Biological Technologies Office, Defense Advanced Research Projects Agency, Arlington, VA, USA.
Department of Pharmacology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Nat Rev Drug Discov. 2022 Jun;21(6):463-473. doi: 10.1038/s41573-022-00421-7. Epub 2022 Mar 17.
Psychedelic drugs including psilocybin, N,N'-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 receptor is a critical mediator of the behavioural effects of psychedelic drugs, uncertainty remains about which aspects of 5-HT 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.
致幻剂包括裸盖菇素、N,N'-二甲基色胺（DMT）和麦角酸二乙基酰胺（LSD），它们正在作为治疗各种神经精神疾病的潜在有用药物重新兴起，具有快速的治疗作用。值得注意的是，二期临床试验表明，在抑郁症和焦虑症中，单次或两次给药后，裸盖菇素可以产生统计学上显著的临床效果。这些发现激发了商业兴趣的“淘金热”，已经有近 60 家公司成立，以探索致幻剂在治疗各种疾病方面的机会。此外，这些显著的现象学和临床观察为潜在的分子作用机制假说提供了信息，需要进一步阐明这些假说，以充分发挥这一研究领域的潜力。特别是，尽管有令人信服的证据表明 5-羟色胺受体是致幻剂行为效应的关键调节剂，但对于中枢神经系统中 5-羟色胺受体活性的哪些方面负责治疗效果以及通过开发具有不同特异性和选择性特征的新型化学探针在多大程度上可以分离它们，仍然存在不确定性。在这里，我们讨论了这一新兴治疗领域，涵盖了与致幻剂和致幻剂启发的治疗方法的机会和危险相关的争议和共识领域。我们强调了基础科学突破如何指导具有潜在改善疗效而没有致幻或奖赏作用的致幻剂启发药物的发现和开发。
