with MS risk and course.
Why It Matters Here
Explains how the gut microbiome is being studied as an environmental factor in multiple sclerosis; context for the MS lifestyle programme in chapter 16 and the autoimmune communities in chapter 06, which this study did not test.
Case–control study — 576 people with multiple sclerosis and 576 healthy household partners at seven sites in the USA, Argentina, Scotland and Spain. Early evidence. Cell 2022;185(19):3467–3486.e16. DOI 10.1016/j.cell.2022.08.021. Free full text in PubMed Central (PMC10143502). Note: A one-off comparison, so it cannot show whether microbes help cause MS or whether MS and its treatments change the microbes.
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Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer — Wirbel et al., Nat Med 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC7984229/
Meta-analysis of 8 case–control stool metagenome studies (N = 768) from 7 countries on 3 continents. Moderate evidence. Nat Med 2019;25(4):679–689. DOI 10.1038/s41591-019-0406-6. Free full text in PubMed Central (PMC7984229). Note: Case–control data cannot show whether the bacteria help cause cancer or the tumour changes the gut; the authors note causality is unresolved.
What It Found
Re-analysing eight stool-sequencing studies of colorectal cancer from seven countries, researchers found a core set of 29 bacterial species consistently enriched in people with the cancer, including Fusobacterium, Porphyromonas and Parvimonas. Cancer-linked microbiomes had more genes for breaking down protein and mucus and fewer for carbohydrates, which the authors say fits known dietary risks (red meat, low fibre). Signatures from one study kept their accuracy in the others.
Why It Matters Here
Explains how gut bacteria are linked with bowel cancer and why diet may be part of that link; context for the gut-health services and gastroenterologist finders in chapter 15.
Meta-analysis of 8 case–control stool metagenome studies (N = 768) from 7 countries on 3 continents. Moderate evidence. Nat Med 2019;25(4):679–689. DOI 10.1038/s41591-019-0406-6. Free full text in PubMed Central (PMC7984229). Note: Case–control data cannot show whether the bacteria help cause cancer or the tumour changes the gut; the authors note causality is unresolved.
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Perturbations in Gut Microbiota Composition in Psychiatric Disorders: A Review and Meta-analysis — Nikolova et al., JAMA Psychiatry 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8444066/
Umbrella review and meta-analysis of 59 case–control studies across eight psychiatric disorders (diversity meta-analysis: 1,519 patients, 1,429 controls). Moderate evidence. JAMA Psychiatry 2021;78(12):1343–1354. DOI 10.1001/jamapsychiatry.2021.2573. Free full text in PubMed Central (PMC8444066) — open access, CC BY. Note: Case–control studies cannot show whether gut bacteria affect mental health or the illness, its medicines and diet change the bacteria; most studies were small to moderate in size.
What It Found
Across 59 case–control studies of depression, bipolar disorder, psychosis, anxiety, anorexia, OCD, PTSD and ADHD, patients overall had lower gut microbial richness (Chao1 standardised mean difference −0.5), consistently so only in bipolar disorder. Rather than disorder-specific patterns, they found a shared one: fewer anti-inflammatory, butyrate-producing bacteria (Faecalibacterium, Coprococcus) and more Eggerthella in depression, bipolar disorder, psychosis and anxiety.
Why It Matters Here
Explains what is known about gut bacteria in mental illness; background for the gut–brain research and information listings in chapter 15 and the food-and-mood course and books in chapter 10. The shared pattern means the microbiome is not a test for any one condition.
Umbrella review and meta-analysis of 59 case–control studies across eight psychiatric disorders (diversity meta-analysis: 1,519 patients, 1,429 controls). Moderate evidence. JAMA Psychiatry 2021;78(12):1343–1354. DOI 10.1001/jamapsychiatry.2021.2573. Free full text in PubMed Central (PMC8444066) — open access, CC BY. Note: Case–control studies cannot show whether gut bacteria affect mental health or the illness, its medicines and diet change the bacteria; most studies were small to moderate in size.
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Machine learning-based meta-analysis reveals gut microbiome alterations associated with Parkinson's disease — Romano et al., Nat Commun 2025

