Psilocybin-assisted psychotherapy for methamphetamine use disorder: A pilot open-label safety and feasibility study

Methamphetamine (MA) is a widely used psychostimulant and, with other amphetamine-type stimulants, ranks as the second most commonly used illicit drug globally. MA use is associated with substantial individual harms (cardiovascular disease, suicidality, psychosis, depression, anxiety, infectious disease risk and mortality) and societal harms (homelessness, family disruption and crime). There are no approved pharmacotherapies for methamphetamine use disorder (MAUD) and psychosocial interventions produce only modest effects; contingency management shows promise but faces implementation barriers. Early-phase clinical trials indicate that psilocybin-assisted psychotherapy (PAT) can be safe and preliminarily efficacious for several mental health conditions and for some substance use disorders, and its putative effects on cognitive and neural plasticity make it a candidate treatment for MAUD. Safety and pragmatic questions remain, however, including limited drug–drug interaction data and uncertainty about how psychedelic effects interact with stimulant-related psychosis risk. Knock and colleagues conducted a pilot open-label study to evaluate the safety and feasibility of outpatient psilocybin-assisted psychotherapy for treatment‑seeking adults with MAUD in a public addiction outpatient setting. The study aimed primarily to assess feasibility metrics and adverse event profiles when delivering a single 25 mg oral psilocybin dose with preparatory and integration psychotherapy; efficacy was not the primary objective given the pilot design.

This was an open-label, single-arm pilot clinical trial conducted at an outpatient stimulant treatment programme at St Vincent's Hospital Sydney, Australia. A target sample size of 15 participants was chosen consistent with pilot conventions for descriptive safety and feasibility assessment; the trial was not powered for hypothesis testing. The intervention comprised three preparatory psychotherapy sessions over about 2 weeks, a single oral psilocybin dosing session (25 mg) the day after the final preparatory session, and two integration psychotherapy sessions (one the day after dosing and one the following week). Follow-up visits to measure outcomes occurred on days 1, 7, 21, 28 and 90 after dosing. Analyses were conducted on a per-protocol basis. Ethical approval and prospective registration were reported. Eligible participants were aged 25 years or older, met DSM‑5 criteria for MAUD and reported MA use on at least four of the 28 days prior to screening. For safety monitoring, the first five enrolees were limited to ≤16 days/month of MA use; this restriction was removed after an initial safety review. Participants agreed to abstain from MA and other non-prescribed substances for 48 hours before dosing, not be intoxicated or in withdrawal on dose day (withdrawal management was offered if needed), engage with an external therapist for ongoing support, and have a safe home environment plus a nominated support person for 24 hours post-dose. Exclusion criteria included recent severe psychiatric hospitalisation, current or lifetime bipolar I/II, any history of psychosis (with some exceptions for transient paranoid symptoms), first- or second-degree relatives with psychotic or bipolar disorder, recent suicidal ideation, current use of MAOIs, mood stabilisers (including lithium) or antipsychotics, uncontrolled hypertension on repeated measures (>140/90 mmHg), unstable cardiopulmonary disease, seizures, recent alcohol or cannabis use disorder, psychedelic use within the prior month, and pregnancy or breastfeeding. Stable opioid agonist therapy did not preclude participation. Screening involved staged visits with a research nurse, an addiction physician and a psychiatrist, with physical and mental examinations, ECG and blood tests. Psychotherapy was delivered by a consistent dyad of therapists trained in PAT and used a semi-structured framework emphasising set and setting, acceptance and commitment therapy (ACT) and motivational interviewing (MI). Psilocybin (25 mg, excipient-free capsule supplied under GMP) was administered in a comfortable clinical space; participants used eyeshades and a curated musical playlist and were monitored for vital signs during an approximately 8-hour session. Safety monitoring included routine elicitation of adverse events (AEs), classification by MedDRA terms, grading of severity and causality by the principal investigator, and measurement instruments including the Brief Psychiatric Rating Scale-4 (BPRS-4), the Challenging Effects Questionnaire (CEQ) and the Persisting Effects Questionnaire (PEQ). Primary feasibility outcomes were enrolment and retention metrics. Secondary outcomes included self‑reported MA and other drug use using timeline follow-back (TLFB-28), urine drug screens at days 7, 28 and 90 to validate abstinence, a single-item 0–100 visual analogue scale for craving, WEMWBS for wellbeing, DASS-21 (reported as DASS-42 for interpretability) for depression/anxiety/stress, SETS for treatment expectancy and the MEQ-30 for acute psychedelic effects. Exploratory measures included BEAQ and AAQ-II (experiential avoidance/psychological flexibility), EQ-5D-3L (quality of life), General Self‑Efficacy Scale and the Watts Connectedness Scale. An independent Data Safety Monitoring Board reviewed safety data. Statistical analysis was primarily descriptive (counts, percentages, medians and interquartile ranges), with change in MA use also reported as reductions from >5 days baseline to fewer days or abstinence; analyses used R 4.2.3. The extracted text references figures and tables for some methodological details that are not present in the provided extraction.

