An Open-Label Trial Protocol to Test Menstrual Cycle Effects and Tolerance to Low-Dose Psilocybin in Healthy Menstruating Persons

BACKGROUND: Research on the therapeutic benefits of psychedelics, particularly psilocybin, is becoming increasingly popular. Unfortunately, most psychedelic research overlooks the menstrual cycle as a biological variable, raising concerns about the safety and efficacy of findings for individuals who menstruate. Given the established effects of estradiol and progesterone (and metabolites) on serotonin receptor density and function, it is plausible that the subjective experience, efficacy, and side effect profile of psychedelics may vary significantly across the different phases of the menstrual cycle. Furthermore, the tolerance effects of psilocybin when taken on consecutive days are unknown. AIMS: The PsiMenis trial will comprises two sub-studies: PsiMen-M, which will assess the potential for the menstrual cycle to affect the response to low-dose psilocybin in healthy menstruating persons, and PsiMen-T, which will test for potential tolerance effects. METHODOLOGY: Psilocybin (5 mg) will be administered during different menstrual cycle phases in 21 healthy participants for PsiMen-M, and 12 for PsiMen-T. Effects on subjective experience, brain/cognitive function, and pharmacokinetics will be measured by the Drug Effects Questionnaire, exploratory task-based electroencephalography (EEG), and blood plasma sampling. Safety and any clinically significant modifications of psilocybin will be monitored by laboratory and vital signs tests. Tolerance to psilocybin will be assessed by administering the drug for three consecutive days. CONCLUSIONS/SIGNIFICANCE: This study will determine whether low-dose psilocybin effects vary across the menstrual cycle, addressing a key gap in psychedelic research. Findings may inform the development of serotonergic treatments for menstrual-cycle-related mood disorders and improve the design of future psychedelic trials by accounting for hormonal fluctuations.