Effects of ayahuasca on sensory and sensorimotor gating in humans as measured by P50 suppression and prepulse inhibition of the startle reflex, respectively

Ayahuasca is a traditional Amazonian plant brew that combines the psychedelic N,N-dimethyltryptamine (DMT), a 5-HT2A/2C agonist, with beta-carboline alkaloids that inhibit monoamine oxidase (MAO), thereby enabling oral activity of DMT. Earlier research has suggested that serotonergic psychedelics, dopaminergic agonists and NMDA antagonists can transiently alter neural mechanisms that normally filter sensory information. Two operational neurophysiological measures of such gating are suppression of the P50 auditory evoked potential (P50 suppression), taken as an index of sensory gating with hippocampal involvement, and prepulse inhibition of the startle reflex (PPI), an index of sensorimotor gating modulated by a forebrain–brainstem circuit. Prior human pharmacological challenge studies had examined PPI after some serotonergic drugs but, according to the authors, P50 suppression had not been previously assessed in humans following a 5-HT2A/2C agonist challenge. Riba and colleagues set out to evaluate the acute effects of ayahuasca on both P50 suppression and PPI in a single sample of healthy volunteers. The study aimed to determine whether ayahuasca would differentially modulate sensory versus sensorimotor gating and to relate any neurophysiological changes to the subjective psychedelic experience induced by the beverage.

Eighteen healthy volunteers (15 males, 3 females) with prior psychedelic experience (at least five prior uses) were recruited; after data quality screening, usable P50 and PPI recordings were available from 15 participants (13 males, 2 females). Inclusion required no current or past axis-I psychiatric or neurological disorder and no first-degree family history of axis-I disorders; participants underwent structured psychiatric interview, trait-anxiety assessment and a medical evaluation. Two volunteers had prior ayahuasca exposure but it was not required. The study complied with ethical standards and participants provided written informed consent. Two oral ayahuasca doses were tested: a low dose of 0.6 mg DMT/kg and a high dose of 0.85 mg DMT/kg. The material was administered as a freeze-dried lyophilizate derived from a 9.6-l batch; reported alkaloid content of the powder was 8.33 mg DMT, 14.13 mg harmine, 0.96 mg harmaline and 11.36 mg tetrahydroharmine (THH) per gram. Individual doses were delivered in gelatin capsules containing measured amounts of freeze-dried material, with lactose placebo capsules added so each session involved the same number of capsules. The investigators used a within-subjects, crossover design. Each volunteer completed four sessions: a first single-blind placebo session to familiarise participants (data from that day were not analysed), then three double-blind, balanced sessions in which participants received placebo, low-dose ayahuasca, and high-dose ayahuasca in a randomised order with a 7-day washout between sessions. Participants abstained from medications, illicit drugs, alcohol, tobacco and caffeine prior to sessions and were drug-screened by urinalysis. Capsules were administered ~10:00 hours; P50 recordings began at 1.5 h post-dose and PPI recordings at 2 h post-dose, corresponding to expected peak subjective effects. Subjective-effect questionnaires were completed 4 h after ingestion. P50 recordings: 120 pairs of auditory stimuli (75 dB[A], 1000 Hz, 4 ms pips) were delivered with a 500 ms inter-stimulus interval and 8 s between pairs while EEG was recorded from 19 scalp electrodes (10/20 system) referenced to averaged mastoids. Data were epoched, artefact-rejected, band-pass filtered and averaged. P50 peaks were scored at Cz as the largest positivity 40–80 ms after stimulus, with amplitude measured relative to the preceding negative trough (N40) or to baseline when N40 was absent. Primary P50 metrics were C and T amplitudes, difference amplitude (C–T) and percentage suppression [1 – (T/C)] × 100; latency to peak after the C stimulus was also measured. Startle/PPI recordings: startle pulses were 1 kHz tones at 116 dB[A] (50 ms); prepulses were 1 kHz tones at 80 dB[A] (20 ms). Trials included pulse-alone and prepulsed trials at prepulse-to-pulse intervals of 60, 120, 240 and 2000 ms. EMG of the orbicularis oculi was recorded (sampling 1000 Hz), rectified and smoothed; peak blink magnitude within 120 ms post-stimulus was the primary outcome. Sequences comprised an acclimation phase and three blocks yielding a total of 50 startle stimuli per session. Variables analysed were pulse-alone reactivity, prepulsed trial magnitudes, percentage PPI ([1 – (prepulsed/pulse-alone)] × 100) for each interval, and percentage habituation across blocks. Statistical analysis employed repeated-measures ANOVAs (drug, stimulus type, block or prepulse condition as within-subject factors) with Greenhouse–Geisser correction where appropriate; significant ANOVAs were followed by paired t-tests. Pearson’s r was used to test correlations between neurophysiological changes and subjective-effect scores (Hallucinogen Rating Scale, HRS; Altered States of Consciousness Questionnaire, APZ).

