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

This placebo-controlled randomized, crossover study (n=17) investigated the impact of LSD (100 μg) and the counteracting influence of the 5-HT2A receptor antagonist ketanserin (40mg) on the autonomic nervous system within healthy subjects. LSD predominantly increased the sympathetic activity, while ketanserin increased the parasympathetic influence, thus antagonizing the effects of LSD on the autonomic nervous system completely. The magnitude of subjective experiences during the interventions was positively correlated with the sympathetic activity and negatively correlated with the parasympathetic activity, independent of the intervention.

Abstract

“The interest in lysergic acid diethylamide (LSD) has sparked again due to its supposed positive effects on psychopathological conditions. Yet, most research focuses on the actions of LSD on the central nervous system. The interaction with the autonomic nervous system (ANS) has been neglected so far. Therefore, the aim was to assess the effects of LSD and the serotonin 2A receptor antagonist ketanserin on the ANS as assessed by heart rate variability (HRV) measures and their correlation with subjective drug‐induced effects in a randomized, placebo‐controlled crossover trial. Thus, ANS activity was derived from electrocardiogram recordings after intake of placebo, LSD or ketanserin, and LSD by calculating R‐peak‐based measures of sympathetic and parasympathetic activity. Repeated measure ANOVA and partial correlation for HRV measures and subjective experience questionnaires were performed. LSD predominantly increased sympathetic activity, while ketanserin counteracted this effect on the ANS via an increase of parasympathetic tone. Sympathetic activity was positively and parasympathetic activity negatively associated with psychedelic effects of LSD. Furthermore, Placebo HRV measures predicted subjective experiences after LSD intake. The association between trait ANS activity and LSD‐induced subjective experiences may serve as a candidate biomarker set for the effectiveness of LSD in the treatment of psychopathological conditions.”

Authors: Sebastian Olbrich, Katrin H. Preller & Franz X. Vollenweider

Summary

1 | INTRODUCTION

There has been renewed interest in the effects of lysergic acid diethylamide (LSD) on the human nervous system, especially the effects of LSD on the autonomic nervous system, but no specific analysis has been carried out using heart rate variability (HRV)- based measures to estimate the effect of LSD on the ANS.

The effects of lysergic acid diethylamide (LSD) and the serotonin 2A receptor antagonist ketanserin on the autonomic nervous system were investigated in a randomized, placebo-controlled crossover trial. Sympathetic activity was positively and parasympathetic activity negatively associated with psychedelic effects of LSD.

LSD has been shown to act on the sympathetic and parasympathetic branches of the autonomic nervous system, with the sympathetic system being mainly responsible for the increased heart rate, blood pressure, and pupil size. The parasympathetic system remains largely unknown.

There are currently no standardized controlled trials that involve objective electrophysiological measurements of the autonomic function in humans after LSD intake and subjective experiences. This information could help in the prediction of the effects of psychedelic drugs.

To close knowledge gaps, this study analyzed the impact of an LSD only condition, a placebo condition, and an agonist (LSD) and antagonist (5-HT2A receptor antagonist ketanserin) condition on the autonomic nervous system in relation to the subjective experiences after administration.

Spectral analysis of consecutive ECG R- peaks in milliseconds can be used to assess the global function of the autonomic nervous system (ANS), and can differentiate between the contributions of the sympathetic and parasympathetic branches.

We hypothesized that LSD alters ANS activity with increases of sympathetic activity, and that this effect would be decreased after blocking the 5- HT2A receptor with ketanserin.

2.1 | Design, participants, and intervention

The study was designed as a double- blinded placebo-controlled trial in healthy participants and was approved by the Cantonal Ethics Committee of Zurich. All subjects provided written informed consent before participation.

Participants were excluded if they had a history of psychiatric disorders, used drugs, drank alcohol, were left-handed, had poor knowledge of the German language, were cardiovascular disease, had a history of head injury or neurological disorder, or had a history of alcohol or illicit drug dependence.

Participants received three different substance combinations in a randomized and counterbalanced order at two different occasions. A lab member randomly allocated the subjects.

Placebo+placebo, placebo+LSD, ketanserin+LSD were tested. Placebo+LSD was tested after pretreatment with placebo, LSD was tested after pretreatment with ketanserin.

2.2 | ECG recording and processing of RR- intervals

ECG was recorded using Philips Physiology Logging System during two consecutive resting-state fMRI sessions. Eight out of 25 subjects showed missing signals at least on one occasion, and the remaining data sets showed clear R- peak time series after visual inspection.

All recordings were segmented into 3 min epochs and the R- peak time series were calculated for further statistical analysis of the ANS activity.

2.3.1 | General measures

The heart rate was calculated from the inverted ratio of consecutive R-peaks averaged over the analyzed segment and the number of milliseconds per minute.

