This methodological paper (2016) outlines the development of a target-controlled intravenous infusion protocol for administering DMT within the context of neuroimaging research. Whereas a single dose does not exert effects beyond 20 minutes, this method maintains a stable brain concentration that enables the investigation of a stable and prolonged DMT experience over an indefinite period.
Abstract
“Introduction: The state of consciousness induced by N,N-dimethyltryptamine (DMT) is one of the most extraordinary of any naturally-occurring psychedelic substance. Users consistently report the complete replacement of normal subjective experience with a novel “alternate universe,” often densely populated with a variety of strange objects and other highly complex visual content, including what appear to be sentient “beings.” The phenomenology of the DMT state is of great interest to psychology and calls for rigorous academic enquiry. The extremely short duration of DMT effects—less than 20 min—militates against single dose administration as the ideal model for such enquiry.
Methods: Using pharmacokinetic modeling and DMT blood sampling data, we demonstrate that the unique pharmacological characteristics of DMT, which also include a rapid onset and lack of acute tolerance to its subjective effects, make it amenable to administration by target-controlled intravenous infusion.
Results: This is a technology developed to maintain a stable brain concentration of anesthetic drugs during surgery.
Discussion: Simulations of our model demonstrate that this approach will allow research subjects to be induced into a stable and prolonged DMT experience, making it possible to carefully observe its psychological contents, and provide more extensive accounts for subsequent analyses. This model would also be valuable in performing functional neuroimaging, where subjects are required to remain under the influence of the drug for extended periods. Finally, target-controlled intravenous infusion of DMT may aid the development of unique psychotherapeutic applications of this psychedelic agent.”
Authors: Andrew R. Gallimore & Rick J. Strassman
Summary
INTRODUCTION
DMT produces some of the most extraordinary changes in consciousness of any naturally-occurring psychedelic substance, and it is produced in humans. This suggests that DMT may have a significant role in human neurophysiology, consciousness, and the visual system.
Clinical psychedelic drug research has resumed after a generation’s hiatus, and is expanding rapidly. However, comparable thoroughgoing analyses of their phenomenology are lacking, which is surprising because of how unusual and highly replicable their subjective effects are.
The first human studies of DMT began in the 1950s, but they simply classified the complex visual effects as “hallucinations” with no further analysis. Most modern studies routinely provide detailed descriptions of the altered state.
DMT administration results in a rapid and overwhelming onset, with full effects noted within 2 min of administration. Users report experiencing a “rush” and dissociating from body awareness, as well as receiving “information”.
Full-psychedelic doses of intravenous DMT administered by bolus injection can be prolonged by continuous intravenous infusion.
Gouzoulis-Mayfrank et al. (2005) used an approach that did not take into account the pharmacokinetics or pharmacodynamics of DMT, and thus resulted in an overly high infusion rate.
METHODS AND RESULTS
Target-controlled intravenous infusion is a methodology used in general anesthesia to ensure drug levels remain within the required therapeutic window. The water-soluble DMT salt used for intravenous administration meets all of the criteria listed in Table 1.
As a drug is introduced into the body by intravenous injection, it is rapidly diluted and distributed by the blood, and equilibrated with peripheral tissues and the effect site itself. It is eliminated from the body by a combination of enzymatic transformation, and urinary and/or biliary excretion.
Drug is introduced into the central compartment and removed from the central compartment by elimination and equilibration with the peripheral compartment. The overall rate of plasma concentration decline obeys the differential equation.
Complete equilibration with the peripheral compartment is modeled as a first-order process with rate constant.
To maintain a constant plasma concentration, the infusion rate must equal the overall removal rate, which is not constant except at steady state.
We used DMT plasma concentration data from a previous study to establish that the pharmacokinetics of DMT make it suitable for target-controlled infusion. Nine subjects were used in the analysis, and 9 sets each of 0.4 and 0.2 mg/kg time series data were fitted to one-, two-, and three-compartment pharmacokinetic models.
