For people suffering from post-traumatic stress disorder — an anxiety condition that develops in the wake of extreme psychological stress or fear — often the only way forward is to confront the very memory that triggers the disorder. While group and cognitive therapies have shown promise, exposure-based therapies have become increasingly popular and successful. Exposure means confronting a distressing memory (a near-death experience, the loss of a loved one or a sexual assault, for example) to emotionally process it in a safe clinical environment — either through imagined scenarios or real-life exposure to reminders of trauma. The therapy is intended to help the patient "re-learn" a non-debilitating response to a trigger of fear. It's a phenomenon known as extinction learning.
Even with this approach, about 40 percent of patients continue to experience some level of post-traumatic stress after therapy. To reduce that number, scientists have been investigating a range of drug therapies in recent years to improve exposure therapy, which is not intended to "erase" a patient's memories but rather to help them process the painful stimulus as merely a memory, and not an event that will happen — or threaten them — again. The therapy requires patients to confront their anxieties, but researchers believe medication — including MDMA — can help by making the patient feel safer, more in control, more able to process emotions and less evasive or dispirited.
Earlier this year, a pair of Norwegian scientists published a paper in the Journal of Psychopharmacology titled "How could MDMA help anxiety disorders? A neurobiological rationale." Authors Pål-Ørjan Johansen and Teri Krebs, who are based at the Norwegian University of Science and Technology and receive funding from the Research Council of Norway, propose that the substance 3,4-methylenedioxymethamphetamine — also known as MDMA or as the street drug ecstasy — holds significant therapeutic promise for patients with post-traumatic stress disorder. As they write, "MDMA [ecstasy] has a combination of pharmacological effects that ... could provide a balance of activating emotions while feeling safe and in control."
To learn more about their studies of MDMA and post-traumatic stress disorder, Miller-McCune conducted an e-mail interview with the two researchers in Norway. They responded jointly.
Miller-McCune: Could you provide an overview of the ideas behind exposure therapy and how MDMA works to quell anxiety in that context?
Krebs & Johansen: A lot of people wonder: How is it possible that a few doses of MDMA, in combination with psychotherapy, could have lasting benefits for anxiety? Doesn't it just make people feel happy for a few hours? Aren't most psychiatric medications taken daily for a long time? There is a common misconception that psychotherapy is a really long process of vaguely defined "talking" and that it probably isn't that effective anyway. Actually, exposure therapy (in particular "prolonged exposure therapy," as developed by Dr. Edna Foa at the University of Pennsylvania) is short-term, structured, based on scientific behavioral principles of conditioning and extinction, and validated by many controlled studies. For most patients, exposure therapy has clinically significant effects on anxiety after a few hours, and for PTSD, exposure therapy has demonstrated long-term positive results after 10 to 12 hourlong weekly therapy sessions.
If MDMA could facilitate exposure, then it is entirely understandable that MDMA-augmented therapy could have lasting long-term effects on PTSD symptoms, after a few four- to six-hour therapy sessions with MDMA, within a course of short-term therapy. This needs to be demonstrated repeatedly in clinical trials, but it is biologically plausible. In the last 10 years, there has been a large amount of research on the molecular mechanisms of fear extinction with an objective of making exposure therapy easier, faster or more effective.
The main point that we want to get across: Fear extinction in exposure therapy requires a balance of activating emotions while feeling safe and in control. MDMA has effects that combine together many of the proposed mechanisms for enhancing fear extinction. Interestingly, MDMA appears to both facilitate exposure as well as augment extinction learning. Therefore, more research on these aspects of MDMA is clearly appreciated.
M-M: How was the therapeutic potential of MDMA first discovered? And what made you begin to think of using MDMA in this therapeutic context?
K & J: MDMA was first synthesized by Merck back in 1912, but it was never tested on humans. It was rediscovered in the late 1960s, and the therapeutic potential was immediately recognized by chemist Alexander Shulgin. Shulgin introduced MDMA to physicians who used MDMA to augment psychotherapy in the early '80s.
We have been in a kind of plateau the last decade; we need to develop new treatments beyond timid half-modifications of treatment models. ... We have acquired a lot of knowledge about the brain circuits of fear and fear extinction from animals. Recently we have started to move over the hump of being stuck in the same place. By translating principles from research on extinction and animal learning into clinical studies of exposure therapy, new strategies for combining pharmacological and exposure-based treatments have emerged.
M-M: What makes post-traumatic stress disorder a particularly viable condition to target with MDMA? Is it specifically because of the use of exposure therapy in treating the disorder?
