This double-blind, randomised, placebo-controlled crossover study and separate open-label dose-escalation study (n=36) in healthy participants examined intravenous DMT and found that it produced very strong but short-lived subjective effects, peaking within 2 minutes and fading within 12 to 30 minutes. The strongest effects levelled off at 15 mg, and dose escalation appeared to improve tolerability compared with blinded dosing.
N,N-dimethyltryptamine (DMT) is a serotonergic psychedelic that produces short-lived peak effects when administered intravenously as a bolus dose. Initial trials suggested therapeutic effects of DMT in depressive disorders. However, systematic data on dose-dependent pharmacokinetics and acute effects of intravenous bolus DMT administration are currently lacking. We used a double-blind, randomized, placebo-controlled, crossover design in 20 healthy participants who received placebo and DMT (5, 10, 15, and 20 mg) within a single test session. In a separate study arm, we used an open-label, DMT dose-escalation administration design where 16 participants received stepwise increases of 5 mg DMT until reaching a maximally tolerated dose (max. 25 mg). Outcome measures included subjective effects, autonomic effects, adverse effects, and pharmacokinetics that were assessed up to 55 min after each bolus administration. Bolus DMT doses induced very strong subjective effects with a very rapid onset and peak within the first 2 min after administration. Subjective effects declined quickly and subsided completely within 12–30 min, consistent with the short elimination half-life of approximately 6–7 min. A ceiling effect for peak subjective effects was reached at the 15 mg dose. No tolerance was observed to acute effects of DMT. The tolerability markedly improved with open-label dose-escalation compared with double-blinded, randomized administration, and at equivalent dose levels, subjective effects were rated as less intense. These findings highlight the impact of blinding and expectancy on the subjective experience and suggest that individual dose-escalation may improve tolerability and help with dose selection for future DMT studies.
DMT is a short-acting serotonergic psychedelic that can produce very rapid and intense effects when given intravenously as a bolus. Earlier work suggested that this route may have therapeutic promise, including in depressive disorders, but the pharmacokinetics, dose-response relationship, acute subjective effects, and the influence of blinding and expectancy had not been characterised systematically for bolus dosing. In addition, bolus administration appeared to be less well tolerated than continuous infusion in some previous studies, raising questions about how dose, context, and the design of administration shape the acute experience. Erne and colleagues set out to compare the dose-dependent pharmacokinetics and acute effects of intravenous bolus DMT in healthy participants across two administration contexts: a double-blind, randomised, placebo-controlled, crossover design and an open-label dose-escalation design. The study also aimed to assess whether stepwise within-session dose escalation could improve tolerability and help inform dosing for future clinical studies of DMT.
The researchers conducted two independent study arms in healthy adults who were screened for medical and psychiatric exclusion criteria. In total, 36 participants were enrolled: 20 in the randomised arm and 16 in the open-label dose-escalation arm. Participants could choose which arm to join. The randomised arm included equal numbers of men and women and used a double-blind, placebo-controlled, crossover design. Participants received placebo and 5 mg, 10 mg, 15 mg, and 20 mg DMT in random order within a single test session. The open-label arm used stepwise escalation, beginning with placebo and then increasing DMT in 5 mg increments from 5 mg up to a maximum of 25 mg, with participants deciding after each dose whether to continue. DMT was administered intravenously as a bolus over 45 seconds in 20 ml solution. The researchers used a 1-hour washout between boluses, based on the short elimination half-life of DMT and prior evidence that acute effects subside within about 20-30 minutes. In the dose-escalation arm, the interval could be extended by up to 30 minutes after an intense or negative experience. The protocols were approved by the relevant ethics and regulatory bodies, and the study was registered at ClinicalTrials.gov. Outcome assessments included repeated measures of subjective drug effects, autonomic effects, adverse effects, and plasma DMT concentrations over 55 minutes after each bolus. Subjective effects were measured with simple verbal rating scales and with validated psychedelic questionnaires, including the 3D-ASC, the PES48, and the NDE-C scale. Blood pressure, heart rate, and adverse complaints were also recorded. Plasma DMT and metabolites were quantified by high-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were estimated using non-compartmental methods. For the randomised arm, peak values or peak change from baseline were analysed using analysis of variance with dose as the within-subject factor, followed by Tukey post hoc testing. Between-arm comparisons used the Wilcoxon rank-sum test, but the authors note that these comparisons were exploratory because the study was powered for within-subject dose comparisons rather than between-group analyses.