Using the Matlab Simbiology toolkit, we fitted the 0.2 and 0.4 mg/kg time-series data separately to a two-compartment model with enzymatic clearance, consistent with Michaelis-Menten kinetics. The population parameter estimates obtained are for an “average” individual, although the dose-concentration response varied considerably among subjects.
We extended the model to include the effect site (brain) concentration and found that the peak effects in each subject occurred at approximately 3 min from the beginning of the infusion. The peak autonomic responses to DMT also reached their highest levels between 2 and 5 min from the end of the infusion.
The peak effect site concentration was reached at 3 min in the simulation, and the resulting plot fits the observations well.
The subject transitions into full dissociation from the external world when the effect site concentration reaches 60 ng/ml, and remains in the space for 6 – 7 min.
Clinical observation of the subjects suggests that the maximum level of absorption in the subjective experience occurred at 4 – 5 min, and that the acute drug effect began to lighten as early as 5 min.
We simulated the infusion protocol used in the original study and developed an infusion protocol that would bring the effect site concentration smoothly to the predetermined level and keep the concentration stable indefinitely.
Since the first term depends only on the plasma concentration, the maintenance infusion rate can be calculated using the RT equation.
Using the estimated model parameters, the steady state infusion rate is 0.93 mg/min. However, during the first few min of the infusion, the exponential term is large, and the infusion rate must be set to compensate for this rapid transfer of drug.
We performed simulations using the Gouzoulis-Mayfrank infusion protocol to examine the possibility of effect site concentration overshoot. The concentration rose steadily and reached 150 ng/ml by the end of the session.
We developed an infusion protocol that maintains an effect site concentration of 100 ng/ml in a 75 kg subject. The infusion begins at 4.2 mg/min and decreases according to the peripheral transfer rate decay.
DISCUSSION
The phenomenology of dream states and hallucinations in psychotic disorders have been studied extensively, but the technology for extending DMT experiences beyond what is achievable using bolus administration would be of great value.
Modern target-controlled infusion protocols can be used to control the level of anesthesia during DMT sessions. This method is suitable because DMT has a rapid and short-acting effect, and lacks acute tolerance to its subjective effects.
This methodology was developed to prove that stable effect site concentrations can be achieved using target-controlled infusion. More extensive sampling and more detailed pharmacokinetic modeling are required.
Subject covariates such as weight, age, gender, and liver function create significant inter-subject and intra-subject variability in the dose-concentration response of DMT administered by target-controlled infusion. However, the variability in the relationship between the dose and the subjective response was much lower.
DMT has 45% lower subjective response variability compared to dose-concentration variability, suggesting that a broader target concentration window exists.
The DMT-containing plant-based decoction ayahuasca provides an extended “DMT experience” lasting several hour. However, the preparation must contain both a DMT-containing plant as well as one containing a beta-carboline MAO inhibitor, such as harmaline.
A target-controlled IV infusion of DMT may address a number of research questions, such as the maximum DMT effect, and the ability to move the individual gradually into a greater level of intoxication while maintaining the characteristic mental clarity associated with fully psychedelic doses.
Studies with psychedelic drugs are being conducted to determine the effectiveness of these drugs for treating conditions such as depression, obsessive-compulsive disorder, dysphoric psychological accompaniments of terminal illness, prisoner recidivism, and substance abuse disorders.
Intravenous DMT effects provide a rapid onset and short duration, allowing users to enter and exit a highly altered state in short order. This characteristic of DMT has therapeutic potential, as demonstrated by normal control volunteers who were able to talk about their experiences.
A continuous target-controlled infusion of DMT could be turned to therapeutic purposes in a patient population, with the duration and intensity of the altered state being titrated for the most useful therapeutic gains.
We have described the rationale for developing a target-controlled intravenous infusion of DMT. This model has broad psycho-heuristic, functional imaging, and clinical applicability.