https://pmc.ncbi.nlm.nih.gov/articles/PMC12059030/
Meta-analysis with machine learning — 22 case–control studies, 4,489 stool samples from 11 countries. Moderate evidence. Nat Commun 2025;16(1):4227. DOI 10.1038/s41467-025-56829-3. Free full text in PubMed Central (PMC12059030) — open access, CC BY 4.0. Note: Case–control data cannot show cause or effect; some differences may reflect Parkinson's medicines, and microbiome tests did not transfer well between studies.
What It Found
Pooling 4,489 stool samples from 22 case–control studies in 11 countries, the gut microbiome of people with Parkinson's disease differed consistently from that of controls, including fewer Faecalibacterium and more microbial genes for breaking down solvents and pesticides, which the authors relate to known environmental risk factors. Microbiome tests sorted patients from controls fairly well within a study (average AUC 71.9%) but poorly in other studies (61%).
Why It Matters Here
Explains what is and is not known about gut bacteria in Parkinson's disease; context for the Parkinson's organisations in chapter 06 and the gut–brain research centres in chapter 15.
Meta-analysis with machine learning — 22 case–control studies, 4,489 stool samples from 11 countries. Moderate evidence. Nat Commun 2025;16(1):4227. DOI 10.1038/s41467-025-56829-3. Free full text in PubMed Central (PMC12059030) — open access, CC BY 4.0. Note: Case–control data cannot show cause or effect; some differences may reflect Parkinson's medicines, and microbiome tests did not transfer well between studies.
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Gut-microbiota-targeted diets modulate human immune status — Wastyk et al., Cell 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC9020749/
Randomised diet study — 18 healthy adults per arm, high-fermented-food vs high-fibre diet for 10 weeks within a 17-week study; no control arm. Early evidence. Cell 2021;184(16):4137–4153.e14. DOI 10.1016/j.cell.2021.06.019. Free full text in PubMed Central (PMC9020749). Note: Small study (18 healthy adults per diet) with no control group, a primary immune outcome that did not change, and no disease outcomes.
What It Found
Healthy adults were randomised to eat more fermented foods (such as yoghurt, kefir, kimchi and kombucha; up from 0.4 to 6.3 servings a day) or more fibre (21.5 to 45.1 g a day). In the fermented-food group, microbiome diversity rose steadily and 19 of 93 inflammatory proteins in the blood fell, including IL-6. The high-fibre diet did not raise diversity, and the main immune outcome did not change in either group.
Why It Matters Here
Backs up the fermentation book and food-and-mood resources in chapter 10 and ISAPP's fermented-food guidance in chapter 15 as a reason fermented foods are being studied; most relevant to people curious about yoghurt, kefir and kimchi.
Randomised diet study — 18 healthy adults per arm, high-fermented-food vs high-fibre diet for 10 weeks within a 17-week study; no control arm. Early evidence. Cell 2021;184(16):4137–4153.e14. DOI 10.1016/j.cell.2021.06.019. Free full text in PubMed Central (PMC9020749). Note: Small study (18 healthy adults per diet) with no control group, a primary immune outcome that did not change, and no disease outcomes.
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Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries — Ghosh et al., Gut 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7306987/
Microbiome sub-study of a 1-year randomised trial — 612 adults aged 65–79 in five European countries (323 Mediterranean-style diet, 289 controls). Early evidence. Gut 2020;69(7):1218–1228. DOI 10.1136/gutjnl-2019-319654. Free full text in PubMed Central (PMC7306987) — open access, CC BY-NC 4.0. Note: The links between microbiome changes and frailty were correlations within the trial, not randomised comparisons, so they do not show the bacteria caused the benefits.
What It Found
In 612 older adults in five European countries, a year of a Mediterranean-style diet tailored to older people (323 people, against 289 controls) did not change overall microbiome diversity, but closer adherence was linked with less loss of diversity and more of certain bacteria. Those diet-linked bacteria were associated with lower frailty, better cognitive function and lower inflammatory markers such as C-reactive protein.
Why It Matters Here
Backs up the Mediterranean-style cooking and eating-well resources in chapter 10 as one way to support the gut microbiome with age; most relevant to older adults and their carers.
Microbiome sub-study of a 1-year randomised trial — 612 adults aged 65–79 in five European countries (323 Mediterranean-style diet, 289 controls). Early evidence. Gut 2020;69(7):1218–1228. DOI 10.1136/gutjnl-2019-319654. Free full text in PubMed Central (PMC7306987) — open access, CC BY-NC 4.0. Note: The links between microbiome changes and frailty were correlations within the trial, not randomised comparisons, so they do not show the bacteria caused the benefits.
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International consensus statement on microbiome testing in clinical practice — Porcari et al., Lancet Gastroenterol Hepatol 2025

