Abstract
Objectives
Classic psychedelics (serotonin 2A receptor agonists) and dissociative hallucinogens (NMDA receptor antagonists), though differing in pharmacology, may share neuropsychological effects. These drugs, however, have undergone limited direct comparison. This report presents data from a double-blind, placebo-controlled within-subjects study comparing the neuropsychological effects of multiple doses of the classic psychedelic psilocybin with the effects of a single high dose of the dissociative hallucinogen dextromethorphan (DXM).
Methods
Twenty hallucinogen users (11 females) completed neurocognitive assessments during five blinded drug administration sessions (10, 20, and 30 mg/70 kg psilocybin; 400 mg/70 kg DXM; and placebo) in which participants and study staff were informed that a large range of possible drug conditions may have been administered.
Results
Global cognitive impairment, assessed using the Mini-Mental State Examination during peak drug effects, was not observed with psilocybin or DXM. Orderly and dose-dependent effects of psilocybin were observed on psychomotor performance, working memory, episodic memory, associative learning, and visual perception. Effects of DXM on psychomotor performance, visual perception, and associative learning were in the range of effects of a moderate to high dose (20 to 30 mg/70 kg) of psilocybin.
Conclusions
This was the first study of the dose effects of psilocybin on a large battery of neurocognitive assessments. Evidence of delirium or global cognitive impairment was not observed with either psilocybin or DXM. Psilocybin had greater effects than DXM on working memory. DXM had greater effects than all psilocybin doses on balance, episodic memory, response inhibition, and executive control.
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References
Aghajanian GK, Marek GJ (1999) Serotonin and hallucinogens. Neuropsychopharmacology 21:16S–23S. https://doi.org/10.1016/S0893-133X(98)00135-3
Banken JA, Foster H (2008) Dextromethorphan. Ann N Y Acad Sci 1139:402–411. https://doi.org/10.1196/annals.1432.003
Bates D, Mächler M, Bolker B, Walker S (2015) Fitting linear mixed-effects models using lme4. J Stat Softw 67. doi: https://doi.org/10.18637/jss.v067.i01
Bem JL, Peck R (1992) Dextromethorphan. An overview of safety issues. Drug Saf 7:190–199
Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PCR, Strassman RJ (2015) Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol 29:289–299. https://doi.org/10.1177/0269881114565144
Braun U, Schäfer A, Bassett DS, Rausch F, Schweiger JI, Bilek E, Erk S, Romanczuk-Seiferth N, Grimm O, Geiger LS, Haddad L, Otto K, Mohnke S, Heinz A, Zink M, Walter H, Schwarz E, Meyer-Lindenberg A, Tost H (2016) Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function. Proc Natl Acad Sci U S A 113:12568–12573. https://doi.org/10.1073/pnas.1608819113
Brown RT, Nicholas CR, Cozzi NV, Gassman MC, Cooper KM, Muller D, Thomas CD, Hetzel SJ, Henriquez KM, Ribaudo AS, Hutson PR (2017) Pharmacokinetics of escalating doses of oral psilocybin in healthy adults. Clin Pharmacokinet 56:1543–1554. https://doi.org/10.1007/s40262-017-0540-6
Carbonaro TM, Johnson MW, Hurwitz E, Griffiths RR (2018) Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: similarities and differences in subjective experiences. Psychopharmacology 235:521–534. https://doi.org/10.1007/s00213-017-4769-4
Carhart-Harris RL, Erritzoe D, Williams T, Stone JM, Reed LJ, Colasanti A, Tyacke RJ, Leech R, Malizia AL, Murphy K, Hobden P, Evans J, Feilding A, Wise RG, Nutt DJ (2012) Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci U S A 109:2138–2143. https://doi.org/10.1073/pnas.1119598109
