Investigation of Psychedelic Effects in Psychoactive Substances

Inclusion Criteria:

• Be 25 to 55 years old

• BMI between 18 and 34 kg/m2

• Agree to consume approximately the same amount of caffeine-containing beverage (e.g., coffee, tea) that he/she consumes on a usual morning, before arriving at theresearch unit on the mornings of drug session days. If the subject does not usuallyconsume caffeinated beverages, he or she must agree not to do so on session days

• Agree to refrain from using any psychoactive drugs, including alcoholic beverages,within 24 hours of each drug administration. Exceptions include daily use ofcaffeine and nicotine.

• Be healthy and psychologically stable as determined by screening for medicalproblems via a personal interview, a medical questionnaire, a physical examination,an electrocardiogram (ECG), and routine medical blood and urinalysis laboratorytests

• Agree not to take any PRN prescription medications on the mornings of the sessionsunless deemed appropriate by study team.

Exclusion Criteria:

• Women who are pregnant (as indicated by a positive urine pregnancy test assessed atintake and before each drug session) or nursing; women who are of child-bearingpotential and sexually active who are not practicing an effective means of birthcontrol (e.g. oral contraceptives, intrauterine device)

• Cardiovascular conditions-coronary artery disease, stroke, angina, uncontrolledhypertension, a clinically significant ECG abnormality (e.g., atrial fibrillation),or transient ischemic attack-that in the clinical opinion of the screening physicianor mid-level provider would put the participant at an especially high risk foradverse effects from the study.

• Epilepsy with history of seizures

• Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history ofhypoglycemia

• Currently taking on a regular (e.g., daily) basis any medications having a primarycentrally acting pharmacological effect on serotonin neurons or medications that areMonoamine oxidase (MAO) inhibitors. For individuals who have intermittent or asneeded (PRN) use of such medications, sessions will not be conducted until at least 5 half-lives of the agent have elapsed after the last dose.

• Use of nonprescription medications, nutritional supplements, or herbal supplementsexcept when approved by the study investigators. Exceptions will be evaluated by thestudy investigators and will include acetaminophen, non-steroidal anti-inflammatorydrugs, and common doses of vitamins and minerals

• History of meeting Diagnostic and Statistical Manual of Mental Disorders (DSM)-5criteria for moderate or severe substance use disorder (including alcohol usedisorder, but excluding tobacco), requiring that at least one of the endorsedcriteria relates to prior loss of control of substance use (e.g. consuming thesubstance in larger amounts and for a longer amount of time than intended;persistent desire to cut down or regulate use; unsuccessful attempts to stop use;spending a great deal of time obtaining, using, or recovering from the effects ofsubstance use).

• Active suicidal ideation and/or behavior at time of screening.

• Psychiatric disorder that in the clinical opinion of the study team would put theparticipant at an especially high risk for adverse effects from the study.

• First-degree relative who meets DSM-5 criteria for a Schizophrenia Spectrum or OtherPsychotic Disorder (unless disorder is Substance/Medication-Induced PsychoticDisorder or Psychotic Disorder Due to Another Medical Condition), Bipolar IDisorder, or Bipolar II disorder.

• Enrolled in another clinical trial or have received any drug as part of a researchstudy within 30 days prior to dosing.

• Known allergy or prior adverse reaction to any of the study drugs judged by theinvestigator and/or medical staff to put the study volunteer at greater risk.

• Known allergy or intolerance to nitroglycerin.

• Concomitant use of any CYP2C9 and CYP3A4 inhibitors.