In this special ‘Ecstasy’ edition many of the published papers will be describing phenomena associated with exactly that; the prohibited recreational drug Ecstasy. However, this paper provides a brief review of the history, proposed pharmacological mechanisms, safety issues and clinical applications of the medicine 3,4-methylenedioxymethamphetamine (MDMA). Most clinical MDMA research in patients to date has focused on MDMA-assisted psychotherapy to treat posttraumatic stress disorder (PTSD). In this review paper other potential therapeutic applications for MDMA therapy are described, including contemporary studies treating anxiety associated with autism and the authors’ ongoing study exploring the potential role for MDMAassisted psychotherapy to treat alcohol use disorder. MDMA therapy for PTSD is now entering the final Phase 3 stage of drug development, with a target set for licensing by the FDA and EMA in 2021. This means that if clinical efficacy criteria are achieved, MDMA would become a medicine.

Sessa B, Higbed L, Nutt D (2018) A Review of 3,4-Methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy. Ann Forensic Res Anal 5(1): 1051.

•    MDMA therapy
•    Posttraumatic stress disorder
•    Recreational ecstasy

In the late 1960’s, after lysergic acid diethylamide (LSD) was banned, some psychedelic therapists began exploring other drugs as tools to enhance psychotherapy. One, Leo Zeff, was first introduced to MDMA in 1976 by chemist, Alexander “Sasha” Shulgin, who had been synthesizing psychedelics since the early 1960s [1]. Zeff went on to successfully and safely give MDMA, then legal, to many thousands of patients [2]. Shulgin, together with chemist David E. Nichols, published the first report into the psychoactivity of MDMA in humans [3].

Not a ‘classic’ psychedelic drug, but an ‘entactogen’ [4], MDMA produces a gentler, more euphoric state than LSD. Shorter-acting and therefore more clinically manageable, it increases feelings of empathy and bonding and allows users to access and process memories of emotional trauma [5].

Psychotherapists using MDMA in the early 1980s, when it was called ‘Adam’ or ‘Empathy’, were keen to keep it within the clinical community. But MDMA became rebranded as the more marketable ‘Ecstasy’ and its non-clinical use spread- especially in the club scene or in large parties called raves. In 1984, in response to rising police seizures of the drug, the DEA announced that it intended to ban the compound. The clinical MDMA research community requested a hearing to debate the DEA’s intention, but in May 1985 MDMA was placed in an emergency Schedule One category, where it has stayed ever since – hugely restricting opportunities for its research [6]. Due to this Catch 22 situation, very little clinical research was able to take place. This prompted the formation of the US-based research organisation, The Multidisciplinary Association for Psychedelic Studies (MAPS), which today is spearheading global clinical research of MDMA.

In the mid-eighties, a series of uncontrolled case studies, conducted before the ban, were published. These described the effective use of MDMA with couples or in groups [7]. In 1988 the Swiss Medical Society for Psycholytic Therapy conducted individual and group psychotherapy with MDMA. Over a hundred patients with a wide range of psychiatric problems received an average of eight therapeutic sessions. Over ninety-percent of patients described improvements at nineteen-months follow-up [8]. But in the wake of growing media hysteria about recreational ecstasy use the project was terminated in 1993.The compassionate use of MDMA has restarted in Switzerland in the recent years and currently a few patients are treated each year based on individual authorizations by the Federal Office of Public Health.

Throughout the 1990s, tensions developed between the clinical MDMA community, who proposed MDMA was safe in controlled circumstances, and the media and politicians who favoured strict prohibition to control recreational use. During this decade the UK brewing industry sponsored widely publicised anti-Ecstasy campaigns in response to their business being eroded by Ecstasy use [9]. Undeterred by the political challenges, MDMA clinical research continued, with a MAPS-sponsored clinical study gaining approval in 2000 to look at MDMA for PTSD in Spain. But after just one year, a political backlash by the Spanish government shut down the study.

 

The first controlled clinical study demonstrating MDMAassisted psychotherapy was eventually published in 2010 – with impressive results [10]. Twenty patients with treatment-resistant PTSD received, during a course of non-drug psychotherapy, either inactive placebo or two or three sessions of MDMA (initial dose of 125 mg, followed two hours later by a further booster of 62.5mg). At two and twelve-month follow-up, 83% of the experimental group no longer met the criteria for PTSD, compared with just 25% of the patients in the placebo group. There were no drugrelated serious adverse events and no adverse neurocognitive effects [10]. Long-term follow-up of the cohort of successfullytreated patients demonstrated that remission from PTSD was maintained for up to four years without having any further doses of MDMA [11].

