Preliminary safety and effectiveness of psilocybin-assisted therapy in adults with fibromyalgia: An open-label, proof-of-concept clinical trial

Fibromyalgia (FM) is described as a common chronic nociplastic pain condition affecting about 2-4% of the population, characterised by widespread pain, disturbed sleep, fatigue and cognitive difficulties. Existing treatments, including pharmacological and physical interventions, show limited and heterogeneous effectiveness, leaving substantial clinical and economic burden. Previous research suggests that psilocybin produces substantial alterations in cognition, mood and neural functional connectivity and that psychedelic-assisted therapy can increase psychological flexibility; early clinical and preclinical studies as well as survey reports have hinted at analgesic effects of psilocybin for certain pain conditions, but no clinical trials had directly evaluated psilocybin-assisted therapy (PAT) for FM prior to this study. Aday and colleagues therefore conducted an open-label, proof-of-concept trial to evaluate the preliminary safety and effectiveness of PAT in people with fibromyalgia. The investigators aimed to assess acute physiological safety during dosing and adverse events over the treatment period as primary endpoints, and to explore changes in pain severity, pain interference, sleep disturbance and related psychosocial outcomes as secondary and exploratory endpoints in a small sample of participants undergoing a structured PAT protocol.

This was an open-label clinical trial conducted at a single academic centre (University of Michigan Chronic Pain and Fatigue Center), approved by the institutional review board and prospectively registered (NCT05128162). The protocol included phenotyping visits with sensory testing and MRI (results to be reported separately). Participants were adults aged 25–64 with a diagnosis of FM or at least a year of FM symptoms who met the 2016 FM survey criteria. Exclusion criteria were extensive and included recent cardiovascular events, epilepsy, insulin-dependent diabetes, active autoimmune disease, clinically significant laboratory abnormalities, recent or current substance use disorder (other than caffeine), psychotic or bipolar disorder, severe depression, pregnancy or nursing, and recent hallucinogen use; a range of medications were prohibited. The protocol was amended during the study to allow concomitant selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs) and bupropion below 300 mg/day. Therapy followed a manual broadly consistent with the Yale Manual for Psilocybin-Assisted Therapy of Depression but modified for fibromyalgia with external consultation. Each participant worked with a consistent therapist dyad (lead doctoral-level psychotherapist and a Masters-level co-therapist) across preparatory, dosing and integration sessions. Preparatory sessions addressed rapport, education about psychedelic experiences, logistics and expectations. During dosing sessions therapists provided an attentive, non-intrusive presence to support inward-focused attention (eyes-shades and music were used) and assisted with immediate comfort or safety needs. Integration began the day after dosing and aimed to help participants verbalise and consolidate insights from dosing. The investigational product was synthetic psilocybin in 15 mg and 25 mg gel capsules. Participants received two oral doses approximately two weeks apart, typically 15 mg first then 25 mg, although one participant chose to repeat 15 mg for the second session. Dosing sessions lasted about 8 hours in a comfortable suite; vitals (heart rate and blood pressure) were monitored intermittently, and participants completed subjective experience questionnaires after sessions (Mystical Experience Questionnaire, Challenging Experiences Questionnaire, Psychological Insight Questionnaire). Primary outcome assessment focused on safety: acute vitals during dosing and adverse events captured from baseline through Day 64; predefined thresholds for clinically significant blood pressure and heart rate changes were specified. Secondary outcomes included daily worst pain intensity (0–10 numeric rating scale averaged over specified 7-day windows), PROMIS measures of pain interference and sleep disturbance (T-scores), the 8-item Chronic Pain Acceptance Questionnaire, and the Patient Global Impression of Change (PGIC). Exploratory outcomes included other PROMIS domains (anxiety, depression, fatigue, physical function, cognitive abilities) and the Challenging Experiences Questionnaire domains. Qualitative data consisted of participant-written narratives after dosing; two researchers independently coded narratives for prominent themes and produced combined thematic summaries. Statistical analysis was descriptive: individual- and aggregate-level reporting, with effect sizes (Cohen's d with 95% confidence intervals) reported for secondary and exploratory outcomes where applicable.

