This randomised, double-blind study (n=13) investigated tolerance of repeated doses of 21mg/70kg DMT fumarate in hallucinogen-experienced users. Tolerance to “psychedelic” subjective effects did not occur according to either clinical interview or Hallucinogen Rating Scale scores.
Tolerance to the behavioral effects of the short-acting, endogenous hallucinogen, N,N-dimethyltryptamine (DMT) is seen inconsistently in animals, and has not been produced in humans. The nature and time course of responses to repetitive, closely spaced administrations of an hallucinogenic dose of DMT were characterized. Thirteen experienced hallucinogen users received intravenous 0.3 mg/kg DMT fumarate, or saline placebo, four times, at 30 min intervals, on 2 separate days, in a randomized, double-blind, design. Tolerance to “psychedelic” subjective effects did not occur according to either clinical interview or Hallucinogen Rating Scale scores. Adrenocorticotropic hormone (ACTH), prolactin, cortisol, and heart rate responses decreased with repeated DMT administration, although blood pressure did not. These data demonstrate the unique properties of DMT relative to other hallucinogens and underscore the differential regulation of the multiple processes mediating the effects of DMT.
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.
Papers cited by this study that are also in Blossom
Gillin, J. C., Kaplan, J., Stillman, R. et al. · American Journal of Psychiatry (1976)
Papers in Blossom that reference this study
Erne, L., Mueller, L., Straumann, I. et al. · Translational Psychiatry (2026)
Erne, L., Vogt, S. B., Müller, L. et al. · Neuropsychopharmacology (2024)
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.
Hallucinogens produce a unique syndrome of psychological effects in humans. Perceptual, cognitive, and affective processes are often profoundly altered, with the maintenance of a relatively clear sensorium). The neuropharmacology of "classic" hallucinogens lysergic acid diethylamideLSD-tolerant individuals showed undiminished responses to DMT. Whether tolerance to DMT in humans can be demonstrated is important for at least two reasons. Although tolerance to longer-acting hallucinogens occurs readily, the time course of this tolerance makes careful study of this process unwieldy. If tolerance to a shorter-acting drug such as DMT could be demonstrated, it might be possible to study tolerance development to subjective and biological effects of the repeated administration of an hallucinogen within a day. The inability of LSD to produce cross-tolerance to DMT challenges the assumption that all "classic" hallucinogens produce their effects by similar mechanisms, and emphasizes the importance of detailed psychopharmacological characterization of individual members of this drug class. If tolerance to DMT were impossible to demonstrate, the agent would no longer would be considered a typical hallucinogen.
Experienced hallucinogen users were recruited as described previously. Witnessed written informed consent was obtained. All volunteers were free of current axis I disorders, determined by a semistructured psychiatric interview (Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised (DSM-IIIR) [SCID-R-OP]), and were medically healthy, determined by physical examination and laboratory screening tests. None was taking any medications regularly. Ages ranged from 22 to 45 years (mean 35.5 years). There were nine men and four women. Women were studied during the early follicular phase of their menstrual cycle. Studies took place in the inpatient unit of the University of New Mexico Hospital's General Clinical Research Center (GCRC). All subjects received nonblind test doses of intravenous (IV) 0.05 and 0.4 mg/kg DMT fumarate on separate days, as described previously. Intravenous (IV) DMT fumarate was administered over 30 s through an indwelling forearm venous catheter, and the IV line was flushed with sterile saline for an additional 15 s. Cardiovascular responses were assessed frequently, and the Hallucinogen Rating Scale (HRS) was administered after drug effects had resolved. Three subjects were dropped in this phase: one because of a vasovagal reaction to 0.4 mg/kg DMT, one because of a hypertensive response to 0.4 mg/kg DMT, and one because of a dysphoric response to 0.05 mg/kg DMT.
