Psilocybin-induced deficits in automatic and controlled inhibition are attenuated by ketanserin in healthy human volunteers

Abstract

The serotonin-2A receptor (5-HT(2A)R) has been implicated in the pathogenesis of schizophrenia and related inhibitory gating and behavioral inhibition deficits of schizophrenia patients. The hallucinogen psilocybin disrupts automatic forms of sensorimotor gating and response inhibition in humans, but it is unclear so far whether the 5-HT(2A)R or 5-HT(1A)R agonist properties of its bioactive metabolite psilocin account for these effects. Thus, we investigated whether psilocybin-induced deficits in automatic and controlled inhibition in healthy humans could be attenuated by the 5-HT(2A/2C)R antagonist ketanserin. A total of 16 healthy participants received placebo, ketanserin (40 mg p.o.), psilocybin (260 μg/kg p.o.), or psilocybin plus ketanserin in a double-blind, randomized, and counterbalanced order. Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response. The effects on psychopathological core dimensions and behavioral inhibition were assessed by the altered states of consciousness questionnaire (5D-ASC), and the Color-Word Stroop Test. Psilocybin decreased PPI at short lead intervals (30 ms), increased all 5D-ASC scores, and selectively increased errors in the interference condition of the Stroop Test. Stroop interference and Stroop effect of the response latencies were increased under psilocybin as well. Psilocybin-induced alterations were attenuated by ketanserin pretreatment, whereas ketanserin alone had no significant effects. These findings suggest that the disrupting effects of psilocybin on automatic and controlled inhibition processes are attributable to 5-HT(2A)R stimulation. Sensorimotor gating and attentional control deficits of schizophrenia patients might be due to changes within the 5-HT(2A)R system.

Figure 1

Effects of placebo, ketanserin (40 mg), psilocybin (260 μg/kg), and psilocybin in combination with a pretreatment of ketanserin on the 5D-ASC (altered states of consciousness) in healthy human volunteers. Significant changes compared with placebo are indicted by ^***p_{Tukey post hoc}=0.001. Mean scores±SEM (n=16). AED, anxious ego dissolution; ASC, altered state of consciousness; OB, oceanic boundlessness; VR, visionary restructuralization.

Figure 2

Effects of placebo, ketanserin (40 mg), psilocybin (260 μg/kg), and psilocybin in combination with a pretreatment of ketanserin on startle amplitude and habituation across three blocks of pulse-alone trials in healthy human volunteers. Mean scores±SEM (n=16).

Figure 3

Effects of placebo, ketanserin (40 mg), psilocybin (260 μg/kg), and psilocybin in combination with a pretreatment of ketanserin on prepulse inhibition (PPI) of the acoustic startle response in healthy human volunteers. Significant differences compared with placebo are indicated by ^**p_{Tukey post hoc}=0.01. Mean scores±SEM (pooled prepulse intensities, n=16). ISI, interstimulus-interval; ket, ketanserin; ket + psi, ketanserin + psilocybin; pla, placebo; psi, psilocybin.

Figure 4

Effects of placebo, ketanserin (40 mg), psilocybin (260 μg/kg), and psilocybin in combination with a pretreatment of ketanserin on errors in the Stroop Test in healthy human volunteers. Mean scores±SEM (n=16). Significant changes compared with placebo are indicted by ^***p_{Tukey post hoc}=0.001. XXXX represents a non-word sequence.

Figure 5

Effects of placebo, ketanserin (40 mg), psilocybin (260 μg/kg), and psilocybin in combination with a pretreatment of ketanserin on response time (RT) in the Stroop Test in healthy human volunteers. Mean scores±SEM (n=16). Significant changes compared with placebo are indicted by ^***p_{Tukey post hoc}=0.001. XXXX represents a non-word sequence.