Psychedelic State Research Articles

A mechanistic model of the neural entropy increase elicited by psychedelic drugs

Psychedelic drugs, including lysergic acid diethylamide and other agonists of the serotonin 2A receptor (5HT2A-R), induce drastic changes in subjective experience, and provide a unique opportunity to study the neurobiological basis of consciousness. One of the most notable neurophysiological signatures of psychedelics, increased entropy in spontaneous neural activity, is thought to be of relevance to the psychedelic experience, mediating both acute alterations in consciousness and long-term effects. However, no clear mechanistic explanation for this entropy increase has been put forward so far. We sought to do this here by building upon a recent whole-brain model of serotonergic neuromodulation, to study the entropic effects of 5HT2A-R activation. Our results reproduce the overall entropy increase observed in previous experiments in vivo, providing the first model-based explanation for this phenomenon. We also found that entropy changes were not uniform across the brain: entropy increased in some regions and decreased in others, suggesting a topographical reconfiguration mediated by 5HT2A-R activation. Interestingly, at the whole-brain level, this reconfiguration was not well explained by 5HT2A-R density, but related closely to the topological properties of the brain’s anatomical connectivity. These results help us understand the mechanisms underlying the psychedelic state and, more generally, the pharmacological modulation of whole-brain activity.

Designing Consciousness: Psychedelics as Ontological Design Tools for Decolonizing Consciousness

Ontological and decolonial designers have called for a reorientation of the fundamental relations between humans, things, and the world away from their entrenchment in modernist and colonial thought. Both ontological and decolonial design therefore share the vision of transcending design’s modern philosophical inheritances to allow for the flourishing of new ontologies of interrelatedness. Whereas some radical design theorists have mobilized border thinking, subjugated knowledges, and alternative ways of being as means of challenging modernist epistemologies and ontologies, this article instead examines the role that alternate states of consciousness may play in the formation of new ontological designs. In drawing on radical design and decolonial theory, I argue that psychedelic experiences and states of consciousness can potentially serve as decolonial tools for designing consciousness, and thereby assist in reorienting human social and environmental relations toward ontologies of relatedness and interconnectedness.

Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans.

Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to normal consciousness. We evaluated whether pre-drug brain 5-HT2AR binding predicted the three phases of psilocybin subjective drug intensity (SDI) and retrospective self-report of mystical type experiences in healthy individuals. Sixteen participants completed a pre-drug [11C]Cimbi-36 positron emission tomography scan to assess 5-HT2AR binding. On a separate day, participants completed a single psilocybin session (oral dose range 0.2-0.3 mg/kg), during which SDI was assessed every 20 min. The Mystical Experience Questionnaire (MEQ) was completed at the end of the session. The three SDI phases were modelled using segmented linear regressions. We evaluated the associations between neocortex 5-HT2AR binding and SDI/MEQ outcomes using linear regression models. Neocortex 5-HT2AR was statistically significantly negatively associated with peak plateau duration and positively with time to return to normal waking consciousness. It was also statistically significantly negatively associated with MEQ total score. This is the first study to investigate how individual brain 5-HT2AR binding predicts subjective effects of a single dose of psilocybin. Our findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience. Future studies should examine whether individual brain levels of 5-HT2AR have an impact on therapeutic outcomes in clinical studies.

Updating the dynamic framework of thought: Creativity and psychedelics

Contemporary investigations regard creativity as a dynamic form of cognition that involves movement between the dissociable stages of creative generation and creative evaluation. Our recently proposed Dynamic Framework of Thought (Christoff et al., 2016) offered a conceptualization of these stages in terms of an interplay between sources of constraint and variability on thought. This initial conceptualization, however, has yet to be fully explicated and given targeted discussion. Here, we refine this framework’s account of creativity by highlighting the dynamic nature of creative thought, both within and between the stages of creative generation and evaluation. In particular, we emphasize that creative generation in particular is best regarded as a product of multiple, varying mental states, rather than being a singular mental state in and of itself. We also propose that the psychedelic state is a mental state with high potential for facilitating creative generation and update the Dynamic Framework of Thought to incorporate this state. This paper seeks to highlight the dynamic nature of the neurocognitive processes underlying creative thinking and to draw attention to the potential utility of psychedelic substances as experimental tools in the neuroscience of creativity.

