As part of the search for novel psychotherapeutic drugs, some investigators have started studying several categories of abused drugs and are demonstrating that some of these may have therapeutic benefits. For instance, ketamine is a close relative of phencyclidine (PCP, angel dust), and ketamine itself has been used as a “recreational” drug. Multiple research groups have shown that ketamine can lead to rapid improvement of symptoms in severely depressed individuals. This drug can also rapidly decrease thoughts of suicide. Drugs related to ketamine are in advanced stages of clinical trials, and it is likely that several medications derived from the work with ketamine will be approved within the next few years.
Similarly, there are ongoing trials involving classic hallucinogens such as psilocybin (“magic mushrooms”) and lysergic acid diethylamide (LSD, “acid”) in treating anxiety, depression, and substance use disorders. We have mentioned some of this work in earlier posts.
Another recreational drug with possible therapeutic benefits is 3,4-methylenedioxymethamphetamine (MDMA – also known as “ecstasy”). This drug is often used at dance parties and raves. Users report increased empathy and euphoria when using the drug, but it can also have adverse side effects, including elevating blood pressure and increasing cardiac arrythmias.
In an article published in Lancet Psychiatry, Michael Mithoefer and colleagues reported that MDMA, when combined with psychotherapy in a controlled setting, was effective in reducing symptoms of chronic post-traumatic stress disorder (PTSD) in a small study of military personnel and emergency first responders. This phase 2 study, together with other phase 2 trials, has led the FDA to designate MDMA-assisted psychotherapy as a “breakthrough therapy,” potentially hastening its approval as a treatment. It should be noted that the Mithoefer et al. study was sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS) – a group that has been promoting the concept of hallucinogenic drugs as therapeutic agents for decades. Although members of this group may have potential conflicts of interests, this study was reasonably well-designed and the evaluators and participants were “blinded” to the dose of MDMA administered. Large phase 3, multisite, double-blind, placebo-controlled trials could soon follow.
Chronic PTSD is a relatively common condition in military personnel returning from active duty. However, it can be a difficult illness to treat. Some individuals respond to antidepressants such as sertraline or paroxetine, and some respond to specific types of psychotherapies. Nevertheless, these treatments do not substantially help many individuals suffering from moderate to severe symptoms of PTSD.
Mithoefer’s group examined the effects of MDMA-assisted psychotherapy in a group of 26 military veterans and first responders who scored above a threshold score on a standardized assessment of PTSD and who had experienced symptoms of PTSD for at least 6 months. (In fact, the mean duration of PTSD in this group of people was 7 years.) Study participants were randomly assigned to receive one of three doses of MDMA —30 mg (7 participants), 75 mg (7 participants), or 125 mg (12 participants) —together with time-intensive therapy. The lowest dose (30 mg) was considered to be an active control. Each person received MDMA on two occasions separated by 3–5 weeks. Prior to the first MDMA session, each individual participated in three 90-minute psychotherapy sessions “to establish a therapeutic alliance and prepare participants for the MDMA experience.” Administration of MDMA was accompanied by an 8-hour session of “non-directive or client-directed psychotherapy.” This was followed by a week of daily phone contact and two 90-minute sessions “aimed at integrating the experience.” By the end of the first phase of this study, each individual had received about 13 hours of therapy not associated with MDMA and 16 hours of therapy accompanying two MDMA treatments. Each participant was assessed with a standardized scale for PTSD, as well as other standardized assessment scales, one month after the last administration of MDMA. True “blinding” of the participants may have been compromised in that there were different behavioral effects of the 75 mg and 125 mg doses compared with the 30 mg dose.
PTSD symptoms were substantially diminished in those receiving 75 mg and 125 mg MDMA when compared to the group receiving 30 mg. Six of the 7 in the 75 mg group and 7 of the 12 in the 125 mg group no longer met criteria for a PTSD diagnosis; only 2 of 7 in the 30 mg group achieved this level of response. Also, global psychological function substantially improved in those receiving 75 mg and 125 mg in comparison to those receiving 30 mg. Results from 75 mg were at least as good as results from 125 mg.
Following the double-blind portion of the study, those who received the 30 mg and 75 mg doses participated in an open-label trial of three additional sessions consisting of 100–125 mg MDMA and accompanying therapy. Those who received the 125 mg dose in the original double-blind portion of the study received one further session. The substantial improvements that occurred one month after the double-blind phase of the study were maintained a year after the open-label phase of the study.
The MDMA treatments appeared to be well tolerated. One person had a serious side effect involving a temporary increase in a cardiac arrhythmia that was possibly related to the study drug. Few individuals dropped out of the study; 24 of the 26 participants remained in the trial for its entire duration.
The exact mechanisms underlying the possible therapeutic benefits of MDMA are unknown. MDMA has strong influences on various neurotransmitter systems including serotonergic functioning, but relating these effects to treatment of PTSD would be speculative. MDMA is thought to increase openness and trust, and the authors suggest that these properties may enhance the effectiveness of the therapy sessions.
The present results are intriguing but have substantial limitations including the small sample size, lack of true controls, possibility that therapists and participants were not always blind to doses used, and use of sessions to prepare subjects for the MDMA exposure. The authors indicate that larger phase 3 studies are under development. If these studies confirm that MDMA together with psychotherapy over a period of several months can lead to substantial symptomatic and functional improvement in military personnel with chronic PTSD, it would be an exciting and remarkable finding. Going forward it will also be very important to define the risks associated with MDMA when used for therapeutic purposes.
Exploring the therapeutic potential of counterculture drugs is a fascinating story. A small group of individuals have dedicated their careers to this cause. If research by other disinterested, non-conflicted scientists can confirm their findings, then this group will deserve credit for their persistence despite marked political resistance.
This post was written by Eugene Rubin MD, PhD and Charles Zorumski MD.