Exploring psilocybin-assisted psychotherapy in the treatment of methamphetamine use disorder

The paper addresses the urgent need for effective treatments for methamphetamine use disorder (MUD), a highly addictive stimulant associated with neurotoxicity and profound personal and societal harms. Despite extensive investigation, no medications are approved for MUD; contingency management and psychotherapy are standard but yield modest benefits with high relapse and dropout rates. Stigma and barriers to care further impede outcomes. The authors explore the hypothesis that psilocybin-assisted psychotherapy may offer a novel, transdiagnostic, and potentially more effective approach for MUD, given preliminary success in other substance use disorders and psychiatric comorbidities common in MUD. The purpose is to review the rationale, potential mechanisms, and practical considerations for testing psilocybin-assisted psychotherapy in MUD, informed by the authors’ experience developing multiple clinical trials.

Evidence from early-phase trials indicates psilocybin-assisted psychotherapy can reduce substance use in other disorders. In alcohol use disorder, an open-label pilot (n=10) showed substantial reductions, and a larger randomized, double-blind trial (n=93) comparing two psilocybin sessions to active placebo (diphenhydramine) plus psychotherapy reported a mean absolute reduction of 13.9% (95% CI: 3.0, 24.7) in percentage of heavy drinking days over 32 weeks in the psilocybin arm. In tobacco use disorder, an open-label trial (n=15) achieved 80% abstinence at 6 months and 67% at 12 months; a multisite RCT is underway (NCT05452772). Preliminary reports from an RCT in cocaine use disorder are promising (NCT02037126). Cross-sectional survey data suggest naturalistic use of classic psychedelics (psilocybin, LSD) associates with reductions in stimulant craving and use. Mechanistically, psilocybin is a non-addictive classic psychedelic (5-HT2A agonist with broader receptor activity) that can induce neuroplasticity and alter brain network connectivity (e.g., default mode network), potentially facilitating cognitive and behavioral flexibility, extinction learning, and improved emotion and reward processing. The strength of mystical-type experiences correlates with outcomes in alcohol and tobacco studies. Psychosocial domains relevant to MUD—such as social connectedness and attachment security—also appear positively influenced by psilocybin in supportive contexts. No published clinical trials yet specifically evaluate psilocybin-assisted psychotherapy for MUD, underscoring the need for systematic investigation.

This is a mini-review informed by the authors’ collective experience designing and initiating four clinical trials of psilocybin-assisted psychotherapy for MUD in the United States and Australia. The authors summarize the scientific rationale, hypothesized mechanisms, and practical considerations for early-phase trial design, including safety, eligibility, dosing, outcomes, representation, and control conditions. Ongoing/registered trials referenced include NCT04982796, NCT05322954 (United States) and ACTRN12622000463774 (Australia). The review synthesizes published clinical and preclinical literature on psilocybin and substance use disorders, epidemiology and treatment challenges in MUD, and pragmatic trial design issues, to guide harmonized protocols and outcomes in early trials.