K & J: Chronic post-traumatic stress disorder is an often-complex disorder that occurs in response to a traumatic event involving perceived personal threat, such as rape, torture, physical assault or combat. Most pharmacological interventions to PTSD are daily treatments involving long-term mechanisms presumed to correct biochemical abnormalities. In contrast, prolonged exposure therapy is a short-term treatment and, consistent with extinction models of fear inhibition, prolonged exposure therapy leads to long-term improvement. Applying psychotherapy to PTSD has gained substantial support and is today regarded as the treatment of choice. However, not all people benefit from the treatment.
People with PTSD often avoid triggers or reminders of the trauma and feel emotionally disconnected or are unable to benefit from the support of others — likely contributing to the development and maintenance of the disorder. A goal during exposure therapy for PTSD is to recall distressing experiences while at the same time remaining grounded in the present, according to Dr. Edna B. Foa. Emotional avoidance is among the most common obstacles in exposure therapy for PTSD, and within a particular session, a high emotional engagement predicts a better outcome.
As illicit versions of MDMA hit the streets in the early 1980s, becoming especially popular in gay night clubs before spreading in the 1990s to underground music parties known as raves, researchers were also taking a renewed interest in its therapeutic potential, and the World Health Organization's Expert Committee decided to examine studies of the drug as an aid to treatment of a variety of mental afflictions. In 1985, the committee called MDMA an "interesting substance" and concluded: "While the Expert Committee found the reports intriguing, it felt that the studies lacked the appropriate methodological design necessary to ascertain the reliability of the observations. There was, however, sufficient interest expressed to recommend that investigations be encouraged to follow up these preliminary findings."
On July 1, 1985, however, MDMA became the first (and still only) drug classified as Schedule I under a new law that allowed the U.S. Drug Enforcement Agency to place an emergency ban on drugs it deemed dangerous to the public. When the government was sued by a group of psychologists, psychiatrists and researchers, Francis L. Young, an administrative law judge for the U.S. Department of Justice, analyzed the literature and concluded that, prior to its being proscribed, MDMA did have "a currently accepted medical use in treatment in the United States. ... [I]t is not presently being used in treatment because it has been proscribed."
Young went on: "In addition, other psychiatrists have been using MDMA in their practices over the past 10 years. Because MDMA cannot be patented, no pharmaceutical company has had the financial incentive to carry out the extensive animal and clinical tests required by the FDA for approval to market the drug on an interstate basis. Nevertheless, the overwhelming weight of medical opinion evidence received in this proceeding concurred that sufficient information on MDMA existed to support a judgment by reputable physicians that MDMA was safe to use under medical supervision. No evidence was produced of any instances where MDMA was used in therapy with less than wholly acceptable safety."
Although Young recommended that MDMA be placed in Schedule III — allowing it to be manufactured, used on a prescription basis and subject to further research — the DEA maintained its Schedule I ruling. It wasn't until 1993 that the Food and Drug Administration approved clinical trials on the effects of MDMA on human volunteers.
In her seminal work on the drug, Ecstasy: The Complete Guide, New York psychiatrist Dr. Julie Holland notes that the drug acquired its street name largely on the basis of its marketing potential, but that even early users acknowledged its empathetic, therapeutic aspects. "It is widely accepted that the name ecstasy was chosen simply for marketing reasons," she writes. "It is a powerful, intriguing name to attach to a psychoactive substance. The person who named the drug, an alleged dealer who wishes to remain anonymous, had this to say: 'Ecstasy was chosen for obvious reasons, because it would sell better than calling it empathy. Empathy would be more appropriate, but how many people know what it means?'"
M-M: Obviously, the public at large will associate MDMA with the recreational drug ecstasy. How do you distinguish between clinical use of MDMA in a controlled setting and the illicit use of ecstasy at raves or parties?
K & J: MDMA has many potential side effects, most notably increased blood pressure and heart rate, which must be considered when screening and monitoring clinical subjects. As with other pharmaceuticals, it is important to distinguish between the risks of controlled clinical use of MDMA in research and hospital settings, and illicit use of "ecstasy" of unknown purity and dosage taken in potentially unsafe circumstances without medical supervision.
It's important to discriminate between medical research and drug policy. One area cannot be used to promote the other, and vice versa. It is inconsistent with traditional medical ethics or outright unethical to block treatment development and research based on drug policy. Drugs with greater potential for dependence and harm than MDMA, such as amphetamines (Adderall) and benzodiazepines (Valium), are widely prescribed for long-term use.
Treatment with MDMA involves only a few doses in combination with psychotherapy taken in a controlled clinical setting with appropriate medical precautions — for example, pre-screening for heart problems. It's also important to note that MDMA is not being considered for daily use or take-home use. In research studies, including in the United States, MDMA has been given to hundreds of healthy volunteers, with no occurrence of serious problems requiring medical attention. There has been a lot of misunderstanding in the past; fortunately a lot of development in this area over the last 10 years has made the climate ready for change.
