Microdosing Psychedelics to Improve Mood

Inclusion Criteria:

Participants must:

• Have given written informed consent.

• Have a high school level of education.

• Be fluent in speaking and reading the study site's predominantly used or recognizedlanguage (i.e., English).

• Be 18 to 65 years old.

• If of childbearing potential, must have a negative pregnancy test at study entry andmust agree to use adequate birth control 10 days after the last Experimental Session (refer to section 9.4.2 for contraceptive guidelines).

• Have a preexisting diagnosis of MDD with dysthymic subtype or receive a diagnosis ofMDD during screening.

• Agree that for one week preceding each psilocybin session, they will refrain fromtaking any nonprescription medication, nutritional supplements, or herbal supplementexcept when approved by the research team. Exceptions will be evaluated by theresearch team and will include acetaminophen, non-steroidal anti-inflammatory drugs,and common doses of vitamins and minerals with the exception of SAM-e, 5-HTP,L-tryptophan, and St. John's Wort.

• Agree to consume approximately the same amount of caffeine-containing beverage (i.e.coffee, tea) that they consume on a usual morning, before arriving at the researchunit on the mornings of psilocybin session days. Caffeine consumption should notexceed more than ≥600mg/day. If the patient does not routinely consume caffeinatedbeverages, they must agree not to do so on psilocybin session days.

• Agree not to take any as needed (PRN) medications on the mornings of psilocybinsessions. Non-routine PRN medications for treating breakthrough pain that were takenin the 24 hours before the psilocybin session may result in rescheduling thetreatment session, with the decision at the discretion of the investigators.

• Agree to refrain from using any psychoactive drugs, including alcoholic beverages,within 24 hours of each psilocybin administration. As described elsewhere,exceptions include daily use of caffeine.

Exclusion Criteria:

• The subject has participated in another investigational study within 60 days priorto the screening visit.

• Cardiovascular conditions: coronary artery disease, uncontrolled hypertension,angina, a clinically significant ECG abnormality (i.e. atrial fibrillation), TIA inthe last 6 months, stroke, peripheral or pulmonary vascular disease (no activeclaudication).

• Blood pressure exceeding screening criteria described below:

○ Cardiovascular screening:

• At the screening and randomization visit, blood pressure will be assessed toqualify to proceed in the trial. Each assessment occasion will involve two ormore blood pressure readings. To qualify for the study, the mean blood pressure (mmHg) of the two readings will not exceed 140 systolic and 90 diastolic.

• Blood pressure (BP) will be taken while subjects are at rest and have beenseated or supine for at least 5 minutes. The assessment will involve theaverage of 2 or more readings separated by fifteen minutes. If the first 2readings differ by more than 5 mmHg, additional readings will be obtained andaveraged. During the BP assessment, the volunteer will be acclimated to theautomated blood pressure monitoring equipment by repeatedly taking bloodpressure (at least 3 readings) with the device.

• Epilepsy with a history of seizures.

• The subject has a history of cerebral ischemia, transient ischemic attack,intracranial aneurysm, or arteriovenous malformation.

• The subject has a clinically significant history of head injury or head trauma perthe judgement of the investigator.

• The subject has a history of cancer.

• Unstable medical condition, severe renal disease (creatinine clearance < 40 ml/minusing the Cockcroft and Gault equation), hepatic disease (known history of liverdisease, abnormal elevations in LFTs), or serious central nervous system pathology.

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

• Are pregnant (positive urine pregnancy test assessed at screening) or nursing, orare of childbearing potential and are not practicing an effective means of birthcontrol (refer to section 9.4.2 for contraceptive guidelines).

• Currently taking on a regular (i.e. daily) basis any psychotropic medicationsincluding: investigational agents, psychoactive prescription medications (i.e.benzodiazepines), antidepressants, medications having a primary pharmacologicaleffect on serotonin neurons (i.e. ondansetron), medications that are MAO inhibitors,opioid medications. If previously on antidepressants a minimum of five half livesmust have passed from the last dose of medication plus an additional seven days ofstabilization before first administration of the drug.

• Current use of any the following of potent metabolic inducers or inhibitors:Inducers - Rifamycin (rifampin, rifabutin, rifapentine), anticonvulsants (carbamazepine, phenytoin, Phenobarbital), Nevirapine, Efavirenz, Taxol,Dexamethasone), St John's Wort; All cytochrome P450 Inhibitors - including all HIVprotease inhibitors, verapamil, diltiazem, itraconazole, ketoconazole, erythromycin,clarithromycin, azithromycin, and troleandomycin.

• Use of steroids within the past two weeks.

• Current use of the following drugs will also meet exclusion criteria: ergotalkaloids, pimozide, midazolam, triazolam, lovastatin, simvastatin, fentanyl.

• Agree to refrain from using any psychoactive drugs, including alcoholic beverageswithin 24 hours of each drug administration. The exception is caffeine.

• Must not be a habitual smoker.

• Refrain from starting any new medications.

• Refrain from starting any new complementary or alternative medicine practices (i.e.nutrition/diet modifications, supplements, meditation practice, etc.).

• Are willing to comply with medication requirements per the protocol (refer toSection 6.2).

• Lifestyle Criteria; Refrain from working night shifts.

Psychiatric Exclusion Criteria:

• Current or past history of meeting DSM-V criteria for Schizophrenia, PsychoticDisorder, or Bipolar I or II Disorder.

• Active Major Depressive Disorder Episode.

• Having a first or second-degree relative with schizophrenia, psychotic disorder (unless substance-induced or due to a medical condition), or bipolar I or IIdisorder.

• Currently meets DSM-V criteria for Dissociative Disorder, Anorexia Nervosa, BulimiaNervosa, or other psychiatric conditions judged to be incompatible with theestablishment of rapport or safe exposure to psilocybin.

• Current or past history within the last 5 years of meeting DSM-V criteria for amoderate or severe alcohol or drug use disorder (excluding caffeine and nicotine).

• Use within 6 months of psychedelic substances.