Molecular Imaging Study of Harmine/DMT: a Basic Research Approach (HaD-PET)

The few reports on effects of psychedelic substances on cerebral metabolic rate (CMRglc) indicate increases (psilocybin; human FDG-PET) or decreases (LSD, rat autoradiography; 5-MeO-DMT rat autoradiography). There are no reports of effects of DMT and/or harmine on cerebral energy metabolism. The primary objective of this study is thus to assess acute cerebrometabolic effects of harmine/DMT in healthy volunteers using quantitative FDG-PET, that is, to measure CMRglc before and after simultaneous treatment with an oral harmine and DMT formulation developed (and already applied) by the investigators' project partners at the University of Zurich. As a secondary objective, the researchers aim to correlate the time-dependent effects on CMRglc as assessed in the PET images with the time-dependent self-reported intensity of participants' psychedelic experience.

Study Overview

• Status: Completed
• Conditions: Neuropharmacological Investigation of Ayahuasca Constituents DMT and Harmine
• Intervention / Treatment: Drug: N,N-dimethyltryptamine (DMT) + harmine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Bern, Switzerland, 3010
    • Department of Nuclear Medicine, Bern University Hospital
  • Zurich, Switzerland, 8032
    • Psychiatric University Hospital Zurich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Between 25-45 years old
• Good command of the German language
• Willing and capable to give consent for the participation in the study after it has been thoroughly explained
• Willing and capable to comply with all study requirements
• Body mass index (BMI) between 18.5 and 35
• Previous experience with psychedelics, but not in the past three months
• Willing to abstain from alcohol, caffeinated drinks, nicotine, food, and sugary drinks for two hours prior to the PET scan on the testing day, and from consuming psychoactive substances for 2 weeks before the first testing day and for the duration of the study

Exclusion Criteria:

• Previous significant adverse response to a psychedelic drug
• Recent or concurrent participation in another study where pharmaceutical compounds will be given
• Presence of Axis I affective, anxiety, or dissociative disorders
• Present or antecedent diagnosis of bipolar disorder (I, II, not otherwise specified), schizophrenia, schizoaffective disorder, psychosis, or other disorders from the psychotic spectrum
• First-degree relatives with present or antecedent schizophrenia, schizoaffective disorder, or bipolar disorder type I
• History of head trauma, seizures, cancer, or cerebrovascular accidents
• Recent cardiac or brain surgery
• Current abuse of medication or psychotropic substances according to SCID I criteria
• Presence of major internal or neurological disorders (including sepsis, pheochromocytoma, thyrotoxicosis, drug-induced fibrosis, familiar or basilar artery migraine)
• Cardiovascular disease (hypertonia, coronary artery disease, heart insufficiency, myocardial infarction, coronary spastic angina) Version 5, 15/11/2023 16/44
• Peripheral vascular disease (thromboangiitis obliterans, luetic arteritis, severe arteriosclerosis, thrombophlebitis, Raynaud's disease)
• Cerebrovascular disease (e.g., stroke, intracranial bleeding / hemorrhage, intracranial aneurysm)
• Diabetes Type 1/2, Metabolic Syndrome
• Serious abnormalities in ECG or blood count/chemistry
• Liver or renal or pulmonary disease
• Inability to lie still in the scanner for about 90 minutes (e.g., because of sneezing, itching, tremor, pain)
• Left-handedness
• Significant radiation exposure (either X-ray or nuclear medicine studies) in the last 12 months
• Presence of claustrophobia or other contraindications to PET scanning
• Presence of contraindications to MRI investigations: Magnetic parts in the body (piercings, brain aneurysm clip, implanted neural stimulator/cardiac pacemaker/defibrillator/Swan Ganz catheter/insulin pump, cochlear implant); metal shrapnel or bullet, ocular foreign body (e.g., metal shavings); current or previous job in metalworking industry
• Current use of medications with significant interaction potential with MAO inhibitors (e.g., antidepressants, antipsychotics, psychostimulants, dopaminergic/serotonergic agents, anticonvulsants)
• High risk of adverse emotional or behavioral reaction based on investigator's clinical evaluation (e.g., evidence of serious personality disorder, serious current stressors, lack of social support).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo first, intervention second; Participants allocated to this arm receive placebo on their first study day and the active drug under investigation on the second study day.	Drug: N,N-dimethyltryptamine (DMT) + harmine; DMT and harmine are the two most abundant chemicals in the Amazonian hallucinogenic plant brew, Ayahuasca, which is used traditionally in spiritual and healing ceremonies. An oral formulation of these two substances will be tested against placebo in the context of an FDG-PET scan.; Drug: Placebo; Placebo will be administered on one of the study days to compare the effects of DMT and harmine with the effects a placebo administration.
Experimental: Intervention first, placebo second; Participants allocated to this arm receive the active drug under investigation on their first study day and placebo on the second study day.	Drug: N,N-dimethyltryptamine (DMT) + harmine; DMT and harmine are the two most abundant chemicals in the Amazonian hallucinogenic plant brew, Ayahuasca, which is used traditionally in spiritual and healing ceremonies. An oral formulation of these two substances will be tested against placebo in the context of an FDG-PET scan.; Drug: Placebo; Placebo will be administered on one of the study days to compare the effects of DMT and harmine with the effects a placebo administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in cerebral metabolic rate for glucose (CMRglc)	Differences in CMRglc during a placebo PET scan vs. active-drug PET scan are measured.	From enrollment to the second PET scan, up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Glucose levels	Glucose levels in blood are measured before and after PET scans to correct PET data to changes in glucose during the scans.	From enrollment to the second PET scan, up to 6 months
Plasma concentrations of DMT, harmine, and their metabolites	Plasma concentrations of DMT, harmine and their main metabolites are assessed at several timepoints, i.e. at baseline, 20, 40, 60, 80, 100, and 180 min after drug or placebo administration. These concentrations serve as a combined outcome measure, as harmine directly influences the metabolism of DMT.	From enrollment to the second PET scan, up to 6 months
Aliveness Task	Behavioral experiment designed to assess the attribution of consciousness and intentionality to animate and inanimate objects.	From enrollment to the second PET scan to a maximum of 6 months
Acute Subjective Effects	Acute substance effects are measured with a questionnaire named APsych and consists of 8 items (i.e. ratings of intensity, challenging, acceptance, clarity, visual hallucinations, emotionality, liking, arousal) rated from 1-10 with 10 being the highest and assessment if bodily or psychiatric symptoms are present are assessed at several timepoints, i.e. at baseline, 20, 40, 60, 80, 100, 120, 140, 160, 180, 240, and 300 min after drug or placebo administration.	From enrollment to the second PET scan, up to 6 months
Blood pressure	Blood pressure is assessed at several timepoints, i.e. at baseline, 20, 40, 80, 180, and 300 min after drug or placebo administration.	From enrollment to the second PET scan, up to 6 months
Heart rate	Heart rate is assessed at several timepoints, i.e. at baseline, 20, 40, 80, 180, and 300 min after drug or placebo administration.	From enrollment to the second PET scan, up to 6 months
Challenging Experiences	Challenging Experiences Questionnaire is administered 240 min after drug or placebo administration. The questionnaire consists of 26 items that are rated from 0 (not at all) to 5 (extreme).	From enrollment to the second PET scan, up to 6 months
Mystical Experience	Mystical Experience Questionnaire is administered 240 min after drug or placebo administration. The questionnaire consists of 30 items that are rated from 0 (not at all) to 5 (extreme).	From enrollment to the second PET scan, up to 6 months
Emotional Breakthrough	Emotional Breakthrough Inventory is administered 240 min after drug or placebo administration. The questionnaire consists of 6 items that are rated from 0 (not at all) to 100 (very much).	From enrollment to the second PET scan, up to 6 months
Altered States of Consciousness	Altered States of Consciousness Questionnaire is administered 240 min after drug or placebo administration. The questionnaire consists of 94 items that are rated from 0 (no, not more than usual) to 100 (yes, much more than usual).	From enrollment to the second PET scan, up to 6 months
Attribution of Consciousness Questionnaire	The Attribution of Consciousness Questionnaire is assessed at baseline (medical screening) and 240 min after drug or placebo administration. The questionnaire consists of 10 items that are rated from 0 (strongly disagree) to 6 (strongly agree).	From enrollment to the second PET scan, up to 6 months
Individual Differences in Anthropomorphism	The Individual Differences in Anthropomorphism Questionnaire is assessed at baseline (medical screening) and 240 min after drug or placebo administration. The questionnaire consists of 30 items that are rated from 0 (not at all) to 10 (very much).	From enrollment to the second PET scan, up to 6 months

