Mindfulness‑assisted Psilocybin Therapy

Eligible participants will be:

* Adults of any race, ethnicity, or gender who are age 25 years or older
* Have not had formal mindfulness training
* Have not previously used classic psychedelics
* 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 morning of the drug session day. If the participant does not routinely consume caffeinated beverages, he/she must agree not to do so on the session day.
* Agree to refrain from using any psychoactive drugs, including alcoholic beverages and nicotine, within 24 hours of each drug administration. The exception is caffeine.
* Agree not to take any PRN medications on the mornings of drug sessions
* Agree not to take sildenafil (Viagra®), tadalafil, or similar medications within 72 hours of psilocybin administration.
* Agree that for one week before the drug session, he/she will refrain from taking any nonprescription medication, nutritional supplement, or herbal supplement except when approved by the study investigators. Exceptions will be evaluated by the study investigators and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals.

Participants will be excluded if they present with any of the following:

* Prior exposure to formal mindfulness or meditation training
* Previous use of psilocybin or other psychedelic drugs (LSD, mescaline, DMT/ayahuasca, 5-methoxy-DMT)
* Current use of tricyclic antidepressants, serotonin reuptake inhibitors, antipsychotics, atypical antipsychotics, monoamine oxidase inhibitors (MAOIs), mood stabilizers (lithium), buspirone, mirtazapine, trazodone, or other drugs that modulate the serotonin system. For individuals who have intermittent or PRN use of such medications, psilocybin sessions will not be conducted until at least 5 half-lives of the agent have elapsed after the last dose.
* Current use of St. John's Wort or 5-hydroxytryptophan
* Currently taking psychoactive prescription medication on a regular (e.g., daily) basis
* Current or lifetime history of schizophrenia, other psychotic disorders, or bipolar I or II disorder; or a first or second degree relative with one of these disorders
* Current or recent past (within the past 5 years) history of alcohol or drug dependence (other than caffeine or nicotine) or major depressive episode
* Current or recent suicidal ideation (within the past month) or behavior (within the past 6 months), as assessed by a response of "yes" to any of questions in the "Suicidal Ideation" or "Suicidal Behavior" on the C-SSRS at the eligibility screen or baseline session
* Current (past two weeks) self-reported risky alcohol use (\>7 drinks/week for women or \>14 drinks/week for men)
* Current obsessive-compulsive disorder, dysthymic disorder, panic disorder, dissociative disorder, anorexia nervosa, or bulimia nervosa
* Has a psychiatric condition judged to be incompatible with establishment of rapport or safe exposure to psilocybin
* Self-reported use of or positive urine drug screen for amphetamines/methamphetamine, opioids, barbiturates, methadone, cocaine, or PCP at the eligibility screen visit or the psilocybin visit
* Positive breath alcohol test at the eligibility screen visit or the psilocybin visit (BrAC \> 0.01)
* Current pregnancy, planned pregnancy in the next 6 months (at phone screen or eligibility screen), positive urine pregnancy test (for participants of childbearing potential) at the eligibility screen or the psilocybin session, or current breastfeeding
* Unwilling to use a medically-accepted highly effective form of birth control (such as hormonal implants, intrauterine devices (IUDs), hormonal birth control pills, surgical sterility, or other methods deemed highly effective (\<1% failure rate) by the study physician) during the study (applies to male participants as well as female participants of childbearing potential)
* Cardiovascular conditions: coronary artery disease, stroke, angina, uncontrolled hypertension, a clinically significant ECG abnormality (e.g., atrial fibrillation, QTc greater than 450 msec), artificial heart valve, or TIA in the past year
* Epilepsy with history of seizures
* Current unstable medical condition (including uncontrolled or poorly controlled hypertension - resting blood pressure greater than 140 (systolic) or 90 (diastolic) mmHg at the eligibility screening will be reviewed by the study physician and participants with stable hypertension will be asked to follow-up with their primary care physician to initiate appropriate hypertensive treatment prior to proceeding)
* Diabetes (type 1 or 2) with insulin dependence; if taking oral hypoglycemic agent, then no history of hypoglycemia
* Any other medical condition that may be incompatible with safe exposure to psilocybin
* Inability to speak English
* Inability to provide informed consent