https://pmc.ncbi.nlm.nih.gov/articles/PMC12343204/
International expert consensus (Delphi process) — 69 experts from 18 countries, 35 statements, each needing at least 80% agreement. Moderate evidence. Lancet Gastroenterol Hepatol 2025;10(2):154–167. DOI 10.1016/S2468-1253(24)00311-X. Free full text in PubMed Central (PMC12343204). Note: Expert consensus rather than trial evidence; it sets standards for good testing but cannot itself show which tests improve health.
What It Found
Sixty-nine microbiome experts from 18 countries agreed that there is not yet enough evidence to recommend routine gut microbiome testing in clinical practice. They discouraged people from ordering tests without a clinical recommendation and testing companies from giving treatment advice, and discouraged reporting the Firmicutes-to-Bacteroidetes ratio, finding too little evidence for any 'dysbiosis index'.
Why It Matters Here
Backs up the warnings about home gut-microbiome tests in chapter 15 (EUFIC explainer, NIST comparison of test services); most relevant to anyone thinking of paying for a stool microbiome test.
International expert consensus (Delphi process) — 69 experts from 18 countries, 35 statements, each needing at least 80% agreement. Moderate evidence. Lancet Gastroenterol Hepatol 2025;10(2):154–167. DOI 10.1016/S2468-1253(24)00311-X. Free full text in PubMed Central (PMC12343204). Note: Expert consensus rather than trial evidence; it sets standards for good testing but cannot itself show which tests improve health.
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Treatment of periodontitis for glycaemic control in people with diabetes mellitus — Simpson et al., Cochrane Database Syst Rev 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9009294/
Cochrane systematic review and meta-analysis — 35 randomised trials, 3,249 people with diabetes and gum disease. Strong evidence. Cochrane Database Syst Rev 2022;(4):CD004714. DOI 10.1002/14651858.CD004714.pub4. Free full text in PubMed Central (PMC9009294). Note: Only two trials were at low risk of bias, few followed people beyond six months, and most did not assess side effects.
What It Found
Thirty-five randomised trials (3,249 people, nearly all with type 2 diabetes) compared professional gum treatment, which removes plaque (the film of bacteria on teeth) and tartar from below the gumline, with no or usual care. Treatment lowered HbA1c by 0.43 percentage points (4.7 mmol/mol; 95% CI 0.28 to 0.59) at 3 to 4 months (30 trials, moderate-certainty evidence) and by 0.30 points at 6 months. Trials that checked for harms found none or only mild ones.
Why It Matters Here
Explains a link between gum disease, which is driven by the bacterial film on teeth, and blood-sugar control: treating it improved diabetes control in trials; relevant to people with diabetes using the metabolic-health resources in chapter 10.
Cochrane systematic review and meta-analysis — 35 randomised trials, 3,249 people with diabetes and gum disease. Strong evidence. Cochrane Database Syst Rev 2022;(4):CD004714. DOI 10.1002/14651858.CD004714.pub4. Free full text in PubMed Central (PMC9009294). Note: Only two trials were at low risk of bias, few followed people beyond six months, and most did not assess side effects.
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Damp, Mould & Indoor Air — What the Research Shows

WHO guidelines for indoor air quality: dampness and mould — WHO 2009

https://iris.who.int/handle/10665/164348
WHO guideline — expert review of epidemiological, clinical and toxicological evidence (WHO working group, 2007). Moderate evidence. Copenhagen: WHO Regional Office for Europe, 2009. ISBN 978 92 890 4168 3. Free from the World Health Organization. Note: Evidence reviewed to 2007 and mostly observational; WHO found consistent links but judged that causation was not yet established and could not identify the microbes responsible.
What It Found
WHO's expert review found sufficient evidence that people in damp or mouldy homes and public buildings are at higher risk of respiratory symptoms, respiratory infections and asthma flare-ups, with some evidence for allergic rhinitis and asthma; mould exposure also raises the risk of rare conditions such as hypersensitivity pneumonitis. As the risk could not be quantified, WHO sets no numeric limits; it advises preventing damp and mould and fixing them when they occur.
Why It Matters Here
Explains that damp and mould are linked with breathing problems, can be prevented, and should be fixed at the source (leaks, condensation, poor ventilation); most relevant to people with asthma or allergies, and to families in damp housing.
WHO guideline — expert review of epidemiological, clinical and toxicological evidence (WHO working group, 2007). Moderate evidence. Copenhagen: WHO Regional Office for Europe, 2009. ISBN 978 92 890 4168 3. Free from the World Health Organization. Note: Evidence reviewed to 2007 and mostly observational; WHO found consistent links but judged that causation was not yet established and could not identify the microbes responsible.
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Respiratory and Allergic Health Effects of Dampness, Mold, and Dampness-Related Agents: A Review of the Epidemiologic Evidence — Mendell et al., Environ Health Perspect 2011

