“One of the inescapable facts of life is that with MDMA, as with everything that combines both promise and threat, there are intense protagonists and intense antagonists. And both groups are vocal”
– Alexander Shulgin10
Going by the street name “Ecstasy”, not everyone would necessarily consider 3,4-methylenedioxymethamphetamine (MDMA) a medical or psychedelic drug. The public conception of it seems to be that of a stimulant drug, which is taken by party-goers at nightclubs and festivals. Moreover, according to media reports, these party-goers appear to frequently fall victim to adulterated pills or other risks of recreational use, leading to severe health consequences. Others, who have made experiences with the drug or its users might know it by the occasionally used name ‘hug-drug’, owed to its empathogenic effects. This conception of MDMA, however, omits the historical roots of MDMA in the psychotherapeutic context, the complexities of its risks and dangers, as well as most recent scientific findings indicating the usefulness of MDMA as an adjunct to psychotherapy. These topics will be addressed in a series of blog posts. This first post of the series presents some insights into the history of MDMA and its scientific investigations.
Discovery and initial investigation
MDMA first came into existence in 1912, when chemists at Merck Pharmaceuticals first produced MDMA and patented it as an intermediate in a chemical reaction used to produce blood clotting agents. After this first description of its chemical formula in 1912, some pharmacological tests were performed at Merck in 1927, though the details of these experiments are unfortunately hardly traceable1. MDMA’s psychological effects in humans were not scientifically investigated until the late 1970s1. This was only done after its apparent use as a street drug, as indicated by police seizures of the substance in the early 1970s2. In 1978 Alexander Shulgin and David Nichols published a book chapter entitled “Characterization of Three New Psychotomimetics”3, describing the psychological effects of substances chemically related to known psychoactive substances. In this publication, they described MDMA as a drug that “appears to evoke an easily controlled altered state of consciousness with emotional and sensual overtones”3and compared its effects to cannabis, low doses of MDA, and psilocybin without sensory hallucinations3. These distinct effects of the drug as compared to classic psychedelic drugs later led Nichols to identify it as part of a subgroup of psychedelics specifically prompted by MDMA: entactogens4.
Popularization and Criminalization
It was Shulgin as well who introduced MDMA to some psychotherapists around the mid-end 70s who subsequently used it as an adjunct to psychotherapy without formal FDA approval. From the late 70s until the mid-80s the use of the drug among therapists slowly but steadily increased, yet no controlled scientific research of its effects in therapy was conducted during this time5. Notably, this was around 10 years after LSD was used in similar underground psychotherapy. As with LSD, over time MDMA increasingly attracted attention for its recreational effects. For the recreational users, the drug was then marketed under the street name “Ecstasy” by some commercial vendors. As opposed to therapists who rather referred to it as “Adam”6,7. With rising popularity amongst recreational users, the drug did not go unnoticed by politicians and the authorities. First and foremost, in response to Texas senator Lloyd Bentsen’s observation of its widespread use in Texas nightclubs, the Drug Enforcement Agency (DEA) declared their plan to regulate MDMA as a Schedule 1 substance in 19845. Therein they asserted the substance lacked any recognized medical use. This planned scheduling was immediately contested by a group of mental health practitioners and researchers who requested the hearing of experts in the process of determining the future legal state of the substance. However, in July 1985, the DEA temporarily banned MDMA for one year on the basis of prior findings on the neurotoxicity of its chemical analogue MDA and the widespread availability of the drug. After the hearings, the responsible judge recommended MDMA to be placed in Schedule 3 in May 1986 stating that he believed MDMA had an accepted medical use; this would have allowed for its research and its use in therapy5.
However, “the DEA’s administrator, John C. Lawn, was not convinced […]”5by the judge’s ruling, and the DEA overruled his decision arguing that MDMA was not a drug regulated by the FDA, and therefore had no accepted medical use. Harvard Psychiatrist Lester Grinspoon and Earth Metabolic Design Laboratories (EMDL, a predecessor of the Multidisciplinary Association for Psychedelic Science – MAPS) subsequently filed an appeal based on the FDA-medical-use argument and misconduct of the DEA, which had performed the emergency scheduling of MDMA before getting the formal authorization to do so, and which had overruled the judge’s decision5,8. The appeal was granted, and thus MDMA remained unscheduled.
Simultaneously multiple articles were published in scientific journals advocating for the therapeutic potentials of the drug. George Greer9, who undertook many MDMA-assisted therapy sessions, published an overview of the subjective effects reported by patients who took the substance during therapy. Alexander Shulgin10 described a comprehensive summary of the chemical background of MDMA and what was known about its pharmacology. Lester Grinspoon11outlined the theoretical background underlying and the anecdotal evidence for psychedelic-assisted psychotherapy with a special emphasis on the potentials of MDMA. San Francisco based psychiatrist Philip Wolfson6presented clinical case studies of MDMA-assisted psychotherapy and tried to specify in which situations it may be helpful, and when it might have severe limitations and perils. Moreover, funded by EMDL, Joseph Downing12investigated the physiological and psychological effects and concluded that from his results “one can only say that MDMA […] has remarkably consistent and predictable psychological effects that are transient and free of clinically apparent major toxicity”12. And, too funded by EMDL, MDMA was given to dogs and rats by Charles Frith and colleagues13. They stated that “neuropathological changes were not evident in either species”, thereby challenging the concerns about a neurotoxicity similar to that of MDA. Despite these attempts to justify the therapeutic use of MDMA, the DEA finally placed the drug in Schedule 1 in March 19885.
