N,N‐dimethyltryptamine (DMT) is a psychedelic substance and is being used as a research tool in investigations of the neurobiology behind the human consciousness using different brain imaging ...techniques. The effects of psychedelics have commonly been studied using electroencephalography (EEG) and have been shown to produce suppression of alpha power and increase in signal diversity. However, the relationship between DMT exposure and its EEG effects has never been quantified. In this work, a population pharmacokinetic/pharmacodynamic analysis was performed investigating the relationship between DMT plasma concentrations and its EEG effects. Data were obtained from a clinical study where DMT was administered by intravenous bolus dose to 13 healthy subjects. The effects on alpha power, beta power, and Lempel‐Ziv complexity were evaluated. DMT was shown to fully suppress alpha power. Beta power was only partially suppressed, whereas an increase in Lempel‐Ziv complexity was observed. The relationship between plasma concentrations and effects were described using effect compartment models with sigmoidal maximum inhibitory response or maximum stimulatory response models. Values of the concentration needed to reach half of the maximum response (EC50,e) were estimated at 71, 137, and 54 nM for alpha, beta, and Lempel‐Ziv complexity, respectively. A large amount of between‐subject variability was associated with both beta power and Lempel‐Ziv complexity with coefficients of variability of 75% and 77% for the corresponding EC50,e values, respectively. Alpha power appeared to be the most robust response, with a between‐subject variability in EC50,e of 29%. Having a deeper understanding of these processes might prove beneficial in choosing appropriate doses and response biomarkers in the future clinical development of DMT.
Abstract
N,N‐dimethyltryptamine (DMT) is a psychedelic compound that is being studied as a therapeutic option in various psychiatric disorders. Due to its short half‐life, continuous infusion of DMT ...has been proposed to extend the psychedelic experience and potential therapeutic effects. The primary aim of this work was to design an infusion protocol for DMT based on a desired level of psychedelic intensity using population pharmacokinetic/pharmacodynamic modeling. As a secondary aim, the impact of choosing a continuous variable or a bounded integer pharmacokinetic/pharmacodynamic model to inform such an infusion protocol was investigated. A previously published continuous variable model and two newly developed bounded integer models were used to assess optimal doses for achieving a target response. Simulations were performed to identify an optimal combination of a bolus dose and an infusion rate. Based on the simulations, optimal doses to achieve intensity ratings between 7 and 9 (possible range = 0–10) were a bolus dose of 16 mg DMT fumarate followed by an infusion rate of 1.4 mg/min based on the continuous variable model and 14 mg with 1.2 mg/min for the two bounded integer models. However, the proportion within target was low (<53%) for all models, indicating that individual dose adjustments would be necessary. Furthermore, some differences between the models were observed. The bounded integer models generally predicted lower proportions within a target of 7–9 with higher proportions exceeding target compared with the continuous variable model. However, results varied depending on target response with the major differences observed at the boundaries of the scale.
Therapeutic psychedelic administration and contact with nature have been associated with the same psychological mechanisms: decreased rumination and negative affect, enhanced psychological ...connectedness and mindfulness-related capacities, and heightened states of awe and transcendent experiences, all processes linked to improvements in mental health amongst clinical and healthy populations. Nature-based settings can have inherently psychologically soothing properties which may complement all stages of psychedelic therapy (mainly preparation and integration) whilst potentiating increases in nature relatedness, with associated psychological benefits. Maximising enhancement of nature relatedness through therapeutic psychedelic administration may constitute an independent and complementary pathway towards improvements in mental health that can be elicited by psychedelics.
Due to their potential impact on mood and wellbeing there has been increasing interest in the potential of serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) in the treatment of major ...depressive disorder (MDD).
The aim of Part A of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) profile of escalating doses of SPL026 (DMT fumarate) in psychedelic-naïve healthy participants to determine a dose for administration to patients with MDD in the subsequent Phase 2a part of the trial (Part B: not presented in this manuscript).
In the Phase 1, randomized, double-blind, placebo-controlled, parallel-group, single dose-escalation trial, psychedelic-naïve participants were randomized to placebo (
= 8) or four different escalating doses 9, 12, 17 and 21.5 mg intravenously (IV) of SPL026 (
= 6 for each dose) together with psychological support from 2 therapy team members. PK and acute (immediately following dosing experience) psychometric measures including mystical experience questionnaire (MEQ), ego dissolution inventory (EDI), and intensity rating visual analogue scale (IRVAS) were determined. Additional endpoints were measured as longer-term change from baseline to days 8, 15, 30 and 90. These measures included the Warwick and Edinburgh mental wellbeing scale and Spielberger's state-trait anxiety inventory.
SPL026 was well tolerated, with an acceptable safety profile, with no serious adverse events. There was some evidence of a correlation between maximum plasma concentration and increased IRVAS, MEQ, and EDI scores. These trends are likely to require confirmation in a larger sample size. Using the analysis of the safety, tolerability, PD, PK results, doses of 21.5 mg SPL026 were the most likely to provide an intense, tolerated experience.
