Not in the drug, not in the brain: Causality in psychedelic experiences from an enactive perspective

Psychedelics are psychoactive substances that receive renewed interest from science and society. Increasing empirical evidence shows that the effects of psychedelics are associated with alterations in biochemical processes, brain activity, and lived experience. Still, how these different levels relate remains subject to debate. The current literature presents two influential views on the relationship between the psychedelic molecule, neural events, and experience: The integration view and the pluralistic view. The main aim of this article is to contribute a promising complementary view by re-evaluating the psychedelic molecule-brain-experience relationship from an enactive perspective. We approach this aim via the following main research questions: (1) What is the causal relationship between the psychedelic drug and brain activity? (2) What is the causal relationship between brain activity and the psychedelic experience? In exploring the first research question, we apply the concept of autonomy to the psychedelic molecule-brain relationship. In exploring the second research question, we apply the concept of dynamic co-emergence to the psychedelic brain-experience relationship. Addressing these two research questions from an enactive position offers a perspective that emphasizes interdependence and circular causality on multiple levels. This enactive perspective not only supports the pluralistic view but enriches it through a principled account of how multi-layered processes come to interact. This renders the enactive view a promising contribution to questions around causality in the therapeutic effects of psychedelics with important implications for psychedelic therapy and psychedelic research

Neuropsychoanalyse: Hirntätigkeit als Zeichenprozess

Fassen wir Geist und Natur nicht als Dichotomie sondern im Sinne von Peirce als Kontinuität auf, dann lässt die genauere Betrachtung des Körpers semiotische Leibphänomene als Zeichen einer Sprache erkennen, deren Grammatik es – im Sinne einer «Bioarchäologie» – zu entschlüsseln gilt. Hierfür stellen die Neurowissenschaften mit modernen Visualisierungstechniken geeignete epistemische Hilfsmittel bereit: Sie machen körperliche Vorgänge des Informationsaustausches sichtbar und heben die semiotisch wenig erschlossene Ebene komplexer neuronaler Zeichentransformationen ans Licht. Um eine Integration der physiologischen und psychologischen Perspektive bemüht sich das transdisziplinäre Projekt der «Neuropsychoanalyse». Sie hebt die Relevanz natürlicher Verarbeitungsmechanismen des Körpers für die subjektiv geprägten Zeichentransformationen des mentalen Erlebens hervor und weicht eine semiotisch allzu undurchlässige Grenzziehung zwischen Psycho- und Neurodynamik etwas auf. Die Hirntätigkeit als potenziell erkenntnisleitenden Zeichenprozess zu verstehen, darf aber nicht in einer unreflektierten Bezugnahme auf neuronale Zeichensysteme münden, wenn die Neuropsychoanalyse mehr als nur eine medienwirksame Neurokarikatur psychodynamischer Konzepte erreichen will

Neuropsychoanalyse: Hirntätigkeit als Zeichenprozess

Fassen wir Geist und Natur nicht als Dichotomie sondern im Sinne von Peirce als Kontinuität auf, dann lässt die genauere Betrachtung des Körpers semiotische Leibphänomene als Zeichen einer Sprache erkennen, deren Grammatik es – im Sinne einer «Bioarchäologie» – zu entschlüsseln gilt. Hierfür stellen die Neurowissenschaften mit modernen Visualisierungstechniken geeignete epistemische Hilfsmittel bereit: Sie machen körperliche Vorgänge des Informationsaustausches sichtbar und heben die semiotisch wenig erschlossene Ebene komplexer neuronaler Zeichentransformationen ans Licht. Um eine Integration der physiologischen und psychologischen Perspektive bemüht sich das transdisziplinäre Projekt der «Neuropsychoanalyse». Sie hebt die Relevanz natürlicher Verarbeitungsmechanismen des Körpers für die subjektiv geprägten Zeichentransformationen des mentalen Erlebens hervor und weicht eine semiotisch allzu undurchlässige Grenzziehung zwischen Psycho- und Neurodynamik etwas auf. Die Hirntätigkeit als potenziell erkenntnisleitenden Zeichenprozess zu verstehen, darf aber nicht in einer unreflektierten Bezugnahme auf neuronale Zeichensysteme münden, wenn die Neuropsychoanalyse mehr als nur eine medienwirksame Neurokarikatur psychodynamischer Konzepte erreichen will

