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Psychedelics 1521-0081/68/2/264–355$25.00 http://dx.doi.org/10.1124/pr.115.011478 PHARMACOLOGICAL REVIEWS Pharmacol Rev 68:264–355, April 2016 Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: ERIC L. BARKER Psychedelics David E. Nichols Eschelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina Abstract ...................................................................................266 I. Introduction . ..............................................................................266 A. Historical Use . ........................................................................268 B. What Are Psychedelics?................................................................268 C. Psychedelics Can Engender Ecstatic States with Persistent Positive Personality Change . ..................................................................271 II. Safety of Psychedelics......................................................................273 A. General Issues of Safety and Mental Health in Psychedelic Users.......................275 B. Adverse Reactions . ..................................................................276 C. Hallucinogen Persisting Perception Disorder . ..........................................277 D. N-(2-methoxybenzyl)-2,5-dimethoxy-4-substituted phenethylamines (NBOMe) Compounds............................................................................278 Downloaded from III. Mechanism of Action.......................................................................279 A. Evidence for Agonist or Partial Agonist Action at Serotonin 5-Hydroxytryptamine 2A Receptors ....................................................280 B. Production of Tolerance ................................................................281 C. Functional Selectivity at the Serotonin 5-Hydroxytryptamine 2A Receptor . .............283 by guest on August 20, 2017 D. Role of Glutamate . ..................................................................290 E. A Role for g-Aminobutyric Acid . ......................................................295 F. Possible Role of Other Receptors . ......................................................295 IV. Where Is the Serotonin 5-Hydroxytryptamine 2A Receptor Expressed? . ...................299 A. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in the Cortex ..................300 B. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in the Thalamus and Reticular Nucleus .................................................................301 C. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in Primary Visual Cortex V1 . 302 D. Effects of Psychedelics on Raphe Cell Firing. ..........................................302 E. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in the Ventral Tegmental Area .......................................................................302 F. Effect of Psychedelics on the Locus Coeruleus ..........................................303 G. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in the Amygdala . .............304 H. A Role for the Claustrum? . ............................................................305 V. Effects on Visual Perception . ............................................................306 VI. Effects on Sleep............................................................................309 VII. Effects on Time Perception.................................................................309 VIII. Use of Animal Models......................................................................311 A. Rat Models ............................................................................312 1. Drug Discrimination................................................................312 2. Effects on Locomotor Activity . ......................................................315 3. Prepulse Inhibition .................................................................315 B. Mouse Models . ........................................................................315 1. Head Twitch Response . ............................................................316 This research was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01DA-02189] and the Robert C. and Charlotte P. Anderson endowment. Address correspondence to: Dr. David E. Nichols, Eschelman School of Pharmacy, University of North Carolina, 120 Mason Farm Road, 2113 Genetic Medicine Bldg, Chapel Hill, NC 27514. E-mail: [email protected] dx.doi.org/10.1124/pr.115.011478. 