https://pmc.ncbi.nlm.nih.gov/articles/PMC3114807/
Review of epidemiological evidence — 103 studies published after the 2004 US Institute of Medicine review, plus that review's 45 studies (to late 2009). Moderate evidence. Environ Health Perspect 2011;119(6):748–756. DOI 10.1289/ehp.1002410. Free full text in PubMed Central (PMC3114807) — public domain. Note: Mostly observational studies to 2009, so for most outcomes it shows consistent links rather than proof that mould is the cause.
What It Found
Updating the US Institute of Medicine's 2004 review with 103 newer studies, the authors found damp or mould seen or smelt indoors consistently linked with new and worsening asthma, wheeze, cough, breathlessness, respiratory infections, bronchitis, allergic rhinitis and eczema, in allergic and non-allergic people. Evidence strongly suggested damp or mould causes asthma flare-ups in children. Evidence did not support measuring specific moulds or microbes to guide action.
Why It Matters Here
Explains which illnesses are linked with visible damp and mould, and why fixing the damp matters more than laboratory testing of a home; relevant to families with asthma, eczema or allergies and to anyone offered mould testing.
Review of epidemiological evidence — 103 studies published after the 2004 US Institute of Medicine review, plus that review's 45 studies (to late 2009). Moderate evidence. Environ Health Perspect 2011;119(6):748–756. DOI 10.1289/ehp.1002410. Free full text in PubMed Central (PMC3114807) — public domain. Note: Mostly observational studies to 2009, so for most outcomes it shows consistent links rather than proof that mould is the cause.
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Indoor mould exposure, asthma and rhinitis: findings from systematic reviews and recent longitudinal studies — Caillaud et al., Eur Respir Rev 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC9489198/
Systematic review for France's health-safety agency ANSES — 61 publications from 2006–2017 (7 meta-analyses, 4 systematic reviews, longitudinal, incident case-control and panel studies). Moderate evidence. Eur Respir Rev 2018;27(148):170137. DOI 10.1183/16000617.0137-2017. Free full text in PubMed Central (PMC9489198) — open access, CC BY-NC 4.0. Note: A narrative synthesis of observational studies without pooled estimates; evidence in adults outside the workplace remains limited.
What It Found
Experts for France's health-safety agency (ANSES) reviewed 61 publications from 2006–2017, focusing on studies that followed people over time. In children, visible mould and mould odour were linked with developing asthma and with asthma attacks, which they judged sufficient evidence of a causal relationship. In adults the evidence was limited, apart from asthma linked with mouldy workplaces. Evidence of a link with allergic rhinitis was sufficient.
Why It Matters Here
Explains the evidence that mouldy homes can bring on and worsen childhood asthma; most relevant to parents of children with asthma or wheeze, and to adults whose breathing is worse in a damp workplace.
Systematic review for France's health-safety agency ANSES — 61 publications from 2006–2017 (7 meta-analyses, 4 systematic reviews, longitudinal, incident case-control and panel studies). Moderate evidence. Eur Respir Rev 2018;27(148):170137. DOI 10.1183/16000617.0137-2017. Free full text in PubMed Central (PMC9489198) — open access, CC BY-NC 4.0. Note: A narrative synthesis of observational studies without pooled estimates; evidence in adults outside the workplace remains limited.
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Childhood asthma and mould in homes—A meta-analysis — Varga et al., Wien Klin Wochenschr 2025

https://pmc.ncbi.nlm.nih.gov/articles/PMC11794369/
Systematic review and meta-analysis — 32 observational studies of children (11 cohort, 21 case-control). Moderate evidence. Wien Klin Wochenschr 2025;137(3–4):79–88. DOI 10.1007/s00508-024-02396-4. Free full text in PubMed Central (PMC11794369) — open access, CC BY 4.0. Note: Observational studies: the stronger cohort studies found a smaller, less consistent effect, and case-control results may be inflated by parents' recall of mould.
What It Found
Pooling 11 cohort and 21 case-control studies of children, the authors found that living in a mouldy home was linked with a higher chance of later developing asthma: 53% higher odds in the case-control studies (OR 1.53, 95% CI 1.42–1.65) and 15% higher in the cohort studies (OR 1.15, 95% CI 1.01–1.31), with no sign of publication bias. Results of the cohort studies varied considerably.
Why It Matters Here
Explains that early-life exposure to a mouldy home may help bring on childhood asthma, not only trigger attacks; most relevant to parents of babies and young children living with damp or mould.
Systematic review and meta-analysis — 32 observational studies of children (11 cohort, 21 case-control). Moderate evidence. Wien Klin Wochenschr 2025;137(3–4):79–88. DOI 10.1007/s00508-024-02396-4. Free full text in PubMed Central (PMC11794369) — open access, CC BY 4.0. Note: Observational studies: the stronger cohort studies found a smaller, less consistent effect, and case-control results may be inflated by parents' recall of mould.
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Association of residential dampness and mold with respiratory tract infections and bronchitis: a meta-analysis — Fisk et al., Environ Health 2010

