Psilocybin, the active compound in psychedelic mushrooms, is being studied as a treatment for depression. Its metabolite psilocin binds to serotonin receptors and the serotonin transporter (5-HTT). In mice lacking 5-HTT, psilocybin failed to cause hyperactivity or head twitches, suggesting 5-HTT might be involved. To test this, researchers gave mice the selective 5-HTT inhibitor escitalopram before psilocybin. Escitalopram did not block psilocybin's effects on movement or head twitches. This indicates that acute blockade of 5-HTT does not directly mediate these behaviors, and the earlier findings in knockout mice likely stem from developmental changes or altered serotonin levels rather than acute transporter function.
Acute psilocybin reduced compulsive grooming in male mice for up to one week and in both sexes shortly after dosing, but chronic psilocybin did not improve anxiety-like, depressive-like, or compulsive-like behaviors or social deficits. The findings suggest acute psilocybin may help reduce compulsive behaviors, while repeated low-dose use offers limited benefits. The study used SAPAP3 knockout mice, a model of obsessive-compulsive disorder, and found differences in serotonin receptor signaling between genotypes. Results highlight the need for caution as psychedelic-assisted therapy gains approval, especially regarding microdosing.