The History of MDMA

This is the first in a series of three blogs examining the use of MDMA as a psychedelic medicine.In this installment, we explore the fascinating history of this compound including the results of the most recently published Phase 3 studies sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS).In the second installment, we will consider the condition that is Post-Traumatic Stress Disorder (PTSD) and why MDMA may be well-suited to provide treatment when it is embedded in a specialized protocol under clinical supervision.In the third installment, we will discuss the FDA’s Expanded Access or Compassionate Use program and how The Pearl Psychedelic Institute is the first site in the United States to begin this program and how it will be conducted.


Although there has been some information regarding the use of MDMA-assisted psychotherapy for the treatment of PTSD peppered throughout this website, this is the first in a series of three blogs digging deeper into this “new” form of treatment that is currently in the final phase of the FDA’s incredibly lengthy testing and approval process.I say “new” because MDMA is not a new drug and it has a history of being used as an adjunct to psychotherapy that goes back to the late 1970s. Before it was made a Schedule I drug in 1985 as a reaction to the growing recreational use in North America and Europe and around the world, there were an estimated 4,000 psychiatrists, psychologists and therapists legally using MDMA in their practices and there were reports of the drug being an important element in their treatment of trauma-related illnesses, relational (couples) issues, clinical depression, addictions and common existential malaise.After years of research and legal use being shut down, the door cracked open again in 1994 when Charles Grob, MD, began the first FDA-approved Phase 1 study at UCLA examining the effects of pharmaceutically pure MDMA on healthy volunteers. But first, let’s go back in time and take a look at some of the important events that shaped the beginning of this reconsideration of MDMA as a tool for psychotherapy and healing…


“But first, let’s go back in time and take a look at some of the important events that shaped the beginning of this reconsideration of MDMA as a tool for psychotherapy and healing….”

The Beginning

MDMA, or 3,4-Methylenedioxymethamphetamine, was first synthesized by a young German chemist, Anton Kollisch, who was working for Merck pharmaceutical company. He was trying to discover a new medicine that could control bleeding and one of the intermediate compounds he synthesized was MDMA. Merck filed a patent for MDMA on Christmas Eve 1912 although at the time the new compound was referred to as “methylsafrylaminc.” Merck documents indicate that there was only sporadic research performed on methylsafrylaminc including a study of its pharmacology in 1927 by chemist Max Oberlin and a brief examination of its toxicology in 1952 by Albert van Schoor.


By the 1950s, various elements of the United States government were interested in exploring the potential uses of mind-altering chemicals for interrogation, mind-control, “deathless war,” espionage and other unsavory practices intended to broaden a range of weapons that could be employed in the increasingly threatening and paranoid Cold War with the Soviet Union (who was believed to already be using drugs like LSD for some of these purposes). In 1953, the U.S. Army studied MDMA as part of its research into these compounds as potential weapons but it was only tested for toxicity and behavioral effects on animals at the University of Michigan with nothing indicating that further study of MDMA was warranted for their purposes.


Alexander “Sasha” Shulgin was a research chemist for Dow Chemical and there are reports that Shulgin first synthesized MDMA in 1965 while working on a project for Dow. It is thought that Shulgin may have shared his process with another chemist on the West Coast which may be what led to the first recreational sample of MDMA being discovered in the Chicago area in 1970. However, it wasn’t until the fall of 1976 that Shulgin resorted to the old school tactic of chemists methodically self-experimenting that he experienced the psychoactive effects of MDMA. Starting with a very small dose, he eventually worked his way up to 81mg and intuitively felt that this could be a useful tool to help people so he then gave it to his friend, Bay Area psychotherapist Leo Zeff, who at the time was considering retirement. Zeff felt that MDMA “stripped away the ego’s defense mechanisms and returned one to a primordial state of innocence,” and he became known as “The Secret Chief” who spent the rest of his career until his death in 1988 treating patients and training therapists in how to use MDMA and other psychedelic drugs safely for healing. One of the earliest reports of how MDMA could be effectively used as an adjunct to psychotherapy was published in 1986 in the Journal of Psychoactive Drugs by psychiatrist George Greer and his wife, nurse Requa Tolbert. They concluded that, “results from eighty patients indicate that MDMA seems to decrease the fear response to a perceived threat to a patient’s integrity, leading to a corrective emotional experience that probably diminishes the pathological effects of previous traumatic experiences.” However, by the time this was published in a respected peer-reviewed journal, MDMA had already been declared a Schedule I drug meaning it had a high risk of abuse and that it had no medical value.