Psychedelic Birth: Bodies, Boundaries and the Perception of Pain in the 1970s

Psychedelic Birth: Bodies, Boundaries and the Perception of Pain in the 1970s

Psilocybin Induces Time-Dependent Changes in Global Functional Connectivity

BackgroundThe use of psilocybin in scientific and experimental clinical contexts has triggered renewed interest in the mechanism of action of psychedelics. However, its time-dependent systems-level neurobiology remains sparsely investigated in humans. MethodsWe conducted a double-blind, randomized, counterbalanced, crossover study comprising 23 healthy human participants who received placebo and 0.2 mg/kg of psilocybin orally on 2 different test days. Participants underwent magnetic resonance imaging at 3 time points between administration and peak effects: 20 minutes, 40 minutes, and 70 minutes after administration. Resting-state functional connectivity was quantified via a data-driven global brain connectivity method and compared with cortical gene expression maps. ResultsPsilocybin reduced associative, but concurrently increased sensory, brain-wide connectivity. This pattern emerged over time from administration to peak effects. Furthermore, we showed that baseline connectivity is associated with the extent of psilocybin-induced changes in functional connectivity. Lastly, psilocybin-induced changes correlated in a time-dependent manner with spatial gene expression patterns of the 5-HT2A (5-hydroxytryptamine 2A) and 5-HT1A (5-hydroxytryptamine 1A) receptors. ConclusionsThese results suggest that the integration of functional connectivity in sensory regions and the disintegration in associative regions may underlie the psychedelic state and pinpoint the critical role of the serotonin 2A and 1A receptor systems. Furthermore, baseline connectivity may represent a predictive marker of the magnitude of changes induced by psilocybin and may therefore contribute to a personalized medicine approach within the potential framework of psychedelic treatment.

Psychedelics and virtual reality: parallels and applications.

Psychedelic drugs and virtual reality (VR) each have the capacity to disrupt the rigidity and limitations of typical conscious experience. This article delineates the parallels among psychedelic and VR states as well as their potential synergistic applications in clinical and recreational settings. Findings indicate that, individually, psychedelics and VR are used in analogous ways to alter sensory experience and evoke awe. They are also both used in tandem with traditional therapies to treat a variety of mood disorders; their shared capacity to transiently alter perspective and disrupt rigid patterns of mental experience may underly their analogous and transdiagnostic therapeutic uses. In terms of their combined applications, a number of recreational users currently utilize psychedelics and VR together to enhance their experience. We propose that VR may be a useful tool for preparing hallucinogen-naïve participants in clinical trials for the sensory distortions experienced in psychedelic states. Given the critical role of “setting” in psychedelic treatment outcomes, we also detail how VR could be used to optimize the environment in psychedelic sessions. Finally, we provide considerations for future studies and detail how advancements in psychedelic and VR research can inform one another. Collectively, this article outlines a number of connections between psychedelics and VR, and, more broadly, is representative of growing scientific interest into the interactions among technology, psychopharmacology, and mental health.

The multi-dimensional approach to drug-induced states: A commentary on Bayne and Carter’s “dimensions of consciousness and the psychedelic state”

Bayne and Carter argue that the mode of consciousness induced by psychedelic drugs does not fit squarely within the traditional account of modes as levels of consciousness, and favors instead a multi-dimensional account according to which modes of consciousness differ along several dimensions—none of which warrants a linear ordering of modes. We discuss the assumption that psychedelic drugs induce a single or paradigmatic mode of consciousness, as well as conceptual issues related to Bayne and Carter’s main argument against the traditional account. Finally, we raise a set of questions about the individuation of dimensions selected to differentiate modes of consciousness that could be addressed in future discussions of the multi-dimensional account.

Improved colour blindness symptoms associated with recreational psychedelic use: Results from the Global Drug Survey 2017

It is well documented that psychedelic drugs can have a profound effect on colour perception. After previous research involving psychedelic drug ingestion, several participants had written to the authors describing how symptoms of their colour blindness had improved. The Global Drugs Survey runs the world’s largest annual online drug survey. In the Global Drugs Survey 2017, participants reporting the use of lysergic acid diethylamide or psilocybin in the last 12 months were asked, We have received reports from some people with colour-blindness that this improves after they use psychedelics. If you have experienced such an effect can you please describe it in the box below, say what drug you took and how long the effect lasted. We received 47 responses that could be usefully categorised of which 23 described improved colour blindness. Commonly cited drugs were LSD and psilocybin; however, several other psychedelic compounds were also listed. Some respondents cited that the changes in colour blindness persisted, from a period of several days to years. Improved colour blindness may be a result of new photisms experienced in the psychedelic state aligning with pre-existing concepts of colour to be ascribed a label. Connections between visual and linguistic cortical areas may be enhanced due to disorder in the brain’s neural connections induced by psychedelics allowing these new photisms and concepts to become linked. This paper provides preliminary data regarding improved colour blindness accompanying recreational psychedelic use which may be further investigated in future iterations of the Global Drugs Survey or in a stand-alone Global Drugs Survey-managed psychedelics survey.

