1521-0081/68/2/264–355$25.00
`PHARMACOLOGICAL REVIEWS
`Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
`
`http://dx.doi.org/10.1124/pr.115.011478
`Pharmacol Rev 68:264–355, April 2016
`
`ASSOCIATE EDITOR: ERIC L. BARKER
`
`Psychedelics
`
`David E. Nichols
`Eschelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
`
`Downloaded from
`
`pharmrev.aspetjournals.org
`
` at Univ of North Carolina-Chapel Hill on February 4, 2016
`
`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
`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
`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: drdave@purdue.edu
`dx.doi.org/10.1124/pr.115.011478.
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`264
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`EXHIBIT B
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`Psychedelics
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`265
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`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)-
`ethanesulfonamide hydrochloride; M100907, (R)-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol; MAO, monoamine oxidase;
`MAPK, mitogen-activated protein kinase; MDD, major depressive disorder; MDL100907, (R)-(+)- a -(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-
`piperinemethanol; MDL11939, a-phenyl-1-(2-phenylethyl)-4-piperidine methanol; MDMA, 3,4-methylenedioxymethamphetamine; MEF, mouse
`embryonic fibroblast; MEG, magnetoencephalography; MEK, mitogen-activated protein kinase kinase; mGluR, metabotropic glutamate receptor;
`MK-212, 6-chloro-2-(1-piperazinyl)pyrazine; MK-801, (5R,10S)-(2)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cylcohepten-5,10-imine; MPEP, 2-methyl-6-
`(phenylethynyl)-pyridine; mPFC, medial prefrontal cortex; MUA, multiunit activity; NE, norepinephrine; NMDA, N-methyl-D-aspartate; NMS, N-
`methylspiperone; NSDUH, National Survey on Drug Use and Health; NT-3, neurotrophin-3; NYU, New York University; OCD, obsessive-compulsive
`disorder; OFC, orbitofrontal cortex; OVA, ovalbumin; PAG, periaqueductal gray matter; PCC, posterior cingulate cortex; PCP, phencyclidine; PCR,
`polymerase chain reaction; PD, Parkinson’s disease; PD98059, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; PET, positron emission
`tomography; PFC, prefrontal cortex; phMRI, pharmacological magnetic resonance imaging; PI, phosphoinositide; PI3K, phosphoinositide 3-kinase;
`PKC, protein kinase C; PLA2, phospholipase A2; PLC, phospholipase C; PMA, phorbol ester; PP2, 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo
`[3,4-d]pyrimidine; PPI, prepulse inhibition; PTSD, post-traumatic stress disorder; RA, rheumatoid arthritis; REM, rapid eye movement; Ro25-6981,
`(aR,bS)-a-(4-hydroxyphenyl)-b-methyl-4-(phenylmethyl)-1-piperidinepropanol; Ro60-0175, (S)-6-chloro-5-fluoro-1H-indole-2-propanamine; ROI, region of
`interest; RS102221, N-{5-[5-(2,4-dioxo-1,3,8-triazaspiro[4.5]dec-8-yl)pentanoyl]-2,4-dimethoxyphenyl}-4-(trifluoromethyl)benzenesulfonamide; RSC, retro-
`splenial cortex; RSK, ribosomal S6 kinase; RT, reverse transcription; SB-206553, 3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b’]dipyrrole-1(2H)-
`carboxamide hydrochloride; SB-242084, 6-chloro-5-methyl-N-{6-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}indoline-1-carboxamide; SB-243213, 2,3-dihydro-
`5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-6-(trifluoromethyl)-1H-indole-1-carboxamide; SCH23390, 7-chloro-3-methyl-1-phenyl-1,2,4,5-tetra-
`hydro-3-benzazepin-8-ol; SCI, spinal cord injury; SER-082 [(+)-cis 4, 5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo[1,7-bc][2,6]-naphthyridine; sEPSC,
`spontaneous excitatory postsynaptic current; SERT, serotonin transporter; SL0101, 3-[(3,4-di-O-acetyl-6-deoxy-a-L-mannopyranosyl)oxy]-5,7-dihydro-2-
`(4-hydroxyphenyl)-4H-1benzopyran-4-one; SNP, single nucleotide polymorphism; SPECT, single-photon emission computed tomography; SSRI, selective
`serotonin reuptake inhibitor; STAI, State-Trait Anxiety Inventory; TCB-2, 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine; TNF, tumor
`necrosis factor; TPN, task positive network; U0126, 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene; U73122, 1-[6-[[(17b)-3-methoxyestra-
`1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione; VEGF, vascular endothelial growth factor; VI, variable interval; VP, ventral pallidum; VTA,
`ventral tegmental area; WAY-100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide; WAY-161503 [(R)-8, 9-
`dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one; WT, wild type; YFP, yellow fluorescent protein.
