The Role of Oxytocin in MDMA’s Prosocial Effects

The link between oxytocin and MDMA is less straightforward than once thought.

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Psychedelic compounds including psilocybin, LSD, and MDMA have been reported to induce feelings of empathy, increase connectedness to others and enhance social behaviors in naturalistic, research, and therapeutic settings.1 These pro-social effects are particularly remarkable and important for the effectiveness of 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct to therapy.2-6

Distinct from classical serotonergic hallucinogens, MDMA, a so-called “empathogen,” has unique subjective effects and a broader mechanism of action involving several brain systems. Specifically, it acts primarily by inducing the release and blocking the reuptake of monoamine neurotransmitters, thus potentiating serotonin, norepinephrine, and dopamine, as well as oxytocin activity.7 Oxytocin is a neuropeptide synthesized in the brain and a hormone that acts centrally and peripherally via the bloodstream, with important roles in social bonding, mating, reproduction, and childbirth.8 

Although the scientific literature is much more nuanced, the so-called “love hormone” is generally thought to underlie our ability to engage in social cognition and behaviours, experience attraction, and form close interpersonal attachments. Consistent with this notion, early research implicated oxytocin as a candidate biological mechanism underpinning the pro-social effects of MDMA.

Preclinical Evidence of Oxytocin’s Role in MDMA’s Effects

Rodent studies suggest that MDMA activates oxytocin-releasing neurons in the hypothalamus, causes a surge of oxytocin in the plasma and brain, and increases social behaviours, including “adjacent lying” (or cuddling) in mice.9,10 These experiments also indicate that MDMA may stimulate oxytocin activity primarily via activation of serotonin 5-HT1A receptors.9,11 

Blocking the oxytocin receptor in mice can prevent the increase in sociability following MDMA administration, although this has not been reported unanimously or for all social behaviors observed.9,10,12  Importantly, MDMA administered to adult mice could reopen the critical period for social reward learning, an important developmental window for social animals, in an oxytocin-dependent manner.13 Overall, the animal data indicate that MDMA induces oxytocin release, which in turn may underlie aspects of its pro-social effects.

Clinical Evidence of Oxytocin’s Role in MDMA’s Effects

Similarly, human studies have consistently found that MDMA acutely increases blood oxytocin concentrations in both recreational “ecstasy” users14 and clinical subjects receiving MDMA.2,4-6,15 However, only one study to-date has reported a significant correlation between MDMA-induced pro-social effects and plasma oxytocin levels,2 emphasizing the difficulty of establishing a causal relationship in humans. Interestingly, studies indicate that genetic variability within the gene encoding the oxytocin receptor may influence the extent of MDMA-induced sociability in healthy subjects.16,17

oxytocin molecule

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Casting significant doubt on the oxytocin theory is a series of studies directly comparing MDMA and intranasal oxytocin administration in healthy subjects.4,5 Findings indicate both treatments boost plasma oxytocin levels, but with stark differences in observed clinical effects. As expected, MDMA promoted social cognition, empathy, and a decreased recognition of negative emotions in others, while the subjective effects of intranasal oxytocin administration, on the other hand, were more ambiguous. Although key differences in the pattern of hormone release induced by the two treatments cannot be excluded, the failure of oxytocin to replicate MDMA’s unique pro-social effects indicates it is unlikely to represent the sole mechanism at play.

Weighing the Evidence on Oxytocin and the Therapeutic Utility of MDMA

Oxytocin has been postulated to be a prominent factor in MDMA’s ability to improve trust, openness, and the quality of the patient-therapist bond in the context of MDMA-assisted therapy.1,18 However, considering the complexities of both human social cognition and MDMA pharmacology, as well as the limited clinical research to-date, the exact role of oxytocin in empathogen action is difficult to establish. Oxytocin release is consistently reported following post-MDMA in both animal and human subjects, but considerable debate remains as to the functional and clinical importance of this.

Increased understanding of oxytocin function in health and disease has prompted some to dispute its straightforward reputation as the “love hormone”, and others to look into promising ways of tapping into this brain system for therapeutic purposes. Currently, intranasal oxytocin is under active investigation for the treatment of autism, addiction, and depression, with mixed preliminary results.19

Curiously, beyond any therapeutic implications, the link between MDMA and oxytocin can potentially be further exploited as a unique diagnostic tool. According to ClinicalTrials.gov, in what is an unusual psychedelic trial, MDMA administration is currently being tested as a provocation test to detect oxytocin deficiency in patients with central diabetes insipidus (a form of diabetes with brain origins).

Meanwhile, an accumulating body of research supports the utility of MDMA-assisted therapy for PTSD and social deficit disorders such as depression and autism.20,21 Regardless of the complex biological mechanisms at play, MDMA’s ability to boost feelings of openness, empathy, and the willingness to engage socially, while possibly reopening the critical period for social reward learning, has important implications for treating neuropsychiatric and neurodevelopmental conditions involving social deficits, social trauma or susceptibility to social influence.

Lily Aleksandrova headshot

Lily is a postdoctoral fellow at the University of British Columbia (UBC), Canada. As a neuroscience researcher and science writer, she looks at the intersection of brain, behaviour, and therapeutics through a multidisciplinary lens. She is passionate about science communication and translational research related to neuroplasticity and novel therapeutic approaches to improve mental health, including ketamine and psychedelics.

