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 symptom duration \>= 6 months
* Have a baseline CAPS-5 score of \>=35
* Currently taking a serotonin reuptake inhibitor (SSRI or SNRI) at a stable dose for at 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 personal interview, 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 the research unit on the mornings of drug session days. If the participant does not routinely consume caffeinated beverages, he/she must agree not to do so on session days.
* Agree to refrain from using alcohol, anxiolytics, stimulants, sedatives or hypnotics, opioids, dissociatives, cannabinoids, or other unapproved substances within 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 before psilocybin dosing.
* Agree not to take sildenafil (Viagra®), tadalafil, or similar medications within 72 hours 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 within two weeks before and after dosing sessions.
* (for male participants) Agree to use contraception and refrain from sperm donation two weeks before and after dosing sessions, as the reproductive safety for psilocybin is not yet established.

Exclusion Criteria:

General medical exclusion criteria:

* Women who are pregnant (as indicated by a positive urine pregnancy test assessed at intake and before each drug session) or nursing; women who are of child- bearing potential and sexually active who are not practicing an effective means of birth control.
* Cardiovascular conditions: coronary artery disease, stroke, angina, hypertension with resting blood pressure systolic \>139 or diastolic \>89, a clinically significant ECG abnormality (e.g., atrial fibrillation), prolonged corrected QT interval (QTc) interval (i.e., QTc \> 450 msec), artificial heart valve, or transient ischemic attack (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 of hypoglycemia
* Currently taking a Monoamine Oxidase Inhibitor

Psychiatric Exclusion Criteria:

* Current or past history of meeting DSM-5 criteria for schizophrenia spectrum or other psychotic disorders (except substance/medication-induced or due to another medical 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 Borderline Personality Disorder.
* Have a first degree relative with schizophrenia spectrum or other psychotic disorders (except substance/medication-induced or due to another medical condition), or Bipolar I.
* Has a psychiatric condition judged to be incompatible with establishment of rapport or 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 significant trauma in daily life.