In order to determine dose and interval parameters for the tolerance study, we performed pilot work with three volunteers. Previous literature reported that four (daily) doses of long-acting hallucinogens elicit tolerance. The only published human DMT tolerance protocol demonstrated no tolerance development with twice daily sessions, separated by 5 hours, for 5 consecutive days. However, "field reports" suggest a "refractory period" of only 15-30 rain. Since plasma DMT levels are nearly undetectable 30 min after IV administration of "psychedelic" doses of 0.2 or 0.4 mg/kg, we believed a 30-60 min interval was an appropriate target. In order to assess tolerability of repeated dosing of IV DMT, and to make certain no sensitization to repeated DMT doses occurred, we gave a minimal dose, 0.05 mg/kg, every hour, four times. The interval was then shortened to 30 min 1 week later. This process was repeated with 0.1, 0.2, 0.3, and 0.4 mg/kg DMT. One volunteer found 3 hourly injections of 0.4 mg/kg IV DMT too taxing, refusing the fourth dose. Thus, 0.3 mg/kg given at 30 min intervals, four times, was chosen as our tolerance regimen.
Subjects were admitted to the GCRC in the morning, having been fasting since midnight. One angiocath-style catheter was placed in an antecubital vein for blood drawing and kept open with a sterile saline drip. Another catheter was placed in the other arm for infusions. This ann also had an automatic blood pressure cuff applied to it. A Yellow-Springs Instruments (Yellow Springs, OH) YSI-400 reusable flexible thermistor probe configured to a Vita-Log PMS-8 physiological monitor (CSP, Inc., Palo Alto, CA) was inserted into the rectum for continuous temperature recording. Accuracy was 0.03°C. Blood samples for ACTH, prolactin, and cortisol were drawn at -30 and -1 min, and samples for DMT were drawn at -1 min. Blood pressure and heart rate measurements, and blood samples, were obtained at +2, 5, 10, 15, and 28 min. Blood was collected for assay of ACTH, prolactin, and DMT for all the time points. Cortisol was drawn only at 28 min after each infusion (2 min before subsequent infusions), to assess the degree of preinjection ("baseline") cortisol negative feedback on ACTH response. All subjects wore black eyeshades to reduce ambient light, and to provide a more introspective experience. We have found that many subjects will overlook subtle effects if their eyes are open and they are looking about the room. An abbreviated version of the HRS, containing only questions that showed significant effects of DMT vs. placebo from our initial dose-response study, was given after the 15 min blood draw. If time remained before the next infusion, discussion focussed on descriptive, rather than psychotherapeutic, topics. However, the rigorousness of the repeated DMT sessions often required psychological support and guidance as the morning progressed. The next infusion began at approximately +29 min 15 s. Thus, +30 for the first session was equivalent to "0" for the subsequent session. The above process was repeated for the second, third, and fourth sessions, with the final time point for data collection being +30, rather than +28, of the fourth session. Although the study was "double-blind" in design, it was apparent quickly whether DMT or saline was administered as the first injection of the first study day. Once this was established, volunteers knew that the day's other injections would also be either DMT or saline. They also could assume what the second study day would entail (i.e., repeated administration of the other study drug); however, they did not know what to expect regarding tolerance development.
Plasma levels of DMT, expressed as the free base, were measured by gas chromatography-mass spectrometry. Limit of detectability was 1 ng/mL. Plasma ACTH was assayed by immunoradiometric assay (Nichols Diagnostic Laboratories, San Juan Capistrano, CA); lower limit of detectability was 0.2 pmol/L. Limits of detectability for cortisol and prolactin radioimmunoassays (Diagnostic Products, Los Angeles, CA) were 6 nmol/L and 1 Dxg/L respectively. DMT assays were performed in triplicate, and all others were performed in duplicate.