“They concluded that, 'results from eighty patients indicate that MDMA seems to decrease the fear response to a perceived threat to a patient’s integrity, leading to a corrective emotional experience that probably diminishes the pathological effects of previous traumatic experiences.' ”

1980's, 1990's, Early 2000's

Beginning around 1984 on the Spanish island of Ibiza, the world began to notice that there was a drug, MDMA, that was being used recreationally by young people who would gather together and dance all night to driving, repetitive electronic music which were the first iterations of what became known as “raves.” As raves spread to the United States and around the world, “rave culture” used MDMA and other drugs to fuel these gatherings and like most large-scale gatherings involving illicit substances, there were casualties. MDMA began showing up in the media as one of the culprits due to ravers suffering from complications of hyponatremia (from consuming too much water) and hyperthermia (overheating) but also because the MDMA being consumed was likely of questionable purity and was often mixed with other drugs. Nevertheless, MDMA or “ecstasy” as it was now being called, began to enter mainstream awareness as a dangerous party drug that could kill.

In 1985, as a result of growing concern about the recreational use of MDMA, the United States’ Drug Enforcement Administration (DEA) reacted with an emergency scheduling of MDMA that placed it in Schedule I, the most restrictive classification for research, and made it illegal to use for recreational or therapeutic purposes. There was an understandable outcry from the thousands of professionals who had been using MDMA with success in their treatment of patients with a range of mental health issues and the DEA began a series of four hearings on MDMA. After considering the arguments put forth by the therapeutic community, DEA Administrative Law Judge Francis Young decided that there were medicinal merits to the clinically supervised use of MDMA and thus ruled that MDMA should be in Schedule III which would essentially make it available for continued research and prescription use. In an unprecedented move, the Director of the DEA overruled Judge Young and on November 13, 1986, MDMA was made a Schedule I drug. Following a respite of a little over three months while Harvard professor Lester Grinspoon appealed this decision (known as “the Grinspoon window”), MDMA was made a “permanent” Schedule I drug by the DEA on March 23, 1988. Of course, this decision effectively made legitimate scientific research more difficult to conduct but it did nothing to deter the use of MDMA recreationally and the therapists determined to continue treating their patients with MDMA were driven underground and quietly risked their careers and reputations.


The previously mentioned Phase 1 studies in the 1990s demonstrated that pharmaceutically pure MDMA could be safely tolerated by healthy volunteers and this set the stage for the Multidisciplinary Association for Psychedelic Studies (MAPS) to begin lobbying the FDA for Phase 2 studies to examine the utility of MDMA-assisted psychotherapy for treating the ravages of Post-Traumatic Stress Disorder (PTSD). But there were a couple of other strange and weird events that seemed to indicate a willingness on the part of some governing bodies to want to stifle any research that was seeking to cast MDMA in a favorable light for both clinical as well as recreational purposes.


On November 9, 2000, graduate student Jose Carlos Bouso administered the first dose of MDMA in the context of psychotherapy for PTSD in Spain. The plan was to treat 29 women suffering from chronic, treatment-resistant PTSD from rape and childhood sexual abuse. However, the Madrid Anti-Drug Authority (with what many believe to be pressure from the U.S. government) lobbied the host hospital to revoke their permission to use the facility and on May 23, 2002, the study was officially terminated after only 4 women were able to receive the treatment.In what seems to be a more nefarious incident a few months later in September 2002, Johns Hopkins researcher Dr. George Ricaurte published findings that MDMA caused severe neurotoxicity in the dopamine systems of monkeys in doses that were comparable to human recreational doses. This revelation was blared all over the media and helped fuel the popular perception in the public that MDMA “ate holes in your brain.”In September 2003, Ricaurte published a full retraction in Science magazine that admitted that he and his team had actually injected the monkeys with very large doses of methamphetamine, a known dopaminergic toxin. How a renowned and highly regarded researcher at a world-class university makes an egregious mistake like that is difficult to explain.


“In an unprecedented move, the Director of the DEA overruled Judge Young and on November 13, 1986, MDMA was made a Schedule I drug. Following a respite of a little over three months while Harvard professor Lester Grinspoon appealed this decision (known as “the Grinspoon window”), MDMA was made a “permanent” Schedule I drug by the DEA on March 23, 1988.

Phase 2

Nevertheless, Rick Doblin and the good folks at MAPS continued to lobby the FDA to be able to launch Phase 2 studies examining if MDMA-assisted psychotherapy could be safe and effective in treating chronic, refractory PTSD and in April 2004, the first participant was enrolled in a double-blind study conducted by Dr. Michael Mithoefer and his wife Annie Mithoefer in Charleston, S.C. This seminal study indicated that MDMA could be safely administered to pre-screened individuals and under clinical supervision in the context of a specialized protocol designed to treat PTSD, three sessions of MDMA-assisted psychotherapy could provide substantial relief of PTSD symptoms. In the long-term follow up, the vast majority of participants from that first study were demonstrating that the positive effects of the treatments with MDMA were maintained 17 to 74 months after the MDMA-assisted sessions concluded. In all, there were six MAPS-sponsored Phase 2 studies and a total of 107 participants were treated who had been suffering from crippling PTSD for an average of 17.8 years. Two months after the conclusion of treatment, 61% of the 107 participants no longer qualified for a PTSD diagnosis and at 12-month follow-up, 86 participants were evaluated and 68% of them no longer qualified for a PTSD diagnosis. Findings indicated that MDMA increases blood pressure, heart rate and body temperature in a dose-dependent manner that returns to baseline as the drug is metabolized and can be tolerated in physically healthy individuals. Therapeutically, it was believed that MDMA was partially effective because it can reduce fear and defensiveness, enhance communication and introspection, and increase empathy and compassion which seemed to help severely traumatized people.


