Adding 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, to intensive psychotherapy can significantly mitigate symptoms of posttraumatic stress disorder (PTSD), new research confirms.
One month after MDMA-assisted psychotherapy, 43% of patients no longer met criteria for PTSD, and 12 months after MDMA-assisted psychotherapy, 76% of participants no longer had PTSD, according to results of the US Food and Drug Administration (FDA)—regulated phase 2 clinical trial.
"The long-term results are the most significant finding from this latest trial, the largest ever completed of MDMA-assisted psychotherapy for PTSD," Brad Burge, director of strategic communications for the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS), which funded the study, told Medscape Medical News.
"The finding that about three quarters of participants no longer had PTSD a full year after receiving their last treatment with MDMA-assisted psychotherapy suggests that the treatment is not just ameliorating symptoms and is instead addressing the root cause of PTSD — specifically, a person's inner relationship with their past traumatic experiences," said Burge.
This treatment has the potential to "greatly improve the lives of people suffering from PTSD, regardless of the source of their trauma," lead investigator Marcela Ot'alora, of Aguazul-Bluewater, Inc, Boulder, Colorado, added in a news release.
"After treatment, a great majority of our participants have reported feeling more connected to themselves and to others, more joy, more compassion, and with new skills for facing life's challenges," Ot'alora noted.
The study was published online October 29 in the Journal of Psychopharmacology.
The double-blind, placebo-controlled, phase 2 pilot study included 28 patients (nine men, 19 women) with chronic PTSD resulting from military service, sexual assault, and other causes. The study compared two active doses of MDMA (100 and 125 mg) with a low dose of MDMA (40-mg active placebo; control group) as an adjunct to psychotherapy.
The course of double-blind treatment included 13.5 hours of nondrug psychotherapy and 16 hours (two day-long sessions) of either full-dose or low-dose MDMA-assisted psychotherapy.
After completing the initial double-blind portion of the study, patients who initially received active-dose MDMA received a third day-long session with active-dose MDMA and 4.5 additional hours of nondrug psychotherapy. Patients initially assigned to the low-dose control group then received three day-long active-dose MDMA sessions and 18 additional hours of nondrug psychotherapy.
The primary outcome was change in total scores on the the Clinician-Administered PTSD Scale–IV (CAPS-IV) 1 month after the second session of MDMA-assisted psychotherapy.
In the intent-to-treat (ITT) set, the active-dose groups demonstrated the largest reduction in PTSD symptoms at the primary endpoint. The mean changes in CAPS-IV total scores were −26.3 with the 125-mg dose and −24.4 with the 100-mg dose, compared with −11.5 with the 40-mg dose. However, the results did not reach statistical significance.
In the per protocol (PP) set, there was a significant main effect in change of CAPS-IV total scores at the 125-mg dose (−37.0; P = .01) and a trend toward significance with the 100-mg dose (−24.4; P = .10), compared to 40-mg dose (mean change, −4.0).
"Although significant group differences were detected only in the PP set for the primary outcome, over half of participants in the ITT set who received active MDMA doses reached a 30% or greater drop in CAPS-IV total scores compared to 16.7% in the 40 mg group," the investigators note in their report.
After the third MDMA session, both the 100-mg and the 125-mg dose groups showed further reductions in CAPS-IV scores, "providing evidence that an additional session significantly improved PTSD outcomes," they note.
"Importantly," they write, the gains were maintained over 12 months after all groups had received active doses of MDMA, with 76% of patients no longer meeting the criteria for a diagnosis of PTSD.
"I would not say that our treatment is a 'cure.' Not meeting criteria for PTSD means that the symptoms are not severe enough to warrant a diagnosis of PTSD," Ot'alora cautioned in email to Medscape Medical New.
The fact that CAPS-IV scores continued to improve between the 2-month and 12-month follow-up assessments supports the theory that MDMA helps to "catalyze a therapeutic process that continues long after the last drug administration," the investigators write.
The secondary outcome measures of depression, sleep problems, and dissociation all showed significant reduction of symptoms at 12 months compared to baseline.