All analyses were performed using Statistical Analysis System for the personal computer (PC-SAS), version 6.04 (Cary, NC). Values are given as means (SEM). p Values <0.05 are considered significant. Our primary statistical analysis was a repeated-measures analysis of variance (ANOVA), with repeated factor session (four occurring in one morning), and a grouping factor dose (placebo or DMT). Dependent variables were several derived values for blood concentrations of prolactin, ACTH, and DMT; heart rate (HR) and mean arterial pressure (MAP); and rectal temperature. The derived variables were baseline, AMax, and A area under the curve (AUC). Baseline values for the first session were means of -30 and -1 min values for all but the temperature data, although the mean values for -5 to -1 min points was used for temperature. For subsequent sessions (2-4), "baseline" values for MAP, HR, and blood levels were those obtained at +28 min, 2 min before the next infusion. For temperature, the "baselines" for sessions 2-4 were the means for the immediately preceding 5 min (+26 to +30). AMax was the maximum response above baseline for each session. AAUC was the area under the response curve above baseline for each session, calculated by the trapezoidal rule. For the HRS, mean scores for previously described "clinical clusters" were calculated. These were somesthesia (visceral/interoceptive, somatic sensations), cognition (thought processes and content), affect, perception, volition (ability to interact willfully with one's mental and physical self, and one's environment), and intensity (a global assessment of robustness of effect). HRS scores also were analyzed by repeated measures ANOVA, with repeated factor session, and grouping factor dose. The dose factor could have been treated as a repeated factor. However, our analysis indicated that adjusting for session first induced independence between doses. We defined "tolerance" using either of two methods. First, when the ANOVA demonstrated significant DMT or placebo effects, we performed post hoc comparisons using paired t tests. We compared responses for the first DMT (D) vs. placebo (P) infusions (P1D1) and for fourth DMT vs. placebo responses (PnD4). If P1D1 demonstrated a significant difference, but P4D4 did not, tolerance may be said to have occurred, since drug and placebo responses no longer differed by the last session. Second, we also compared changes in responses from session 1 to 4 for drug (DAD1) and placebo (P4P1). Another indication of "tolerance" is if responses decreased significantly by session for either drug or placebo. This is a less robust indication, however, if D4P 4 were still significantly different (i.e., responses to DMT decreased over time but never reached placebo values).
The most important findings of this study were that tolerance to the subjective effects of four closely spaced injections of IV DMT fumarate, assessed by clinical interview, and quantified by Hallucinogen Rating Scale (HRS) subscores, did not occur; ACTH and prolactin blood level and heart rate responses showed tolerance, but mean arterial BP responses did not; and peak DMT levels differed significantly across sessions; however, levels were very low before, and did not differ among, sessions.
Figure 1. Mean DMT free base levels in 13 volunteers after four doses of 0.3 mg/kg intravenous DMT fumarate, administered at 30 rain intervals. The number after "DMT" corresponds to the session (e.g., "DMT 2" refers to the second DMT injection). Time "0" values for sessions 2-4 are +28 min values for sessions 1-3, respectively.
There was no measurable DMT before any first session (DMT or placebo days), nor at 2 min after any first placebo session. Thus, our assay elicited no "false-positive" readings. DMT Amax values differed across sessions (F = 4.76; p = 0.007), ranging from 44.5 (5.7) ng/mL (session 2) to 62.5 (6.6) ng/mL (session 4). In addition, AAUC values differed significantly by session (F = 4.40; p = 0.01). Residual DMT levels before sessions 2-4, however, did not differ from each other (F = 0.58; p = 0.57). Figurepresents these data graphically.
