The abuse potential of classic psychedelics—serotonergic 5-HT2A agonists such as psilocybin—has not been systematically assessed using modern methods since they were placed in Schedule I of the Controlled Substances Act in 1970. This paper reviews the scientific evaluation of their abuse potential and outlines the data required to support a rescheduling recommendation if a classic psychedelic drug product receives FDA approval. The authors argue that renewed clinical research necessitates revisiting these drugs' regulatory classification, given that Schedule I status assumes high abuse potential and no accepted medical use, a designation that may no longer align with current evidence.
Hallucinogens are among the oldest drugs used by humanity, often in spiritual contexts. Classic hallucinogens like LSD, psilocybin, DMT, mescaline, and DOM produce perceptual changes, cognitive shifts, and emotional alterations primarily by acting as agonists at serotonin 5-HT2A receptors, with additional activity on dopamine and glutamate systems. These drugs also include non-classic agents like ketamine and MDMA. Negative effects include 'bad trips', rare flashbacks, and psychotic breaks. After a long hiatus, human clinical studies have resumed, building on earlier animal research to advance understanding of pharmacology and psychiatric conditions.