Pilot study of psilocybin in patients with post-treatment lyme disease

This was an open-label pilot intervention conducted by the researchers to investigate psilocybin-assisted treatment in patients meeting clinical criteria for post-treatment Lyme disease (PTLD). Recruitment primarily targeted prior participants from the Johns Hopkins Lyme Disease Research Center who had consented to re-contact, supplemented by online advertisements and word of mouth. Interested individuals completed online and telephone screening before in-person evaluation. Of 486 pre-screened individuals, 25 were consented for in-person screening and 20 were ultimately enrolled and received the intervention. Eligibility required adults (≥ 18 years) able to give informed consent, with medical-record documentation consistent with CDC/IDSA definitions of prior Lyme disease and current PTLD-defining symptoms (widespread pain, fatigue, or neurocognitive dysfunction) arising within two years of the first evidence of Lyme disease. Participants had to be medically stable on examination and routine laboratory testing. Concomitant stable treatment with selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs) or bupropion was permitted if doses had been stable for at least two months; bupropion was limited to ≤ 300 mg/day. A comprehensive set of exclusion criteria was applied, including recent hallucinogen use, current antipsychotic or monoamine oxidase inhibitor use, history of psychotic or bipolar disorders (or a first-degree relative with schizophrenia/psychotic disorder/bipolar I), significant cardiovascular or renal disease, pregnancy/nursing, recent cancer, seizures, and other conditions listed in the methods. The 8-week intervention comprised preparatory psychological support, two supervised psilocybin dosing sessions, and integration/follow-up. Preparatory work included three weekly sessions with two facilitators (one clinician-level, one co-facilitator) providing psychoeducation, a brief life review, and participant-driven treatment goal setting using a person-centred, minimally scripted approach. The first psilocybin session (week 4) administered a single 15 mg oral dose. Per protocol, the second session (week 6) delivered either 25 mg or 15 mg depending on the intensity of the first-session response; two participants received 15 mg twice and 18 received 15 mg then 25 mg. Integration meetings occurred within three days after each session and weekly through week 8. Most visits were virtual (secure video chat) except screening, dosing sessions, week 8 and 6-month follow-up visits which were in person. Follow-up assessments were conducted approximately 2 weeks and 1 month after the second dosing session, and again at 3 and 6 months. Primary and secondary outcomes assessed multi-system symptom burden and quality of life, using validated instruments: the General Symptom Questionnaire-30 (GSQ-30) for PTLD symptom burden, SF-36 for health-related quality of life, Beck Depression Inventory-II (BDI-II) for depressive symptoms, Pittsburgh Sleep Quality Index (PSQI) for sleep quality, Fatigue Severity Scale (FSS) for fatigue, and the Short-Form McGill Pain Questionnaire (SF-MPQ) for pain. Adverse events (AEs) were recorded at each visit by direct questioning and classified with MedDRA v.28.0. The researchers pre-registered primary and secondary endpoints for changes from baseline at 2 weeks and 1 month after the final session, with exploratory endpoints at 3 and 6 months. For analysis, separate linear mixed-effects models (restricted maximum likelihood) were fitted for each outcome with time as a five-level categorical fixed effect and a random intercept for participant to account for repeated measures. Pairwise contrasts against baseline were reported for each post-treatment time point. Confidence intervals and p-values used the Kenward–Roger approximation. Within-subject effect sizes were reported as Cohen's d_z with bootstrap 95% confidence intervals (2,000 resamples). Robustness checks excluded multivariate outliers defined by Mahalanobis distance; p-values were adjusted for multiple comparisons using the Benjamini–Hochberg procedure. Model diagnostics (residual normality, homoscedasticity) were examined. Analyses were performed in R (v4.4.1) using lme4, lmerTest, performance, and boot packages.

