The goal of this phase 1 study is to investigate the safety and efficacy of dimethyltryptamine (DMT) in individuals with depression and healthy controls. We hypothesize that administration of DMT will result in decreases in depression, associated symptoms, and neuroplastic changes in depressed subjects. We expect that DMT will induce changes in neuroplasticity as indexed using electroencephalographic (EEG) measures and tasks in both depressed individuals and healthy volunteers, though to different degrees. These neuronal changes may in parallel cause changes in mood measured both in healthy and depressed subjects, which will be captured using appropriate psychometric measures of mood.

Some Common Inclusion Criteria:

1. Males and females
2. Age 21 to 65 years
3. Body mass index between 18-35 kg/m2
4. Willing to refrain from taking any medications not approved by the study physician
5. Willing to refrain from using street drugs and alcohol
6. Negative urine drug screen
7. Willing and able to abstain from smoking throughout each test session
8. Women who are of child-bearing potential (WOCBP) and sexually active must be willing to practice an effective means of birth control
9. Willing not to drive to and from the testing session

Some Inclusion Criteria for Subjects with MDD:

1. Diagnosed with Major Depressive Disorder (MDD)
2. Unsatisfactory response to antidepressants
3. Engaged in treatment for depression with a clinician and willing to continue treatment for the duration of the study
4. Not engaged in treatment
5. Consent to allow the research team to communicate with mental health provider.
6. Only subjects who get support for participation in the trial from their mental health clinician will be eligible to be enrolled in the study

Some Common Exclusion Criteria:

1. Medications that might significantly interfere with the effects of the study medications
2. Cognitive dysfunction that could interfere with study participation
3. Alcohol or substance use disorder
4. Any lifetime history of hallucinogen use disorder
5. Regular use or misuse of hallucinogens
6. History of intolerance to perceptual altering drugs
7. Significant blood pressure problems
8. Pregnancy or currently breast feeding (lactation)
9. Any unstable medical conditions
10. Significant cardiovascular disease
11. Significantly abnormal laboratory test results
12. History of serotonin syndrome

Some Exclusion criteria for MDD subjects:

1. Current primary psychiatric disorder other than MDD
2. Medically significant condition rendering unsuitability for the study

Some Exclusion criteria for healthy controls:

1. No current DSM-V psychiatric disorder, excluding nicotine and caffeine use disorder
2. No family history of serious mental illness (e.g., schizophrenia, bipolar disorder)

Some 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)