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Pharmacological, Neural, and Psychological Mechanisms underlying Psychedelics: A Critical Review

This review (2022) explores three analysis levels of psychedelic therapeutic mechanisms; 1) biochemical (e.g. neuroplasticity), 2) neural (e.g. less top-down signalling), and 3) psychological level (e.g. belief change). The review then maps out how the levels can be bridged and provide directions for future studies.

Authors

  • David Yaden
  • Michiel Van Elk

Published

Neuroscience and Biobehavioral Reviews
meta Study

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.

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Research Summary of 'Pharmacological, Neural, and Psychological Mechanisms underlying Psychedelics: A Critical Review'

Introduction

Van Elk and colleagues situate their paper within a resurgence of scientific interest in classic psychedelics (e.g., LSD, psilocybin, DMT) and note that these substances produce pronounced changes in perception, cognition, and emotion. The introduction frames the review around three nested levels of analysis—pharmacological/biochemical, neural/neurocognitive, and psychological—and highlights the longstanding but understudied importance of extra‑pharmacological factors such as set (expectations, mindset) and setting (environment, socio-cultural context). The authors emphasise that, although they recognise broader social and cultural influences, this review focuses on contemporary empirical work addressing pharmacological, neural and psychological mechanisms and on how these levels might interrelate. The stated aim is to critically evaluate candidate mechanisms at each level, to consider whether a unifying multi‑level account is plausible, and to propose an agenda to clarify causal pathways that could explain both acute psychedelic phenomenology and therapeutic effects. Van Elk and colleagues further signal that they will contrast an integrative model with a pluralistic causation perspective and conclude by identifying methodological challenges and priorities for future research.

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Study Details

References (121)

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Mind the Psychedelic Hype: Characterizing the Risks and Benefits of Psychedelics for Depression

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Double-Blind Comparison of the Two Hallucinogens Dextromethorphan and Psilocybin: Experience-Dependent and Enduring Psychological Effects in Healthy Volunteers

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6 cited
Psilocybin induces acute and persisting alterations in immune status in healthy volunteers: An experimental, placebo-controlled study

Mason, N. L., Szabo, A., Kuypers, K. P. C. et al. · Brain Behavior and Immunity - Health (2023)

Back from the rabbit hole. Theoretical considerations and practical guidelines on psychedelic integration for mental health specialists

Greń, J., Tylš, F., Lasocik, M. et al. · Frontiers in Psychology (2023)

Psilocybin therapy for females with anorexia nervosa: a phase 1, open-label feasibility study

Peck, S. K., Shao, S., Grue, T. et al. · Nature Medicine (2023)

Learned Helplessness As a Potential Transdiagnostic Therapeutic Mechanism of Classic Psychedelics

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Association between mystical-type experiences under psychedelics and improvements in well-being or mental health - A comprehensive review of the evidence

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58 cited
Self-reported effects of classic psychedelics on stuttering

Gold, N. D., Goldway, N., Gerlach-Houck, H. et al. · Biorxiv (2023)

Can psychedelics enhance group psychotherapy? A discussion on the therapeutic factors

Ponomarenko, P., Seragnoli, F., Calder, A. et al. · Journal of Psychopharmacology (2023)

Therapeutic effect of psilocybin in addiction: A systematic review

van der Meer, P. B., Fuentes, J. J., Kaptein, A. A. et al. · Frontiers in Psychiatry (2023)

Classic and dissociative psychedelics induce similar hyper-synchronous states in the cognitive-limbic cortex-basal ganglia system

Brys, I., Barrientos, S. A., Ward, J. et al. · Biorxiv (2022)

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