https://pmc.ncbi.nlm.nih.gov/articles/PMC3000394/
Meta-analysis — 23 observational studies (mostly cross-sectional). Moderate evidence. Environ Health 2010;9:72. DOI 10.1186/1476-069X-9-72. Free full text in PubMed Central (PMC3000394) — open access, CC BY 2.0. Note: Mostly one-off surveys with self-reported damp, so other factors may explain part of the link; the authors say causation is not yet confirmed.
What It Found
Across 23 studies, damp or mould at home was linked with about 45% higher odds of bronchitis (OR 1.45, 95% CI 1.32–1.59) and of respiratory infections (OR 1.44, 1.31–1.59) in studies adjusted for age, sex, smoking and socioeconomic status, and 48% higher odds of respiratory infections in children (OR 1.48, 1.33–1.65). If the link is causal, damp and mould would account for an estimated 8–20% of these infections.
Why It Matters Here
Explains why children and adults in damp or mouldy homes may get more respiratory infections and bronchitis; relevant to families dealing with frequent coughs and colds.
Meta-analysis — 23 observational studies (mostly cross-sectional). Moderate evidence. Environ Health 2010;9:72. DOI 10.1186/1476-069X-9-72. Free full text in PubMed Central (PMC3000394) — open access, CC BY 2.0. Note: Mostly one-off surveys with self-reported damp, so other factors may explain part of the link; the authors say causation is not yet confirmed.
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Damp mouldy housing and early childhood hospital admissions for acute respiratory infection: a case control study — Ingham et al., Thorax 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6824607/
Case-control study — 188 children under 2 admitted with acute respiratory infection and 454 controls, Wellington, New Zealand (2011–2013). Early evidence. Thorax 2019;74(9):849–857. DOI 10.1136/thoraxjnl-2018-212979. Free full text in PubMed Central (PMC6824607) — open access, CC BY-NC 4.0. Note: Observational study in one city; the broader housing-quality score lost significance after adjustment, although the damp-mould score held.
What It Found
Independent building assessors, who did not know which children were cases, inspected the homes of 642 children under two in Wellington, New Zealand. Each one-point rise on an 8-item damp-mould index was linked with 15% higher odds of hospital admission for a respiratory infection (adjusted OR 1.15, 95% CI 1.02–1.30). The authors estimate that removing damp and mould could cut these admissions by 19%, about 1,700 fewer a year in New Zealand.
Why It Matters Here
Explains the link between damp, mouldy homes and respiratory infections serious enough to need hospital care in babies and toddlers; relevant to parents of young children and to renters seeking repairs.
Case-control study — 188 children under 2 admitted with acute respiratory infection and 454 controls, Wellington, New Zealand (2011–2013). Early evidence. Thorax 2019;74(9):849–857. DOI 10.1136/thoraxjnl-2018-212979. Free full text in PubMed Central (PMC6824607) — open access, CC BY-NC 4.0. Note: Observational study in one city; the broader housing-quality score lost significance after adjustment, although the damp-mould score held.
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A State-of-the-Science Review of the Effect of Damp- and Mold-Affected Housing on Mental Health — Gatto et al., Environ Health Perspect 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11334706/
State-of-the-science review — 19 observational studies, 2003–2023 (63% cross-sectional). Early evidence. Environ Health Perspect 2024;132(8):086001. DOI 10.1289/EHP14341. Free full text in PubMed Central (PMC11334706) — public domain. Note: Mostly one-off surveys the authors judged low quality; it shows a link, not cause, and the link may partly reflect other housing problems or run both ways.
What It Found
University of Melbourne researchers reviewed 19 studies from 2003–2023 on damp or mould at home and mental health. Most reported links with poorer mental health: depression, stress and anxiety in adults, postnatal depression in mothers, and emotional symptoms and difficulty regulating emotions in children. The authors judged the studies generally low in quality and call for better research.
Why It Matters Here
Explains that a damp, mouldy home may weigh on mental as well as physical health, through stress and worry and possibly biological effects; relevant to people whose low mood or anxiety is tied up with poor housing.
State-of-the-science review — 19 observational studies, 2003–2023 (63% cross-sectional). Early evidence. Environ Health Perspect 2024;132(8):086001. DOI 10.1289/EHP14341. Free full text in PubMed Central (PMC11334706) — public domain. Note: Mostly one-off surveys the authors judged low quality; it shows a link, not cause, and the link may partly reflect other housing problems or run both ways.
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Remediating buildings damaged by dampness and mould for preventing or reducing respiratory tract symptoms, infections and asthma — Sauni et al., Cochrane Database Syst Rev 2015

