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

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!

Find this paper

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

https://doi.org/10.3389/fphar.2021.711255

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Published in
Frontiers in Pharmacology
July 13, 2021
19 citations

Study details

Compounds studied
LSD

Topics studied
Personality

Study characteristics
Original Placebo-Controlled Active Placebo Double-Blind Within-Subject Randomized

Participants
16 Humans

Authors

Authors associated with this publication with profiles on Blossom

Matthias Liechti
Matthias Emanuel Liechti is the research group leader at the Liechti Lab at the University of Basel.

Institutes

Institutes associated with this publication

University of Basel
The University of Basel Department of Biomedicine hosts the Liechti Lab research group, headed by Matthias Liechti.

Compound Details

The psychedelics given at which dose and how many times

LSD 100 - 200
μg | 5x

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