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

David J Heal, Jane Gosden, Sharon L. Smith, C.k. Atterwill

Neuropharmacology December 15, 2022 DOI: 10.1016/j.neuropharm.2022.109375 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Review Peer reviewed
Topics LSD MDMA Psilocybin Serotonin
Keywords Hallucinogen Pharmacology Drug
Citations 18
Key findings Novel serotonergic psychedelics and entactogens require non-clinical screening strategies—including a screening cascade, hallucinogenic activity models, differentiation models, PLOT screening, and modified animal models—to predict clinical efficacy and address safety and toxicity risks.

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'.

Comparable studies

Other narrative reviews on LSD, most cited first.

Study Year Design Participants
Study of a New Schizophrenomimetic Drug—Sernyl 1959 Review
Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population 2019 Integrative review
The Pharmacology of Lysergic Acid Diethylamide: A Review 2008 Review
Serotonin research: contributions to understanding psychoses 2008 Review
ADVERSE REACTIONS TO PSYCHEDELIC DRUGS. A REVIEW OF THE LITERATURE 1984 Review

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LSD MDMA Psilocybin Serotonin Addiction DMT