Ketamine, a mixture of two mirror-image molecules called (S)-ketamine and (R)-ketamine, is used as an anesthetic and, more recently, as an antidepressant, but it carries a risk of abuse. The (S)-form is FDA-approved for treatment-resistant depression, while the (R)-form shows promise in animal models but has not been tested in people. In rats and mice, (S)-ketamine, but not (R)-ketamine, produced behaviors linked to abuse potential, such as self-administration, increased movement, and preference for places where the drug was given. (S)-ketamine also boosted activity and dopamine levels in a brain region called the medial prefrontal cortex, partly by activating opioid receptors. These findings indicate that the abuse liability of racemic ketamine stems mainly from its (S)-enantiomer.
Psychedelic compounds like psilocybin, MDMA, LSD, and DMT show promise for treating mental health conditions, with the FDA granting Breakthrough Therapy designations for several uses. Despite this, most remain Schedule I under the Controlled Substances Act, indicating no accepted medical use and high abuse potential, which imposes strict regulations. Over 150 active clinical trials are assessing their safety and efficacy, and federal research agencies, bipartisan congressional activities, and state-level reforms support their medical applications. A recent Executive Order calls for federal reforms to accelerate research and access, including timely rescheduling after Phase 3 trials. Rescheduling could reduce costs and administrative barriers while maintaining safety. The article outlines potential paths for rescheduling various Schedule I psychedelics given emerging clinical applications.