Study of the Safety, Tolerability, Electrophysiological Effects and Efficacy of DMT in Humans

Phase 1

Recruiting

• Conditions: Major Depression Disorder; Depression
• Interventions: Drug: DMT-Low Dose; Drug: DMT-Medium Dose; Drug: THC-Medium Dose; Drug: THC-Low Dose

• Registration Number: NCT06671977
• Lead Sponsor: Deepak C. D'Souza

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2024-10-16
• Study First Submitted QC: 2024-10-31
• Study First Posted: 2024-11-04
• Study Start: 2025-03-14
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-01
• Last Update Posted: 2025-05-02
• Primary Completion: 2027-12-01
• Study Completion: 2027-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
10 mg slow intravenous push (bolus) over 5 minutes and then 0.01 mg/kg/min for 55 minutes	DMT-Low Dose	Low dose DMT
14 mg slow intravenous push (bolus) over 5 minutes and then 0.015 mg/kg/min for 55 minutes.	DMT-Medium Dose	Medium Dose DMT
0.5 mg over 5 minutes and then 2 mg over and 55 minutes	THC-Medium Dose	THC-Medium Dose
Placebo	DMT-Medium Dose	-
Placebo	DMT-Low Dose	-
Placebo	THC-Medium Dose	-
Placebo	THC-Low Dose	-
0.1 mg slow intravenous push (bolus) over 5 minutes and then I mg over 55 minutes	THC-Low Dose	Low Dose THC

Primary Outcome Measures

Name	Time	Method
Safety of Physiological indices	Time Frame: -60 and -30 minutes before DMT administration; 0, +5, +10, +15, +20, +30, +45, +60, and +120 minutes after DMT administration]blood pressure and heart rate will be measured before, during, and after the dosing on each test day.	Pulse oximetry will be measured continuously.
Psychedelic Effects	From start Test Day Time points (Minutes): -60, +30, +120.	The 30-item revised Mystical Experience Questionnaire (MEQ30) will be used to measure mystical/psychedelic experiences associated with drugs like psilocybin
Psychotomimetic Effects	Test Day Time points (Minutes): -60, +30, +120	To capture the effects of DMT/THC/placebo on perception, thought, and sensory processing, participants will be measured using the Psychotomimetic States Inventory
Anxiety	Test Day Time points (Minutes): -60, +30, +120	Will be assessed using a visual analog scale that subjects will be asked to score from 0 (not at all) to 100 (worst ever) to capture anxiety.
Depression	From start of test day (-60), +30, and +120.	subjects will be asked to score from 0 (not at all) to 100 (worst ever) to capture the depression.
Intensity of the Experience	Test Day Time points (Minutes): +150 - +180	The Challenging Experience Questionnaire (CEQ) a 26 item likert-scale style survey will be used to provide a phenomenological profile specifically of challenging aspects of experiences with psilocybin
Drug Reinforcing Effects	Test Day Time points (Minutes): +120	Will be assessed with questions such as: * How likely are you to use this drug recreationally? 0 (not at all) ------------------------100 (most of all); * How much are you willing to pay for the acute effects that you experienced during the dosing session? $0-------------------$100 Shortly after resolution of effects, participants will be instructed to retroactively rate the highest effects experienced since the last time they were prompted to provide a rating.
Tolerability of Overt Adverse Effects	Test Day Time points (Minutes): -60, +30, +120, 180 (end of test day)	Tolerability defined by the US FDA as "the degree to which overt adverse effects can be tolerated" by a subject was assessed \[60\]. At the end of the test day, after all drug effects have worn off, participants will be asked to score 1) the overall experience on a visual analog scale \[VAS\] (0 = intolerable to 100 = well-tolerated).
Electrophysiological	Resting State EEG: Will be collected the day after each dosing session. [Time Frame: -60 minutes before DMT administration until +180 minutes after DMT administration].

Secondary Outcome Measures

Name	Time	Method
Expectancy Effects	Subjects will be tested for expectancy effects at screening, and before each dosing session.
Adequacy of blinding	Time Frame: 0; immediately after DMT administration, and +180 minutes at the end of the study	Subjects will be asked to guess their treatment assignment, the degree of certainty of their guess and the reason for their guess both immediately after the psychedelic dosing session(s) and at the end of the study. Either the James' blinding index (BI) or Bang's BI, will be used to measure the adequacy of the blind.
Blood	Blood sample measurements will be repeated approximately 0, 20, 30, and 60 minutes after drug administration
Changes in personality domains (NEO personality inventory)	[Time Frame: -60 minutes before DMT administration; 0, +30, and +60 minutes after DMT administration]
Psychological Flexibility	Time Frame: +180 minutes after DMT administration	The Acceptance and Action Questionnaire (AAQ) is a one-factor, likert scale assessment of psychological inflexibility

Trial Locations

Locations (1)

Biological Studies Unit at the VA Connecticut Healthcare System, Yale School of Medicine,; 🇺🇸 West Haven, Connecticut, United States