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Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: similarities and differences in subjective experiences

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Abstract

Rationale

Although psilocybin and dextromethorphan (DXM) are hallucinogens, they have different receptor mechanisms of action and have not been directly compared.

Objective

This study compared subjective, behavioral, and physiological effects of psilocybin and dextromethorphan under conditions that minimized expectancy effects.

Methods

Single, acute oral doses of psilocybin (10, 20, 30 mg/70 kg), DXM (400 mg/70 kg), and placebo were administered under double-blind conditions to 20 healthy participants with histories of hallucinogen use. Instructions to participants and staff minimized expectancy effects. Various subjective, behavioral, and physiological effects were assessed after drug administration.

Results

High doses of both drugs produced similar increases in participant ratings of peak overall drug effect strength, with similar times to maximal effect and time-course. Psilocybin produced orderly dose-related increases on most participant-rated subjective measures previously shown sensitive to hallucinogens. DXM produced increases on most of these same measures. However, the high dose of psilocybin produced significantly greater and more diverse visual effects than DXM including greater movement and more frequent, brighter, distinctive, and complex (including textured and kaleidoscopic) images and visions. Compared to DXM, psilocybin also produced significantly greater mystical-type and psychologically insightful experiences and greater absorption in music. In contrast, DXM produced larger effects than psilocybin on measures of disembodiment, nausea/emesis, and light-headedness. Both drugs increased systolic blood pressure, heart rate, and pupil dilation and decreased psychomotor performance and balance.

Conclusions

Psilocybin and DXM produced similar profiles of subjective experiences, with psilocybin producing relatively greater visual, mystical-type, insightful, and musical experiences, and DXM producing greater disembodiment.

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References

  • Aghajanian GK, Marek GJ (1999) Serotonin and hallucinogens. Neuropsychopharmacology 21(2 Suppl):16S–23S

    Article  CAS  PubMed  Google Scholar 

  • Banken JA, Foster H (2008) Dextromethorphan. Ann N Y Acad Sci 1139:402–411

    Article  CAS  PubMed  Google Scholar 

  • Barrett FS, Griffiths RR (2017) Classic hallucinogens and mystical experiences: phenomenology and neural correlates. Curr Top Behav Neurosci. https://doi.org/10.1007/7854_2017_474

  • Barrett FS, Johnson MW, Griffiths RR (2015) Validation of the revised mystical experience questionnaire in experimental sessions with psilocybin. J Psychopharmacol 29(11):1182–1190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barrett FS, Bradstreet MP, Leoutsakos JS, Johnson MW, Griffiths RR (2016) The challenging experience questionnaire: characterization of challenging experiences with psilocybin mushrooms. J Psychopharmacol 30(12):1279–1295

    Article  PubMed  PubMed Central  Google Scholar 

  • Barrett FS, Robbins H, Smooke D, Brown JL, Griffiths RR (2017). Qualitative and quantitative features of music reported to support peak mystical experiences during psychedelic therapy sessions. Front Psychol 8:1238

  • Bonny HL, Pahnke WN (1972) The use of music in psychedelic (LSD) psychotherapy. J Music Therapy IX:64–87

    Article  Google Scholar 

  • 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. https://doi.org/10.1007/s40262-017-0540-6

  • Carbonaro TM, Eshleman AJ, Forster MJ, Cheng K, Rice KC, Gatch MB (2015) The role of 5-HT2A, 5-HT 2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N,N-dimethyltryptamine and N,N-diisopropyltryptamine in rats and mice. Psychopharmacology 232(1):275–284

    Article  CAS  PubMed  Google Scholar 

  • 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(11):2537–2551

    Article  CAS  PubMed  Google Scholar 

  • Delille HK, Becker JM, Burkhardt S, Bleher B, Terstappen GC, Schmidt M, Meyer AH, Unger L, Marek GJ, Mezler M (2012) Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades. Neuropharmacology 62:2184–2191

    Article  CAS  PubMed  Google Scholar 

  • Dittrich A (1998) The standardized psychometric assessment of altered states of conciousness (ACSs) in humans. Pharmacopsychiatry 31(Suppl 2):80–84

    Article  PubMed  Google Scholar 

  • Fantegrossi WE, Murnane KS, Reissig CJ (2008) The behavioral pharmacology of hallucinogens. Biochem Pharmacol 75(1):17–33

