Age as a Moderator of Psychoactive-Assisted Psychotherapies Outcomes: A Systematic Literature Review and Meta-Analysis

Abstract

This project will use a PRISMA-guided systematic review and meta-analysis to examine whether age moderates anxiety and depression outcomes following psychoactive-assisted treatments. In this review, psychoactive-assisted treatments are defined as clinically structured treatments involving classic serotonergic psychedelics, MDMA, ketamine, or esketamine. The term is intentionally broader than “psychedelic-assisted treatments” because MDMA and ketamine-related treatments differ from classic psychedelics in their pharmacology and acute effects. At the same time, it is narrower than psychoactive medication generally. Unlike SSRIs, whose intended therapeutic effects are generally evaluated following sustained daily dosing rather than during a discrete subjective state, the substances included in this review are typically administered intermittently within structured clinical sessions. Their acute, time-limited effects—including changes in perception, mood, cognition, emotional processing, and sense of self—may be clinically relevant to the treatment process. Although the underlying evidence and mechanisms differ across substance classes, these substances may create a temporary period of increased neuroplasticity, psychological flexibility, or openness to new experiences. This provides a broader framework for studying treatments in which an acute psychoactive state may interact with biological, psychological, relational, and contextual factors to influence longer-term outcomes. Outcomes may therefore reflect both the experience of the treatment—the acute subjective effects produced by the substance—and the treatment of that experience—how those effects are prepared for, supported, interpreted, and, when applicable, integrated within structured clinical care. The systematic review will include empirical quantitative, qualitative, and mixed-methods studies involving adults and reporting anxiety or depression symptoms, affective distress, treatment response, or participant experiences. Studies with extractable quantitative outcomes will also be included in the meta-analysis. Effect sizes will be calculated using Hedges’ g and synthesized using random-effects models. Mean participant age will be examined as a continuous, study-level moderator through meta-regression rather than being divided into predetermined age groups. Additional subgroup analyses will be conducted by substance class when sufficient data are available. The project is guided by a biopsychosocial-spiritual framework that does not treat chronological age as the mechanism responsible for differences in treatment response. Instead, age will be treated as an imperfect study-level proxy because biological, psychological, social, and spiritual characteristics tend to show meaningful average changes across adulthood. These may include changes in neuroplasticity and other biological capacities; personality, emotion regulation, and accumulated life experience; social roles, relationships, and perceptions of remaining time; and meaning-making, religious involvement, or spirituality. Considerable individual variation exists within every age group, and age alone cannot determine which of these factors may influence an outcome. However, if mean participant age accounts for a significant portion of between-study heterogeneity in anxiety or depression outcomes, the finding would support directly investigating these lifespan-related biopsychosocial-spiritual factors in future research. The expected outcome is a clearer understanding of whether treatment effects vary across the adult lifespan and whether age helps explain heterogeneity in the existing literature. The review will also identify methodological limitations and areas where more age-inclusive and lifespan-informed research is needed.