Role of the 5-HT2A receptor in acute effects of LSD on empathy and circulating oxytocin

This double-blind placebo-controlled crossover study (n=16) finds that LSD (200 µg) improves emotional empathy, and moderately increases plasma oxytocin levels. Ketanserin reduced the elevation of oxytocin but not the increase in emotional empathy (arguing that the latter isn’t dependent on the 5HT-2a receptor pathway).

Abstract

“Introduction: The psychedelic lysergic acid diethylamide (LSD) has experienced a revival in research, including clinical trials that evaluate LSD-assisted psychotherapy. LSD induces perceptual alterations and influences emotion processing in ways that may support psychotherapy.

Methods: Here, we investigated the effects of LSD on emotional empathy and mediating role of the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor by administering 25, 50, 100, and 200 µg LSD alone and 200 µg LSD combined with pretreatment with the 5-HT2A receptor antagonist ketanserin (40 mg) using a placebo-controlled, double-blind, random-order, crossover design in 16 healthy subjects. The Multifaceted Empathy Test (MET) was used to assess the effects of LSD on emotional empathy. Plasma oxytocin levels were also measured.

Results: LSD dose-dependently increased implicit and explicit emotional empathy, with the highest 200 µg LSD dose having a significant effect compared with placebo. The 200 µg dose of LSD also moderately increased plasma oxytocin levels compared with placebo. Ketanserin reduced the LSD-induced elevations of oxytocin but not the LSD-induced increases in emotional empathy.

Discussion: These findings confirm that LSD enhances empathy, and this effect may be partially independent of its primary action on 5-HT2A receptors to induce subjective psychedelic effects. In contrast, LSD-induced oxytocin release may depend on 5-HT2A receptor stimulation, which is consistent with the psychedelic effect of LSD. Further studies are needed to investigate whether LSD may also enhance empathy and potentially produce therapeutic effects in patients who have deficits in empathy and impairments in social functioning.“

Authors: Friederike Holze, Isidora Avedisian, Nimmy Varghese, Anne Eckert & Matthias E. Liechti

Summary

INTRODUCTION

The prototypical psychedelic lysergic acid diethylamide (LSD) is experiencing a revival in psychiatric research, with possible medical benefits being investigated in Phase 2 trials in patients with anxiety, depression, and cluster headache. LSD produces potential therapeutic effects in different disorders by targeting serotonin 5-hydroxytryptamine-2A (5-HT2A) receptors, but also 5-HT1A and dopamine receptors. These effects include increased neuroplasticity, altered brain network connectivity, socioemotional effects, and related changes in emotion processing. LSD has been shown to increase feelings of subjective well-being, happiness, closeness to others, openness, and trust, and to enhance emotional empathy, trust, and positive communication. LSD also increases plasma oxytocin levels, although to a lesser extent than MDMA.

The subjective and autonomic effects of LSD were investigated in the present study, and the effects of LSD on emotional empathy and circulating plasma oxytocin levels were mediated by 5-HT2A receptors.

Study Design

In this study, six experimental test sessions were conducted with placebo, 25 g LSD, 50 g LSD, 100 g LSD, 200 g LSD, and 200 g LSD 1 h after ketanserin administration (40 mg). All subjects provided written consent before participating in the study.

Participants

Sixteen healthy subjects were recruited by word of mouth or an advertisement that was posted on the web market platform of the University of Basel. They were asked to consume no more than 10 standard alcoholic drinks/week and have no more than one drink on the day before the test sessions.

Study Procedures

The study included a screening visit, six 25-h test sessions, and an end-of-study visit. Ketanserin (40 mg) or placebo was administered at 8:00 AM, LSD at 9:00 AM, and standardized lunches and dinners were served at 1:30 PM and 6:00 PM, respectively.

Study Drug

LSD base was administered as an oral solution in which 100 or 25 mg were dissolved in 1 ml of 96% ethanol. Ketanserin was encapsulated with opaque capsules to ensure blinding, and a double-dummy method was used.

Measures

The Multifaceted Empathy Test (MET) is a reliable and valid task that assesses cognitive and emotional aspects of empathy. It was performed 6 h after LSD administration and consisted of 40 photographs that showed people in emotionally charged situations.

Subjective mood was assessed repeatedly over 24 h, and 6 h after drug administration, immediately before the MET was performed.

Oxytocin concentrations were measured in blood plasma 1, 3, and 8 h after LSD or placebo administration using an oxytocin enzyme-linked immunosorbent assay kit. The concentrations were determined from a standard curve that was calculated from a four-parameter logistics curve fit.

