Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action
Open accessAbstract
Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT 2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.
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Exploring Psychedelics for Unmet Needs in Women’s Reproductive Health
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- Authors
- dos Santos, R. G., Hallak, J. E., Baker, G., & Dursun, S.
- Affiliations
- Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University of São Paulo, SP, Brazil
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (BR)
- Venue
- Journal of Psychopharmacology
- Publisher
- SAGE Publications
- Published
- 2021-03-19
- Volume
- 35
- Issue
- 4
- Pages
- 453-458
- ISSN
- 0269-8811 (ISSN-L)
- 1461-7285
- OpenAlex
- W3137933781
- Cited by
- 55
- References
- 63
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 5 · 2023: 14 · 2022: 11 · 2021: 5
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- 5-HT2A receptor agonists, psychedelics, major depressive disorder, rapid-acting antidepressants, ketamine, LSD, psilocybin, ayahuasca, treatment-resistant depression, serotonin receptors, mechanism of action, antidepressant efficacy and safety
- MeSH terms
- Antidepressive Agents, Clinical Trials as Topic, Depressive Disorder, Drug Evaluation, Preclinical, Hallucinogens, Humans, Ketamine, Lysergic Acid Diethylamide, Psilocybin, Serotonin 5-HT2 Receptor Agonists
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