Classic Psychedelic Drugs: Update on Biological Mechanisms
This review synthesises recent molecular-to-systems evidence that classic psychedelics act primarily at serotonergic receptor subtypes in cortico‑thalamic and cortico‑cortical feedback circuits, modulating excitatory–inhibitory balance and promoting neuroplasticity in regions that integrate sensation, cognition, emotion and the sense of self. Neuroimaging and behavioural data link these circuit-level changes to altered self‑experience, emotion regulation and social cognition, which may help explain psychedelics' therapeutic potential in psychiatric disorders.
Authors
- Franz Vollenweider
- John Smallridge
Published
Abstract
Renewed interest in the effects of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. During the past two decades, state-of-the-art studies of animals and humans have yielded new important insights into the molecular, cellular, and systems-level actions of psychedelic drugs. These efforts have revealed that psychedelics affect primarily serotonergic receptor subtypes located in cortico-thalamic and cortico-cortical feedback circuits of information processing. Psychedelic drugs modulate excitatory-inhibitory balance in these circuits and can participate in neuroplasticity within brain structures critical for the integration of information relevant to sensation, cognition, emotions, and the narrative of self. Neuroimaging studies showed that characteristic dimensions of the psychedelic experience obtained through subjective questionnaires as well as alterations in self-referential processing and emotion regulation obtained through neuropsychological tasks are associated with distinct changes in brain activity and connectivity patterns at multiple-system levels. These recent results suggest that changes in self-experience, emotional processing, and social cognition may contribute to the potential therapeutic effects of psychedelics.
Research Summary of 'Classic Psychedelic Drugs: Update on Biological Mechanisms'
Introduction
Classic psychedelics, or serotonergic hallucinogens, include indoleamines (for example DMT and psilocybin/psilocin), phenylalkylamines (for example mescaline) and ergolines (for example LSD), plus several synthetic amphetamine-like compounds. These substances produce profound, dose-dependent alterations in perception, cognition, emotion and self-consciousness and have a long history of ritual and medicinal use. Human research on their clinical potential expanded in the 1950s–1960s but largely stalled after restrictive scheduling; renewed research since the 1990s has combined modern brain imaging and cognitive neuroscience to probe mechanisms of action. Vollenweider and colleagues set out to update current knowledge about the biological mechanisms of classic psychedelics across multiple levels of analysis. The review first describes the phenomenology and psychometric measurement of psychedelic states and potential state and trait predictors of acute responses. It then summarises molecular and cellular pharmacology, neuroplastic effects, and circuit- and whole-brain models (including thalamic gating and entropy-based accounts), and relates neural correlates of altered self- and emotion-processing to the therapeutic potential for affective disorders. The authors frame this synthesis as a foundation for developing targeted interventions and prognostic tools in psychedelic-assisted therapies.
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Vollenweider, F. X., & Smallridge, J. W. (2022). Classic Psychedelic Drugs: Update on Biological Mechanisms. Pharmacopsychiatry, 55(03), 121-138. https://doi.org/10.1055/a-1721-2914
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