An in-depth look at the origin and fascinating underground history of a recreational drug turned therapy aid.
MDMA (3,4-methylenedioxymethamphetamine), the drug commonly referred to as “Ecstasy” or “Molly”, has been one of the most popular recreational psychoactive drugs since the mid-1980s. The term “Molly” typically refers to powdered MDMA, whereas “ecstasy” refers to MDMA in pill form, however, both words are used interchangeably.
MDMA, then called ‘Methylsafrylamin’, was synthesized by Merck chemist Dr. Anton Köllisch way back in 1912, who was trying to develop pathways leading to hemostatic substances, despite the widely reported false claim that Merck planned to market MDMA as an ‘anorectic drug’ or ‘appetite suppressor’.
The first mechanistic studies investigating the pharmacology of MDMA (which at this stage was called ‘Safryl-Methyl-Amin’) were conducted decades later by Merck chemist Max Oberlin, who despite being forced to halt research due to material price increases, urged interested spectators to “keep an eye on this field.”
In 1970, MDMA was detected in tablets for the very first time in the family-owned business littered streets of Chicago. Not long afterward the pioneering and fearless chemist Alexander “Sasha” Shulgin was leading the first studies exploring the pharmacological and subjective effects of Molly in humans.
Increasingly often through the 1970s, MDMA was detected in street samples and clandestine laboratories. Molly began being distributed on a large scale in the 1980s, before eventually becoming a schedule I controlled substance in the U.S. in 1985.
According to a carefully researched review detailing MDMA’s history as an underground drug in the U.S., Molly’s more psychedelic chemical relation, Sally (MDA), was the first to gain popularity on the streets. It wasn’t until the scheduling of MDA in 1970 that demand for a molecularly-altered legal alternative began to grow.
Enter stage left, via new, relatively straightforward chemical synthesis, Molly.
Demand for the shorter-acting, benignly euphoric Molly quickly surpassed that of the significantly more intense, more psychedelic MDA. In 1981, an anonymous distributor of Molly revealed in the quirky underground magazine ‘WET’, that distribution on a large scale started in 1976.
In 1977, Alexander Shulgin gave some MDMA to Leo Zeff, a psychologist and psychotherapist, who, by the late 1960s, had pioneered the use of psychedelics as a psychotherapeutic adjunct. Zeff was so impressed by MDMA that he postponed his retirement to educate hundreds of psychotherapists on the drug’s ability to break down emotional barriers. He would later coin the drug “penicillin for the soul”.
By the end of the 1970s, approximately 10,000 MDMA pills were being distributed across the U.S. per year. By 1983, the number had risen to 30,000 pills per month. Then, in 1984, when self-proclaimed MDMA “missionary” Michael Clegg began openly selling them, it became impossible for the growing number of therapists (reportedly up to 4000), chemists, and recreational users to maintain stealth mode.
The former seminal student turned Molly proselytizer was reportedly distributing 500,000 pills a month to Dallas, Texas.
Escalating use led to intervention by U.S. senators who urged the Drug Enforcement Agency (DEA) to schedule it for endangering the youth, which they attempted to do without holding legally required public hearings on the matter. The DEA eventually did initiate the proper procedures necessary for its ban, hiring Judge Francis Young to hear the case.
After several long, drawn-out hearings, Judge Francis rejected the DEA’s arguments, much to their annoyance, declaring that MDMA was safe when used under medical supervision, did not have a high potential for abuse, and had legitimate medical use. Judge Francis argued that it would be illegal to place MDMA higher than schedule III, a category that would have allowed psychotherapists to continue using it.
Seemingly unswayed by Judge Francis’ findings, which were based on science and the law, DEA administrator John Lawn assigned MDMA to Schedule I on 1 July 1985.
MDMA is a synthetic drug that falls under the phenethylamine class. It is structurally similar to amphetamine and possesses both stimulant and psychedelic-like effects.
However, MDMA differs in important ways both pharmacologically and phenomenologically from classic psychedelics and amphetamines. As a consequence, it is considered a member of a relatively new class of psychoactive drugs called “empathogens” or “entactogens”, labeled so because of their ability to increase empathy and produce emotional communion.
Pharmacologically, MDMA stimulates the release of norepinephrine, serotonin, and dopamine and blocks their reuptake, resulting in increased concentration levels of these neurotransmitters in the space between the neurons at a synapse. Serotonin (mood elevation) and norepinephrine (physical effects) are released in greater amounts than dopamine.
MDMA has been shown to decrease activity in the limbic system, a set of brain structures involved in emotional responses, and reduce communication between the medial temporal lobe and medial prefrontal cortex. These connectivity patterns are contrary to those typically seen in patients who suffer from anxiety.
MDMA also increases communication between the amygdala, where we process fear, and the hippocampus, an area involved in the formation, organization, and storage of memories. These effects may be central to MDMA’s impressive efficacy as a therapeutic aid in the treatment of post-traumatic stress disorder (PTSD), potentially enabling patients to fearlessly access heretofore inaccessible memories of traumatic life events.
