{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T07:14:51Z","timestamp":1791616491047,"version":"4.3.4"},"reference-count":32,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"unspecified","delay-in-days":15,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Australian Government Medical Research Future Fund","award":["2032847"],"award-info":[{"award-number":["2032847"]}]},{"DOI":"10.13039\/501100025520","name":"MRFF","doi-asserted-by":"crossref","award":["2034238"],"award-info":[{"award-number":["2034238"]}],"id":[{"id":"10.13039\/501100025520","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100025520","name":"MRFF","doi-asserted-by":"crossref","award":["2035160"],"award-info":[{"award-number":["2035160"]}],"id":[{"id":"10.13039\/501100025520","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2026,6,19]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Long covid is a debilitating chronic condition, and the effect of low-dose naltrexone (LDN) on its symptoms is unclear. We aimed to determine the effectiveness of LDN on symptoms of long covid.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Systematic review and meta-analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data sources<\/jats:title>\n                    <jats:p>PubMed, Embase and Cochrane Library for published studies; ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) for registered ongoing studies were searched through 5 May 2026.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Eligibility criteria<\/jats:title>\n                    <jats:p>We included randomised controlled trials and pre\u2013post studies of patients with long covid reporting on fatigue, quality of life, cognitive symptoms or function and other long covid symptoms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data extraction and synthesis<\/jats:title>\n                    <jats:p>Two independent reviewers used standardised methods to search, screen and select included studies. Risk of bias was assessed using the Newcastle-Ottawa Scale. Meta-analysis was conducted using random effects models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 397 titles and abstracts screened, no randomised controlled trials were identified. Four observational pre\u2013post studies from the USA and Ireland (n=155) met inclusion criteria. LDN doses varied from 1 mg\/day to 6\u2009mg\/day. Pooled pre\u2013post analyses showed moderate effects for reducing fatigue (Hedges\u2019 g=\u22120.74; 95%\u2009CI \u22121.11 to \u22120.37; p&lt;0.001), brain fog (Hedges\u2019 g=\u22120.53; 95%\u2009CI \u22121.01 to \u22120.05; p=0.03) and improving sleep quality (Hedges\u2019 g=\u22120.60; 95%\u2009CI \u22120.91 to \u22120.30; p=0.0001), and large effects for pain (Hedges\u2019 g=\u22120.93; 95%\u2009CI \u22121.29 to \u22120.57; p&lt;0.001) and daily functioning (Hedges\u2019 g=\u22120.93; 95%\u2009CI \u22121.29 to \u22120.57; p&lt;0.0001) in favour of LDN. Heterogeneity ranged from 0% to 62%. No serious adverse events were reported in the two studies that assessed safety.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Limited evidence from small pre\u2013post studies suggests LDN may improve fatigue, cognition, sleep, pain and functioning in long covid. However, certainty of evidence is low. Well-powered trials are needed to confirm efficacy, determine dosing and duration and identify subgroups most likely to benefit.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/doi.org\/10.17605\/OSF.IO\/C2VKX\">https:\/\/doi.org\/10.17605\/OSF.IO\/C2VKX<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-111253","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T15:25:34Z","timestamp":1784215534000},"page":"e111253","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Effect of low-dose naltrexone for long COVID: a systematic review and meta-analysis"],"prefix":"10.1136","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8641-1286","authenticated-orcid":false,"given":"Oyungerel","family":"Byambasuren","sequence":"first","affiliation":[{"name":"Institute for Evidence-Based Healthcare, Bond University, Robina, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Atkins","sequence":"additional","affiliation":[{"name":"Institute for Evidence-Based Healthcare, Bond University, Robina, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaira","family":"Baptista","sequence":"additional","affiliation":[{"name":"Australian Living Evidence Collaboration, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7564-073X","authenticated-orcid":false,"given":"Paul","family":"Glasziou","sequence":"additional","affiliation":[{"name":"Institute for Evidence-Based Healthcare, Bond University, Robina, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9708-4532","authenticated-orcid":false,"given":"Samantha","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Australian Living Evidence Collaboration, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"2026090306254587000_16.7.e111253.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00846-2"},{"key":"2026090306254587000_16.7.e111253.2","doi-asserted-by":"crossref","DOI":"10.1016\/j.socscimed.2020.113426","article-title":"How and why patients made Long Covid","volume":"268","author":"Callard","year":"2021","journal-title":"Soc Sci Med"},{"key":"2026090306254587000_16.7.e111253.3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.8823"},{"key":"2026090306254587000_16.7.e111253.4","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-021-95565-8","article-title":"More than 50 long-term effects of COVID-19: a systematic review and meta-analysis","volume":"11","author":"Lopez-Leon","year":"2021","journal-title":"Sci Rep"},{"key":"2026090306254587000_16.7.e111253.