Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans

Hallucinogens evoke profound alterations of perception, cognition, and affect while often leaving a relatively clear sensorium. Previous research indicates that longer-acting classic hallucinogens (for example LSD, psilocybin, mescaline) readily produce tolerance after repeated daily exposure, but DMT (N,N-dimethyltryptamine), a short-acting endogenous compound, has shown inconsistent tolerance in animals and has not reliably produced tolerance in humans. The absence of cross-tolerance between LSD and DMT in prior work also challenges the assumption that all classic hallucinogens act by identical mechanisms, highlighting the need to characterise DMT’s time course and regulatory mechanisms more precisely. Strassman and colleagues designed the present study to determine whether tolerance to both subjective (psychedelic) and biological (neuroendocrine, cardiovascular, thermoregulatory) effects could be produced within a single day by closely spaced repeated intravenous doses of DMT. The aim was to compare responses across four 30-minute-spaced injections and to determine whether subjective reports and physiological biomarkers showed parallel patterns of attenuation (tolerance) or differential regulation, thereby clarifying DMT’s pharmacological uniqueness among classic hallucinogens.

Experienced hallucinogen users were recruited and screened for medical and psychiatric health using a semistructured diagnostic interview; written informed consent was obtained. The analysed sample comprised 13 volunteers (nine men, four women), aged 22–45 years (mean 35.5 years). Women were studied in the early follicular phase. All procedures took place on the inpatient General Clinical Research Center of the University of New Mexico. Before the tolerance experiment, subjects had received non-blind test doses of 0.05 and 0.4 mg/kg DMT on separate days and three volunteers were excluded during that initial phase for adverse reactions. Pilot dosing in three volunteers guided selection of the tolerance regimen. Based on tolerability and pharmacokinetic considerations (plasma DMT declines to near undetectable levels by 30 min), the investigators selected 0.3 mg/kg DMT fumarate administered intravenously over 30 s, with a 15 s saline flush, given four times at 30 min intervals. Each subject underwent two study days in a randomized, double-blind design: one day with four DMT injections, the other with four saline injections. Although the protocol was double blind, the investigators note that subjects usually discerned drug versus placebo after the first injection, so later sessions were effectively known to participants. Physiological monitoring and blood sampling were dense. Blood for ACTH, prolactin and DMT was drawn at -30 and -1 min (pre-session) and at +2, +5, +10, +15 and +28 min after each infusion; cortisol was sampled only at +28 min (immediately before the next infusion) to assess pre-injection baseline feedback. Continuous rectal temperature, frequent blood pressure and heart rate recordings, and an abbreviated Hallucinogen Rating Scale (HRS) were obtained (HRS administered after the 15 min blood draw). Plasma DMT was measured by gas chromatography–mass spectrometry (limit of detectability 1 ng/mL); ACTH, prolactin and cortisol assays had stated detection limits. DMT assays were run in triplicate; other assays in duplicate. Statistical analysis used repeated-measures ANOVA with session (four repeated sessions within a morning) as the within-subject factor and dose (DMT vs placebo) as the grouping factor. Dependent variables included baseline, session-specific peak above baseline (AMax), and area under the curve above baseline (AAUC) for hormones and cardiovascular measures. Baseline definitions varied by measure and session as described by the investigators. For the HRS, mean cluster scores were computed for somesthesia, cognition, affect, perception, volition and intensity. The authors defined tolerance two ways: loss of a significant difference between drug and placebo by session 4 (paired comparisons), and a significant decrease in response from session 1 to session 4 for the drug condition (D4D1). A p value <0.05 was considered significant.