`
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`266
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`Nichols
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`G. Cognitive Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
`H. Creativity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
`I. 3,4-Methylenedioxymethamphetamine in Post-Traumatic Stress Disorder . . . . . . . . . . . . . . . 332
`J. Use as Ocular Hypotensives for Glaucoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
`K. Tissue Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
`L. Effects on Immune Response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
`M. Effects on Cell Differentiation and Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
`X. Models of Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
`XI. Use as Tools to Study Brain Function and Connectivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
`XII. Conclusion and Outlook. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
`Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
`
`Abstract——Psychedelics (serotonergic hallucino-
`gens) are powerful psychoactive substances that alter
`perception and mood and affect numerous cognitive
`processes. They are generally considered physiologi-
`cally safe and do not lead to dependence or addiction.
`Their origin predates written history, and they were
`employed by early cultures in many sociocultural and
`ritual contexts. After the virtually contemporaneous
`discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide
`(LSD)-25 and the identification of serotonin in the
`brain, early research focused intensively on the
`possibility that LSD and other psychedelics had a
`serotonergic basis for their action. Today there is a
`consensus that psychedelics are agonists or partial
`agonists at brain serotonin 5-hydroxytryptamine 2A
`receptors, with particular importance on those expressed
`on apical dendrites of neocortical pyramidal cells in layer
`V. Several useful rodent models have been developed over
`the years to help unravel the neurochemical correlates of
`
`serotonin 5-hydroxytryptamine 2A receptor activation in
`the brain, and a variety of imaging techniques have
`been employed to identify key brain areas that are
`directly affected by psychedelics. Recent and exciting
`developments in the field have occurred in clinical
`research, where several double-blind placebo-controlled
`phase 2 studies of psilocybin-assisted psychotherapy in
`patients with cancer-related psychosocial distress have
`demonstrated unprecedented positive relief of anxiety
`and depression. Two small pilot studies of psilocybin-
`assisted psychotherapy also have shown positive benefit
`in treating both alcohol and nicotine addiction. Recently,
`blood oxygen level–dependent functional magnetic
`resonance imaging and magnetoencephalography have
`been employed for in vivo brain imaging in humans
`after administration of a psychedelic, and results
`indicate that intravenously administered psilocybin
`and LSD produce decreases in oscillatory power in
`areas of the brain’s default mode network.
`
`I. Introduction
`I was delighted when the editors invited me to write a
`review on “psychedelics,” perhaps a watershed moment,
`representing a shift in opinion that has been developing
`for more than 3 decades with respect to research and
`understanding of psychedelics. When I began my
`graduate studies in 1969, it was politically correct in
`scientific circles to refer to these substances only as
`psychotomimetics, a negative term suggesting that they
`fostered a mental state resembling psychosis (Hoffer,
`1967). Later, as it was realized that these compounds
`did not provide very realistic models of psychosis or
`mental illness, it became more correct to refer to them
`as hallucinogens, again a pejorative term suggesting
`that they principally produce hallucinations. Yet that is
`not what they do in most users at ordinary doses, so this
`term likewise is not particularly descriptive or useful,
`although it is still widely used and seems to remain the
`preferred name for these substances in most scientific
`writing. In addition, the term hallucinogen is often used
`as a rather broad category to include all kinds of
`psychoactive molecules, including cannabinoids, “ec-
`stasy,” dissociative agents, and others.
`This review will focus exclusively on the so-called
`classic serotonergic hallucinogens (psychedelics), which
`
`are substances that exert their effects primarily by an
`agonist (or partial agonist) action on brain serotonin
`5-hydroxytryptamine (5-HT) 2A receptors, as discussed
`later. The discussion will not consider cannabinoids,
`dissociatives such as ketamine, salvinorin A (a specific
`opioid k agonist), or entactogens such as 3,4-methyl-
`enedioxymethamphetamine (MDMA). In certain con-
`texts, all of these and some related agents have been
`swept into the catchall category “hallucinogens.” Al-
`though they all can produce profound changes in
`consciousness, they have a different mechanism of
`action and will not be discussed unless there is a
`specific reason to do so.
`The name psychedelics for these substances was
`coined by Humphrey Osmond in 1957, connoting that
`they have a mind-manifesting capability, revealing
`useful or beneficial properties of the mind (Osmond,
`1957). This name has been popular among the lay public
`for more than 5 decades, but it has generally been
`frowned upon by the scientific community because it
`implies that these substances have useful properties.