https://pmc.ncbi.nlm.nih.gov/articles/PMC6769180/
Cochrane systematic review — 12 studies, 8,028 people (3 randomised trials, one a cluster trial of 4,407 people, and 9 controlled before-after studies). Moderate evidence. Cochrane Database Syst Rev 2015;(2):CD007897. DOI 10.1002/14651858.CD007897.pub3. Free full text in PubMed Central (PMC6769180). Note: Few, varied studies (only three randomised) with mostly self-reported symptoms; evidence ranged from moderate to very low quality, and searches ended in 2014.
What It Found
Twelve studies (8,028 people) tested repairing damp, mouldy homes, schools or an office. Pooling two trials in homes, repairs reduced wheeze in adults (OR 0.64, 95% CI 0.55–0.75) and rhinitis, counted as a respiratory infection (OR 0.57, 0.49–0.66), with moderate-quality evidence. In one trial in children with asthma, home repairs did not clearly reduce symptom days or emergency visits compared with information only. School repairs gave inconsistent results.
Why It Matters Here
Explains that fixing the cause of damp and removing mould may ease asthma symptoms and respiratory infections in adults; relevant to people with asthma, renters seeking repairs and anyone weighing whether remediation is worth it.
Cochrane systematic review — 12 studies, 8,028 people (3 randomised trials, one a cluster trial of 4,407 people, and 9 controlled before-after studies). Moderate evidence. Cochrane Database Syst Rev 2015;(2):CD007897. DOI 10.1002/14651858.CD007897.pub3. Free full text in PubMed Central (PMC6769180). Note: Few, varied studies (only three randomised) with mostly self-reported symptoms; evidence ranged from moderate to very low quality, and searches ended in 2014.
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Effect of insulating existing houses on health inequality: cluster randomised study in the community — Howden-Chapman et al., BMJ 2007

https://pmc.ncbi.nlm.nih.gov/articles/PMC1808149/
Cluster randomised trial — 1,350 households, 4,407 people in seven low-income New Zealand communities. Moderate evidence. BMJ 2007;334(7591):460. DOI 10.1136/bmj.39070.573032.80. Free full text in PubMed Central (PMC1808149). Note: Health outcomes were self-reported by occupants who knew their home had been insulated, and the fall in hospital admissions was not significant.
What It Found
Insulating 1,350 low-income New Zealand homes made bedrooms slightly warmer (0.5 °C) and drier (relative humidity 2.3% lower) in winter while using less energy. People in insulated homes were less likely to report fair or poor health (OR 0.50, 95% CI 0.38–0.68), wheezing (OR 0.57, 0.47–0.70), children's days off school (OR 0.49, 0.31–0.80) and GP visits (OR 0.73, 0.62–0.87). The fall in hospital admissions for breathing problems was not statistically significant.
Why It Matters Here
Explains that insulating homes, making them warmer and drier, improved self-reported health and breathing in a randomised trial; relevant to renters, families and people with asthma in cold, damp housing.
Cluster randomised trial — 1,350 households, 4,407 people in seven low-income New Zealand communities. Moderate evidence. BMJ 2007;334(7591):460. DOI 10.1136/bmj.39070.573032.80. Free full text in PubMed Central (PMC1808149). Note: Health outcomes were self-reported by occupants who knew their home had been insulated, and the fall in hospital admissions was not significant.
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Indoor air quality at home — NICE 2020