A second, smaller MAPS-sponsored study in 2013 again explored the potential for MDMA Psychotherapy for treatmentresistant PTSD and showed substantial improvements [12]. This study by Oehen was smaller than Mithoefer’s and although there was a definite trend in the direction of MDMA therapy being superior to placebo, at first sight the statistics failed to demonstrate a significant reduction in CAPS for the experimental subjects [12]. However, a further review of the data, using effect size as a measure, concluded that Oehen had been overly conservative and the results were indicative of MDMA psychotherapy providing substantial improvements for treatment-resistant PTSD [13].

Further teams in the USA, Israel and Canada then began conducting Phase 2 MDMA trials for PTSD. In 2018 a team based in Boulder, Colorado, USA submitted their results of a dose response model from multiple therapy teams on twenty-eight participants [14]. Two active doses (100 and 125 mg) were compared with a low dose (40 mg) session, and later the low dose group crossed over for three open-label active dose sessions. The active groups had the largest reduction in CAPS scores at the primary endpoint. Whilst falling outside of statistical significance, PTSD symptoms remained lower than baseline at 12-month follow-up. There were no drug-related serious adverse events and the treatment was well-tolerated. A further study demonstrated successful treatment of veterans and first responders with treatmentresistant PTSD [15]. All of the contemporary MDMA-assisted psychotherapy studies to date have only been carried out on relatively small numbers of patients. Despite the overwhelmingly positive results and good tolerability of the treatments described in these studies above, larger, multisite trials are necessary to demonstrate the level of clinical efficacy and safety required to see MDMA become a licensed medicine. This phase of clinical MDMA research is now underway.

In collaboration with the Food and Drugs Administration (FDA) in America and the European Medicines Agency (EMA) in Europe, the pooled data from all of the MAPS-sponsored Phase 2 trials formed the basis for expansion into multi-site Phase 3 trials of MDMA therapy for PTSD, with FDA-granting Breakthrough Therapy designation. Study centres for the MAPS phase 3 programme in the USA, the UK, Netherlands, Germany and the Czech Republic are now underway, putting MDMA on course to becoming a licensed treatment in 2021 [16].

In the early 2000s – at the height of Ecstasy’s demonization in the media – a debate around safety dominated the scientific and popular literature. But comparing clinical MDMA use with recreational ecstasy carries no scientific validity. Clinical subjects are screened, monitored throughout, are given pure drug and are closely followed-up for months afterwards. In contrast recreational ecstasy use frequently involves impure samples of MDMA, taking multiple other drugs and often paying little attention to the physiological aspects of the drug experience. Nevertheless, even when one does look at recreational ecstasy, which is used by around 750,000 people every weekend in the UK [17], the rates of morbidity and mortality are low. One study demonstrated that after removing confounding factors of concomitant drugs, there were only three deaths per year attributed solely to MDMA [18]. Further studies that control for confounding factors show no evidence of neurotoxicity with MDMA when used in isolation [19] and no lasting neurocognitive impairments [20]. Given that Ecstasy has such widespread use – second only to cannabis in popularity as an illicit drug – these epidemiological and experimental data demonstrate its relative safety.

Despite the absence of evidence for chronic adverse effects from clinical MDMA therapy, acutely the MDMA experience may be associated with transient neurocognitive effects, including verbal and spatial memory deficits, slow processing speeds and executive functioning impairments [21]. But these resolve after the acute subjective psychological effects of the drug have worn off [22]. Over 1600 doses of clinical MDMA have being administered in research settings in recent years, with only one report of a self-limiting serious adverse event and no deaths [16]. A large analysis on 166 subjects given MDMA in a controlled setting by Vizeli et al. (2017) [23], demonstrated no serious adverse events and showed that MDMA “produced predominantly acute positive subjective drug effects”. The analysis also showed that subjective negative drug effects and other adverse effects were significantly more common in women. The paper concluded that, “MDMA administration was overall safe in physically and psychiatrically healthy subjects and in a medical setting.”

Compared to other stimulants (particularly cocaine, amphetamine and methamphetamine) addiction to MDMA is very rare. And in the last fifteen years of clinical studies with medical MDMA, illicit use of ecstasy after having used it clinically is seldom observed [11].

Clinical MDMA administration typically causes increased blood pressure and heart rate, increased body temperature [23,24], jaw tightness, bruxism, reduced appetite, poor concentration and impaired balance [10]. More serious adverse effects have not been observed in the last 15 years of monitored sessions with clinical MDMA [25]. Similarly, the low mood, irritability and fatigue described by Ecstasy users (and dubbed the ‘mid-week blues’) is rarely observed in the clinical setting [11,26], though low mood has also been reported in healthy subjects after administration of MDMA in controlled settings [27- 29]. Studies suggest these “blues” are related to recreational users missing sleep, dancing excessively, using other drugs (including alcohol), and going without food [30,31] – none of which occur in a clinical setting.

