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

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.

Study at a glance

Abstract

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.