Activation of Serotonin 2A Receptors Underlies the Psilocybin-Induced Effects on   Oscillations, N170 Visual-Evoked Potentials, and Visual Hallucinations

Abstract

Visual illusions and hallucinations are hallmarks of serotonergic hallucinogen-induced altered states of consciousness. Although the serotonergic hallucinogen psilocybin activates multiple serotonin (5-HT) receptors, recent evidence suggests that activation of 5-HT2A receptors may lead to the formation of visual hallucinations by increasing cortical excitability and altering visual-evoked cortical responses. To address this hypothesis, we assessed the effects of psilocybin (215 g/kg vs placebo) on both ␣ oscillations that regulate cortical excitability and early visual-evoked P1 and N170 potentials in healthy human subjects. To further disentangle the specific contributions of 5-HT2A receptors, subjects were additionally pretreated with the preferential 5-HT2A receptor antagonist ketanserin (50 mg vs placebo). We found that psilocybin strongly decreased prestimulus parieto-occipital ␣ power values, thus precluding a subsequent stimulus-induced ␣ power decrease. Furthermore, psilocybin strongly decreased N170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. All of these effects were blocked by pretreatment with the 5-HT2A antagonist ketanserin, indicating that activation of 5-HT2A receptors by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. Specifically, activation of 5-HT2A receptors may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through the modulation of ␣ oscillations. Furthermore, the observed reduction of N170 visual-evoked potentials may be a key mechanism underlying 5-HT2A receptor-mediated visual hallucinations. This change in N170 potentials may be important not only for psilocybin-induced states but also for understanding acute hallucinatory states seen in psychiatric disorders, such as schizophrenia and Parkinson's disease.

The Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 2A Receptor Activation

“…Furthermore, ketanserin also reduced psychedelic effects of the structurally related 5-HT2A/1AR agonists psilocybin and ayahuasca [16,17]. The present results demonstrate for the first time that in particular 5-HT2AR activation is the key mechanism of action in mediating the unique human experience of psychedelic effects induced by the prototypical hallucinogen LSD.…”

A Bidirectional Link between Brain Oscillations and Geometric Patterns

“…One might even imagine that the abovementioned pattern formation mechanisms in V1 might be frequency independent but instrumental in providing, through feedback circuits, the missing shape input to frequencyselective higher brain regions (Billock andTsou, 2007, 2010). This idea is compatible with recent experimental and theoretical observations suggesting that geometric hallucinations could originate, at least in part, in higher visual brain regions (Ffytche, 2008;Kometer et al, 2011Kometer et al, , 2013Froese et al, 2013). It is also consistent with the topography of the EEG effects (Fig.…”

“…These hallucinations are often accompanied by a modulation of brain rhythmic activity (Shevelev et al, 2000;Crotogino et al, 2001;Wilkinson, 2004;Becker and Elliott, 2006;ter Meulen et al, 2009;Allefeld et al, 2011;Dubois and Vanrullen, 2011;Kometer et al, 2013;Muthukumaraswamy et al, 2013). During full-field flicker in particular, the exact class of geometric pattern experienced-radial, spiral, grid, etc.-depends on the precise flicker rate (Becker and Elliott, 2006;Allefeld et al, 2011;, and thus presumably on the frequency of rhythmic brain activity.…”

“…During full-field flicker in particular, the exact class of geometric pattern experienced-radial, spiral, grid, etc.-depends on the precise flicker rate (Becker and Elliott, 2006;Allefeld et al, 2011;, and thus presumably on the frequency of rhythmic brain activity. While theoretical work (Ermentrout and Cowan, 1979;Bressloff et al, 2002) has established a direct correspondence between the geometrical structure of visual hallucinations and the spatial organization of visual cortex (retinotopy and cortical magnification), the contribution of brain oscillations is recognized but not fully understood (Shevelev et al, 2000;Rule et al, 2011;Billock and Tsou, 2012;Kometer et al, 2013;Muthukumaraswamy et al, 2013). To shed light on this issue, we conducted a two-part experiment testing whether the effect of oscillatory frequency on the formation of geometric visual patterns is reciprocal.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…The hallucinogen-induced head shaking response can be restored in transgenic mice lacking the 5-HT 2A receptor by selectively restoring this receptor in cortical pyramidal neurons (Gonzalez-Maeso et al, 2007), although the discriminative stimulus properties of LSD and subjective effects of hallucinogens can be fully blocked by 5-HT 2A antagonists in both experimental animals and humans Gresch et al, 2007). Furthermore, the 5-HT 2A/C antagonist ketanserin blocks the effect of psilocybin on visual EEG and event-related potentials and on prepulse inhibition of the acoustic startle in healthy volunteers (Quednow et al, 2012;Kometer et al, 2013). This indicates that the hallucinogenic effects of serotonergic hallucinogens are primarily mediated by the 5-HT 2A receptor.…”