Psilocybin-assisted psychotherapy for substance use disorders as a complex intervention: A systematic review of efficacy, mechanisms and psychotherapeutic frameworks.

Abstract

Background: Psychedelic-assisted psychotherapy (PAP) shows promise for substance use disorders (SUDs), yet the respective contributions of pharmacological, experiential, psychotherapeutic, and contextual factors remain insufficiently understood.

Objective: To synthesize contemporary clinical evidence on PAP for SUDs, with particular attention to therapeutic frameworks, dosing strategies, safety, and mechanisms of action.

Methods: A systematic review of clinical studies published between 2000 and 2026 was conducted through structured database searches and manual surveillance. Eligibility criteria involved classic psychedelic administration within defined psychotherapeutic frameworks in individuals with a primary SUD diagnosis. Data were narratively analyzed and synthesized.

Results: Seventeen studies, encompassing 10 primary clinical trials, met inclusion criteria: ten focused on alcohol use disorder, five on tobacco use disorder, one on methamphetamine use disorder, and one on cocaine use disorder. All trials investigated psilocybin within structured psychotherapeutic protocols, primarily based on cognitive-behavioral and third-wave approaches. PAP was associated with reductions in substance use, higher abstinence rates, and improved psychological well-being, although findings remained heterogeneous and design-dependent. Trials combining repeated high-dose sessions with extended psychotherapeutic engagement consistently reported sustained clinical benefits. Findings further suggest that outcomes may arise from interactions between neurobiological, experiential, psychological, psychotherapeutic, and contextual processes.

Conclusion: Current evidence supports PAP as a promising but still emerging intervention for SUDs, although available clinical research remains exclusively based on psilocybin-assisted interventions. Findings further support conceptualizing PAP as a complex intervention embedded within an integrated psychotherapeutic process rather than as a pharmacological treatment alone. Larger controlled trials with active comparators, longer follow-up, and systematic investigation of psychotherapeutic and contextual mechanisms remain needed.