Multiple receptors, neurotransmitters and intermediary processes probably account for MDMA’s effects. MDMA mainly acts as a releaser of serotonin (5-HT) and noradrenaline, and to a lesser extent also of dopamine [32]. Typical effects of MDMA can be predominantly attributed to the activation of the 5-HT system [33-35].

Activity at 5-HT1A and 5-HT1B receptors attenuates feelings of depression and anxiety, reduces the amygdala fear response and increases levels of self-confidence [36]. Increased feelings of closeness, greater compassion and increased empathy for oneself and others further contribute to positive mood [37,38]. Increased dopamine and noradrenaline raise levels of arousal and awareness [39,40], motivating engagement in therapy and promoting fear extinction [41].

MDMA’s effects at alpha-2 receptors, which contribute to the drug’s effects on thermoregulation [42], may also contribute a paradoxical relaxation / sedation effect [43], which could be beneficial in the context of trauma-induced hypervigilance. While adrenergic alpha-1 receptors are involved in the thermogenic response to MDMA in humans [38], alpha-2 receptors do not appear to be critically involved in the psychological effects of MDMA in humans [44].

MDMA has been shown to facilitate the release of oxytocin, the hormone associated with early infantile bonding, which may increase levels of empathy and closeness [45-49] and dampen fear-related amygdala activity, causing a decrease in stress response and social anxiety [50,51].

Animal studies have demonstrated MDMA increases fear extinction through a mechanism dependent on elevated levels of brain derived neurotropic factor (BDNF) in the amygdala [52,53], which might account for the observed phenomenon of MDMA psychotherapy allowing for patients’ safe recall of painful emotional memories without being overwhelmed by the negative affect that usually accompanies recall of such events. Increased prosocial feelings [54], improved tolerance for unpleasant memories [55] and enhanced empathy and self-compassion [56], can promote a strong therapeutic alliance to effectively process traumatic memories.

In summary, the combined pharmacological effects of MDMA and the associated subjective psychological experience provide a unique selective impairment of the fear response whilst leaving the other faculties intact. Therefore, MDMA could be ‘the perfect drug for trauma-related psychotherapy’ [57].

Psychotherapy with MDMA borrows much of its methodology from the earliest research with LSD in the 1950s. The concept of set and setting is central to the totality of the user’s experience; where set refers to the user’s mindset and setting refers to the environment in which the drug is taken. Much effort goes into developing the optimum psycho-environmental conditions for a clinical MDMA-assisted session [58]. A comprehensive study with a 125 mg MDMA dose taken by 166 subjects in a clinical environment, showed 64% of the subjects reported that the controlled setting was important for their type of experience and was reassuring and made them feel safe [23].

Therapeutic sessions with MDMA are delivered by a malefemale co-therapist dyadic pair. The drug-assisted sessions are non-directive; encouraging the patient to ‘go with the experience’ and ‘let the drug do the work’ [59,60]. The therapists create a sense of safety and communicate trust in their patient’s ability to explore their issues. Eyeshades are frequently employed in MDMA-assisted sessions and the use of music played through headphones is commonplace. Physiological observations such as regular measurements of blood pressure and temperature are also commonplace throughout the MDMA experience.

As well as the MDMA-assisted sessions, the non-drug therapeutic sessions that make up a total course of MDMA psychotherapy are essential for preparation before taking the drug and subsequent integration of the emergent material after the drug sessions. Taken on its own, without adequate pre-drug preparation or post-drug support, MDMA is less likely to have a positive beneficial effect [61]. In training MDMA Therapists for the future, MAPS are currently leading the way with their manualised approach for MDMA-assisted psychotherapy for PTSD.

Up till now most MDMA therapy research has been conducted with patients with PTSD. But many people suffering with other chronic mental disorders will describe some degree of premorbid trauma, often secondary to sexual or physical child abuse, or more commonly emotional abuse and neglect, which are no less damaging to a person’s subsequent development [62]. Given that such child maltreatment is particularly prevalent in cases of adult addictions [63], we are now exploring the potential role for MDMA therapy in cases of adult alcohol use disorder.

