Short- and Long-Acting Psychedelics: Structure-Activity Relationships, Pharmacology, and Implications for Neuropsychiatric Therapeutics.
Anoushka Bhat, Elmira Zolali, Mahfuz A Sakib, Mohammad Rahimian, Lance R Mcmahon, Nadezhda German, Samuel Obeng
ACS chemical neuroscience June 17, 2026 Peer reviewed DOI: 10.1021/acschemneuro.6c00202 via PubMed
Summary
Psychedelics are being reconsidered as treatments for neuropsychiatric disorders, with their effects linked to the activation of serotonin 2A (5-HT2A) receptors. There are significant differences between short-acting psychedelics, like DMT, which may be beneficial for brief therapeutic sessions, and long-acting ones, such as LSD, which could lead to better clinical outcomes. This review discusses the chemistry and pharmacology of these compounds to guide the development of new antidepressants and anxiolytics.
Study at a glance
| Design | review |
|---|---|
| Key finding | Short-acting psychedelics may be advantageous for brief therapeutic sessions, while long-acting agents may be more effective for clinical outcomes. |
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.