This thesis investigates the acute phenomenology of altered states of consciousness induced through psychedelics and various Zen practices through the lens of comparative mysticism. Through inductive reasoning, tentative conclusions are drawn regarding how the acute phenomenological qualities of these states compare to one another. This topic had not been meaningfully studied, so the data from which these conclusions were drawn is limited. Though these findings are tentative, they have important implications for the study of comparative mysticism involving psychedelics, and for policy decisions regarding the credentialing of newly trained psychedelic therapists. Further research is required to draw more definitive conclusions on whether psychedelics users and Zen practitioners are having the same sorts of experiences, and this thesis identifies some of the theoretical challenges that can be expected with such research, particularly with regards to the reliability of qualitative data collection methods. To address these challenges, a novel theoretical approach to the study of comparative mysticism involving psychedelic and non-psychedelic altered states of consciousness has been developed.

Recent research studies and clinical trials have suggested that psychedelic therapy with psychological support can offer beneficial and synergistic effects in reducing or eliminating substance use disorder (SUD) patterns and symptoms. However, very little is known about SUD healthcare providers' perceptions of the usage of psychedelic-assisted therapy in SUD treatment. The present study assesses biomedical SUD healthcare providers' perceptions and concerns to better understand potential barriers to the effective implementation of psychedelic-based therapies and formulate further recommendations for research efforts surrounding them. This study collected data through a short survey and qualitative semi-structured interviews from nine participants involved in SUD patient treatment and care. Open discussion was encouraged in the interviews which were recorded and transcribed using the Otter app. Data was analyzed using Charmaz's two-step coding process, which identified common themes and specific issues about translating psychedelic-assisted therapy into clinical application. Four interconnected themes were identified: personal responsibility, patient safety and expectations, a call for further research, and societal structures as barriers. The findings of this study indicate that SUD healthcare providers have optimism and openness surrounding psychedelic-assisted therapy and generally view it as a positive treatment. However, this optimism was often followed by concerns for safety, legality, and the providers' role in this treatment. Participants also expressed a critical need for further research with rigorous clinical trials to explore the effectiveness of psychedelics in a therapeutic setting. The results provided in this study act as basis for engaging with biomedical SUD healthcare providers to address concerns about psychedelic-assisted therapy in future research for SUD treatment.

Human cultures have used classic psychedelics for healing purposes for millennia, emphasizing their subjective effects. In the 21st century, research has been revived to investigate the therapeutic effects of these substances. These substances show promising results in the treatment of various mental-related disorders such as depression, post-traumatic stress disorder, and others, necessitating ethical considerations and guidelines for researchers, psychotherapists, and policymakers. The subjective effects of the psychedelic experience that these substances evoke, such as the feeling of oneness and interconnectedness, infallibility, the sense of reduced one's self-importance, the encounter with the "ultimate" reality or with God, radically distinguish them from typical psychiatric medications such as selective serotonin reuptake inhibitors (SSRIs). In their essay "Ethics and Ego Dissolution: the Case of Psilocybin", William R. Smith and Dominic Sisti argue that the special properties of psychedelics entail certain novel risks that warrant "enhanced" informed consent that is "one that is more comprehensive than what may be typical for other psychiatric medications". They emphasize the unique effects of these substances, including 1) the potential for significant personality changes, 2) the short duration of treatment, and 3) the potential for profound and transformative experiences. They highlight the importance of explicitly addressing these potential changes as part of the informed consent process to ensure patient understanding, autonomy, and well-being. This current paper substantially complements Smith and Sisti's work by discussing in more detail the differences between psychedelics and typical psychiatric medications with respect to informed consent. I first support their arguments and then further argue that there are three other critical reasons why psychedelics should not be treated like other psychiatric medications that should be considered when discussing the enhancement of informed consent and disclosure. 1) potential changes in ethical values, 2) set and setting, and 3) suggestibility. To clarify my argument, I propose a distinction between changes in worldview and ethical values induced by the psychedelic experience and emphasize their differential impact on individuals undergoing psychedelic therapy. I introduce the term "ethical limbo", characterized as a state of uncertainty or ambiguity regarding the ethical implications or consequences of a particular action, decision, or situation due to conflicting ethical values, to highlight a potential risk of the psychedelic experience that should be considered in informed consent. Finally, I address potential objections to my arguments before concluding the paper and addressing some limitations of the research.

