The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval

This double-blind, placebo-controlled, randomized, counterbalanced, within-subjects study (n=16) investigated the effects of psilocybin (8, 15, & 22mg/70kg) on prepulse inhibition, and found that it inhibited this startle reflex at short interstimulus intervals in a dose-dependent manner. Results indicated the impairment of attention and an inability to filter out unnecessary sensory information under the influence of psilocybin, which is similar to patients with schizophrenia.

Abstract

“Introduction: Schizophrenia patients exhibit impairments in prepulse inhibition (PPI) of the startle response. Hallucinogenic 5-HT_2A receptor agonists are used for animal models of schizophrenia because they mimic some symptoms of schizophrenia in humans and induce PPI deficits in animals. Nevertheless, one report indicates that the 5-HT_2A receptor agonist psilocybin increases PPI in healthy humans. Hence, we investigated these inconsistent results by assessing the dose-dependent effects of psilocybin on PPI in healthy humans.

Methods: Sixteen subjects each received placebo or 115, 215, and 315 μg/kg of psilocybin at 4-week intervals in a randomized and counterbalanced order. PPI at 30-, 60-, 120-, 240-, and 2000-ms interstimulus intervals (ISIs) was measured 90 and 165 min after drug intake, coinciding with the peak and post-peak effects of psilocybin. The effects of psilocybin on psychopathological core dimensions and sustained attention were assessed by the Altered States of Consciousness Rating Scale (5D-ASC) and the Frankfurt Attention Inventory (FAIR).

Results: Psilocybin dose-dependently reduced PPI at short (30 ms), had no effect at medium (60 ms), and increased PPI at long (120–2000 ms) ISIs, without affecting startle reactivity or habituation. Psilocybin dose-dependently impaired sustained attention and increased all 5D-ASC scores with exception of Auditory Alterations. Moreover, psilocybin-induced impairments in sustained attention performance were positively correlated with reduced PPI at the 30 ms ISI and not with the concomitant increases in PPI observed at long ISIs.

Discussion: These results confirm the psilocybin-induced increase in PPI at long ISIs and reveal that psilocybin also produces a decrease in PPI at short ISIs that is correlated with impaired attention and consistent with deficient PPI in schizophrenia.”

Authors: Franz X. Vollenweider, Philipp A. Csomor, Bernhard Knappe, Mark A. Geyer & Boris B. Quednow

Summary

INTRODUCTION

PPI is a measure of sensorimotor gating that is reduced in schizophrenia, schizotypal personality disorder, and psychotic bipolar mania patients. PPI is considered as an example of mechanisms that limit sensory information overflow, facilitate selective attention, and enable efficient processing of relevant information.

To enhance our knowledge of the pathophysiology responsible for the PPI deficits in schizophrenia, investigators have increasingly utilized psychopharmacological modulation of PPI in normal humans and animals. These studies have led to the suggestion that the PPI deficits in schizophrenia patients are linked to alterations in central serotonergic, glutamatergic, and/or dopaminergic neurotransmission.

In rodents, the 5-HT2A receptor plays a critical role in the modulation of PPI. In contrast, in human volunteers, the 5-HT2A/1A receptor was not involved in PPI, and attention may have influenced the results of Gouzoulis-Mayfrank et al (1998b).

We measured the PPI of ASR in 16 healthy volunteers under placebo and three different doses of the 5-HT2A/1A agonist psilocybin. We expected a dose-dependent decrease of PPI in our human volunteers.

Subjects

Twenty healthy subjects were recruited through advertisement from local universities. Sixteen showed robust startle reactions, four were excluded, and all were screened using the DIA-X diagnostic expert system, a semi-structured psychiatric interview, and standard psychometric instruments.

Some subjects had minimal prior drug experiences, all others were drug-na ve. Six of the 16 subjects had tried cannabis, two MDMA, three a hallucinogen, and four were light smokers.

Study Design

A study was conducted on four experimental days with three graded doses of psilocybin administered in a randomized and counterbalanced order separated by 4 week intervals. Participants were told to abstain from alcohol the day prior to each session and not to drink caffeine-containing beverages or to eat 2 h prior to each session.

Startle Response Measurement

Acoustic startle stimuli were presented through headphones to subjects who were instructed to relax and stay awake while staring at a fixed point. The eye-blink component of the acoustic startle response was measured using an EMG startle system. Each session began with a 2-min acclimation period of 70-dB background broadband noise. There were 58 trials in total, with 115-dB pulse-alone (PA) trials, PP trials preceded by a 86-dB (16 dB above background) prepulse of 20 ms duration, and a non-stimulus condition (NS). Data were analyzed with the DOS-based software SRRED2 (San Diego Instruments Inc.), and error trials were defined as trials in which no startle response was recorded because of a baseline shift.

The Altered State of Consciousness Rating Scale

The Altered State of Consciousness (5D-ASC) Rating Scale was used to assess the subjective effects under placebo and psilocybin. The 5D-ASC questionnaire consists of five scales comprising several item clusters, and the results are given as percentage scores of maximum absolute scale values.

