Short- and Long-Acting Psychedelics: Structure-Activity Relationships, Pharmacology, and Implications for Neuropsychiatric Therapeutics.
ACS chemical neuroscience June 17, 2026 Anoushka Bhat, Elmira Zolali, Mahfuz A Sakib et al.
Psychedelics are being studied again as treatments for depression, anxiety, PTSD, and substance use disorders. Their beneficial effects are mostly due to activating the serotonin 2A (5-HT2A) receptor, but they differ greatly in chemical structure, how they bind to receptors, how they are broken down, and how long they last. Short-acting psychedelics like DMT and 5-methoxy-DMT may be better for brief therapy sessions, while long-acting ones like LSD and mescaline might be more effective for some outcomes. This review covers the chemistry, structure-activity relationships, and pharmacology of both types, and discusses how small chemical changes affect receptor binding and duration. It aims to guide development of next-generation treatments with controlled effects.