Psilocybin-Induced Deficits in Automatic and Controlled Inhibition are Attenuated by Ketanserin in Healthy Human Volunteers

Automatic and controlled information-processing deficits, including impairments in early and late inhibitory gating, are considered core features of schizophrenia and have been linked to the serotonin system. Quednow and colleagues note that early automatic inhibition (sensorimotor gating) and controlled behavioural inhibition have been associated specifically with serotonin-2A receptors (5-HT2A R), and that changes at this receptor might contribute to the inhibitory deficits seen in schizophrenia. The hallucinogen psilocybin is metabolised to psilocin, which acts at multiple 5-HT receptor subtypes including 5-HT2A and 5-HT1A, and prior studies have shown that psilocybin alters prepulse inhibition (PPI) and certain measures of cognitive control in humans; however, it remained unclear which receptor actions (5-HT2A vs 5-HT1A or others) mediate these effects. This study set out to test whether the 5-HT2A/2C receptor antagonist ketanserin would attenuate psilocybin-induced deficits in automatic and controlled inhibition in healthy volunteers. Using a placebo-controlled, double-blind, randomized, counterbalanced design, the investigators examined effects on sensorimotor gating (PPI), behavioural inhibition and attentional control (a trial-by-trial Color–Word Stroop Test), and subjective altered states of consciousness (5D-ASC), comparing placebo, ketanserin, psilocybin, and psilocybin plus ketanserin conditions. The working hypothesis was that ketanserin pretreatment would reduce psilocybin-induced disruptions of PPI and Stroop interference and prevent the altered state of consciousness induced by psilocybin.

Sixteen healthy volunteers (13 males, 3 females; mean age 29.7 years, range 24–39), mostly students or academics, were recruited and screened for medical and psychiatric health. Screening included medical examination, ECG, blood tests, a semi-structured psychiatric interview, and psychometric questionnaires; high scores on FPI subscales associated with adverse reactions to hallucinogens were exclusionary but did not lead to exclusions in this sample. Limited prior recreational drug exposure was reported by a few participants. The study received ethical approval and participants gave written informed consent. Psilocybin capsules (prepared as 1 mg and 5 mg doses) and ketanserin (40 mg, oral) plus matched lactose placebo were administered in identical gelatin capsules. Each subject completed four experimental sessions separated by 4-week intervals in a randomized, counterbalanced, double-blind manner, receiving: placebo, psilocybin (reported in the extracted text as 260 mg/kg, oral), ketanserin (40 mg, oral), and psilocybin plus ketanserin. Ketanserin or placebo was given approximately 1 hour after arrival (0900 hours) and psilocybin or placebo given 40 minutes later. Startle/PPI measures were taken 60 minutes after psilocybin administration, the Stroop task at 85 minutes, and the 5D-ASC questionnaire at about 125 minutes, aligning with the reported plateau of psilocybin effects. Prepulse inhibition of the acoustic startle response was assessed in a 15-minute session with 52 trials presented in pseudorandom order on a continuous 70-dB background. The session included pulse-alone trials and three trial types: pulse-alone, prepulse–pulse trials (prepulse durations 20 ms, prepulse intensities 78 dB or 86 dB, interstimulus intervals (ISIs) 30 ms or 120 ms), and no-stimulus trials. Prepulse intensity conditions were pooled for analysis. Startle measures analysed were mean startle reactivity, % habituation, and %PPI (standard formula). Trials with no recorded startle were counted as errors and subjects with >50% error/rejections would have been excluded; none were excluded. Subjective effects were measured with the 5D-ASC visual-analogue questionnaire assessing oceanic boundlessness (OB), anxious ego dissolution (AED), and visionary restructuralization (VR). Cognitive control was tested using a computerized trial-by-trial Color–Word Stroop Test with 192 trials across four conditions (congruent, conflict, neutral non-word XXXX, neutral word), with spoken responses recorded for reaction time (RT) and errors. Stroop facilitation, interference, and total Stroop effect were computed from condition contrasts. Statistical analysis used repeated-measures ANOVA for startle/PPI (factors: drug, prepulse intensity, ISI), for Stroop (drug, condition), and for 5D-ASC (drug, dimension), with Tukey post-hoc tests where indicated; Pearson correlations explored relationships between PPI, Stroop measures, and 5D-ASC change scores. Significance threshold was p<0.05.