In the randomised arm, DMT produced very rapid and dose-dependent subjective effects. Significant effects were observed from 5 mg onwards compared with placebo. Peak effects occurred within the first 1-3 minutes after administration and then declined quickly, with subjective effects fully subsiding within 12-30 minutes. A ceiling effect for peak subjective intensity was observed at 15 mg, indicating that higher doses did not increase peak ratings proportionally. However, the duration of effect increased with dose, and the area under the effect-time curve for “any drug effect” was higher at 20 mg than at 15 mg. Positive ratings were generally much higher than negative ones, but the 15 mg and 20 mg doses produced more “bad drug effect” and “fear” than lower doses. Psychedelic measures showed similar dose-response patterns. The 10 mg, 15 mg, and 20 mg doses produced pronounced psychedelic experiences, whereas 5 mg caused only mild changes. Most 3D-ASC and PES48 subscales reached a ceiling at 15 mg in the randomised arm, with no clear additional increase at 20 mg. Higher doses also increased negative experiences, including anxious ego dissolution, anxiety, impaired control and cognition, and distressing experience. Autonomic and adverse effects included headache, impaired concentration, weakness, and palpitations. One participant required psychiatric follow-up after later reporting anxiety and panic attacks that began shortly after the study session; these symptoms resolved within 2 months, recurred 3 months later, and the participant was subsequently treated with psychotherapy and escitalopram. Pharmacokinetically, DMT concentrations rose and fell very rapidly. In the randomised arm, mean peak plasma concentrations were 11 ng/ml, 20 ng/ml, 37 ng/ml, and 45 ng/ml after 5 mg, 10 mg, 15 mg, and 20 mg, respectively, with peak concentrations reached at roughly 2.3-2.7 minutes. The initial plasma half-life was about 6.1-6.8 minutes during the first 20-30 minutes after dosing. A slower decline was suggested from 30 to 55 minutes, but the authors say the later phase could not be estimated reliably because of limited sampling. The concentration-effect relationship suggested no acute pharmacological tolerance with repeated hourly boluses. At 5 mg and 10 mg, subjective effects closely tracked plasma levels, whereas at 15 mg and 20 mg, the effects remained near peak for longer despite declining concentrations, consistent with a ceiling effect rather than tolerance. In the open-label dose-escalation arm, a ceiling effect appeared only at 20 mg and 25 mg, and repeated dosing did not reduce ratings, again indicating no acute tolerance. Blinding was only partly successful. Most conditions were correctly identified at the end of the study, once all doses could be compared, but immediate post-dose guesses were often incorrect for 10 mg to 20 mg, typically mistaken for the next higher or lower dose. Placebo and 5 mg were guessed correctly in more than 80% of cases after administration. Compared with the open-label dose-escalation arm, subjective effects were generally lower at equivalent doses. Ratings of “good drug effect” were similar between arms, but “bad drug effect” and fear were higher in the randomised arm. Several psychedelic subscales were also higher in the randomised arm. In contrast, the dose-escalation arm showed dose-proportional increases in positive effects up to 25 mg, with no ceiling effect until higher doses. Ten of 16 participants escalated to 25 mg, including three psychedelic-naive participants.
