Pilot RECAP Study in Healthy Volunteers

The PILOT RECAP Study will investigate the effect of co- administering the amnestic agent midazolam with a single 25 mg dose of psilocybin on the induction of a psychedelic experience and subsequent memory for the experience with the goal of identifying an optimal dosing regimen of midazolam that will allow a psychedelic experience to occur while also inducing amnesia for the experience. Identifying this midazolam dosing regimen will allow us in a subsequent stage of the RECAP program to test whether memory for the psychedelic experience is required/important for psilocybin to produce longer-term antidepressant effects. This is a phase 1 study in psychiatrically and medically healthy volunteers. Given this, there is no disease background for PILOT RECAP per se. However, the purpose of PILOT RECAP is to identify an optimal midazolam dosing schedule to be used in a subsequent study (RECAP) in patients with major depressive disorder (MDD).

The investigational treatment for PILOT RECAP is a single 25 mg dose of psilocybin combined with repeated intravenous (IV) boluses of midazolam dosed at levels known to maintain conscious experience while inducing subsequent amnesia for the experience upon its conclusion. Because PILOT RECAP is the first study to examine this drug combination, no data are currently available on this approach. Psilocybin + midazolam will be administered within a "Set and Setting" (SaS) protocol that provides psychoeducation and therapeutic support prior to, during, and following psychedelic dosing, and that has been standard procedure for recent studies of psilocybin in humans. It is believed that this SaS approach enhances clinical efficacy and safety. SaS is an integral component of the PILOT RECAP intervention.

The PILOT RECAP study will not enroll vulnerable populations. During this study, participants are asked to:

• Refrain from use of psychotropic medications. Use of such medications prior to psilocybin/midazolam dosing will result in a participant being discontinued from the study.
• Refrain from use of any illegal psychoactive substances from screening until study termination.
• Refrain from using legal psychoactive substance for the following defined time periods (the exception is caffeine):

• Tobacco and Nicotine: from screening until study termination
• Alcohol: 72 hours prior to the Dosing Visit

Inclusion criteria

• Age 21 to 65 years at screening
• Medically healthy (does not meet criteria for an exclusionary medical condition)
• No current DSM-5 psychiatric diagnosis
• No current use of psychotropic medications
• Ability/willingness to complete all study activities
• Use of acceptable contraceptive methods (sexually active males and women of childbearing potential)
• Speaks and reads English
• No use of psychedelic drugs within prior 3 months of dosing visit
• Able to swallow oral medications

Exclusion criteria

• Pregnancy
• Current exclusionary medical illness
• Current DSM-5 psychiatric diagnosis and/or suicidal thoughts/behavior within prior 12 months
• Clinically significant safety lab abnormalities (i.e., Complete Blood Count with Differential, Comprehensive Metabolic Panel, and urinalysis)
• Clinically significant electrocardiogram (ECG)
• Hypertension or tachycardia
• First degree relative(s) with a history of schizophrenia, schizophreniform disorder, bipolar I disorder, bipolar II disorder, major depressive disorder with psychotic features