Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants

Vogt and colleagues situate N,N-dimethyltryptamine (DMT) within the class of classic serotonergic psychedelics, noting its distinguishing feature of very short-lasting effects after parenteral administration. Earlier studies have examined intramuscular, inhalation and intravenous routes and suggested that intravenous DMT allows rapid, controllable induction of a psychedelic state. Despite growing experimental and therapeutic interest, the authors identify a gap in detailed clinical pharmacology data on different intravenous DMT regimens, including time-course of subjective effects, tolerability and pharmacokinetics. This study aimed to characterise the acute subjective, autonomic and adverse effects, plasma pharmacokinetics, and short-term neuroendocrine markers (oxytocin, brain-derived neurotrophic factor/BDNF) of several intravenous DMT administration regimens in healthy volunteers. Specifically, the investigators tested two continuous infusion rates (0.6 and 1 mg/min over 90 min) and each infusion combined with an initial loading bolus (15 mg or 25 mg), using a randomized, double-blind, placebo-controlled crossover design to inform dose-finding for research and possible therapeutic use.

Using a double-blind, placebo-controlled, crossover design, Vogt and colleagues tested five conditions in each participant: placebo; low infusion (0.6 mg/min); high infusion (1 mg/min); low bolus (15 mg) + low infusion (0.6 mg/min); and high bolus (25 mg) + high infusion (1 mg/min). The order of conditions was randomised and counterbalanced, with washout periods of at least one week. The study was approved by appropriate ethics and regulatory bodies and registered on ClinicalTrials.gov. Twenty-seven healthy adults (12 men, 15 women; mean age 33 years, range 25–58) were enrolled. Key exclusion criteria included pregnancy, personal or first‑degree family history of major psychiatric disorders, use of contraindicated medications, significant physical illness, heavy tobacco smoking (>10 cigarettes/day), recent illicit drug use and lifetime hallucinogen use >20 times. Most participants had limited prior psychedelic experience; lifetime DMT exposure was reported in three participants (1–6 times). Written informed consent was obtained. DMT hemifumarate was manufactured to good‑practice standards and provided in vials at 5 mg/ml (for bolus preparation) and 18 mg/ml (for infusion preparation). Placebo vials contained purified water. For each session, vials were diluted into saline and administered intravenously: a 20 ml bolus infused over 45 s at t = 0, followed by a continuous 50 ml infusion over 90 min beginning at t = 1 min, delivered via an infusion pump. Participants retrospectively guessed treatment assignment to assess blinding. Sessions comprised a screening visit, five 4‑hour test sessions separated by ≥1 week, and an end‑of‑study visit. Sessions took place in a calm hospital room with one subject and two investigators. Urine drug screens and pregnancy tests were performed before each session. Outcome measures were repeatedly assessed for 150 min after DMT/placebo administration, and participants were discharged approximately 15 min after the final measurement. Subjective effects were measured repeatedly using verbal Likert ratings (any drug effect; good drug effect; bad drug effect; anxiety) and validated questionnaires. The 5 Dimensions of Altered States of Consciousness (5D‑ASC) was the primary outcome and was administered at 150 min as a retrospective peak rating; mystical experiences were assessed using the States of Consciousness Questionnaire including the MEQ30. Autonomic measures (blood pressure, heart rate) were sampled frequently from baseline through 150 min. Adverse effects were captured with a List of Complaints. Oxytocin was assayed before and at 60 min, and plasma BDNF at baseline, 90 and 150 min. Blood samples for DMT and metabolites were collected, processed and stored at −80 °C and analysed by validated HPLC‑tandem mass spectrometry. Pharmacokinetic parameters were estimated with non‑compartmental methods in Phoenix WinNonlin 8.3. Statistical analyses used within‑subject ANOVA with drug as factor, Tukey post hoc tests, and a significance threshold of p < 0.05; order effects were tested and excluded.