Decreased directed functional connectivity in the psychedelic state

Neuroimaging studies of the psychedelic state offer a unique window onto the neural basis of conscious perception and selfhood. Despite well understood pharmacological mechanisms of action, the large-scale changes in neural dynamics induced by psychedelic compounds remain poorly understood. Using source-localised, steady-state MEG recordings, we describe changes in functional connectivity following the controlled administration of LSD, psilocybin and low-dose ketamine, as well as, for comparison, the (non-psychedelic) anticonvulsant drug tiagabine. We compare both undirected and directed measures of functional connectivity between placebo and drug conditions. We observe a general decrease in directed functional connectivity for all three psychedelics, as measured by Granger causality, throughout the brain. These data support the view that the psychedelic state involves a breakdown in patterns of functional organisation or information flow in the brain. In the case of LSD, the decrease in directed functional connectivity is coupled with an increase in undirected functional connectivity, which we measure using correlation and coherence. This surprising opposite movement of directed and undirected measures is of more general interest for functional connectivity analyses, which we interpret using analytical modelling. Overall, our results uncover the neural dynamics of information flow in the psychedelic state, and highlight the importance of comparing multiple measures of functional connectivity when analysing time-resolved neuroimaging data.

From Egoism to Ecoism: Psychedelics Increase Nature Relatedness in a State-Mediated and Context-Dependent Manner.

(1) Background: There appears to be a growing disconnection between humans and their natural environments which has been linked to poor mental health and ecological destruction. Previous research suggests that individual levels of nature relatedness can be increased through the use of classical psychedelic compounds, although a causal link between psychedelic use and nature relatedness has not yet been established. (2) Methods: Using correlations and generalized linear mixed regression modelling, we investigated the association between psychedelic use and nature relatedness in a prospective online study. Individuals planning to use a psychedelic received questionnaires 1 week before (N = 654), plus one day, 2 weeks, 4 weeks, and 2 years after a psychedelic experience. (3) Results: The frequency of lifetime psychedelic use was positively correlated with nature relatedness at baseline. Nature relatedness was significantly increased 2 weeks, 4 weeks and 2 years after the psychedelic experience. This increase was positively correlated with concomitant increases in psychological well-being and was dependent on the extent of ego-dissolution and the perceived influence of natural surroundings during the acute psychedelic state. (4) Conclusions: The here presented evidence for a context- and state-dependent causal effect of psychedelic use on nature relatedness bears relevance for psychedelic treatment models in mental health and, in the face of the current ecological crisis, planetary health.

Characterization and prediction of acute and sustained response to psychedelic psilocybin in a mindfulness group retreat

Meditation and psychedelics have played key roles in humankind’s search for self-transcendence and personal change. However, neither their possible synergistic effects, nor related state and trait predictors have been experimentally studied. To elucidate these issues, we administered double-blind the model psychedelic drug psilocybin (315 μg/kg PO) or placebo to meditators (n = 39) during a 5-day mindfulness group retreat. Psilocybin increased meditation depth and incidence of positively experienced self-dissolution along the perception-hallucination continuum, without concomitant anxiety. Openness, optimism, and emotional reappraisal were predictors of the acute response. Compared with placebo, psilocybin enhanced post-intervention mindfulness and produced larger positive changes in psychosocial functioning at a 4-month follow-up, which were corroborated by external ratings, and associated with magnitude of acute self-dissolution experience. Meditation seems to enhance psilocybin’s positive effects while counteracting possible dysphoric responses. These findings highlight the interactions between non-pharmacological and pharmacological factors, and the role of emotion/attention regulation in shaping the experiential quality of psychedelic states, as well as the experience of selflessness as a modulator of behavior and attitudes. A better comprehension of mechanisms underlying most beneficial psychedelic experiences may guide therapeutic interventions across numerous mental conditions in the form of psychedelic-assisted applications.

