Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles
The review summarises evidence that classical hallucinogens exert their effects mainly via 5‑HT2A receptor agonism and broader modulation of serotonergic tone, thalamocortical sensory gating and cortical connectivity. Limited clinical trials suggest rapid antidepressant potential with favourable tolerability, but the neurobiology remains speculative and research is constrained by legislative barriers.
Authors
- Tracy, D.
- Baumeister, D.
- Barnes, G.
Published
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-HT2Areceptor, 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.
Research Summary of 'Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles'
Introduction
Classical hallucinogens have a long history of ceremonial and spiritual use, but widespread criminalisation in the mid-20th century curtailed scientific investigation. Tracy and colleagues note that international scheduling and political responses to counter-culture movements created regulatory barriers that have left the neuropharmacology and clinical potential of these substances incompletely characterised. This review aims to synthesise available information on the pharmacodynamics of serotonergic (classical) hallucinogens and to summarise the limited clinical literature addressing their therapeutic potential in mood and anxiety disorders. Because recent empirical work is sparse, the authors state that a systematic review was not feasible and consequently present a narrative overview of molecular mechanisms, neurobiological models, safety data and the small number of contemporary human studies.
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Study Details
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- APA Citation
Baumeister, D., Barnes, G., Giaroli, G., & Tracy, D. (2014). Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles. Therapeutic Advances in Psychopharmacology, 4(4), 156-169. https://doi.org/10.1177/2045125314527985
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