Pharmacological, neural, and psychological mechanisms underlying psychedelics: a critical review

This critical review examines multiple levels of mechanisms behind psychedelics' effects and therapeutic potential. At the biochemical level, they primarily act on 5-HT2A receptors, increase neuroplasticity, open a critical period for social reward learning, and have anti-inflammatory properties. At the neural level, they reduce thalamo-cortical filtering efficacy, loosen top-down predictive signaling, increase sensitivity to bottom-up prediction errors, and activate the claustro-cortical circuit. At the psychological level, they induce altered and affective states, affect cognition, change beliefs, exert social effects, and produce lasting behavioral changes. The authors contrast a potential unifying account with pluralistic causation and propose a research agenda for better understanding causal-mechanistic pathways to enable targeted therapies.

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Abstract

This paper provides a critical review of several possible mechanisms at different levels of analysis underlying the effects and therapeutic potential of psychedelics. At the (1) biochemical level, psychedelics primarily affect the 5-HT2A receptor, increase neuroplasticity, offer a critical period for social reward learning, and have anti-inflammatory properties. At the (2) neural level, psychedelics have been associated with reduced efficacy of thalamo-cortical filtering, the loosening of top-down predictive signaling and an increased sensitivity to bottom-up prediction errors, and activation of the claustro-cortical-circuit. At the (3) psychological level, psychedelics have been shown to induce altered and affective states, they affect cognition, induce belief change, exert social effects, and can result in lasting changes in behavior. We outline the potential for a unifying account of the mechanisms underlying psychedelics and contrast this with a model of pluralistic causation. Ultimately, a better understanding of the specific mechanisms underlying the effects of psychedelics could allow for a more targeted therapeutic approach. We highlight current challenges for psychedelic research and provide a research agenda to foster insight in the causal-mechanistic pathways underlying the efficacy of psychedelic research and therapy.