Assessing the Psychedelic “After-Glow” in Ayahuasca Users: Post-Acute Neurometabolic and Functional Connectivity Changes Are Associated with Enhanced Mindfulness Capacities

International Journal of Neuropsychopharmacology (2017) 20(9): 698–711 doi:10.1093/ijnp/pyx036 Advance Access Publication: June 13, 2017 Regular Research Article regular research article Assessing the Psychedelic “After-Glow” in Ayahuasca Users: Post-Acute Neurometabolic and Functional Connectivity Changes Are Associated with Enhanced Mindfulness Capacities Frederic Sampedro, MSc; Mario de la Fuente Revenga, PhD; Marta Valle, PhD; Natalia Roberto, MSc; Elisabet Domínguez-Clavé, MSc; Matilde Elices, PhD; Luís Eduardo Luna, PhD; José Alexandre S. Crippa, PhD; Jaime E. C. Hallak, PhD; Draulio B. de Araujo, PhD; Pablo Friedlander, MSc; Steven A. Barker, PhD; Enrique Álvarez, PhD; Joaquim Soler, PhD; Juan C. Pascual, PhD; Amanda Feilding, MSc; Jordi Riba, PhD School of Medicine, Autonomous University of Barcelona, Barcelona, Spain (Mr Sampedro); Human Neuropsychopharmacology Research Group, Sant Pau Institute of Biomedical Research, Barcelona, Spain (Dr de la Fuente Revenga, Ms Roberto, and Dr Riba); Pharmacokinetic and Pharmacodynamic Modelling and Simulation, Sant Pau Institute of Biomedical Research, Barcelona, Spain (Dr Valle); Centre d’Investigació de Medicaments, Servei de Farmacologia Clínica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (Drs Valle and Riba); Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain (Drs Valle, Elices, Álvarez, Soler, Pascual, and Riba); Department of Pharmacology and Therapeutics, Autonomous University of Barcelona, Barcelona, Spain (Dr Valle); Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (Ms Domínguez-Clavé and Drs Elices, Álvarez, Soler, and Pascual); Department of Psychiatry and Forensic Medicine, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain (Ms Domínguez-Clavé and Drs Elices, Álvarez, and Pascual); Research Center for the Study of Psychointegrator Plants, Visionary Art and Consciousness, Florianópolis, Santa Catarina, Brazil (Dr Luna); Department of Neuroscience and Behavior, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil and National Institute for Translational Medicine, Ribeirão Preto, Brazil (Drs Crippa and Hallak); Brain Institute/Hospital Universitario Onofre Lopes, Natal, Brazil (Dr de Araujo); The Beckley Foundation, Beckley Park, Oxford, United Kingdom (Mr Friedlander and Mrs Feilding); Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Drive at River Road, Baton Rouge, Louisiana (Dr Barker); Department of Clinical and Health Psychology, School of Psychology, Autonomous University of Barcelona, Barcelona, Spain (Dr Soler). Correspondence: Jordi Riba, PhD, Human Neuropsychopharmacology Research Group, IIB-Sant Pau.C/Sant Antoni María Claret 167, 08025, Barcelona, Spain (). Received: October 4, 2016; Revised: May 10, 2017; Accepted: May 17, 2017 © The Author 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact 698 Sampedro et al. | 699 Significance Statement Psychedelics are intriguing drugs that induce transient but intense modifications in perception, emotion, and cognition. Despite human use dating back millennia, their mechanism of action is still poorly understood. Recent research in patients has shown that ayahuasca, a plant psychedelic used traditionally in the Amazon for religious and medicinal purposes, exerts rapid and potent antidepressant effects in treatment-resistant patients. These beneficial effects are observed after a single dose and intriguingly persist for weeks, long after the immediate acute effects have disappeared. Here we demonstrate using 2 neuroimaging techniques that during the post-acute phase, that is within 24 hours after intake, ayahuasca leads to metabolic and connectivity changes in the brain. These changes are associated with enhanced psychological capacities that are beneficial in the therapeutic context. These findings provide a biological basis for the post-acute or “after-glow” stage of psychedelic effects, and contribute to elucidate the therapeutic mechanisms of these substances. Abstract Background: Ayahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyltryptamine and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network, purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here, we investigated in an open-label uncontrolled study in 16 healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications and their association with mindfulness measures. Methods: Using 1H-magnetic resonance spectroscopy and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior and anterior cingulate cortex after a single ayahuasca dose. Results: Magnetic resonance spectroscopy showed post-acute reductions in glutamate+glutamine, creatine, and N-acetylaspartate+N-acetylaspartylglutamate in the posterior cingulate cortex. Connectivity was increased between the posterior cingulate cortex and the anterior cingulate cortex, and between the anterior cingulate cortex and limbic structures in the right medial temporal lobe. Glutamate+glutamine reductions correlated with increases in the “nonjudging” subscale of the Five Facets Mindfulness Questionnaire. Increased anterior cingulate cortex-medial temporal lobe connectivity correlated with increased scores on the self-compassion questionnaire. Post-acute neural changes predicted sustained elevations in nonjudging 2 months later. Conclusions: These results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the posterior cingulate cortex, a key region within the default mode network, and increased connectivity between the anterior cingulate cortex and medial temporal lobe structures involved in emotion and memory potentially underlie the post-acute psychological effects of ayahuasca. Keywords: ayahuasca, psychedelic after-effects, magnetic resonance imaging, mindfulness, human Introduction Psychedelics are the object of renewed interest as potential therapeutic tools in psychiatry (Sessa, 2005; Vollenweider and Kometer, 2010; Grob et al., 2011). Among these substances is ayahuasca (...truncated)