Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α 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 μg/kg vs placebo) on both α 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 α power values, thus precluding a subsequent stimulus-induced α 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 α 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.

Figure 1.

A, Effects of psilocybin and ketanserin on group-averaged event-related potential waveforms for the three parieto-occipital ROIs. Placebo + placebo (black), placebo + psilocybin (red), ketanserin + placebo (blue), and ketanserin + psilocybin (green). B, Correlation between the psilocybin-induced reduction of N170 amplitudes and the psilocybin-induced perceptual visual alterations as measured by the main scales (B1) and subscales (B2) of the 5D-ASC questionnaire.

Figure 2.

The scalp topographic maps depict the difference between the placebo + placebo condition and the placebo + psilocybin condition in the P1 amplitude (80 to 120 ms), in the N170 amplitude (150 to 190 ms) and in the prestimulus α power values (−600 to −200 ms).

Figure 3.

Effects of psilocybin treatment and ketanserin pretreatment on α power values in three parieto-occipital ROIs. A, Time course for α power values (8–12 Hz) as a function of placebo + placebo (black), placebo + psilocybin (red), ketanserin + placebo (blue), and ketanserin + psilocybin (green). B, Time course for the difference in power values between placebo + psilocybin and placebo + placebo for all frequencies (4–52 Hz).

Figure 4.

Effects of psilocybin and ketanserin on the phase-locking index for the three parieto-occipital ROIs. Placebo + placebo (black), placebo + psilocybin (red), ketanserin + placebo (blue), and ketanserin + psilocybin (green).