Participants were enrolled from February to December 2023. Of 56 people who expressed interest and were prescreened, 16 progressed to formal screening and 15 were enrolled (27% of those prescreened). Fourteen participants completed the intervention and 13 completed the 90-day follow-up; one person withdrew after the third preparatory session because they did not feel ready to change their drug use. Two participants underwent inpatient withdrawal management before dosing. At baseline, participants reported a median of 12 days of MA use in the prior 28 days (IQR = 7–16). Feasibility outcomes showed that 15 participants were enrolled from 56 prescreened contacts, 14 completed the full treatment protocol and 13 completed 90-day follow-up. The extracted text does not provide detailed timelines for enrolment rate beyond these counts. Safety: 13 of the 14 participants who received psilocybin experienced at least one adverse event (AE). No serious adverse events (SAEs) occurred, no participants reported suicidality during the study, and no participants withdrew due to AEs. The extracted text contains a transcription error and does not clearly report the exact number of participants with at least one treatment‑related adverse event (TRAE); however, several TRAEs were reported. Three TRAEs occurred during or within 24 hours of dosing: an episode of elevated systolic blood pressure (n = 1; 185 mmHg at 2.5 hours post-dose, which fell below 180 mmHg within 30 minutes), nausea (n = 1) and headache (n = 2). A further set of mild to moderate TRAEs occurred between 24 hours and 7 days post-dose: noise sensitivity (n = 1) and headache (n = 2). No additional treatment-related adverse events were reported during the remainder of follow-up. Measures of negative psychological effects assessed by BPRS-4, CEQ and PEQ were reported as negligible across timepoints. Secondary outcomes: Among the 14 participants who completed the intervention, self-reported MA use by TLFB-28 was stable from screening (median 12 days, IQR = 7–16) to the day before dosing (median 11 days, IQR = 5–14). Median self-reported MA use declined to 0 days (IQR = 0–2) at day 28 post-dose and to 2 days (IQR = 1–4) at day 90. Using the study’s definition of reduced use (from >5 days at baseline to fewer days), 13 participants (93%) showed reduced MA use at day 28 and 10 participants (71%) at day 90. Continuous abstinence confirmed by negative urine drug screens at days 7 and 28 was observed in 8 participants (57%); at day 90, 4 participants (29%) had continuous abstinence. Measures of MA craving, mental wellbeing (WEMWBS), and depression, anxiety and stress (DASS-42) were reported to improve from baseline to days 28 and 90, though precise numerical changes for these scales are presented in figures/tables not included in the extraction. According to the MEQ-30, 11 of 14 participants (78%) reported a 'complete mystical experience' (≥60% of maximum score in each MEQ subdomain). Scores on experiential avoidance and psychological flexibility measures (BEAQ and AAQ-II) were observed to be lower at day 28 versus baseline. The extraction notes missing data in tables but does not quantify it in the prose provided.

Knock and colleagues describe this work as the first study to examine psilocybin-assisted psychotherapy for MAUD. They note that enrolling 27% of those pre-screened and achieving completion of the treatment protocol by 14 of 15 participants—13 of whom completed 90-day follow-up—is encouraging, particularly in light of historically high dropout rates (~40%) in prior MAUD treatment studies. The authors interpret the absence of SAEs and the occurrence of mostly mild or moderate, self‑limiting treatment-related adverse events as consistent with prior PAT safety data and supportive of an acceptable safety profile for a selected MAUD population. Participants reported intense acute subjective effects, with 78% meeting criteria for a complete mystical experience on the MEQ-30; the authors contrast this with a prior randomised trial in alcohol use disorder where a substantial minority reported low subjective effects, suggesting that a 25 mg fixed dose may produce robust psychedelic effects in people with dependent MA use. Secondary outcomes showed reductions in MA use and improvements in craving, mood and wellbeing, with the largest effects at day 28 and some attenuation by day 90. The authors emphasise that these efficacy signals are preliminary given the open‑label, uncontrolled design and small sample size, and that positive baseline treatment expectancy may have confounded outcomes. In discussing mechanisms, the authors highlight observed increases in connectedness, increases in self‑efficacy and decreases in experiential avoidance as plausible mediators of enduring therapeutic change, consistent with prior literature on prosocial and psychological‑flexibility effects of psilocybin. They suggest future efficacy trials consider multiple dosing sessions and additional psychotherapy to enhance durability of effects. Key limitations acknowledged by the study team include the small sample size, non‑randomised uncontrolled design, inability to control for expectancy effects, limited follow-up density between days 28 and 90, follow-up restricted to 90 days (limiting understanding of long‑term durability), a gender imbalance in recruitment and exclusion of people with histories of stimulant‑induced psychosis or hypertension, which constrain generalisability.