https://www.nice.org.uk/guidance/ng149
National guideline (England) — evidence reviews and committee recommendations, developed with Public Health England. Moderate evidence. NICE guideline NG149, published 8 January 2020. Free to read on the NICE website. Note: Written for England's housing and legal system; the committee found limited evidence for some links and relied partly on its own judgement.
What It Found
NICE recommends advising people how to cut damp and condensation (background ventilation, extractor fans, avoiding drying clothes indoors where possible, fixing leaks), to ventilate when cooking, especially with gas, to choose low-VOC and low-formaldehyde products, and not to smoke indoors. Health professionals should explain that damp, mould, nitrogen dioxide and other pollutants can worsen asthma, and ask about housing when cough or wheeze keeps returning.
Why It Matters Here
Explains practical steps to keep the air at home healthy and when to ask a landlord or council for help; most relevant to people with asthma, COPD or heart disease, pregnant women and families with young children.
National guideline (England) — evidence reviews and committee recommendations, developed with Public Health England. Moderate evidence. NICE guideline NG149, published 8 January 2020. Free to read on the NICE website. Note: Written for England's housing and legal system; the committee found limited evidence for some links and relied partly on its own judgement.
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Diagnosis of Hypersensitivity Pneumonitis in Adults. An Official ATS/JRS/ALAT Clinical Practice Guideline — Raghu et al., Am J Respir Crit Care Med 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7397797/
International clinical practice guideline (American Thoracic Society, Japanese Respiratory Society, Asociación Latinoamericana del Tórax) — six systematic reviews, GRADE recommendations. Moderate evidence. Am J Respir Crit Care Med 2020;202(3):e36–e69. DOI 10.1164/rccm.202005-2032ST. Free full text in PubMed Central (PMC7397797). Note: About diagnosis rather than prevention; it rests on limited direct evidence, and the trigger is not found in up to 60% of patients.
What It Found
Hypersensitivity pneumonitis is an immune-driven lung disease, sometimes with scarring, that develops in susceptible people exposed to an inhaled trigger. The guideline lists flooded or contaminated houses, humidifiers and home ventilation or cooling systems among sources of moulds and microbes that cause it, alongside birds and some chemicals. People with the non-scarring form who avoid the trigger may stabilise or recover fully; the scarring form has worse survival.
Why It Matters Here
Explains a rare but serious lung disease that household mould can cause, and why finding and removing the source matters; relevant to anyone with persistent, unexplained breathlessness or cough linked to a damp home or humidifier.
International clinical practice guideline (American Thoracic Society, Japanese Respiratory Society, Asociación Latinoamericana del Tórax) — six systematic reviews, GRADE recommendations. Moderate evidence. Am J Respir Crit Care Med 2020;202(3):e36–e69. DOI 10.1164/rccm.202005-2032ST. Free full text in PubMed Central (PMC7397797). Note: About diagnosis rather than prevention; it rests on limited direct evidence, and the trigger is not found in up to 60% of patients.
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AWMF mold guideline “Medical clinical diagnostics for indoor mold exposure” – Update 2023 AWMF Register No. 161/001 — Hurraß et al., Allergol Select 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11097193/
Consensus clinical guideline (AWMF S2k) of German-speaking medical societies — literature review with formal consensus (>95% agreement on key messages). Moderate evidence. Allergol Select 2024;8:90–198. DOI 10.5414/ALX02444E. Free full text in PubMed Central (PMC11097193) — open access, CC BY 2.5. Note: A consensus guideline rather than a formal systematic review; 'insufficient evidence' means a link is unproven, not disproven.
What It Found
German-speaking medical societies graded the evidence on indoor mould and disease: sufficient for links with allergic rhinitis, allergic asthma, hypersensitivity pneumonitis, respiratory infections, bronchitis and fungal infections in vulnerable people, but inadequate for chronic fatigue syndrome, autoimmune disease, multiple chemical sensitivity, neurotoxic effects, cancer or 'mycotoxicosis'. They advise against urine or blood mycotoxin tests.
Why It Matters Here
Explains what is and is not established about mould and illness: context for readers of the environmental-illness educator ISEAI (chapter 16) and for anyone offered a 'mould illness' diagnosis or mycotoxin test, including by some functional-medicine practitioners (chapter 01).
Consensus clinical guideline (AWMF S2k) of German-speaking medical societies — literature review with formal consensus (>95% agreement on key messages). Moderate evidence. Allergol Select 2024;8:90–198. DOI 10.5414/ALX02444E. Free full text in PubMed Central (PMC11097193) — open access, CC BY 2.5. Note: A consensus guideline rather than a formal systematic review; 'insufficient evidence' means a link is unproven, not disproven.
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Exposure to formaldehyde and asthma outcomes: A systematic review, meta-analysis, and economic assessment — Lam et al., PLoS One 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8011796/
Systematic review (Navigation Guide method, PROSPERO-registered) and meta-analysis — 90 human studies assessed in detail (51% cross-sectional). Moderate evidence. PLoS One 2021;16(3):e0248258. DOI 10.1371/journal.pone.0248258. Free full text in PubMed Central (PMC8011796) — public domain. Note: About half the studies were one-off surveys and exposure measures varied; a broader 2015 review of household VOCs found that evidence poor and inconsistent.
What It Found
Formaldehyde is given off by pressed-wood products such as particleboard, foam insulation and some household products. Reviewing 90 studies and pooling those in children, the authors linked each 10 µg/m³ rise with 20% higher odds of an asthma diagnosis (OR 1.20, 95% CI 1.02–1.41); the link with worse symptoms was smaller and not significant (OR 1.08, 0.92–1.28). They rated the evidence moderate quality and 'sufficient' for asthma in children and adults.
Why It Matters Here
Explains why choosing low-formaldehyde furniture, flooring and building materials may matter for people with asthma, especially in new homes or after renovation.
Systematic review (Navigation Guide method, PROSPERO-registered) and meta-analysis — 90 human studies assessed in detail (51% cross-sectional). Moderate evidence. PLoS One 2021;16(3):e0248258. DOI 10.1371/journal.pone.0248258. Free full text in PubMed Central (PMC8011796) — public domain. Note: About half the studies were one-off surveys and exposure measures varied; a broader 2015 review of household VOCs found that evidence poor and inconsistent.
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Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies — Darby et al., BMJ 2005