Seeing without self: Discovering new meaning with psychedelic-assisted psychotherapy

ABSTRACTNew research in psychedelic-assisted psychotherapy merits a reexamination of the neurobiology and phenomenology of psychedelic states. First person accounts of psychedelic-assisted psychotherapy are used to re-conceptualize the ego boundary as a defense mechanism which regulates the significance that objects hold for the self. Therapeutic action is attributed to ego dissolution, which enables subjects to see new significance in things. This process coincides neurobiologically with uncoupling certain midline cortical structures, and psychodynamically, with deactivating defense mechanisms which mitigate the threat of losing the loved object. It also enables the dreamlike imagery, symbols, and metaphor of the primary process, a regression to earlier ways of relating to objects, and feelings of love and connectivity. The process supports Freud's ideas about the oceanic mode of relating to the world existing alongside the narrower, mature ego feeling. The former is better suited for finding meaning in life, while the latter is better suited for survival. The noetic quality of the psychedelic state derives from an unconscious recognition that experiences without character defenses feel more genuine than others, and conform to earlier ways of feeling and thinking. The accessibility of the primary process makes psychedelic-assisted psychotherapy transformative, not just informative. An analogy is drawn to Fonagy's developmental model of mentalization. Absent the defensive, self-critical lens of a prior self-concept, psychedelic-assisted psychotherapy serves as an ideal paradigm for the transformative experience of seeing oneself through the eyes of another, leading to greater self-acceptance. Flight instructions for navigating this royal road to the unconscious are considered.

Corrigendum: A Single Dose of 5-MeO-DMT Stimulates Cell Proliferation, Neuronal Survivability, Morphological and Functional Changes in Adult Mice Ventral Dentate Gyrus.

[This corrects the article DOI: 10.3389/fnmol.2018.00312.].

Is Psychedelic Medicine on the Horizon?

Is Psychedelic Medicine on the Horizon?

A First-in-Man Study with 4-Fluoroamphetamine Demonstrates it Produces a Mild Psychedelic State

ABSTRACTThe phenethylamine 4-fluoroamphetamine (4-FA) is a so-called novel psychoactive substance with a chemical structure resembling that of amphetamine and MDMA. Since 4-FA users report their subjective experience ranges between the effects induced by amphetamine and MDMA, and it is known that both substances can produce an altered state of consciousness, this study tests whether 4-FA induces a psychedelic state. A placebo-controlled two-way crossover study in 12 healthy poly-drug users was conducted to test subjective and behavioral effects of 4-FA. 4-FA concentrations were determined in serum up to 12 hours after administration and a series of questionnaires and the picture concept test were administered between one hour and 11 hours post-administration. Findings showed that 4-FA induced a psychedelic state which was highest one hour after 4-FA administration, at peak 4-FA serum concentrations. The 4-FA-induced psychedelic state decreased over time and was in general associated with the decreasing 4-FA serum concentrations. There was no 4-FA-induced change in creative (flexible) thinking. It is concluded that while the 4-FA-induced psychedelic state is mild in intensity and in between that produced by amphetamine and MDMA as hypothesized, more research is needed to indicate whether 4-FA can change creative thinking.

The novel psychoactive phenetylamine 4-fluoroamphetamine produces a mild psychedelic state without affecting creative thinking

Economic losses incurred because of diseases are caused by morbidity, mortality, and costs incurred due to disease management, vaccination, deworming, antibiotic resistance, and restrictions on worldwide trade. The annual cost associated with parasitic diseases in sheep and cattle in Australia has been estimated at one billion dollars and is estimated to be tens of billions of dollars worldwide. In India at the annual 10% incidence level, the estimated total loss due to peste des petits ruminants in sheep and goats was INR 5041.5 million and INR 11,074.6 million respectively. Cutaneous myiasis (fly strike) has a great effect on the wool industry, and economic involvement for preventive techniques to fight the infestation is approximately AU$4 per sheep. Mastitis, foot-and-mouth disease, and avian influenza have been observed as economically important diseases that result in the incurment of heavy financial losses. Total disease costs have been estimated at up to 20% of the turnover in developed countries and as high as 35%–50% of turnover within the livestock sector in the developing world.

Informativeness of Auditory Stimuli Does Not Affect EEG Signal Diversity.