264 An erratum has been published: /content/68/2/356.full.pdf Psychedelics 265 2. Drug Discrimination................................................................317 3. Effects on Locomotor Activity . ......................................................318 C. Rabbit Models . ........................................................................319 D. Zebrafish Models ......................................................................321 E. Drosophila melanogaster. ............................................................321 F. Monkey Models ........................................................................322 IX. Potential Therapeutic Value for Psychedelics ...............................................323 A. Alleviation of Anxiety and Depression in Life-Threatening Illness.......................323 B. Possible Use in Depression. ............................................................326 C. Obsessive-Compulsive Disorder . ......................................................328 D. Treatment of Alcoholism or Nicotine Addiction .........................................329 E. Cluster Headaches. ..................................................................329 F. Autism . ..............................................................................330 ABBREVIATIONS: 2C-I, 2-(4-iodo-2,5-dimethoxyphenyl)aminoethane; 2C-T-7, 2,5-dimethoxy-4-n-propylthiophenethylamine; 5-CSRTT, five-choice serial reaction time task; 5-HT, 5-hydroxytryptamine (serotonin); 5-HTP, L-5-hydroxytryptophan; 5-MeO-DIPT, 5-methoxy-N,N-diisopropyltryptamine; 5-MeO-DMT, 5-methoxy-N,N-dimethyltryptamine; 5D-ASC, five-dimensional altered states of consciousness; 8-OH-DPAT, 7-(dipropylamino)-1,2,3,4- tetrahydronaphthalene; A-381393, 2-[4-(3,4-dimethylphenyl)piperazin-1-ylmethyl]-1H-benzoimidazole; AA, arachidonic acid; ABT-724, 2-[(4-pyridin-2- ylpiperazin-1-yl)methyl]-1H-benzimidazole); ACC, anterior cingulate cortex; ACh, acetylcholine; ACP-103, N-(4-fluorophenylmethyl)-N-(1-methylpiper- idin-4-yl)-N9-(4-(2-methylpropyloxy)phenylmethyl)carbamide; AD, Alzheimer’s disease; AMRS, Adjective Mood Rating Scale; AMS, a-methylserotonin; APZ, Abnormal Mental States; ASC, altered state of consciousness; ASR, acoustic startle response; BDI, Beck Depression Inventory; BDNF, brain- derived neurotrophic factor; BOL, BOL-148, 2-bromo-lysergic acid-N,N-diethylamide; BOLD, blood oxygen level–dependent; BP554, 1-[3-(3,4- methylenedioxyphenoxy)propyl]-4-phenyl-piperazine; BPD, borderline personality disorder; BPM, behavioral pattern monitor; CBF, cerebral blood flow; CHO, Chinese hamster ovary; CIMBI-5, N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine; Cimbi-36, N-(2-[11C]methoxybenzyl)-2,5-dimethoxy- 4-bromophenethylamine; CMRglu, cerebral metabolic rate of glucose; CNS, central nervous system; CRPD, cancer-related psychosocial distress; CSTC, cortico–striato–thalamocortical; CT, complete transection; DH, double hemisection; DMN, default mode network; DMT, N,N-dimethyltryptamine; DOB, 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane; DOC, 1-(4-chloro-2,5-dimethoxyphenyl)-2-aminopropane; DOI, 1-(4-iodo-2,5-dimethoxyphenyl)-2- aminopropane; DOM, 2,5-dimethoxy-4-methylamphetamine; DPT, N,N-dipropyltryptamine; DSA, dichoptic stimulus alternation; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; EEG, electroencephalography; EGF, epidermal growth factor; EGFP, enhanced green fluorescent protein; EMD 281014, 7-[[4-[2-(4-fluorophenyl)ethyl]-1-piperazinyl]carbonyl]-1H-indole-3-carbonitrile hydrochloride; EPSC, excitatory postsynaptic current; EPSP, excitatory postsynaptic potential; ERK, extracellular signal-regulated kinase; FAIR, Frankfurt Attention Inventory; FDG, fludeoxyglucose; fMRI, functional magnetic resonance imaging; FR, fixed ratio; GAD, glutamate decarboxylase; GPCR, G protein–coupled receptor; GTPgS, guanosine 59-3-O-(thio)triphosphate; H-reflex, Hoffman reflex; HAM-A, Hamilton Rating Scale for Anxiety; HAM-D, Hamilton Rating Scale for Depression; HEK-293, human embryonic kidney 293; HPPD, hallucinogen persisting perception disorder; HTR, head twitch response; i3, intracellular loop 3; IL, interleukin; IOP, intraocular pressure; IP, inositol phosphate; ISI, interstimulus interval; JHU, Johns Hopkins University; KO, knockout; L- 745,870, 3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-1-1H-pyrrolo[2,3-b]pyridine; LC, locus coeruleus; LFCO, low frequency cortical oscillation; LFP, local field potential; LOC, lateral occipital complex; LSD, (5R,8R)-(+)-lysergic acid-N,N-diethylamide; LY293558, (3S,4aR,6R,8aR)-6-[2-(2H-tetrazol-5-yl) ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid; LTP, long-term potentiation; LY294002, 2-morpholin-4-yl-8-phenylchromen-4-one; LY341495, 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine; LY354740, (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; LY379268 [(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid; LY566332, N-(49-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-
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