Using data from 13 healthy volunteers given intravenous DMT, the authors developed a population PK/PD model (two‑compartment PK, high clearance ≈26 L/min, effect‑site sigmoid Emax with EC50 ≈95 nM) linking plasma concentrations to subjective psychedelic intensity. Simulations translate exposure into dose–response predictions (median maximum intensity ratings for 1–20 mg), providing a tool to guide dose selection in clinical investigations.
N,N‐dimethyltryptamine (DMT) is a psychedelic compound that is believed to have potential as a therapeutic option in several psychiatric disorders. The number of clinical investigations with DMT is increasing. However, very little is known about the pharmacokinetic properties of DMT as well as any relationship between its exposure and effects. This study aimed to characterize population pharmacokinetics of DMT as well as the relationship between DMT plasma concentrations and its psychedelic effects as measured through subjective intensity ratings. Data were obtained from 13 healthy subjects after intravenous administration of DMT. The data were analyzed using nonlinear mixed‐effects modeling in NONMEM. DMT plasma concentrations were described by a two‐compartment model with first‐order elimination leading to formation of the major metabolite indole 3‐acetic acid. The relationship between plasma concentrations and psychedelic intensity was described by an effect site compartment model with a sigmoid maximum effect (Emax) response. DMT clearance was estimated at 26 L/min, a high value indicating elimination of DMT to be independent of blood flow. Higher concentrations of DMT were associated with a more intense experience with the concentration of DMT at the effect site required to produce half of the maximum response estimated at 95 nM. The maximum achievable intensity rating was 10 and the simulated median maximum rating was zero, 2, 4, 8, and 9 after doses of 1, 4, 7, 14, and 20 mg, respectively. The model can be useful in predicting suitable doses for clinical investigations of DMT based on the desired intensity of the subjective experience.
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Depressive and anxiety disorders affect hundreds of millions worldwide, and a substantial fraction of patients do not respond to available treatments. Renewed interest in classic serotonergic psychedelics has been driven by preliminary evidence of lasting therapeutic effects after single or few doses. N,N-dimethyltryptamine (DMT) is a naturally occurring psychedelic found in ayahuasca and is believed to act primarily via 5-HT2A receptor agonism; however, DMT is rapidly metabolised (principally by monoamine oxidase A (MAO‑A)) and, despite growing clinical investigation, its human pharmacokinetic (PK) and pharmacodynamic (PD) properties remain poorly characterised. Eckernäs and colleagues set out to characterise population PK of intravenously administered DMT and to quantify the PKPD relationship between plasma DMT concentrations and the psychedelic experience as measured by real‑time subjective intensity ratings. The stated aim was to provide a model that could support dose selection for future clinical studies, including decisions about doses producing sub‑psychedelic versus fully psychedelic experiences and the design of extended administration regimens.
The analysis used data from a placebo‑controlled clinical trial in 13 healthy volunteers (seven males; median age 33 years, range 22–48) conducted at an NIHR clinical research facility. The trial employed a fixed‑order design: each participant received placebo on their first visit and an intravenous bolus of DMT fumarate one week later. Individual subjects received one of four dose levels: 7 mg (n=3), 14 mg (n=4), 18 mg (n=1) or 20 mg (n=5). For PK sampling, nine blood draws per subject were taken via an indwelling catheter up to 60 minutes post‑dose. Subjective psychedelic intensity was recorded every minute during the first 20 minutes on a 0–10 scale (0 = no effect, 10 = most intense imaginable). Plasma concentrations of DMT, DMT N‑oxide and indole 3‑acetic acid (IAA) were quantified by a validated liquid chromatography–tandem mass spectrometry method. Calibration ranges were 0.25–200 nM (DMT), 15–200 nM (DMT N‑oxide) and 500–5000 nM (IAA); lower limits of quantification were 0.25, 15 and 500 nM respectively. IAA was reported as change from baseline due to high endogenous levels. Samples above the upper limit were diluted and re‑analysed. Samples below the LLOQ were excluded (n=3 for DMT, n=9 for IAA) and one sample with an implausibly high DMT concentration was removed. Population PK and PKPD modelling was performed using nonlinear mixed‑effects methods in NONMEM (FOCE with interaction), with Pirana and PsN for workflow and R for diagnostics and plots. A sequential modelling strategy was used: a population PK model for DMT was developed, extended to include IAA, and finally a PKPD model was built using a PPP&D approach (population PK parameters fixed while individual PK parameters and PD parameters were estimated). Between‑subject variability (BSV) was modelled with exponential terms (log‑normal). For the PK stage, one‑ and two‑compartment models with first‑order elimination were evaluated; IAA was modelled as a one‑compartment primary metabolite with the metabolic fraction (fm) fixed to 1. For PD, effect‑compartment models with Emax or sigmoid Emax relationships were considered. The PD model used a logit transform to constrain predicted intensity to the 0–10 scale. Model selection used changes in objective function value (ΔOFV), diagnostic plots, visual predictive checks (VPCs) and sampling importance resampling to derive parameter precision and 95% confidence intervals. Simulations were performed in R/mrgsolve for five bolus doses (1, 4, 7, 14 and 20 mg), each simulated in 100 virtual subjects, to predict distributions of maximum achieved intensity.
