Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles.
David Baumeister, Georgina Barnes, Giovanni Giaroli, Derek K. Tracy
Therapeutic Advances in Psychopharmacology August 1, 2014 DOI: 10.1177/2045125314527985 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Anxiety Depression LSD Psilocybin |
| Keywords | Antidepressants 5-ht2a Hallucinogen |
| Key findings | Hallucinogens appear to exert psychedelic effects primarily through agonist or partial agonist activity at the 5-HT2A receptor, with additional effects on other serotonin receptors and brain circuits. The authors argue that while clinical trials over the past decade generally show positive therapeutic potential and the drugs appear well tolerated, the evidence base is extremely limited, the neurobiology of therapeutic effects remains speculative, and legislative policy has had a freezing effect on evaluation. |
Abstract
Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. This review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. These drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-HT 2A receptor, though they also have affinity for other metabotropic serotonin receptors. Hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. They alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory control of sensory input via the thalamus to the cortex. The serotonergic system has long been implicated in anxiety and depressive disorders, and is a major target of most existing antidepressants. Classical hallucinogens alter the functioning of this system, but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time. There is currently an extremely limited but growing literature on hallucinogen safety and clinical application. The drugs appear well tolerated by healthy controls and clinical populations, and the rapid tolerance to repeated administration might reduce the possibility of dependency. Clinical trials reported over the past decade have generally shown positive therapeutic potential, but they are notably few in number. Legislative policy has had a freezing effect on evaluation of these compounds, a better understanding of which might improve our knowledge of the processes involved in consciousness, the neuropathology of depression, and potentially open up new pharmacological therapies.
Comparable studies
Other narrative reviews on LSD for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Registered clinical studies investigating psychedelic drugs for psychiatric disorders. Registered clinical trials on clinicaltrials.gov evaluating psychedelics for... | 2021 | Review | n = 70 |
| Top Ten Tips Palliative Care Clinicians Should Know About Psychedelic-Assisted Therapy in the Context of Serious Illness. Palliative care clinicians and patients | 2022 | Review | |
| Serotonergic psychedelics for depression: What do we know about neurobiological mechanisms of action? | 2023 | Narrative review | |
| Role of psilocybin in the treatment of depression | 2016 | Review |
Citations in the library
Cited by 90
- Classic psychedelic use is associated with reduced psychological distress and suicidality in the United States adult population. Journal of Psychopharmacology March 1, 2015
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years Therapeutic Advances in Psychopharmacology March 18, 2016
- Psychedelics not linked to mental health problems or suicidal behavior: A population study Journal of Psychopharmacology March 1, 2015
- Classical psychedelics for the treatment of depression and anxiety: A systematic review. Journal of Affective Disorders November 1, 2019
and 85 more in the library
Cites 33
- Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Psychopharmacology July 7, 2006
- Default Mode Network Activity and Connectivity in Psychopathology Annual Review of Clinical Psychology March 29, 2012
- Meditation experience is associated with differences in default mode network activity and connectivity Proceedings of the National Academy of Sciences November 23, 2011
- Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer Archives of General Psychiatry September 7, 2010
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
and 28 more in the library