Short- and Long-Acting Psychedelics: Structure-Activity Relationships, Pharmacology, and Implications for Neuropsychiatric Therapeutics.

Psychedelics have re-emerged as promising therapeutics for neuropsychiatric disorders, including depression, anxiety, post-traumatic stress disorder, and substance use disorders. While their beneficial effects are largely attributed to serotonin 2A (5-HT2A) receptor activation, psychedelics exhibit substantial diversity in chemical structure, receptor binding kinetics, metabolism, and duration of action. These differences underpin the distinction between short-acting psychedelics like N,N-dimethyltryptamine (DMT) and 5-methoxy-DMT, and long-acting compounds like lysergic acid diethylamide (LSD) and mescaline. Short-acting psychedelics may offer advantages in clinical settings where brief therapeutic sessions are preferred, while long-acting agents may be relatively more effective for clinical outcomes. This review highlights the chemistry, structure-activity relationships, and pharmacology of both short- and long-acting psychedelics. We examine key functional group modifications that influence receptor binding affinity, efficacy, and duration. By integrating insights from synthetic chemistry, pharmacology, and clinical effects, this review provides a framework for rational psychedelic drug development aimed at producing next-generation antidepressants, anxiolytics, and substance use disorder treatments with controlled and predictable clinical effects.