Fifteen participants provided complete and usable P50 and PPI data across the three analysed sessions. P50 measures showed dose-dependent reductions in gating: although the amplitude of the P50 to the conditioning (C) stimulus decreased with dose without reaching significance (placebo 2.93 ± 0.42 μV, low 2.56 ± 0.28 μV, high 2.05 ± 0.22 μV; ANOVA F2,28 = 2.57, P = 0.10), a two-way ANOVA (drug × stimulus type) found a significant stimulus-type main effect and a drug × stimulus-type interaction (interaction F2,28 = 4.96, P < 0.05). Difference amplitude (C–T) decreased with ayahuasca (means: placebo 2.12 ± 0.42 μV, low 0.93 ± 0.34 μV, high 0.52 ± 0.31 μV), with the ANOVA showing F2,28 = 4.96, P < 0.05 and pair-wise comparisons indicating that both low and high doses differed significantly from placebo (t14 = 2.29, P < 0.05; t14 = 2.59, P < 0.05, respectively). Percentage suppression was markedly reduced by ayahuasca (placebo 71.86% ± 8.41, low 24.57% ± 17.17, high 6.00% ± 18.10), with a significant drug effect (F2,28 = 4.78, P < 0.05) and significant pair-wise contrasts versus placebo for both doses (t14 ≈ 2.82–2.83, P < 0.05). Latency to peak after the C stimulus showed a non-significant trend toward shortening with dose. Startle and PPI measures did not show significant drug-related changes. Startle magnitude decreased across the session blocks (habituation effect significant: F2,28 = 12.91, P < 0.01), with mean pulse-alone magnitudes of 104.96 ± 19.63 μV (first block), 66.97 ± 13.39 μV (second) and 50.16 ± 11.33 μV (third). No significant main effect of drug on pulse-alone magnitude was observed (means across sessions: placebo 68.13 ± 17.58 μV, low dose 59.62 ± 11.27 μV, high dose 94.35 ± 21.61 μV; F2,28 = 1.97, ns), nor any significant drug × block interaction. Percentage habituation did not differ between drug conditions. Across prepulse conditions there was a robust main effect of prepulse condition on magnitude/PPI (e.g. ANOVA main effect F3,42 = 11.85, P < 0.001), reflecting expected interval-dependent inhibition, but no significant effects of drug and no significant drug × prepulse-condition interaction were detected. Subjective-effects ratings on the HRS and APZ showed the characteristic psychedelic profile after ayahuasca, with statistically significant increases on all subscales except for HRS-volition. The subjective state typically lasted 4–6 h and peaked between ~90 and 120 minutes post-dose, with frequent somatosensory and visual alterations but no loss of insight or full psychotic symptoms. Correlation analyses found no significant relationships between drug-induced changes in P50 measures and PPI, nor between P50 changes and subjective-effect scores.

Riba and colleagues interpret the findings as demonstrating divergent acute effects of ayahuasca on two gating measures: a dose-dependent reduction in P50 suppression, indicating impaired sensory gating, and no clear effect on sensorimotor gating as measured by PPI. The lack of change in startle habituation further supports an absence of pronounced effects on startle plasticity at the tested doses. Subjective reports confirmed a typical moderate psychedelic syndrome without frank psychosis. The authors situate the P50 disruption within prior pharmacological literature showing impaired P50 suppression after drugs that increase catecholaminergic transmission (for example amphetamine and yohimbine), and mixed findings for NMDA antagonists; they note that, before this study, effects of 5-HT2A/2C agonists on human P50 had not been reported. Animal data on the homologous N40 potential implicate cholinergic, noradrenergic and dopaminergic systems in gating, and the authors discuss the complexity of receptor actions: some rodent studies showed 5-HT2A/2C agonists impairing filtering, whereas other 5-HT2 manipulations produced opposite effects, reflecting species- and receptor-subtype differences. Concerning PPI, the absence of a significant ayahuasca effect contrasts with reports of modest PPI enhancement after psilocybin and MDMA in humans and with many animal studies where 5-HT2A/2C agonists disrupted PPI. The investigators suggest that interspecies differences, and the involvement of multiple serotonin receptor subtypes (notably 5-HT1A and 5-HT2A/2C) that can have opposing behavioural effects, might account for the discrepant results. They also highlight that P50 suppression and PPI index different processing stages and brain circuits—hippocampal mechanisms for P50 versus a broader limbic–striatal–pontine network for PPI—so divergent drug effects are plausible. Key limitations acknowledged by the authors include the small sample size, the moderate dose range tested, and the pharmacological complexity of ayahuasca, which contains MAO inhibitors plus DMT and other alkaloids; these factors limit generalisation to pure 5-HT2A/2C agonists. The absence of correlations between neurophysiological changes and subjective ratings was noted. The authors conclude that their findings are preliminary and recommend future studies using wider dose ranges and further pharmacological characterisation to clarify how ayahuasca and serotonergic agents modulate sensory and sensorimotor gating in humans.