CLINICAL INTERVIEWS. 0.3 mg/kg IV DMT produced a typical spectrum of "psychedelic" effects. Effects developed before the saline flush was completed, peaked at 1-2 min, and were well resolved by 28 min. Residual intoxication at +15 min was not sufficient to prevent any subject from completing the HRS, although many volunteers felt tired and "altered" before the third and fourth doses of DMT. DMT effects included the nearly instantaneous onset of a physical/somatic "rush," beginning in the head, which quickly led to a dissociated state. Volunteers "braced" for the effects of 0.4 mg/kg DMT, which all had received before, although only two had received 0.3 mg/kg in pilot work. Subsequent sessions were experienced with less anticipatory anxiety, although emotional responses to consecutive DMT sessions were similar. An abstract, geometric, rapidly moving, intensely colored, kaleidoscopic display of visual effects followed the "rush," and would often lead to the perceiving of more representational images, such as people, "creatures," and complex scenes. Auditory effects were less common and were relatively indistinct sounds rather than spoken words. Transient anxiety accompanied the onset of effects, and changed to elation and euphoria in most subjects. The fear of losing control lessened throughout the morning, which is reflected in the "volition" score on the HRS, below. Cognition was relatively unimpaired, although most spoke of a heightening of evaluative processes, or "faster" and "clearer" thinking. On the saline placebo treatment day, all volunteers experienced a "rush" of varying intensity as the first dose was administered. Once it became clear that no DMT was to be administered that morning, subjects' responses to placebo were negligible for the remaining three sessions. HALLUCINOGEN RATING SCALE. Mean HRS cluster scores all showed a robust effect of 0.3 mg/kg DMT relative to placebo, consistent with our previous data demonstrating "psychedelic" effects at dosages of 0.2 mg/kg and higher. Despite isolated session effects, inspection of the means (Table, Fig.) reveals little if any reduction of DMT effects across sessions. The HRS cluster demonstrating the greatest decrease across DMT sessions was volition, although a direct comparison of D4D l revealed only a trend (p --0.06) toward significance. These questions were related to the following effects: "change in effort to breathe"; "ability to follow sequence of events"; "ability to 'let go'"; "ability to focus attention"; "feeling in control"; and "ability to move around if asked to." Every volition question demonstrated the same pattern of decreasing response scores across DMT sessions. Somaesthesia, or interoceptive/visceral/somatic effects, showed a slight decrease across sessions for both drug and placebo conditions, although significant reductions were not seen in individual comparisons (neither D4D 1 nor PAP1). Of interest was the effect of placebo on affect scores. Although a significant P4P1 reduction is seen across placebo sessions, the effect primarily is due to changes in scores between Px and P2, suggesting a reduction in anxiety, or sense of relief, as it became clear that the day would involve only repeated placebo injections. Figureand Tabledisplay these data. DMT or placebo. Cortisol blood levels taken at 28 min after each injection (i.e., baseline, and not maximum response values before each DMT injection) followed different patterns for DMT and placebo, and showed dose and session effects, whether or not the 28 min sample from the fourth session was included in the ANOVA. Levels rose significantly in the DMT condition, and then returned to initial baseline values after the fourth injection. In the placebo condition, they fell gradually and significantly after every session. PROLACTIN, Tableand Figuredemonstrate the gradual decrease of values for placebo across session (P4PI), and values after DMT sessions were unchanged (D4D1). Thus, although initial baseline values were similar (PIDI), by session four, they differed significantly (P4D4). As for ACTH, baseline adjustments (i.e., calculation of "A values") are relevant for prolactin responses. AMax and AAUC prolactin values for DMT fell significantly over session (D4D1), suggesting some degree of tolerance, although placebo responses were similar across
ACTH. These data are displayed in Tableand graphically in Figure. Baseline values showed significant dose and session effects. For session 1, baseline values did not differ (PID1), but did so by session 4 (PnD4). Baseline values for the DMT treatment remained stable over session (D4D 1), yet those for placebo fell significantly (P4 P l)-Since there were significant baseline effects, but no apparent ceiling effects, the adjustment for baseline differences here is justified. AMax and 2~AUC ACTH demonstrated significant dose and session effects. Placebo responses were not significantly different across sessions (PAP1). For Amax and AAUC, DMT-induced responses were initially significantly greater than placebo (DiPl), and decreased across session (D4D1). AMax values remained significantly greater than placebo by session 4 (PAD4), but were not significantly different for AAUC. Thus, tolerance appears more robust using AAUC for ACTH. Of note is the apparent conditioned response of ACTH after the first placebo dose, similar to that seen in response to placebo in our initial dose-response study. Although D 4 and PI were not compared directly here, response patterns seen in Figuresuggest that by the fourth dose of DMT, the development of tolerance had reduced ACTH responses nearly to the level of the conditioned response to initial placebo administration.
