A Study of Psilocybin for PTSD

Inclusion criteria:

• Be at least 21 years old

• Have given written informed consent

• Have a confirmed DSM-5 diagnosis of Post-Traumatic Stress Disorder with symptomduration >= 6 months

• Have a baseline CAPS-5 score of >=35

• Currently taking a serotonin reuptake inhibitor (SSRI or SNRI) at a stable dose forat least 3 months.

• Be judged by study team clinicians to be at low acute risk for suicidality

• Be medically stable as determined by screening for medical problems via a personalinterview, a medical questionnaire, a physical examination, an electrocardiogram (ECG), and routine medical blood and urinalysis laboratory tests

• 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 participant does notroutinely consume caffeinated beverages, he/she must agree not to do so on sessiondays.

• Agree to refrain from using alcohol, anxiolytics, stimulants, sedatives orhypnotics, opioids, dissociatives, cannabinoids, or other unapproved substanceswithin 24 hours of psilocybin administration. Caffeine and nicotine are exceptions.

• Agree not to take any as needed (PRN) medications on the mornings of drug sessions

• Agree to stop taking 5HT2A antagonist medications at least 5 half-lives beforepsilocybin dosing.

• Agree not to take sildenafil (Viagra®), tadalafil, or similar medications within 72hours of each drug administration.

• Have no classic psychedelic use in the past five years.

• Have at least a high school level of education or equivalent (e.g. GED).

• Weigh at least 40kg.

• (for female participants) Agree to use highly effective birth control measure withintwo weeks before and after dosing sessions.

• (for male participants) Agree to use contraception and refrain from sperm donationtwo weeks before and after dosing sessions, as the reproductive safety forpsilocybin is not yet established.

Exclusion Criteria:

General medical 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.

• Cardiovascular conditions: coronary artery disease, stroke, angina, hypertensionwith resting blood pressure systolic >139 or diastolic >89, a clinically significantECG abnormality (e.g., atrial fibrillation), prolonged corrected QT interval (QTc)interval (i.e., QTc > 450 msec), artificial heart valve, or transient ischemicattack (TIA) in the past year

• Family history of Torsades de Pointes and sudden cardiac death

• Epilepsy with history of seizures

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

• Currently taking a Monoamine Oxidase Inhibitor

Psychiatric Exclusion Criteria:

• Current or past history of meeting DSM-5 criteria for schizophrenia spectrum orother psychotic disorders (except substance/medication-induced or due to anothermedical condition), or Bipolar I or II Disorder

• Current or history within one year of meeting DSM-5 criteria for a severe alcohol,tobacco, or other drug use disorder (excluding caffeine)

• Current or history within one year of meeting DSM-5 criteria for BorderlinePersonality Disorder.

• Have a first degree relative with schizophrenia spectrum or other psychoticdisorders (except substance/medication-induced or due to another medical condition),or Bipolar I.

• Has a psychiatric condition judged to be incompatible with establishment of rapportor safe exposure to psilocybin

• History of a medically significant suicide attempt

• Unwilling or unable to pause concurrent psychotherapy during the study.

• Determined to be at risk for re-exposure to the index trauma or other significanttrauma in daily life.