The authors interpret the study as showing that intravenous bolus DMT produces extremely rapid, short-lived, and dose-dependent psychedelic effects in healthy participants, with peak subjective effects reached within about 1-3 minutes. They emphasise that the peak intensity reached a ceiling around 15 mg in the blinded randomised arm, while the effect duration continued to increase with dose. They also state that the pharmacokinetic findings support a very rapid elimination profile, with an initial half-life of about 6-7 minutes, consistent with prior work. The discussion positions these findings alongside earlier studies, noting that the rapid onset and short duration are broadly consistent with previous intravenous DMT research. The authors suggest that differences across studies, such as delayed peaks in one earlier report, may relate to injection volume and the speed at which the drug reaches the circulation. They also compare bolus administration with continuous infusion, arguing that bolus dosing appears less tolerable, mainly because of its intensity and abruptness. Despite the intense and sometimes anxiety-provoking effects at higher doses, all participants in the randomised arm completed the within-day protocol, which the authors present as evidence that the experience remained acceptable overall. A major theme in the discussion is the absence of acute tolerance with intermittent bolus dosing. The authors report no clockwise hysteresis, no decline in response across repeated doses, and no order effects, and they contrast this with moderate acute tolerance reported for continuous DMT infusion. They suggest that tolerance depends more on the dosing pattern than on a specific property of DMT itself, and they mention possible mechanisms such as receptor desensitisation and downstream signalling changes during sustained exposure. The authors also interpret the comparison between blinded and open-label dosing as evidence that blinding, expectancy, and perceived control strongly shape the psychedelic experience. In the randomised arm, placebo and the 5 mg dose were often identified correctly, illustrating how difficult it is to maintain blinding with a psychoactive drug. In the open-label dose-escalation arm, participants reported lower subjective intensity and markedly fewer negative effects at the same doses, which the authors attribute to preparation, reassurance, and the ability to anticipate and control dose increases. They argue that this context may have reduced anxiety and made higher doses more tolerable. The authors note several strengths, including the crossover, placebo-controlled design; the direct comparison of two administration contexts; the use of standardised psychometric measures; and the inclusion of both men and women. They also acknowledge important limitations. Participants self-selected into study arms rather than being randomised, which may have introduced bias; for example, the dose-escalation group included more cautious and less psychedelic-experienced individuals. They also note that the dose-escalation arm may have been biased towards those who tolerated the drug better, because some participants stopped early. Finally, the between-arm comparison was exploratory because the study was not powered for those differences. The discussion closes by framing dose escalation as a practical approach to improving tolerability and individualising dosing in future DMT studies, including potential therapeutic applications.
The study comprised two independent study arms: a blinded, randomized arm and an open-label, dose-escalation arm. After successful screening, participants were allowed to select their preferred study arm. The randomized arm used a double-blind, placebo-controlled, crossover design to investigate responses to (i) placebo, (ii) 5 mg DMT, (iii) 10 mg DMT, (iv) 15 mg DMT, and (v) 20 mg DMT. Participants were informed that they would receive five bolus doses in randomized order, consisting of placebo (saline) and DMT doses of 5, 10, 15, and 20 mg, and that higher doses could produce rapid onset, very intense, but short-lived subjective effects. The dose-escalation arm used an open-label design, in which the participants first received placebo, followed by ascending doses of DMT, starting at 5 mg and increasing in 5 mg increments up to a maximum of 25 mg. After each dose, the participants could decide whether to stop or proceed to the next dose level. The dose selection was based on prior empirical data and pharmacodynamic considerations. In a previous clinical trial, an intravenous DMT dose of 25 mg produced very strong subjective effects with limited tolerability. Moreover, a ceiling effect was present between the 15 mg and 25 mg dose, reflected by a less-than-proportional increase in subjective intensity between these two doses. Accordingly, a maximum target dose of 20 mg was selected for the randomized arm, while doses up to 25 mg were permitted in the dose-escalation arm to account for interindividual differences (e.g., participants experiencing lower subjective effects or demonstrating higher tolerability). The washout periods between dose administrations were 1 h. The washout period was based on pharmacokinetic considerations and prior empirical evidence. Given DMT's short elimination half-life of approximately 5-7 minutes, most of the drug was expected to be eliminated within 1 hour. In addition, previous clinical studies have demonstrated that subjective effects fully subside within approximately 20-30 minutes following the cessation of a continuous intravenous DMT infusion, even at very high doses. In cases of an intense or negative prior bolus experience, the participants were allowed to extend the time between two bolus administrations by a maximum of 30 min. All experimental protocols were approved by the Ethics Committee of Northwest and Central Switzerland (EKNZ) and the Swiss Federal Office for Public Health (BASEC 2022-01224). The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Guidelines in Good Clinical Practice. Written informed consent was obtained from all participants prior to participation. All methods were performed in accordance with the relevant guidelines and regulations. The study was registered at ClinicalTrials.gov (NCT05695495).
Thirty-six healthy participants 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. Of these, 20 participants (10 men and 10 women; mean age ± SD: 34 ± 9 years; range: 25-56 years) and 16 participants (8 men and 8 women; mean age ± SD: 39 ± 13 years; range: 25-65 years) were included in the randomized arm and dose-escalation arm, respectively. The participants were allowed to choose their preferred study arm. 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 the 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, by a trained physician), the use of medications that may interfere with the study medication (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 9 -tetrahydrocannabinol), and illicit drug use during the study period (screened 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. Four participants (20%) in the randomized arm and six participants (37%) in the dose-escalation arm were psychedelically naive. Detailed data on lifetime substance use are provided in the Supplement (Supplementary Table).
