Supplemental Material can be found at: /content/suppl/2020/12/18/73.1.202.DC1.html 1521-0081/73/1/202–277$35.00 https://doi.org/10.1124/pharmrev.120.000056 PHARMACOLOGICAL REVIEWS Pharmacol Rev 73:202–277, January 2021 Copyright © 2020 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: MICHAEL NADER Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanismss Antonio Inserra, Danilo De Gregorio, and Gabriella Gobbi Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada Abstract ...................................................................................205 Significance Statement. ..................................................................205 I. Introduction . ..............................................................................205 A. Review Outline ........................................................................205 B. Psychiatric Disorders and the Need for Novel Pharmacotherapies .......................206 C. Psychedelic Compounds as Novel Therapeutics in Psychiatry: Overview and Comparison with Current Available Treatments . .....................................206 D. Classical or Serotonergic Psychedelics versus Nonclassical Psychedelics: Definition ......208 Downloaded from E. Dissociative Anesthetics................................................................209 F. Empathogens-Entactogens . ............................................................209 G. Full Dosing versus Microdosing . ......................................................209 H. Historical Studies ......................................................................210 I. Ongoing Clinical Trials.................................................................210 by guest on September 26, 2021 II. Psychedelic Compounds as Neuroplastic Agents . ..........................................211 A. Neuroplasticity Impairments in Psychiatric Disorders . ...............................211 B. Effects of Psychedelic Compounds on Neuronal and Synaptic Plasticity..................223 1. Ketamine. ........................................................................223 2. N,N-Dimethyltryptamine, 5-Methoxy-N,N-dimethyltryptamine, and Ayahuasca ......224 3. Lysergic Acid Diethylamide . ......................................................226 4. Psilocybin . ........................................................................227 5. 3,4-Methylenedioxymethamphetamine...............................................227 III. Psychedelic Compounds as Immunomodulatory and Anti-Inflammatory Agents. .............227 A. Inflammation . ........................................................................227 B. Inflammation-Induced Psychiatric Symptoms . ..........................................228 C. Anti-Inflammatory Therapies in the Treatment of Psychiatric Disorders.................228 D. Immunomodulatory and Anti-Inflammatory Pathways Activated by Psychedelics . .......228 1. N,N-Dimethyltryptamine, 5-Methoxy-N,N-dimethyltryptamine, and Ayahuasca ......230 2. Psilocybin . ........................................................................230 3. Lysergic Acid Diethylamide . ......................................................231 4. 2,5-Dimethoxy-4-iodoamphetamine . ................................................231 5. 3,4-Methylenedioxymethamphetamine...............................................231 6. Ketamine. ........................................................................231 E. s1 Receptor............................................................................232 Address correspondence to: Gabriella Gobbi, Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, 1033, Av. des Pins Ouest, Montreal, QC H3A 1A1, Canada. E-mail: [email protected] This work was supported by the Canadian Institute for Health Research (CIHR) [Grant # 436986] and by the Réseau Québécois sur le Suicide, les Troubles de l’Humeur et les Troubles Associés (RQSHA) [Grant # 268065]. D.D.G. is recipient of Fond Recherche Québec-Santé (FRQS) and Canadian Institutes for Health Research (CIHR) postdoctoral fellowships. G.G. is a consultant for Diamond Therapeutic Inc. The other authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. s This article has supplemental material available at pharmrev.aspetjournals.org. https://doi.org/10.1124/pharmrev.120.000056. 202 Psychedelics in Psychiatry: Therapeutic Mechanisms 203 IV. Psychedelic Compounds as Modulators of Neurotransmitter Systems........................232 A. Neurotransmitter Dysfunctions in Psychiatric Disorders . ...............................232 B. Serotonin ..............................................................................234 1. Lysergic Acid Diethylamide . ......................................................234 2. 