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      Neural correlates of the LSD experience revealed by multimodal neuroimaging.

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          Abstract

          Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD's marked effects on the visual cortex did not significantly correlate with the drug's other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of "ego-dissolution" and "altered meaning," implying the importance of this particular circuit for the maintenance of "self" or "ego" and its processing of "meaning." Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.

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          Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study.

          Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms.
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            Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction.

            Despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow-up has not been conducted. To determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment we conducted an open-label pilot study administering moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin within a structured 15-week smoking cessation treatment protocol. Participants were 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of six previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake. Biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. The observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically <35%). Although the open-label design does not allow for definitive conclusions regarding the efficacy of psilocybin, these findings suggest psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models. The present study illustrates a framework for future research on the efficacy and mechanisms of hallucinogen-facilitated treatment of addiction.
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              Is Open Access

              The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs

              Entropy is a dimensionless quantity that is used for measuring uncertainty about the state of a system but it can also imply physical qualities, where high entropy is synonymous with high disorder. Entropy is applied here in the context of states of consciousness and their associated neurodynamics, with a particular focus on the psychedelic state. The psychedelic state is considered an exemplar of a primitive or primary state of consciousness that preceded the development of modern, adult, human, normal waking consciousness. Based on neuroimaging data with psilocybin, a classic psychedelic drug, it is argued that the defining feature of “primary states” is elevated entropy in certain aspects of brain function, such as the repertoire of functional connectivity motifs that form and fragment across time. Indeed, since there is a greater repertoire of connectivity motifs in the psychedelic state than in normal waking consciousness, this implies that primary states may exhibit “criticality,” i.e., the property of being poised at a “critical” point in a transition zone between order and disorder where certain phenomena such as power-law scaling appear. Moreover, if primary states are critical, then this suggests that entropy is suppressed in normal waking consciousness, meaning that the brain operates just below criticality. It is argued that this entropy suppression furnishes normal waking consciousness with a constrained quality and associated metacognitive functions, including reality-testing and self-awareness. It is also proposed that entry into primary states depends on a collapse of the normally highly organized activity within the default-mode network (DMN) and a decoupling between the DMN and the medial temporal lobes (which are normally significantly coupled). These hypotheses can be tested by examining brain activity and associated cognition in other candidate primary states such as rapid eye movement (REM) sleep and early psychosis and comparing these with non-primary states such as normal waking consciousness and the anaesthetized state.
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                Author and article information

                Journal
                Proc. Natl. Acad. Sci. U.S.A.
                Proceedings of the National Academy of Sciences of the United States of America
                1091-6490
                0027-8424
                Apr 26 2016
                : 113
                : 17
                Affiliations
                [1 ] Centre for Neuropsychopharmacology, Department of Medicine, Imperial College London, W12 0NN, London, United Kingdom; r.carhart-harris@imperial.ac.uk.
                [2 ] Department of Psychology, Cardiff University Brain Research Imaging Centre, CF10 3AT, Cardiff, United Kingdom; School of Pharmacy, University of Auckland, 1142 Auckland, New Zealand; School of Psychology, University of Auckland, 1142 Auckland, New Zealand;
                [3 ] Centre for Neuropsychopharmacology, Department of Medicine, Imperial College London, W12 0NN, London, United Kingdom; Computational, Cognitive and Clinical Neuroscience Laboratory, Department of Medicine, Imperial College London, W12 0NN, London, United Kingdom;
                [4 ] Centre for Neuropsychopharmacology, Department of Medicine, Imperial College London, W12 0NN, London, United Kingdom;
                [5 ] Department of Psychology, Cardiff University Brain Research Imaging Centre, CF10 3AT, Cardiff, United Kingdom;
                [6 ] Institute of Medical Psychology, Christian Albrechts University, 24118 Kiel, Germany; Brain Imaging Center and Neurology Department, Goethe University, 60528 Frankfurt am Main, Germany;
                [7 ] Centre for Neuropsychopharmacology, Department of Medicine, Imperial College London, W12 0NN, London, United Kingdom; Department of Psychiatry, Universidade Federal de São Paulo, 04038-020, São Paulo, Brazil; Instituto Plantando Consciencia, 05.587-080, São Paulo, Brazil;
                [8 ] Department of Psychiatry, McGill University, H3A 1A1, Montréal, Canada;
                [9 ] Computational, Cognitive and Clinical Neuroscience Laboratory, Department of Medicine, Imperial College London, W12 0NN, London, United Kingdom;
                [10 ] Department of Psychiatry, University of Bristol, BS8 2BN, Bristol, United Kingdom;
                [11 ] Centre for Neuropsychopharmacology, Department of Medicine, Imperial College London, W12 0NN, London, United Kingdom; Department of Neuroscience, Cardiff University, CF24 4HQ, Cardiff, United Kingdom;
                [12 ] Birkbeck-UCL Centre for Neuroimaging, WC1H 0AP, London, United Kingdom;
                [13 ] Eschelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27514;
                [14 ] Clinical Psychopharmacology Unit, University College London, WC1E 6BT, London, United Kingdom;
                [15 ] The Beckley Foundation, Beckley Park, OX3 9SY, Oxford, United Kingdom.
                Article
                1518377113
                10.1073/pnas.1518377113
                27071089
                1b24fad5-3c5d-41c8-9474-3b0e35bbedc6
                History

                LSD,brain,consciousness,psychedelic,serotonin
                LSD, brain, consciousness, psychedelic, serotonin

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