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Therapeutic mechanisms of psychedelics and entactogens.

Boris D. Heifets, David E. Olson

Neuropsychopharmacology July 24, 2023 DOI: 10.1038/s41386-023-01666-5 (opens in new tab)

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AI-extracted from the abstract
Characteristics Theoretical or philosophical paper Peer reviewed
Topics Neuroplasticity Psychedelic-assisted therapy
Keywords Mental health Therapeutic compounds
Citations 66
Key points Proposes that the rapid and sustained therapeutic mechanisms of psychedelics and entactogens are best described by the collection of circuits they modulate rather than their actions at any single molecular target.

Abstract

Recent clinical and preclinical evidence suggests that psychedelics and entactogens may produce both rapid and sustained therapeutic effects across several indications. Currently, there is a disconnect between how these compounds are used in the clinic and how they are studied in preclinical species, which has led to a gap in our mechanistic understanding of how these compounds might positively impact mental health. Human studies have emphasized extra-pharmacological factors that could modulate psychedelic-induced therapeutic responses including set, setting, and integration-factors that are poorly modelled in current animal experiments. In contrast, animal studies have focused on changes in neuronal activation and structural plasticity-outcomes that are challenging to measure in humans. Here, we describe several hypotheses that might explain how psychedelics rescue neuropsychiatric disease symptoms, and we propose ways to bridge the gap between human and rodent studies. Given the diverse pharmacological profiles of psychedelics and entactogens, we suggest that their rapid and sustained therapeutic mechanisms of action might best be described by the collection of circuits that they modulate rather than their actions at any single molecular target. Thus, approaches focusing on selective circuit modulation of behavioral phenotypes might prove more fruitful than target-based methods for identifying novel compounds with rapid and sustained therapeutic effects similar to psychedelics and entactogens.

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A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics 2020 Theoretical or philosophical paper
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A complex systems perspective on psychedelic brain action. 2023 Theoretical or philosophical paper
Critical Period Plasticity as a Framework for Psychedelic-Assisted Psychotherapy 2021 Theoretical or philosophical paper
On the varieties of conscious experiences: Altered Beliefs Under Psychedelics (ALBUS). 2025 Theoretical or philosophical paper

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