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 5 mg/ml DMT in 1 ml of purified water. The exact analytically confirmed DMT hemifumarate content of the vials (mean ± SD) was 4.76 ± 0.05 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. In the randomized study arm, each bolus consisted of the content of four vials that contained either 5 mg/ml DMT or placebo, which were aspirated into a syringe and diluted with saline (0.9% NaCl) to a volume of 20 ml. In the dose-escalation study arm, one to five open-label DMT vials of 5 mg/ml or one placebo vial, depending on the target dose, were aspirated into a syringe and diluted with saline (0.9% NaCl) to a volume of 20 ml. The 20 ml intravenous bolus dose was administered over 45 s. After each bolus administration and at the end-of-study visit, the participants in the randomized study arm were asked to retrospectively guess their treatment assignment to evaluate blinding.
The study included a screening visit, one 6-h test session, and an end-of-study visit. The sessions were conducted in a calm hospital room. One research participant and two investigators were present during each session. The test sessions began at approximately 9:00 AM. A urine sample was taken to verify abstinence from drugs of abuse, and a urine pregnancy test was performed in women before each session. The participants then underwent baseline measurements. The first DMT or placebo dose was administered at 10:00 AM, followed by the next administration 1 h later. The outcome measures were repeatedly assessed for 55 min after each bolus administration. The participants were sent home approximately 15 min after the last measurement.
Subjective effects were assessed repeatedly using subjective effect scales 1 h before and 0, 2, 4, 8, 12, 18, 30, and 55 min after the administration of a bolus dose. Subjective effect scales included verbal ratings of "any drug effect," "good drug effect," "bad drug effect," and "fear" (Likert scale; 0 to 10 for no to maximal effect). The short version of the Altered States of Consciousness scale (3D-ASC), comprising 42 core items from the 5D-ASC scale, was administered after each bolus dose to retrospectively assess psychedelic peak effects once all subjective effects had subsided. Psychedelic experiences were also similarly assessed after each bolus dose using the 48-item Psychedelic Experience Scale (PES48), which includes the widely used Mystical Experience Questionnaire. Additionally, near-death experience-like effects were assessed retrospectively using the Near-Death Experience Content (NDE-C) scale after each bolus dose. Subjective effect measurements are described in more detail in the Supplementary Methods online.
Blood pressure and heart rate were measured at baseline and 2, 4, 8, 12, 18, 30, and 55 min after bolus administration. Acute adverse effects were assessed 1 h before administration of the first bolus dose and at the end of the session day 30 min after administration of the last bolus dose for all doses together using the List of Complaints.
Blood was collected into lithium heparin tubes at baseline and 2, 4, 8, 12, 18, 30, and 55 min after bolus administration. The blood samples were immediately centrifuged, and plasma was subsequently stored at -20°C and later at -80°C until analysis. Plasma concentrations of DMT and its metabolites were determined by high-performance liquid chromatography-tandem mass spectrometry using a validated method as previously described.
Pharmacokinetic parameters were estimated using non-compartmental methods as described previously. Analyses were conducted using Phoenix WinNonlin 8.4 (Certara, Princeton, NJ, USA).
Peak (E max ) or peak change from baseline (ΔE max ) values were determined for repeated measures. For the randomized study arm, the values were then analyzed using analysis of variance, with dose as the within-subjects factor, followed by the Tukey post hoc test. The criterion for significance was p < 0.05. For the comparison of outcomes between the randomized and doseescalation arms, the Wilcoxon Rank Sum test was used; however, these p-values should be considered exploratory, as the study was powered for within-subject rather than between-subject comparisons. Statistical tests were performed with R 4.3.3 software.. In the randomized study arm, DMT dose-dependently elicited subjective responses that were significantly different from placebo, starting with the 5 mg dose (Figure). All doses of DMT very rapidly induced strong subjective effects that peaked within the first 2 min after bolus administration and rapidly decreased and completely subsided within 12-30 min. A ceiling effect for the peak response was observed at the 15 mg dose (Figure). The effect duration increased with higher doses and increased further at the 20 mg dose, reflected by the significantly higher Area under the effect-time curve (AUEC) value for "any drug effect" following the 20 mg DMT dose compared with the 15 mg dose (Figureand Supplementary Table). On average, negative drug effect ratings were low compared with the much higher positive drug effect ratings. Nevertheless, the higher DMT doses of 15 and 20 mg induced more negative drug effects compared with the lower doses, reflected by higher "bad drug effect" and "fear" scores.
