Discussion
reduction of sensory effects, Anxiety, anxiety, Disembodiment’, ’, MEQ-30
EFFECTS INCREASED, ADVERSE EFFECTS, ADVERSE EVENTS, AUDITORY ALTERATION
The present dose-response study tested a novel methodology designed to extend the typically transient DMT experience via continuous IV infusion. This was combined with a bolus loading dose aiming to achieve prolonged effects within a short time span. Our results showed that IV infusions of DMT – at doses ranging from 6 mg + 0.6 mg/min to 18 mg + 1.9 mg/min – were psychologically and physiologically well tolerated, and that the protocol was effective at extending the duration of the psychological effects of DMT, achieving a steady-state of subjective effects, with low-to-negligible changes in anxiety. Subjective drug effects appeared within 1 min of the start of the bolus injection, peaked at 2 min, and settled at a slightly lower-than-peak intensity for the duration of the infusion. Subjective drug effects decreased in intensity shortly after the end of infusion, resolving almost entirely 20 min after the end of infusion. Intensity of the drug effects increased dose-dependently. Ratings of anxiety generally remained low during the duration of the infusion, with a transient increase in anxiety seen just around the start of DMT administration, suggesting psychological tolerability of the tested continuous infusion protocol. Significant differences between all DMT doses and placebo were found for all ASC subscales except ‘Dread of ego-dissolution’ and ‘Auditory alterations’ on the 5D-ASC, as well as, ‘Disembodiment’ and ‘Impaired cognition’ on the 11D-ASC, which showed significant increases only for the higher doses, and ‘Vigilance reduction’ on the 5D-ASC as well as ‘Anxiety’ and ‘Audio/visual synaesthesia’ on the 11D-ASC, which showed no significant differences. Conversely, there were significant increases between all DMT doses and placebo for the MEQ-30 total and all subscales. An initial peak in average plasma DMT concentrations was observed corresponding to the bolus IV injection. A second increase was observed corresponding to the continuous infusion, starting at minute 5–10 and continuing steadily until the end of infusion, at which point plasma levels dropped exponentially, reaching <1 nM within 90 min of the end of infusion. Plasma DMT concentrations increased dose-dependently. Finally, HR peaked quickly after the bolus IV injection, then exhibited significant decreases with respect to baseline within 10 min of the start of the bolus injection, suggesting it was in part anxiety-related and showing that longer infusions do not overload the autonomic system. This habituation of physiological effects while subjective effects remain elevated indicates physiological safety of extended DMT infusions and is consistent with previous findings showing the development of physiological tolerance following the administration of four closely spaced bolus injections of 20 mg of DMT fumarate (Importantly, although subjective ratings of intensity largely followed plasma concentrations of DMT during the first 20 min, a decoupling was observed from minute 20 onwards. While subjective intensity of drug effects decreased after an initial peak and remained stable with a slight downward slope for the remainder of the infusion, plasma levels of DMT generally increased throughout the infusion. These findings may suggest a progressive development of acute psychological tolerance to DMT during continuous infusion, a finding not seen in previous studies employing this compound. One potential explanation for the dissociation between subjective intensity and DMT plasma concentrations in the later part of the infusion is the development of psychological habituation to the effects over time, that is, effects of the same strength lose salience over time, whereas sharp transitions (i.e., as the one induced by the bolus), induce a stronger psychological response. However, the observed variability between individuals makes it difficult to draw any final conclusions based on this analysis. Future studies are needed to address the cause and extent of short-term tolerance induced by continuous DMT to better understand and develop infusion protocols that elicit desired subjective effects.Based on the apparent reduction of sensory effects over time, a refined infusion protocol may be required to better pair the subjective effects achieved through the bolus injection of DMT with those maintained by the continuous infusion and avoid a decrease over time. Additionally, the slight mismatch between peak concentrations achieved at the end of infusion and those achieved after the bolus dose could likely be avoided with slightly adjusted combinations of bolus doses and infusion rates. At the conception of this study, DMT plasma concentration data was only available from one previous study using bolus IV injections of DMT (Importantly, inter-individual variability in dose-concentration response and dose-effects response was large. A roughly two-fold range was observed for both plasma concentrations and intensity ratings for a single dose. Although variability in dose-response of this size is not unique to DMT – similar effects are seen for anaesthetic substances administered via bolus injection (Psychedelic therapy is increasingly showing transdiagnostic relevance for treating several mental health conditions (Psychedelics present an intriguing challenge in psychiatry as their psychological response is known to be highly variable and, at times, unpredictable. This unpredictability is usually accounted for by both dose and so-called non-pharmacological, or contextual variables, commonly described as (mind-) ‘set’ and ‘setting’ (This pilot study tested a novel method of DMT administration and assessed the stability and tolerability of different doses of the drug delivered via continuous IV infusions. DMT exhibits pharmacokinetic properties that make it suitable for continuous IV infusion, and this study demonstrated the safety and feasibility of this method of administration. Continuous IV infusions of DMT administered in doses of up to 18 mg + 1.9 mg/min were psychologically and physiologically well-tolerated in healthy, psychedelic-experienced volunteers. No significant acute or persistent adverse effects were observed. It is important to note some limitations of this study. Firstly, this study was conducted on a small sample of eleven participants. Due to the small number of resulting observations, we tested the effects of Dose 1 compared to placebo, and the added effects of higher doses compared to Dose 1. Dose-related effects between higher doses were only assessed in a qualitative fashion. Future studies including larger sample sizes may be able to investigate the differences between each pair of doses of interest. Secondly, due to safety considerations (i.e., participants receiving a maximum of four DMT doses) and dropouts, there was variability in doses administered, with not all participants receiving all doses investigated. Relatedly, although several of the dropouts occurred for personal reasons, it is not possible to rule out the possibility that participants did not wish to receive more doses. However, it is important to acknowledge that all tested doses seemed psychologically safe for most participants, as can be seen from ratings of anxiety and the adverse events presented in This study lays the groundwork for further explorations with extended IV infusions of DMT. The extended DMT experience may be valuable to explore further the phenomenology, neurobiology, and clinical outcomes associated with this unique state of consciousness. Furthermore, the successful and flexible extension of DMT administration poses a significant opportunity for the application of DMT in clinical and therapeutic settings, where the length, strength and dynamics of the psychedelic experience can be adjusted according to the needs of the individual.