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

Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans

Hallucinogens are a loosely defined group of compounds including LSD, N,N-dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), which can evoke intense visual and emotional experiences. We are witnessing a renaissance of research interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or single photon emission computer tomography (SPECT). In general, molecular imaging can depict the uptake and binding distribution of labelled hallucinogenic compounds or their congeners in the brain, as was shown in an early PET study with N1-([11C]-methyl)-2-bromo-LSD ([11C]-MBL); displacement with the non-radioactive competitor ketanserin confirmed that the majority of [11C]-MBL specific binding was to serotonin 5-HT2A receptors. However, interactions at serotonin 5HT1A and other classes of receptors and pleotropic effects on second messenger pathways may contribute to the particular experiential phenomenologies of LSD and other hallucinogenic compounds. Other salient aspects of hallucinogen action include permeability to the blood–brain barrier, the rates of metabolism and elimination, and the formation of active metabolites. Despite the maturation of radiochemistry and molecular imaging in recent years, there has been only a handful of PET or SPECT studies of radiolabeled hallucinogens, most recently using the 5-HT2A/2C agonist N-(2[11CH3O]-methoxybenzyl)-2,5-dimethoxy- 4-bromophenethylamine ([11C]Cimbi-36). In addition to PET studies of target engagement at neuroreceptors and transporters, there is a small number of studies on the effects of hallucinogenic compounds on cerebral perfusion ([15O]-water) or metabolism ([18F]-fluorodeoxyglucose/FDG). There remains considerable scope for basic imaging research on the sites of interaction of hallucinogens and their cerebrometabolic effects; we expect that hybrid imaging with PET in conjunction with functional magnetic resonance imaging (fMRI) should provide especially useful for the next phase of this research

Adverse effects of ayahuasca: Results from the Global Ayahuasca Survey

Introduction Ayahuasca is a plant-based decoction native to Amazonia, where it has a long history of use in traditional medicine. Contemporary ritual use of ayahuasca has been expanding throughout the world for mental health purposes, and for spiritual and personal growth. Although researchers have been conducting clinical trials and observational studies reporting medical and psychological benefits, most of these do not report ayahuasca’s immediate or medium-term adverse effects, so these are underrepresented in the literature. With the expansion of ayahuasca ceremonies from their traditional contexts to countries around the world, there is an important public health question regarding the risk/benefit balance of its use. Methods We used data from an online Global Ayahuasca Survey (n = 10,836) collected between 2017 and 2019 involving participants from more than 50 countries. Principal component analysis was performed to assess group effects. Logistic regression analysis was performed to test for adverse effects associated with history of ayahuasca use, clinical, context of use and spiritual effect variables. Results Acute physical health adverse effects (primarily vomiting) were reported by 69.9% of the sample, with 2.3% reporting the need for subsequent medical attention. Adverse mental health effects in the weeks or months following consumption were reported by 55.9% of the sample, however, around 88% considered such mental health effects as part of a positive process of growth or integration. Around 12% sought professional support for these effects. Physical adverse effects were related to older age at initial use of ayahuasca, having a physical health condition, higher lifetime and last year ayahuasca use, having a previous substance use disorder diagnosis, and taking ayahuasca in a non-supervised context. Mental health adverse effects were positively associated with anxiety disorders; physical health conditions; and the strength of the acute spiritual experience; and negatively associated with consumption in religious settings. Conclusions While there is a high rate of adverse physical effects and challenging psychological effects from using ayahuasca, they are not generally severe, and most ayahuasca ceremony attendees continue to attend ceremonies, suggesting they perceive the benefits as outweighing any adverse effects. Knowing what variables might predict eventual adverse effects may serve in screening of, or providing additional support for, vulnerable subjects. Improved understanding of the ayahuasca risk/benefit balance can also assist policy makers in decisions regarding potential regulation and public health responses

Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker

Background: Growing evidence underscores the utility of ketamine as an effective and rapid-acting treatment option for major depressive disorder (MDD). However, clinical outcomes vary between patients. Predicting successful response may enable personalized treatment decisions and increase clinical efficacy. Methods: We here explored the potential of pregenual anterior cingulate cortex (pgACC) activity to predict antidepressant effects of ketamine in relation to ketamine-induced changes in glutamatergic metabolism. Prior to a single i.v. infusion of ketamine, 24 patients with MDD underwent functional magnetic resonance imaging during an emotional picture-viewing task and magnetic resonance spectroscopy. Changes in depressive symptoms were evaluated using the Beck Depression Inventory measured 24 hours pre- and post-intervention. A subsample of 17 patients underwent a follow-up magnetic resonance spectroscopy scan. Results: Antidepressant efficacy of ketamine was predicted by pgACC activity during emotional stimulation. In addition, pgACC activity was associated with glutamate increase 24 hours after the ketamine infusion, which was in turn related to better clinical outcome. Conclusions: Our results add to the growing literature implicating a key role of the pgACC in mediating antidepressant effects and highlighting its potential as a multimodal neuroimaging biomarker of early treatment response to ketamine. Keywords: antidepressant effects; ketamine; multimodal neuroimaging biomarker; pgACC; pregenual anterior cingulate cortex

