Christopher Timmermann

Responses to psychedelics are notoriously difficult to predict, yet significant work is currently underway to assess their therapeutic potential and the level of interest in psychedelics among the general public appears to be increasing. We aimed to collect prospective data in order to improve our ability to predict acute- and longer-term responses to psychedelics. Individuals who planned to take a psychedelic through their own initiative participated in an online survey (www.psychedelicsurvey.com). Traits and variables relating to set, setting and the acute psychedelic experience were measured at five different time points before and after the experience. Principle component and regression methods were used to analyse the data. Sample sizes for the five time points included N= 654, N= 535, N= 379, N= 315, and N= 212 respectively. Psychological well-being was increased two weeks after a psychedelic experience and remained at this level after four weeks. This increase was larger for individuals who scored higher for a ‘mystical-type experience’, and smaller for those who scored higher for ‘challenging experience’. Having ‘clear intentions’ for the experience was conducive to mystical-type experiences. Having a positive ‘set’, as well as having the experience with intentions related to ‘recreation’, were both found to decrease the likelihood of having a challenging experience. The trait ‘absorption’ and higher drug doses promoted both mystical-type and challenging experiences. When comparing different types of variables, traits variables seemed to explain most variance in the change in well-being after a psychedelic experience. These results confirm the importance of extra-pharmacological factors in determining responses to a psychedelic. We view this study as an early step towards the development of empirical guidelines that can evolve and improve iteratively with the ultimate purpose of guiding crucial clinical decisions about whether, when, where and how to dose with a psychedelic, thus helping to reduce risks while maximising potential benefits in an evidence-based manner.

Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck's depression inventory was the primary outcome measure ( MR/J00460X/1 ). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo ('psilocybin arm') or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) ('escitalopram arm'). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose ( NCT03429075 ). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin's antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.

Abstract 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.

Near-death experiences (NDEs) are complex subjective experiences, which have been previously associated with the psychedelic experience and more specifically with the experience induced by the potent serotonergic, N,N-Dimethyltryptamine (DMT). Potential similarities between both subjective states have been noted previously, including the subjective feeling of transcending one's body and entering an alternative realm, perceiving and communicating with sentient 'entities' and themes related to death and dying. In this within-subjects placebo-controled study we aimed to test the similarities between the DMT state and NDEs, by administering DMT and placebo to 13 healthy participants, who then completed a validated and widely used measure of NDEs. Results revealed significant increases in phenomenological features associated with the NDE, following DMT administration compared to placebo. Also, we found significant relationships between the NDE scores and DMT-induced ego-dissolution and mystical-type experiences, as well as a significant association between NDE scores and baseline trait 'absorption' and delusional ideation measured at baseline. Furthermore, we found a significant overlap in nearly all of the NDE phenomenological features when comparing DMT-induced NDEs with a matched group of 'actual' NDE experiencers. These results reveal a striking similarity between these states that warrants further investigation.

Abstract Can the use of psychedelic drugs induce lasting changes in metaphysical beliefs? While it is popularly believed that they can, this question has never been formally tested. Here we exploited a large sample derived from prospective online surveying to determine whether and how beliefs concerning the nature of reality, consciousness, and free-will, change after psychedelic use. Results revealed significant shifts away from ‘physicalist’ or ‘materialist’ views, and towards panpsychism and fatalism, post use. With the exception of fatalism, these changes endured for at least 6 months, and were positively correlated with the extent of past psychedelic-use and improved mental-health outcomes. Path modelling suggested that the belief-shifts were moderated by impressionability at baseline and mediated by perceived emotional synchrony with others during the psychedelic experience. The observed belief-shifts post-psychedelic-use were consolidated by data from an independent controlled clinical trial. Together, these findings imply that psychedelic-use may causally influence metaphysical beliefs—shifting them away from ‘hard materialism’. We discuss whether these apparent effects are contextually independent.

Psychedelics have attracted medical interest, but their effects on human brain function are incompletely understood. In a comprehensive, within-subjects, placebo-controlled design, we acquired multimodal neuroimaging [i.e., EEG-fMRI (electroencephalography-functional MRI)] data to assess the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT) on brain function in 20 healthy volunteers. Simultaneous EEG-fMRI was acquired prior to, during, and after a bolus IV administration of 20 mg DMT, and, separately, placebo. At dosages consistent with the present study, DMT, a serotonin 2A receptor (5-HT2AR) agonist, induces a deeply immersive and radically altered state of consciousness. DMT is thus a useful research tool for probing the neural correlates of conscious experience. Here, fMRI results revealed robust increases in global functional connectivity (GFC), network disintegration and desegregation, and a compression of the principal cortical gradient under DMT. GFC × subjective intensity maps correlated with independent positron emission tomography (PET)-derived 5-HT2AR maps, and both overlapped with meta-analytical data implying human-specific psychological functions. Changes in major EEG-measured neurophysiological properties correlated with specific changes in various fMRI metrics, enriching our understanding of the neural basis of DMT's effects. The present findings advance on previous work by confirming a predominant action of DMT-and likely other 5-HT2AR agonist psychedelics-on the brain's transmodal association pole, i.e., the neurodevelopmentally and evolutionarily recent cortex that is associated with species-specific psychological advancements, and high expression of 5-HT2A receptors.

Introduction: As their name suggests, ‘psychedelic’ (mind-revealing) compounds are thought to catalyse processes of psychological insight; however, few satisfactory scales exist to sample this. This study sought to develop a new scale to measure psychological insight after a psychedelic experience: the Psychological Insight Scale (PIS). Methods: The PIS is a six- to seven-item questionnaire that enquires about psychological insight after a psychedelic experience (PIS-6) and accompanied behavioural changes (PIS item 7). In total, 886 participants took part in a study in which the PIS and other questionnaires were completed in a prospective fashion in relation to a planned psychedelic experience. For validation purposes, data from 279 participants were analysed from a non-specific ‘global psychedelic survey’ study. Results: Principal components analysis of PIS scores revealed a principal component explaining 73.57% of the variance, which displayed high internal consistency at multiple timepoints throughout the study (average Cronbach’s α = 0.94). Criterion validity was confirmed using the global psychedelic survey study, and convergent validity was confirmed via the Therapeutic-Realizations Scale. Furthermore, PIS scores significantly mediated the relationship between emotional breakthrough and long-term well-being. Conclusion: The PIS is complementary to current subjective measures used in psychedelic studies, most of which are completed in relation to the acute experience. Insight – as measured by the PIS – was found to be a key mediator of long-term psychological outcomes following a psychedelic experience. Future research may investigate how insight varies throughout a psychedelic process, its underlying neurobiology and how it impacts behaviour and mental health.

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.

No contemporary unifying framework has been provided for the study of non-ordinary states of consciousness (NSCs) despite increased interest in hypnosis, meditation, and psychedelics. NSCs induce shifts in experiential contents (what appears to the experiencer) and/or structure (how it appears). This can allow the investigation of the plastic and dynamic nature of experience from a multiscale perspective that includes mind, brain, body, and context. We propose a neurophenomenological (NP) approach to the study of NSCs which highlights their role as catalysts of transformation in clinical practice by refining our understanding of the relationships between experiential (subjective) and neural dynamics. We outline the ethical implications of the NP approach for standard conceptions of health and pathology as well as the crucial role of experience-based know-how in NSC-related research and application.

Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes, such as personality changes. These findings are particularly intriguing, given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g., from wakefulness to sleep). However, little is known about how context impacts the entropy-enhancing effect of psychedelics, which carries important implications for how it can be exploited in, for example, psychedelic psychotherapy. This article investigates how brain entropy is modulated by stimulus manipulation during a psychedelic experience by studying participants under the effects of lysergic acid diethylamide (LSD) or placebo, either with gross state changes (eyes closed vs open) or different stimuli (no stimulus vs music vs video). Results show that while brain entropy increases with LSD under all of the experimental conditions, it exhibits the largest changes when subjects have their eyes closed. Furthermore, brain entropy changes are consistently associated with subjective ratings of the psychedelic experience, but this relationship is disrupted when participants are viewing a video─potentially due to a "competition" between external stimuli and endogenous LSD-induced imagery. Taken together, our findings provide strong quantitative evidence of the role of context in modulating neural dynamics during a psychedelic experience, underlining the importance of performing psychedelic psychotherapy in a suitable environment.

Healthful behaviours such as maintaining a balanced diet, being physically active and refraining from smoking have major impacts on the risk of developing cancer, diabetes, cardiovascular diseases and other serious conditions. The burden of the so-called 'lifestyle diseases'-in personal suffering, premature mortality and public health costs-is considerable. Consequently, interventions designed to promote healthy behaviours are increasingly being studied, e.g., using psychobiological models of behavioural regulation and change. In this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. Psilocybin has a low toxicity, is non-addictive and has been shown to predict favourable changes in patients with depression, anxiety and other conditions marked by rigid behavioural patterns, including substance (mis)use. While it is still early days for modern psychedelic science, research is advancing fast and results are promising. Here we describe psychedelics' proposed mechanisms of action and research findings pertinent to health behaviour change science, hoping to generate discussion and new research hypotheses linking the two areas. Therapeutic models including psychedelic experiences and common behaviour change methods (e.g., Cognitive Behaviour Therapy, Motivational Interviewing) are already being tested for addiction and eating disorders. We believe this research may soon be extended to help promote improved diet, exercise, nature exposure and also mindfulness or stress reduction practices, all of which can contribute to physical and psychological health and well-being.

A general feeling of disconnection has been associated with mental and emotional suffering. Improvements to a sense of connectedness to self, others and the wider world have been reported by participants in clinical trials of psychedelic therapy. Such accounts have led us to a definition of the psychological construct of 'connectedness' as 'a state of feeling connected to self, others and the wider world'. Existing tools for measuring connectedness have focused on particular aspects of connectedness, such as 'social connectedness' or 'nature connectedness', which we hypothesise to be different expressions of a common factor of connectedness. Here, we sought to develop a new scale to measure connectedness as a construct with these multiple domains. We hypothesised that (1) our scale would measure three separable subscale factors pertaining to a felt connection to 'self', 'others' and 'world' and (2) improvements in total and subscale WCS scores would correlate with improved mental health outcomes post psychedelic use.To validate and test the 'Watts Connectedness Scale' (WCS).Psychometric validation of the WCS was carried out using data from three independent studies. Firstly, we pooled data from two prospective observational online survey studies. The WCS was completed before and after a planned psychedelic experience. The total sample of completers from the online surveys was N = 1226. Exploratory and confirmatory factor analysis were performed, and construct and criterion validity were tested. A third dataset was derived from a double-blind randomised controlled trial (RCT) comparing psilocybin-assisted therapy (n = 27) with 6 weeks of daily escitalopram (n = 25) for major depressive disorder (MDD), where the WCS was completed at baseline and at a 6-week primary endpoint.As hypothesised, factor analysis of all WCS items revealed three main factors with good internal consistency. WCS showed good construct validity. Significant post-psychedelic increases were observed for total connectedness scores (η2 = 0.339, p < 0.0001), as well as on each of its subscales (p < 0.0001). Acute measures of 'mystical experience', 'emotional breakthrough', and 'communitas' correlated positively with post-psychedelic changes in connectedness (r = 0.42, r = 0.38, r = 0.42, respectively, p < 0.0001). In the RCT, psilocybin therapy was associated with greater increases in WCS scores compared with the escitalopram arm (ηp2 = 0.133, p = 0.009).The WCS is a new 3-dimensional index of felt connectedness that may sensitively measure therapeutically relevant psychological changes post-psychedelic use. We believe that the operational definition of connectedness captured by the WCS may have broad relevance in mental health research.

Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents-lysergic acid diethylamide, psilocybin, and ayahuasca-modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics.

To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain's rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically induced macroscale functional reorganization, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from positron emission tomography, and the regional changes in functional magnetic resonance imaging connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, lysergic acid diethylamide (LSD), psilocybin, N,N-Dimethyltryptamine (DMT), ayahuasca, 3,4-methylenedioxymethamphetamine (MDMA), modafinil, and methylphenidate. Our results reveal a many-to-many mapping between psychoactive drugs' effects on brain function and multiple neurotransmitter systems. The effects of both anesthetics and psychedelics on brain function are organized along hierarchical gradients of brain structure and function. Last, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganization of the brain's functional architecture.

Psychedelic drugs are potent modulators of conscious states and therefore powerful tools for investigating their neurobiology. N,N, Dimethyltryptamine (DMT) can rapidly induce an extremely immersive state of consciousness characterized by vivid and elaborate visual imagery. Here, we investigated the electrophysiological correlates of the DMT-induced altered state from a pool of participants receiving DMT and (separately) placebo (saline) while instructed to keep their eyes closed. Consistent with our hypotheses, results revealed a spatio-temporal pattern of cortical activation (i.e. travelling waves) similar to that elicited by visual stimulation. Moreover, the typical top-down alpha-band rhythms of closed-eyes rest were significantly decreased, while the bottom-up forward wave was significantly increased. These results support a recent model proposing that psychedelics reduce the ‘precision-weighting of priors’, thus altering the balance of top-down versus bottom-up information passing. The robust hypothesis-confirming nature of these findings imply the discovery of an important mechanistic principle underpinning psychedelic-induced altered states.

N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date have addressed the neural and psychological effects of N,N-dimethyltryptamine alone, either administered intravenously or inhaled in freebase form, and none have been conducted in natural settings.Our primary aim was to study the acute effects of inhaled N,N-dimethyltryptamine in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (i.e. "set" and "setting"), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming N,N-dimethyltryptamine in familiar and comfortable settings.We combined state-of-the-art wireless electroencephalography with psychometric questionnaires to study the neural and subjective effects of naturalistic N,N-dimethyltryptamine use in 35 healthy and experienced participants.We observed that N,N-dimethyltryptamine significantly decreased the power of alpha (8-12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1-4 Hz) and gamma (30-40 Hz) oscillations. Gamma power increases correlated with subjective reports indicative of some features of mystical-type experiences. N,N-dimethyltryptamine also increased global synchrony and metastability in the gamma band while decreasing those measures in the alpha band.Our results are consistent with previous studies of psychedelic action in the human brain, while at the same time the results suggest potential electroencephalography markers of mystical-type experiences in natural settings, thus highlighting the importance of investigating these compounds in the contexts where they are naturally consumed.

