The Science of 3,4-methylenedioxymethamphetamine (MDMA)

Overview: MDMA, also known as ecstasy or molly, belongs to the entactogen or empathogen drug class. It induces bodily euphoria, emotional empathy, breaks down emotional barriers, and promotes prosocial behavior. It gained popularity in the 1980s but was classified as a controlled substance despite limited evidence. Recent studies highlight its therapeutic potential, especially in treating post-traumatic stress disorder. The drug's pharmacokinetics are nonlinear, influenced by the saturation of the CYP2D6 enzyme. MDMA metabolizes into various compounds with longer elimination half-lives. MDMA-assisted psychotherapy shows promise in PTSD treatment and has received breakthrough designation from the FDA. MDMA use carries risks, such as uncertain dosing, purity variations, hyperthermia, hyponatremia, and potential harm to the heart, brain, and liver. Education and harm reduction practices are essential in mitigating these risks.

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The Emergence of MDMA: From Obscurity to Promising Treatment

MDMA (3,4-methylenedioxymethamphetamine,) also called “ecstasy” or “molly”, is a popular recreational drug of the phenethylamine class.

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While MDMA is sometimes grouped together with traditional psychedelic substances like mescaline, psilocybin, LSD, and DMT, some argue that it belongs to a distinct drug class known as "entactogens" or “empathogens.” Entactogens, including MDMA, are known for their ability to induce a sense of bodily euphoria, foster emotional empathy, facilitate the breakdown of emotional barriers, and promote prosocial behavior.

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Since its synthesis in 1912, MDMA remained relatively obscure until 1976 when renowned chemist Alexander "Sasha" Shulgin, widely recognized as the "Godfather of Ecstasy," developed a new synthesis method for the drug in his private laboratory in Lafayette, California. Shulgin, known for his extensive exploration of psychedelic compounds, personally tested MDMA and was highly impressed by its unique effects. He introduced it to his friend and psychologist, Dr. Leo Zeff, who successfully incorporated MDMA into psychotherapy and shared its therapeutic qualities with other therapists.

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During the 1980s, MDMA gained increasing popularity. As its production increased, MDMA started appearing more frequently in illicit labs and street samples, which ultimately led to its classification as a controlled substance in 1985, despite the lack of substantial evidence supporting the decision.

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Recent studies have demonstrated that MDMA also has profound therapeutic effects, particularly in the treatment of post-traumatic stress disorder. 

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The Origins of MDMA: A Historical Perspective on its Synthesis

In 1912, a chemist named Dr. Anton Köllisch, employed by the pharmaceutical company Merck in Germany, synthesized MDMA which was initially referred to as 'methylsafrylamin'. Contrary to popular belief, Merck's intention was not to develop MDMA as an appetite suppressant, but rather to create and patent new substances with hemostatic properties, which aid in blood clotting.

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In an effort to work around a competitor's existing patent for synthesizing a natural clotting agent called 'Hydrastinin', which is derived from the herb Hydrastis canadensis L. (goldenseal), Merck, a pharmaceutical company, turned to their chief chemists, Dr. Walter Beckh and Dr. Otto Wolfes. They asked Dr. Anton Köllisch to create a modified version of hydrastinin called methylhydrastinin. This newly synthesized compound showed comparable effectiveness to other hemostatics and was subjected to human testing in a Berlin hospital, where it exhibited promising results.

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MDMA was mentioned as a chemical intermediate in the patent documentation, along with some of its chemical properties such as color and boiling point. However, there was no apparent significant interest among Merck chemists in MDMA at that time, apart from its relevance as an intermediate compound in the production of other substances.

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Understanding MDMA's Impact on Neurotransmitters: Serotonin, Norepinephrine, and Dopamine

The pharmacologic effects of MDMA were first studied in the late 1920s by chemist Dr. Max Oberlin, who was primarily interested in adrenaline. At that time, MDMA was known as 'Safryl-Methyl-Amin.' Despite having to halt his research due to rising material costs, Oberlin successfully provided the oldest known structural formula of MDMA. He encouraged others to stay informed about further developments in this area of research.

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After a few decades, interest in Safryl-Methyl-Amin was reignited by several chemists in the 1950s. Dr. Albert van Schoor conducted a toxicological experiment with flies in 1952, and stimulant chemist Dr. Wolfgang Fruhstorfer briefly considered its potential use in aviation medicine.

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Further significant investigations were initiated by Alexander Shulgin in 1978, who explored both the subjective and pharmacologic effects of MDMA. Shulgin described it as evoking an easily controlled altered state of consciousness with emotional and sensual qualities.

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Pharmacologically, MDMA stimulates the release of three important neurotransmitters: serotonin, norepinephrine, and dopamine.

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In a pivotal paper published in 1986, chemist David Nichols demonstrated that MDMA binds to the serotonin transporter (SERT), preventing the reuptake of serotonin from the synaptic cleft back into the presynaptic neuron. This allows serotonin to remain in the synapse, continuing to produce chemical signals and stimulating receptors in various brain regions such as the striatum, hippocampus, and cortex.

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The release of norepinephrine and dopamine follows a similar mechanism, although MDMA's inhibition of their reuptake is less potent. Notably, MDMA leads to a greater release of norepinephrine than dopamine. Consequently, the inhibition of norepinephrine and dopamine reuptake is less significant in terms of MDMA's subjective effects. However, the release of norepinephrine likely contributes to the drug's stimulating and physical effects.