Alcohol use disorder represents a serious clinical, social and personal burden on its sufferers and a significant financial strain on society. Current treatments, both psychological and pharmacological, are poor, with high rates of relapse after medical detoxification and dedicated treatment programs. The earliest historical roots of psychedelic drug-assisted psychotherapy in the 1950s for alcoholism were associated with LSD-assisted psychotherapy [64]. Indeed, Bill Wilson, the founder of Alcoholics Anonymous, testified to the powerful potential of psychedelic-assisted therapies for treating alcoholism [65]. And contemporary pilot studies with psilocybin therapy for alcohol addiction [66] and psilocybin therapy for nicotine addiction [67] have demonstrated positive results. But MDMA-assisted psychotherapy has never been explored as a treatment for any form of substance use disorder. However, MDMA could be well suited to allow a patient using alcohol as a form of selfmedication against a history of childhood trauma to explore and address painful memories without being overwhelmed by negative affect. Furthermore, the acute psychological effects of MDMA are more easily tolerated than the classical psychedelics, with less perceptually disturbing effects and not all patients are able to tolerate the classical psychedelic experience. Given that compliance is a critical part of addiction therapy, there are good grounds for exploring MDMA therapy for alcoholism [68]. However, it must be borne in mind that the cardiovascular tolerability of MDMA is lower compared with hallucinogens [23,69], which prompts the requirement for more robust vital signs monitoring during MDMA therapy compared to classic psychedelic drug-assisted psychotherapy.

The capacity for MDMA to increase feelings of empathy and compassion for the self and others may contribute to improved self-awareness and subsequently reduce the denial of alcohol misuse [70]. Similarly, MDMA has been shown to increase feelings of mindfulness, which has been increasingly explored as a potential approach for treating alcohol use disorder [71]. This is the hypothesis behind the UK’s first ever clinical MDMA Therapy study, the Bristol-Imperial MDMA-for-Alcoholism (BIMA) study [68]. The BIMA study enrols participants into an 8-week course of supportive psychotherapy employing elements of Motivational Interviewing. As with all psychedelic-drug assisted psychotherapy courses, most of therapeutic sessions are face-to-face non-drug-assisted sessions. Only on two occasions participants are administered open-label sessions of MDMAassisted therapy. On each drug-assisted session participants receive an initial dose of 125mg MDMA, followed two hours later by a ‘booster dose’ of 62.5mg to prolong the experience. Throughout the drug-assisted session, vital signs, including blood pressure and body temperature, are monitored. Participants remain in the treatment centre overnight after taking MDMA. Mood, sleep and suicide risk are monitored daily for a week. Participants are followed-up for 9-months post-detox, and outcome measures include safety and tolerability data, quality of life measures, physical and mental health status and drinking behaviours. This study will be completed by the end of 2019.

Another area of contemporary research with MDMA therapy is exploring the potential for relief of social anxiety associated with autism, with an ongoing MAPS-sponsored randomized, doubleblind, placebo-controlled pilot study underway at Harbor-UCLA Medical Center and Stanford University [72]. One of the cardinal features of autism is a tendency for a sufferer to lack empathy. It is a recognized anecdotal observation that autistic adults often report reduced empathy-impairments during, and for some time after, taking MDMA [72].

Other contemporary areas of research with MDMA therapy include the potential for MDMA-assisted psychotherapy in treating mood disorders [73] and, relatedly as an alternative to electro-convulsive therapy [74].

As MAPS pushes ahead with Phase 3 studies in the USA and Europe for MDMA therapy for PTSD, we are seeing a broadening of the clinical possibilities for the compound. Meanwhile psychiatrists are increasingly recognising the role played by early psychological trauma in a range of mental disorders beyond that of PTSD.

Due to its association with recreational Ecstasy, MDMA has a long-standing label of controversy in the UK. But this narrative must be tackled; partly because the compound is demonstrably safe and efficacious in the clinical setting and partly because politics and erroneous media-driven opinion must not be allowed to dictate the progress of medical research [75]. Like everything else, MDMA is not 100% safe. As with all medical interventions - from sticking plasters to cancer chemotherapy –MDMA may be simultaneously both invasive and beneficial and therefore the same principles of evidence-based clinical governance must be applied to psychedelics as they are to other therapeutic approaches [76]. Clinical MDMA and recreational ecstasy are incomparable in terms of drug purity, administration and the screening and monitoring of selected participants. “Prohibition of MDMA and other illicit drugs increases, not reduces, the potential harms of recreational drug use, [75], adds unnecessary costs that put research beyond the financial capabilities of many academic institutions, and therefore hold back progress [77].”

There remains much work to be done to convince critics that a compound that is experienced recreationally by so many people may also, in its clinical form, have benefits for patients suffering with treatment-resistant mental disorders. Meanwhile, psychedelic culture is enjoying a palpable renaissance in both medicine and the media. Against this backdrop, psychiatry and society continue to be burdened with far-from-perfect treatment outcomes for many mental disorders. In this context, given the clinical burden, the lack of treatment efficacy and their continued distress, perhaps the only question we should be asking is: Can we afford not to explore MDMA therapy for our worthy patients?

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