Subjective effects differed markedly by regimen. Both 15 mg and 25 mg bolus doses produced very rapid and intense psychedelic effects that peaked within the first 2–3 min after the 45‑s bolus administration and declined substantially within ~15 min. These bolus conditions yielded similar maximal ratings across the four verbal scales and were experienced as simultaneously positive and overwhelmingly intense; they produced greater negative effects and anxiety than infusion regimens. In contrast, the infusion‑only conditions (0.6 or 1 mg/min) induced slowly rising effects that reached a plateau after ~30 min and remained stable until the infusion ended at 90 min. The higher infusion rate produced greater ‘‘any drug effect’’ (p < 0.001) and ‘‘good drug effect’’ (p < 0.01) than the lower infusion. Infusions produced minimal ‘‘bad drug effects’’ and no increase in anxiety versus placebo. Across all DMT conditions, 5D‑ASC and MEQ30 scores indicated pronounced psychedelic and mystical‑type experiences relative to placebo, with generally greater peak effects at higher dose conditions and the high bolus showing greater anxious ego dissolution and ‘‘nadir’’ (negative) effects. Cardiovascular stimulant effects and transient unpleasant responses were more marked at bolus onset than with infusions. The most frequently reported adverse event within 48 h was headache (seven participants, eight occurrences), all associated with DMT sessions (split evenly between bolus and infusion). No flashbacks were reported during the study, but one participant experienced several flashbacks after study completion, beginning two weeks post‑study and resolving after several weeks. Two severe adverse events occurred but were judged unrelated to DMT (COVID infection with syncope; elective surgery). Plasma pharmacokinetics showed distinct profiles by regimen. Mean maximum plasma concentrations (Cmax) for the 15 mg and 25 mg bolus doses were 29 ng/ml and 61 ng/ml, respectively, reached at mean Tmax values of 2.5 and 2.9 min. For infusion‑only conditions, Cmax values were 24 ng/ml (low infusion) and 39 ng/ml (high infusion), reached at Tmax ~72–73 min. After stopping the infusion at 90 min, two elimination phases were apparent: an early half‑life (t1/2α) of 5.0–5.8 min and a later half‑life (t1/2β) of 14–16 min; the transition from early to late elimination occurred ~16–18 min after infusion stop at plasma concentrations of ~2.1–4.2 ng/ml. Approximately 75–79% of DMT was cleared during the early elimination phase. Apparent volume of distribution (Vz) estimates were 746–831 L and clearance estimates were 36–39 l/min. The concentration‑effect relationship showed clockwise hysteresis, consistent with moderate acute tolerance during continuous infusion: subjective effects did not increase from 30 to 90 min despite rising plasma concentrations. Sex and prior substance experience did not systematically moderate pharmacokinetic parameters or acute effects. Endocrine markers were largely unchanged: only the high infusion increased plasma oxytocin at the 60‑min sample, whereas none of the DMT conditions altered plasma BDNF levels compared with placebo. Blinding was imperfect: most conditions were identified correctly by participants, although the low infusion was sometimes mistaken for placebo or the high infusion.

Vogt and colleagues interpret their findings as showing clear differences between rapid bolus and slower infusion regimens. Bolus administration produced very fast, intense and often overwhelming subjective effects that peaked within minutes and subsided within ~15 min, whereas continuous infusions produced gradually developing, stable psychedelic states that could be maintained for the duration of administration and terminated rapidly after infusion stop. The authors suggest that the rate of increase of brain and plasma DMT concentrations—faster with bolus—largely accounts for greater subjective intensity and greater initial negative effects and anxiety with boluses, even when plasma concentrations achieved by some infusions exceeded those of lower bolus doses. Pharmacokinetically, the study documents rapid initial clearance consistent with MAO‑mediated metabolism and distributional kinetics: a fast early elimination phase (t1/2α ~5–6 min) responsible for most clearance (75–79%) and a slower late phase (t1/2β ~14–16 min). The presence of two elimination phases and large apparent volumes of distribution indicate redistribution from tissues and suggest that compartmental models may be needed to fully describe DMT kinetics. The observed clockwise hysteresis indicates moderate acute tolerance during continuous infusion but not necessarily with intermittent bolus dosing; the authors note that tolerance may emerge with sustained high exposure but less so when short boluses are separated in time. Regarding endocrine effects, only the high infusion increased oxytocin at the 60‑minute sample, while BDNF was unchanged; the authors note that timing of sampling might have missed transient oxytocin responses after bolus dosing and that prior literature is mixed on BDNF effects. They highlight study strengths including a relatively large within‑subject sample (n = 27, 108 DMT administrations), rigorous pharmacological characterisation and frequent plasma sampling, and standardised psychometric measures. Key limitations acknowledged are the highly controlled hospital setting and enrolment of healthy volunteers, which limit generalisability to clinical populations, and imperfect blinding because intense psychedelic effects make allocation recognisable. The authors also suggest that slower induction regimens (for example, gradual bolus over several minutes or moderate infusion rates) might be better tolerated than very rapid boluses, and they call for further studies including longer infusion durations and investigations in patient groups.

The study characterised multiple intravenous DMT regimens and their pharmacology in healthy volunteers. Bolus dosing produced rapid, intense and short‑lasting psychedelic effects that were moderately well tolerated but associated with more negative and anxiety‑related responses at onset, whereas continuous infusions produced stable, intense and better‑tolerated psychedelic states that could be started and stopped rapidly. The investigators conclude that intravenous DMT—particularly as an infusion—may serve as a controllable pharmacological tool to induce, maintain and terminate a psychedelic state in a tailored manner for research and potential therapeutic applications.