The promises and perils of psychedelic pharmacology for psychiatry

Psychedelic drugs including psilocybin, N , N ʹ-dimethyltryptamine (DMT) and lysergic acid diethylamide (LSD) are undergoing a renaissance as potentially useful drugs for various neuropsychiatric diseases, with a rapid onset of therapeutic activity. Notably, phase II trials have shown that psilocybin can produce statistically significant clinical effects following one or two administrations in depression and anxiety. These findings have inspired a ‘gold rush’ of commercial interest, with nearly 60 companies already formed to explore opportunities for psychedelics in treating diverse diseases. Additionally, these remarkable phenomenological and clinical observations are informing hypotheses about potential molecular mechanisms of action that need elucidation to realize the full potential of this investigative space. In particular, despite compelling evidence that the 5-HT 2A receptor is a critical mediator of the behavioural effects of psychedelic drugs, uncertainty remains about which aspects of 5-HT 2A receptor activity in the central nervous system are responsible for therapeutic effects and to what degree they can be isolated by developing novel chemical probes with differing specificity and selectivity profiles. Here, we discuss this emerging area of therapeutics, covering both controversies and areas of consensus related to the opportunities and perils of psychedelic and psychedelic-inspired therapeutics. We highlight how basic science breakthroughs can guide the discovery and development of psychedelic-inspired medications with the potential for improved efficacy without hallucinogenic or rewarding actions. Psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have emerging therapeutic potential for neuropsychiatric diseases such as depression and anxiety. In this Perspective, McClure-Begley and Roth discuss the promises and pitfalls of psychedelic pharmacology, including complex activity profiles beyond canonical 5-HT 2A receptor activation that continue to be elucidated. They consider progress and challenges for clinical studies, as well as prospects for parsing the therapeutic from psychedelic effects of this class of compounds to develop ‘cleaner’ drugs.