This study examines how the psychedelic substance DMT affects the human brain when administered by the intravenous (IV) route. DMT is a naturally occurring chemical in the body that is thought to help improve mood when ingested in a continuously monitored medical setting. Previous research has shown that a single IV injection of DMT can be given safely, but its effects, which include changes in perception, emotions, and thinking, usually wear off within 15-20 minutes.

To better understand what happens when DMT's effects last longer, researchers have developed a method to give DMT slowly and continuously through an IV, which safely extends its effects for up to an hour or more. In this study, healthy volunteers who have prior experience using DMT will receive low and medium doses of DMT in this extended manner through an IV for 1 hour while undergoing a brain scanning technique known as functional magnetic resonance imaging (fMRI). These scans allow researchers to see changes in brain activity and blood flow in real time.

Participants will complete psychological assessments before and after receiving DMT, and additional brain scans without DMT will be used for comparison. The researchers will also use advanced computer techniques to help identify brain patterns linked to the visual experiences people report during DMT.

Overall, the goal of the study is to better understand how DMT affects the brain during an extended experience and to learn more about the biological processes behind its psychological effects.

Inclusion Criteria:

• 18 to 65 years of age
• Able to fluently communicate in English
• Agree to sign the consent and HIPAA authorization
• Not taking serotonergic antidepressant medication
• Willing to refrain from using any non-prescribed psychoactive drugs, including alcohol, within 24 hours before and after study drug administration
• Willing to refrain from consumption of illicit psychoactive substances during the study
• Agree not to use any nonprescription medications, herbal medications, or supplements during the week prior to each drug session unless an exception is approved by the study investigators
• Willing to refrain from smoking or use of nicotine from 8:00 AM on the morning of drug sessions until discharge at the end of the session
• Have used classic serotonergic hallucinogens (e.g., LSD, psilocybin mushrooms, ayahuasca) without untoward/adverse effects and report "liking" psychedelic drugs with no previous adverse reactions to DMT or other psychedelics
• Report at least 20 lifetime uses of psychedelics, including at least 5 uses of DMT (any form), at least one via inhalation, at least once within the past 2 years, and not within the past 3 months
• Able to remain in an fMRI scanner without sedation and pass fMRI safety screening
• Refrain from caffeine use prior to fMRI scanning
• Women of childbearing potential must agree to use effective birth control from screening through the final visit
• Have a relative or friend available to provide transportation after the drug session
• Not taking medications acting as serotonin antagonists (e.g., cyclobenzaprine, ondansetron), dopamine antagonists (e.g., metoclopramide, promethazine, prochlorperazine), dopamine agonists (e.g., levodopa, pramipexole, apomorphine), psychostimulants (e.g., modafinil, armodafinil, solriamfetol, methylphenidate, dexmethylphenidate, atomoxetine, dextroamphetamine, mixed amphetamine salts, lisdexamfetamine), anticholinergics (e.g., benztropine, trihexyphenidyl, scopolamine, hyoscyamine), or NMDA receptor antagonists (e.g., amantadine, memantine, ketamine)

Exclusion Criteria:

• Pregnant or nursing females
• Females of childbearing potential who are sexually active but not using birth control
• MRI contraindications (e.g., pacemakers, metal implants, spinal cord stimulators)
• Current DSM-5 diagnosis of depression or anxiety (or within past 6 months), bipolar disorder, schizophrenia, or other psychotic disorder
• First-degree relative with bipolar disorder, schizophrenia, or other psychotic disorder
• Suicide risk as determined by clinician assessment and/or C-SSRS
• Active substance use disorder (excluding tobacco and caffeine)
• Use of serotonergic dietary supplements (e.g., 5-hydroxytryptophan, St. John's wort, SAM-e) if unwilling to discontinue for study duration
• Neurological conditions affecting cognition or perception (e.g., dementia, traumatic brain injury, mild cognitive impairment)
• Positive urine drug screen for amphetamines, barbiturates, buprenorphine, cocaine, methamphetamine, MDMA, methadone, opiates, or phencyclidine
• Use of DMT or another serotonergic hallucinogen within the past 3 months
• Concomitant treatment with antipsychotic medications
• Concomitant treatment with antidepressants, MAO inhibitors, or serotonin reuptake inhibitors (trazodone ≤50 mg/day for insomnia allowed but not within 48 hours of DMT session)
• Severe hearing or visual impairment
• History of seizure disorder or epilepsy
• History of adverse reactions to rescue medications used in the study (benzodiazepines, antipsychotics, labetalol, nitroglycerin, ondansetron)
• Cardiovascular disease or hypertension (SBP >140 mmHg or DBP >90 mmHg)
• Resting heart rate >90 bpm
• Hypotension (SBP <90 mmHg or DBP <60 mmHg)
• QTc prolongation (>0.045 sec for men, >0.047 sec for women)
• History of stroke, angina, clinically significant ECG abnormality, or artificial heart valve
• Severe renal impairment (GFR <30 mL/min/1.73 m²)
• Clinically significant laboratory abnormalities
• History of syncope
• History of vertigo
• Myocardial infarction within 12 months
• Child-Pugh class B or higher, or with alanine aminotransferase or aspartate aminotransferase >2x upper limit of normal
• Concomitant medications associated with serotonin syndrome (e.g., carbamazepine, dextromethorphan, lithium, linezolid, buspirone)
• Severely compromised hepatic function
• Trypanophobia (fear of needles/blood)
• Treatment with another investigational drug within 30 days of screening