Psychedelic effects on the 3D-ASC and PES48 and NDE-C are shown in Figureand Supplementary Figure, respectively. Statistics are summarized in Supplementary Table. In the randomized arm, DMT produced pronounced psychedelic experiences at the 10, 15, and 20 mg doses (Figureand Supplementary Table). There was a ceiling effect on most subscale ratings on the 3D-ASC and PES48 at the 15 mg dose of DMT, with no significant differences between the 15 and 20 mg doses. The 5 mg dose of DMT elicited only mild psychedelic effects, with minimal increases across most 3D-ASC and PES48 subscales compared with placebo (Figureand Supplementary Table). Consistent with the subjective effect scale ratings, the 15 and 20 mg bolus doses resulted in stronger negative drug effects than the lower doses, reflected by significantly higher "anxious ego dissolution," "anxiety," and "impaired control and cognition" scores on the 3D-ASC and "distressing experience" scores on the PES48 (Figuresandand Supplementary Table). The lower tolerability of the 15 and 20 mg doses was also
Subjective effects on the "any drug effect" scale were nominally higher across all dose conditions in the randomized study arm compared with the dose-escalation study arm (Figureand Supplementary Table). Ratings of "good drug effect" were similar between the study arms, whereas "bad drug effect" and "fear" scores were nominally higher in the randomized study arm compared with the dose-escalation study arm at the same doses of DMT (Figureand Supplementary Table). Consistent with these findings, participants in the randomized arm reported nominally higher scores on most subscales of the 3D-ASC and PES48 (Figureand Supplementary Table). Additionally, significant between-study-arm group differences were observed in the 3D-ASC total score and "anxious ego dissolution" and "impaired control and cognition" scores at the 10, 15, and 20 mg dose conditions. Moreover, positive drug effect increased overall dose-proportionally and linearly with no ceiling effect in the dose-escalation study arm, indicated by dose-proportional increases in ratings of "good drug effect" on the subjective effect scale (Figure), ratings of "oceanic boundlessness," "blissful state," "spiritual experience," and "insightfulness" on the 3D-ASC (Figureand Supplementary Table), and ratings of "mystical" and "positive mood" on the PES48 (Figureand Supplementary Table) up to the maximal dose of 25 mg.
Autonomic effects over time and related peak effects are shown in Supplementary Figureand Supplementary Table. Frequent complaints included headache, impaired concentration, feeling of weakness, and palpitations. One participant required follow-up care by the study psychiatrist because of the onset of anxiety and panic attacks that the participant retrospectively reported as beginning shortly after the study session. These symptoms resolved within 2 months but reappeared 3 months later, and the participant has since been treated with outpatient psychotherapy and escitalopram.
Tableand Supplementary Tableshow pharmacokinetic parameters of DMT based on noncompartmental analyses of the randomized and dose-escalation study arms, respectively. Concentration-time curves of DMT are shown in Figureand Supplementary Figure.and(Tableand Figure). In the randomized arm, the mean maximum plasma concentrations (C max ) for the 5, 10, 15, and 20 mg doses were 11, 20, 37, and 45 ng/ml, respectively, and were reached (T max ) after 2.3, 2.7, 2.4, and 2.5 min, respectively. After an initial distribution phase of 2-4 min, the mean plasma half-life of DMT was 6.1-6.8 min (Table). From 30 to 55 min, a longer half-life was observed based on inspection of the semilogarithmic plots (Supplementary Figure).
Because of limited pharmacokinetic sampling in the period between 30 and 55 min, the longer half-life could not be reliably estimated (Table). The DMT concentration-response relationship over time is shown in Figureand Supplementary Figurefor the randomized and dose-escalation arms, respectively. In the randomized arm, subjective effects closely mirrored plasma DMT concentrations at 5 and 10 mg, with no hysteresis and thus no evidence of acute pharmacological tolerance. At 15 and 20 mg, subjective effects remained near peak levels at 4 min after bolus administration despite declining plasma concentrations, indicating a ceiling effect at these doses. In contrast, in the doseescalation arm, a ceiling effect was observed only at the 20 and 25 mg doses. "Any drug effect" ratings were similar at equivalent doses with repeated hourly dosing (Supplementary Table), indicating no tolerance to acute effects of repeated bolus DMT administrations.
