LSD acutely impairs fear recognition and enhances emotional empathy and sociality

This double-blind placebo-controlled study (n=40) found that LSD (100-200 μg) enhanced emotional empathy and sociality, but decreased recognition of sad/fearful faces (fear cognition).

Abstract

“Lysergic acid diethylamide (LSD) is used recreationally and has been evaluated as an adjunct to psychotherapy to treat anxiety in patients with life-threatening illness. LSD is well-known to induce perceptual alterations, but unknown is whether LSD alters emotional processing in ways that can support psychotherapy. We investigated the acute effects of LSD on emotional processing using the Face Emotion Recognition Task (FERT) and Multifaceted Empathy Test (MET). The effects of LSD on social behavior were tested using the Social Value Orientation (SVO) test. Two similar placebo-controlled, double-blind, random-order, crossover studies were conducted using 100 μg LSD in 24 subjects and 200 μg LSD in 16 subjects. All of the subjects were healthy and mostly hallucinogen-naive 25- to 65-year-old volunteers (20 men, 20 women). LSD produced feelings of happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy on the MET, and impaired the recognition of sad and fearful faces on the FERT. LSD enhanced the participants’ desire to be with other people and increased their prosocial behavior on the SVO test. These effects of LSD on emotion processing and sociality may be useful for LSD-assisted psychotherapy.“

Authors: Patrick C. Dolder, Yasmin Schmid, Felix Müller, Stefan Borgwardt & Matthias E. Liechti

Notes

This paper is included in the meta-analytical review by Galvão-Coelho and colleagues (2021) that found psychedelics to improve mood (for those with mood disorders) both in the short and long-term (up to 60 days).

A further analysis of of the pharmacokinetics/dynamics is done in Dolder and colleagues (2017).

Summary

INTRODUCTION

The serotonergic psychedelic/hallucinogen lysergic acid diethylamide (LSD) was widely studied in humans in the 1950s to 1970s, but little to no clinical research has been conducted since then. Today, LSD is again the focus of clinical investigations, including experimental studies in healthy subjects and clinical trials that evaluate LSD-assisted psychotherapy.

LSD and psilocybin have been found to produce beneficial effects that last beyond the acute drug response in both patients and healthy subjects. These effects appear to be associated with an acute psychedelic response, including a ‘peak’ or ‘mystical’ experience.

LSD and psilocybin are 5-HT2A receptor agonists, and their psychedelic effects are mediated by 5-HT2A receptor stimulation. MDMA, on the other hand, is considered an empathogen, and may have similar acute and long-term effects on emotion processing. LSD impairs the recognition of negative emotions on the Face Emotion Recognition Task, enhances emotional empathy on the Multifaceted Empathy Test, and enhances prosociality on the Social Value Orientation Test.

Study Design

We pooled data from two studies using double-blind, placebo-controlled, crossover designs with at least 7 days between experimental test sessions. All subjects provided written consent before participating in either study, and they were paid for their participation.

Participants

We recruited 40 healthy participants from the University of Basel campus via online advertisement.

Subjects younger than 25 years of age and those with a history of major psychiatric disorders were excluded from the study. Additionally, participants were asked to abstain from excessive alcohol consumption between test sessions and to limit their use of xanthine-containing liquids after midnight before the study day.

Study Procedures

Each study included a screening visit, psychiatric interview, two 25-h experimental sessions, and an end-of-study visit. LSD or placebo was administered at 0900 hours and effects on emotion processing and prosociality were assessed 5 and 7 h after drug administration.

Measures

We used the Facial Emotion Recognition Task to measure the effects of LSD and other psychoactive substances. The task includes neutral faces and 160 faces that express one of four basic emotions.

The Multifaceted Empathy Test (MET) is a reliable and valid task that assesses the cognitive and emotional aspects of empathy. It was performed 5 h and 30 min and 7 h and 30 min after the 100 g LSD dose and 200 g LSD dose, respectively.

The SVO test measures social behavior by asking participants to allocate resources in a way that maximizes the sum of resources for the self and others and minimizes the difference between the two. A smaller SVO angle indicates more individualistic or competitive behavior, and a larger SVO angle indicates more prosocial behavior.

Plasma LSD levels were measured using liquid-chromatography tandem mass spectrometry after administration of 100 and 200 g doses of LSD, respectively.

Statistical Analyses

All data were analyzed using repeated measures analysis of variance (ANOVA) with drug and dose as within-subjects factors and Tukey’s post hoc test as between-subjects factors.

Facial Emotion Recognition

The effects of LSD on the FERT are shown in Figure 1. LSD impaired the recognition of fearful and sad faces, but not neutral, happy, or angry facial expressions.

Empathy

LSD increased explicit and implicit emotional empathy ratings compared with placebo, but decreased cognitive empathy. The valence-specific analysis showed that LSD increased explicit and implicit emotional empathy scores for positive emotional stimuli, but only trend effects for negative emotional stimuli.

Subjective Mood Effects

LSD increased maximal VAS rating scores, including those reflecting empathy and prosociality, and produced small dose-dependent increases in ‘bad drug effect’ and ‘fear’. It also increased ratings of ‘well-being’ and ’emotional excitation’ on the AMRS.

Vital Signs and Adverse Effects

LSD increased blood pressure, heart rate, body temperature, and pupil size in the dark and after a light stimulus, and increased the total acute and subacute adverse effects compared with placebo.

Plasma Drug Levels and Correlations Between Effects

LSD concentrations in plasma correlated with explicit emotional empathy scores on the MET for positive, but not for negative emotional situations. LSD-induced ratings of trust were also associated with greater explicit empathy for positive emotional stimuli.

DISCUSSION

LSD decreased the recognition of fearful and sad faces, enhanced emotional empathy and prosociality, and increased explicit and implicit emotional empathy for positive emotionally charged situations.

LSD affected emotion processing similarly to MDMA and psilocybin, but did not facilitate perception of happiness. It also impaired cognitive empathy and decreased the recognition of neutral faces, indicating nonspecific performance effects.

LSD has dose-dependent subjective effects on empathogenic mood, including feelings of closeness to others, wanting to be with others, happiness, openness, and trust. These effects were maintained up to 6 – 12 h after LSD administration, and may be beneficial to acutely facilitating the therapeutic alliance. Future research should address the relative contributions of psychedelic peak experience and empathogenic emotional effects to LSD’s potential therapeutic effects.

LSD was well tolerated in healthy subjects, with moderate sympathomimetic effects including elevated blood pressure, heart rate, body temperature, and mydriasis.

The present study used two doses of LSD within a clinically relevant dose range, and the subjects typically had no or very limited hallucinogen experience. Additionally, previous hallucinogen use did not alter the responses to LSD.

The tests were performed approximately 3 h after the peak effects of LSD, and the participants had adjusted to the altered state of consciousness. Nevertheless, the tests were conducted when the subjective effects and plasma concentrations of LSD were still at 50% of the peak responses.

The study has limitations, such as studying different participants and not within-subject, and assessing only emotion recognition and no other measures such as face muscle responses to emotions. It is possible that LSD affected attention and motivation and thereby task performance.

LSD impaired emotion recognition of negative emotions and enhanced emotional empathy, which had subjective and behaviorally tested prosocial effects.