Psilocybin produced robust subjective alterations on the 5D-ASC. A two-way ANOVA (drug by 5D-ASC dimension) showed a main effect of drug (F(3,45)=48.3, p<0.0001) and post-hoc tests indicated psilocybin versus placebo increases on all scales (all p<0.0002). The effect was most pronounced on oceanic boundlessness (OB) (drug by dimension interaction F(6,90)=17.2, p<0.0001). Ketanserin alone did not induce symptoms but significantly reduced psilocybin-induced psychotomimetic effects on OB and VR (psilocybin vs ketanserin+psilocybin, both p<0.0002); reduction of AED was present but not significant overall, although subscale analyses showed ketanserin significantly attenuated psilocybin-induced thought disorder (p<0.00005) and fear of losing control over thinking (p<0.02). Startle reactivity and habituation were largely unchanged by psilocybin. A block by drug ANOVA revealed significant main effects of block (F(2,30)=79.2, p<0.0001) and drug (F(3,45)=8.13, p=0.0002). Post-hoc tests showed psilocybin alone did not alter startle amplitude (NS), whereas ketanserin (p<0.0015) and ketanserin plus psilocybin (p<0.015) reduced startle reactivity. There was no significant drug by block interaction, indicating no differences in habituation across conditions. For %PPI, an initial four-way ANOVA (pretreatment * treatment * intensity * ISI) identified an interaction of pretreatment by treatment and ISI (F(1,15)=4.21, p<0.05), reflecting differential drug effects at the two ISIs. Post-hoc comparisons showed that psilocybin decreased %PPI at the short 30 ms ISI (p<0.008), and this deficit was reversed by ketanserin pretreatment (effect no longer significant). At the long 120 ms ISI, psilocybin produced a slight non-significant increase in %PPI while ketanserin produced a slight non-significant decrease. Main effects of prepulse intensity (F(1,15)=43.4, p<0.0001) and ISI (F(1,15)=36.7, p<0.0001) were present. Adjusting for smoking status did not alter these outcomes. On the Stroop task, psilocybin selectively impaired performance in the conflict condition. Error rates showed main effects of drug (F(3,45)=6.26, p<0.001), condition (F(3,45)=17.9, p<0.0001), and a drug by condition interaction (F(9,135)=2.39, p<0.015); post-hoc tests indicated increased errors under psilocybin in the conflict condition (p<0.0001), an effect reversed by ketanserin (p<0.0001). Reaction time analyses showed main effects of drug (F(3,45)=9.51, p<0.0001), condition (F(3,45)=61.6, p<0.00001), and their interaction (F(9,135)=3.62, p<0.0005). Psilocybin increased RTs across all conditions (all p<0.00003), and ketanserin substantially reduced these latency increases; ketanserin alone had no significant effects. Psilocybin significantly increased Stroop interference and the total Stroop effect compared with placebo and ketanserin, and these increases were neutralised by ketanserin co-administration. Psilocybin alone did not change facilitation, although the psilocybin+ketanserin condition showed enhanced facilitation; ketanserin alone did not alter interference, Stroop effect, or facilitation. Correlation analyses pooling peak-effect data for psilocybin and psilocybin+ketanserin (n=32) found that the reduction in %PPI at the 30 ms ISI correlated with increases in OB (R=0.47, p<0.01) and VR (R=0.40, p<0.05) scores, but not with Stroop measures. Changes in AED scores correlated with Stroop interference in the neutral X (R=0.40, p<0.05) and neutral W (R=0.35, p<0.05) conditions; subscale analyses implicated thought disorder and loss of control over thinking/body as driving these associations.

Quednow and colleagues interpret their findings as evidence that the disruptive effects of psilocybin on both automatic (sensorimotor gating) and controlled (Stroop interference) inhibition are mediated predominantly by stimulation of 5-HT2A receptors, because pretreatment with the 5-HT2A/2C antagonist ketanserin abolished the psilocybin-induced deficits and substantially attenuated the subjective hallucinogenic effects. The authors replicate a prior pattern in which psilocybin reduced PPI at short ISIs and observed a non-significant increase at a longer ISI; they propose that short-interval PPI disruption is attributable to 5-HT2A R action, whereas long-interval effects might involve 5-HT1A or interactions among receptor subtypes, noting that ketanserin did not block the small PPI enhancement at 120 ms. The investigators discuss that psilocybin increased Stroop interference and error rates in the conflict condition, a profile similar to findings in schizophrenia, and argue that these results reflect impaired conflict monitoring and response inhibition rather than a primary working memory deficit. Ketanserin’s prevention of Stroop deficits supports a role for 5-HT2A R stimulation in those processes. The authors consider potential contributions of 5-HT2C R but present several lines of animal and pharmacological evidence suggesting 5-HT2C R agonism is unlikely to account for the observed impairments. They also note that, unlike some prior reports, ketanserin produced a slight reduction in startle amplitude in their study and that methodological differences between studies may explain inconsistent ketanserin effects on PPI. Although PPI and Stroop performance appear to be modulated by similar 5-HT2A R mechanisms, the lack of a direct correlation between PPI and Stroop measures in this study leads the authors to propose that different regional 5-HT2A R populations mediate the two effects: subcortical structures implicated in the startle circuit (for example striatum or thalamus) for PPI, and cortical regions such as the anterior cingulate cortex and dorsolateral prefrontal cortex for Stroop interference. They cite imaging and receptor-occupancy data consistent with strong psilocybin effects in prefrontal areas. The study is presented as the first challenge experiment to examine both automatic and controlled inhibition and associated psychopathological symptoms with a hallucinogenic drug in healthy humans, and the authors propose that 5-HT2A R alterations across cortical and subcortical regions may contribute to the varied inhibitory deficits observed in schizophrenia.