Based on the data obtained from this part of the trial, a dose of 21.5 mg SPL026 given as a 2-phase IV infusion over 10 min (6 mg/5 min and 15.5 mg/5 min) was selected as the dose to be taken into patients in Part B (to be presented in a future manuscript).
www.clinicaltrials.gov, identifier NCT04673383; https://www.clinicaltrialsregister.eu, identifier 2020-000251-13; https://www.isrctn.com/, identifier ISRCTN63465876.
Many people who have had a near-death experience (NDE) describe, as part of it, a disturbed sense of having a “distinct self”. However, no empirical studies have been conducted to explore the ...frequency or intensity of these effects. We surveyed 100 NDE experiencers (Near-Death-Experience Content NDE-C scale total score ≥27/80). Eighty participants had their NDEs in life-threatening situations and 20 had theirs not related to life-threatening situations. Participants completed the Ego-Dissolution Inventory (EDI) and the Ego-Inflation Inventory (EII) to assess the experience of ego dissolution and inflation potentially experienced during their NDE, respectively. They also completed the Nature-Relatedness Scale (NR-6) which measures the trait-like construct of one’s self-identification with nature. Based on prior hypotheses, ratings of specific NDE-C items pertaining to out-of-body experiences and a sense of unity were used for correlational analyses. We found higher EDI total scores compared with EII total scores in our sample. Total scores of the NDE-C scale were positively correlated with EDI total scores and, although less strongly, the EII and NR-6 scores. EDI total scores were also positively correlated with the intensity of OBE and a sense of unity. This study suggests that the experience of dissolved ego-boundaries is a common feature of NDEs.
Psychedelic drugs show promise as safe and effective treatments for neuropsychiatric disorders, yet their mechanisms of action are not fully understood. A fundamental hypothesis is that psychedelics ...work by dose-dependently changing the functional hierarchy of brain dynamics, but it is unclear whether different psychedelics act similarly. Here, we investigated the changes in the brain’s functional hierarchy associated with two different psychedelics (LSD and psilocybin). Using a novel turbulence framework, we were able to determine the vorticity, that is, the local level of synchronization, that allowed us to extend the standard global time-based measure of metastability to become a local-based measure of both space and time. This framework produced detailed signatures of turbulence-based hierarchical change for each psychedelic drug, revealing consistent and discriminate effects on a higher level network, that is, the default mode network. Overall, our findings directly support a prior hypothesis that psychedelics modulate (i.e., “compress”) the functional hierarchy and provide a quantification of these changes for two different psychedelics. Implications for therapeutic applications of psychedelics are discussed.
Significant progress has been made in understanding the effects of psychedelics on brain function. One of the main hypotheses is that psychedelics work by changing the functional hierarchy of brain dynamics in a dose-dependent manner, modulating the encoding of the precision of priors, beliefs, or assumptions in the brain. We used a novel turbulence framework to investigate the changes in the brain’s functional hierarchy associated with two different psychedelics (LSD and psilocybin). This framework produced detailed signatures of turbulence-based hierarchical change for each psychedelic drug, revealing consistent and discriminate effects on a higher level network, that is, the default mode network.
A striking feature of psychedelics is their ability to increase attribution of truth and meaningfulness to specific contents and ideas experienced, which may persist long after psychedelic effects ...have subsided. We propose that processes underlying conferral of meaning and truth in psychedelic experiences may act as a double-edged sword: while these may drive important therapeutic benefits, they also raise important considerations regarding the validation and mediation of knowledge gained during these experiences. Specifically, the ability of psychedelics to induce noetic feelings of revelation may enhance the significance and attribution of reality to specific beliefs, worldviews, and apparent memories which might exacerbate the risk of iatrogenic complications that other psychotherapeutic approaches have historically faced, such as false memory syndrome. These considerations are timely, as the use of psychedelics is becoming increasingly mainstream, in an environment marked by the emergence of strong commercial interest for psychedelic therapy. We elaborate on these ethical challenges via three examples illustrating issues of validation and mediation in therapeutic, neo-shamanic and research contexts involving psychedelic use. Finally, we propose a pragmatic framework to attend to these challenges based on an ethical approach which considers the embeddedness of psychedelic experiences within larger historical and cultural contexts, their intersubjective character and the use of practices which we conceptualise here as forms of psychedelic apprenticeship. This notion of apprenticeship goes beyond current approaches of preparation and integration by stressing the central importance of validation practices based on empathic resonance by an experienced therapist or guide.
Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT - a fast-acting tryptamine psychedelic) offers a safe and powerful means ...of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced and neurophenomenological analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience - particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the subjective experience, thus advancing our understanding of the neurobiological underpinnings of immersive states of consciousness.
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