Data on the participants' retrospective identification of the DMT dose conditions are shown in Supplementary Table. Most conditions were correctly identified by the participants at the end-of-study visit once all conditions could be compared. However, when asked after each administration, the 5, 10, 15, and 20 mg doses were misclassified by two (13%), nine (56%), five (31%), and seven (44%) participants, respectively. In most of these cases, the conditions were mistaken as the next higher or lower dose.
In the present study, we characterized pharmacokinetics and acute dose-dependent effects of intravenous DMT administration as bolus doses in healthy participants. Subjective peak effects of DMT were reached rapidly within 1-3 min. There was a ceiling effect for the peak subjective response intensity, with high effect ratings reached at the 15 mg dose. Subjective effects of the 5 and 10 mg doses declined rapidly after peaking at 2 min after bolus administration but remained close to peak intensity for approximately 4 min at the 15-25 mg doses. Thus, the effect duration was dose-dependent, ranging from 12 to 30 min across the 5-20 mg doses. The present findings are consistent with prior studies, in which subjective peak effects were reached within 1-3 min, and effect durations were up to 20-30 min at high doses of intravenous DMT administration. One study reported delayed peak effects that occurred 5-10 min after bolus administration, likely attributed to the smaller injection volume (1 ml) that was used. In contrast, both our studiesand otherslikely achieved more rapid drug availability in the circulation by using a larger injection volume (20 ml), as in our case, or a saline flush following the bolus. Intravenous bolus DMT administration in the present study produced very intense effects, including moderate anxiety, at the higher doses. Consistent with a previous study, intravenous bolus doses were less well tolerated than continuous infusions of DMT, primarily because of the overwhelming intensity and rapid onset of at doses of 15 mg and 25 mg. Participants in the present study described similar experiences, characterizing the initial drug effects as simultaneously intense, good, bad, and anxiety-inducing, particularly at the higher doses of 15 mg and 20 mg. Notably, despite these often overwhelming effects, all of the participants in the randomized study arm of the present study completed the full study, which involved multiple bolus administrations of DMT within a single day, each separated by only 1 h. Nevertheless, the intense subjective effects were experienced as positive overall, indicating acceptable tolerability. These findings are consistent with other studies that used intravenous bolus or inhalation DMT administration. The present study also determined pharmacokinetic parameters of DMT across a wide dose range of intravenous bolus doses. DMT was cleared very rapidly from plasma, with an initial half-life of 6-7 min during the first 20-30 min post-administration. Plasma concentrations then declined more slowly until 55 min. However, because of the limited sampling during this later phase, a second half-life could not be reliably estimated. These pharmacokinetic findings are consistent with our previous studies that described an early half-life of DMT of 5-7 min during the first 20 min and a late half-life of 15-19 min following the cessation of continuous DMT infusion after 90 and 120 min, respectively. Another study reported an overall longer mean plasma half-life of 9-12 min for DMT but did not differentiate between the early short and later long plasma half-lives. We observed no acute pharmacological tolerance to acute effects of bolus DMT doses in the present study. Specifically, there was no clockwise hysteresis curve in the Additionally, there was no decline in the response to multiple DMT dose administrations, and no order effects were detected. These findings are consistent with early studies byreported no tolerance to subjective effects in a study that involved closely spaced bolus DMT doses of 0.3 mg/kg. In contrast, moderate acute tolerance has been described with continuous intravenous DMT administration. This phenomenon, in which continuous infusions induce tolerance but intermittent dosing does not, has been observed for other substances, including nitroglycerin, benzodiazepines, and opioids. Thus, the presence or absence of tolerance depends on the type of administration (intermittent/short-lasting vs. continuous/longer-lasting) rather than a property of DMT itself. Possible mechanisms that could explain this differential tolerance include receptor desensitization, internalization, and downstream adaptations in signaling efficiency that are caused by sustained agonist exposure with continuous administration. In the double-blinded randomized study arm, blinding was relatively well maintained in the present study because of the use of different doses. Typically, doses of 10-20 mg were mistaken as the next higher or lower dose. Conversely, placebo and the 5 mg dose conditions were guessed correctly in > 80% of cases. The relatively high accuracy in identifying placebo and the low-dose condition immediately after the session (i.e., before receiving further doses) highlights the difficulty of maintaining blinding with psychoactive compounds. The findings suggest that even an active placebo, such as the 5 mg DMT dose condition in this context, may not always be sufficient to maintain adequate blinding against high doses. The