by Dr. Mark Gold
In May, in a reflection on her religious upbringing, societal strictures, and individual spiritual development, The New Yorker’s Jia Tolentino wrote that she first tried ecstasy, or MDMA, in college:
“We swallowed pills that had been crushed into Kleenex, and then we slipped into a sweaty black box of a music venue down the street, and I felt weightless, like I’d come back around to a truth that I had first been taught in church: that anything could happen, and a sort of grace that was both within you and outside you would pull you through."
Some individuals who have used MDMA in non-scientific settings claim that it provides them with energy and reduces social inhibitions through mind-expanding spiritual uplift. It is the substance of choice at night parties, one of the major synthesized club drugs, and linked to accidents, dehydration, overheating, and dangerous behaviors.1 Recreational use is certainly not without its risks.
But what’s the difference between the substance’s purported therapeutic function and its dangerous side? MDMA is ecstasy’s main ingredient, but individuals who use the substance recreationally are sometimes misinformed about levels of adulteration. It can also be harmful in street versions, which may mix or combine other substances with MDMA. MDMA is not perfectly unique in its effects on sociability and human connection — adages about “moderation” in use abound in part because some substances have both relaxing and stimulating properties that can make social engagements more convivial. Yet the substance is often misused, and can lead to substance use disorder (SUD). In a recent Stanford study, researchers note, “It is unknown, however, whether the mechanisms underlying [MDMA’s] prosocial therapeutic effects and abuse potential are distinct.”
Through controlled doses and experimental administration, MDMA is currently being studied for therapeutic benefits. Early reports by some researchers reviewing MDMA as one option for treating post-traumatic stress disorder (PTSD) have been most promising so far. Carefully observed and administered scientific settings dramatically reduce the likelihood of withdrawal, overdose, and diversion.2 This Stanford study tested mice to try to distinguish between MDMA’s beneficial and harmful effects.
What did this study find about MDMA’s prosocial and nonsocial effects?
This Stanford study found that MDMA generates positive social effects in a distinct way from its addictive effects. MDMA releases large amounts of dopamine in the brain, producing addictive and other negative consequences over time. But this study notes that MDMA also releases a lot of serotonin in the brain, producing sensations of happiness. This is hard to study in rodents, which are generally in a positive mood. But this study wanted to determine how MDMA’s serotonin production leads to positive social engagement outcomes. It concluded that MDMA-released serotonin produces positive effects in the mind and body. How did these researchers do this?
Researchers in this study modified a serotonin receptor in part of the mice’s brains. This modification obstructed the receptor, limiting serotonin production. The result was a steep decline in positive social effects from MDMA. Researchers gauged the sociability of their mice in part by giving them different MDMA dosages and observing their interest in interacting with other mice, compared to those given non-MDMA solutions. This study also compared MDMA in the mice’s brains to another substance that releases large amounts of serotonin. The compared substance also boosted sociability in the mice, bolstering the finding that serotonin is MDMA’s key ingredient in the positive side of ecstasy. Co-author Boris Heifets said that blocking the serotonin receptor “completely” eliminated the beneficial effects of MDMA: “maybe we can recreate MDMA’s prosocial effect and nothing else, just by hitting this one receptor.”
Why is this important?
The authors of this study argue that their research trials, as well as previous research on the effects of MDMA in humans, suggest that their findings of MDMA in mice likely translate to humans. But it is not clear what the therapeutic endpoints might be for human trials. This study did a very good job of attributing psychotherapeutic effects to serotonin. But the authors also list limitations in their work. These include tolerance to these pro-social effects, developed connections between patients and therapists, restarted social reward sensations, and “extinction of learned fear through nonsocial mechanisms.” MDMA is a complicated substance, and its use in therapeutic settings is complicated, too. We need new safe and effective psychopharmacological treatments. Separating therapeutic from addictive effects is a good start. There’s a long way to go in showing that a treatment is both safe and effective and offers advantages over current treatments.
