Psilocybin disrupts sensory and higher order cognitive processing but not pre-attentive cognitive processing—study on P300 and mismatch negativity in healthy volunteers
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Disruption of auditory event-related evoked potentials (ERPs) P300 and mismatch negativity (MMN), electrophysiological markers of attentive and pre-attentive cognitive processing, is repeatedly described in psychosis and schizophrenia. Similar findings were observed in a glutamatergic model of psychosis, but the role of serotonergic 5-HT2A receptors in information processing is less clear.
We studied ERPs in a serotonergic model of psychosis, induced by psilocybin, a psychedelic with 5-HT2A/C agonistic properties, in healthy volunteers.
Twenty subjects (10M/10F) were given 0.26 mg/kg of psilocybin orally in a placebo-controlled, double-blind, cross-over design. ERPs (P300, MMN) were registered during the peak of intoxication. Correlations between measured electrophysiological variables and psilocin serum levels and neuropsychological effects were also analyzed.
Psilocybin induced robust psychedelic effects and psychotic-like symptoms, decreased P300 amplitude (p = 0.009) but did not affect the MMN. Psilocybin’s disruptive effect on P300 correlated with the intensity of the psychedelic state, which was dependent on the psilocin serum levels. We also observed a decrease in N100 amplitude (p = 0.039) in the P300 paradigm and a negative correlation between P300 and MMN amplitude (p = 0.014).
Even though pre-attentive cognition (MMN) was not affected, processing at the early perceptual level (N100) and in higher-order cognition (P300) was significantly disrupted by psilocybin. Our results have implications for the role of 5-HT2A receptors in altered information processing in psychosis and schizophrenia.
KeywordsPsilocybin Model of psychosis Human ERP MMN P300
The authors would like to thank to Craig Hampson, BSc (Hons) for helpful comments and language correction. This work was supported by projects MICR VI20172020056, MHCR—DRO (NIMH-CZ, 00023752), NV15-33250A and by projects 260388/SVV/2017, PROGRES Q35 and LO1611 with a financial support from the Ministry of Education, Youth and Sports of the Czech Republic under the NPU I program.
- Bebbington P, Nayani T (1995) The psychosis screening questionnaire. Int J Methods Psychiatr Res 5:11–19Google Scholar
- Brockhaus-Dumke A, Schultze-Lutter F, Mueller R, Tendolkar I, Bechdolf A, Pukrop R, Klosterkoetter J, Ruhrmann S (2008) Sensory gating in schizophrenia: P50 and N100 gating in antipsychotic-free subjects at risk, first-episode, and chronic patients. Biol Psychiatry 64(5):376–384. https://doi.org/10.1016/j.biopsych.2008.02.006 CrossRefPubMedGoogle Scholar
- Butcher JN, Graham JR, Fowler RD (1991) Special series: The MMPI-2. J Pers Assess 57(2):203–204. https://doi.org/10.1207/s15327752jpa5702_1
- Carhart-Harris RL, Leech R, Erritzoe D, Williams TM, Stone JM, Evans J, Sharp DJ, Feilding A, Wise RG, Nutt DJ (2013) Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis. Schizophr Bull 39(6):1343–1351. https://doi.org/10.1093/schbul/sbs117 CrossRefPubMedGoogle Scholar
- 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, 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 (2016) Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc Natl Acad Sci U S A 113(17):4853–4858. https://doi.org/10.1073/pnas.1518377113 CrossRefPubMedPubMedCentralGoogle Scholar
- Carter OL, Burr DC, Pettigrew JD, Wallis GM, Hasler F, Vollenweider FX (2005) Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors. J Cogn Neurosci 17(10):1497–1508. https://doi.org/10.1162/089892905774597191 CrossRefPubMedGoogle Scholar
- del Re EC, Spencer KM, Oribe N, Mesholam-Gately RI, Goldstein J, Shenton ME, Petryshen T, Seidman LJ, McCarley RW, Niznikiewicz MA (2015) Clinical high risk and first episode schizophrenia: auditory event-related potentials. Psychiatry Res 231(2):126–133. https://doi.org/10.1016/j.pscychresns.2014.11.012 CrossRefPubMedGoogle Scholar
- Gouzoulis-Mayfrank E, Schreckenberger M, Sabri O, Arning C, Thelen B, Spitzer M, Kovar KA, Hermle L, Bull U, Sass H (1999) Neurometabolic effects of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine in healthy volunteers. A double-blind, placebo-controlled PET study with [18F]FDG. Neuropsychopharmacology 20(6):565–581. https://doi.org/10.1016/S0893-133X(98)00089-X CrossRefPubMedGoogle Scholar
