Study design

The study used a double-blind, placebo-controlled, cross-over design with five randomized test sessions to investigate responses to (i) placebo, (ii) 0.6 mg/min DMT, (iii) 1.2 mg/min DMT, (iv) 1.8 mg/min DMT, and (v) 2.4 mg/min DMT. The dose selection was based on our previous study that used 0.6 and 1.0 mg/min DMT [5]. Self-guided titration was also tested in the sixth test session that was not randomized. The washout periods between sessions were at least 7 days, a duration expected to result in no carry-over effects [5]. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Guidelines in Good Clinical Practice and approved by the Ethics Committee of Northwest Switzerland (EKNZ) and Swiss Federal Office for Public Health. The study was registered at ClinicalTrials.gov (NCT05384678).

Participants

Twenty-two healthy participants (11 men and 11 women; mean age ± SD: 30 ± 5 years; range: 25–45 years) were recruited by word of mouth or from a pool of volunteers who had contacted our research group because they were interested in participating in a clinical trial that investigated psychedelics. All participants provided written informed consent and were paid for their participation. Exclusion criteria were age <25 years or >65 years, pregnancy (urine pregnancy test at screening and before each test session), personal or family (first-degree relative) history of major psychiatric disorders (assessed by a semi-structured clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, 5th edition [14], by a trained physician), the use of medications that may interfere with the study medications (e.g., antidepressants, antipsychotics, or sedatives), chronic or acute physical illness (e.g., abnormal physical exam, electrocardiogram, or hematological and chemical blood analyses), tobacco smoking (>10 cigarettes/day), lifetime prevalence of psychedelic drug use >20 times, illicit drug use within the last 2 months (except for Δ9-tetrahydrocannabinol), and illicit drug use during the study period (screened for by urine drug tests). The participants were asked to consume no more than 20 standard alcoholic drinks/week and have no more than one drink on the day before the test sessions. Twenty participants had previously used a psychedelic, including lysergic acid diethylamide (LSD; 10 participants, 1–10 times), psilocybin (12 participants, 1–5 times), DMT (including ayahuasca; seven participants, 1–7 times), mescaline (2 participants, once), and 4-bromo-2,5-dimethoxyphenylethylamine (4 participants, 1–5 times). Twenty-one participants had previously used 3,4-methylenedioxymethamphetamine (1–50 times). Eighteen participants had previously used a stimulant, including methylphenidate (3 participants, 1–30 times), amphetamine (9 participants, 1–9 times), and cocaine (12 participants, 1–5 times). Thirteen participants had previously used ketamine (1–5 times).

Study drugs

DMT hemifumarate (99.9% high-performance liquid chromatography purity, ReseaChem GmbH, Burgdorf, Switzerland) was formulated according to Good Manufacturing Practice and prepared in sterile vials that contained 72 mg/ml of DMT in 1 ml of purified water. The exact analytically confirmed DMT hemifumarate content of the vials (mean ± SD) was 70.34 ± 0.52 mg (n = 10 samples). The stability of DMT in the vials was confirmed for the study duration. Placebo consisted of identical vials that were filled with sterile water only. For the randomized sessions (study days 1–5), the content of four vials that contained either 72 mg/ml DMT or placebo was aspirated into the infusion pump syringe and diluted with saline solution (0.9% NaCl) to a volume of 50 ml. For the nonrandomized self-guided titration session, the content of three 72 mg/ml DMT vials was aspirated into the syringe and diluted with saline solution (0.9% NaCl) to a volume of 50 ml. Each participant received a continuous infusion of 50 ml over 120 min, starting at t = 0 min. In the sixth session, participants started at a dose rate of 1.2 mg/min. After 40 and 80 min, the participants were asked whether they wanted to adjust the dose rate slightly (±0.2), moderately (±0.4), or strongly (±0.6 mg/min). Thus, the maximum attainable dose rate was 2.4 mg/min, which corresponded to the highest dose that was used during the blinded study part. The participants were encouraged to self-titrate to a level of subjective effects they found the most pleasurable. At the end of each randomized session and at the end of the study, the participants were asked to retrospectively guess their treatment assignment to evaluate blinding.

