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Ecstasy’s Therapeutic and Abuse Potential

New research shows that ecstasy affects reward and social behaviors differently.

Often used at dance clubs and concerts, the recreational drug known as ecstasy (MDMA) is dangerous and, in some cases, may even prove deadly (1-2). Even so, a growing body of evidence shows that, in modest doses, it might help treat symptoms of depression, post-traumatic stress disorder, and even autism (3-5).

How is this disparity possible? How does a drug with addictive liability also have therapeutic potential? Perhaps most importantly, is there any way to tease these effects apart, to take the good without the bad? As shown by recent findings from the Nancy Pritzker Laboratory at Stanford University, the answers lie in the ways that ecstasy simultaneously impacts addictive and prosocial brain mechanisms (6).

The neurotransmitters dopamine and serotonin are implicated in a variety of behaviors, including reward and social behaviors. Dopamine, for example, regulates rewarding behaviors, such as eating and sex, but is also involved in disorders of reward, like drug addiction. Decades of research have established this link, and it continues to be a topic of great interest to many behavioral neuroscientists.

The details of the dopamine-reward interaction are beyond the scope of this entry, so for the purposes of understanding this exciting new study, I will say simply that increases in dopamine signaling are associated with increased reward, and that this relationship occurs primarily in a brain region called the nucleus accumbens. In fact, both dopamine and serotonin act in the nucleus accumbens to influence reward.

This serotonergic role has also been carefully examined. Consider, for example, studies showing that increasing serotonin in the nucleus accumbens promoted sociability while inhibiting it reduced social interactions in mice (7).

So, what about ecstasy’s diverging addictive and therapeutic properties? At the cellular level, ecstasy blocks the transporter mechanism that clears dopamine and serotonin from the synapse (the site of communication between cells), meaning that ecstasy prolongs these chemicals’ messages. Ecstasy also reverses the transporters’ function, which causes an increase in the number of chemical messengers floating in the synapse.

Effectively, ecstasy’s impact on the brain is a double whammy: It increases the amount of dopamine and serotonin in the synapse while also blocking their removal from the active zone. This leads to ecstasy’s behavioral effects, which include enhanced trust, emotional openness, and empathy (3), while also enhancing its abuse potential (8,9), largely through increased dopamine in the nucleus accumbens (10-12).

Employing genetic and pharmacological manipulations, Rob Malenka’s group set out to dissect the mechanisms responsible for ecstasy’s effects on reward and sociability (6) using a mouse model. Behaviorally, the mice receiving ecstasy spent more time exploring a chamber that contained a “stranger” mouse—they displayed increased social approach. Social interactions between animals were greatest when both experimental and “stranger” mice received ecstasy.

We know that this effect is specifically on sociability and not simply from decreased anxiety because ecstasy did not impact anxiety in an animal model that tests for such. Interestingly, however, while a lower dose of ecstasy elicited increased social interactions without increasing a “liking” for the drug, higher doses induced both prosocial and “liking” responses. This mimicked drug-liking responses seen in humans when they use higher doses of the drug before it becomes “enjoyable,” which is also when ecstasy has the greatest abuse liability.

To determine how ecstasy may modulate reward and prosocial responses, the research team administered another drug that inhibits the reuptake of serotonin by binding the reuptake mechanism, preventing ecstasy’s effects on the serotonin system. This blocked the prosocial effects of ecstasy, meaning that ecstasy’s effects on sociability occur through changes in serotonin transporters. Additionally, they discovered that mice undergoing genetic deletion of the serotonin transporter experienced prosocial responses with ecstasy, but showed no marked changes in the “liking” of the drug.

