LSD and ketanserin and their impact on the human autonomic nervous system

The trial was a double-blind, placebo-controlled, randomised crossover study in healthy volunteers. Participants underwent screening including medical history, physical examination, ECG and blood tests plus structured psychiatric interviews to exclude current or past psychiatric disorders. Subjects abstained from prescribed and illicit drugs for at least two weeks, from alcohol for 24 hours before test days, from smoking for 60 minutes prior to recordings and from caffeine on test days. The protocol and ethics approvals are reported; trial registration is provided in the extracted text. Three test-session conditions were delivered in counterbalanced order, two weeks apart: placebo pretreatment then placebo (Plac+Plac), placebo pretreatment then LSD 100 µg oral (Plac+LSD), and ketanserin 40 mg oral pretreatment 60 minutes before LSD 100 µg oral (Ket+LSD). Random allocation was performed by a lab member not otherwise involved in subject contact. Electrocardiography (ECG) was recorded during two resting-state fMRI sessions at approximately 75 minutes (T1) and 300 minutes (T2) after the second drug administration. Signals were sampled at 500 Hz with four chest electrodes and a respiration belt. MRI-related artefacts were removed and R peaks were detected automatically and manually validated; datasets with >10% noisy segments or otherwise unreliable R-peak detection were excluded. Due to differing available recording lengths across participants, ECG was analysed in 3-minute epochs taken from the start of the first resting-state scan. Very low frequency HRV metrics were not calculated because of the short segments. Heart and HRV parameters computed included general measures (heart rate, total power), sympathetic markers (normalized low-frequency power, LF power 0.04–0.15 Hz, SNS index, Stress Index) and parasympathetic markers (high-frequency power 0.15–0.4 Hz, PNS index, RMSSD-derived indices). Power measures were log-transformed when non-normal. Subjective psychedelic effects were measured with the 5D-ASC scale: a short 45-item version at about 180 minutes (peak effects) and the full 94-item version at 720 minutes. For statistics, a nested repeated-measures ANOVA was used with intervention (three levels) and time (two levels) as within-subject factors; Greenhouse–Geisser correction and Bonferroni post hoc tests were applied. A second repeated-measures model included age and body-mass index (BMI) as covariates to examine between-subject effects. Exploratory partial correlations (controlling for age and BMI) were computed between HRV parameters at each time point and 5D-ASC scores.

Twenty-five participants were enrolled, but eight were excluded from the repeated-measures ANOVA because of missing or artifactual ECG traces in at least one condition, leaving n = 17 for the within-subject ANOVA. Demographics reported in the extract show a mean age of 22.5 years (SD 3.7) and mean BMI 22.2 (SD 1.5). The number of datasets entering the various correlation analyses varied by condition and time point and is reported where results are presented. Across interventions, LSD (Plac+LSD) produced greater sympathetic activity than placebo (Plac+Plac) and the ketanserin plus LSD condition (Ket+LSD), whereas Ket+LSD showed a shift toward parasympathetic activity versus the other conditions. Repeated-measures ANOVA demonstrated significant intervention effects for general ANS parameters including heart rate, Stress Index and LFnu (normalized low-frequency power). Post hoc tests indicated heart rate was significantly higher under Plac+LSD compared with Plac+Plac and Ket+LSD; Ket+LSD had a lower heart rate than Plac+Plac (all p < .05). LFnu was significantly lower for Ket+LSD than for both Plac+Plac and Plac+LSD. The SNS index showed a main effect of intervention, with Plac+LSD producing a larger SNS index than Plac+Plac and Ket+LSD. There were no main effects for LF log power, HF power or Total Power, but the PNS index was larger for Ket+LSD than for Plac+LSD. No significant intervention×time interactions were observed. When age and BMI were included as covariates, BMI had a between-subject influence on LF log (p = .04); no other covariate interactions were reported. Partial correlation analyses (controlling for age and BMI) revealed a consistent pattern in the LSD condition (Plac+LSD, n = 20 datasets): sympathetic measures correlated positively with subjective 5D-ASC scores and parasympathetic measures correlated negatively. For example, Anxiety correlated positively with heart rate (r = 0.46, p = .04) and negatively with the PNS index at T1 (r = -0.47, p = .03); at T2 Anxiety correlated with HR (r = 0.50, p = .02), SNS index (r = 0.53, p = .01) and Stress Index (r = 0.50, p = .02). Audio–visual synesthesia, elementary imagery and spiritual experience showed similar positive associations with sympathetic markers (SNS index, HR, LFnu) and negative associations with parasympathetic markers (PNS index, HF, Total Power). The short 5D-ASC at the 180-minute peak showed the same directional pattern though only Spiritual experience reached significance (r = 0.48, p = .03). Analyses in the Ket+LSD (n = 21) and Plac+Plac (n ≈ 21–22) conditions produced some correlations in the same directions, but these were largely driven by very few subjects (five in Plac+Plac and four in Ket+LSD) and therefore require cautious interpretation. Finally, correlating baseline ANS markers from the placebo session with subjective responses during the LSD session yielded predictive relationships: higher baseline sympathetic markers (HR, SNS index, LFnu) were positively associated with stronger subjective effects (for example, Experience of unity and Impaired control and cognition), while higher baseline parasympathetic measures were negatively associated with those same subjective outcomes. Overall, the data show a coherent pattern of positive associations between sympathetic ANS activity and psychedelic subjective effects and inverse associations for parasympathetic activity.

Olbrich and colleagues interpret their findings as evidence that LSD predominantly activates the sympathetic branch of the ANS, whereas pretreatment with the 5-HT2A antagonist ketanserin shifts autonomic balance toward parasympathetic dominance and effectively counters LSD's autonomic effects. The SNS index and heart rate increases support a sympathomimetic action of LSD; the average heart rate increase with LSD versus placebo was about 10 beats per minute, which the authors consider clinically meaningful though not dangerous. Ketanserin reduced heart rate modestly relative to placebo (≈4 bpm) and produced lower LFnu and higher PNS index values, indicating decreased sympathetic and increased parasympathetic tone. A prominent result is the consistent relationship between autonomic state and subjective experience: greater sympathetic activation was associated with stronger scores across multiple 5D-ASC domains, while parasympathetic markers showed inverse associations. This pattern held within the LSD condition and, to a lesser extent, in placebo and Ket+LSD conditions (the latter correlations being based on few subjects). The investigators note that baseline (placebo) HRV measures predicted the magnitude of later subjective responses to LSD, suggesting ANS activity might function as a trait marker that forecasts individual sensitivity to psychedelic effects. They propose that such electrophysiological baseline markers could be explored as candidate predictors of treatment response if LSD were used therapeutically, analogous to prior findings that baseline sympathetic activity predicts antidepressant outcomes with SSRIs/SNRIs. The authors acknowledge limitations: ECG recordings were obtained inside an MRI scanner so the setting may have influenced ANS activity; only cardiac measures were collected, so other ANS indices (electrodermal responses, pupil responses) were not assessed; and the sample comprised healthy volunteers, limiting generalisability to clinical populations. They also caution that correlations do not establish causality—subjective experience may drive autonomic changes or vice versa. In sum, the study suggests that ANS measures derived from HRV reliably reflect LSD's autonomic effects and relate to subjective psychedelic states, and that baseline autonomic tone merits further investigation as a biomarker in psychedelic research.