Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action
Rafael G. Dos Santos, Jaime Ec Hallak, Glen B. Baker, Serdar Dursun
Journal of Psychopharmacology March 19, 2021 DOI: 10.1177/0269881120986422 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Anxiety Ayahuasca LSD Psilocybin Serotonin |
| Keywords | Hallucinogen Antidepressant Pharmacology Serotonin antagonists 5-HT Receptor |
| Citations | 51 |
| Key findings | Psychedelics such as LSD, psilocybin, and ayahuasca show promising but limited evidence of fast-acting antidepressant effects, primarily through agonism at serotonin 5-HT2A receptors. |
Abstract
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.
Comparable studies
Other narrative reviews on ayahuasca for anxiety, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ayahuasca: Pharmacology, neuroscience and therapeutic potential | 2016 | Review | |
| Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies | 2016 | Review | |
| Ayahuasca, an ancient substance with traditional and contemporary use in neuropsychiatry and neuroscience | 2019 | Review | |
| Dimethyltryptamine: Endogenous Role and Therapeutic Potential Humans | 2019 | Review | |
| Psychedelics and Personality | 2018 | Review |
Citations in the library
Cited by 43
- Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics TIPS - Trends in Pharmacological Sciences September 24, 2021
- Investigation of self-treatment with lysergic acid diethylamide and psilocybin mushrooms: Findings from the Global Drug Survey 2020 Journal of Psychopharmacology March 6, 2023
- The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: Serotonergic Psychedelic Treatments for Major Depressive Disorder The Canadian Journal of Psychiatry August 17, 2022
- Low doses of lysergic acid diethylamide (LSD) increase reward-related brain activity. Neuropsychopharmacology 2023
- Serotonergic psychedelics for depression: What do we know about neurobiological mechanisms of action? Frontiers in Psychiatry February 10, 2023
and 38 more in the library
Cites 47
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer Archives of General Psychiatry September 7, 2010
and 42 more in the library