Potential therapeutic effects of an ayahuasca-inspired N,N-DMT and harmine formulation: a controlled trial in healthy subjects

Background: There is growing scientific evidence for the therapeutic benefits of the Amazonian plant-based psychedelic “ayahuasca” for neuropsychiatric disorders such as depression and anxiety. However, there are certain challenges when incorporating botanical ayahuasca into biomedical research and clinical therapy environments. Formulations inspired by ayahuasca, which contain specific and standardized active components, are a potential remedy. Methods: We investigated subjective acute and persisting effects of a novel formulation containing the reversible monoamine oxidase inhibitor harmine (orodispersible tablet containing 100 mg MAO-I) and N,N-dimethyltryptamine (incremental intranasal dosing of up to 100 mg DMT), compared with two other conditions, namely harmine alone and placebo, in a crossover RCT in 31 healthy male subjects. Results: DMT + harmine, but not harmine alone, induced a psychedelic experience assessed with the 5D-ASC rating scale [global score: F(2,60) = 80.21, p < 0.001] and acute experience sampling items over time, characterized by psychological insights [PIQ, F(2,58.5) = 28.514, p < 0.001], emotional breakthroughs [EBI, F(2,60) = 26.509, p < 0.001], and low scores on the challenging experience questionnaire [CEQ, F(2,60) = 12.84, p < 0.001]. Participants attributed personal and spiritual significance to the experience (GSR) with mainly positive persisting effects (PEQ) at 1- and 4-months follow-up. Acute drug effects correlated positively with persisting effects. We found no changes in trait measures of personality, psychological flexibility, or general well-being, and no increases in psychopathology (SCL-90-R) were reported. Discussion and Conclusion: Our results suggest that the experience induced by the standardized DMT + harmine formulation induces a phenomenologically rich psychedelic experience, demonstrates good psychological safety and tolerability, is well tolerated, and induces beneficial psychological processes that could possibly support psychotherapy. Further studies are required to investigate the psychotherapeutic potential in patients

Overcoming the clinical challenges of traditional ayahuasca: a first-in-human trial exploring novel routes of administration of N,N-Dimethyltryptamine and harmine

Recently, the Amazonian plant medicine “ayahuasca”—containing the psychedelic compound N,N-dimethyltryptamine (DMT) and numerous β-carboline alkaloids, such as harmine—has been suggested to exhibit beneficial effects in patients with affective and other mental health disorders. Although ayahuasca ingestion is considered safe, its pharmacokinetics/pharmacodynamics and tolerability profile pose some challenges and may limit the clinical applicability in vulnerable patient populations. While overdosing and the admixture of intolerable plant constituents may explain some of the common adverse reactions, the peroral route of administration may represent another relevant source of gastro-intestinal intolerabilities and unpredictable pharmacokinetics across users. To overcome these challenges, the present work aimed at creating ayahuasca-analogue formulations with improved pharmacokinetics and tolerability profiles. To this end, we developed peroral formulas and compared them with parenteral formulas specifically designed to circumvent the gastro-intestinal tract. In more detail, peroral administration of a capsule (containing purified DMT and harmine) was tested against a combined administration of an oromucosal harmine tablet and an intranasal DMT spray at two dose levels in an open-label within-subject study in 10 healthy male subjects. Pharmacokinetic and pharmacodynamic profiles were assessed by means of continuous blood sampling, vital sign monitoring, and psychometric assessments. Common side effects induced by traditional herbal ayahuasca such as nausea, vomiting, and diarrhea were significantly attenuated by our DMT/harmine formulations. While all preparations were well tolerated, the combined buccal/intranasal administration of harmine and DMT yielded substantially improved pharmacokinetic profiles, indicated by significantly reduced variations in systemic exposure. In conclusion, the combined buccal/intranasal administration of harmine and DMT is an innovative approach that may pave the way towards a safe, rapid-acting, and patient-oriented administration of DMT/harmine for the treatment of affective disorders.Clinical Trial Registration:clinicaltrials.gov, identifier NCT0471633