Thirteen subjects completed the tolerance protocol. The principal outcomes were a dissociation between subjective and some biological effects: subjective psychedelic effects did not show tolerance across the four closely spaced DMT injections, whereas certain neuroendocrine measures and heart rate responses diminished over sessions; mean arterial pressure (MAP) did not diminish, and temperature data were difficult to interpret. DMT plasma kinetics: Pre-session (pre-first injection) DMT was undetectable. Peak DMT concentrations (AMax) and AAUC differed across sessions (AMax: F = 4.76, p = 0.007; AAUC: F = 4.40, p = 0.01). Reported AMax values ranged from 44.5 (SEM 5.7) ng/mL in session 2 to 62.5 (SEM 6.6) ng/mL in session 4. Residual DMT concentrations measured immediately before sessions 2–4 were very low and did not differ across those pre-injection baselines (F = 0.58, p = 0.57), indicating minimal carryover. Subjective effects: Clinical interviews and abbreviated HRS scores confirmed robust psychedelic effects of 0.3 mg/kg DMT compared with placebo, characterised by a rapid onset (peaking at 1–2 min) and resolution by 28 min. Visual, somatic and affective phenomena were prominent; cognition was relatively intact. HRS cluster analyses showed strong drug-versus-placebo effects but little reduction of DMT subjective intensity across the four sessions. The greatest decrement was seen in the volition cluster (questions about control, ability to focus and ‘‘letting go’’), which trended toward reduction across sessions (D4D1 comparison p≈0.06) but did not meet conventional significance for tolerance. Some decline in somatic/interoceptive scores occurred across sessions for both drug and placebo, and placebo affect scores declined across placebo sessions as subjects realised they were not receiving DMT. Neuroendocrine effects: Cortisol levels sampled at +28 min showed divergent patterns for DMT and placebo. In the DMT condition cortisol rose and returned to baseline by the fourth injection; in the placebo condition cortisol fell across sessions. Prolactin showed a gradual decrease across placebo sessions, whereas prolactin after DMT sessions was relatively unchanged in baseline comparisons but AMax and AAUC prolactin values for DMT fell significantly across sessions (D4D1), indicating some tolerance. ACTH data showed baseline and session effects; after adjusting for baseline, both AMax and AAUC ACTH responses demonstrated significant dose and session effects. DMT-induced ACTH responses decreased across sessions (D4D1), and while AMax remained significantly greater than placebo at session 4, AAUC ACTH was no longer significantly different by session 4, suggesting tolerance is more evident using AAUC for ACTH. Cardiovascular and temperature effects: Heart rate (HR) showed significant dose and session effects; DMT-induced HR responses decreased across sessions (D4D1) and did not differ from placebo by the fourth session (D4P4), consistent with tolerance of the HR response. By contrast, MAP responses were consistently higher after DMT than placebo but showed no session effect, indicating no tolerance to blood pressure changes. Temperature interpretation was limited: DMT produces a slow-rising temperature effect beginning after 15 min, so repeated dosing led to cumulative baseline increases and physiologic ceiling effects (for example sweating); missing values required non-repeated-measures analysis, and the investigators judged these results uninterpretable for tolerance assessment. Safety and blinding: The study notes that the double blind was effectively broken early because DMT’s unmistakable acute effects revealed drug versus saline to participants. Earlier in the screening/dose-ranging phase three volunteers were excluded for adverse reactions (vasovagal, hypertensive, dysphoric) to other doses, but no comparable acute serious adverse events during the tolerance sessions are described in the extracted Results.

Strassman and colleagues interpreted the findings as evidence that repeated, closely spaced hallucinogenic doses of DMT do not produce tolerance to its psychological (subjective) effects within a single morning, while some biological responses—specifically ACTH, prolactin and heart rate—diminish with repetition. Blood pressure responses did not show tolerance, and temperature data were confounded by the slow time course of thermoregulatory effects and cumulative dosing. The investigators emphasised DMT’s distinctiveness among classic hallucinogens. They argued that the pattern—subjective effects persisting while several peripheral and neuroendocrine responses attenuate—suggests differential regulation of the mechanisms mediating these effects rather than a purely pharmacokinetic explanation. Pharmacodynamic hypotheses advanced include rapid desensitisation or downregulation at serotonergic receptor subtypes implicated in hallucinogen action (notably 5-HT2 receptors), interactions between 5-HT1A and 5-HT2 receptor families, and involvement of intracellular signalling pathways such as protein kinase C; the authors note that DMT has nearly equal affinities for 5-HT1A and 5-HT2 sites, and that such complex receptor interactions could yield unequal tolerance phenomena across endpoints. They further observed that animal and human data consistently show atypical tolerance for DMT compared with LSD and related drugs, and that earlier reports of no cross-tolerance between LSD and DMT support a pharmacodynamic difference. The authors acknowledged several limitations: the double-blind was compromised because drug effects were self-evident to subjects; temperature measures could not be interpreted reliably because of cumulative effects and missing data; and although DMT plasma peaks varied across sessions, the magnitude of those differences was small and unlikely to explain the dissociation between subjective and biological tolerance. Finally, they suggested methodological adjustments for future work—longer inter-session intervals or continuous infusion, or a greater number of injections—to clarify whether subjective tolerance can be produced and to dissect pharmacokinetic from pharmacodynamic contributions.

These data support the conclusion that DMT is pharmacologically distinct among classic hallucinogens: closely spaced repeated injections produced tolerance for some biological measures but not for subjective psychedelic effects. The investigators propose that differential regulation of mechanisms mediating neuroendocrine, cardiovascular and subjective effects underlies this dissociation, and they recommend future studies using continuous infusion or additional injections to further probe tolerance development.