Mechanisms of Action and Change in Psychedelic-Assisted Therapies: A Holistic Framework for Ethical, Competent Clinical Care

Psychedelic-assisted therapies (PATs) are emerging as novel combination treatments for selected stress- and trauma-related psychiatric conditions, particularly in cases where existing pharmacologic and psychotherapeutic approaches have provided limited benefit. Although current mechanistic models emphasize neuroplasticity, large-scale network changes, and modulation of neurotransmitter systems, these are insufficient to explain how therapeutic change emerges within the broader context of preparation, altered states of consciousness, interpersonal relationships, meaning-making, and integration. The authors introduce a non-neuroreductionist, multilevel framework that distinguishes mechanisms of action from mechanisms of change, highlighting how neuroplasticity, memory updating, relational processes, contextual factors, and meaning-making may interact to support therapeutic change. They draw on relevant evidence and clinical theory to describe how these treatments may create time-limited windows that support experiential relearning. Ethical considerations; limitations; and implications for practice, including the possibility that vulnerability may be increased when safeguards are inadequate, are discussed. Guidance is provided for clinicians who encounter PATs in practice.