• No published clinical trials have yet evaluated psilocybin-assisted psychotherapy for MUD; however, early-phase evidence in other SUDs is encouraging.
• Alcohol use disorder: In a randomized, double-blind trial (n=93), psilocybin plus psychotherapy reduced percentage of heavy drinking days by a mean absolute 13.9% (95% CI: 3.0, 24.7) over 32 weeks versus active placebo plus psychotherapy; an open-label pilot (n=10) also showed substantial reductions.
• Tobacco use disorder: Open-label trial (n=15) reported 80% abstinence at 6 months and 67% at 12 months post-psilocybin-assisted therapy; a multisite RCT is underway (NCT05452772). Preliminary reports in cocaine use disorder are promising (NCT02037126).
• Mechanistic rationale: Psilocybin (via psilocin) is a 5-HT2A receptor agonist with broader serotonergic activity; it induces neuroplasticity (e.g., dendritic spine growth), alters brain network integrity and default mode network connectivity, and may reduce precision-weighting of maladaptive predictive models. These effects could enhance psychological flexibility, facilitate extinction learning, and remediate neural dysfunctions seen in addiction.
• Psychosocial relevance: Psilocybin, in supportive settings, increases emotional empathy, attachment security, connectedness, and pro-social effects—domains impaired in MUD and correlated with poorer outcomes.
• Clinical population considerations: Stimulant-induced psychosis prevalence among methamphetamine users is high (37–43%); trial eligibility should balance safety (e.g., exclude primary psychotic disorders; consider age <25, self-harm/violence risks, psychosis endophenotypes) with access and generalizability. Polysubstance use and psychiatric comorbidity are common; exclusion of participants on antidepressants may reduce generalizability, with mixed evidence on psilocybin-blunting by serotonergic antidepressants.
• Dosing: Potential for blunted psychedelic effects in some populations (e.g., 30% dose escalation to 40 mg/70 kg after a 25 mg/70 kg session in an AUD Phase II trial due to low mystical experience scores). Methamphetamine’s monoaminergic effects may alter serotonergic systems and potentially modify psilocybin response; optimal dose and number of sessions for MUD remain unknown. One trial includes 25 mg with optional escalation to 50 mg (NCT05322954).
• Outcomes: Early trials should prioritize rigorous safety and feasibility measures and select clinically meaningful primary outcomes that may include harm-reduction (reductions in use, quality of life), not only abstinence. Secondary outcomes could include craving, motivation/self-efficacy, comorbid symptoms (depression, anxiety, PTSD), disability, quality of life, connectedness, psychological flexibility, biomarkers (inflammation, cortisol, HRV), and neuroimaging.
• Representation and health equity: MUD increases disproportionately affect marginalized communities (e.g., 10-fold increase among African American individuals 2015–2019 vs 3-fold in White individuals; higher prevalence among Aboriginal Australians). Trials should improve representation, address barriers (transportation, phone access), and involve community stakeholders.
• Blinding and comparators: High-dose psychedelic trials face blinding challenges; regulators favor randomized, double-blind designs. Alternative comparators include evidence-based psychosocial treatments, treatment-as-usual, or waitlist (though ethical concerns exist in high-risk populations).

The review argues that psilocybin-assisted psychotherapy is a plausible and potentially impactful intervention for MUD based on converging evidence from other SUDs and mechanistic neuroscience. By enhancing neuroplasticity and altering maladaptive brain network dynamics, psilocybin may enable rapid and durable changes in cognition, affect, and behavior when combined with targeted psychotherapy. Its transdiagnostic potential may address common psychiatric comorbidities in MUD, simplifying treatment planning and potentially improving retention and outcomes in a population with high dropout and relapse rates. Practical trial design recommendations aim to responsibly balance safety (e.g., psychosis risk) with inclusivity and real-world applicability, particularly among marginalized groups disproportionately affected by MUD. The authors propose harmonizing outcome measures across early trials and incorporating patient-centered harm-reduction endpoints and mechanistic assessments (e.g., mystical-type experience, connectedness, psychological flexibility, biomarkers) to inform later-phase studies and optimize treatment protocols.

Methamphetamine use disorder remains a growing public health crisis with limited effective treatments. Psilocybin-assisted psychotherapy, supported by promising data in other substance use and psychiatric disorders and by plausible neurobiological and psychosocial mechanisms, warrants rigorous investigation for MUD. The authors outline key considerations for early-phase trials—eligibility and safety, dosing strategies, outcome selection, representativeness, and control conditions—and advocate for collaboration and harmonized measures across studies. If early outcomes are favorable, these efforts will facilitate efficient progression to larger, definitive trials and may offer urgently needed therapeutic options for MUD.

• No published clinical trials specifically assess psilocybin-assisted psychotherapy for MUD; conclusions are extrapolated from other SUDs and related literature.
• Potential safety concerns in MUD (e.g., high rates of stimulant-induced psychosis) necessitate cautious eligibility criteria that may limit generalizability.
• Uncertain optimal dosing and number of sessions for MUD; potential interactions with methamphetamine-related monoaminergic changes and with concomitant psychotropic medications.
• Blinding challenges for high-dose psychedelic trials and the lack of ideal active placebos may complicate regulatory pathways and interpretation.
• Heterogeneity in treatment-as-usual and ethical concerns with waitlist controls in high-risk populations.
• Potential attenuation of psilocybin effects by serotonergic antidepressants remains unresolved, affecting inclusivity and real-world applicability.