Mescaline is a naturally occurring psychoactive phenethylamine found in several cacti and historically used ceremonially by Indigenous and Latin American populations. Broader recognition of its possible therapeutic value in Western science began in the 1950s; however, knowledge of the safety profile of mescaline and the extent of its use remains limited. The primary aim of this study is to examine the epidemiology of mescaline use among English-speaking adults.About 452 respondents completed a web-based survey designed to assess their previous experience with mescaline (subjective effects, outcome measures, and mescaline type used).Most respondents reported that they had consumed mescaline infrequently (⩽once/year), for spiritual exploration or to connect with nature (74%). A small number of respondents reported drug craving/desire (9%), whereas very few reported legal (1%), or psychological problems (1%) related to its use, and none reported seeking any medical attention. Overall, respondents rated the acute mystical-type effects as "moderate," ego-dissolution and psychological insight effects as "slight," and challenging effects as "very slight." Most respondents reported that they used Peyote and San Pedro in their most memorable mescaline experience. Overall, the intensity of acute mescaline effects did not differ between mescaline types. About 50% of the sample reported having a psychiatric condition (i.e. depression, anxiety, etc.), and most (>67%) reported improvements in these conditions following their most memorable experience with mescaline.Findings indicate that the mescaline in any form may produce a psychedelic experience that is associated with the spiritual significance and improvements in the mental health with low potential for abuse.

Understanding the phenomenology and content of the inhaled N, N, dimethyltryptamine (N, N-DMT) experience is critical to facilitate and support ongoing research and therapeutic models targeting mental health conditions and central nervous system pathology. A qualitative analysis was conducted of all N, N-DMT experiences posted to the r/DMT Reddit community over a 10-year period from 2009 to 2018. A total of 3778 experiences from 3305 posts were included in this study. A median dose of N, N-DMT of 40.0 mg [interquartile range (IQR), 27.5 to 50.0] and a median experience duration of 10 min (IQR, 5.0 to 15.0) were identified. The most common somatic effects were somaesthesias (n = 1415, 37.5%) and an auditory ringing (n = 583, 15.4%). Visualizations predominantly consisted of fractals, shapes, patterns (n = 1231, 32.6%) and vivid colours (n = 953, 25.2%). Entity encounters were reported in 45.5% (n = 1719) of the experiences and involved predominantly a feminine phenotype (n = 416, 24.2%); deities (n = 293, 17.0%); aliens (n = 281, 16.3%); creature-based entities (n = 158, 9.2%, including reptilian and insectoid beings); mythological beings (n = 144, 8.4%, including machine elves); and jesters (n = 112, 6.5%). Entity interactions were predominantly positive (n = 600, 34.9% of encounters) involving benevolent, comforting, protecting, or outwardly caring interactions. A companion-type, pedagogical, or guide-type interaction was identified 32.4% of encounters (n = 557). Common typology, architecture, and structural features of the "DMT world" included descriptions of alternate or higher dimensions (n = 952, 25.2%); rooms [n = 582, 15.4%, including the "waiting room" (n = 105, 2.8%)], and a tunnel (n = 390, 10.3%). Features of mystical and ego-dissolution experiences were common. Additional rewarding aspects were identified, including a sense of familiarity and the acceptance/removal of the fear of death. Challenging and difficult responses were less frequent but also documented. Statements of profundity were identified in 232 experiences (6.1%), including pronouncing the experience or an aspect of the experience as the most "beautiful" or feeling the most "beautiful" of their life (n = 47, 1.2%). This study identified common phenomenological themes and content of naturalistic inhaled N, N-DMT experiences. Major thematic domains included (1) physical and somatic experiences; (2) visualizations and imagery; (3) entity encounters including entity phenotype, descriptors, attributes, disposition, and characteristics of the interaction; (4) typology, architectural features, structural characteristics, and scenery of the "DMT world"; (5) alerations in consciousness (including mystical experiences, out-of-body experiences, and ego-dissolution); (6) emotional responses (including positive, rewarding, difficult, and challenging); and (7) statements of profundity.

Abstract 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 (EC 50,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 EC 50,e values, respectively. Alpha power appeared to be the most robust response, with a between‐subject variability in EC 50,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.

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 (n = 8) or four different escalating doses [9, 12, 17 and 21.5 mg intravenously (IV)] of SPL026 (n = 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).Clinical trial registration:www.clinicaltrials.gov, identifier NCT04673383; https://www.clinicaltrialsregister.eu, identifier 2020-000251-13; https://www.isrctn.com/, identifier ISRCTN63465876.

Abstract Psilocybin, a serotonergic psychedelic, is being increasingly researched in clinical studies for the treatment of psychiatric disorders. The relatively lengthy duration of oral psilocybin’s acute effects (4–6 h) may have pragmatic and cost-effectiveness limitations. Here, we explored the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT), a closely related, but faster-acting psychedelic intervention, on mental health outcomes in healthy volunteers. Data is reported from two separate analyses: (1) A comparison of mental health-related variables 1 week after 7, 14, 18, and 20 mg of IV DMT versus IV saline placebo (n = 13) and, (2) A prospective dataset assessing effects before versus 2 weeks after 20 mg of IV DMT (n = 17). Mental health outcomes included measures of depression severity (QIDS-SR16), trait anxiety (STAI-T), Neuroticism (NEO-FFI), wellbeing (WHO-5), meaning in life (MLQ), optimism (LOT-R), and gratitude (GQ-6). In both the prospective and placebo-controlled datasets, significant improvements in scores of depression were found 1–2 weeks after DMT administration. Significant reductions in trait Neuroticism were only found for the placebo-controlled sample. Finally, changes in depression and trait anxiety correlated with acute peak experiences (assessed via ‘Oceanic Boundlessness’). While the use of two separate cohorts in pooled analysis limits the generalizability of these correlational findings, these results suggest that DMT may reduce depressive symptomatology by inducing peak experiences. The short half-life of IV DMT and its potential for flexible dosing via controlled infusions makes it an appealing candidate for psychedelic medicine. Further research in clinical samples is needed to corroborate the therapeutic potential of DMT.

Under the predictive coding framework, perceptual learning and inference are dependent on the interaction between top-down predictions and bottom-up sensory signals both between and within regions in a network. However, how such feedback and feedforward connections are modulated in the state induced by lysergic acid diethylamide (LSD) is poorly understood. In this study, an auditory oddball paradigm was presented to healthy participants (16 males, 4 female) under LSD and placebo, and brain activity was recorded using magnetoencephalography (MEG). Scalp level Event Related Fields (ERF) revealed reduced neural adaptation to familiar stimuli, and a blunted neural ‘surprise’ response to novel stimuli in the LSD condition. Dynamic causal modelling revealed that both the presentation of novel stimuli and LSD modulate backward extrinsic connectivity within a task-activated fronto-temporal network, as well as intrinsic connectivity in the primary auditory cortex. These findings show consistencies with those of previous studies of schizophrenia and ketamine but also studies of reduced consciousness – suggesting that rather than being a marker of conscious level per se, backward connectivity may index modulations of perceptual learning common to a variety of altered states of consciousness, perhaps united by a shared altered sensitivity to environmental stimuli. Since recent evidence suggests that the psychedelic state may correspond to a heightened ‘level’ of consciousness with respect to the normal waking state, our data warrant a re-examination of the top-down hypotheses of conscious level and suggest that several altered states may feature this specific biophysical effector. This article is part of the Special Issue entitled ‘Psychedelics: New Doors, Altered Perceptions’.