A group of neuroscientists at Johns Hopkins University recently demonstrated that MDMA releases oxytocin, a.k.a the “love hormone”, and stimulates oxytocin-mediated-plasticity. Oxytocin’s ability to promote empathy, trust and the processing of bonding cues likely plays a pivotal role in the development of a solid therapeutic rapport between therapist and patient.
The acute subject effects of Molly typically begin 30–60 minutes after consumption. After a 15-30 minute “come up” period, the drug’s peak effects set in, lasting for 90–150 minutes.
There is no reliable way of predicting what an MDMA experience will be like, however, ensuring that the drug is used in the right circumstances is likely to facilitate a positive experience. Preparing properly, being in a good mood, and being in a safe and comfortable physical environment (“set and setting”) significantly reduces the probability of experiencing negative effects.
The effects of set and setting are rightly emphasized when discussing the use of mind-altering substances, but equally important, despite often being neglected, is the dose. Clinical trial participants are typically given between 80 and 150mg of MDMA, before receiving a top-up dose 90-150 minutes later.
An elegant 2006 review described the most commonly reported acute subjective effects of MDMA which are divided into the following 3 categories.
Emotional effects of Molly include:
Sensory effects of Molly include:
Somatic/physical effects of Molly include:
People may also experience stomach/intestinal pain, inability to urinate, shakiness, nausea, headache, or dizziness, however, these are quite rare.
Also, it is important to note that the MDMA that people have access to today, particularly in pill form, is mostly nominal and almost always adulterated with compounds that increase morbidity and mortality. A recent study found that 40% of 529 Molly samples contained no MDMA at all.
Widely considered to be the most dangerous Molly adulterants are paramethoxyamphetamine (PMA) and paramethoxymethamphetamine (PMMA), two phenethylamine derivatives which have led to cases of fatal overdose.
Molly is considered relatively safe, especially when compared to other more socially accepted recreational drugs like tobacco and alcohol. Generally speaking, Molly doesn't cause any serious or life-threatening effects by itself, however, there are some potentially dangerous health risks associated with its use that, thankfully, can be mitigated by employing harm reduction practices.
MDMA interferes with the body’s ability to effectively regulate temperature, which in conjunction with continuous physical activity (e.g. dancing) and prolonged exposure to warm and stuffy environments can put one’s body at risk of overheating (hyperthermia). This is the leading cause of MDMA-related deaths, which are quite low compared to other recreational drugs.
To protect against the risk of overheating, users are advised to take regular rest breaks from physical activity and ensure they are sufficiently hydrated. Users must be careful not to over-hydrate however, as MDMA causes water retention and has been associated with death from low blood sodium levels caused by water intoxication (hyponatremia).
To prevent this from happening, users are advised to pay very close attention to the amount of water they consume, not drinking too much or too little. Users are also advised against combining MDMA with diuretics like alcohol which may put them at increased risk of hyponatremia.
The neurotoxicity of MDMA has been the subject of much debate in the past couple of decades. Although the general scientific consensus is that MDMA is safe when taken responsibly, continuous use, especially at high doses, is most likely neurotoxic in one form or another. As a consequence, long-term high dose use is highly discouraged.
It remains unclear how much of this risk applies to the typical recreational user who consumes MDMA sparingly. In any case, users are advised to wait for one to three months between each use to allow serotonin levels to return to baseline and attenuate the risk of neurotoxicity.
Due to MDMA’s high affinity for 5-HT2B serotonin receptors, long-term heavy use can lead to the development of valvulopathy, a disease affecting the proper functioning of one or more heart valves.
A 2007 study investigated the occurrence of valvular heart disease in 33 people who were regular consumers or had regularly consumed MDMA. 28% of participants were found to have pathologic echocardiographic results according to the FDA criteria, compared to 0% of the control group.
Important to mention, however, is that those found to have developed valvular heart disease were consuming 3 doses of MDMA per week for at least 6 years. The results of this study indicate that the development and sincerity of MDMA-induced valvulopathy may be dependent on high-dose, cumulative use.
In 2003, The US Food and Drug Administration (FDA) gave approval for human testing of MDMA for the treatment of PTSD to the Multidisciplinary Association for Psychedelic Studies (MAPS). After years of carefully conducted clinical trials produced remarkably positive outcomes, the FDA granted Breakthrough Therapy Designation for MDMA-assisted psychotherapy for PTSD in 2017, and agreed on special protocol assessment for phase III trials.
The results of MAPS first phase III trial were published last year, and the findings were striking. More than two thirds of participants who received MDMA-assisted psychotherapy no longer met diagnostic criteria for PTSD just two months post treatment.
MAPS’ final phase III trial — the last stage of studying a drug before it can become a legal medicine —is now fully enrolled, and with positive results likely, it is expected that MDMA-assisted psychotherapy will become a legal medicine by the end of 2023.
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