Safety, Pharmacokinetics, and Pharmacodynamics of a 6-h N,N-Dimethyltryptamine (DMT) Infusion in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

The serotonergic psychedelic N,N-dimethyltryptamine (DMT) presumably stimulates neuroplasticity in vitro and in vivo, by which it may exert neuroprotective effects during acute ischemic stroke. Since neuroplasticity has been implicated in the mechanism of action of rehabilitative therapy in stroke recovery, a pharmacological augmentation strategy facilitating neuroplasticity could be beneficial. To optimize this treatment strategy, a detailed understanding of the safety, pharmacokinetics, and pharmacodynamics of prolonged DMT administration is required. This randomized, double-blind, placebo-controlled, single ascending dose study administered three intravenous doses of DMT as a 30-s bolus followed by a 6-h infusion: 1.5 mg + 0.105 mg/min, 7.5 mg + 0.525 mg/min, and 5.0 mg + 0.7875 mg/min. Twelve female and seventeen male psychedelic-experienced and naïve healthy participants, with a mean age of 27.3 (SD 10.2, range 19-57) years, were included. No serious adverse events occurred, and all adverse events were mild in intensity and self-limiting. No significant abnormalities in vital signs or 12-lead electrocardiography, and no suicidality or treatment-emergent psychopathology occurred. Moderate interindividual pharmacokinetic variability was observed. Mild psychedelic effects were accompanied by decreases in sustained attention, postural stability, and occipital alpha electroencephalographic power at the highest dose, which peaked rapidly after bolus administration and remained relatively stable or decreased over time. Together, DMT administered intravenously as a 30-s bolus followed by a 6-h infusion and reaching maximal exposures of approximately 35 ng/mL in healthy volunteers was safe and demonstrated rapidly occurring but mild psychedelic effects, providing the basis for future proof-of-mechanism studies in patient populations. Trial Registration: ClinicalTrial.gov identifier: NCT05559931.

Keywords: N,N‐dimethyltryptamine; healthy volunteers; intravenousinfusion; neuroplasticity; pharmacodynamics; pharmacokinetics; psychedelic; safety; stroke.

FIGURE 1

Study flow chart.

FIGURE 2

Mean plasma concentration ± SD (ng/mL) of DMT up to 10 h after the start of infusion. (A) Linear scale and (B) logarithmic scale.

FIGURE 3

Subjective drug effects of DMT on (A) RTIS bodily intensity, RTIS emotional and metacognitive intensity, and RTIS visual intensity, (B) VAS Bowdle Feeling high, External Perception, and Internal perception, and (C) VAS Bond and Lader Alertness, Mood, and Calmness. Values are represented as the least square mean change compared to baseline, with 95% CI error bars, up to 8 h (A) and 24 h (B, C) after start of infusion. p‐values represent a statistically significant effect compared to placebo.

FIGURE 4

Effects of DMT on the 11D‐ASC and HRS. Values are represented as the mean (SD) value 2 h after dosing in (A) 11D‐ASC and (B) HRS score. The 11D‐ASC scale was adjusted from 0–100 to 0–60 to improve visualization of the data.

FIGURE 5

Effects of DMT on the NeuroCart test battery for body sway, pupil‐iris ratio, adaptive tracking, and saccadic peak velocity as well as occipital alpha wave power. Values are represented as the least square mean change compared to baseline, with 95% CI error bars, up to 24 h after start of infusion. p‐values represent a statistically significant effect compared to placebo.