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.

Psychedelics offer a profound window into the functioning of the human brain and mind through their robust acute effects on perception, subjective experience, and brain activity patterns. In recent work using a receptor-informed network control theory framework, we demonstrated that the serotonergic psychedelics lysergic acid diethylamide (LSD) and psilocybin flatten the brain's control energy landscape in a manner that covaries with more dynamic and entropic brain activity. Contrary to LSD and psilocybin, whose effects last for hours, the serotonergic psychedelic N,N-dimethyltryptamine (DMT) rapidly induces a profoundly immersive altered state of consciousness lasting less than 20 minutes, allowing for the entirety of the drug experience to be captured during a single resting-state fMRI scan. Using network control theory, which quantifies the amount of input necessary to drive transitions between functional brain states, we integrate brain structure and function to map the energy trajectories of 14 individuals undergoing fMRI during DMT and placebo. Consistent with previous work, we find that global control energy is reduced following injection with DMT compared to placebo. We additionally show longitudinal trajectories of global control energy correlate with longitudinal trajectories of EEG signal diversity (a measure of entropy) and subjective ratings of drug intensity. We interrogate these same relationships on a regional level and find that the spatial patterns of DMT's effects on these metrics are correlated with serotonin 2a receptor density (obtained from separately acquired PET data). Using receptor distribution and pharmacokinetic information, we were able to successfully recapitulate the effects of DMT on global control energy trajectories, demonstrating a proof-of-concept for the use of control models in predicting pharmacological intervention effects on brain dynamics.

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic that induces a rapid and transient altered state of consciousness when inhaled or injected via bolus administration. Its marked and novel subjective effects make DMT a powerful tool for the neuroscientific study of consciousness and preliminary results show its potential role in treating mental health conditions. In a within-subjects, placebo-controlled study, we investigated a novel method of DMT administration involving a bolus injection paired with a constant-rate infusion, with the goal of extending the DMT experience. Pharmacokinetic parameters of DMT estimated from plasma data of a previous study of bolus intravenous DMT were used to derive dose regimens necessary to keep subjects in steady levels of immersion into the DMT experience over an extended period of 30 min, and four dose regimens consisting of a bolus loading dose and a slow-rate infusion were tested in eleven healthy volunteers (seven male, four female, mean age ± SD = 37.09 ± 8.93 years). The present method is effective for extending the DMT experience in a stable and tolerable fashion. While subjective effects were maintained over the period of active infusion, anxiety ratings remained low and heart rate habituated within 15 min, indicating psychological and physiological safety of extended DMT. Plasma DMT concentrations increased consistently starting 10 min into DMT administration, whereas psychological effects plateaued into the desired steady state, suggesting the development of acute psychological tolerance to DMT. Taken together, these findings demonstrate the safety and effectiveness of continuous IV DMT administration, laying the groundwork for the further development of this method of administration for basic and clinical research.

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.

The medial prefrontal cortex (mPFC) and ACC have been consistently implicated in learning predictions of future outcomes and signaling prediction errors (i.e., unexpected deviations from such predictions). A computational model of ACC/mPFC posits that these prediction errors should be modulated by outcomes occurring at unexpected times, even if the outcomes themselves are predicted. However, unexpectedness per se is not the only variable that modulates ACC/mPFC activity, as studies reported its sensitivity to the salience of outcomes. In this study, mediofrontal negativity, a component of the event-related brain potential generated in ACC/mPFC and coding for prediction errors, was measured in 48 participants performing a Pavlovian aversive conditioning task, during which aversive (thus salient) and neutral outcomes were unexpectedly shifted (i.e., anticipated or delayed) in time. Mediofrontal ERP signals of prediction error were observed for outcomes occurring at unexpected times but were specific for salient (shock-associated), as compared with neutral, outcomes. These findings have important implications for the theoretical accounts of ACC/mPFC and suggest a critical role of timing and salience information in prediction error signaling.

Abstract 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.

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.

A highly sensitive LC-MS/MS method for the quantification of N,N-dimethyltryptamine (DMT) and its metabolites indole-3-acetic acid and DMT N-oxide in human plasma has been developed and validated. Chromatography was performed using a diphenyl column with gradient elution (0.1% formic acid in methanol/water). The mass spectrometer was operated in multiple reaction monitoring mode. A methanolic solution containing internal standards 2-methylindole 3-acetic acid and deuterated DMT, was added to plasma samples, followed by protein precipitation with acetonitrile. The samples were centrifuged and supernatants transferred to new tubes and evaporated to dryness before reconstitution in aqueous mobile phase. The method was validated with regards to accuracy, precision, sensitivity, selectivity, recovery, matrix effects, stability, carry-over and dilution integrity. The validated linear range was 0.25-200 nM for DMT and 15-250 nM for DMT N-oxide. For the endogenous compound indole-3-acetic acid a different approach was taken due to its significant presence in blank samples. The change in signal response from a blank sample was used when constructing the calibration curve with linearity demonstrated between elevations of 500-5000 nM above the blank. Applicability of the described method was demonstrated through analysis of plasma samples from healthy volunteers having received intravenous injections of DMT. The presented method for rapid and sensitive quantification of DMT and its metabolites in human plasma can be applied to future studies aiming to characterize DMT disposition and its relationship to immediate psychedelic or long-term antidepressive effects.

Background: N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic that when injected as a bolus intravenous injection induces a rapid and transient altered state of consciousness. Its marked and novel subjective effects make DMT a powerful tool for the neuroscientific study of consciousness and preliminary results show its potential role in treating mental health conditions. Aims: In a within-subjects, placebo-controlled study, we investigated a novel method of DMT administration involving a bolus injection paired with a constant-rate infusion, with the goal of extending the DMT experience. Methods: Pharmacokinetic parameters of DMT estimated from plasma data of a previous study of bolus intravenous DMT were used to derive dose regimens necessary to keep subjects in steady levels of immersion into the DMT experience over an extended period of 30 minutes, and four dose regimens were tested. Results: The present method is effective for extending the DMT experience in a stable and tolerable fashion. While subjective effects were maintained over the period of active infusion, anxiety ratings remained low and heart rate habituated within 15 minutes, indicating psychological and physiological safety of extended DMT. Plasma DMT concentrations increased consistently starting ten minutes into DMT administration, whereas psychological effects plateaued into the desired steady state, suggesting the development of acute psychological tolerance to DMT. Conclusion: Taken together, these findings demonstrate the safety and effectiveness of continuous IV DMT administration, laying the groundwork for the further development of this method of administration for basic and clinical research.