present study included an additional dose-escalation study arm. In the open-label dose-escalation study arm, 10 of 16 participants (63%) increased dosing up to the maximum dose of 25 mg, including three who had never had a psychedelic previously. One participant stopped after the 10 mg dose, three stopped after the 15 mg dose, and two stopped after the 20 mg dose. Notably, at equivalent dose levels, participants in the dose-escalation arm reported lower ratings of acute subjective effects compared to the randomized arm, with ratings of negative effects nearly 50% lower. Moreover, a ceiling effect for the peak subjective effect response emerged only at 20 mg or higher, whereas in the randomized arm, a ceiling effect was already observed at 15 mg. Consistent with this, overall peak psychedelic effect ratings (total 3D-ASC scores) were 50% lower on scales that reflected positive effects, such as "oceanic boundlessness," and 60% lower on scales that reflected negative effects, such as "anxious ego dissolution," in the dose-escalation arm compared with the randomized study arm. Psychedelically experienced individuals could be expected to report weaker subjective effects compared with psychedelically naive individuals. However, participants in the dose-escalation arm were less experienced than those in the randomized arm, but they consistently rated their experiences as less intense. The open-label dose-escalation design likely allowed participants to be more prepared for the gradually increasing psychedelic effects, whereas participants in the randomized arm might have been overwhelmed and surprised by the sudden onset and intensity of effects of the randomly ordered doses and not knowing whether a next dose might even be higher. Additionally, expectancy effects-in this case, knowing the dose and even being in control of the dose escalation-may have provided participants with a sense of control and reassurance before each administration, thus minimizing especially negative effects. Similarly, in a previous study, in which participants were allowed to self-titrate the dose rate to their individually preferred level during a continuous DMT infusion, negative effects were minimal, despite many participants increasing the dose rate to induce strong psychedelic effects. These findings highlight the importance of context in psychedelic research. In particular, the findings illustrate the role of open-label vs. blinded administration in moderating the subjective psychedelic experience. Previous trials demonstrated the good tolerability of psychedelics in healthy participantsand patientswho implement dose titration, which is commonly practiced for many medications and may further enhance tolerability. This approach is simple for intravenous DMT administration, in which bolus doses can be steadily increased as in the present study within a session or adjusted during a continuous intravenous infusion. DMT that is administered as an intravenous bolus or via inhalation produced rapid-acting antidepressant effects in initial studies. The present study indicates that the tolerability of DMT could be enhanced by escalation dosing, and the findings may optimize dosing in future clinical studies. The present study has several notable strengths. Four different doses of DMT were administered in a cross-over design and compared with placebo under double-blind conditions in a controlled laboratory setting. Thus, we able to accurately describe the dose-response relationship of DMT bolus doses across a wide dose range. We also included equal numbers of male and female participants and used internationally established standardized and validated psychometric outcome measures. Moreover, we tested a dose-escalation regimen that could be used in the future in patients to enhance tolerability and individualize treatment with DMT. Lastly, the direct comparison between the double-blind, randomized arm and open-label, doseescalation arm allowed the evaluation of how design, dosing, blinding, and associated expectancy effects can influence subjective responses. Notwithstanding these strengths, the present study also has limitations. First, participants with lower tolerability of DMT were more likely to drop out early during dose escalation, potentially introducing a bias toward more positive effects at higher doses in that arm. However, all but one participant reached the 15 mg dose, and 12 of 16 participants (75%) received the 20 mg dose. Therefore, the direct comparison between the randomized and dose-escalation arms can be considered valid at least up to the 15 mg dose. Second, participants were not randomly assigned to the two study arms but were allowed to choose their preferred arm. This self-selection introduces a potential bias; one would expect more cautious or less psychedelically experienced individuals to opt for the dose-escalation arm, which was indeed the case. Moreover, the study was powered for within-subject dose comparisons within each study arm rather than betweensubject differences across the two study arms, making this comparison between study armsand. DMT produced dose-dependent subjective psychedelic peak effects. A ceiling effect was observed for ratings on most subscales on the 3D-ASC and PES48 starting at 15 mg in the randomized arm. The 15 and 20 mg doses resulted in higher ratings of "anxious ego dissolution" on the 3D-ASC and "distressing experience" on the PES48 compared with the 5 and 10 mg dosesand.
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