Because ecstasy affects both serotonin and dopamine transporters, it was important to resolve whether the drug’s prosocial effects resulted from changes in the dopamine or serotonin transporter system. Pretreating mice with another drug that binds the dopamine transporter and prevents ecstasy from interacting with it helped answer this question—this manipulation did not impair ecstasy’s prosocial influences, pointing to the importance of serotonin, and not dopamine, on the increased sociability resulting from ecstasy. Finally, the administration of ecstasy directly into the nucleus accumbens increased social interactions, showing that ecstasy’s effect on sociability occurred through serotonin in the accumbens.

Together these findings showed that ecstasy’s addictive and prosocial profile occur via separate cellular systems, each in the nucleus accumbens. It increases the levels of both dopamine and serotonin, but its abuse potential likely results from influences on dopamine transporters, while its prosocial properties result from changes to the serotonin transporter.

Given this discovery, is it possible that a drug that mimics ecstasy’s serotonergic profile, but not dopaminergic, would have the same prosocial therapeutic outcome without the acute “addictive” potential? Using the same mouse model, the research team replicated the above findings but did so using a different drug, fenfluramine. Fenfluramine shows no addictive properties at therapeutic doses.

This time, they found that fenfluramine also increased prosocial behaviors and induced cellular changes on the serotonin system that were similar to those observed with ecstasy. This points to the potential therapeutic effects of drugs like fenfluramine for their acute prosocial effects as alternatives to ecstasy in a therapeutic environment. When considering ecstasy’s long history of abuse liability and potential toxicity, approaches like this one might be especially prudent.


1. McCann, UD, Ricaurte, GA. (2013). in The Effects of Drug Abuse on the Human Nervous System, B. Madras, M. Kuhar, Eds. Elsevier, New York, pp. 475-497.

2. Greer, G, Tolbert, R. (1986). Subjective reports of the effects of MDMA in a clinical setting. Journal of Psychoactive Drugs 18: 319-327.

3. Kamilar-Britt, P, Bedi, G. (2015). The prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA): Controlled studies in humans and laboratory animals. Neuroscience and Biobehavioral Reviews, 57: 433-446.

4. Feduccia, AA, Holland, J, Mithoefer, MC. (2018). Progress and promise for the MDMA drug development program. Psychopharmacology 235: 561-571.

5. Danforth AL, Grob CS, Struble CA, Feduccia A, Walker N, Jerome L, Yazar-Klosinski B, Emerson A. (2018). Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: A randomized, double-blind, placebo-controlled pilot study. Psychopharmacology 235: 3137-3148.

6. Heifets BD, Salgado JS, Taylor MD, Hoerbelt P, Cardozo Pinto DF, Steinberg EE, Walsh JJ, Sze JY, Malenka RC. (2019). Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. Science Translational Medicine 2019 Dec 11;11(522).

7. Walsh JJ, Christoffel DJ, Heifets BD, Ben-Dor GA, Selimbeyoglu A, Hung LW, Deisseroth K, Malenka RC. (2018). 5-HT release in nucleus accumbens rescues social deficits in mouse autism model. Nature 560: 589-594.

8. de Wit H, Phillips TJ. (2012). Do initial responses to drugs predict future use or abuse? Neuroscience and Biobehavioral Reviews, 36: 1565-1576.

9. Koob GF, Volkow ND. (2010). Neurocircuitry of addiction. Neuropsychopharmacology 35: 217-238.

10. Brennan KA, Carati C, Lea RA, Fitzmaurice PS, Schenk S. (2009). Effect of D1-like and D2-like receptor antagonists on methamphetamine and 3,4-methylenedioxymethamphetamine self-administration in rats. Behavioral Pharmacology. 20: 688-694.

11. Vidal-Infer A, Roger-Sánchez C, Daza-Losada M, Aguilar MA, Miñarro J, Rodríguez-Arias M. (2012). Role of the dopaminergic system in the acquisition, expression and reinstatement of MDMA-induced conditioned place preference in adolescent mice. PLOS ONE 7, e43107.

12. Liechti ME, Vollenweider FX. (2001). Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies. Human Psychopharmacology. 16: 589-598.

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