Blood samples were collected repeatedly in lithium heparin tubes and analyzed by ultra-high-performance liquid chromatography tandem mass spectrometry.

Statistical Analyses

LSD dose-response effects on emotional empathy were assessed using repeated-measures analysis of variance (ANOVA), with drug as the within-subjects factor, followed by the Tukey post hoc test based on significant main effects.

Plasma Drug Levels

Plasma LSD concentrations were 2.2 1.0 ng/ml (6 h after administration of the 200 g dose) and 2.5 0.9 ng/ml (6 h after administration of 200 g LSD + ketanserin), respectively.

DISCUSSION

LSD enhanced explicit and implicit emotional empathy and increased plasma oxytocin concentrations at a dose of 200 g, confirming previous findings. The 5-HT2A receptor agonist ketanserin only weakly attenuated the LSD-induced increases in explicit and implicit empathy, but ratings remained elevated compared with placebo.

LSD showed strong binding to 5-HT1A receptors and increased plasma oxytocin levels at the 200 g dose, but a lower dose of 100 g LSD did not increase plasma oxytocin levels. Therefore, LSD may less effectively induce the release of oxytocin compared with MDMA. Preclinical data indicate that MDMA induces oxytocin release via serotonin release and consecutive 5-HT1 receptor stimulation, while ketanserin prevented the moderate LSD-induced increase in plasma oxytocin. The mechanisms that result in oxytocin release may be distinct for MDMA and LSD and need further investigation. LSD-induced psychological stress may moderately increase oxytocin levels, but this increase was not blocked by ketanserin. This indicates that other factors and receptors are likely involved in emotion processing. The present study used a pharmaceutically well-defined investigational drug product and a highly valid double-blind, multi-dose, random-order design to assess emotional empathy.

The present study has limitations, including a small sample size of 16 participants, a within-subjects design, and a MET conducted 6 h after LSD administration. However, lower doses of LSD may also significantly increase empathy.

LSD enhances empathy in healthy subjects and may also be beneficial for therapeutic application in patients. It remains to be investigated whether LSD also enhances empathy in patients with deficits in empathy and impairments in social functioning.

FUNDING

This work was supported by the Swiss National Science Foundation and University of Basel, and was licensed to Mind Medicine, Inc.

Notes

MDMA produces prosocial bonding and strong empathogenic effects, but these phenomena have received comparatively less attention with respect to other psychedelic substances. A recent line of research has shown that LSD enhances emotional empathy and sociality, a complex phenomenon that is typically assessed by showing pictures of other people with emotional content. For instance, by showing someone a picture of a crying child within a war scene, and asking them to rate how much they feel for the other person (i.e., explicit emotional empathy) and how much arousal they feel in response to each scene (i.e., implicit emotional empathy).

The current study sought to investigate how LSD increases implicit and explicit empathy, whether these effects are mediated by the 5-HT2A receptor, or by proxy of increased oxytocin circulating in the blood flow. The study used a double-blind, placebo-controlled, crossover design and administered a wide dose range (25, 50, 100, and 200μg) across multiple sessions. Additionally, they included a ketanserin pretreatment condition in conjunction with 200μg LSD to selective block 5-HT2A activity. The empathy test was administered 6 hours after LSD administration.

What did they find?

• Explicit and implicit emotional empathy were enhanced by LSD and only by the highest 200 μg dose and not by doses of 100 μg or lower. This was only weakly attenuated by ketanserin
• LSD alone significantly increased plasma oxytocin concentrations at the 200 μg dose, whereas a dose of 100 μg LSD did not increase plasma oxytocin levels in another study
• Ketanserin prevented the moderate LSD-induced increase in plasma oxytocin, indicating that the effects of LSD on the oxytocin system involve 5-HT2A receptors
• LSD-induced increase in oxytocin was only 1.25 to 3-fold higher compared with placebo, compared to MDMA which increases plasma oxytocin levels 3 to 11-fold compared with placebo

Taken together, the present findings indicate that LSD-induced empathogenic effects are neither mediated via oxytocin release nor via direct 5-HT2A receptor activation. LSD also binds with high affinity to 5-HT1A and dopamine receptors, although similar empathogenic effects have also been observed for psilocybin (Pokorny et al., 2017), which does not have an affinity to dopamine receptors. The involvement of other factors and receptors in emotion processing are thus likely to contribute to this process. The question of whether LSD also enhances empathy in patients with impairments in social functioning awaits further investigation!