M-M: From reading your paper, it seems the key role MDMA plays is helping patients overcome "emotional avoidance" of the trauma they experienced in the past. What are the biological reasons that MDMA works so well in this context?
K & J: In order for extinction to begin at all, the PTSD client has to be able to bearably remember and describe the traumatic memory. This is difficult for most PTSD clients. Activation of the fear is required for extinction. Anxiety-reducing pharmaceuticals like benzodiazepines can be counterproductive during exposure therapy (because they can merely suppress the memory for a period of time).
MDMA is found to do several things: It increases the level of oxytocin related to pro-social behavior and bonding, it increases activity in prefrontal brain areas involved in fear inhibition, and it increases the levels of norepinephrine and acetylcholine, which are neurotransmitters involved in emotional arousal and consolidation of emotional memories, including extinction learning. Consistent with fear inhibition models and translational research, we suggest that MDMA co-administered with prolonged exposure therapy will improve the therapeutic alliance, increase emotional processing and lead to enhanced extinction of fear responses.
M-M: Why do you think MDMA's potential in this area has been under-appreciated? Is it because of the negative attention on ecstasy?
K & J: MDMA and treatment research has been caught up with drug policy. However, it is common for new treatments to take a couple of decades to be fully tested and accepted. There is a great deal of interest among clinicians and scientists in the therapeutic potential of MDMA. It has been a silent story for 20 years. Previously, the only published results were open-label case studies. Now we have randomized, placebo-controlled studies.
We will see more research on the possible therapeutic applications of MDMA. It has been under-appreciated that the neurobiological effects of MDMA fit well with the current understanding of emotional learning and evidence-based treatments for anxiety. There has been a lot of research on MDMA, including clinical studies in over 300 healthy volunteers, but almost all research has focused on the possible risks in a recreational setting.
Krebs and Johansen would like to see more basic research on the impacts of MDMA on empathy, positive emotions and trust. That means studies in both animals and humans that more closely examine the acute effects of MDMA on behavior, endocrine levels and brain activity in response to emotional stimuli, particularly during the process of fear extinction wherein people can learn to suppress a reaction to fright by repeatedly confronting, in a safe environment, whatever memory or stimulus spurs their anxiety. But so far, there have only been a few studies, which have taken years to get approval, taking a close look at MDMA's therapeutic benefits.
The Multidisciplinary Association for Psychedelic Studies, a nonprofit group that funds therapeutic trials of MDMA, LSD, psilocybin and marijuana in accordance with FDA, European and international guidelines, has been working since its founding in 1986 to spur research into MDMA therapy. In February 2004, after approval from the FDA and on-site inspections of laboratories, the DEA gave its first consent to a study of MDMA and post-traumatic stress disorder by Dr. Michael Mithoefer, a psychiatrist in South Carolina. The $1 million project wound down last year, after what MAPS called an "outstanding demonstration of the safety and efficacy of MDMA-assisted psychotherapy in subjects with treatment-resistant PTSD."
MAPS has also initiated a study of MDMA-assisted psychotherapy in subjects with both anxiety and advanced-stage cancer at Harvard Medical School's McLean Hospital, led by Dr. John H. Halpern. There is also a study under way in Israel under the direction of Dr. Moshe Kotler, chair of the department of psychiatry at the Sackler School of Medicine at Tel Aviv University and former chief psychiatrist of the Israeli Defense Forces; a similar study has begun in Switzerland. The results of those studies should be released this year, while MAPS is working on initiating additional trials in Canada, Spain, France and Jordan.
But it's not all progress. MAPS' first study of MDMA's effects on post-traumatic stress disorder began in Spain in February 2000, but the study was halted in May 2002, in spite of sustained positive media attention throughout the country. As the doctor who led the study, Jose Carlos Bouso, wrote to the Spanish Medical Journal: "In May 2002, a news article appeared in the newspaper El Pais informing the public about the realization of that trial. The next day, our research team received an inspection from the General Direction of Pharmacy and Sanitary Products (Dirección General de Farmacía y Productos Sanitarios) belonging to the State of Madrid ... on May 13, 2002, the manager of the Hospital Psiquiatrico de Madrid decided to disassociate the Hospital from the study. Since then, because we have no other hospital in which to finish the study, the study cannot be restarted yet and it is now interrupted." Before the trial's close, six subjects had been treated without any lingering side effects, and there were hints of the program's efficacy.
In their interview with Miller-McCune, Krebs and Johansen said: "The biological basis of empathy and positive emotions is currently very interesting for neuroscientists. Many scientists would like to study MDMA, in humans and laboratory animals, but they are unsure how to approach this. We hope that our rationale will provide a framework for future studies and a nice reference for grant authorities. It's a promising treatment, being developed internationally, including at Harvard Medical School. Our overall goal is to reduce fear and increase acceptance around the concept of therapeutic use of MDMA."
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