A total of 93 DMT and 87 IAA plasma concentration observations were included (distributed across the four dose groups), together with 273 subjective intensity ratings. No measurable DMT concentrations or subjective effects were observed after placebo, so placebo data were not modelled. PK findings: DMT concentrations were best described by a two‑compartment model with first‑order elimination that was assumed to form IAA as the primary metabolite. A two‑compartment fit improved the model substantially over a one‑compartment alternative (ΔOFV = -41.64). The estimated apparent plasma clearance of DMT was high (reported as 26 L/min). Between‑subject variability was included on clearance; IAA was described by a one‑compartment model with BSV on apparent volume. Proportional residual error models were used for both compounds. Parameter precisions met pre‑specified criteria (%RSE ≤ 30% for fixed effects and ≤ 50% for BSV) except for intercompartmental clearance (Q), for which %RSE was 37%. Goodness‑of‑fit plots and VPCs indicated acceptable predictive performance of the final PK model. PKPD findings: A short delay between plasma DMT and reported intensity led to selection of an effect‑compartment model with a sigmoid Emax relationship. The effect‑site equilibrium rate constant (ke0) was estimated at 1.38 min‑1, implying an approximate 2‑minute equilibration between blood and the effect compartment. Emax was fixed to 10 and baseline intensity was zero for all subjects. The effect‑site EC50 (EC50,e) was estimated at 95 nM and the Hill coefficient (γ) was approximately 3, indicating a steep concentration–effect slope in the mid‑response range. BSV was estimated at 39% for EC50,e and 77% for γ. A high correlation (93%) between the BSV terms was observed in exploratory fits but was not retained because it produced model ill‑conditioning. VPCs and GOF diagnostics supported the final PKPD model. Simulations: Using the final model, simulated median maximum intensity ratings at doses of 1, 4, 7, 14 and 20 mg were 0, 2, 4, 8 and 9 respectively. The proportion of simulated subjects achieving a maximum rating above 5 rose across doses: 0% (1 mg), 4% (4 mg), 42% (7 mg), 92% (14 mg) and 100% (20 mg).
Eckernäs and colleagues present what they describe as the first population PKPD characterisation linking plasma DMT concentrations to real‑time subjective intensity ratings. The investigators interpret the two‑compartment PK model and the PKPD effect‑compartment with a sigmoid Emax as consistent with a short distribution delay between blood and the presumed brain effect site, and with steep concentration dependence of subjective intensity within the mid‑response range. A notable finding is the very high estimated plasma clearance of DMT (26 L/min), well above average cardiac output. The authors suggest this implies elimination processes that are not limited by organ blood flow and hypothesise that widespread MAO‑A expression (including in blood vessels) could contribute; they caution that further work is required to confirm mechanisms and refine clearance estimates. The modelling assumed complete conversion of DMT to IAA (fm set to 1) to permit metabolite parameter estimation; the authors acknowledge that DMT metabolic pathways after intravenous dosing are incompletely understood and that other metabolites (notably DMT N‑oxide) were absent in these plasma samples. On the PD side, the effect‑site equilibrium rate constant (ke0 ≈ 1.38 min‑1) corresponds to about two minutes for blood–brain equilibration, and the Hill coefficient (~3) denotes a steep concentration–effect relationship where small concentration changes within 20–80% of maximal response produce large effect changes. The EC50,e of 95 nM is reported to be in the range of in vitro EC50 values for 5‑HT2A receptor activation reported elsewhere, which the authors suggest is supportive of 5‑HT2A mediation of the psychedelic effects. The authors highlight substantial between‑subject variability in EC50,e and γ, and note the limitations imposed by the small sample (13 subjects) which prevented a formal covariate analysis. They also describe modelling choices and limitations related to the subjective intensity ratings: the integer 0–10 scale was treated as continuous and constrained by a logit transform, which cannot predict exact 0 or 10 but can approximate boundary values closely. Simulations using the model are presented as practical guidance: a 14 mg bolus yields a median maximal intensity of 8 with 92% of subjects predicted above an arbitrarily chosen intensity threshold of 5, whereas doses ≤7 mg are more compatible with sub‑psychedelic or modest intensity responses. The authors suggest the model may therefore aid dose selection for clinical development, including choices about sub‑psychedelic regimens and parameters for extended administration, but they emphasise the need for larger studies to explore covariates and refine these findings.