Abstract The human brain is a complex system, whose activity exhibits flexible and continuous reorganisation across space and time. The decomposition of whole-brain recordings into harmonic modes has revealed a repertoire of gradient-like activity patterns associated with distinct brain functions. However, the way these activity patterns are expressed over time with their changes in various brain states remains unclear. In this study, we develop the Harmonic Decomposition of Spacetime (HADES) framework that characterises how different harmonic modes defined in space are expressed over time , and, as a proof-of-principle, demonstrate the sensitivity and robustness of this approach to specific changes induced by the serotonergic psychedelic N,N-Dimethyltryptamine (DMT) in healthy participants. HADES demonstrates significant decreases in contributions across most low-frequency harmonic modes in the DMT-induced brain state. When normalizing the contributions by condition (DMT and non-DMT), we detect a decrease specifically in the second functional harmonic, which represents the uni- to transmodal functional hierarchy of the brain, supporting the hypothesis that functional hierarchy is changed in psychedelics. Moreover, HADES’ dynamic spacetime measures of fractional occupancy, life time and latent space provide a precise description of the significant changes of the spacetime hierarchical organization of brain activity in the psychedelic state.

Non-ordinary states of consciousness induced by psychedelics can be accompanied by so-called peak experiences, characterized at the emotional level by their intensity and positive valence. These experiences are strong predictors of positive outcomes following psychedelic-assisted therapy, and it is therefore important to better understand their biology. Despite growing evidence that the autonomic nervous system (ANS) plays an important role in mediating emotional experiences, its involvement in the psychedelic experience is poorly understood. The aim of this study was to investigate to what extant changes in the relative influence of the sympathetic (SNS) and parasympathetic nervous systems (PNS) over cardiac activity may reflect the subjective experience induced by the short-acting psychedelic N,N-Dimethyltryptamine (DMT). We derived measures of SNS and PNS activity from the electrocardiogram data of 17 participants (11 males, 6 females, mean age = 33.8 y, SD = 8.3) while they received either DMT or placebo. Results show that the joint influence of SNS and PNS (sympatho-vagal coactivation) over cardiac activity was robustly correlated with participants ratings of Spiritual Experience and Insightfulness during the DMT experience, while also being related to improved wellbeing scores two weeks after the session. In addition, we found that the state of balance between the two ANS branches (sympatho-vagal balance) before DMT injection predicted scores of Insightfulness during the DMT experience. These findings demonstrate the important involvement of the ANS in psychedelic-induced peak experiences and have the potential to lead to the development of biofeedback-based tools to enhance psychedelic-therapy.

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 of 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.

Abstract The transition towards the brain state induced by psychedelic drugs is frequently neglected in favor of a static description of their acute effects. We used a time-dependent whole-brain model to reproduce large-scale brain dynamics measured with fMRI from 15 volunteers under 20 mg intravenous N,N-Dimethyltryptamine (DMT), a short-acting psychedelic. To capture its transient effects, we parametrized the proximity to a global bifurcation using a pharmacokinetic equation. Simulated perturbations revealed a transient of heightened reactivity concentrated in fronto-parietal regions and visual cortices, correlated with serotonin 5HT2a receptor density, the primary target of psychedelics. These advances suggest a mechanism to explain key features of the psychedelic state and also predicts that the temporal evolution of these features aligns with pharmacokinetics. Our results contribute to understanding how psychedelics introduce a transient where minimal perturbations can achieve a maximal effect, shedding light on how short psychedelic episodes may extend an overarching influence over time.

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic, known to rapidly induce short-lasting alterations in conscious experience, characterized by a profound and immersive sense of physical transcendence alongside rich and vivid auditory distortions and visual imagery. Multimodal neuroimaging data paired with dynamic analysis techniques offer a valuable approach for identifying unique signatures of brain activity - and linked autonomic physiology - naturally unfolding during the altered state of consciousness induced by DMT. We leveraged simultaneous fMRI and EKG data acquired in 14 healthy volunteers prior to, during, and after intravenous administration of DMT, and, separately, placebo. EKG data was used to derive continuous heart rate; fMRI data was preprocessed to derive individual dynamic activity matrices, reflecting the similarity of brain activity in time, and community detection algorithms were applied on these matrices to identify brain activity substates. We identified a brain substate occurring immediately after DMT injection, characterized by increased superior temporal lobe activity, and hippocampal and medial parietal deactivations under DMT. Superior temporal lobe hyperactivity correlated with the intensity of the auditory distortions, while hippocampus and medial parietal cortex hypoactivity correlated with scores of meaningfulness of the experience. During this first post-injection substate, increased heart rate under DMT correlated negatively with the meaningfulness of the experience and positively with hippocampus/medial parietal deactivation. These results suggest a chain of influence linking sympathetic regulation to hippocampal and medial parietal deactivations under DMT, which combined may contribute to positive mental health outcomes related to self-referential processing following psychedelic administration.

Abstract The human brain is a complex system, whose activity exhibits flexible and continuous reorganisation across space and time. The decomposition of whole-brain recordings into harmonic modes has revealed a repertoire of gradient-like activity patterns associated with distinct brain functions. However, the way these activity patterns are expressed over time with their changes in various brain states remains unclear. Here, we investigate healthy participants taking the serotonergic psychedelic N, N-Dimethyltryptamine (DMT) with the Harmonic Decomposition of Spacetime (HADES) framework that can characterise how different harmonic modes defined in space are expressed over time. HADES demonstrates significant decreases in contributions across most low-frequency harmonic modes in the DMT-induced brain state. When normalizing the contributions by condition (DMT and non-DMT), we detect a decrease specifically in the second functional harmonic, which represents the uni- to transmodal functional hierarchy of the brain, supporting the leading hypothesis that functional hierarchy is changed in psychedelics. Moreover, HADES’ dynamic spacetime measures of fractional occupancy, life time and latent space provide a precise description of the significant changes of the spacetime hierarchical organization of brain activity in the psychedelic state.

Background: Reference to an intrinsic healing mechanism or an ‘inner healer’ is commonplace amongst psychedelic drug-using cultures. The ‘inner healer’ refers to the belief that psychedelic compounds, plants or concoctions have an intrinsically regenerative action on the mind and brain, analogous to intrinsic healing mechanisms within the physical body, for example, after sickness or injury. Aims: Here, we sought to test and critique this idea by devising a single subjective rating item pertaining to perceived ‘inner healing’ effects. Methods: The item was issued to 59 patients after a single high (25 mg, n = 30) or ‘placebo’ (1 mg, n = 29) dose of psilocybin in a double-blind randomised controlled trial of psilocybin for depression. Results: Inner healer scores were higher after the high versus placebo dose of psilocybin ( t = 3.88, p &lt; 0.001). Within the high-dose sub-sample only, inner healer scores predicted improved depressive symptomatology at 2 weeks post-dosing. Conclusions: The principle of activating inner healing mechanisms via psychedelics is scientifically nascent; however, this study takes a positivist and pragmatic step forward, asking whether it warrants further examination.

Psychedelics are recognised for their therapeutic potential and ability to re-orient beliefs. However, the prospect that psychedelics can induce false or maladaptive beliefs has been under- considered. Here, we review experimental work on false insights and false memories. We then connect this to insights and belief formation under psychedelics using active inference. We propose that the acute plasticity associated with psychedelics increases the quantity and precision of insights and thence beliefs, including false ones. We offer directions for future research in minimising epistemic harm during psychedelics. Ultimately, knowing how psychedelics solicit false insights and beliefs is crucial if we are to optimally leverage their therapeutic potential.