After the Schedule 1 Listing
Soon after the scheduling, George Ricaurte et al.14published a first investigation into the neurological risks of MDMA based on findings in nonhuman primates. The group of Johns Hopkins researchers was the first to show that serotonin depletion, as well as structural changes in the serotonin system, are among the consequences of MDMA consumption. Simultaneously, the recreational use of MDMA in the form of ecstasy pills and electronic dance music started to spread around the globe. Since MDMA was illegal pretty much everywhere, the surge in what was now deemed ‘illegal abuse’ enabled policymakers to provide generous funding to investigate the risks and dangers of the illicit use of the substance. And this risk-centered paradigm was set to dominate MDMA research for the subsequent decades. The bulk of research on the substance’s risks that accumulated over that time was critically examined by Liverpool psychologist Jonathan Cole15, who argues the last 30 years of ecstasy research and its results have to be understood in context of what he calls the ‘ecstasy paradigm’: Since MDMA has become an illegal drug, its scientific investigation and the public discourse have become subject to moral norms concerning the consumption of drugs. He posits that it became imperative for scientists to show that MDMA is dangerous, which presumably led to multiple flaws in reasoning and methodologies and thereby to biased scientific findings. For instance, he asserts a systematic publication bias in the risk-centered literature. He exemplifies this by a situation in which one of his papers, indicating that ecstasy-users may not be psychiatrically impaired in the way that has been suggested by others, was rejected. One of the anonymous peer reviewers, whom Cole implicates as part of this issue, commented that he found the data was hard to believe15. Since the available literature on the risks of MDMA is quite extensive, some of the main findings and Cole’s, as well as others’ analyses of the results will be addressed in a following blog post.
Scientific research on the therapeutic effects of MDMA was effectively halted by the Schedule 1 listing. However, organized efforts to enable research into these aspects of MDMA were already made around the time of the scheduling. The aforementioned EMDL was founded to challenge the DEA’s scheduling of MDMA. In response to the Schedule 1 listing of the drug and the lack of evidence to tackle it, one of the EMDL’s co-founders, namely Rick Doblin, went on to start MAPS. The idea behind this was to create a non-profit pharmaceutical company which would “facilitate research into the therapeutic uses of MDMA-assisted psychotherapy”8. However, the political climate remained unfavorable until fairly recently. Throughout the years, some further writings along the lines of and building upon the 1986 journal articles have been published to advocate for substance-assisted psychotherapy and specifically MDMA-assisted psychotherapye.g. 14–18. And eventually, the first MAPS-funded randomized controlled clinical trial investigating MDMA assisted psychotherapy was conducted by José Bouso et al.21. Their study, for which they started enrolling patients with post-traumatic stress disorder (PTSD) in 2000, was prematurely shut down in 2002 due to political pressure, leaving 23 out of 29 patients untreated and insufficient data for statistical analysis8,21. Subsequently, MAPS funded Michael Mithoefer’s22–24trials in the US and Peter Oehen’s25trial in Switzerland. Despite minor inconsistencies in the results, possibly due to the small sample sizes, the studies indicate that MDMA-assisted psychotherapy is a promising therapeutic approach for PTSD26,27. Additionally, a recent MAPS-funded study indicates that MDMA-assisted psychotherapy may decrease symptoms of social anxiety in autistic adults28. Some of the insights and intricacies of this science of the health-promoting effects of MDMA will be addressed in a third blog post.
As opposed to applied clinical and forensic research, throughout the last ten years MDMA has also increasingly been studied from a more basic scientific perspective; this approach does not focus on the positive or negative effects of MDMA but on neutrally investigating the effects of the substance in humans. While pharmacological data has already been obtained in the context of forensic science, some fields have only emerged after the 2000s revival of research on MDMA-assisted-psychotherapy. For example, the effects of MDMA on human socio-emotional cognition and behavior are under investigation since 2009e.g. 29–31.Furthermore, some perform mechanistic studies in which certain receptors are blocked pharmacologically to illuminate the neurobiology underpinning the psychological effectse.g. 32–34. Both these approaches not only expand our knowledge of MDMA and its effects but also provide unique insights into the neurobiology underlying complex cognitive and affective processes. While these advances partly bear less imminent implications for practice, they offer great potential for general scientific advancement and translational science at a later point.
Changing Paradigms – Future Directions
For years, research of MDMA has been limited to investigating the risks of its recreational use. This seems to be largely due to the limited evidence base on the substance’s therapeutic effects at the time of the DEA scheduling. Only due to the persistent work of MAPS, we can now distinguish between several strands of MDMA research. These strands partially correspond to the dual use of the drug in recreational and therapeutic contexts, but most recently also include basic scientific investigations. This research seeks to enable not only more precise management of the risks of recreational use and better treatment of mental health conditions, but also to bring general scientific advancement.