https://pmc.ncbi.nlm.nih.gov/articles/PMC546066/
Pooled analysis of individual data — 13 case-control studies in nine European countries, 7,148 people with lung cancer and 14,208 controls. Moderate evidence. BMJ 2005;330(7485):223. DOI 10.1136/bmj.38308.477650.63. Free full text in PubMed Central (PMC546066). Note: Observational (case-control) data from Europe; radon levels vary widely between regions, and most of the absolute risk falls on smokers.
What It Found
Radon is a natural radioactive gas that can build up indoors from the ground. Pooling 13 European studies, lung-cancer risk rose 16% (95% CI 5–31%) for every 100 Bq/m³ of long-term home radon, in a straight line with no sign of a safe threshold. By age 75, estimated risk at 0, 100 and 400 Bq/m³ was about 0.4%, 0.5% and 0.7% for lifelong non-smokers but about 10%, 12% and 16% for smokers. Radon was estimated to cause about 2% of cancer deaths in Europe.
Why It Matters Here
Explains a common, invisible indoor cause of lung cancer and why the risk is far greater for smokers; relevant to people in high-radon areas deciding whether to test their home.
Pooled analysis of individual data — 13 case-control studies in nine European countries, 7,148 people with lung cancer and 14,208 controls. Moderate evidence. BMJ 2005;330(7485):223. DOI 10.1136/bmj.38308.477650.63. Free full text in PubMed Central (PMC546066). Note: Observational (case-control) data from Europe; radon levels vary widely between regions, and most of the absolute risk falls on smokers.
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Important Disclaimer
This directory is provided for educational and informational purposes only and does not constitute medical advice, diagnosis, or treatment. Always consult with a qualified healthcare professional before making changes to your medication regimen or starting any new therapy.

This document does not guarantee the legitimacy, quality, or suitability of any business, organization, or practitioner listed within. The inclusion of any listing does not constitute an endorsement, recommendation, or verification of credentials. All organizations listed are independent entities over which the creators of this directory have no control or oversight.

This directory is intended to be used as a starting point and reference for the reader to conduct their own research, exercise their own judgment, and apply their own discretion before engaging with any listed organization or professional. Readers are strongly encouraged to independently verify credentials, read reviews, check licensing, and confirm current pricing and availability directly with each organization before committing to any services.

Costs, availability, contact details, and services may change at any time without notice. Information was accurate to the best of our knowledge at the time of publication.

About Notbroken.io: this directory and the accompanying Breathe, Calm, Sleep, Move, Eat, Track and Build tools were created by Nathan Leary, who runs and updates them. How each tool works, its safety notes, the privacy policy and terms of use are at notbroken.io/about, notbroken.io/privacy and notbroken.io/terms. The tools are general wellness aids, not medical devices, and Track is a personal journal that never gives medication advice.

If you are in crisis: Please contact your local emergency services immediately, or reach out to one of the following helplines:

International: Chapter 02 of this directory lists free helplines by situation and country; elsewhere use Find A Helpline — findahelpline.com
United States: 988 Suicide & Crisis Lifeline (call or text 988) • Crisis Text Line (text HOME to 741741)
United Kingdom: Samaritans — 116 123 (free, 24/7)
Canada: Talk Suicide Canada — 988 (call or text, 24/7)
Australia: Lifeline — 13 11 14 (24/7) • Beyond Blue — 1300 22 4636
New Zealand: Need to Talk? — 1737 (free, 24/7)
Europe: European Emergency Number — 112
India: iCall — 9152987821 • Vandrevala Foundation — 1860 2662 345
Singapore: Samaritans of Singapore — 1-767 (24/7)
Japan: TELL Lifeline — 03-5774-0992

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