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Collaborators: Psychiatric University Hospital, Zurich
• Investigators: Principal Investigator: Paul K Cumming, PhD, Insel Group AG

Publications and helpful links

General Publications

• Vollenweider FX, Leenders KL, Scharfetter C, Maguire P, Stadelmann O, Angst J. Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology. 1997 May;16(5):357-72. doi: 10.1016/S0893-133X(96)00246-1.
• Berlowitz I, Egger K, Cumming P. Monoamine Oxidase Inhibition by Plant-Derived beta-Carbolines; Implications for the Psychopharmacology of Tobacco and Ayahuasca. Front Pharmacol. 2022 May 2;13:886408. doi: 10.3389/fphar.2022.886408. eCollection 2022.
• Egger K, Gudmundsen F, Jessen NS, Baun C, Poetzsch SN, Shalgunov V, Herth MM, Quednow BB, Martin-Soelch C, Dornbierer D, Scheidegger M, Cumming P, Palner M. A pilot study of cerebral metabolism and serotonin 5-HT2A receptor occupancy in rats treated with the psychedelic tryptamine DMT in conjunction with the MAO inhibitor harmine. Front Pharmacol. 2023 Sep 28;14:1140656. doi: 10.3389/fphar.2023.1140656. eCollection 2023.

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2024
• Primary Completion (Actual): February 17, 2025
• Study Completion (Actual): March 5, 2025

Study Registration Dates

• First Submitted: February 1, 2024
• First Submitted That Met QC Criteria: February 1, 2024
• First Posted (Actual): February 9, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 18, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: PET; Brain; FDG; Glucose; Metabolism; DMT; Ayahuasca; Harmine
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Neurotransmitter Agents; Psychotropic Drugs; Monoamine Oxidase Inhibitors; Serotonin Antagonists; Serotonin Agents; Hallucinogens; Serotonin Receptor Agonists; N,N-Dimethyltryptamine; Harmine
• Other Study ID Numbers: HaD-PET; 320030_204978 (Other Grant/Funding Number: Swiss National Science Foundation (SNSF))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No