The intent of this study was to compare life value differences using the Life Values Inventory. Differences among non-psychedelic users and psychedelic users were examined. Participants, ranging from age 18 to 48 from the University of Central Florida (UCF), a large state university, were recruited on a voluntarily basis. This was primarily done through online message board, the Sona System, and classroom announcements. The study was presented through the Sona System provided by UCF. In addition, all participants were students of the university. Results indicated significant differences among three out of 14 life values measured. The three life values that were shown to be significantly different among the non-psychedelic users and psychedelic users were: 1) concern for others, 2) loyalty to family or group, and 3) responsibility. In addition, the life value of spirituality was only found to be marginally significant.

Objective: To investigate whether there is an association between use of cocaine, amphetamines, or psychedelics and psychotic symptoms. Method: Cumulated data from a prospective, longitudinal community study of 2588 adolescents and young adults in Munich, Germany were used. Substance use was assessed at baseline, 4-year and 10-year follow-up using the Munich Composite International Diagnostic Interview; psychotic symptoms were assessed at 4-year and 10-year follow-up. Multinomial logistic regression analyses, adjusted for sociodemographic factors, common mental disorders, other substance use, and childhood adversity (adjusted odds ratios, AOR), revealed associations between cocaine, amphetamine or psychedelic use and psychotic symptoms. Results: Lifetime experience of psychotic symptoms was associated with lifetime use of cocaine (AOR 1.94; 95%CI 1.10-3.45), amphetamines (AOR 1.69; 95%CI 0.98-2.93), psychedelics (AOR 2.37; 95%CI 1.20-4.66) and all three substances (AOR 1.95; 95%CI 1.19-3.18). Conclusion: Associations between psychotic symptoms and use of cocaine, amphetamines, and/or psychedelics in adolescents and young adults call for further studies to elucidate risk factors and developmental pathways.