3,4-Methylenedioxymethamphetamine...............................................234 3. N,N-Dimethyltryptamine, 5-Methoxy-N,N-dimethyltryptamine, and Ayahuasca ......235 4. Ketamine. ........................................................................236 5. Psilocybin . ........................................................................236 C. Dopamine..............................................................................237 1. Ketamine. ........................................................................237 2. Lysergic Acid Diethylamide . ......................................................237 3. 3,4-Methylenedioxymethamphetamine...............................................237 4. N,N-Dimethyltryptamine, 5-Methoxy-N,N-dimethyltryptamine, and Ayahuasca ......238 D. Glutamate .............................................................................238 1. Lysergic Acid Diethylamide . ......................................................238 2. Psilocybin . ........................................................................239 3. Ketamine. ........................................................................239 4. 3,4-Methylenedioxymethamphetamine...............................................239 5. N,N-Dimethyltryptamine, Ayahuasca, 5-Methoxy-N,N-dimethyltryptamine...........240 E. GABA . ..............................................................................240 1. Ketamine. ........................................................................240 2. Lysergic Acid Diethylamide . ......................................................241 3. 3,4-Methylenedioxymethamphetamine...............................................241 4. Psilocybin . ........................................................................241 5. N,N-Dimethyltryptamine, 5-Methoxy-N,N-dimethyltryptamine, Ayahuasca...........241 F. Norepinephrine ........................................................................241 1. Ketamine. ........................................................................242 ABBREVIATIONS: ACC, anterior cingulate cortex; ACTH, adrenocorticotropic hormone; AD, Alzheimer’s disease; ADRA, a adrenergic receptor; ADRB, b adrenergic receptor; AIDS, acquired immunodeficiency syndrome; ALD-52, 1-acetyl-LSD; ALT, alternative lengthening of telomeres; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AN, anorexia nervosa; ANIA3, activity and neurotransmitter-in- duced early gene 3; AR, androgen receptor; ASD, autism spectrum disorder; AUD, alcohol use disorder; BD, bipolar disorder; BDNF, brain- derived neurotrophic factor; 1B-LSD, 1-butanoyl-LSD; CA, cornu ammonis; CACNA1A, voltage-dependent P/Q-type calcium channel subunit alpha-1A; CAMK2, calcium/calmodulin-dependent protein kinase 2; CCL5, C-C motif chemokine 5; CEBPB, CCAAT/enhancer-binding protein beta; cFOS, proto-oncogene c-Fos; CHRM, muscarinic acetylcholine receptor M2; COMT, catechol O-methyltransferase; CORT, cortisol; CREB, cAMP response element-binding protein; CRF, corticotropin-releasing factor; CSTC, cortico-striato-thalamo-cortical; CX3CL1, fractalkine CXCL10 C-X-C motif chemokine 10; DA, dopamine; DAT, dopamine transporter; DHEA, dehydroepiandrosterone; D2L, dopamine 2 receptor (long splice variant); DMN, default mode network; DMT, N,N-dimethyltryptamine; DOI, 2,5-dimethoxy-4-iodoamphetamine; DRN, dorsal raphe nucleus; EAAT, excitatory amino acid transporter; EEG, electroencephalogram; EGR, early growth response; EPAC1, rap guanine nucleotide exchange factor 3; ERK, extracellular signal–regulated kinase; FDA, Food and Drug Administration; fMRI, functional magnetic resonance imaging; FPTC, frontoparietal task control network; GAT, GABA transporter; GABR, gamma-aminobutyric acid type B receptor; GH, growth hormone; GLU, glutamate; GPCR, G protein–coupled receptor; 5-GSyl-a-MeDA, 5-(glutathion-Syl)-a-methyldopamine; 6-HO- MDMA, 2-hydroxy-4,5(methylenedioxy)methamphetamine; HPA, hypothalamic-pituitary-adrenal axis; HRH, histamine receptor; 5-HT, se- rotonin; I1, imidazoline receptor 1; ICAM, intercellular adhesion molecule; IDO, indoleamine 2,3-dioxygenase; IFN-g, interferon-g; IKB, inhibitor of kB kinase; IL, interleukin; iNOS, inducible nitric oxide synthase; IP3R, inositol trisphosphate receptor; KROX20, early growth response protein 2; LC, locus coeruleus; LSD, lysergic acid diethylamide; M3, muscarinic receptor subtype 3; M5, muscarinic receptor subtype 5; MAOI, monoamine oxidase inhibitor; MAPK1, mitogen-activated protein kinase 1; MCI, mild cognitive impairment; MCP1, monocyte chemoattractant