Schizophrenia and states induced by certain psychotomimetic drugs may share some physiological and phenomenological properties, but they differ in fundamental ways: one is a crippling chronic mental disease, while the others are temporary, pharmacologically-induced states presently being explored as treatments for mental illnesses. Building towards a deeper understanding of these different alterations of normal consciousness, here we compare the changes in neural dynamics induced by LSD and ketamine (in healthy volunteers) against those associated with schizophrenia, as observed in resting-state M/EEG recordings. While both conditions exhibit increased neural signal diversity, our findings reveal that this is accompanied by an increased transfer entropy from the front to the back of the brain in schizophrenia, versus an overall reduction under the two drugs. Furthermore, we show that these effects can be reproduced via different alterations of standard Bayesian inference applied on a computational model based on the predictive processing framework. In particular, the effects observed under the drugs are modelled as a reduction of the precision of the priors, while the effects of schizophrenia correspond to an increased precision of sensory information. These findings shed new light on the similarities and differences between schizophrenia and two psychotomimetic drug states, and have potential implications for the study of consciousness and future mental health treatments.

Are psychedelics able to induce lasting changes in metaphysical beliefs? While it is popularly believed that they can, this has never been systematically tested. Here we exploited a large sample derived from prospective online surveying to determine whether and how beliefs concerning the nature of reality, consciousness, and free-will, change after psychedelic use. Results revealed significant shifts away from ‘physicalist’ or ‘materialist’ views, and towards panpsychism and fatalism, post use. These changes remained detectable at 6 months, and were associated with the extent of past use and improved mental-health outcomes. Path modelling suggested that the belief-shifts were moderated by impressionability at baseline and mediated by perceived emotional synchrony with others during the psychedelic experience. The observed belief-shifts post psychedelic use were confirmed by data from an independent controlled clinical trial. Together, these findings imply that psychedelic use has a causal influence on metaphysical beliefs – shifting them away from ‘hard materialism’.

The capability of donor-substituted alkynes to link different metal ions in a side-on carbon donor-chelate coordination mode is extended from the donor centers S and P to the second period element N. The complex [Tp'W(CO)2 {η(2) -C2 (S)(NHBn)}] (Tp'=hydrido-tris(3,5-dimethylpyrazolyl)borate, Bn=benzyl) bearing a terminal sulfur atom and a secondary amine substituent is accessible by a metal-template synthesis. Subsequent deprotonation allowed the formation of remarkably stable heterobimetallic complexes with the [(η(5) -C5 H5 )Ru(PPh3 )] and the [Ir(ppy)2 ] moiety. Electrochemical and spectroscopic investigations (cyclic voltammetry, IR, UV/Vis, luminescence, EPR), as well as DFT calculations, and X-ray structure determinations of the W-Ru complex in two oxidation states reveal a strong metal-metal coupling but also a limited delocalization of excited states.

Abstract Background N,N-Dimethyltryptamine (DMT) is a short acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date addressed the neural and psychological effects of DMT alone, either administered intravenously or inhaled in freebase form, and none conducted in natural settings. Aims Our primary aim was to study the acute effects of inhaled DMT in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (i.e. “set” and “setting”), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming DMT in familiar and comfortable settings. Methods We combined state-of-the-art wireless electroencephalography (EEG) with psychometric questionnaires to study the neural and subjective effects of naturalistic DMT use in 35 healthy and experienced participants. Results We observed that DMT significantly decreased the power of alpha (8-12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1-4 Hz) and gamma (30-40 Hz) oscillations. Gamma power increases correlated with subjective reports indicative of mystical-type experiences. DMT also increased/decreased global synchrony and metastability in the gamma/alpha band, and resulted in widespread increases in signal complexity. Conclusions Our results are consistent with previous studies of psychedelic action in the human brain, while at the same time suggesting potential EEG markers of mystical-type experiences in natural settings, thus highlighting the importance of investigating these compounds in the contexts where they are naturally consumed.

The regulatory role of the serotonergic system on conscious perception can be investigated perturbatorily with psychedelic drugs such as N,N-Dimethyltryptamine. There is increasing evidence that the serotonergic system gates prior (endogenous) and sensory (exogenous) information in the construction of a conscious experience. Using two generative deep neural networks as examples, we discuss how such models have the potential to be, firstly, an important medium to illustrate phenomenological visual effects of psychedelics-besides paintings, verbal reports and psychometric testing-and, secondly, their utility to conceptualize biological mechanisms of gating the influence of exogenous and endogenous information on visual perception.

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.

Integrating independent but converging lines of research on brain function and neurodevelopment across scales, this article proposes that serotonin 2A receptor (5-HT2AR) signalling is an evolutionary and developmental driver and potent modulator of the macroscale functional organization of the human cerebral cortex. A wealth of evidence indicates that the anatomical and functional organization of the cortex follows a unimodal-to-transmodal gradient. Situated at the apex of this processing hierarchy-where it plays a central role in the integrative processes underpinning complex, human-defining cognition-the transmodal cortex has disproportionately expanded across human development and evolution. Notably, the adult human transmodal cortex is especially rich in 5-HT2AR expression and recent evidence suggests that, during early brain development, 5-HT2AR signalling on neural progenitor cells stimulates their proliferation-a critical process for evolutionarily-relevant cortical expansion. Drawing on multimodal neuroimaging and cross-species investigations, we argue that, by contributing to the expansion of the human cortex and being prevalent at the apex of its hierarchy in the adult brain, 5-HT2AR signalling plays a major role in both human cortical expansion and functioning. Owing to its unique excitatory and downstream cellular effects, neuronal 5-HT2AR agonism promotes neuroplasticity, learning and cognitive and psychological flexibility in a context-(hyper)sensitive manner with therapeutic potential. Overall, we delineate a dual role of 5-HT2ARs in enabling both the expansion and modulation of the human transmodal cortex.

A growing body of work shows that autonomic signals provide a privileged evidence-stream to capture various aspects of subjective and neural states. This work investigates the potential for autonomic markers to track the effects of psychedelics — potent psychoactive drugs with important scientific and clinical value. For this purpose, we introduce a novel Bayesian framework to estimate the entropy of heart rate dynamics under psychedelics. We also calculate Bayesian estimates of mean heart rate and heart rate variability, and investigate how these measures relate to subjective reports and neural effects. Results on datasets covering four drugs — lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), psilocybin, and sub-anaesthetic doses of the dissociative agent ketamine — show consistent increases in mean heart rate, high-frequency heart rate variability, and heart rate entropy during the psychedelic experience. Moreover, these effects have predictive power over various dimensions of the psychedelic experience. Changes in heart rate entropy were found to be correlated with increases in brain entropy, while other autonomic markers were not. Overall, our results show that a cost-efficient autonomic measure has the potential to reveal surprising detail about subjective and brain states, opening up a range of new research avenues to explore in both basic and clinical neuroscience.

The article The hidden therapist: evidence for a central role of music in psychedelic therapy, written by Mendel Kaelen, Bruna Giribaldi, Jordan Raine, Lisa Evans, Christopher Timmerman, Natalie Rodriguez, Leor Roseman, Amanda Feilding, David Nutt, Robin Carhart-Harris, was originally published electronically on the publisher's internet portal.

