5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice

Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in depression and anxiety symptoms in early clinical studies. However relatively little is known about the behavioral effects and neural mechanisms of 5-MeO-DMT in animal models. Here we characterized the effects of 5-MeO-DMT on innate behaviors and dendritic architecture in mice. We showed that 5-MeO-DMT induces a dose-dependent increase in head-twitch response that is shorter in duration than that induced by psilocybin at all doses tested. 5-MeO-DMT also substantially suppresses social ultrasonic vocalizations produced during mating behavior. 5-MeO-DMT produces long-lasting increases in dendritic spine density in the mouse medial frontal cortex that are driven by an elevated rate of spine formation. However, unlike psilocybin, 5-MeO-DMT did not affect the size of dendritic spines. These data provide insights into the behavioral and neural consequences underlying the action of 5-MeO-DMT and highlight similarities and differences with those of psilocybin. ### Competing Interest Statement A.C.K. is a member of the Scientific Advisory Board of Empyrean Neuroscience and Freedom Biosciences. A.C.K. has consulted for Biohaven Pharmaceuticals. No-cost compounds were provided to A.C.K. for research by Usona Institute. C.P. has served as a consultant in the past year for Biohaven Pharmaceuticals, Teva Pharmaceuticals, and Brainsway Therapeutics and has performed research under contract with Biohaven and with Blackthorn Therapeutics, Ltd., on unrelated projects. C.P. and A.P.K have performed research under contract with Transcend Therapeutics on unrelated projects. C.P. and S.J.S. have a sponsored research agreement with Freedom Biosciences. The sponsor of this research was not involved in the analyses or writing of the manuscript. The duties had no influence on the content of this article.