“Two months after the conclusion of treatment, 61% of the 107 participants no longer qualified for a PTSD diagnosis and at 12-month follow-up, 86 participants were evaluated and 68% of them no longer qualified for a PTSD diagnosis.”

Recent History, Phase 3

In November 2018, recruitment for participants in MAPS’ Phase 3 studies began and these studies are currently taking place at 14 sites in the United States, Canada and Israel and are generally following the same double-blind protocol from the Phase 2 studies. Phase 3 is the stage of the new drug treatment investigative process where a larger number of people are exposed to the treatment and it is the final stage before the FDA considers approval for MDMA-assisted psychotherapy. In May 2021, the results of the treatment of 90 participants who had been suffering with treatment-resistant PTSD for an average of 14.8 years was published in Nature Medicine. Of the patients who received three sessions of MDMA-assisted psychotherapy, 67% no longer qualified for a diagnosis of PTSD 18 weeks after baseline measurements were taken and there were also “significantly mitigated depressive symptoms.” In another observation, it was noted that a number of these participants had presented with a dissociative subtype of PTSD (which usually makes their PTSD especially difficult to treat with conventional psychotherapeutic techniques) and this did not seem to negatively affect their outcomes. On May 10. 2021, MAPS noted, “the highly statistically significant results and excellent safety record suggest that MDMA-assisted therapy will be an effective treatment for severe, chronic PTSD.”


It is interesting (and sad) to note that Big Pharma has been conspicuously absent from supporting any of the research into MDMA-assisted psychotherapy for PTSD. One of the reasons for this is that the patent for MDMA expired long ago and therefore no one company is going to be able to corner the market entirely for a long period of time. In addition, Big Pharma does not like the fact that with MDMA (and the other psychedelic medicines) one will likely take the drug only a handful of times with their doctor for the course of treatment. Unlike the SSRIs and other popular psychiatric medications, one will not have to take MDMA every day for years (or for the rest of one’s life) to derive benefit. The fact that Big Pharma does not see a way to vastly profit from MDMA seems to be reason enough for them to completely turn their backs on funding this research and should give folks another reminder of the main motivations of Big Pharma: making ungodly amounts of money for their shareholders. The funding needed to shepherd a new drug treatment through the FDA’s approval process is staggeringly high (Phase 3 studies alone are expected to cost $26 million) and all the funding for the research into MDMA-assisted psychotherapy has come from MAPS and the generosity of private donors.

If the safety and the efficacy data of the Phase 3 studies continues to be robust, it is expected that the FDA will consider MDMA-assisted psychotherapy for PTSD for approval sometime in 2023. If this occurs, this does not mean that one can swing by their local pharmacy and pick up a dose of MDMA and take it home with them. MDMA will be available only by prescription and it will be taken only in authorized clinic locations where patients can take it safely with the intention of experiencing healing trauma work in a safe and supportive environment with well-trained professionals. Another factor to consider will be the speed with which the insurance companies get on board with reimbursing providers for this treatment so that there can be wider accessibility and affordability. Training thousands of professionals in how to safely and responsibly provide this unique treatment will also need to occur.


“If the safety and the efficacy data of the Phase 3 studies continues to be robust, it is expected that the FDA will consider MDMA-assisted psychotherapy for PTSD for approval sometime in 2023.”

Conclusion

As mentioned in the beginning of this blog, MDMA is not a new compound since it was originally synthesized in 1912 and it already has a rather long and interesting history. Like many of the other psychedelic medicines, MDMA has stimulated curiosity, awe, hope, concern and fear in the fields of psychiatry, psychology and in the minds of the general public. Although there is still much work to be done to increase our understanding of these medicines, the fascinating story of MDMA warrants continuation and it is hoped that well-designed and well-controlled research studies will continue to elucidate the healing potentials of this interesting compound.

Coming Next: An examination of PTSD and why MDMA may be well-suited for its treatment .


“Like many of the other psychedelic medicines, MDMA has stimulated curiosity, awe, hope, concern and fear in the fields of psychiatry, psychology and in the minds of the general public.”

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