`The notion that psychedelics can have beneficial effects
`has thus far not been embraced in most medical or
`scientific circles; indeed, federal funding agencies (e.g.,
`the National Institutes of Health National Institute
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`267
`
`on Drug Abuse and the National Institute of Mental
`Health) have no mission to support research on poten-
`tially useful properties of psychedelics. Yet this term
`has remained popular with the public and even appears
`to be gaining popularity. As I intend to show in this
`discussion, however, the idea that psychedelics may
`have useful properties is not at all farfetched, and very
`recent clinical studies have reinforced the belief by
`many that psychedelics are well worth studying from a
`number of different perspectives. Indeed, one of the
`most striking developments in this field has been the
`initiation and successful completion of a variety of
`clinical studies of psychedelics in the past 15 years,
`most of which have been targeted to specific medical
`indications. As will be discussed later, the results have
`been, in the main, remarkably positive.
`It should be kept in mind that the relative dearth of
`research on psychedelics in the past half century did not
`result from a lack of scientific interest, but rather
`occurred as a consequence of political forces that
`manifested principally in the United States in the
`1960s and 1970s (Grinspoon and Bakalar, 1979). Use
`of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and
`marijuana by so-called hippies who demonstrated
`against the Vietnam War during the 1960s created
`great consternation among authorities and legislative
`bodies, both at the federal and state levels. Antiwar
`attitudes and rejection of conventional social norms by
`adolescents and college students were often perceived
`by the mainstream culture to be a consequence of drug
`use; hence, these substances were often believed to be
`“perverting” the minds of our youth. Furthermore, the
`outspoken Harvard University professor and firebrand
`Timothy Leary encouraged young people to “turn on, tune
`in, and drop out,” essentially coaching them to take drugs,
`discover their true selves, and abandon convention. Such
`messages did not play well with the mainstream culture, all
`while the mass media fanned the flames of public hysteria
`with greatly exaggerated reports of drug-induced insanity,
`chromosomal damage, attempts to fly, and so forth.
`Strict laws were quickly passed. After the passage of
`the Controlled Substances Act of 1970, LSD and other
`psychedelics known at the time were placed into the
`most restrictive category of drugs, Schedule 1. This
`classification made them virtually impossible to study
`clinically and effectively ended any significant research
`into the pharmacology and medical value of psyche-
`delics for more than 3 decades. Nevertheless, there can
`be no doubt that psychedelics played a substantial role
`in defining the youth culture of the 1960s and 1970s,
`with books and essays too numerous to cite being
`written on this topic. It is believed that more than 30
`million people have used LSD, psilocybin, or mescaline
`(Krebs and Johansen, 2013). One suspects that had LSD
`never been discovered, the world might look very
`different today than it does now, for better or worse,
`depending on one’s perspective.
`
`Despite the recreational use of psychedelics, a quote
`from a book by Grinspoon and Bakalar (1979 Pg 192)
`needs to be kept in mind:
`
`Many people remember vaguely that LSD and other psyche-
`delic drugs were once used experimentally in psychiatry, but
`few realize how much and how long they were used. This was
`not a quickly rejected and forgotten fad. Between 1950 and the
`mid-1960s there were more than a thousand clinical papers
`discussing 40,000 patients, several dozen books, and six in-
`ternational conferences on psychedelic drug therapy. It aroused
`the interest of many psychiatrists who were in no sense cultural
`rebels or especially radical in their attitudes.
`
`One very important scientific consequence of the
`discovery of LSD also is often overlooked. The powerful
`psychologic effect of LSD was accidently discovered in
`1943 (Hofmann, 1979a), followed only a decade later in
`1953 by the detection of serotonin in the mammalian
`brain (Twarog and Page, 1953). The presence of the
`tryptamine moiety within LSD was also quickly seen to
`be the scaffold for the chemical structure of serotonin
`(Fig. 1).
`This recognition led to a proposal only 1 year later by
`Woolley and Shaw (1954) that “mental disturbances
`caused by lysergic acid diethylamide were to be attrib-
`uted to an interference with the action of serotonin
`in the brain.” Therefore, one could reasonably argue
`that the whole field of serotonin neuroscience, and
`especially the role of serotonin in brain function, was
`catalyzed by the discovery of LSD! By way of illustra-
`tion, in 1952, there were only 10 publications in the
`National Library of Medicine concerning serotonin,
`nearly all of them dealing with some aspect of its ability
`to constrict blood vessels. Only 8 years later, in 1960,
`there were 300 publications on serotonin, 35 of which
`were now focused on studies of serotonin in the brain.
`For comparison, in 1960, there were only 197 publica-
`tions about norepinephrine (NE)/noradrenaline, a
`neurotransmitter that had been discovered and stud-
`ied in the mid-1940s. Green (2008) provides an in-
`teresting overview of the 1950–1970 period of intense
`research activity after the discovery of serotonin in the
`brain.
`There have been numerous recent reviews on this
`topic, usually titled as hallucinogens, and the reader is
`encouraged to consult these works for further details
`
`Fig. 1. Chemical structures of serotonin and LSD.