MDMA is not in the same drug class as the classic hallucinogens in clinical trials today for a variety of psychiatric and addictive diseases.3 The classic psychedelics, which one study observes “have been administered as sacraments since ancient times”, include serotonin 2A receptor (5-HT2AR) agonists such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. These are being studied at Hopkins, Yale, Stanford and other major psychiatric research centers. The authors of this Stanford study add, “Given MDMA’s long history of abuse and potential toxicity, it would be prudent to develop drugs or other therapies that mimic its prosocial effects with reduced associated morbidities.” But MDMA does show promise in treating PTSD, as an adjunct to psychotherapy and as a research probe to separate prosocial therapeutic effects and abuse potential.
MDMA and PTSD
PTSD may be a good target illness. PTSD is a common psychiatric disorder associated with significant suffering, disability, and a large economic burden. Despite the range of therapies to treat PTSD, response to antidepressants is limited. But research indicates that MDMA-assisted psychotherapy may help in treatment. In terms of existing treatments for PTSD, such as SSRIs, MDMA can be directly compared to the standard pharmacological therapies, and may be found in controlled studies to be superior. One study says, “MDMA-assisted psychotherapy appears to be a potentially safe, effective, and durable treatment for individuals with chronic, treatment-refractory PTSD.”4 These studies are quite promising.5As a schedule 1 controlled substance, MDMA is not legally permitted beyond careful scientific study. The Food and Drug Administration (FDA) would first have to give therapeutic MDMA the green light, though advocates and researchers are hopeful about the prospects of Phase 3 trials, as they told Kaiser Health News in August.
It’s important to emphasize this point: this Stanford study, and others like it, do not suggest in any way that individual therapeutic self-medication with substances like MDMA is safe or appropriate. The substance is still potentially quite dangerous for many individuals who may use it. The therapeutic value of MDMA should be determined by scientists in regulated and carefully controlled environments that minimize the potential for harm and employ rigorous methods to measure outcomes. Pharmaceutical companies and scientists might then develop new medications based on the separate mechanisms of MDMA's prosocial effects, and minimize abuse liability. Additional research may determine that MDMA or related substances offer great promise for patients with limited treatment options available at the moment. That would be great news, and this study is an important first step in a long research and pharmaceutical discovery process. But we should still assume that drugs of abuse, like medications in trials, are dangerous until proven safe and effective.
References:
Betzler, F., Ernst, F., Helbig, J., Viohl, L., Roediger, L., Meister, S., Romanczuk-Seiferth, N., Heinz, A., Ströhle, A., Köhler, S. (2019) Substance Use and Prevention Programs in Berlin's Party Scene: Results of the SuPrA-Study. Eur Addict Res.Feduccia, A.A., Jerome, L., Yazar-Klosinski, B., Emerson, A., Mithoefer, M.C., Doblin, R. (2019) Breakthrough for Trauma Treatment: Safety and Efficacy of MDMA-Assisted Psychotherapy Compared to Paroxetine and Sertraline. Front Psychiatry.Garcia-Romeu, A., Davis, A.K., Erowid, F., Erowid, E., Griffiths, R.R., Johnson, M.W. (2019) Cessation and reduction in alcohol consumption and misuse after psychedelic use. Journal of PsychopharmacologyBahji, A., Forsyth, A., Groll, D., Hawken, E.R. (2020) Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry.Vermetten, E., Yehuda, R. (2020) MDMA-assisted psychotherapy for posttraumatic stress disorder: A promising novel approach to treatment. Neuropsychopharmacology
Citation:
1. Heifets, B.D., Salgado, J.S., Taylor, M.D., Hoerbelt, P., Cardozo Pinto, D.F., Steinberg, E.E., Walsh, J.J., Sze, J.Y., Malenka, R.C. (2019) Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. Science Translational Medicine. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31826983
Dr. Mark S. Gold is a teacher of the year, translational researcher, author, mentor and inventor best known for his work on the brain systems underlying the effects of opiate drugs, cocaine and food. Read more by Dr. Gold here.