Nous évoluons dans un monde incertain. De ce fait, notre survie dépend de notre capacité à prendre rapidement des décisions, et ce de manière fiable et adaptative. Il est possible de mieux comprendre cette capacité en considérant la perception comme un processus d’inférence probabiliste au cours duquel les informations sensorielles sont combinées à nos attentes pour produire une interprétation plausible de notre environnement. Les théories récentes de psychiatrie computationnelle suggèrent par ailleurs que la grande variabilité des troubles psychiatriques, au rang desquelles figure la schizophrénie, pourrait résulter d’une altération de ces mêmes processifs prédictifs. L’Inférence Circulaire est l’une de ces théories. Ce cadre de pensée stipule qu’une propagation incontrôlée d’information dans la hiérarchie corticale pourrait générer des percepts ou des croyances aberrantes. Afin d’explorer le rôle joué par l’Inférence Circulaire en condition normale ou pathologique, ce travail de thèse s’est appuyé sur des tâches de prise de décision en conditions perceptives ambigües. Dans une première partie, nous nous sommes intéressés au rôle joué par la circularité dans la perception bistable. Le phénomène de bistabilité survient lorsque deux interprétations se succèdent à intervalle régulier pour un même percept. Nous présentons les résultats d’une tâche conduite en population saine où nous avons manipulé les informations sensorielles et à priori utilisées par les participants lors de la visualisation d’un cube de Necker (article 1). Nous avons pu montrer un effet propre à chaque manipulation, mais également une interaction entre ces deux sources d’information, incompatible avec une intégration Bayésienne optimale. Résultat confirmé par la comparaison de divers modèles computationnels ajustés aux données, qui a pu mettre en évidence la supériorité de l’Inférence Circulaire sur les modèles Bayésiens classiques. Nous avons ensuite voulu tester un modèle fonctionnel de la bistabilité (article 2). Nous avons donc dérivé la dynamique du modèle et montré que la présence de boucles descendantes dans la hiérarchie corticale, transformait ce qui était jusque là un intégrateur imparfait du bruit sensoriel en modèle à attracteur bistable. Ce modèle ne reproduit pas seulement le phénomène de bistabilité, mais également l’ensemble de ces caractéristiques phénoménologiques. Dans un 3ème article, nous avons testé une prédiction, notamment en cas de présentation discontinue d’un stimulus bistable. Deux expériences complémentaires utilisant un paradigme de présentation intermittente du cube de Necker ont donc été conduites en population générale. Nos résultats étaient compatible avec les prédictions faites par le modèle de l’Inférence Circulaire Dynamique, suggérant que la circularité puisse être un mécanisme générique à l’origine de notre façon de voir le monde. Dans la seconde partie de ce travail, nous avons étudié l’Inférence Circulaire en condition pathologique, notamment lors d’expériences psychotiques (schizophrénie, psychédéliques). Nous avons utilisé la perception bistable pour explorer les mécanismes computationnels à l’œuvre dans la schizophrénie (article 4,5). Nous avons comparé les performances de patients présentant des symptômes psychotiques à des témoins sains appariés lors d’une tâche de perception bistable. Nous avons pu montrer chez les patients une amplification des informations sensorielles combinée à une surestimation de la volatilité environnementale. Enfin nous terminons ce travail en proposant une approche transversale de l’effet des psychédéliques (article 6), sur la base des résultats précédents et de la spécificité clinique de ces expériences sensorielles cross-modales, afin de relier l’échelle macroscopique (i.e., comportement et phénoménologie), mésoscopique (i.e., les boucles inférentielles) et microscopique (i.e., les différents neurotransmetteurs impliqués aboutissant à un microcircuit canonique). / We live in an uncertain world, yet our survival depends on how quickly and accurately we can make decisions and act upon them. To address this problem, modern neuroscience reconceptualised perception as an inference process, in which the brain combines sensory inputs and prior expectations to reconstruct a plausible image of the world. In addition to that, influential theories in the emerging field of computational psychiatry suggest that various psychiatric disorders, including schizophrenia, could be the outcome of impaired predictive processing. Among those theories, the circular inference framework suggests that an unconstrained propagation of information in the cortex, underlain by an excitatory to inhibitory imbalance, can generate false percepts and beliefs, similar to those exhibited by schizophrenia patients. In the present thesis, we probed the role of circular inference from normal to pathological brain functioning, gaining insights from perceptual decision making in the presence of high ambiguity. In the first part of the thesis, we focused on the role of circularity in bistable perception in the general population. Bistability occurs when two mutually exclusive interpretations compete and switch as dominant percepts every few seconds. In a 1st article, we manipulated sensory evidence and priors in a Necker cube task, asking how the brain combines low-level and high-level information to form perceptual interpretations. We found a significant effect of each manipulation but also an interaction between the two, a finding incompatible with Bayes optimal integration. Bayesian model comparison further supported this observation, showing that a circular inference model outperformed purely Bayesian models. Having established a link between circular inference and bistable perception, we then put forward a functional theory of bistability, based on circularity (2nd article). In particular, we derived the dynamics of a dynamical circular inference model, showing that descending loops (i.e. a form of circularity resulting in aberrant amplification of the priors) transform what is normally a leaky integration of noisy evidence into a bistable attractor with two highly trusted stable states. Importantly, this model can explain both the existence and the phenomenological properties of bistable perception, making a number of testable predictions. Finally, in a 3rd article, we tested one of the model’s predictions, namely the perceptual behaviour when the stimulus is presented discontinuously. We ran two Necker cube experiments using a novel intermittent-presentation methodology, and we calculated the stabilisation curves (i.e. persistence as a function of blank durations). We found that participants’ behaviour was compatible with the model’s prediction for a system with descending loops, suggesting that circularity constitutes a general mechanism that shapes the way healthy individuals perceive the world. In the second part, we studied circular inference in pathological conditions related to psychosis. We notably focused on two varieties of the psychotic experience, namely schizophrenia-related psychosis and drug-induced psychosis. After discussing the links between behaviour, aberrant message-passing and the corresponding neural networks (4th article), we used bistable perception to probe the computational mechanisms underlying schizophrenia in a 5th article. We compared patients with prominent positive symptoms with matched healthy controls in two bistable perception tasks. Our results suggest an enhanced amplification of sensory inputs in patients, combined with an overestimation of the environmental volatility. In the last article (6th), we delineated a multiscale account of psychedelics, ultimately linking the macroscale (i.e. phenomenological considerations such as the crossmodal character of the psychedelics experience), the mesoscale (i.e. loops) and the microscale (i.e. neuromodulators and canonical microcircuits).

No description available.

