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.

Psychedelics

“…The authors suggest that their findings have implications not only for the pathophysiology of dysfunctional emotional biases, but they may also provide a framework to delineate the mechanisms underlying psilocybin's putative antidepressant effects. Quednow et al (2012) investigated the role of 5-HT 2A receptors in automatic (sensorimotor gating) and controlled (Stroop interference) inhibition processes in a model psychosis approach using psilocybin (260 mg/kg) in 16 healthy humans pretreated either with the 5-HT 2A -selective receptor antagonist ketanserin (40 mg) or placebo, using a placebo-controlled, crossover, counterbalanced, and double-blind design. They found that psilocybin-induced deficits in automatic and 280 Nichols controlled inhibition were significantly attenuated by ketanserin.…”

“…This model suggests that the inability to filter, inhibit, and screen out exteroceptive and interoceptive stimuli may lead to sensory overload and a breakdown of cognitive integrity, leading to hallucinations and alterations of ego functioning. Deficits in preattentive sensorimotor gating have been reported repeatedly after psilocybin and LSD administration Quednow et al, 2012;Schmid et al, 2015) and have been related to alterations in cognitive functioning Quednow et al, 2012). The CSTC model proposes that the thalamus plays a key role within CSTC feedback loops for gating external and internal information to the cortex, and therefore is crucially involved in the regulation of the level of awareness and attention Geyer and Vollenweider, 2008).…”

Parkinson's disease, visual hallucinations and apomorphine: A review of the available evidence

“…receptor antagonist ketanserin, used to block the effects of psilocybin in healthy volunteers [47,48,54].…”

Effect of Psilocin on Extracellular Dopamine and Serotonin Levels in the Mesoaccumbens and Mesocortical Pathway in Awake Rats

“…12,13) The effects of psilocybin are blocked by pretreatment with the 5-HT 2A antagonist ketanserin, indicating that the hallucinogenic effects of psilocybin are mediated primarily by 5-HT 2A stimulation. [14][15][16] Thus, 5-HT 2A receptor activation is necessary for the indoleamine hallucinogenic effects of psilocybin. On the other hand, a human imaging study using radiolabeled raclopride, a dopamine (D 2 ) receptor antagonist, showed reduced binding in the caudate and putamen after psilocybin administration, suggesting that psilocybin indirectly increases dopamine levels in the brain, probably through 5-HT 2A receptor activation.…”