Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine

This review (2018) examines the synthesis of MDMA as well as its pharmacology, metabolism, adverse effects, and potential use in medicine.

Abstract

“Better known as “ecstasy”, 3,4-methylenedioxymethamphetamine (MDMA) is a small molecule that has played a prominent role in defining the ethos of today’s teenagers and young adults, much like lysergic acid diethylamide (LSD) did in the 1960s. Though MDMA possesses structural similarities to compounds like amphetamine and mescaline, it produces subjective effects that are unlike any of the classical psychostimulants or hallucinogens and is one of the few compounds capable of reliably producing prosocial behavioral states. As a result, MDMA has captured the attention of recreational users, the media, artists, psychiatrists, and neuropharmacologists alike. Here, we detail the synthesis of MDMA as well as its pharmacology, metabolism, adverse effects, and potential use in medicine. Finally, we discuss its history and why it is perhaps the most important compound for the future of psychedelic science—having the potential to either facilitate new psychedelic research initiatives, or to usher in a second Dark Age for the field.“

Authors: Lee E. Dunlap, Anne M. Andrews & David E. Olson

Summary

■ INTRODUCTION

The psychoactive compound 3,4-methylenedioxymethamphetamine (MDMA) is related to amphetamine and contains the phenethylamine core structure common to this class of psychostimulants. MDMA produces effects reminiscent of both psychostimulants and hallucinogens, but its interoceptive effects are distinct from either of these well-known classes of psychoactive compounds.

In rodent drug discrimination studies, MDMA only partially substitutes for S-(+)-amphetamine, the ergoline hallucinogen lysergic acid diethylamide (LSD), and the phenethylamine hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM).

MDMA produces subjective effects that last for several hours, including context-dependent feelings of closeness with others, reduced social inhibition, positive mood, and increased alertness. The visual hallucinations induced by MDMA are not well-formed, and instead are often described as flashes of light in the peripheral visual field.

MDMA and related molecules have been classified as a separate family of psychoactive compounds, distinct from both stimulants and hallucinogens, due to their unique ability to induce empathy and feelings of connectedness. These drugs are often used interchangeably with LSD.

MDMA and more potent 5-HT2A agonists like psilocybin should be classified as psychedelics, and can be subdivided into classical hallucinogens and entactogens.

MDMA’s stimulant and prosocial effects led to its widespread recreational use and cemented its place in rave (dance party) culture. Females are more likely to use MDMA than males.

MDMA is a controlled substance in the United States and many other countries, making its production and sale illegal. However, due to its popularity, MDMA may possess potential as a neurochemical tool for elucidating the mechanisms of social behaviors and the neural underpinnings of empathy and social bonding.

MDMA is synthesized from safrole or piperonal. It can be made from either compound by hydrobromination, displacement of the bromide with methylamine, or by Wacker oxidation followed by reductive amination of 12 with methylamine and sodium cyanoborohydride.

MDMA can be synthesized from piperonal (13) by a Henry reaction between 13 and nitroethane. MDMA can then be purified by vacuum distillation of the freebase and/or crystallization of the hydrochloride salt.

The first asymmetric synthesis of MDMA was reported by Nichols and co-workers. The use of removable chiral auxiliaries has proven to be more effective than traditional resolution via selective crystallization of diastereomeric salt forms.

The chiral pool has been exploited to produce enantiopure MDMA. Using a method developed by Nenajdenko and co-workers, (S)-alaninol can be protected and converted to the aziridine 24, and then (S)-MDMA can be produced.

MDMA is a potent inhibitor of monoamine transporters, and a potent releaser of these neurochemicals, and accomplishes this via several mechanisms, including binding to and inhibiting the serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET).

MDMA reverses the flux of monoamines through their transporters, expelling intracellular serotonin, dopamine, and norepinephrine into the extracellular space. This is achieved by directly binding to vesicular amine transporters (VMAT) and passively diffusing across vesicular membranes to collapse the pH gradient established by VMAT.

MDMA has been shown to release DA and 5-HT in the striatum and frontal cortex of rats. However, some studies suggest that the release of monoamines might be due to inhibition of monoamine reuptake.

MDMA has been shown to bind with modest affinities to a variety of neuroreceptors, and likely induces most of its effects indirectly by modulating monoamine levels. MDMA binds to 5-HT2B receptors with submicromolar affinity, though the role of this receptor in the effects of MDMA is unclear. MDMA is unable to displace radiolabeled monoamine transporter inhibitors in functional assays, which is consistent with its proposed role as a monoamine releaser.

MDMA activates the trace-amine associated receptor (TAAR1), which is a key target mediating the effects of MDMA on extracellular monoamine levels. It is unclear if TAAR1 plays any role in the effects of MDMA in humans.