- Gunduz-Bruce H, Reinhart RM, Roach BJ, Gueorguieva R, Oliver S, D'Souza DC, Ford JM, Krystal JH, Mathalon DH (2012) Glutamatergic modulation of auditory information processing in the human brain. Biol Psychiatry 71(11):969–977. https://doi.org/10.1016/j.biopsych.2011.09.031 CrossRefPubMedGoogle 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. https://doi.org/10.1007/s00213-003-1640-6 CrossRefPubMedGoogle Scholar
- 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(1):77–88. https://doi.org/10.1007/s00213-008-1129-4 CrossRefPubMedPubMedCentralGoogle Scholar
- Kahkonen S, Ahveninen J, Jaaskelainen IP, Kaakkola S, Naatanen R, Huttunen J, Pekkonen E (2001) Effects of haloperidol on selective attention: a combined whole-head MEG and high-resolution EEG study. Neuropsychopharmacology 25(4):498–504. https://doi.org/10.1016/S0893-133X(01)00255-X CrossRefPubMedGoogle Scholar
- Kometer M, Schmidt A, Bachmann R, Studerus E, Seifritz E, Vollenweider FX (2012) Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors. Biol Psychiatry 72(11):898–906. https://doi.org/10.1016/j.biopsych.2012.04.005 CrossRefPubMedGoogle Scholar
- Kometer M, Schmidt A, Jancke L, Vollenweider FX (2013) Activation of serotonin 2A receptors underlies the psilocybin-induced effects on alpha oscillations, N170 visual-evoked potentials, and visual hallucinations. J Neurosci : Off J Soc Neurosci 33(25):10544–10551. https://doi.org/10.1523/JNEUROSCI.3007-12.2013 CrossRefGoogle Scholar
- Kraehenmann R, Preller KH, Scheidegger M, Pokorny T, Bosch OG, Seifritz E, Vollenweider FX (2015) Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers. Biol Psychiatry 78(8):572–581. https://doi.org/10.1016/j.biopsych.2014.04.010 CrossRefPubMedGoogle Scholar
- Lee M, Sehatpour P, Hoptman MJ, Lakatos P, Dias EC, Kantrowitz JT, Martinez AM, Javitt DC (2017) Neural mechanisms of mismatch negativity dysfunction in schizophrenia. Mol Psychiatry 22(11):1585–1593. https://doi.org/10.1038/mp.2017.3
- Mueller SC (2011) The influence of emotion on cognitive control: relevance for development and adolescent psychopathology. Front Psychol 2:327. https://doi.org/10.3389/fpsyg.2011.00327
- 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(2):508–525. https://doi.org/10.1016/j.neuroimage.2011.06.045 CrossRefPubMedGoogle Scholar
- Muthukumaraswamy SD, Carhart-Harris RL, Moran RJ, Brookes MJ, Williams TM, Errtizoe D, Sessa B, Papadopoulos A, Bolstridge M, Singh KD, Feilding A, Friston KJ, Nutt DJ (2013) Broadband cortical desynchronization underlies the human psychedelic state. J Neurosci: Off J Soc Neurosci 33(38):15171–15183. https://doi.org/10.1523/JNEUROSCI.2063-13.2013 CrossRefGoogle Scholar
- Nekovarova T, Fajnerova I, Horacek J, Spaniel F (2014) Bridging disparate symptoms of schizophrenia: a triple network dysfunction theory. Front Behav Neurosci 8:171. https://doi.org/10.3389/fnbeh.2014.00171
- Overall JE, Hollister LE, Pichot P (1967) Major psychiatric disorders. A four-dimensional model Archives of general psychiatry 16(2):146–151. https://doi.org/10.1001/archpsyc.1967.01730200014003 CrossRefPubMedGoogle Scholar
- Palenicek T, Hlinak Z, Bubenikova-Valesova V, Novak T, Horacek J (2010) Sex differences in the effects of N,N-diethyllysergamide (LSD) on behavioural activity and prepulse inhibition. Prog Neuro-Psychopharmacol Biol Psychiatry 34(4):588–596. https://doi.org/10.1016/j.pnpbp.2010.02.008 CrossRefGoogle Scholar
- Rambousek L, Palenicek T, Vales K, Stuchlik A (2014) The effect of psilocin on memory acquisition, retrieval, and consolidation in the rat. Front Behav Neurosci 8:180. https://doi.org/10.3389/fnbeh.2014.00180
- Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33 quiz 34-57PubMedGoogle 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(2):98–108. https://doi.org/10.1001/archpsyc.1994.03950020022002 CrossRefPubMedGoogle Scholar
- Sumiyoshi T, Higuchi Y, Uehara T (2013) Neural basis for the ability of atypical antipsychotic drugs to improve cognition in schizophrenia. Front Behav Neurosci 7:140. https://doi.org/10.3389/fnbeh.2013.00140
- Timmermann C, Spriggs MJ, Kaelen M, Leech R, Nutt DJ3, Moran RJ, Carhart-Harris RL, Muthukumaraswamy SD (2017) LSD modulates effective connectivity and neural adaptation mechanisms in an auditory oddball paradigm. Neuropharmacology [Epub ahead of print]. https://doi.org/10.1016/j.neuropharm.2017.10.039
- Umbricht D, Schmid L, Koller R, Vollenweider FX, Hell D, Javitt DC (2000) Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch Gen Psychiatry 57(12):1139–1147. https://doi.org/10.1001/archpsyc.57.12.1139 CrossRefPubMedGoogle Scholar
- Umbricht D, Vollenweider FX, Schmid L, Grubel C, Skrabo A, Huber T, Koller R (2003) Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia. Neuropsychopharmacology 28(1):170–181. https://doi.org/10.1038/sj.npp.1300005 CrossRefPubMedGoogle Scholar