HEART RATE. Figureand Tabledemonstrate that baseline HR values were significantly different for DMT and placebo conditions. Before the first session, there was no effect of dose; however, as the sessions progressed, there was a gradual increase of baseline values for DMT and a decrease for placebo. In a repeated measures ANOVA, Amax HR demonstrated significant dose and session effects. Placebo response values were unchanged across session (P4PI). DMT response values decreased significantly across session (D4D1), and did not differ from placebo values by the fourth session (D4P4). It is, however, apparent in Figurethat D 1 is the only curve that differs, and this could be due to anxiety when the subjects realize that they are receiving DMT for the first time, and experience some fear with respect to the intensity of drug effect. This anxietyproducing factor would be gone in subsequent sessions, and the reduction in HR after that may have little to do with "tolerance." There were no significant drug or session effects on AAUC HR. MEAN ARTERIAL PRESSURE. Figureand Tabledemonstrate no dose or session effects on baseline MAP. AMax and AAUC MAP responses differed by dose but not by session. The responses were essentially parallel across sessions, with DMT responses being consistently higher than those of placebo. Responses for the fourth DMT session did not differ significantly from the first (DAD1), suggesting no tolerance to MAP responses. TEMPERATURE. Interpretation of these data is confounded by the slow time course for this response to DMT. Our previous study demonstrated that temperature did not begin to rise until 15 min after administration of either 0.2 or 0.4 mg/kg DMT, and had not begun falling by 60 min postinjection. Thus, the current data are more likely due to cumulative effects of repeated DMT administration (Fig., Table). It is clear that baseline and physiologically mandated ceiling effects (e.g., sweating) must be taken into consideration. Baseline values rose for drug treatment (D4D1) and remained stable for placebo (P4P1). The Amax and AAUC values, therefore, were smaller than baseline value changes and the ANOVA results are of questionable value. In addition, because of missing values, a nonrepeated measures ANOVA was used, and results of these analyses are not strictly comparable to those of the other variables.
Four closely spaced hallucinogenic doses of N,N-dimethyltryptamine (DMT) fumarate did not produce tolerance to psychological effects of this short-acting compound. Neuroendocrine effects and heart rate responses diminished to varying degrees with repeated dosing, suggesting tolerance development. Blood pressure effects were unchanged, and temperature data were uninterpretable because of their slow response time. We interpret these data as supporting the unique pharmacological properties of DMT relative to other "classic" hallucinogens, and the differential regulation of mechanisms mediating subjective and biological responses to DMT.
Tolerance has been demonstrated for neuropharmacological, electroencephalographic, and whole animal behavioral (Freedman et al 1958) assays of hallucinogen effects. However, DMT effects are not typical in this regard, probably due to DMT's unique pharmacodynamic properties. Current research implicates the 5-HT 2 receptor family in mediating behavioral responses to hallucinogens in lower animals. Downregulation of the 5-HT2 receptor occurs within 2-3 days after treatment with phenethylamine hallucinogens, in a time domain comparable to human studies demonstrating tolerance to hallucinogens. Even more rapid changes occur with short-term exposure to nonhallucinogenic agonists, similar to the time parameters of this study. Hallucinogens, via 5-HT 2 sites (Conn and Sanders-Bush 1986), likewise increase phosphoinositide turnover, which, via receptor phosphorylation, desensitizes the site for agonists. Desensitization of 5-HT 2 responses mediating PI hydrolysis is seen in 20 rain, and downregulation of receptor number occurs within 1 hour. The rapidity of desensitization may relate to phosphorylation of protein kinase C (PKC), which can occur within 10 rain of phorbol ester application. Because this rapid desensitization can be prevented by PKC inhibitors, it would be of interest to determine the effects of DMT on PKC function. Behavioral tolerance to closely spaced, repetitive injections of DMT is seen inconsistently in lower animals, including cat, rat, mice, and primates. Even injections of DMT every 2 hours for 21 days in rat failed to produce complete tolerance. Cross-tolerance for hallucinogens occurs when different drugs produce tolerance to each other, and supports a similar mechanism of action). DMT resistance is not, however, seen in LSD-or DOM-tolerant animals. In humans, tolerance develops after three or four daily exposures to psychoactive doses of LSD, DOM, psilocybin, and mescaline. LSD sensitivity returns to naive values just as quickly, even after high-dose treatment for over 2 months. Consistent with animal data, human DMT tolerance is difficult to demonstrate. A fully hallucinogenic dose of DMT twice a day for 5 days did not evoke tolerance in humans, and "field reports" of closely spaced, repetitive smoking of DMT free base are conflicting regarding tolerance development. Human studies have shown that both LSD and mescaline, as well and LSD and psilocybin, demonstrate cross-tolerance to each other, supporting a similar mechanism of action. However, humans highly tolerant to LSD show no cross-tolerance to a fully hallucinogenic dose of DMT. We believe that these chronic administration and crosstolerance data in both humans and other animals support unique pharmacodynamic, rather than pharmacokinetic, properties of DMT relative to other classic hallucinogens, as mediating its inability to elicit tolerance. The recent description of the equipotency of DMT to that of 5-HT in decreasing resting potassium conductance, compared to low intrinsic activity seen with other hallucinogensmay contribute to understanding these differences.
