- Research on the use of psychedelic drugs as medicine is increasingly common and more widely accepted by the general public.
- A new study of MDMA-assisted psychotherapy suggests that it might have potential for the treatment of PTSD.
- More research is needed to clarify risks and benefits before MDMA-assisted psychotherapy would ever be approved by the FDA.
We are living in the midst of a cultural shift in how we view the therapeutic potential of psychedelic drugs like lysergic acid diethylamide (LSD or "acid"), psilocybin (the active ingredient in "magic mushrooms") and 3,4-methylenedioxymethaphetamine (MDMA, also known as "ecstasy" when used recreationally), especially in psychiatry. Increasingly touted in the mainstream by the likes of bestselling authors Michael Pollan and the late Oliver Sacks, the hope behind the use of psychedelic drugs as medicine isn't new and—no surprise—actually dates back to at least the 1960s. Research has been hampered by federal restrictions on studying Schedule I drugs through the years, but that has been changing over the past decade1 and in 2017, the FDA granted "breakthrough therapy" status to MDMA making it easier to study it as a treatment for PTSD here in the US.
Now, a new and soon-to-be published randomized, placebo-controlled clinical by lead author Jennifer Mitchell from the University of California, San Francisco builds on earlier evidence that MDMA-assisted psychotherapy might be helpful for the treatment of post-traumatic stress disorder (PTSD). I was approached by a reporter for The New York Times to comment on this new study and the broader topic of psychedelics in psychiatry—although my quotations were edited out of the final story, here is the complete transcript of our interview:
What are your general thoughts on the new research study on MDMA for PTSD?
Interest in investigating whether psychedelics such as lysergic acid diethylamide (LSD), psilocybin, and 3,4-methylenedioxymethamphetamine (MDMA) might be helpful to “assist” psychotherapy dates back to the 1960s when preliminary work was being done by some of the pioneers in the field of psychedelic research including Timothy Leary and Alexander Shulgin. However, subsequent governmental regulation and legislation—both related to legitimate concerns about risks as well as the political “war on drugs”—effectively put an end to such research over the next several decades. More recently, however, and under the leadership and lobbying power of the Multidisciplinary Association for Psychedelic Studies (MAPS), research on the potential therapeutic role of psychedelics has enjoyed a kind of renaissance, along with a significant rise in public interest.
MDMA was being used and studied to assist psychotherapy back in the 1980s when it was often referred to as “Empathy,” with several case studies published touting its potential benefits. However, MDMA soon became more widely used as the “club drug” known as “Ecstasy” such that the DEA declared it a Schedule I drug in 1985. As with other psychedelics, this put a stop to research on MDMA for many years, but starting in 2010, research started up again with a number of smaller controlled clinical trials since then exploring the possible benefits of “MDMA assisted therapy” for the treatment of post-traumatic stress disorder (PTSD). The treatment protocol typically involves several weeks of psychotherapy with MDMA administered during only a few of the sessions over the course of a longer period of talk therapy. The results of a handful of studies that compared MDMA to placebo controls have been encouraging, with MDMA demonstrating benefits over placebo in some studies, though overall the number of patients in the studies has been small.2,3
This new study—the first Phase 3 trial of MDMA assisted psychotherapy—included 90 subjects, more than the sum total of patients from all of the previous controlled trials before it. This is an important study because it’s the largest study done to date, with results that—similar to previous smaller studies—are encouraging.
Similar to the other trials, it involved the administration of MDMA during 3 psychotherapy sessions out of a total of 15 psychotherapy sessions performed over the course of several months. Those subjects randomized to treatment with MDMA plus psychotherapy had a statistically significant amount of greater improvement in PTSD symptoms compared to those with placebo plus psychotherapy (who also improved, but not as much). Overall, side effects were relatively mild but included known adverse events associated with MDMA including muscle tightness, decreased appetite, nausea, sweating, feeling cold, restlessness, and teeth grinding.
Do you think the study was well done? Any misgivings or issues concerning the design or interpretation of the findings?
As the authors acknowledge, the study population was homogenous, lacking in racial and ethnic diversity. Also, as is typical for preliminary studies, a long list of psychiatric conditions precluded study participation, such as psychosis, bipolar disorder, and active substance use disorders. We therefore can’t assume the positive results apply to those with greater ethnic diversity or psychiatric comorbidity.
This study also used an “inactive placebo control,” unlike the previous smaller trials that mostly used “active controls” in the form of very low-dose MDMA. The use of active controls in psychedelic trials is often done to “preserve the blind,” in other words to ensure that the “blinded” subjects (and the ‘blinded” raters) don’t know what they’re being given. Since this study used an inactive placebo, it may be that subjects who received MDMA were more aware that they were getting the study medication, which could in turn bias the results in favor of MDMA.