Brain signal diversity constitutes a robust neuronal marker of the global states of consciousness. It has been demonstrated that, in comparison to the resting wakefulness, signal diversity is lower during unconscious states, and higher during psychedelic states. A plausible interpretation of these findings is that the neuronal diversity corresponds to the diversity of subjective conscious experiences. Therefore, in the present study we varied an information rate processed by the subjects and hypothesized that greater information rate will be related to richer and more differentiated phenomenology and, consequently, to greater signal diversity. To test this hypothesis speech recordings (excerpts from an audio-book) were presented to subjects at five different speeds (65, 83, 100, 117, and 135% of the original speed). By increasing or decreasing speed of the recordings we were able to, respectively, increase or decrease the presented information rate. We also included a backward (unintelligible) speech presentation and a resting-state condition (no auditory stimulation). We tested 19 healthy subjects and analyzed the recorded EEG signal (64 channels) in terms of Lempel-Ziv diversity (LZs). We report the following findings. First, our main hypothesis was not confirmed, as Bayes Factor indicates evidence for no effect when comparing LZs among five presentation speeds. Second, we found that LZs during the resting-state was greater than during processing of both meaningful and unintelligible speech. Third, an additional analysis uncovered a gradual decrease of diversity over the time-course of the experiment, which might reflect a decrease in vigilance. We thus speculate that higher signal diversity during the unconstrained resting-state might be due to a greater variety of experiences, involving spontaneous attention switching and mind wandering.

Psychedelics, Meditation, and Self-Consciousness.

In recent years, the scientific study of meditation and psychedelic drugs has seen remarkable developments. The increased focus on meditation in cognitive neuroscience has led to a cross-cultural classification of standard meditation styles validated by functional and structural neuroanatomical data. Meanwhile, the renaissance of psychedelic research has shed light on the neurophysiology of altered states of consciousness induced by classical psychedelics, such as psilocybin and LSD, whose effects are mainly mediated by agonism of serotonin receptors. Few attempts have been made at bridging these two domains of inquiry, despite intriguing evidence of overlap between the phenomenology and neurophysiology of meditation practice and psychedelic states. In particular, many contemplative traditions explicitly aim at dissolving the sense of self by eliciting altered states of consciousness through meditation, while classical psychedelics are known to produce significant disruptions of self-consciousness, a phenomenon known as drug-induced ego dissolution. In this article, we discuss available evidence regarding convergences and differences between phenomenological and neurophysiological data on meditation practice and psychedelic drug-induced states, with a particular emphasis on alterations of self-experience. While both meditation and psychedelics may disrupt self-consciousness and underlying neural processes, we emphasize that neither meditation nor psychedelic states can be conceived as simple, uniform categories. Moreover, we suggest that there are important phenomenological differences even between conscious states described as experiences of self-loss. As a result, we propose that self-consciousness may be best construed as a multidimensional construct, and that “self-loss,” far from being an unequivocal phenomenon, can take several forms. Indeed, various aspects of self-consciousness, including narrative aspects linked to autobiographical memory, self-related thoughts and mental time travel, and embodied aspects rooted in multisensory processes, may be differently affected by psychedelics and meditation practices. Finally, we consider long-term outcomes of experiences of self-loss induced by meditation and psychedelics on individual traits and prosocial behavior. We call for caution regarding the problematic conflation of temporary states of self-loss with “selflessness” as a behavioral or social trait, although there is preliminary evidence that correlations between short-term experiences of self-loss and long-term trait alterations may exist.

A Single Dose of 5-MeO-DMT Stimulates Cell Proliferation, Neuronal Survivability, Morphological and Functional Changes in Adult Mice Ventral Dentate Gyrus.

The subgranular zone (SGZ) of dentate gyrus (DG) is one of the few regions in which neurogenesis is maintained throughout adulthood. It is believed that newborn neurons in this region encode temporal information about partially overlapping contextual memories. The 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring compound capable of inducing a powerful psychedelic state. Recently, it has been suggested that DMT analogs may be used in the treatment of mood disorders. Due to the strong link between altered neurogenesis and mood disorders, we tested whether 5-MeO-DMT is capable of increasing DG cell proliferation. We show that a single intracerebroventricular (ICV) injection of 5-MeO-DMT increases the number of Bromodeoxyuridine (BrdU+) cells in adult mice DG. Moreover, using a transgenic animal expressing tamoxifen-dependent Cre recombinase under doublecortin promoter, we found that 5 Meo-DMT treated mice had a higher number of newborn DG Granule cells (GC). We also showed that these DG GC have more complex dendritic morphology after 5-MeO-DMT. Lastly, newborn GC treated with 5-MeO-DMT, display shorter afterhyperpolarization (AHP) potentials and higher action potential (AP) threshold compared. Our findings show that 5-MeO-DMT affects neurogenesis and this effect may contribute to the known antidepressant properties of DMT-derived compounds.