Role of the 5-HT2A receptor in acute effects of LSD on empathy and circulating oxytocin
In a placebo‑controlled, double‑blind crossover study in 16 healthy volunteers, LSD dose‑dependently increased implicit and explicit emotional empathy and modestly elevated plasma oxytocin at 200 µg; pretreatment with the 5‑HT2A antagonist ketanserin reduced the oxytocin response but did not block the empathy enhancement. These findings indicate LSD enhances empathy by mechanisms at least partly independent of 5‑HT2A receptor activation, whereas LSD‑induced oxytocin release appears 5‑HT2A‑dependent.
Authors
- Matthias Liechti
- Friederike Holze
- Nikhil Varghese
Published
Abstract
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. 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. 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. 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.
Research Summary of 'Role of the 5-HT2A receptor in acute effects of LSD on empathy and circulating oxytocin'
Introduction
Psychedelic lysergic acid diethylamide (LSD) has re-emerged in psychiatric research and is being tested in Phase II trials for conditions such as anxiety and depression. Earlier work has established that the acute subjective psychedelic effects of LSD are primarily mediated via the serotonin 5-HT2A receptor, because these effects are largely blocked by the 5-HT2A antagonist ketanserin. LSD also produces socioemotional effects—such as increased closeness, trust and emotional empathy—and modestly raises plasma oxytocin, a peptide implicated in emotion processing. However, whether LSD’s empathy-enhancing and oxytocin-releasing effects vary across doses and whether they are mediated by 5-HT2A receptor activation remained unclear. Holze and colleagues designed the present study to address those gaps. The investigators tested graded oral doses of LSD (0, 25, 50, 100 and 200 µg) on emotional empathy using the Multifaceted Empathy Test (MET) in healthy volunteers, and they examined the contribution of 5-HT2A receptors by administering ketanserin (40 mg) prior to the highest LSD dose (200 µg). Plasma oxytocin and LSD concentrations, and subjective drug effects, were also measured to relate physiological and subjective responses to empathic performance.
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Study Details
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- APA Citation
Holze, F., Avedisian, I., Varghese, N., Eckert, A., & Liechti, M. E. (2021). Role of the 5-HT2A receptor in acute effects of LSD on empathy and circulating oxytocin. Frontiers in Pharmacology, 12. https://doi.org/10.3389/fphar.2021.711255
References (30)
Papers cited by this study that are also in Blossom
Barrett, F. S., Preller, K. H., Herdener, M. et al. · Cerebral Cortex (2017)
Bershad, A. K., Miller, M. A., Baggot, M. J. et al. · Journal of Psychopharmacology (2016)
Carhart-Harris, R. L., Kaelen, M., Bolstridge, M. et al. · Psychological Medicine (2016)
Carhart-Harris, R. L., Kaelen, M., Whalley, M. G. et al. · Psychopharmacology (2014)
Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L. et al. · PNAS (2016)
de Wit, H., Bershad, A. K., Grob, C. S. · Journal of Psychopharmacology (2021)
Dolder, P. C., Müller, F., Schmid, Y. et al. · Psychopharmacology (2017)
Dolder, P. C., Schmid, Y., Haschke, M. et al. · International Journal of Neuropsychopharmacology (2015)
Dolder, P. C., Schmid, Y., Müller, F. et al. · Neuropsychopharmacology (2016)
Dumont, G., Sweep, F., van der Steen, R. et al. · Social Neuroscience (2009)
Show all 30 referencesShow fewer
Gasser, P., Holstein, D., Michel, Y. et al. · Journal of Nervous and Mental Disease (2014)
Griffiths, R. R. · Journal of Psychopharmacology (2008)
Holze, F., Duthaler, U., Vizeli, P. et al. · British Journal of Clinical Pharmacology (2019)
Holze, F., Vizeli, P., Ley, L. et al. · Neuropsychopharmacology (2020)
Holze, F., Vizeli, P., Müller, F. et al. · Neuropsychopharmacology (2019)
Hutten, N. R. P. W., Mason, N. L., Dolder, P. C. et al. · ACS Pharmacology and Translational Science (2020)
´dric, C., Hysek, M., Schmid, Y. et al. · Social Cognitive and Affective Neuroscience (2013)
Sumiyoshi, T., Kraehenmann, R., Pokorny, D. et al. · Frontiers in Pharmacology (2017)
Kraehenmann, R. ;., Pokorny, D. ;., Vollenweider, L. ;. et al. · Psychopharmacology (2017)
Ly, C., Greb, A. C., Cameron, L. P. et al. · Cell Reports (2018)
Mueller, F., Lenz, C., Dolder, P. C. et al. · Translational Psychiatry (2017)
Müller, F., Dolder, P. C., Schmidt, A. et al. · NeuroImage (2018)
Lenz, C., Dolder, P. C., Lang, U. E. et al. · Acta Psychiatrica Scandinavica (2017)
Preller, K. H., Burt, J. B., Adkinson, B. et al. · eLife (2018)
Preller, K. H., Herdener, M., Pokorny, T. et al. · Current Biology (2017)
Rickli, A., Moning, O. D., Hoener, M. C. et al. · European Neuropsychopharmacology (2016)
Schmid, Y., Enzler, F., Gasser, P. et al. · Biological Psychiatry (2015)
Schmid, Y., Gasser, P., Oehen, P. et al. · Journal of Psychopharmacology (2020)
Schmid, Y., Liechti, M. E. · Psychopharmacology (2017)
Strajhar, P., Schmid, Y., Liakoni, E. et al. · Journal of Neuroendocrinology (2016)
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