Contribution of serotonin 5-HT2A receptor to antidepressant effect of serotonergic psychedelics

Mar 29, 2023Nihon yakurigaku zasshi. Folia pharmacologica Japonica

Role of serotonin 5-HT2A receptor in the antidepressant effects of psychedelic drugs

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Abstract

30-40% of patients with major depressive disorder exhibit treatment resistance to antidepressants.

Ketamine is an NMDA receptor antagonist approved for treatment-resistant depression but is associated with serious side effects.
Psilocybin, a substance found in magic mushrooms, has shown fast-acting and long-lasting antidepressant effects in resistant patients.
Psilocybin is considered relatively harmless compared to ketamine and has been designated as a 'breakthrough therapy approach' by the FDA.
Psychedelics like psilocybin and LSD may show potential in treating depression, anxiety, and addiction.
The mechanism by which psychedelics exert their therapeutic effects, particularly related to serotonin receptors, remains unclear.
Future research is needed to understand the molecular and neural mechanisms of psychedelics in treating psychiatric disorders.

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Major depressive disorder presents a substantial global health burden, and at least 30-40% of patients exhibit treatment resistance to antidepressants. Ketamine, an NMDA receptor antagonist, is used as an anesthetic agent. In 2019, the U.S. Food and Drug Administration (FDA) approved esketamine (the S-enantiomer of ketamine) as a therapeutic agent for treatment-resistant depression; however, this drug has reportedly been associated with serious side effects such as dissociative symptoms, thus limiting its clinical use as an antidepressant. Recently, various clinical studies have reported that psilocybin, the psychoactive substance found in magic mushrooms, has a fast-acting and long-lasting antidepressant effect in patients with major depressive disorder, including those resistant to conventional treatment. Furthermore, psilocybin is a psychoactive drug that is relatively harmless compared to ketamine and other similar substances. Accordingly, the FDA has designated psilocybin as a "breakthrough therapy approach" for the treatment of major depressive disorder. Additionally, serotonergic psychedelics such as psilocybin and lysergic acid diethylamide show some potential in the treatment of depression, anxiety, and addiction. The increased attention the use of psychedelics has attracted as a psychiatric disorder treatment approach is referred to as the "psychedelic renaissance". Pharmacologically, psychedelics cause hallucinations by stimulating cortical serotonin 5-HTreceptors (5-HT2A), although whether 5-HT2A is responsible for the manifestation of their therapeutic effects remains unclear. Furthermore, it is unclear whether the hallucinations and "mystical experience" that the patients go through because of 5-HT2A activation by psychedelics is essential for the therapeutic effect of these substances. Future research should elucidate the molecular and neural mechanisms underlying the therapeutic effects of psychedelics. This review summarizes the therapeutic effects of psychedelics on psychiatric disorders such as major depressive disorder in clinical and pre-clinical studies, and discusses the possibility of 5-HT2A as a novel therapeutic target. 2A

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Contribution of serotonin 5-HT2A receptor to antidepressant effect of serotonergic psychedelics

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