Recruitment began broadly: 368 people expressed interest, 265 were pre-screened, 54 were eligible for screening, 17 attended screening, and 7 met eligibility; two of those consenting were withdrawn by the study team for concerns about study procedure adherence or rapport, leaving five participants who completed the protocol. All five completers were female; four identified as White/Caucasian and one as Black/African American. The authors note they stopped recruitment early because of recruitment challenges, concerns about generalisability given stringent exclusions, and evolving regulatory guidance during the trial. Regarding safety (primary outcome), the dosing regimen was generally well tolerated with no serious adverse events. Blood pressure and heart rate remained within prespecified ranges during dosing and were not associated with cardiovascular symptoms. Adverse events occurring on or the day after dosing were mostly minor or moderate: headache (n=4), diarrhoea (n=2), stomach ache (n=1), and migraine (n=1); headaches resolved within two days and some participants used over-the-counter analgesics. On the Challenging Experiences Questionnaire, the physical distress and grief domains were the most commonly endorsed challenging experiences. One participant (001) elected to receive 15 mg at both sessions rather than escalate to 25 mg. Secondary outcomes showed clinically suggestive changes at end of treatment: three of five participants reported a greater than 2-point decrease in worst pain severity (0–10 scale), four reported greater than 4-point decreases in pain interference (PROMIS), and four reported greater than 6-point decreases in sleep disturbance (PROMIS). Chronic pain acceptance increased in three participants and decreased slightly in two. For exploratory PROMIS domains, four of five participants reported decreases in anxiety and fatigue; the extracted text also reports decreases in physical function for four participants, and three participants reported improvements in cognitive abilities. Note: according to PROMIS scoring described in Methods, higher scores indicate worse symptoms for many subscales while lower scores indicate worse physical function; the extraction does not clearly reconcile the direction of the physical function change with clinical interpretation. The Patient Global Impression of Change ratings at end of treatment were: one participant "very much improved," two "much improved," and two "minimally improved." Qualitative narratives revealed recurring themes across participants, including vivid, dreamlike visual imagery, feelings of connection to family, ancestors or nature, and experiences interpreted as psychologically meaningful or insight-generating. Examples include a participant describing "time travel to ancient Egypt" and another reporting a forest saying, "We're in trouble. Humans are destroying us. We are all connected." Experiences ranged from painful or challenging for one participant to profound gratitude, reconnection and reductions in perceived pain for others. Some participants described concrete behavioural responses after sessions (for example, increased engagement in yoga or changes in coping perspectives).

Aday and colleagues interpret these open-label, proof-of-concept results as preliminary evidence that psilocybin-assisted therapy can be administered safely to a small, carefully screened sample of people with fibromyalgia when delivered with intensive psychological support; no serious adverse events were observed and transient physiological changes and minor to moderate adverse events resolved shortly after dosing. The investigators report clinically meaningful improvements across several secondary outcomes—pain severity, pain interference, sleep disturbance—and note concordant PGIC ratings, while acknowledging mixed effects on chronic pain acceptance. The authors situate their findings alongside prior clinical and naturalistic literature suggesting analgesic or symptom-relieving effects of psilocybin for various pain conditions and with broader evidence for PAT producing transdiagnostic benefits in mood, anxiety and wellbeing. They highlight that the qualitative themes—vivid imagery, connections with loved ones and ancestors, increased gratitude—are consistent with previous reports and may represent psychological processes relevant to therapeutic change, though they stop short of causal claims. Key limitations are emphasised. The single-centre, open-label design without a control group or blinding makes outcomes vulnerable to expectancy and placebo effects. The small sample size and stringent exclusion criteria limit generalisability, and the intensive therapeutic model used (therapist dyads present during dosing) may not be clinically scalable, so safety and effectiveness could differ in larger or more pragmatic settings. The authors also note that standards for psychedelic research changed during the conduct of their trial and that further work is needed to delineate the specific contribution of psychotherapy to safety and outcomes. They conclude that these preliminary findings justify larger randomised controlled trials and mention that additional trials of PAT for fibromyalgia are underway elsewhere.