Carhart-Harris RL, Leech R, Hellyer PJ, Shanahan M, Feilding A, Tagliazucchi E, Chialvo DR, Nutt D (2014) The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Front Hum Neurosci 8:20. https://doi.org/10.3389/fnhum.2014.00020
Carhart-Harris RL, Bolstridge M, Rucker J, Day CMJ, Erritzoe D, Kaelen M, Bloomfield M, Rickard JA, Forbes B, Feilding A, Taylor D, Pilling S, Curran VH, Nutt DJ (2016a) Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry 3:619–627. https://doi.org/10.1016/S2215-0366(16)30065-7
Carhart-Harris RL, Muthukumaraswamy S, Roseman L, Kaelen M, Droog W, Murphy K, Tagliazucchi E, Schenberg EE, Nest T, Orban C, Leech R, Williams LT, Williams TM, Bolstridge M, Sessa B, McGonigle J, Sereno MI, Nichols D, Hellyer PJ, Hobden P, Evans J, Singh KD, Wise RG, Curran HV, Feilding A, Nutt DJ (2016b) Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc Natl Acad Sci U S A 113:4853–4858. https://doi.org/10.1073/pnas.1518377113
Carter OL, Pettigrew JD, Burr DC, Alais D, Hasler F, Vollenweider FX (2004) Psilocybin impairs high-level but not low-level motion perception. Neuroreport 15:1947–1951
Carter LP, Richards BD, Mintzer MZ, Griffiths RR (2006) Relative abuse liability of GHB in humans: a comparison of psychomotor, subjective, and cognitive effects of supratherapeutic doses of triazolam, pentobarbital, and GHB. Neuropsychopharmacology 31:2537–2551. https://doi.org/10.1038/sj.npp.1301146
Carter LP, Reissig CJ, Johnson MW, Klinedinst MA, Griffiths RR, Mintzer MZ (2013) Acute cognitive effects of high doses of dextromethorphan relative to triazolam in humans. Drug Alcohol Depend 128:206–213. https://doi.org/10.1016/j.drugalcdep.2012.08.025
Curran HV, Morgan C (2000) Cognitive, dissociative and psychotogenic effects of ketamine in recreational users on the night of drug use and 3 days later. Addiction 95:575–590
Daumann J, Heekeren K, Neukirch A, Thiel CM, Möller-Hartmann W, Gouzoulis-Mayfrank E (2008) Pharmacological modulation of the neural basis underlying inhibition of return (IOR) in the human 5-HT2A agonist and NMDA antagonist model of psychosis. Psychopharmacology 200:573–583. https://doi.org/10.1007/s00213-008-1237-1
Daumann J, Wagner D, Heekeren K, Neukirch A, Thiel CM, Gouzoulis-Mayfrank E (2010) Neuronal correlates of visual and auditory alertness in the DMT and ketamine model of psychosis. J Psychopharmacol 24:1515–1524. https://doi.org/10.1177/0269881109103227
Deakin JFW, Lees J, McKie S, Hallak JEC, Williams SR, Dursun SM (2008) Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Arch Gen Psychiatry 65:154–164. https://doi.org/10.1001/archgenpsychiatry.2007.37
Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198
Giorgetti R, Marcotulli D, Tagliabracci A, Schifano F (2015) Effects of ketamine on psychomotor, sensory and cognitive functions relevant for driving ability. Forensic Sci Int 252:127–142. https://doi.org/10.1016/j.forsciint.2015.04.024
Gouzoulis-Mayfrank E, Heekeren K, Thelen B, Lindenblatt H, Kovar KA, Sass H, Geyer MA (1998) Effects of the hallucinogen psilocybin on habituation and prepulse inhibition of the startle reflex in humans. Behav Pharmacol 9:561–566
Gouzoulis-Mayfrank E, Heekeren K, Neukirch A, Stoll M, Stock C, Daumann J, Obradovic M, Kovar KA (2006) Inhibition of return in the human 5HT2A agonist and NMDA antagonist model of psychosis. Neuropsychopharmacology 31:431–441. https://doi.org/10.1038/sj.npp.1300882
Griffiths RR, Richards WA, McCann U, Jesse R (2006) Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology 187:268–283; discussion 284–292. https://doi.org/10.1007/s00213-006-0457-5
Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R (2011) Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology 218:649–665. https://doi.org/10.1007/s00213-011-2358-5
Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA (2016) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol 30:1181–1197. https://doi.org/10.1177/0269881116675513