Tolerance development to some, but not all, of the acute effects of DMT suggests that the mechanisms mediating these response are differentially regulated. DMT has nearly equal affinities for the 5-HT1A and 5-HT z sites. Complex functional interactions between these two subtypes have been described in single-cellto behavioral (Arnt and Hyttel 1989) systems. The effect of 5-HT1A agonism on 5-HT z desensitization processes also may contribute to differential tolerance development to DMT. For example, tolerance to the 5-HT~A agonist 8-OH-DPAT produced cross-tolerance to LSD (with nearly equal 5-HTIA and 5-HT 2 affinities), although LSD-tolerant animals were not tolerant to DOI, a relatively pure 5-HT 2 compoundThe affinity of DMT for the 5-HT2c subtype is not known. If, however, it were significant, the differential acuteand compensatoryinteractions of this and the 5-HT2A subtypes would contribute to unequal tolerance phenomena seen in this study. Direct DMT-induced desensitization of 5-HT sites mediating its acute effects on heart rate responsesmay underlie the tolerance seen here. Differential responsiveness of cardiovascular effects to peripheral catecholaminesrelative to direct brainstem activation) may contribute to the dissociation of blood pressure and heart rate responses. In addition to directing affecting 5-HT sites responsible for cortisoland prolactin responses, DMT may elicit neuroendocrine tolerance because of negative feedback inhibition. Hypotheses regarding prolactin negative inhibitor feedback are limited by the early stages of characterization of central prolactin receptors. Hypothalamic-pituitary-adrenal (HPA) fast and intermediate feedback can occur during the time domain of this study. Repetitive, closely spaced injections of CRH to humans, however, did not produce tolerance to ACTH or cortisol responses, although cortisol levels remained elevated during a continuous CRH infusion. We interpret our HPA data as supporting a direct effect of DMT on 5-HT receptor function, because ACTH responses fell in the face of relatively stable cortisol levels. It should be emphasized that although DMT levels differed significantly among sessions, these differences were relatively small. It seems unlikely that the biological and subjective effects noted, either tolerance or lack thereof, are the result of these differences in DMT levels. HRS clinical clusters are more sensitive to dose effects than the biological variables, and it is possible that the lack of tolerance to the psychological effects of DMT may be due to the slightly higher levels of DMT seen in subsequent sessions. Separating sessions by 60 or 90 rain in future studies may help to clarify this issue.
These data support the uniqueness of DMT among classic hallucinogens. Whether this is based upon pharmacodynamic or pharmacokinetic differences remains to be determined. Tolerance to some, but not all, of the effects of DMT suggest differential regulation of mechanisms involved in tolerance to neuroendocrine, cardiovascular, and subjective effects of hallucinogenic drugs. Future studies attempting to develop tolerance to DMT may use either a continuous infusion of DMT or a greater number of injections.
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