Normalized Low-Frequency Power (nLF) describes the proportion of the sympathetic activity from the whole autonomic nervous system activity.

2.3.2 | Sympathetic measures

SNS Index: This index is calculated using mean HR, Baevsky’s stress index, and standard deviation 2, and represents sympathetic activity.

2.3.3 | Parasympathetic measures

The Parasympathetic Index is calculated based on mean R-peak intervals, RMSSD and standard deviation and provides an easy to interpret value for parasympathetic activity.

2.4 | Assessment of subjective experiences

Psychometric data were assessed 720 min after the second administration using the 5D- ASC scale, which includes 94 items. The short version of the scale includes 45 items and is used for control reasons.

2.5 | Statistics

To assess the effects of different interventions on HRV, a nested repeated measures model was computed with intervention (3 levels), time (2 levels), and constant covariates as nested within-subject factors. The influence of age and BMI on HRV was also assessed using a second repeated measures model.

An exploratory partial correlation analysis was performed between the 5D- ASC scale scores and the HRV parameters of each time point of intervention by controlling for BMI and age.

3 | RESULTS

A total of 25 subjects participated in the study, eight of whom had missing ECG traces or too many artifacts in the ECG recordings. Thus, 17 subjects were used in the two-nested factor design.

3.1 | Repeated measures ANOVA for within- subject factors

The Plac+LSD intervention showed higher activity of the sympathetic branch in comparison to Plac+Plac and Ket+LSD conditions, while the Ket+LSD intervention showed a significant shift toward the parasympathetic activity in comparison to Plac+Plac and Plac+LSD conditions.

The sympathetic measures showed a main effect of intervention on the SNS index, but no main effect was found for the LF log power, HF power, or Total Power.

3.3 | Partial correlation for LSD condition

The Plac+LSD intervention positively correlated with HR, SNS index and Stress Index at T1 and T2, and negatively correlated with parasympathetic PNS index at T1.

At T1, imagery was positively correlated with HR and the SNS index, while the parasympathetic measure PNS index was negatively correlated with spiritual experience. Four out of five sympathetic ANS measures showed a dominant pattern of positive correlation with the subjective experience.

We calculated partial correlations between parasympathetic activity and subjective experience after 180 min, and found a positive correlation between sympathetic activity and subjective experience.

3.4 | Partial correlation for placebo and ketanserin condition

Although subjective effects during the placebo and ketamine conditions were low, the same direction of the effects was present. For the ketamine condition, only the item Disembodiment showed several significant correlations within T2.

The correlations for the Plac+Plac intervention showed that Experience of unity was positively associated with HR, SNS index, and LFnu, and that Impaired cognitive control was positively associated with HR and negatively associated with PNS index.

3.5 | Partial correlation for ANS trait markers during placebo for subjective experience during LSD condition

A partial correlation of HRV parameters between Plac+Plac and Plac+LSD condition was computed to find possible trait markers of the ANS that might predict subjective responses to LSD. It revealed negative correlations for parasympathetic measures and positive correlations for sympathetic measures.

The correlation between ANS activity and subjective experiences after LSD intake was positive for sympathetic activity and negative for parasympathetic activity.

4 | DISCUSSION

In this paper, we reveal that LSD increases sympathetic activity, while ketanserin increases parasympathetic activity, thus antagonizing the effects of LSD on the ANS.

The HR and HRV measures during the placebo (Plac+Plac) condition were in line with recently shown measures of short-term recording in healthy adults reported in a meta-analysis. The HR was increased significantly by LSD administration, although this increase was not clinically relevant.

Ketanserin, a 5-HT2A -receptor antagonist, decreased the sympathetic activity of the ANS and increased the parasympathetic activity, indicating a switch toward parasympathetically driven action. This action might go beyond the antagonizm of the sympathomimetic LSD effects on the ANS.

The correlations between the ANS measures and LSD-induced subjective experiences were very consistent: All subjective effects were positively correlated with sympathetic parameters and negatively correlated with parasympathetic measures.

LSD has recently been discussed as a potential treatment option in depression. HRV parameters at baseline were associated with subjective experiences of unity and audio-visual synesthesia after LSD intake, while parasympathetic measures were negatively correlated.

This study was limited by the fact that all ECGs were recorded in an MRI scanner during resting state, and no other measures of ANS activity, such as electrodermal response or pupil response, were assessed.

This study showed that LSD predominantly affects the sympathetic branch of the autonomic nervous system (ANS), while ketanserin antagonizes this effect. Subjective experience was also associated with ANS activity.

AUTHOR CONTRIBUTIONS

Sebastian Olbrich, Katrin H. Preller, Franz X. Vollenweider contributed to conceptualization, formal analysis, methodology, software, visualization, writing, and review & editing.