A total of 93 (19, 29 ,6 and 39 for the 7, 14, 18 and 20 mg doses, respectively) and 87 (18, 27, 6 and 36 for the 7, 14, 18 and 20 mg doses, respectively) plasma concentration observations of DMT and IAA respectively, as well as 273 (84, 63, 21 and 105 for the 7, 14, 18 and 20 mg doses, respectively) subjective intensity ratings, were included in the analysis. The individual concentration-time curves of DMT and IAA have been previously published elsewhere. No subjective psychedelic effects or measurable concentrations of DMT were observed after placebo administration. Consequently, observations after placebo administration were not modelled.
DMT is one of several serotonergic psychedelics that have recently gained an increased amount of attention as potential therapeutic tools in treatment of a number of psychiatric disorders. Despite the increasing number of clinical investigations with DMT, very little is known about the PK and PKPD properties of DMT. In this work the population PK of DMT and its metabolite IAA as well as the PKPD relationship between DMT concentrations and subjective psychedelic intensity was characterized. To the best of our knowledge, this is the first time the relationship between DMT plasma concentrations and its effects have been characterized using a modeling approach. DMT plasma concentrations were best described using a two-compartment PK model. To be able to estimate any PK parameters of the metabolite, the assumption was made that DMT was completely metabolized into IAA via a first-order elimination pathway. The estimated PK parameters of DMT and IAA are summarized in Table. Noteworthy is the extremely high clearance obtained for DMT. The obtained plasma clearance of 26 L/min is clearly above the cardiac output of an average healthy individual (approximately 5 L/min). Although blood clearance of DMT might be lower, it seems unlikely that the blood:plasma ratio should be sufficiently high to fully account for this large clearance value. This is also supported by a separate experiment where DMT was added in known amounts to whole blood. Plasma was harvested and the measured concentrations of DMT in plasma corresponded well with the nominal concentrations in whole blood (data not shown). Hence, the results indicate a degradation of DMT that is independent of organ blood flow. Since DMT is primarily metabolized by MAO A, this could potentially be explained by the presence of MAO A in tissues throughout the body, including the blood vessels. However, further research is needed to confirm this and to obtain a better understanding of the elimination of DMT from the human body. In addition, a relatively high BSV in clearance was observed. No full covariate analysis was performed in this work due to the low number of individuals. However, no trends were observed with regards to sex or age (data not shown). Nevertheless, there are several potential factors that could cause variability in clearance between different individuals including for example body size. In addition, polymorphisms in MAO-A affecting drug metabolism have been previously reportedand we believe this should be further investigated as a potential source of variability in DMT pharmacokinetics in future studies. The assumption was made that DMT is completely metabolized into IAA via a single elimination pathway. The metabolic pattern of DMT has not yet been fully elucidated. Previous studies have identified several other metabolites of DMT after intake of ayahuasca, however the inclusion of MAO inhibitors might shift the metabolic pathways and it is unclear which metabolites are formed after intravenous injection of DMT. For example, we have previously shown that DMT N-oxide, a metabolite that has been observed after oral intake of ayahuasca, was not present in plasma samples from the individuals in the present study. Consequently, setting the metabolic fraction to one was deemed to be the most appropriate option with the data available. Although, IAA is not believed to be an active metabolite it was incorporated in the model for descriptive purposes. A complete understanding of DMT metabolism and any potential active metabolites might however improve the understanding of both PK and PD aspects in the future. In the present analysis, we first established a PK model, whereafter typical parameters were fixated when modelling subjective intensity ratings. The study subjects had been asked to rate their experience on a scale from 0-10 right before and during the first 20 minutes after DMT administration. For the purpose of modeling, the observed data was treated as continuous, even though it was actually integer scale. However, to avoid producing predictions outside the boundaries of the scale, a logit transformation was used to restrict the values between 0 and 10. The applied transformation only allows predictions to approach the boundaries of the scale asymptotically. Hence, exact values of 0 or 10 cannot be predicted. However, for obtaining a basic understanding of the achieved effect at different concentrations, values of 9.99 or 0.001 can be assumed to be equivalent to 10 and 0 respectively. A slight delay in response as compared to DMT concentrations were observed. Since changes in perception are usually coupled to changes in brain signaling, something