Clinical Research Directory

Inclusion Criteria: * Veteran * Depression determined by the Structured Clinical Interview for DSM-5 (SCID) collected at screening visit * Hamilton Depression Rating Scale (HAMD-6) of 8 or higher, assessed at screening visit * No medication changes or psychiatric hospitalization in the past month (30 days prior to informed consent) * No planned medication changes or psychotherapy treatment changes for duration of trial * At least one attempt with a antidepressant medication * Agree to consume the same amount of caffeine-containing beverages that they usually consume before arriving at the research space on the mornings of their drug administration session * Agree to refrain from taking any non-prescription medication, nutritional supplement, or herbal supplement except those approved by the study medical provider * Agree to abstain from all tobacco and nicotine use for the at least 24 hours before and after the drug administration session * Agree to avoid sedative-hypnotic medications (e.g., benzodiazepines, zolpidem, zopiclone, zaleplon) taken on an as-needed basis for a minimum of 5 half-lives prior and for 24 hours after the drug administration session, or the duration chosen by the study medical provider * Agree to avoid opioid medications taken on an as-needed basis for a minimum of 5 half-lives prior and for 24 hours after each drug administration session, or the duration chosen by the study medical provider * Agree not to use products or substances containing 9-tetrahydrocannabinol (THC) and/or cannabidiol for at least 7 days prior to and for 24 hours after each drug administration session * Agree not to consume alcoholic beverages for at least 24 hours prior to and 24 hours following each drug administration session * Agree to have a trusted adult accompany them from the research space upon discharge after drug administration Exclusion Criteria: * Meeting DSM-5 criteria for moderate or higher substance use disorder in the past 6 months, measured at screening visit. Nicotine and cannabis is permissible as long as inclusion criteria can be met * Meeting DSM-5 criteria for a lifetime history of a bipolar or psychotic disorder determined at screening (family history permissible) * Medical conditions contraindicated for psilocybin, modafinil, pimavanserin, or zolpidem, including uncontrolled hypertension, significant cardiac abnormality, or cognitive disorder (Mini-Mental State Examination \<23) determined at screening * Severe traumatic brain injury (Glasgow Outcome Scale-Extended Interview "Severe disability" or worse) determined at screening visit * History of meeting DSM-5 criteria for Hallucinogen Persisting Perception Disorder (HPPD) determined at screening visit * Active suicidal ideation with plan and intent requiring immediate emergency management at any point in the study * Suicide attempt requiring hospitalization in last year determined at screening visit * High dose psychedelic use in past 3 years or ≥10 lifetime uses determined at screening visit * Current use of any of the following medications or inability or unwillingness to stop (see Medication Exclusions and Restrictions section below): * Clozapine * Tricyclic antidepressants * Monoamine oxidase inhibitors * Pregnancy as indicated by a positive urine pregnancy test during screening or prior to drug administration; lactation, or the intention of becoming pregnant within 3 months of entry into this trial * Refusal to use highly effective contraception from entry into the trial through Day 90 and refuse to not breastfeed. Acceptable methods of contraception are: An intrauterine device (IUD), hormone-based contraceptives (birth control pills), condoms (internal or external) must be used with another method (other than spermicide), complete abstinence from sexual activity that could result in pregnancy. * Currently in another therapeutic interventional clinical trial (e.g. a study focused on improving symptoms using a drug or non-drug treatment) * Other medical condition or diagnosis, physical exam finding, laboratory abnormality, or health risk identified that precludes participation in study procedures due to safety or feasibility concerns at the discretion of the investigators