Griffiths RR, Johnson MW, Richards WA, Richards BD, Jesse R, MacLean KA, Barrett FS, Cosimano MP, Klinedinst MA (2018) Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. J Psychopharmacol 32:49–69. https://doi.org/10.1177/0269881117731279
Gur RC, Ragland JD, Moberg PJ, Turner TH, Bilker WB, Kohler C, Siegel SJ, Gur RE (2001) Computerized neurocognitive scanning: I. Methodology and validation in healthy people. Neuropsychopharmacology 25:766–776. https://doi.org/10.1016/S0893-133X(01)00278-0
Gur RC, Richard J, Hughett P, Calkins ME, Macy L, Bilker WB, Brensinger C, Gur RE (2010) A cognitive neuroscience-based computerized battery for efficient measurement of individual differences: standardization and initial construct validation. J Neurosci Methods 187:254–262. https://doi.org/10.1016/j.jneumeth.2009.11.017
Heekeren K, Neukirch A, Daumann J, Stoll M, Obradovic M, Kovar KA, Geyer MA, GouzouLis-Mayfrank E (2007) Prepulse inhibition of the startle reflex and its attentional modulation in the human S-ketamine and N,N-dimethyltryptamine (DMT) models of psychosis. J Psychopharmacol 21:312–320. https://doi.org/10.1177/0269881107077734
Heekeren K, Daumann J, Neukirch A, Stock C, Kawohl W, Norra C, Waberski TD, Gouzoulis-Mayfrank E (2008) Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis. Psychopharmacology 199:77–88. https://doi.org/10.1007/s00213-008-1129-4
Heitz RP (2014) The speed-accuracy tradeoff: history, physiology, methodology, and behavior. Front Neurosci 8:150. https://doi.org/10.3389/fnins.2014.00150
Honey GD, Honey RA, O’Loughlin C et al (2005) Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: an fMRI study. Cereb Cortex 15:749–759. https://doi.org/10.1093/cercor/bhh176
Johnson MW, Griffiths RR (2017) Potential therapeutic effects of psilocybin. Neurotherapeutics 14:734–740. https://doi.org/10.1007/s13311-017-0542-y
Johnson M, Richards W, Griffiths R (2008) Human hallucinogen research: guidelines for safety. J Psychopharmacol 22:603–620. https://doi.org/10.1177/0269881108093587
Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR (2014) Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol 28:983–992. https://doi.org/10.1177/0269881114548296
Johnson MW, Garcia-Romeu A, Griffiths RR (2017) Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abuse 43:55–60. https://doi.org/10.3109/00952990.2016.1170135
Joules R, Doyle OM, Schwarz AJ, O’Daly OG, Brammer M, Williams SC, Mehta MA (2015) Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile. Psychopharmacology 232:4205–4218. https://doi.org/10.1007/s00213-015-3951-9
Kaelen M, Roseman L, Kahan J, Santos-Ribeiro A, Orban C, Lorenz R, Barrett FS, Bolstridge M, Williams T, Williams L, Wall MB, Feilding A, Muthukumaraswamy S, Nutt DJ, Carhart-Harris R (2016) LSD modulates music-induced imagery via changes in parahippocampal connectivity. Eur Neuropsychopharmacol 26:1099–1109. https://doi.org/10.1016/j.euroneuro.2016.03.018
Kearney-Ramos TE, Fausett JS, Gess JL, Reno A, Peraza J, Kilts CD, James GA (2014) Merging clinical neuropsychology and functional neuroimaging to evaluate the construct validity and neural network engagement of the n-back task. J Int Neuropsychol Soc 20:736–750. https://doi.org/10.1017/S135561771400054X
Koen JD, Barrett FS, Harlow IM, Yonelinas AP (2017) The ROC toolbox: a toolbox for analyzing receiver-operating characteristics derived from confidence ratings. Behav Res Methods 49:1399–1406. https://doi.org/10.3758/s13428-016-0796-z
Kometer M, Vollenweider FX (2018) Serotonergic hallucinogen-induced visual perceptual alterations. Curr Top Behav Neurosci 36:257–282. https://doi.org/10.1007/7854_2016_461
Kometer M, Cahn BR, Andel D, Carter OL, Vollenweider FX (2011) The 5-HT2A/1A agonist psilocybin disrupts modal object completion associated with visual hallucinations. Biol Psychiatry 69:399–406. https://doi.org/10.1016/j.biopsych.2010.10.002