Frankfurt Attention Inventory

Psilocybin’s effects on sustained attention were assessed using the Frankfurt Attention Inventory (FAIR), a paper – pencil test that consists of 640 items with four kinds of similar stimuli. The FAIR test provides excellent test – retest reliability scores between 0.85 and 0.91 (Cronbach’s alpha).

Statistical Analysis

All data were analyzed using STATISTICA 7.1 for Windows. A three-way ANOVA was performed on startle and PPI data, a two-way ANOVA on FAIR attentional task data, and a Pearson’s product moment correlation was conducted on 5D-ASC data.

Psychological Effects of Psilocybin

Psilocybin produced an altered state that was characterized by derealization and depersonalization phenomena, affective changes, thought disorder, and perceptual alterations. The effects of psilocybin gradually subsided and were completely absent 6 h after drug intake.

Psilocybin significantly increased most of the 5D-ASC scores in a dose-dependent manner, and the drug 5D-ASC dimension interaction resulted in significant increases in OB, AED, VR, and RV. The psilocybin-induced elevation in OB scores was due mainly to increases in positively experienced depersonalization and derealization, heightened mood, euphoria, and with increasing dose also mania-like symptoms. The increase in AED scores was due mostly to moderate anxious ego-disintegration, thought disorder, and fear of losing control.

DISCUSSION

Psilocybin, a mixed 5-HT2A/1A though preferential 5-HT2A agonist, reduced PPI of acoustic startle in humans, had no effect at medium ISIs, and increased PPI at long ISIs in a dose-dependent manner, while startle reactivity and habituation remained unaffected.

Psilocybin increased prepulse-to-pulse interval (PPI) at longer ISIs in healthy volunteers, but had no effect on startle reactivity or habituation. Moreover, the PPI-enhancing effect was dose-dependent. Ayahuasca DMT failed to affect PPI in humans, but DOI and mescaline disrupted PPI in rats at short ISIs. Psilocybin enhanced PPI in humans at long ISIs, but DOI was blocked by 5-HT2A antagonists but not by 5-HT2C antagonists.

Psilocybin increases prepulse interval in the rat by 5-HT2A receptors, but not by 5-HT2C receptors. This suggests that the physiological significance of these increases is unknown. Psilocybin had no effect on startle reactivity, and does not affect startle circuits involved in inhibitory processes. This is also consistent with animal studies demonstrating that comparable doses of the 5-HT2A/2C agonist DOI did not alter startle reactivity.

Psilocybin disrupts PPI in humans at a short ISI of 30 ms, in contrast to the effect of DOI, which disrupts PPI across a wide range of ISIs from 25 to 180 ms.

Psilocybin-induced attentional deficits correlated positively with PPI reduction at the short 30 ms ISI but not with PPI increases seen at longer ISIs. This finding supports the general concept that deficits in early pre-attentive information processing may underlie complex attentional and cognitive abnormalities in schizophrenia.

Unmedicated first-episode schizophrenia patients exhibit marked PPI deficits at 30 and 60 ms and a moderate PPI deficit at 120 ms prepulse intervals, and these deficits are correlated with lower attentional performance on the CANTAB rapid visual information processing task. The serotonergic system is involved in the modulation of PPI and cognitive impairments in schizophrenia. Atypical antipsychotics with higher affinity at 5-HT2A than D2 receptors may be superior in reversing PPI deficits.

Psilocybin has dual ISI-dependent actions on PPI in humans, possibly due to stimulation of 5-HT2A or 5-HT1A receptors, although downstream effects upon the glutamate and dopamine systems may also be implicated. Psilocybin reduces PPI at short ISIs and increases PPI at longer ISIs, and this effect may be due to 5-HT2A receptor stimulation in the striatum and thalamus, or to 5-HT1A receptor stimulation in cortical pyramidal cells.

Psilocybin may have affected PPI by stimulating 5-HT1A receptors, which in turn may have masked or counteracted potential 5-HT2A receptor-mediated PPI deficits at longer ISIs.

There may be differences in transducing mechanisms between humans and animals, which may explain why certain serotonergic agonists have opposite effects on PPI.

We cannot fully exclude the possibility that psilocybin’s effects on PPI in humans are due to a drug-induced stimulation of 5-HT1A receptors, but more research is needed to clarify the mechanisms and sites of action of psilocybin on PPI in humans.

The highest dose of psilocybin used in this study might not have been high enough to induce a full-blown psychotic state, but only moderate anxious ego-disintegration, thought disorder, and fear of losing control.

This study revealed complexities regarding the role of the serotonergic system in the modulation of PPI in humans. Furthermore, the agonistic properties of psilocybin at 5-HT1A and/or 5-HT2A receptors are responsible for the apparent disparity between the PPI-enhancing effects of psilocybin in humans and the PPI-disruptive effects of DOI in animals.

ACKNOWLEDGEMENTS

We thank the Heffter Research Institute, the Swiss Federal Office for Public health, the Deutsche Forschungsgemeinschaft, and the US Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center for their support.