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Steven
3 years ago

Does oxytocin play a role? Sure, but the propensity for medical science to engage in primitive reductionistic thinking is hugely problematic. Glad to see some evidence in the language they understand demonstrating “it’s not that simple”.

    References
  1. Preller KH, Vollenweider FX. Modulation of Social Cognition via Hallucinogens and “Entactogens.” Frontiers in Psychiatry. 2019;10(December):1-13. doi:10.3389/fpsyt.2019.00881
  2. Dumont GJH, Sweep FCGJ, van der Steen R, et al. Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration. Social Neuroscience. 2009;4(4):359-366. doi:10.1080/17470910802649470
  3. Bedi G, Hyman D, De Wit H. Is ecstasy an “empathogen”? Effects of ±3,4- methylenedioxymethamphetamine on prosocial feelings and identification of emotional states in others. Biological Psychiatry. 2010;68(12):1134-1140. doi:10.1016/j.biopsych.2010.08.003
  4. Kirkpatrick MG, Lee R, Wardle MC, Jacob S, De Wit H. Effects of MDMA and intranasal oxytocin on social and emotional processing. Neuropsychopharmacology. 2014;39(7):1654-1663. doi:10.1038/npp.2014.12
  5. Kirkpatrick MG, Francis SM, Lee R, De Wit H, Jacob S. Plasma oxytocin concentrations following MDMA or intranasal oxytocin in humans. Psychoneuroendocrinology. 2014;46:23-31. doi:10.1016/j.psyneuen.2014.04.006
  6. Hysek CM, Schmid Y, Simmler LD, et al. MDMA enhances emotional empathy and prosocial behavior. Social Cognitive and Affective Neuroscience. 2014;9(11):1645-1652. doi:10.1093/scan/nst161
  7. Liechti ME, Vollenweider FX. Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies. Human Psychopharmacology. 2001;16(8):589-598. doi:10.1002/hup.348
  8. Ishak WW, Kahloon M, Fakhry H. Oxytocin role in enhancing well-being: A literature review. Journal of Affective Disorders. 2011;130(1-2):1-9. doi:10.1016/j.jad.2010.06.001
  9. Thompson MR, Callaghan PD, Hunt GE, Cornish JL, McGregor IS. A role for oxytocin and 5-HT1A receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine (“ecstasy”). Neuroscience. 2007;146(2):509-514. doi:10.1016/j.neuroscience.2007.02.032
  10. Ramos L, Hicks C, Caminer A, Goodwin J, McGregor IS. Oxytocin and MDMA ('Ecstasy’) enhance social reward in rats. Psychopharmacology. 2015;232(14):2631-2641. doi:10.1007/s00213-015-3899-9
  11. Hunt GE, McGregor IS, Cornish JL, Callaghan PD. MDMA-induced c-Fos expression in oxytocin-containing neurons is blocked by pretreatment with the 5-HT-1A receptor antagonist WAY 100635. Brain Research Bulletin. 2011;86(1-2):65-73. doi:10.1016/j.brainresbull.2011.06.011
  12. Thompson MR, Hunt GE, McGregor IS. Neural correlates of MDMA (“Ecstasy”)-induced social interaction in rats. Social Neuroscience. 2009;4(1):60-72. doi:10.1080/17470910802045042
  13. Nardou R, Lewis EM, Rothhaas R, et al. Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature. 2019;569(7754):116-120. doi:10.1038/s41586-019-1075-9
  14. Wolff K, Tsapakis EM, Winstock AR, et al. Vasopressin and oxytocin secretion in response to the consumption of ecstasy in a clubbing population. Journal of Psychopharmacology. 2006;20(3):400-410. doi:10.1177/0269881106061514
  15. Holze F, Vizeli P, Müller F, et al. Distinct acute effects of LSD, MDMA, and d-amphetamine in healthy subjects. Neuropsychopharmacology. 2020;45(3):462-471. doi:10.1038/s41386-019-0569-3
  16. Bershad AK, Weafer JJ, Kirkpatrick MG, Wardle MC, Miller MA, de Wit H. Oxytocin receptor gene variation predicts subjective responses to MDMA. Social Neuroscience. 2016;11(6):592-599. doi:10.1080/17470919.2016.1143026
  17. Vizeli P, Liechti ME. Oxytocin receptor gene variations and socio-emotional effects of MDMA: A pooled analysis of controlled studies in healthy subjects. Kavushansky A, ed. PLOS ONE. 2018;13(6):e0199384. doi:10.1371/journal.pone.0199384
  18. Sessa B, Higbed L, Nutt D. A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy. Frontiers in Psychiatry. 2019;10(MAR):1-7. doi:10.3389/fpsyt.2019.00138
  19. Erdozain AM, Peñagarikano O. Oxytocin as Treatment for Social Cognition, Not There Yet. Frontiers in Psychiatry. 2020;10(January):1-8. doi:10.3389/fpsyt.2019.00930
  20. Danforth AL, Struble CM, Yazar-Klosinski B, Grob CS. MDMA-assisted therapy: A new treatment model for social anxiety in autistic adults. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2016;64:237-249. doi:10.1016/j.pnpbp.2015.03.011
  21. Danforth AL, Grob CS, Struble C, et al. Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study. Psychopharmacology. 2018;235(11):3137-3148. doi:10.1007/s00213-018-5010-9