Sample and recruitment: Of 486 individuals pre-screened, 461 were disqualified or declined, leaving 25 in-person screened and 20 enrolled and dosed (4.1% of those pre-screened). One consented individual dropped out prior to dosing because they were unwilling to engage in the psychological support component. The final sample (N = 20) had a mean age of 44.05 years (SD = 10.10), 11 (55.0%) were female, and 90.0% identified as White. Median duration from Lyme disease onset to screening was 5.74 years (range 2.06–21.78). Initial Lyme presentations varied: viral-like illness with positive test only (60.0%), late Lyme arthritis (20.0%), neurologic disease (10.0%), and erythema migrans only (10.0%). At screening, 25.0% met criteria for major depression, 25.0% for ADHD, and one participant (5.0%) met criteria for panic disorder and PTSD. Three participants (15.0%) remained on antidepressants, five (25.0%) were on ADHD medications, and four (20.0%) reported prior hallucinogen use. Dosing and retention: All 20 participants received the planned dosing intervention; two participants (10.0%) received 15 mg in both sessions per pre-specified response criteria, and 18 (90.0%) received 15 mg followed by 25 mg approximately two weeks later. All participants returned for both dosing sessions per protocol, and follow-up assessments were conducted at the scheduled post-treatment time points. Data reported here were collected between 1 July 2022 and 7 April 2025. Adverse events and physiological responses: No serious adverse events were judged related to the study intervention. All participants reported at least one adverse event during the study period, and all 20 experienced events during or immediately after dosing that the investigators deemed related or probably related to the intervention. The most common AEs attributed to psilocybin were hypertension (90%), headache (65%), tachycardia (35%), pain (20%), and fatigue (15%). One participant experienced passive suicidal ideation after starting a new SNRI approximately seven weeks after their final psilocybin exposure; this resolved after stopping the antidepressant and was judged unrelated to psilocybin. One participant was diagnosed with Stage 3 rectal cancer at the 6-month visit; this was deemed unrelated. Peak vital signs during sessions showed modest, anticipated elevations: mean (SD) systolic blood pressure 142.10 (9.79) and 143.65 (11.40) mmHg for sessions 1 and 2, diastolic 89.00 (9.21) and 91.25 (6.17) mmHg, and heart rate 81.05 (11.53) and 89.70 (17.05) bpm. These resolved without intervention beyond over-the-counter symptomatic treatment when used. Primary and secondary outcome changes: Linear mixed-effects models showed a significant main effect of time for all nine reported outcomes (all F(4, 76) ≥ 4.56, all p ≤ .002), indicating statistically detectable change from baseline across follow-up visits. Quality of life measures (reported as increased scores) were described as remaining approximately 13–17% higher through 6 months (F(4, 76) = 5.07, p = .001). Depressive symptoms measured by the BDI-II were approximately 50–60% lower at all follow-up points (F(4, 76) = 12.87, p < .001). Sleep disturbance (PSQI) scores were reported to have improved by roughly 40%, although the extracted text for the PSQI result is truncated and does not fully report the test statistics or exact time-course. The researchers state that other secondary outcomes assessing mood, sleep, fatigue and pain also showed significant and durable improvements relative to baseline. The extracted text does not provide the full set of numerical estimates, confidence intervals, or p-values for each outcome or each follow-up time point beyond the statistics noted above.

The researchers characterise this trial as the first systematic investigation of moderate and higher-dose, medically supervised psilocybin-assisted treatment in a well-characterised PTLD sample. They emphasise that the findings are preliminary and should be interpreted cautiously given the pilot open-label design. Nevertheless, the authors suggest the results indicate the possibility that psilocybin-assisted treatment may substantially reduce key PTLD symptoms across physical and neuropsychiatric domains and improve quality of life, with effects that can persist for months after dosing in some participants. The discussion situates these results within broader psilocybin literature showing rapid and durable antidepressant and anxiolytic effects, and improved quality of life in other serious-illness populations. The authors highlight mechanistic hypotheses supported by prior preclinical and human work: increased cognitive flexibility and psychological insight, subjective experiential phenomena (e.g., ego-dissolution, mystical-type experiences or emotional breakthroughs) that correlate with therapeutic outcomes, neuroplastic and gene-expression changes, large-scale brain network and electrophysiological alterations, and anti-inflammatory effects. They note PTLD has been associated with markers of neuroinflammation (activated microglia, altered kynurenine levels) and argue these biological pathways merit further investigation; the trial collected biological samples to be analysed separately. On safety and feasibility, the researchers report that the nondirective, person-centred psychological support model used (psychoeducation, life review, goal setting, integration) facilitated safe administration without formal psychotherapy and appeared appropriate for this population. No study-related serious adverse events occurred, all participants completed dosing sessions, and adverse events were transient and manageable, consistent with prior controlled psilocybin research. The authors acknowledge several important limitations. The open-label design without randomisation or control conditions, and absence of blinding, limit causal inference and may inflate within-subject effect-size estimates through expectancy, demand characteristics, or regression to the mean. Expectancy was not measured in this trial. The combined intervention (two psilocybin doses plus psychological support) prevents disaggregation of the relative contributions of drug dose and psychosocial support. PTLD diagnosis is clinical with no definitive laboratory test; while the researchers applied stringent criteria and exclusions, precise aetiology of participants’ symptoms cannot be determined from the study data. The sample’s heterogeneity (comorbid psychiatric diagnoses and concurrent psychotropic medications) was deliberate to increase generalisability but complicates interpretation. The cohort was socio-demographically homogenous (predominantly White and relatively highly educated), limiting generalisability. Finally, cognitive functioning, a core PTLD feature, was not assessed pre- and post-treatment and should be included in future research. Overall, the authors conclude these preliminary findings justify further rigorous research including randomised, controlled trials and mechanistic studies (for example, neuroimaging and biomarker analyses) to clarify efficacy, safety, and biological mechanisms of psilocybin-assisted treatment for PTLD and related post-infectious chronic conditions.

The researchers conclude that in this small, open-label pilot cohort, psilocybin-assisted treatment was safe and well tolerated and was associated on average with significant improvements in general symptom burden and quality of life that typically persisted up to 6 months after the final dose. They indicate that biomarker analyses and qualitative reports from participants will be published separately. Based on these findings, the authors advocate for additional randomised controlled trials of psilocybin in PTLD and further characterisation of biological mechanisms (for example using neuroimaging). They also propose exploring psilocybin and other classic psychedelics as potential treatments for other infection-associated chronic conditions such as ME/CFS, post-acute sequelae of SARS-CoV-2 infection (PASC), and fibromyalgia.