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An intriguing study conducted in 2000 revealed that MDMA enhances the release of acetylcholine in the rat brain through the activation of histamine H1 receptors. Acetylcholine is a neurotransmitter involved in muscle contraction, alertness, learning, and memory. Subsequent research in rodents confirmed that MDMA increases the concentration of acetylcholine in specific brain regions, such as the prefrontal cortex and hippocampus.

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The exact relevance of acetylcholine release in relation to the effects of MDMA is yet to be established.

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How Long Does MDMA Stay in your System?

In humans, MDMA concentration decreases to half of its starting dose after approximately 8–9 hours. This is known as MDMA’s elimination half-life.

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MDMA can generally be detected:

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• In blood for up to 2 days
• In saliva for up to 2 days
• In urine for up to 4 days
• In hair for up to 90 days

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The detection window, however, depends on several factors, including dose, how it is administered, how frequently it is used, the user’s physical characteristics, age, health conditions, activity level, and the presence of adulterants.

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For example, snorted MDMA has a shorter detection window because it more rapidly enters and exits the bloodstream than orally ingested pills. Similarly, chronic use of MDMA, or ingestion of atypically large doses, is likely to widen the detection window. 

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How is MDMA Metabolized? 

The pharmacokinetics of common doses of MDMA may be nonlinear. That is, studies have shown that variations in the length of time from absorption to excretion may not be related to the dose ingested. 

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The non-linear behavior of MDMA in the body is thought to be influenced by the saturation of a key enzyme called CYP2D6, which plays a major role in metabolizing MDMA. Additionally, the temporary alterations in the structure of this enzyme caused by its interaction with MDMA as a substrate may also contribute to these effects.

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Metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA). Both MDMA and MDA are then further O-demethylenated to 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), and both HHMA and HHA are subsequently O-methylated mainly to 4-hydroxy-3-methoxy-methamphetamine (HMMA) and 4-hydroxy-3-methoxy-amphetamine (HMA).

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The elimination half-life of these MDMA metabolites is considerably longer than MDMA. 

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MDMA-Assisted Psychotherapy: A Breakthrough for PTSD Treatment

In 2010, the Multidisciplinary Association for Psychedelic Studies (MAPS) conducted the first randomized-controlled pilot study investigating the efficacy of MDMA as a therapeutic aid in the treatment of PTSD.

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In this trial, 12 patients with chronic treatment-resistant PTSD were given MDMA on two occasions in conjunction with supportive psychotherapy. At the end of the study, 83% of participants no longer met the criteria for a PTSD diagnosis. 

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A long-term follow-up (17-74 months after the participants' last MDMA session) demonstrated that the majority of participants maintained “statistically and clinically significant gains in symptom relief,” with no participants reporting any harm from the study. 

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Since then, six phase 2 clinical trials have produced similar results, with over two-thirds of all study participants no longer meeting diagnostic criteria for PTSD after receiving MDMA-assisted psychotherapy. These results prompted the US Food and Drug Administration (FDA) to grant “Breakthrough Therapy” designation for MDMA-assisted psychotherapy for the treatment of PTSD.

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The results of MAPS first phase III trial (MAPP1) published in 2021 were equally compelling — 67% of participants in the MDMA-assisted psychotherapy group no longer had PTSD, with 88% experiencing clinically significant reductions in symptoms. MAPS conducted a second Phase 3 trial called MAPP2 to study the use of MDMA-assisted therapy for people with PTSD. MAPS has reported that the results of MAPP2 align with the findings of the first trial, showing that no serious adverse events were observed among the participants.

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The complete data from MAPP2, expected to be published in a scientific journal later this year, will support an application to the FDA for approval of this new treatment.

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Researchers are now evaluating the therapeutic potential of MDMA-assisted psychotherapy for the treatment of alcohol-use disorder, eating disorders, anxiety related to life-threatening illness, and social anxiety in autistic adults. 

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Exploring the Risks of MDMA Use in Recreational Settings

When compared to other recreational drugs, MDMA is commonly regarded as relatively safe, with research indicating it has a lower potential for harm among mind-altering substances.

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That said, recreational use of MDMA can pose risks to health. These risks include issues like uncertain and inconsistent dosing, variations in purity, the possibility of adulteration with other substances, increased body temperature (hyperthermia), and a potentially dangerous condition called hyponatremia, which is low sodium levels in the blood.

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Furthermore, prolonged use of MDMA can lead to harmful effects on the heart (cardiotoxicity), the brain (neurotoxicity), and the liver (hepatotoxicity). Additionally, MDMA use is often followed by an unpleasant comedown, which refers to a period of negative aftereffects experienced following MDMA use. MDMA comedowns are primarily caused by the depletion of serotonin in the brain and other factors such as exhaustion and dehydration.

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However, it's important to note that by spreading reliable information based on scientific research and implementing harm reduction strategies, it is possible to significantly reduce or even prevent these negative health effects associated with MDMA use.

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Through education and the implementation of harm reduction practices, individuals can make well-informed decisions and take proactive measures to safeguard their well-being when engaging in recreational MDMA consumption.

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In conclusion, MDMA, the popular recreational drug, has a fascinating history and unique effects. While it shares similarities with traditional psychedelics, it belongs to the entactogen or empathogen drug class, known for inducing euphoria, empathy, and prosocial behavior. Recent studies have shown its therapeutic potential in treating PTSD. However, recreational use comes with risks, and education and harm reduction strategies are crucial.

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By understanding the science behind MDMA and promoting responsible use, we can navigate its complexities and prioritize well-being.