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03173-6"},{"key":"2026090306254587000_16.7.e111253.6","doi-asserted-by":"crossref","first-page":"1582967","DOI":"10.3389\/fmolb.2025.1582967","article-title":"Low-Dose naltrexone restored TRPM3 ion channel function in natural killer cells from long COVID patients","volume":"12","author":"Sasso","year":"2025","journal-title":"Front Mol Biosci"},{"key":"2026090306254587000_16.7.e111253.7","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2024.1264702","article-title":"Investigation into the restoration of TRPM3 ion channel activity in post-COVID-19 condition: a potential pharmacotherapeutic target","volume":"15","author":"Sasso","year":"2024","journal-title":"Front Immunol"},{"key":"2026090306254587000_16.7.e111253.8","doi-asserted-by":"crossref","DOI":"10.1186\/s12916-018-1242-0","article-title":"Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis","volume":"17","author":"Bolton","year":"2019","journal-title":"BMC Med"},{"key":"2026090306254587000_16.7.e111253.9","doi-asserted-by":"publisher","DOI":"10.1002\/phar.2086"},{"key":"2026090306254587000_16.7.e111253.10","doi-asserted-by":"publisher","DOI":"10.1002\/art.37734"},{"key":"2026090306254587000_16.7.e111253.11","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1093\/ehjcvp\/pvac014","article-title":"Repurposing low-dose naltrexone for the prevention and treatment of immunothrombosis in COVID-19","volume":"8","author":"Pitt","year":"2022","journal-title":"Eur Heart J Cardiovasc Pharmacother"},{"key":"2026090306254587000_16.7.e111253.12","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-014-2517-2"},{"key":"2026090306254587000_16.7.e111253.13","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"2026090306254587000_16.7.e111253.14","doi-asserted-by":"publisher","DOI":"10.1001\/jama.283.15.2008"},{"key":"2026090306254587000_16.7.e111253.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2020.01.008"},{"key":"2026090306254587000_16.7.e111253.16","doi-asserted-by":"crossref","first-page":"e102","DOI":"10.1016\/S1473-3099(21)00703-9","article-title":"A clinical case definition of post-COVID-19 condition by a Delphi consensus","volume":"22","author":"Soriano","year":"2022","journal-title":"Ancet Infect Dis"},{"key":"2026090306254587000_16.7.e111253.17","unstructured":"Wells G , Shea B , O\u2019Connell J . The Newcastle-Ottawa Scale (NOS) for Assessing The Quality of Nonrandomised Studies in Meta-analyses. Ottawa Health Research Institute Web Site 2014;7."},{"key":"2026090306254587000_16.7.e111253.18","unstructured":"Wilson DB . Practical meta-analysis effect size calculator(version 2023.11.27). Campbell Collaboration; 2023."},{"key":"2026090306254587000_16.7.e111253.19","unstructured":"Higgins JP , et al . Cochrane handbook for systematic reviews of interventions . Cochrane, 2024."},{"key":"2026090306254587000_16.7.e111253.20","first-page":"155","volume-title":"A power primer psychol bull","volume":"112","author":"Cohen","year":"1992"},{"key":"2026090306254587000_16.7.e111253.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110966"},{"key":"2026090306254587000_16.7.e111253.22","doi-asserted-by":"crossref","first-page":"100733","DOI":"10.1016\/j.bbih.2024.100733","article-title":"Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19","volume":"36","author":"Isman","year":"2024","journal-title":"Brain Behav Immun Health"},{"key":"2026090306254587000_16.7.e111253.23","doi-asserted-by":"crossref","first-page":"100485","DOI":"10.1016\/j.bbih.2022.100485","article-title":"Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study","volume":"24","author":"O\u2019Kelly","year":"2022","journal-title":"Brain Behav Immun Health"},{"key":"2026090306254587000_16.7.e111253.24","doi-asserted-by":"crossref","first-page":"e101","DOI":"10.1016\/j.clinthera.2023.12.009","article-title":"Low-dose Naltrexone Improves post-COVID-19 condition Symptoms","volume":"46","author":"Tamariz","year":"2024","journal-title":"Clin Ther"},{"key":"2026090306254587000_16.7.e111253.25","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2024-085272","article-title":"Low-dose naltrexone for post-COVID fatigue syndrome: a study protocol for a double-blind, randomised trial in British Columbia","volume":"14","author":"Naik","year":"2024","journal-title":"BMJ Open"},{"key":"2026090306254587000_16.7.e111253.26","unstructured":"NCT05430152 . Low-dose Naltrexone for Post-COVID Fatigue Syndrome. 2022."},{"key":"2026090306254587000_16.7.e111253.27","unstructured":"ACTRN12623001042639 . Low Dose Naltrexone for the treatment of long COVID-19. 2023."},{"key":"2026090306254587000_16.7.e111253.28","unstructured":"ACTRN12624001162505 . Low Dose Naltrexone for the treatment of Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (ME\/CFS) and Long COVID Condition. 2024."},{"key":"2026090306254587000_16.7.e111253.29","unstructured":"NCT06366724 . LIFT: Life Improvement Trial. 2025."},{"key":"2026090306254587000_16.7.e111253.30","doi-asserted-by":"crossref","DOI":"10.1186\/s12967-024-05412-3","article-title":"Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS) and the therapeutic effect of low-dose naltrexone","volume":"22","author":"L\u00f6hn","year":"2024","journal-title":"J Transl Med"},{"key":"2026090306254587000_16.7.e111253.31","unstructured":"Bateman Horne Center . Clinical care guide: managing ME\/CFS, long COVID, & infection-associated chronic conditions . 2025: USA,"},{"key":"2026090306254587000_16.7.e111253.32","unstructured":"The Cohen Center for Recovery from Complex Chronic Illness . Infection-associated chronic illness provider manual. New York: Mount Sinai, 2025."}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2025-111253","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:26:33Z","timestamp":1788441993000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2025-111253"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7]]},"references-count":32,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7,16]]},"published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1136\/bmjopen-2025-111253"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2025-111253","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7]]}}}