Kometer M, Schmidt A, Jäncke L, Vollenweider FX (2013) Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations. J Neurosci 33:10544–10551. https://doi.org/10.1523/JNEUROSCI.3007-12.2013
Kraehenmann R, Schmidt A, Friston K, Preller KH, Seifritz E, Vollenweider FX (2015) The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity. Neuroimage Clin 11:53–60. https://doi.org/10.1016/j.nicl.2015.08.009
Kraguljac NV, Frölich MA, Tran S, White DM, Nichols N, Barton-McArdle A, Reid MA, Bolding MS, Lahti AC (2017) Ketamine modulates hippocampal neurochemistry and functional connectivity: a combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers. Mol Psychiatry 22:562–569. https://doi.org/10.1038/mp.2016.122
Kuznetsova A, Brockhoff PB, Christensen RHB (2016) lmerTest: tests in linear mixed effects models
Luck SJ, Gold JM (2008) The translation of cognitive paradigms for patient research. Schizophr Bull 34:629–644. https://doi.org/10.1093/schbul/sbn036
McLeod DR, Griffiths RR, Bigelow GE, Yingling J (1982) An automated version of the digit symbol substitution test (DSST). Behav Res Methods Instrum 14:463–466. https://doi.org/10.3758/BF03203313
Moore TM, Reise SP, Gur RE, Hakonarson H, Gur RC (2015) Psychometric properties of the Penn Computerized Neurocognitive Battery. Neuropsychology 29:235–246. https://doi.org/10.1037/neu0000093
Mumford GK, Rush CR, Griffiths RR (1995) Alprazolam and DN-2327 (pazinaclone) in humans: psychomotor, memory, subjective, and reinforcing effects. Exp Clin Psychopharmacol 3:39–48
Musso F, Brinkmeyer J, Ecker D, London MK, Thieme G, Warbrick T, Wittsack HJ, Saleh A, Greb W, de Boer P, Winterer G (2011) Ketamine effects on brain function—simultaneous fMRI/EEG during a visual oddball task. Neuroimage 58:508–525. https://doi.org/10.1016/j.neuroimage.2011.06.045
Nagels A, Kirner-Veselinovic A, Krach S, Kircher T (2011) Neural correlates of S-ketamine induced psychosis during overt continuous verbal fluency. Neuroimage 54:1307–1314. https://doi.org/10.1016/j.neuroimage.2010.08.021
Nichols DE (2016) Psychedelics. Pharmacol Rev 68:264–355. https://doi.org/10.1124/pr.115.011478
Passie T, Seifert J, Schneider U, Emrich HM (2002) The pharmacology of psilocybin. Addict Biol 7:357–364. https://doi.org/10.1080/1355621021000005937
Quednow BB, Kometer M, Geyer MA, Vollenweider FX (2012) Psilocybin-induced deficits in automatic and controlled inhibition are attenuated by ketanserin in healthy human volunteers. Neuropsychopharmacology 37:630–640. https://doi.org/10.1038/npp.2011.228
R Core Team (2015) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna
Reissig CJ, Carter LP, Johnson MW, Mintzer MZ, Klinedinst MA, Griffiths RR (2012) High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens. Psychopharmacology 223:1–15. https://doi.org/10.1007/s00213-012-2680-6
Rose NS, Craik FIM (2012) A processing approach to the working memory/long-term memory distinction: evidence from the levels-of-processing span task. J Exp Psychol Learn Mem Cogn 38:1019–1029. https://doi.org/10.1037/a0026976
Roseman L, Sereno MI, Leech R, Kaelen M, Orban C, McGonigle J, Feilding A, Nutt DJ, Carhart-Harris RL (2016) LSD alters eyes-closed functional connectivity within the early visual cortex in a retinotopic fashion. Hum Brain Mapp 37:3031–3040. https://doi.org/10.1002/hbm.23224
Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z, Corby P, Schmidt BL (2016) Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol 30:1165–1180. https://doi.org/10.1177/0269881116675512
SAMHSA (2015) 2014 National Survey on Drug Use and Health: detailed tables. Center for Behavioral Health Statistics and Quality. Substance Abuse and Mental Health Services Administration Rockville, MD
