Neuropsychopharmacology of hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists

Abstract

Psychedelic drugs such as LSD and psilocin were once relegated to the fringes of medical research because of their association with counterculture movements and a perceived concern about harm through recreational use, and their consequent legal prohibition in the early 1970s. However, these drugs are now experiencing a renaissance in the field of psychiatry based on increasing evidence that they can produce long-lasting improvements in health across a wide variety of mental illnesses, including major depression, addictions and anxiety disorders. These drugs interact with many different 5-HT receptor subtypes but the powerful psychedelic experience, which (depending on set and setting) includes profound alterations in perception, mood and cognition, accompanied by vivid hallucinations, is now widely considered mediated by an agonist action at 5-HT_2A receptors. However, the link between the psychedelic experience, 5-HT_2A receptor agonism and therapeutic effects is currently uncertain. Indeed, recent research has revealed a new class of 5-HT_2A receptor agonists which appear to retain the therapeutic potential of psychedelics drugs without inducing disorienting hallucinatory experiences. Biased signalling, partial agonism and non-selectivity at the 5-HT_2A receptor are amongst the possible explanations for the differential properties of these drugs, whereas increased neuroplasticity offers a likely account of their common therapeutic effects. This article explores the neuropsychopharmacological properties of hallucinogenic and non-hallucinogenic 5-HT_2A receptor agonists in the context of their promise as novel drug treatments in psychiatry.

Keywords: 5‐HT; 5‐HT2A receptor; antidepressant; hallucinogens; psychedelics; serotonin.