Recently, alkyne complexes with terminal thiolate/amide substitution have been shown to act as S,N-chelate ligands in dinuclear complexes. In this study, the detailed synthesis and reactivity of W(II) alkyne complexes bearing different amino groups in the α-position are reported. The preparative scheme starts with cationic alkyne complexes [Tp′W(CO)2-η2-C,C′-C2Br(SR)]PF6 {Tp′ = hydridotris(3,5-dimethylpyrazolyl)borate, R = benzyl (Bn), C2H4SiMe3}, which are obtained by applying free bromo alkynes. Subsequent nucleophilic substitution of the bromine substituent led to unsymmetrical substituted alkyne complexes [Tp′W(CO)2-η2-C,C′-C2(SR)(NHBn)]PF6 with S,N substitution in the α position of the coordinated alkyne. Depending on the base used, deprotonation of the secondary amine resulted in either neutral iminoketenyl complexes [Tp′W(CO)2-η2-C,C′-C2(SR)(NBn)] or a zwitterionic PF5 adduct. Reductive removal of the benzyl protective group was primarily observed at the imine substituent, causing a side-on/end-on rearrangement to the cyanide substituted carbene complex K[Tp′W(CO)2-η1-C(CN)(SBn)]. The reversibility of the rearrangement was proven with HBF4/Et2O, because double protonation led to [Tp′W(CO)2-η2-C,C′-C2(SR)(NH2)]BF4 exhibiting an unprecedented primary amine substitution at the coordinated alkyne. The reaction sequence starting with the thiol SC2H4SiMe3 derivative leading to the desired [Tp′W(CO)2-η2-C,C′-C2S(NHBn)] with a terminal S atom as well as the bonding situation in those complexes is discussed based on full spectroscopic characterization including X-ray structure analyses. Finally, a trinuclear complex assembled by homoleptic coordination of Pd(II) by two anionic S,N-chelates [Tp′W(CO)2-η2-C,C′-C2S(NBn)]− is presented.

The prototype ketenyl ligand is bound end-on despite a formal 16 valence electron count at the metal. This situation opens a reaction pathway for a multicomponent cyclization centred on the migration of the ketenyl ligand.

Aim: N,N-dimethyltryptamine (DMT) is a psychedelic compound under development for the treatment of major depressive disorder (MDD). This study evaluated the in vitro metabolism and clinical pharmacokinetics (PK) of DMT fumarate (SPL026) in healthy subjects. Methods: Results are from the Phase I component of an ongoing Phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial. Healthy adults received escalating doses of SPL026 via a 2-phase intravenous (IV) infusion. Dosing regimens were calculated based on PK modelling and predictions, with progression to each subsequent dose level according to safety and tolerability. In vitro experiments assessed hepatic clearance and metabolism of DMT by monoamine oxidase (MAO) and cytochrome P450 enzymes. Results: 24 healthy subjects received escalating doses of SPL026 which were safe and well-tolerated. Dose-proportional increases in DMT exposure were observed over the range of 9–21.5 mg. For all doses, median time to peak plasma concentration was ~10 min and mean elimination half-life was 9–12 min. There was no relationship between peak DMT plasma concentration and body mass index, weight or age. In vitro hepatic mitochondrial fraction clearance of SPL026 was inhibited by MAO-A, but not MAO-B, inhibition. CYP2D6 and CYP2C19 modified SPL026 clearance in vitro. The unbound fraction of SPL026 was approximately 70%. Conclusion: This is the first study to determine, in detail, the full PK profile of DMT in humans, confirming rapid attainment of peak plasma concentrations followed by accelerated clearance. These findings provide evidence which support the development of novel DMT infusion regimens for the treatment of MDD.

Abstract Schizophrenia and states induced by certain psychotomimetic drugs may share some physiological and phenomenological properties, but they differ in fundamental ways: one is a crippling chronic mental disease, while the others are temporary, pharmacologically-induced states presently being explored as treatments for mental illnesses. Building towards a deeper understanding of these different alterations of normal consciousness, here we compare the changes in neural dynamics induced by LSD and ketamine (in healthy volunteers) against those associated with schizophrenia, as observed in resting-state M/EEG recordings. While both conditions exhibit increased neural signal diversity, our findings reveal that this is accompanied by an increased transfer entropy from the front to the back of the brain in schizophrenia, versus an overall reduction under the two drugs. Furthermore, we show that these effects can be reproduced via different alterations of standard Bayesian inference applied on a computational model based on the predictive processing framework. In particular, the effects observed under the drugs are modelled as a reduction of the precision of the priors, while the effects of schizophrenia correspond to an increased precision of sensory information. These findings shed new light on the similarities and differences between schizophrenia and two psychotomimetic drug states, and have potential implications for the study of consciousness and future mental health treatments.

Abstract Psychedelic drugs are potent modulators of conscious states and therefore powerful tools for investigating their neurobiology. N,N, Dimethyltryptamine (DMT) is a particularly interesting serotonergic psychedelic that can rapidly induce an extremely immersive state of consciousness characterized by vivid and elaborate visual imagery. In the present study, we investigated the electrophysiological correlates of the DMT-induced altered state, by recording EEG signals from a pool of participants receiving DMT and (separately) placebo (saline), intravenously, while instructed to keep their eyes closed (i.e. ‘resting state’). Consistent with our prior hypotheses, results revealed a spatio-temporal pattern of cortical activation (i.e., travelling waves) similar to that elicited by visual stimulation. Moreover, the typical top-down alpha-band rhythms of closed-eyes rest (i.e. a backward travelling wave) were significantly decreased, while the bottom-up ‘forward travelling wave’, was significantly increased. These results support a recent model proposing that psychedelics reduce the ‘precision-weighting of priors’, thus altering the balance of top-down versus bottom-up information passing, where properties of backward waves are considered correlates of this precision weighting. The robust hypothesis-confirming nature of the present findings imply the discovery of an important mechanistic principle underpinning psychedelic-induced altered states – i.e. reduced backward and increased forward travelling waves - and lend further support to prior assumptions about the functional significance of cortical travelling waves.

Experiences of collective creative activities play an essential role in human societies, yet these experiences are particularly hard to capture, making their scientific scrutiny extremely challenging. Here we investigate the experience of audience members during a musical concert associated with collective improvisation by analysing the audience's subjective reports and movement patterns. Our results show that performance with improvisational elements affect movement synchronisation dynamics between performers and audience members differently at different timescales, which are predictive of changes in the subjective perception of music. These results provide a first step towards the quantification of some of the fundamental aspects of these collective experiences. Moreover, the reported findings shed new light on the relevance of the often-neglected multiscale coordination between audiences and performers, and explains how this rich tapestry of physical behaviour is connected with the quality of the collective subjective experience.

This study investigated the sense of familiarity attributed to N, N-dimethyltryptamine (DMT) experiences. 227 naturalistic inhaled-DMT experiences reporting a sense of familiarity were included. No experiences referenced a previous DMT or psychedelic experience as the source of the familiarity. A high prevalence of concomitant features discordant from ordinary consciousness were identified: features of a mystical experience (97.4%), ego-dissolution (16.3%), and a “profound experience of death” (11.0%). The Sense of Familiarity Questionnaire (SOF-Q) was developed assessing 19 features of familiarity across 5 themes: (1) Familiarity with the Feeling, Emotion, or Knowledge Gained; (2) Familiarity with the Place, Space, State, or Environment; (3) Familiarity with the Act of Going Through the Experience; (4) Familiarity with Transcendent Features; and (5) Familiarity Imparted by an Entity Encounter. Bayesian latent class modeling yielded two stable classes of participants who shared similar SOF-Q responses. Class 1 participants responded, “yes” more often for items within “Familiarity Imparted by an Entity Encounter” and “Familiarity with the Feeling, Emotion, or Knowledge Gained.” Results catalogued features of the sense of familiarity imparted by DMT, which appears to be non-referential to a previous psychedelic experience. Findings provide insights into the unique and enigmatic familiarity reported during DMT experiences and offer a foundation for further exploration into this intriguing phenomenon.