"These findings are noteworthy," the researchers say, "given that participants had moderate to extreme PTSD and had previously failed to benefit from psychotherapy, including approaches thought to be relatively effective (cognitive behavioral therapy [CBT] and eye movement desensitization reprocessing [EMDR]), and pharmacological treatment, including medications for depression and anxiety."
The study replicated previous studies that showed an acceptable risk profile for MDMA, with no MDMA-related serious adverse events, the researchers say. The most frequent adverse reactions (reported by at least 40%) during treatment sessions were anxiety and jaw clenching/tight jaw, followed by headache, muscle tension, dizziness, fatigue, and low mood.
The most common adverse reactions reported 1 week following treatment included insomnia, low mood, irritability, and ruminations. Most were mild to moderate and decreased in frequency dduring the week following treatment. Temporary elevations in heart rate, systolic blood pressure, and temperature were recorded during MDMA sessions and did not require medical intervention.
This is the first MDMA trial to use multiple therapy teams with newly trained therapists implementing the manualized approach.
"Our study demonstrated that different therapy teams were able to get similarly robust results, further strengthening the case for MDMA-assisted psychotherapy as a promising option for the treatment of PTSD," Ot'alora said in the release.
If approved, "the only people with permission to do this treatment will be clinicians who have gone through MAPS training," Ot'alora told Medscape Medical News.
As reported by Medscape Medical News, the FDA granted breakthrough therapy designation to MDMA-assisted psychotherapy for PTSD in August 2017. The FDA stated that the approach "may demonstrate substantial improvement over existing therapies" and agreed to expedite its development and review.
Pivotal phase 3 clinical trials of MDMA-assisted psychotherapy for PTSD began in September 2018. They will enroll up to 300 patients across 16 sites in the United States, Canada, and Israel. If the phase 3 trials demonstrate significant efficacy and an acceptable safety profile, FDA approval is expected by 2021.
Potential for "Dramatic Improvement"
Reached for comment, Matthew Johnson, PhD, of the Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, said the results are "very promising" and clearly warrant further, larger-scale research into MDMA in the treatment of PTSD.
"The best treatments we have for PTSD are trauma-based psychotherapies, with the strongest evidence for prolonged exposure therapy and cognitive processing therapy. However, the rates at which patients are able to adhere to these long-term therapies is very low," noted Johnson, who was not involved in the study.
"Some medications have been shown to work better than placebo, but the magnitude of improvement is very small, much smaller than for those who are able to complete trauma-based psychotherapies. The present study results are consistent with previous research on MDMA treatment for PTSD, with long-term results showing that a substantial portion of participants no longer met criteria for having PTSD," Johnson told Medscape Medical News.
As for limitations, he noted that the study was relatively small for a group-comparison study.
"The low-dose group, which served as a comparison group, actually showed substantial improvements of a similar magnitude as the higher-dose groups after blinded MDMA sessions," said Johnson.
"This was stated to be driven by a single participant. It is unknown whether this was a result of placebo (expectation) effect, a result of the interactions during preparation, or a result of even the low dose of 40 mg having efficacy.
"A larger trial would help to address this ambiguity. However, these are understandable limitations of a smaller trial, and the results are consistent with the potential for dramatic improvement of PTSD," he added.
Mayer Bellehsen, PhD, director, Mildred and Frank Feinberg Division of the
Unified Behavioral Health Center for Military Veterans and their Families in Bay Shore, New York, said new treatments for PTSD are needed.
"PTSD can be a disabling condition that affects people from all backgrounds. While first-line treatments such as cognitive-behavior therapies can be effective, a good number of individuals are unable to complete these treatments. It is therefore necessary to develop novel treatments for individuals suffering from PTSD," Bellehsen told Medscape Medical News.
He agreed that further research on a larger scale is needed, but added, "the positive results in this study and from prior studies suggest that MDMA-assisted psychotherapy is gaining attention as a promising new treatment approach."
The Multidisciplinary Association for Psychedelic Studies funded the study. Several authors have financial relationships or are employee of MAPS Public Benefit Corporation. Dr Johnson and Dr Bellehsen have disclosed no relevant financial relationships.
J Psychopharmacol. Published online October 29, 2018. Full text
Medscape Medical News © 2018
Cite this: MDMA-Assisted Psychotherapy Provides Lasting Benefit for PTSD - Medscape - Nov 01, 2018.