Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics
This review (2023) discusses the investigation of psychedelics for their therapeutic potential in neuropsychiatric and substance use disorders. Clinical trials have shown promise in alleviating symptoms of depression, anxiety, and reducing nicotine and alcohol use. The underlying molecular mechanisms for these therapeutic effects are not yet fully understood, with ongoing preclinical studies exploring the role of serotonin 5-HT2A receptors and other pathways.
Authors
- Jaster, A. M.
- González-Maeso, J.
Published
Abstract
Psychedelics, also known as classical hallucinogens, have been investigated for decades due to their potential therapeutic effects in the treatment of neuropsychiatric and substance use disorders. The results from clinical trials have shown promise for the use of psychedelics to alleviate symptoms of depression and anxiety, as well as to promote substantial decreases in the use of nicotine and alcohol. While these studies provide compelling evidence for the powerful subjective experience and prolonged therapeutic adaptations, the underlying molecular reasons for these robust and clinically meaningful improvements are still poorly understood. Preclinical studies assessing the targets and circuitry of the post-acute effects of classical psychedelics are ongoing. Current literature is split between a serotonin 5-HT2A receptor (5-HT2AR)-dependent or -independent signaling pathway, as researchers are attempting to harness the mechanisms behind the sustained post-acute therapeutically relevant effects. A combination of molecular, behavioral, and genetic techniques in neuropharmacology has begun to show promise for elucidating these mechanisms. As the field progresses, increasing evidence points towards the importance of the subjective experience induced by psychedelic-assisted therapy, but without further cross validation between clinical and preclinical research, the why behind the experience and its translational validity may be lost.
Research Summary of 'Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics'
Introduction
Psychedelics are pharmacologically active compounds that induce profound alterations in perception, cognition and sensory processing, with a history of ceremonial and medicinal use across many cultures. Early experimental psychiatry explored their effects in relation to schizophrenia and other psychiatric conditions, and interest in therapeutic applications rose through the mid-20th century before regulatory restrictions curtailed research. In the 21st century a resurgence of clinical trials has reported promising, sometimes long-lasting improvements in depression, anxiety and substance use disorders, but the molecular mechanisms that might explain those sustained therapeutic adaptations remain incompletely understood. Jaster and colleagues set out to review contemporary preclinical and clinical evidence on molecular targets, intracellular signalling and neural circuits implicated in the acute and post-acute effects of classical serotonergic psychedelics. The review focuses on serotonin receptor pharmacology, receptor structure and biased agonism, intracellular and circuit-level mechanisms of plasticity, and the translational links between rodent models and human clinical outcomes, highlighting unresolved questions about which molecular targets mediate therapeutic benefits versus subjective hallucinogenic experiences.
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Jaster, A. M., & González-Maeso, J. (2023). Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics. Molecular Psychiatry, 28(9), 3595-3612. https://doi.org/10.1038/s41380-023-02274-x
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