Neuropharmacology
December 15, 2022
David J. Heal, Jane Gosden, Sharon L. Smith et al.
18 citations
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.
Journal of Psychopharmacology
October 16, 2025
David J. Heal, Jane Gosden, Sharon L. Smith
4 citations
Psychedelic research is advancing rapidly, creating new challenges for drug developers, regulators, and legislators. Most classic psychedelics under clinical investigation are Schedule I controlled substances with high abuse potential and no accepted medical use. These and next-generation psychedelic drug-candidates require scientific and clinical assessment of their abuse and dependence potential before being placed into a lower controlled drug schedule (C-II to C-V). The FDA is likely to conduct the first regulatory assessment of a classic psychedelic and has provided guidance on addressing clinical and regulatory challenges. This review builds on that foundation, discussing areas of abuse and dependence evaluation that remain unclear.
Frontiers in psychiatry
January 1, 2024
David J Heal, Jane Gosden, Sharon L Smith
Cannabis has moderate levels of abuse and dependence risk, substantially lower than those of many illegal and legal substances like tobacco and alcohol, but far from negligible. Delta-9 tetrahydrocannabinol (Δ9-THC) and other psychoactive cannabinoids have moderate reinforcing effects, rapidly induce pharmacological tolerance, and produce a withdrawal syndrome of moderate severity lasting 2 to 6 days. Non-psychoactive cannabinoids do not produce intoxicating, cognitive, or rewarding properties in humans. Most evidence shows cannabidiol (CBD) does not attenuate the central nervous system effects of Δ9-THC, though uncertainty warrants further research. Potent synthetic cannabinoid receptor agonists pose substantial risk for abuse and harm.