`
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`268
`
`Nichols
`
`(Nichols, 2004; Nichols and Chemel, 2006; Fantegrossi
`et al., 2008a; Green, 2008; Passie et al., 2008; Winter,
`2009; Griffiths and Grob, 2010; Vollenweider and Kometer,
`2010; Brandt and Passie, 2012; Beck and Bonnet, 2013;
`Halberstadt and Geyer, 2013b; Baumeister et al., 2014;
`Halberstadt, 2014; Tyls et al., 2014). I wrote a com-
`prehensive review on the subject in 2004, so the
`literature considered for this review will focus pri-
`marily, but not exclusively, on the years from 2004
`to the present.
`
`A. Historical Use
`Psychedelics are a class of drug that cannot be fully
`understood without reference to a number of other fields
`of research, including anthropology, ethnopharmacol-
`ogy, psychiatry, psychology, sociology, and others. This
`review will focus mostly on pharmacology, both pre-
`clinical and clinical, but on occasion reference will be
`made to aspects of some of those other areas.
`Psychedelics may be the oldest class of psychophar-
`macological agents known to man. Important examples
`of these substances include a substance used in ancient
`India known as Soma, which was highly revered and is
`frequently mentioned in the Rigveda, with numerous
`Vedic hymns written in praise of Soma (Wasson and
`Ingalls, 1971). In the ancient village of Eleusis, outside
`Athens, for more than 2000 years there was an annual
`all-night secret ceremony that is believed to have
`involved ingestion of a hallucinogenic brew known as
`kck«on (Wasson et al., 1978). We know almost nothing
`about the ceremony other than that profound insights
`about life could be achieved, and it was apparently a
`treasured once-in-a-lifetime opportunity for any Greek
`citizen who had not been convicted of murder.
`Psilocybin mushrooms were used by the Aztec sha-
`man in healing and in a variety of religious and
`divinatory rituals. These mushrooms were known as
`teonanacatl, meaning “god’s flesh” (Ott and Bigwood,
`1978; Schultes and Hofmann, 1979). The use of various
`psychoactive plant materials and substances was com-
`mon in pre-Columbian Mesoamerican societies, includ-
`ing the Olmec, Zapotec, Maya, and Aztec cultures
`(Carod-Artal, 2015). In the Bradshaw rock art in the
`Kimberly region of Australia and in the Sandawe rock
`art in the Kolo region of Eastern Tanzania, one finds
`
`uniquely shared images such as the “mushroom head”
`symbol of psilocybin use, suggesting that the two
`cultures were linked and had shamanic practices that
`used psychoactive mushrooms (Pettigrew, 2011).
`Peyote (Lophophora williamsii) is a small cactus
`native to the American Southwest and Northern Mexico
`that has been used for millennia and is consumed as a
`sacrament during services of the Native American
`Church. Two peyote samples from a cave on the Rio
`Grande River in Texas were analyzed and subjected to
`radiocarbon dating. The average age of the samples,
`both of which contained mescaline, dated to 3780–3660
`BCE (El-Seedi et al., 2005). This evidence supports the
`use of peyote by Native North Americans as long ago as
`5700 years (Bruhn et al., 2002). Classic psychedelics
`that have been extensively studied include LSD, shown
`earlier, mescaline, psilocybin, and N,N-dimethyltrypta-
`mine (DMT) (Fig. 2).
`Ayahuasca, also known as yagé or hoasca, has a long
`history of use by natives in the Amazon valley of South
`America (Dobkin de Rios, 1971; Schultes and Hofmann,
`1979). Ayahuasca is a decoction prepared from an
`admixture of two plants: the pounded bark from
`Banisteriopsis caapi vines and leaves from Psychotria
`viridis. The latter contains the hallucinogen DMT, a
`Schedule 1 controlled substance under U.S. law, and it
`is generally considered that the psychoactive effects of
`ayahuasca can be attributed to its DMT content.
`Although DMT is not orally active, B. caapi contains
`b-carboline alkaloids that inhibit the liver monoamine
`oxidase (MAO) that normally breaks down DMT; thus,
`ayahuasca is taken orally as a “tea.” Its use has been
`incorporated as a sacrament into the religious practices
`of two syncretic Brazilian churches [União do Vegetal
`(UDV) and the Santo Daime] that have branches in the
`United States, with the U.S. Supreme Court rendering
`a 2006 decision to allow the use of ayahuasca by the
`UDV under the Religious Freedom Restoration Act.
`
`B. What Are Psychedelics?
`In view of the widespread historical use of psyche-
`delics as sacraments in a variety of other cultures,
`Jaffe’s (1990) definition for the class of psychedelics can
`perhaps be appreciated: “…the feature that distin-
`guishes the psychedelic agents from other classes of
`
`Fig. 2. Chemical structures of classic psychadelics mescaline, psilocybin, and DMT.
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`269
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`drug is their capacity reliably to induce states of altered
`perception, th