Beyond the substance: A systematic review of psychological treatment frameworks in psychedelic-assisted therapy

Background: Classic psychedelics show potential for treating psychiatric disorders, yet the psychological framework of psychedelic-assisted therapy (PAT) remains underspecified. As regulatory approval approaches, defining the contribution of psychological interventions to clinical outcomes is critical for both mechanism inference and implementation.

Objectives: To systematically review the structure, content, and duration of psychological interventions in contemporary clinical trials of serotonergic psychedelics for psychiatric symptoms, and to map the state of current approaches to inform future trial designs.

Design: A systematic review following PRISMA guidelines. Data Sources and Methods A systematic literature search was performed across PubMed, PsycINFO, and SCOPUS. Inclusion criteria targeted clinical trials administering serotonergic psychedelics (lysergic acid diethylamide (LSD), psilocybin, or dimethyltryptamine (DMT)) for psychiatric symptoms. Two reviewers independently screened studies and extracted data on dosing frameworks and psychological interventions.

Results: We identified 44 trials (1,537 participants), covering depressive symptoms (n=20), substance use disorders (n=8), life-threatening illness-related distress (n=8), anxiety disorders (n=2), and other indications (n=6). Nearly all trials followed a three-phase preparation–dosing–integration structure, and dosing regimens showed increasing standardization. Psychological support, however, varied substantially: non-dosing sessions ranged from zero to 17, and frameworks spanned minimal/non-directive support to manualized established approaches (e.g., ACT, CBT). These interventions were frequently tailored by clinical indication, such as utilizing motivational enhancement for substance use disorders and addressing existential themes for life-threatening illnesses.

Conclusion: Despite convergence on a shared procedural structure, PAT protocols remain highly heterogeneous in psychological embedding and orientation, reflecting tension between clinical depth and scalability. Because psychedelics are typically administered within a psychological context, this heterogeneity complicates efforts to isolate pharmacological from contextual effects, and existing evidence suggests the therapeutic context may itself moderate safety and efficacy. Advancing the field requires dismantling trials isolating psychological components and applying the same empirical rigor to psychotherapeutic as to pharmacological parameters.