But more importantly, beyond that methodologic limitation, the results should be considered along with the larger backdrop of what we know about for PTSD and psychotherapy. This study, and the previous ones like it, isn’t so much as a study of MDMA as a therapeutic agent, as it is a study of MDMA to assist a more involved and drawn-out psychotherapy protocol. In the study, both the MDMA and the placebo groups improved, though the MDMA group improved more. But MDMA shouldn’t be thought of as an “adjunctive” or “add-on” therapy—it’s intended to provide a pharmacologic “assist” to a specific form of psychotherapy structured around the MDMA administration.4 This study, and any other similar study done to date, provides no evidence that MDMA, by itself, represents a treatment for PTSD.
With PTSD, a pathological avoidance of triggers—which can include psychotherapy—is a core feature of the disorder that often worsens anxiety and fear. Too often, I see people hoping for a kind of “quick fix” in the form of a pill instead of “doing the work” of therapy. Again, there’s no evidence that MDMA offers anything in the way of a quick fix.
In much the same way, the psychotherapy protocol studied here was integrated with the MDMA treatment. So, the study provides no evidence that adding MDMA to other existing or “evidence-based” forms of psychotherapy for PTSD, like psychodynamic therapy, cognitive processing therapy, or prolonged exposure therapy would be either safe of effective. We also don’t yet have comparative data—we don’t yet know if MDMA assisted therapy is superior, or inferior, to these other established forms of psychotherapy or whether certain types of patients might respond better to one or another.
Based on these findings, do you think MDMA-assisted therapy could or will play a role in treating PTSD? If so, is this a welcome or needed development (and if so, for which patient population(s) and why)? Do you foresee MDMA-assisted therapy having any other potential mental health applications?
There’s certainly significant public interest in psychedelics at the moment, vocal proponents like Michael Pollan who have touted them as miracle cures, and a well-funded apparatus in MAPS to continue studying them as therapeutic agents. We can expect more studies in PTSD and if other results are also “positive,” FDA approval and clinical use is a definite possibility down the road. We can also expect further research studies investigating MDMA for other psychiatric disorders in the coming years. Whether such studies find MDMA to be safe and effective remains to be seen.
But generally speaking, any time we learn about another effective and safe treatment for medical and psychiatric conditions like PTSD, which are often chronic in nature and only respond partially to existing therapies, that’s a plus.
As MDMA therapy and further medical and scientific research likely proceed, are there caveats we should keep in mind in terms of safety and risks?
All medications, and drugs more broadly, have the potential for side effects and serious side effects. For example, the serotonergic activity of MDMA has raised concerns about suicidality as a side effect, though that’s also true of FDA-approved antidepressants like SSRIs. Oftentimes, we become more aware of side effects in the years after a medication has been approved, so it’s too early to judge the risk potential of MDMA without further clinical trials and clinical experience. And certainly, there’s a well-established abuse potential for MDMA including risks of overdose, which also creates a potential problem of both “abuse” as well as “diversion” (obtaining prescription medications to be sold as drugs of abuse). Among psychiatric disorders, PTSD has one of the highest rates of illicit drug use co-morbidity (“substance use disorders” or “addiction”), so such concerns deserve careful attention.
In which direction(s) would you like to see MDMA-related research go in the future? And what important questions are left to be addressed? Anything else you would like to add about this paper, or about MDMA in general?
Psychedelic research is still in its infancy in terms of therapeutic potential for psychiatric conditions. In general, I would say that the distinction between “drug” and “medication” is often blurred, with artificial lines drawn between them. There’s both a lot of stigma and concern about psychedelics based on their “mind-altering” properties and potential for abuse as well as a lot of potentially unwarranted enthusiasm that they represent a new era of miracle cures. A more conservative or neutral perspective would be to regard all chemical compounds as both potentially therapeutic and potentially harmful, with the risks and benefits to be worked out through careful research. We’re seeing that happen now with psychedelics.
1. Reiff CM, Richman EE, Nemeroff CB, et al. Psychedelics and psychedelic-assisted psychotherapy. Am J Psychiatry 2020; 177:391-410.
2. Illingworth BJG, Lewis DJ, Lambarth AT, et al. A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: a systematic review and meta-analysis. J Psychopharmacol 2021 (in press).
3. Hoskins MD, Sinnerton R, Nakamura A, et al. Pharmacologic-assisted psychotherapy for post-traumatic stress disorder: a systematic review and meta-analysis. Eur J Psychotraumatol 2021; 12:1853379.
4. Morgan L. MDMA-assisted psychotherapy for people diagnosed with treatment-resistant PTSD: what it is and what it isn't. Ann Gen Psychiatry 2020:19:33.