MDMA binds to both sigma-1 and sigma-2 receptors, and treatment with BD1063, a selective sigma-1 antagonist, blocks the effects of MDMA on rodent locomotion.

MDMA leads to increased levels of several hormones, including cortisol, prolactin, dehydroepiandrosterone (DHEA), vasopressin, and oxytocin. The effects of MDMA on oxytocin levels are often invoked to explain the drug’s prosocial effects, but the correlation between oxytocin levels and prosocial feelings is currently controversial.

MDMA produces behavioral effects in rodents consistent with serotonin syndrome, including flat body posture, hind limb abduction, and forepaw treading. These behavioral effects are enhanced following repeated administration of MDMA, demonstrating that MDMA is capable of producing behavioral sensitization.

In rodent models of anxiety, MDMA produces complex effects. At high acute and subchronic doses, MDMA produces anxiolytic effects.

MDMA has been shown to decrease aggressive behaviors in rats and increase the time spent engaging in social behaviors such as sniffing, following, crawling under, crawling over, mutual grooming, and adjacent lying.

Systemic MDMA increases plasma levels of oxytocin in rats and activates oxytocinergic neurons in the hypothalamus, as measured by Fos immunohistochemistry. A 5-HT1A antagonist and a 5-HT1A agonist prevented MDMA-induced adjacent lying, but C25,116, a systemically administered non-peptidic antagonist of oxytocin receptors, could not.

MDMA has been shown to promote fear extinction learning in mice, which is a mechanistic explanation for its therapeutic efficacy in patients suffering from treatment-resistant PTSD.

MDMA causes changes in gene expression and protein levels associated with neural plasticity. Acute and chronic treatment with MDMA causes increases in BDNF transcript levels in several cortical regions and decreases in BDNF expression in the hippocampus.

Most studies assessing the psychoplastogenic effects of MDMA have observed a reduction in dendritic branching and/or dendritic spine numbers. However, more modest doses of MDMA administered over short periods of time would likely yield increases in dendritic branching and spine density.

Recent genetic findings suggest that several cytochrome P450s are involved in the demethylation of MDMA, including CYP2C19, CYP2B6, and CYP1A2. Decreased CYP2C19 function is associated with greater cardiovascular responses and faster onset times.

MDMA has a half-life of approximately 89 h and yields plasma Cmax and tmax values of 222.5 ng/mL and 2.3 h, respectively, but exhibits nonlinear pharmacokinetics in humans and squirrel monkeys.

MDMA produces a number of adverse effects, including trismus, tachycardia, bruxism, dry mouth, palpitations, diaphoresis, and insomnia. The more severe side-effects are potentially exacerbated by the intense exercise and hot environment characteristic of raves.

MDMA can cause heart problems, including arrhythmias, myocarditis, and myocardial infarction. Valvular heart disease can also occur after long-term use of MDMA.

MDMA does seem to have reinforcing properties, but these are significantly weaker than those of cocaine. It is self-administered by a variety of species, and its pleasurable effects diminish with repeated use, but its side effects increase.

MDMA’s potential to induce neurotoxicity is controversial, as some “MDMA” sold on the street does not contain any MDMA at all, while other batches of illegally produced “MDMA” are adulterated. Additionally, consuming MDMA as a part of a drug mixture can be extremely dangerous due to drugdrug interactions.

People who consume MDMA regularly and in high doses perform poorly on various tests related to attention, learning, and memory, and are more likely to be afflicted with mental illnesses including depression, psychotic disorders, eating disorders, and anxiety disorders.

While retrospective studies on MDMA use are important, they are often contaminated with other drugs of abuse and neurotoxic compounds, and are often consumed at crowded dance parties. Furthermore, it is unclear if the cognitive impairments and neuropsychiatric disorders observed in groups who have used MDMA reflect a cause or consequence of MDMA use.

Researchers have used model systems in the laboratory to investigate MDMA neurotoxicity. However, the relevance of these models to human neurotoxicity is often questioned, and the concentration of MDMA required to produce substantial neurotoxic effects in these studies is >200 m.

Studies using cultured neurons and in vivo animal models have suggested that MDMA has neurotoxic effects, but the relevance of these models to human neurotoxicity is highly debated.

In mice, MDMA tends to produce dopaminergic, but not serotonergic, neurotoxicity, whereas in rats, the opposite seems to be true. Additionally, large doses of MDMA produce reductions in levels of 5-HT, 5-HIAA, and SERT, which can be prevented by blocking SERT with fluoxetine. MDMA doses used in animals to induce neurotoxicity are much higher than those often used by humans. However, it has been argued that species differences in metabolism and neurotoxicity may be responsible for the neurotoxic effects of MDMA.

