Psilocybin for Opioid Use Disorder in Two Adults Stabilized on Buprenorphine: A Technical Report on Study Modifications and Preliminary Findings

Opioid use disorder (OUD) remains a major public health problem in the United States despite established medications for OUD (MOUD) such as methadone and buprenorphine, which reduce mortality and improve retention. Previous trials of psilocybin-assisted therapy (PAT) have shown preliminary efficacy and acceptable safety for several mental health conditions and for substance use disorders such as alcohol and nicotine use disorders. However, modern clinical data on psilocybin for OUD are lacking, although earlier population-based and historical LSD work suggest potential relevance. Proposed therapeutic mechanisms for PAT that could apply to OUD include increases in psychological flexibility, mindfulness, motivation, prosociality, and experiences described as mystical or awe-related, possibly mediated by neuroplasticity and changes in predictive models of addiction-related cognition and behaviour. Nicholas and colleagues reported a technical safety–feasibility study that aimed to evaluate coadministration of psilocybin with buprenorphine in adults stabilised on buprenorphine/naloxone. The report focuses on study design decisions, logistical and safety considerations, and preliminary outcomes from the first two enrolled participants, to inform future trials and methodology for evaluating psilocybin in outpatient, community-based OUD populations.

The study received institutional review board approval and oversight from an independent data monitoring committee. Procedures were overseen by a principal investigator who was a study physician and licensed buprenorphine prescriber, together with a licensed clinical psychologist. The extracted text does not clearly report the planned sample size beyond reporting the first two enrolled participants; this document is presented as a technical report of safety and feasibility rather than a fully powered clinical trial. Eligible participants were adults aged 21–65, living within 80 miles of the study site, and prescribed buprenorphine for at least 6 months to treat OUD. Screening required normal vital signs (≤140/90 mmHg; ≤120 bpm) and use of structured diagnostic assessment (SCID) prior to treatment. The paper refers to additional eligibility details in a Supplementary Table; those specifics are not fully reproduced in the extracted text. Study procedures followed established psilocybin trial practices: three preparatory psychotherapy sessions, two supervised dosing sessions, and six post-dosing integration sessions, all delivered by licensed clinicians within a client-centred set-and-setting framework. Dosing consisted of 25 mg psilocybin at the first session, and a second session approximately 4 weeks later with either 25 mg or an escalated dose (initially up to 50 mg) decided jointly by participant and staff. The escalation rationale cited tolerability data and the possibility that some people with SUD may require higher doses; later modifications reduced the planned maximum second dose for safety (see Discussion). Safety monitoring included the suicidality module of the Mini-International Neuropsychiatric Interview (MINI) at each visit, regular adverse-event (AE) surveillance informed by prior psilocybin safety data, urine drug screens (UDS) at screening, pre-dose, and follow-up, and opioid-specific measures: the Clinical Opioid Withdrawal Scale (COWS) at screening and dosing sessions, the Opioid Craving Scale (OCS), and timeline follow-back (TLFB) for opioid use (TLFB limited to opioid use to reduce participant burden). Psychedelic-related subjective measures included the 11-Dimensional Altered States of Consciousness Questionnaire (11-D ASC) and the Mystical Experience Questionnaire (MEQ) within 24 hours of dosing; a ‘‘complete mystical experience’’ was defined as ≥60% of the maximum score across each MEQ subscale. The persisting effects questionnaire was used at study termination to capture longer-term self-reported changes. Recruitment and screening were challenging; the extracted text reports numerous exclusions prior to phone screen for geographic distance and several exclusions during screening for reasons such as ADHD diagnosis, elevated blood pressure, or disallowed medications. Figures and tables referenced in the text apparently summarise recruitment flow and eligibility modifications, but exact numeric targets and randomisation details are not provided in the extracted material.