Schadel M, Wu D, Otton SV, Kalow W, Sellers EM (1995) Pharmacokinetics of dextromethorphan and metabolites in humans: influence of the CYP2D6 phenotype and quinidine inhibition. J Clin Psychopharmacol 15:263–269
Schmid Y, Enzler F, Gasser P, Grouzmann E, Preller KH, Vollenweider FX, Brenneisen R, Müller F, Borgwardt S, Liechti ME (2015) Acute effects of lysergic acid diethylamide in healthy subjects. Biol Psychiatry 78:544–553. https://doi.org/10.1016/j.biopsych.2014.11.015
Schmidt A, Müller F, Lenz C, Dolder PC, Schmid Y, Zanchi D, Lang UE, Liechti ME, Borgwardt S (2018) Acute LSD effects on response inhibition neural networks. Psychol Med 48:1464–1473. https://doi.org/10.1017/S0033291717002914
Snodgrass JG, Corwin J (1988) Pragmatics of measuring recognition memory: applications to dementia and amnesia. J Exp Psychol Gen 117:34–50
Tylš F, Páleníček T, Horáček J (2014) Psilocybin—summary of knowledge and new perspectives. Eur Neuropsychopharmacol 24:342–356. https://doi.org/10.1016/j.euroneuro.2013.12.006
Vollenweider FX, Kometer M (2010) The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 11:642–651. https://doi.org/10.1038/nrn2884
Vollenweider FX, Leenders KL, Oye I et al (1997) Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol 7:25–38
Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A et al (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9:3897–3902
Vollenweider FX, Csomor PA, Knappe B, Geyer MA, Quednow BB (2007) The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval. Neuropsychopharmacology 32:1876–1887. https://doi.org/10.1038/sj.npp.1301324
Wilson MD, Ferguson RW, Mazer ME, Litovitz TL (2011) Monitoring trends in dextromethorphan abuse using the National Poison Data System: 2000-2010. Clin Toxicol (Phila) 49:409–415. https://doi.org/10.3109/15563650.2011.585429
Yonelinas AP, Parks CM (2007) Receiver operating characteristics (ROCs) in recognition memory: a review. Psychol Bull 133:800–832. https://doi.org/10.1037/0033-2909.133.5.800
Yoran-Hegesh R, Kertzman S, Vishne T, Weizman A, Kotler M (2009) Neuropsychological mechanisms of digit symbol substitution test impairment in Asperger disorder. Psychiatry Res 166:35–45. https://doi.org/10.1016/j.psychres.2007.11.015
Acknowledgements
We thank Mary Cosimano, M.S.W., Taylor Marcus, Darrick May, M.D., Albert Garcia-Romeu, Ph.D., Mary Sweeney, Ph.D., William Richards, Ph.D., Brennan Kersgaard, and Eileen Rosello for their roles as session monitors; Dr. Annie Umbricht, M.D., and the medical staff at the Behavioral Pharmacology Research Unit for medical screening and medical coverage; and Lisa Schade for the technical assistance. We also thank David Nichols, Ph.D., for synthesizing the psilocybin. The study was conducted in compliance with United States laws.
Funding
This research was supported by NIH grant R01DA03889 to RRG. FSB and TC were supported in part by NIH grant 5T32 DA007209. FSB was supported in part by NIH grant R03DA042336. MWJ was supported in part by R01DA035277. TC is an employee of the U.S. Food and Drug Administration (FDA); however, the views presented in this article do not necessarily reflect those of the FDA and no official support or endorsement of this article by the FDA is intended or should be inferred.
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RRG is a board member of the Heffter Research Institute. The remaining authors declare that they have no conflicts of interest.
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Barrett, F.S., Carbonaro, T.M., Hurwitz, E. et al. Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: effects on cognition. Psychopharmacology 235, 2915–2927 (2018). https://doi.org/10.1007/s00213-018-4981-x
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DOI: https://doi.org/10.1007/s00213-018-4981-x