    Article  CAS  PubMed  Google Scholar 

  • Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R, Park G, Adnewy SK, Hatcher C, Eltit JM, Ruta JD, Albizu L, Li Z, Umali A, Shim J, Fabiato A, MacKerell AD Jr, Brezina V, Sealfron SC, Filizola M, Gonzalez-Maeso J, Logothetis DE (2011) Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell 147(5):1011–1023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonzalez-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA (2007) Hallucinogens recruit specific cortical 5-HT(2A) receptormediated signaling pathways to affect behavior. Neuron 53:439–452

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC (2008) Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452:93–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gouzoulis-Mayfrank E, Heekeren K, Neukirch A, Stoll M, Stock C, Obradovic M, Kovar K-A (2005) Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double blind, cross-over study in healthy volunteers. Pharmacopsychiatry 38:301–311

    Article  CAS  PubMed  Google Scholar 

  • 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(3):268–283 discussion 284-92

    Article  CAS  PubMed  Google Scholar 

  • 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(4):649–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hasler F, Bourquin D, Brenneisen R, Bar T, Vollenweider FX (1997) Determinaton of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmokinetic profiles of oral and intravenous psilocybin in man. Pharm Acta Helv 72(3):175–184

    Article  CAS  PubMed  Google Scholar 

  • Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX (2004) Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology 172(2):145–156

    Article  CAS  PubMed  Google Scholar 

  • Hood RW, Hill PC, Bernard S (2009) The psychology of religion: an empirical approach. Guilford Press, New York

    Google Scholar 

  • Jansen KLR (2004) Ketamine: dreams and realities. Multidisciplinary Association for Psychedelic Studies (MAPS), Sarasota, FL

    Google Scholar 

  • Johnson M, Richards WA, Griffiths RR (2008) Human hallucinogen research: guidelines for safety. J Psychopharmacol 22(6):603–620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaelen M, Barrett FS, Roseman L, Lorenz R, Family N, Bolstridge M, Carhart-Harris RL (2015) LSD enhances the emotional response to music. Psychopharmacology 232(19):3607–3614

    Article  CAS  PubMed  Google Scholar 

  • MacLean KA, Leoutsakos JM, Johnson MW, Griffiths RR (2012) Factor analysis of the mystical experience questionnaire: a study of experiences occasioned by the hallucinogen psilocybin. J Sci Study Relig 51(4):721–737

    Article  PubMed  PubMed Central  Google Scholar 

  • MacLean KA, Johnson MW, Griffiths RR (2015) Hallucinogens and club drugs. In: Galanter M, Kleber HD, Bradu L (eds) The American Psychiatric Press Textbook of Substance Abuse Treatment, Fifth ed. The American Psychiatric Press, Arlington, VA, pp 209–222

  • Metzner R, Litwin G, Weil G (1965) The relation of expectation and mood to psilocybin reactions: a questionnaire study. Psychedelic Review 5:3–39

    Google Scholar 

  • Moreno JL, Holloway T, Albizu L, Sealfon SC, González-Maeso J (2011) Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett 493:76–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morris H, Wallach J (2014) From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. Drug Test Anal 7(5):358–367

    PubMed  Google Scholar 

  • Mumford GK, Rush CR, Griffiths RR (1995) Abecarnil and alprazolam in humans: behavioral, subjective and reinforcing effects. J Pharmacol Exp Ther 272(2):570–580

    CAS  PubMed  Google Scholar 

  • Narby J (1999) The cosmic serpent DNA and the origins of knowledge. Jeremy P. Tarcher/Putnam, New York, NY

    Google Scholar 

  • Nguyen L, Thomas KL, Lucke-Wold BP, Cavendish JZ, Crowe MS, Matsumoto RR (2016) Dextromethorphan: an update on its utility for neurological and neuropsychiatric disorders. Pharmacol Ther 159:1–22

    Article  CAS  PubMed  Google Scholar 

  • Nichols DE (2016) Psychedelics. Pharmacol Rev 68:264–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Passie T, Seifert J, Schneider U, Emrich HM (2002) The pharmacology of psilocybin. Addict Biol 7(4):357–364

    Article  CAS  PubMed  Google Scholar 

  • Preller KH, Vollenweider FX (2016) Phenomenology, structure, and dynamic of psychedelic states. Curr Top Behav Neurosci. https://doi.org/10.1007/7854_2016_459

  • 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):1–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rickli A, Moning OD, Hoener MC, Liechti ME (2016) Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. Eur Neuropsychopharmacol 26:1327–1337

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • SAMHSA (2016) 2015 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

    Google Scholar 

  • Schartner MM, Carhart-Harris RL, Barrett AB, Seth AK, Muthukumaraswamy SD (2017) Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin. Sci Rep 7:46421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmid B, Bircher J, Preisig R, Kupfer A (1985) Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther 38(6):618–624

