Inclusion Criteria:
1. Males and females
2. Age 21 to 65 years;
3. Body mass index between 18-35 kg/m2;
4. English speaking
5. Able to provide informed consent;
6. Willing to refrain from taking any medications not approved by the study physician;
7. Willing to refrain from using street drugs and alcohol the day before, the day of, and the day after each test session;
8. Negative urine drug screen on the morning of each test session (the following drugs will be tested for: cocaine, opioids, benzodiazepines, cannabinoids, stimulants);
9. Willing and able to abstain from smoking throughout each test session;
10. Women who are of child-bearing potential (WOCBP) and sexually active must be willing to practice an effective means of birth control;
11. Willing not to drive to and from the testing session.
Inclusion Criteria for Subjects with MDD:
1. Diagnosed with Major Depressive Disorder (MDD), single or recurrent episode, and currently experiencing a Major Depressive Episode (MDE), of a moderate to severe degree (Score ≥17 on the 21-item clinician-rated HAMD);
2. Unsatisfactory response to at least one adequate antidepressant trial (at least 6 weeks on a therapeutic dose) during the current depressive episode and/or unable to tolerate existing antidepressants, assessed with the Antidepressant Treatment History Form - Short Form (ATHF-SF) and confirmed with the primary mental health provider (see clinician contact form);
3. Engaged in treatment for depression with a clinician and willing to continue treatment for the duration of the study;
4. Those not engaged in treatment t the time of screening will be required to engage in treatment as a condition of study participation.
5. Consent to allow the research team to engage the primary mental health provider.
Exclusion Criteria:
1. Recent clinically significant current risk for suicidal behavior as assessed by chart review, opinion of mental health provider and Columbia Suicide Rating Scale (CSSRS);
2. Recent clinically significant aggressive behavior assessed by chart review, opinion of mental health provider and psychiatric screening;
3. Psychosis:
1. Current or past history of any psychotic disorder including Schizophrenia, Bipolar I Disorder, Delusional Disorder, Paranoid Personality Disorder, or Schizoaffective Disorder (clinical judgement will be exercised);
2. History of psychotic symptoms in the current or previous depressive episodes;
4. Currently taking an antidepressant medication (including SSRIs, SNRIs, TCAs, and MAOIs) or other medications (e.g., efavirenz, locanserin) that may alter the effects of 5HT2A agonists. Exceptions are medications used at low doses for sleep. If a subject meets all other study criteria, he/she may consider discontinuation of antidepressant under clinical supervision contingent upon the approval of the patient's clinician. Subjects will need to be off prohibited medications for at least five half-lives of the medication's major metabolites prior to the first test session;
5. Currently taking over the counter products such as 5-hydroxytryptophan and St. John's wort, due to potential interactions with DMT;
6. Cognitive dysfunction that could interfere with study participation;
7. Recent history of meeting criteria for alcohol or substance use disorder (excluding caffeine and nicotine);
8. Alcohol use of ≥7 drinks in females and 14 in males per week (NIAAA guidelines);
9. Any lifetime history of hallucinogen use disorder;
10. Regular (≥once per month) use or misuse of serotonergic hallucinogens including DMT, psilocybin, LSD, and related compounds;
11. History of intolerance to drugs known to significantly alter perception, e.g., DMT, THC ketamine, psilocybin, LSD, Salvinorin A, mescaline, etc.;
12. Hypotension, as defined as a baseline blood pressure \< 90/60 mmHg or orthostatic hypotension as defined as a sustained reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of 10 mm Hg within 3 min of standing or head-up tilt;
13. Pregnancy or currently breast feeding (lactation);
14. Medical conditions deemed by the PI (D'Souza), or his designee, to be unstable including but not limited to uncontrolled hypertension (e.g., \>140/90 averaged across four assessments, uncontrolled insulin-dependent diabetes, renal or hepatic failure, seizure disorder, etc.;
15. Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation;
16. Any current or past history of any physical condition or abnormal screening laboratory test that, in the investigator's opinion, might put the subject at risk or interfere with study results interpretation.
17. First degree relatives with a history of psychosis
IQ \< 80 measured by the Weschler Test of Adult Reading (WTAR).Exclusion criteria for depressed subjects:
1. Current primary psychiatric disorder other than MDD;
2. Medically significant condition rendering unsuitability for the study;
3. History of mania;
Exclusion criteria for healthy controls:
1. No current DSM-V psychiatric disorder, excluding nicotine and caffeine use disorder;
2. No lifetime use of psychiatric medication \>3 months (proxy for psychiatric disorders).
3. No family history of serious mental illness (e.g., schizophrenia, bipolar disorder)
Inclusion criteria for healthy controls:
1. no current DSM-5 psychiatric disorder, excluding nicotine and caffeine use disorder;
2. no lifetime use of psychiatric medication \>3 months (proxy for psychiatric disorders).
Alcohol and street drug use that does not meet criteria for use disorder will be evaluated by the researchers on a case-by-case basis.