This study translated and tested the psychometric properties of acute psychedelic effects measures among Spanish-speaking people. The Psychological Insight Questionnaire (PIQ), Challenging Experiences Questionnaire (CEQ), and Mystical Experiences Questionnaire (MEQ) were translated before being incorporated into a web-based survey. We recruited native Spanish-speakers (N = 442; Mage = 30.8, SD = 10.9; Latino/Latina = 62%; Hispanic = 91.4%; male = 71.5%) to assess their previous experience with one of two psychedelics (LSD = 58.4%; Psilocybin = 41.6%) and their acute and enduring effects. Confirmatory factor analysis (confirming factor structure based on the English version) revealed a good fit for the MEQ, PIQ and the CEQ. Repeating our analysis in each drug subsample revealed consistency in factor structure for each assessment tool. Construct validity was supported by significant positive associations between the PIQ and MEQ, and between the PIQ and MEQ and changes in cognitive fusion and negative associations between changes in prosocial behaviors. As a signal of predictive validity, persisting effects (PEQ) were strongly related to scores on the MEQ and PIQ. Findings demonstrate that the Spanish versions of these measures can be reliably employed in studies of psychedelic use or administration in Spanish-speaking populations.

Abstract 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 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, and 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 relevant subjective experience and thus further our understanding of the neurobiological underpinnings of immersive states of consciousness.

Background: Psilocybin is a serotonin type 2A (5-HT 2A ) receptor agonist and naturally occurring psychedelic. 5-HT 2A receptor density is known to be associated with body mass index (BMI), however, the impact of this on psilocybin therapy has not been explored. While body weight-adjusted dosing is widely used, this imposes a practical and financial strain on the scalability of psychedelic therapy. This gap between evidence and practice is caused by the absence of studies clarifying the relationship between BMI, the acute psychedelic experience and long-term psychological outcomes. Method: Data were pooled across three studies using a fixed 25 mg dose of psilocybin delivered in a therapeutic context to assess whether BMI predicts characteristics of the acute experience and changes in well-being 2 weeks later. Supplementing frequentist analysis with Bayes Factors has enabled for conclusions to be drawn regarding the null hypothesis. Results: Results support the null hypothesis that BMI does not predict overall intensity of the altered state, mystical experiences, perceptual changes or emotional breakthroughs during the acute experience. There was weak evidence for greater ‘dread of ego dissolution’ in participants with lower BMI, however, further analysis suggested BMI did not meaningfully add to the combination of the other covariates (age, sex and study). While mystical-type experiences and emotional breakthroughs were strong predictors of improvements in well-being, BMI was not. Conclusions: These findings have important implications for our understanding of pharmacological and extra-pharmacological contributors to psychedelic-assisted therapy and for the standardization of a fixed therapeutic dose in psychedelic-assisted therapy.

Abstract Background: Understanding the phenomenology and content of the inhaled N, N, dimethyltryptamine (N, N-DMT) experience is critical to facilitate and support ongoing research and therapeutic models targeting mental health conditions and central nervous system pathology. Methods: Qualitative analysis of all N, N-DMT experiences posted to the r/DMT Reddit community over a 10-year period from 2009-2018. Results: A total of 3778 experiences from 3305 posts were included in this study. A median dose of N, N-DMT of 40.0 mg [interquartile range (IQR), 27.5 to 50.0] and a median experience duration of 10 minutes (IQR, 5.0 to 15.0) were identified. The most common somatic effects were somaesthesias (n=1415, 37.5%) and an auditory ringing (n=583, 15.4%). Visualizations predominantly consisted of fractals, shapes, patterns (n=1231, 32.5%) and vivid colours (n=953, 25.2%). Entity encounters occurred in 45.5% (n=1719) of the experiences and involved predominantly a feminine phenotype (n=416, 24.2%); aliens (n=281, 16.3%); deities (n=238, 13.8%); creature-based entities (n=158, 9.2%, including reptilian and insectoid beings); mythological beings (n=138, 8.0%, including machine elves); and jesters (n=112, 6.5%). Entity interactions were predominantly positive (n=600, 34.9% of encounters) involving benevolent, comforting, protecting, or outwardly caring interactions. A companion-type, pedagogical, or guide-type interaction was identified 32.4% of encounters (n=557). Common typology, architectural, and structural features of the “DMT world” were descriptions of alternate or higher dimensions (n=952, 25.2%); room(s) [n=582, 15.4%, including the “waiting room” (n=105, 2.8%)], and a tunnel (n=390, 10.3%). Features of mystical and ego-dissolution experiences were common and additional rewarding aspects were reported, including familiarity and acceptance/removal of the fear of death. Challenging and difficult responses were less frequent but also documented. Statements of profundity were identified in 232 experiences (6.1%), including pronouncing the experience or an aspect of the experience as the most “beautiful” or feeling the most “beautiful” of their life (n=47, 1.2%). Conclusion: This study identified common phenomenological themes and content of naturalistic inhaled N, N-DMT experiences. Major thematic domains included (1) physical and somatic experiences; (2) content of visualizations and imagery; (3) entity encounters including entity phenotype, descriptors, attributes, disposition, and characteristics of the interaction; (4) typology, architectural features, structural characteristics, and scenery of the “DMT world”; (5) emotional responses (including positive, rewarding, difficult, and challenging); and (6) statements of profundity.

Healthful behaviors such as maintaining a balanced diet, being physically active, and refraining from smoking have major impacts on the risk of developing cancer, diabetes, cardiovascular diseases, and other serious conditions. The burden of the so-called “lifestyle diseases” - in personal suffering, premature mortality, and public health costs - is considerable. Consequently, interventions designed to promote healthy behaviors are increasingly being studied, e.g. using psychobiological models of behavioral regulation and change. In this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. Psilocybin has a low toxicity, is non-addictive, and has been shown to predict favorable changes in patients with depression, anxiety, and other conditions marked by rigid behavioral patterns, including substance (mis)use. While it is still early days for modern psychedelic science, research is advancing fast and results are promising. Here we describe psychedelics’ proposed mechanisms of action and research findings pertinent to health behavior change science, hoping to generate discussion and new research hypotheses linking the two areas. Therapeutic models including psychedelic experiences and common behavior change methods (e.g., Cognitive Behavior Therapy, Motivational Interviewing) are already being tested for addiction and eating disorders. We believe this research may soon be extended to help promote improved diet, exercise, nature exposure, and also mindfulness or stress reduction practices, all of which can contribute to physical and psychological health and wellbeing.

Raw EEG data (DMT, eyes open and eyes closed) and psychometric scales for the 35 participants of "Neural and subjective effects of inhaled DMT in natural settings".

Raw EEG data (DMT, eyes open and eyes closed) and psychometric scales for the 35 participants of "Neural and subjective effects of inhaled DMT in natural settings".