Study procedures

The study included a screening visit, five 5-h randomized test sessions, a subsequent sixth 5-h self-guided titration session, and an end-of-study visit. The sessions were conducted in a calm hospital room. Only one research participant and two investigators were present during each session. The test sessions began at ~1:00 PM, with starting times that remained consistent within each participant across all six sessions. A urine sample was taken to verify abstinence from drugs of abuse, and a urine pregnancy test was performed in women prior to each session. The participants then underwent baseline measurements. DMT or placebo was administered at 2:00 PM in sessions 1–5. Open-label DMT was administered at 2:00 PM in the sixth session. The outcome measures were repeatedly assessed for 180 and 160 min in sessions 1–5 and session 6, respectively. The participants were sent home ~15 min after the last measurement.

Subjective drug effects

Subjective effects were assessed repeatedly using subjective effect scales 1 h before and 0, 2.5, 5, 7.5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 122.5, 125, 130, 135, 140, 150,160, 170, and 180 min after starting the infusion in sessions 1–5. In session 6, subjective effects were assessed 1 h before and 0, 2.5, 5, 10, 15, 20, 30, 40, 42.5, 45, 50, 60, 70, 80, 82.5, 85, 90, 100, 110, 120, 122.5, 125, 130, 135, 140, 150, and 160 min after starting the drug administration. Subjective effect scales included verbal ratings of “any drug effect,” “good drug effect,” “bad drug effect,” and “anxiety” (Likert scale; 0–10 for no to maximal effect). The 5 Dimensions of Altered States of Consciousness (5D-ASC) scale [15, 16] was administered at the end of each test session. Mystical experiences were assessed at the end of each study session using the States of Consciousness Questionnaire (SOCQ) [17,18,19] that includes the 30-item Mystical Effects Questionnaire (MEQ30) [20], the 40-item Mystical Effects Questionnaire (MEQ40), and the 48-item Psychedelic Experience Scale 48 (PES48) [19]. Subjective effect measurements are described in more detail in the Supplementary Methods online.

Autonomic and adverse effects

Blood pressure and heart rate were measured at baseline and 2.5, 7.5, 15, 20, 30, 40, 60, 80, 100, 120, 125, 130, 135, 140, 150,160, 170, and 180 min after the start of the infusion in sessions 1–5. In session 6, blood pressure and heart rate were measured at baseline and 10, 30, 50, 70, 90, 110, 130, and 150 min after the start of the infusion. Adverse effects were assessed 1 h before and 180 and 160 min after drug administration in sessions 1–5 and the sixth session, respectively, using the List of Complaints [21].

Endocrine effects and brain-derived neurotrophic factor levels

Plasma concentrations of oxytocin, cortisol, and prolactin and serum concentrations of brain-derived neurotrophic factor (BDNF) were determined as previously described [22, 23] in sessions 1–5. Oxytocin, cortisol, and prolactin were measured at baseline and 110 and 180 min after the start of the infusion. BDNF was measured at baseline and 110 min after the start of the infusion.

Plasma DMT concentrations

Blood was collected into lithium heparin tubes at baseline and 2.5, 5, 7.5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 122.5, 125, 130, 135, 140, 150, 160, 160, 170, and 180 min after the start of the infusion in sessions 1–5. The blood samples were immediately centrifuged, and plasma was subsequently stored at −20 °C and −80 °C until analysis. Plasma concentrations of DMT and metabolites were determined by high-performance liquid chromatography-tandem mass spectrometry using a validated method as previously described [24].

Pharmacokinetic analyses

Pharmacokinetic parameters were estimated using non-compartmental methods as described previously [5, 25]. Two participants who stopped the infusion prematurely were excluded from the pharmacokinetic analysis. Analyses were conducted using Phoenix WinNonlin 8.4 (Certara, Princeton, NJ, USA).

Data analysis

Peak (Emax) or peak change from baseline (ΔEmax) values were determined for repeated measures. The values were then analyzed using analysis of variance (ANOVA), with dose as the within-subjects factor, followed by the Tukey post hoc test, using R 4.2.1 software. The criterion for significance was p < 0.05.