Two participants completed the protocol and received two psilocybin dosing sessions each. Participant 1 was female, stabilised on 12 mg buprenorphine/3 mg naloxone daily for over a year; Participant 2 was male, stabilised on 2.6 mg buprenorphine/0.7 mg naloxone daily for over 5 years. Neither met criteria for a current mental health disorder or SUD at enrolment; both had lifetime histories of OUD and alcohol use disorder, and Participant 2 additionally had past cocaine use disorder. No serious adverse events (SAEs) were reported. Most anticipated AEs were transient and mild, consistent with prior psilocybin literature. Participant 1 experienced two moderate AEs (nausea and vomiting) almost immediately after her first dosing session; both resolved by the end of the visit. Her COWS score rose to 14 shortly after the first dose (it had been 3 pre-dose), but the study physician judged the event unlikely to reflect opioid withdrawal given recent buprenorphine dosing and the timing of symptom onset; the participant attributed her symptoms to anticipatory anxiety and having an empty stomach. Despite the initial vomiting episode and minimal subjective effects after the first dose, Participant 1 reported mood improvement afterwards and completed a second dosing session (25 mg) preceded by anti-nausea measures; that second session produced a substantial subjective response. Subjective-effect measures (MEQ and 11-D ASC) fell within expected ranges for psilocybin trials, with variability between sessions and individuals. Reported MEQ total scores were: Participant 1, 18 (12%) for the first dose and 124 (83%) for the second dose (the second session met the study’s criteria for a complete mystical experience); Participant 2, 120 (80%) after his first 25 mg dose (meeting criteria for a complete mystical experience) and 100 (67%) after his second 50 mg dose (which the authors report did not meet criteria for a complete mystical experience, noting that meeting the complete mystical-experience definition requires ≥60% on each MEQ subscale rather than only a total percentage). Neither participant discontinued buprenorphine at any point, and no other opioid use was detected on UDS during study participation. Opioid craving and withdrawal measures remained minimal throughout follow-up. Operational difficulties affected timing for Participant 2: his second dose was delayed by 5 weeks after a positive UDS for an illicit substance and a further 4 weeks following a positive COVID-19 test. Overall, the two enrolled participants completed all study visits and most outcomes suggested no observable negative pharmacological interaction between buprenorphine and psilocybin on subjective effects or opioid craving/withdrawal in this very small sample.

Nicholas and colleagues interpreted these preliminary data as supporting the short-term safety and feasibility of administering moderate-to-high dose psilocybin to adults stabilised on buprenorphine, at least within the limited sample reported. The absence of SAEs, lack of detected illicit opioid use, and generally low opioid craving and withdrawal across visits led the investigators to conclude that coadministration did not produce obvious contraindicating effects on buprenorphine effectiveness or psilocybin subjective effects in these two cases. Reported subjective experiences were comparable to those observed in other clinical psilocybin trials, and the investigators noted that buprenorphine exposure did not have a discernible blunting effect on psilocybin-related subjective changes in this sample. Feasibility challenges were prominent in the authors’ account. Recruitment was limited by geographic eligibility constraints, a paucity of provider referrals from local buprenorphine prescribers despite outreach efforts, pandemic-related delays and provider burnout, and the large number of study visits. To address these barriers, study procedures were amended to permit virtual visits, provide additional financial and transportation support, and allow more flexible scheduling. Eligibility criteria were also revised to increase generalisability and inclusiveness: for example, the study was modified to allow adults with active OUD recently initiated on buprenorphine (≤4 weeks from screening) or those willing to initiate buprenorphine at enrolment under study supervision; restrictions related to stimulant use and ADHD were relaxed with provisions for tapering or screening; the exclusion window for several psychiatric diagnoses was shortened from 5 years to 2 years; nicotine-use rules were adjusted for the dosing day; and the maximum planned second dose was reduced (from 50 mg to 40 mg) to maximise safety in a more vulnerable population. The investigators also planned to broaden recruitment strategies to include community advertising and medical-record review to improve enrolment. The authors acknowledged the study’s principal limitations insofar as this report reflects only two participants and was designed primarily to assess safety and feasibility. They emphasised that transitioning to a recruitment population with active OUD will present new challenges but should enhance the clinical relevance and generalisability of future work. Finally, the report was framed as a contribution to ongoing methodological refinement and dialogue about best practices when evaluating psilocybin in populations with OUD and co-occurring conditions.

In this preliminary technical report of two adults stabilised on buprenorphine, moderate-to-high dose psilocybin was not associated with serious adverse events or with increased opioid withdrawal, and psilocybin-related subjective effects appeared broadly consistent with normative clinical samples. The investigators highlighted the importance of multidisciplinary clinical expertise and psychological support to assess and manage adverse events. Due to low enrollment and pandemic-related and logistical constraints, the study team implemented modifications to recruitment strategies and eligibility criteria to improve accessibility and generalisability, and plans to include people with more active OUD in future iterations. The report is intended to inform refinement of methodology and support ongoing discussion about safely studying psilocybin in OUD populations at elevated risk of adverse outcomes.