Psilocybin disrupts sensory and higher order cognitive processing but not pre-attentive cognitive processing—study on P300 and mismatch negativity in healthy volunteers, Anna Bravermanová et al., 2017

Psilocybin disrupts sensory and higher order cognitive processing but not pre-attentive cognitive processing—study on P300 and mismatch negativity in healthy volunteers

Anna Bravermanová, Michaela Viktorinová, Filip Tylš, Tomáš Novák, Renáta Androvičová,
Jakub Korčák, Jiří Horáček, Marie Balíková, Inga Griškova-Bulanova, Dominika Danielová,
Přemysl Vlček, Pavel Mohr, Martin Brunovský, Vlastimil Koudelka, Tomáš Páleníček,

Psychopharmacology, 2018

Received: 12 May 2017 /Accepted: 29 November 2017
# Springer-Verlag GmbH Germany, part of Springer Nature 2018


Rationale 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.

Objectives : We studied ERPs in a serotonergic model of psychosis, induced by psilocybin, a psychedelic with 5-HT2A/C agonistic properties, in healthy volunteers.

Methods : Twenty subjects (10M/10F) were given 0.26 mg/kg of psilocybin orally in a placebo-controlled, double-blind, crossover 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.

Results : 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).

Conclusions : 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.

Keywords : Psilocybin . Model of psychosis . Human . ERP .MMN . P300

One of the characteristic features in schizophrenia is the impairment of sensory and informational processing, which is believed to contribute to disturbed cognitive functioning in this disorder (Javitt and Sweet 2015). Event-related potentials (ERPs) represent electrophysiological tools for studying these deficits. Early components of ERPs such as P50 and N100 reflect sensory-related processing, whereas later components like mismatch negativity (MMN) and P300 reflect preattentive and attentive informational and cognitive processing (Donchin and Coles 1988; Rosburg et al. 2008; Sur and Sinha 2009). Deficits in both early as well as late ERPs are frequently reported as being a trait marker of schizophrenia,with MMN and P300 consistently referred as an endophenotype (del Re et al. 2015; Earls et al. 2016; Polich 2007). Auditory MMN is a negative component of ERPs generated with a latency of 100–200 ms after the presentation of a stimulus that deviates in one of its physical dimensions (pitch, intensity, duration, and location) from the preceding frequently repeated standard stimuli (Näätänen and Alho 1995; Näätänen et al. 2014). It is considered to be an index of automatic context-dependent information processing and auditory sensory memory (Umbricht and Krljes 2005). A decrease in
MMN amplitude is one of the most robust electrophysiological features in chronic schizophrenia with an overall large (> 0.95) effect size (Erickson et al. 2016; Haigh et al. 2017; Umbricht and Krljes 2005). MMN deficits have also been found to be linked with poor global functioning in schizophrenia (Light and Braff 2005). P300 is typically elicited in oddball paradigms, where subjects attend and actively discriminate between stimuli that differ from each other in certain dimensions. Such discrimination produces a large-positive waveform with a modal latency of approximately 300 ms (Polich and Kok 1995; Sutton et al. 1965). Hence, it is suggested that P300 reflects cortical postsynaptic neuro-electric activity related to cognitive processes such as attention allocation, stimulus evaluation, and categorization with activation of immediate and working memory (Polich and Kok 1995). While the P3a component is thought to represent a mechanism involved in the rapid orienting of attention to events that are unexpected and contextually deviant, the P3b component probably reflects a mechanism involved in the updating of contextual representations in working memory (del Re et al. 2015). The reduced amplitude of P300 response also represents very robust electrophysiological abnormalities associated with psychosis and schizophrenia, being replicated across a number of studies with a large (> 0.8) effect size (Bramon et al. 2004; Jeon and Polich 2003). Despite the fact that schizophrenia is believed to be a neurodevelopmental disorder, the most phenomenologically relevant animal and human models are induced by acute administration of three classes of psychotomimetic drugs: dopaminergic stimulants (e.g. amphetamines and cocaine), glutamate N-methyl-D-Aspartate (NMDA) receptor antagonists (e.g. ketamine, phencyclidine (PCP) and dizocilpine (MK- 801)), and serotonergic 5-HT2A/C agonists (e.g. psilocybin, N,N-diethyllysergamide (LSD) and N,N-dimethyltryptamine (DMT)) (Frohlich and Van Horn 2014; Horacek et al. 2006; Nichols 2016). A growing body of evidence describes the effects of these pharmacological models on ERPs. Specifically, P300 disruption was shown to be induced by amphetamines (Albrecht et al. 2011; Silber et al. 2012) aswell as by ketamine in humans (Gunduz-Bruce et al. 2012; Musso et al. 2011; Oranje et al. 2000). Robust evidence also exists for MMN attenuation in this model, e.g., (Gunduz-Bruce et al. 2012; Oranje et al. 2000; Schmidt et al. 2012; Umbricht
et al. 2000) with a recently published effect size of d = 0.49 reported in a meta-analysis (Rosburg and Kreitschmann- Andermahr 2016). Furthermore, ketamine and MK-801 also disrupted MMN-like responses in rodents (Ehrlichman et al. 2008; Tikhonravov et al. 2008). Compared to the previous models, the effects of serotonergic psychedelics on both ERPs are less clear. At the time of planning our experiments, only one study employed an auditory MMN paradigm during psilocybin intoxication (Umbricht et al. 2003) and another one during DMT intravenous infusion (Heekeren et al. 2008). In both cases, psychedelics failed to affect MMN; however, a disruptive effect on MMN during the later stages of LSD intoxication (after the peak had worn off) has recently been reported (Timmermann et al. 2017). Furthermore, until now there have been no human or animal studies with these serotonergic models exploring the effects on auditory P300 and P3-like potential. The only report of attenuated P300 by psilocybin was described by Kometer et al. (2012) in a visual task. On the other hand, serotonergic psychedelics have been shown to alter several parameters in the cognitive domain and sensorimotor processing in healthy individuals in a manner that is characteristic for psychosis, e.g., alterations of temporal processing (Nichols 2016; Uyeno 1968; Wittmann 2015), disruption of prepulse inhibition (PPI) (Quednow et al. 2012), or emotional processing (Kraehenmann et al. 2015). Cognitive functions and sensorimotor processing are also affected in animal models with serotonergic psychedelics (Geyer 2015; Palenicek et al. 2008; Palenicek et al. 2010; Rambousek et al. 2014; Tyls et al. 2016). Therefore, in order to elucidate whether the disruption of pre-attentive and/or attentive processing is present in a serotonergic psilocybin model of psychosis and to see possible relations between them, we evaluated both MMN and P300 in the same volunteers within the same session. This was possible due to psilocybin’s intermediate duration of effects, which varies between 3 and 6 h (Hasler et al. 2004), producing a sufficient time window for measuring both ERPs in one subject. We hypothesized that psilocybin (1) will decrease P300 amplitude, (2) will reduce MMN when tested at later stages of intoxication, and (3) that these effects will be dependent on the plasma levels of psilocin as well as the magnitude.