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Although antibiotics effectively treat most cases, an estimated 10\u201320% of patients develop post-treatment Lyme disease (PTLD), a chronic syndrome marked by fatigue, pain, cognitive difficulties, mood disturbance, and reduced quality of life. There are no established treatments for PTLD. The serotonin 2A receptor agonist psychedelic psilocybin has recently shown potential antidepressant and anxiolytic effects in clinical trials as well as preliminary evidence for anti-inflammatory effects in animals. This open-label, single-arm pilot study evaluated the effects of psilocybin in 20 participants with well-characterized PTLD. The 8-week intervention included two psilocybin sessions (15\u00a0mg in week 4; 15 or 25\u00a0mg in week 6) with psychological support. Participants (11 women, 9 men, mean age 44, median illness duration 5.7 years) showed significant improvements in PTLD symptom burden and quality of life from study enrollment through 1-month following the second dose of psilocybin (primary endpoint), with significant benefits sustained through 6 months. At the 6-month follow-up, general PTLD symptom burden (GSQ-30) was decreased 40% from baseline (\n                    <jats:italic>p<\/jats:italic>\n                    &lt; .001; Cohen\u2019s d\n                    <jats:sub>z<\/jats:sub>\n                    = \u2212 1.22, 95% CI [\u2212 2.12, \u2212 0.78]), and health-related quality of life improved across both SF-36 domains, with Mental (MCS) and Physical (PCS) component scores increasing 13% (\n                    <jats:italic>p<\/jats:italic>\n                    \u2264 .013; Cohen\u2019s d\n                    <jats:sub>z<\/jats:sub>\n                    = 0.46\u20130.59). Secondary outcomes assessing mood, fatigue, sleep quality, and pain also showed significant and sustained improvement through 6 months (all\n                    <jats:italic>p<\/jats:italic>\n                    \u2264 .003; Cohen\u2019s d\n                    <jats:sub>z<\/jats:sub>\n                    = 0.56\u20131.25). No serious adverse events (AEs) related to the study intervention occurred. The most common AEs attributed to psilocybin were transient hypertension (90%), headache (65%), tachycardia (35%), pain (20%), and fatigue (15%). Preliminary findings support that psilocybin-assisted treatment was feasible and well-tolerated among the sample. Clinical outcomes indicated potentially long-lasting benefits of psilocybin-assisted treatment, warranting further investigation for PTLD.\n                  <\/jats:p>\n                  <jats:p>Trial registration: ClinicalTrials.gov Identifier NCT05305105, registered 22\/03\/2022.<\/jats:p>","DOI":"10.1038\/s41598-026-38091-9","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T10:02:47Z","timestamp":1772013767000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pilot study of psilocybin in patients with post-treatment lyme disease"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2182-1644","authenticated-orcid":false,"given":"Albert","family":"Garcia-Romeu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon P.","family":"Naud\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison W.","family":"Rebman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"So","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Yaffe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Geithner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica A.","family":"Kozero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Soloski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John N.","family":"Aucott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"38091_CR1","doi-asserted-by":"crossref","unstructured":"Mead, P. 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