Experimental strategies to discover and develop the next generation of psychedelics and entactogens as medicines

Classical psychedelics (psilocybin, LSD, DMT) and the entactogen MDMA are being investigated as treatments for psychiatric, neurological, and peripheral disorders. These drugs act through 5-HT2A and other serotonergic receptors or monoamine transporters. Serotonin acts as a neurotransmitter and hormone with vasoconstrictor, pro-inflammatory, and pro-nociceptive effects throughout the brain and body. While existing psychedelics and entactogens have known safety and toxicity risks assessed through human experience, novel drug-candidates require non-clinical testing to predict efficacy and address risks. The authors define challenges for developing novel serotonergic psychedelics and entactogens, describing screening techniques including a non-clinical cascade, models for hallucinogenic activity, differentiation of hallucinogens from entactogens, preclinical lead optimization technology, and modified animal models for abuse and dependence risks. The goal is to reset the benefit-harm balance for safer clinical psychedelics.

Study at a glance

Abstract

Research on classical psychedelics (psilocybin, LSD and DMT) and entactogen, MDMA, has produced a renaissance in the search for more effective drugs to treat psychiatric, neurological and various peripheral disorders. Psychedelics and entactogens act though interaction with 5-HT2A and other serotonergic receptors and/or monoamine reuptake transporters. 5-HT, which serves as a neurotransmitter and hormone, is ubiquitously distributed in the brain and peripheral organs, tissues and cells where it has vasoconstrictor, pro-inflammatory and pro-nociceptive actions. Serotonergic psychedelics and entactogens have known safety and toxicity risks. For these drugs, the risks been extensively researched and empirically assessed through human experience. However, novel drug-candidates require thorough non-clinical testing not only to predict clinical efficacy, but also to address the risks they pose during clinical development and later after approval as prescription medicines. We have defined the challenges researchers will encounter when developing novel serotonergic psychedelics and entactogens. We describe screening techniques to predict clinical efficacy and address the safety/toxicity risks emerging from our knowledge of the existing drugs: 1) An early-stage, non-clinical screening cascade to pharmacologically characterise novel drug-candidates. 2) Models to detect hallucinogenic activity. 3) Models to differentiate hallucinogens from entactogens. 4) Non-clinical preclinical lead optimisation technology (PLOT) screening to select drug-candidates. 5) Modified animal models to evaluate the abuse and dependence risks of novel psychedelics in Safety Pharmacology testing. Our intention has been to design non-clinical screening strategies that will reset the balance between benefits and harms to deliver more effective and safer novel psychedelics for clinical use. This article is part of the Special Issue on 'National Institutes of Health Psilocybin Research Speaker Series'.