    Article  CAS  PubMed  Google Scholar 

  • Schmidt A, Kometer M, Bachmann R, Seifritz E, Vollenweider F (2013) The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions. Psychopharmacol 225:227–239

    Article  CAS  Google Scholar 

  • Shulgin A, Shulgin A (1997) TiHKAL. Transform Press, Berkeley, CA

    Google Scholar 

  • Strassman R (2001) DMT: the spirit molecule. Park Street Press, Rochester, VA

    Google Scholar 

  • Strassman RJ, Qualls CR, Uhlenhuth EH, Kellner R (1994) Dose response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale. Arch Gen Psychiatry 51:98–108

  • Studerus E, Gamma A, Vollenweider FX (2010) Psychometric evaluation of the altered states of consciousness rating scale (OAV). PLoS One 5(8):e12412

    Article  PubMed  PubMed Central  Google Scholar 

  • Taylor CP, Traynelis SF, Siffert J, Pope LE, Matsumoto RR (2016) Pharmacology of dextromethorphan: relevance to dextromethorphan/quinidine (nuedexta(R)) clinical use. Pharmacol Ther 164:170–182

    Article  CAS  PubMed  Google Scholar 

  • Tyls F, Palenicek T, Horacek J (2014) Psilocybin—summary of knowledge and new perspectives. Eur Neuropsychopharmacol 24(3):342–356

    Article  CAS  PubMed  Google Scholar 

  • Vengurlekar SS, Heitkamp J, McCush F, Velagaleti PR, Brisson JH, Bramer SL (2002) J Pharm Biomed Anal 30(1):113–124

    Article  CAS  PubMed  Google Scholar 

  • Vollenweider FX, Kometer M (2010) The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 11(9):642–651

    Article  CAS  PubMed  Google Scholar 

  • Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9(17):3897–3902

    Article  CAS  PubMed  Google Scholar 

  • White W (2002) The DXM experience. https://www.erowid.org/chemicals/dxm/faq/dxm_experience.shtml#toc.5. Accessed 15 July 2017

  • Winter JC (2009) Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines. Psychopharmacology 203:251–263

    Article  CAS  PubMed  Google Scholar 

  • Winter JC, Eckler JR, Rabin RA (2004) Serotonergic/glutamatergic interactions: the effects of mGlu2/3 receptor ligands in rats trained with LSD and PCP as discriminative stimuli. Psychopharmacology 172:233–240

    Article  CAS  PubMed  Google Scholar 

  • Zentner M, Grandjean D, Scherer KR (2008) Emotions evoked by the sound of music: characterization, classification, and measurement. Emotion 8:494–521

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Mary Cosimano, M.S.W, Taylor Marcus, Darrick May, M.D., and five other staff members for their roles as session monitors, Dr. Annie Umbricht for medical management, Frederick Barrett, Ph.D., for contributing to the study design, Lisa Schade for technical assistance, Linda Felch for statistical assistance, and the pharmacy and medical staff. We also thank David Nichols, Ph.D., for synthesizing the psilocybin and Michelle Rudek, Pharm.D., Ph.D., and Nichole Anders of the Analytical Pharmacology Core for analyzing dextromethorphan metabolism. The study was conducted in compliance with US laws.

Funding

Conduct of this research was supported by NIH R01DA03889 and T32 DA07209. Support for dextromethorphan metabolic analysis was supported by NIH grants P30CA006973 and UL1TR001079 and the Shared Instrument Grant S10OD020091 to the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD, 21224-6823, USA

    Theresa M. Carbonaro, Matthew W. Johnson, Ethan Hurwitz & Roland R. Griffiths

  2. Department of Neuroscience, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD, 21224-6823, USA

    Roland R. Griffiths

Authors
  1. Theresa M. Carbonaro
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  2. Matthew W. Johnson
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  3. Ethan Hurwitz
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  4. Roland R. Griffiths
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Corresponding author

Correspondence to Roland R. Griffiths.

Ethics declarations

The study was approved by the Institutional Review Board of the Johns Hopkins University School of Medicine. Participants gave their written informed consent before beginning the study procedures and were paid for their participation.

Conflict of interest

Dr. Carbonaro 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. Roland Griffiths is on the Board of Directors of the Heffter Research Institute.

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Carbonaro, T.M., Johnson, M.W., Hurwitz, E. et al. Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: similarities and differences in subjective experiences. Psychopharmacology 235, 521–534 (2018). https://doi.org/10.1007/s00213-017-4769-4

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  • DOI: https://doi.org/10.1007/s00213-017-4769-4

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