Using model systems that more closely recapitulate the pharmacokinetics of MDMA in humans may be more useful. Multiple subcutaneous doses produce greater neurotoxic effects than a single oral dose, and a single, modest (5 mg/kg), oral dose still produces serotonin depletion in the thalamus and hypothalamus 2 weeks after administration.

MDMA may cause neurotoxicity in high doses, multiple doses, polydrug use, high temperatures, prolonged physical activity, dehydration, and other factors. However, in controlled studies in the clinic using low doses to assist psychotherapy, MDMA may be safe and well tolerated.

In recent years, there has been renewed interest in using psychedelic compounds like MDMA to treat neuropsychiatric disorders. However, most of the studies conducted during this period yielded only anecdotal reports, and no placebo-controlled clinical trials were conducted. Patients are screened for medical conditions, receive training sessions, and are assessed at baseline using the Clinician-Administered PTSD Scale (CAPS). They then receive MDMA treatment in a controlled environment with nurturing physical contact whenever necessary to help ease tension or distress.

Oehen and co-workers established an effective dosing paradigm utilizing low dose MDMA as an active placebo. The use of an active placebo was an important part of the experimental design implemented by Oehen and co-workers.

MDMA is most commonly used as an adjunct to psychotherapy for treating anxiety disorders. Recent clinical work has shown that MDMA can produce beneficial effects in treatment-resistant PTSD patients when it is paired with psychotherapy, and the effects are long-lasting.

Recent clinical work has revealed that MDMA impacts the processing of emotionally salient information. This drug improves the performance of people during the Reading the Mind in the Eyes Test, and increases the rating of positive and negative memories, respectively, while under the influence of MDMA.

MDMA may hold some promise for treating substance use disorders. It has been shown to decrease response rates during a cocaine self-administration paradigm in squirrel monkeys, and may offer a distinct advantage over the classical hallucinogens.

Racemic MDMA is used recreationally and in clinical trials, but there are distinct differences between the R- and S-enantiomers of MDMA.

MDMA is a monoamine releasing and reuptake inhibiting compound. Its S-enantiomer is more potent, but its R-enantiomer is more potent direct binder of 5-HT2A receptors, which may explain why it has a greater propensity for causing perceptual disturbances.

The enantiomers of MDMA have differential effects on hormone levels, with S-(+)-MDMA being a more potent inducer of oxytocin release than the racemate, while R-()-MDMA having no effect.

In squirrel monkeys, both enantiomers of MDMA increased social interaction and facilitated fear extinction learning. In mice, the R-enantiomer did not increase locomotor activity.

The primary concern for using MDMA in the clinic is its potential neurotoxicity. However, a recent study found that the R-enantiomer of MDMA lacks many of the negative effects associated with the racemate, while still maintaining the ability to promote social interaction and to facilitate fear extinction learning.

The researchers suggest that the term “MDMA” be replaced by the terms “armdma”, “esmdma”, and “racmdma” to avoid negative connotations. This will eliminate any potential stigma associated with using a perceived “party-drug” as a medicine.

Urban legend, rumor, and myth have clouded the true history of MDMA. It was originally synthesized in 1912 by Merck to sidestep a patent on hydrastinine, but its biological activity was not assessed until 15 years after its initial synthesis.

The US military began using mescaline-like compounds, including MDMA, as part of pharmacologically assisted interrogation programs in the 1950s. One patient died after being administered several compounds, and the military later conducted pharmacokinetic and safety studies on mice, rats, guinea pigs, dogs, and monkeys.

MDMA was first reported in the peer-reviewed literature in 1960. Alexander Shulgin tested MDMA on himself in 1976 and distributed it to friends and psychotherapists in northern California, who began using MDMA to facilitate psychotherapy.

During the period from 1978 to 1985, thousands of patients were treated with MDMA, but the initial studies did not adhere to the same rigorous standards that we demand of clinical trials today. Furthermore, MDMA was widely used in social situations, leading to its legalization in 1988.

A 2002 paper published in Science suggested that MDMA might put users at risk for developing Parkinson’s disease. However, the authors could not reproduce their results and retracted their paper a year later.

The Ricaurte study dealt a serious blow to the credibility of MDMA as a safe therapeutic, but multiple clinical trials have shown that MDMA can be administered safely under these conditions.

MDMA-assisted psychotherapy for alleviating treatment-resistant PTSD was published in 2011 and was granted “breakthrough therapy” status by the FDA in 2017. If the results of these trials warrant approval by the FDA, MDMA will be removed from the Schedule I list.

Since 2012, there has been an upswing in the number of songs and pop culture references to “molly,” a trend that parallels that seen for LSD in the 1960s and 1970s. If public discourse on MDMA takes a similar course to that of LSD, we may be doomed to repeat the mistakes of the past.