Objective: To investigate whether there is an association between use of cocaine, amphetamines, or psychedelics and psychotic symptoms. Method: Cumulated data from a prospective, longitudinal community study of 2588 adolescents and young adults in Munich, Germany were used. Substance use was assessed at baseline, 4-year and 10-year follow-up using the Munich Composite International Diagnostic Interview; psychotic symptoms were assessed at 4-year and 10-year follow-up. Multinomial logistic regression analyses, adjusted for sociodemographic factors, common mental disorders, other substance use, and childhood adversity (adjusted odds ratios, AOR), revealed associations between cocaine, amphetamine or psychedelic use and psychotic symptoms. Results: Lifetime experience of psychotic symptoms was associated with lifetime use of cocaine (AOR 1.94; 95%CI 1.10-3.45), amphetamines (AOR 1.69; 95%CI 0.98-2.93), psychedelics (AOR 2.37; 95%CI 1.20-4.66) and all three substances (AOR 1.95; 95%CI 1.19-3.18). Conclusion: Associations between psychotic symptoms and use of cocaine, amphetamines, and/or psychedelics in adolescents and young adults call for further studies to elucidate risk factors and developmental pathways.

No description available.

Psychiatric disorders are believed to result from the combination of genetic predisposition and many environmental triggers. While the large number of disease-associated genetic variations have been recognized by previous genome-wide association studies (GWAS), the role of epigenetic mechanisms that mediate the effects of environmental factors on CNS gene activity in the etiology of most mental illnesses is still largely unclear. A growing body of evidence suggested that the abnormalities (changes in gene expression, formation of neural circuits, and behavior) involved in most psychiatric syndromes are preserved by epigenetic modifications identified in several specific brain regions. In this thesis, we developed the second generation of one of our microfluidic technologies (MOWChIP-seq) and used it to profile genome-wide histone modifications in three mental illness-related biological studies: the effect of psychedelics in mice, schizophrenia, and the effect of maternal immune activation in mice offspring. The second generation of MOWChIP-seq was designed to generate histone modification profiles from as few as 100 cells per assay with a throughput as high as eight assays in each run. Then, we applied the new MOWChIP-seq and SMART-seq2 to profile the histone modification H3K27ac and transcriptome, respectively, using NeuN+ neuronal nuclei from the mouse frontal cortex after a single dose of psychedelic administration. The epigenomic and transcriptomic changes induced by 2,5-Dimethoxy-4-iodoamphetamine (DOI), a subtype of psychedelics, in mouse neuronal nuclei at various time points suggest that the long-lasting effects of the psychedelic are more closely related to epigenomic alterations than the changes in transcriptomic patterns. Next, we comprehensively characterized epigenomic and transcriptomic features from the frontal cortex of 29 individuals with schizophrenia and 29 individually matched controls (gender and age). We found that schizophrenia subjects exhibited thousands of neuronal vs. glial epigenetic differences at regions that included several susceptibility genetic loci, such as NRXN1, RGS4 and GRIN3A. Finally, we investigated the epigenetic and transcriptomic alterations induced by the maternal immune activation (MIA) in mice offspring's frontal cortex. Pregnant mice were injected with influenza virus at GD 9.5 and the frontal cortex from mice pups (10 weeks old) were examined later. The results offered us some insights into the contribution of MIA to the etiology of some mental disorders, like schizophrenia and autism. / Doctor of Philosophy / While this field is still in its early stage, the epigenetic studies of mental disorders present promise to expand our understanding about how environmental stimulates, interacting with genetic factors, contribute to the etiology of various psychiatric syndromes, like major depression and schizophrenia. Previous clinical trials suggested that psychedelics may represent a promising long-lasting treatment for patients with depression and other psychiatric conditions. These research presented the therapeutic potential of psychedelic compounds for treating major depression and demonstrated the capability of psychedelics in increasing dendritic density and stimulating synapse formation. However, the molecular mechanism mediating the clinical effectiveness of psychedelics remain largely unexplored. Our study revealed that epigenomic-driven changes in synaptic plasticity sustain psychedelics' long-lasting antidepressant action. Another serious mental illness is schizophrenia, which could affect how an individual feels, thinks, and behaves. Like most other mental disorders, schizophrenia results from a combination of genetic and environmental causes. Epigenetic marks allow a dynamic impact of environmental factors, including antipsychotic medications, on the access to genes and regulatory elements. Despite this, no study so far has profiled cell-type-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects or the effect of antipsychotic treatment on such epigenetic marks. Here we show the first comprehensive epigenomic characterization of the frontal cortex of 29 individuals with schizophrenia and 29 matched controls. The process of brain development is surprisingly sensitive to a lot of environmental insults. Epidemiological studies have recognized maternal immune activation as a risk factor that may change the normal developmental trajectory of the fetal brain and increase the odds of developing a range of psychiatric disorders, including schizophrenia and autism, in its lifetime. Given the prevalence of the coronavirus, uncovering the molecular mechanism underlie the phenotypic alterations has become more urgent than before, for both prevention and treatment.