that occurs rapidly as a response to a stimulus, it was concluded that the most likely explanation would be a delay in distribution to the effect site rather than a delay in developing the response. Consequently, an effect compartment model with a sigmoid E max response was chosen as the final model since it appropriately represents the hypothesized mechanism behind the observed delay. The effect compartment model assumes that drug needs to be distributed from plasma to the effect compartment, and that only the drug in the effect compartment contributes to the observed effects. The value of k e0 provides information of the effect delay. The estimated value of 1.38 min -1 can be seen to indicate that it takes approximately two minutes for DMT concentrations in the brain to equilibrate with blood. The addition of a Hill coefficient, estimated to be approximately 3, significantly improved the model fit. The Hill factor describes the sigmoidicity of the relationship between effect and concentration with a higher value indicating a steeper slope. Hence, a Hill factor of 3 indicates that within 20-80% of maximal response, a small change in concentration results in a large change in response. A BSV of 39 and 77% were estimated for EC 50,e and gamma respectively. Since the intensity rating is a subjective effect measure and thus error-prone, it is not surprising that some variability in EC 50,e would be observed. Most likely, there will be some inconsistency in the reporting of intensity even within the same individual. In general, there are difficulties in working with subjective response measures in terms of robustness. However, in studies with DMT as well as with other psychedelics, the experience must be taken into consideration as some evidence suggests a correlation between subjective measures assessing the quality of the psychedelic experience and therapeutic outcomes related to improvements in mood and addictive disorders. Consequently, understanding how plasma concentrations of DMT relate to the intensity of this experience is a key factor in setting appropriate dose levels in future clinical studies. The EC 50,e of the psychedelic intensity was estimated at 95 nM in this study. Interestingly, this is similar to in vitro EC 50 values associated with activation of the 5-HT2A receptor (201-269 nM). This potentially supports the idea that the psychedelic effects of DMT are mainly mediated through agonism at the 5-HT2A receptor. While this model may not allow for accurate predictions of how the response varies over time in a diverse population, due to the limited data, we believe it can be useful in understanding what effect and associated variability can be expected at different concentrations and doses. To illustrate this, simulations were performed to predict the maximum achieved psychedelic intensity rating at different dose levels. The median maximum achieved effect rating increased from 4 to 8 between the 7 mg and 14 mg dose respectively, while the corresponding proportion of the population achieving a maximum response above 5 increased from 42 to 92%. At the highest dose level (20 mg) the median maximum effect was 9 and the predicted proportion achieving a maximum effect above 5 was 100%. For the purpose of illustrating the applicability of the obtained results, an intensity rating of 5 was set as an arbitrary limit of what would constitute a fully psychedelic experience. Hence, if the psychedelic experience is used as the target outcome these results indicate that increasing the dose above 14 mg might not provide any substantial increase in benefit as 92% of the population is predicted to already achieve an intensity above 5. This is consistent with previous research suggesting the intravenous bolus dose for a psychedelic threshold to be close to 14 mg of DMT fumarate. Further, some research suggests that DMT might be effective in protection and recovery from ischemic injuriesand, in contrast to when treating psychiatric disorders, this might call for doses where the aim is to keep the response at a "sub-psychedelic" level, here assumed to correspond to a rating below 5. In this case, the results indicate that a dose at or below 7 mg would be needed. However, it is clear from the spread in the maximum achieved effect across the population at the 4 and 7 mg doses that if a "medium" intensity is desirable, individually tailored doses will most likely be necessary. Overall, the final model adequately described the PK and psychedelic intensity data. Even though this was a relatively small study, it is a first step towards gaining an increased understanding of the PKPD characteristics of DMT. We believe that this model can be useful in predicting suitable doses for clinical investigations of DMT based on the desired intensity of the subjective experience (and its potential relationship to desired therapeutic effects). This model may also provide the basis for determining dose parameters suitable for extended administration of DMT, which would be a significant step forward in the clinical development of DMT. However, the large variability observed in the data highlights the need for larger studies with the ability to investigate potential covariates and causes for these observations.
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