This study will test the effects of psilocybin on memory and cognition in healthy participants using computerized tasks and magnetic resonance imaging (MRI).

In a double-blind, placebo-controlled, repeated measures design in healthy participants, this study will test the effects of psilocybin on memory and cognition in healthy individuals using computerized tasks and magnetic resonance imaging (MRI). A better understanding of the basic neurocognitive effects of psilocybin may allow for minimizing potential harms and maximizing potential benefits of psilocybin therapy.

Inclusion Criteria:

• 21 to 45-years-old.
• 3-30 lifetime psychedelic uses.
• English as a first language.
• High school education (or equivalent)
• Psychiatrically healthy (as assessed by the SCID-5).
• Medically healthy (as assessed by a physical examination and ECG).
• Willingness to attend all study sessions and complete all procedures.
• BMI between 19 and 30.

Exclusion Criteria:

• Current or past diagnosis of psychiatric disorders except panic attacks, depressive disorder, or anxiety, or disorder from ≥1 year prior.
• Current or past medical conditions that might interfere with study participation or be contraindicated for psilocybin administration (e.g., hypertension, history of stroke, cardiovascular disease, etc.)
• Current daily medications except birth control (females).
• Pregnant, nursing, or planning to become pregnant (assessed with urine pregnancy test).
• Ingestion of a psychedelic <2 months prior to an experimental session (with the exception of psilocybin administered in the context of the current study's repeated measures design).
• History of serious adverse event with a psychedelic and/or self-reported hypersensitivity to psychedelics.
• Inability to abstain from alcohol 48 hours prior to an experimental session.
• Use of other psychoactive drugs (other than caffeine or nicotine) 1 week prior to an experimental session.
• Positive urine drug screening for drugs of abuse during experimental sessions.
• Self-reported ferrous metal, metallic implants, or implanted medical devices that would preclude participation in MRI procedures, including but not limited to cochlear implants, implanted brain stimulators, and aneurysm clips.
• Self-reported past penetrating brain injury or any head injury resulting in a loss of consciousness for 30 minutes or more or post-concussive symptoms for more than seven days following a head injury.
• Self-reported claustrophobia (prohibiting MRI acquisition).
• Any other factors such as unstable housing or life-threatening circumstances, erratic behavior, etc. that are judged by the investigators to be a significant barrier to participation in the study protocol and/or to establishing rapport necessary for safe administration of psilocybin.
• Participant unwillingness to not ingest or use additional serotonergic psychedelics outside the context of study procedures for the duration of the study.
• Resting blood pressure >140/90 mm hg at study entry.
• Lifetime history of cardiomyopathy, stroke, heart disease, heart attack, tachycardia, elongated QT-interval corrected by Friderichia (> 450ms for men and > 470ms for women); clinically significant cardiac arrhythmia within 1 year of study entry; and/or abnormal electrocardiogram on study entry.
• Left-handedness (given that functional lateralizations may differ from those of right-handed individuals).

De-identified behavioral and fMRI data

Data will be available following publication of the primary findings.

Anyone will be able to access the de-identified behavioral and fMRI data from Open Science Framework and OpenNeuro.

Double-blind, placebo-controlled, crossover masking