Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics.

Clinical trials show psychedelics can alleviate depression and anxiety and reduce nicotine and alcohol use, but the molecular mechanisms behind these lasting therapeutic effects remain poorly understood. Preclinical research is split between pathways dependent on the serotonin 5-HT2A receptor and those that are independent. Combining molecular, behavioral, and genetic techniques in neuropharmacology is beginning to clarify these mechanisms. The subjective experience during psychedelic-assisted therapy appears important, but without cross-validation between clinical and preclinical studies, the reasons for the experience and its translational validity may be lost.

Study at a glance

Abstract

Psychedelics, also known as classical hallucinogens, have been investigated for decades due to their potential therapeutic effects in the treatment of neuropsychiatric and substance use disorders. The results from clinical trials have shown promise for the use of psychedelics to alleviate symptoms of depression and anxiety, as well as to promote substantial decreases in the use of nicotine and alcohol. While these studies provide compelling evidence for the powerful subjective experience and prolonged therapeutic adaptations, the underlying molecular reasons for these robust and clinically meaningful improvements are still poorly understood. Preclinical studies assessing the targets and circuitry of the post-acute effects of classical psychedelics are ongoing. Current literature is split between a serotonin 5-HT2A receptor (5-HT2AR)-dependent or -independent signaling pathway, as researchers are attempting to harness the mechanisms behind the sustained post-acute therapeutically relevant effects. A combination of molecular, behavioral, and genetic techniques in neuropharmacology has begun to show promise for elucidating these mechanisms. As the field progresses, increasing evidence points towards the importance of the subjective experience induced by psychedelic-assisted therapy, but without further cross validation between clinical and preclinical research, the why behind the experience and its translational validity may be lost.