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Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine (MDMA)

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Official websites use. Share sensitive information only on official, secure websites. All authors edited the manuscript. 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. Keywords: 3,4-methylenedioxymethamphetamine; MDMA; psychedelic; entactogen; empathogen. As such, it is not surprising that MDMA produces effects reminiscent of both psychostimulants and hallucinogens. However, the interoceptive effects of MDMA i. Structural relationships between MDMA and other psychoactive compounds. The common phenethylamine core is highlighted in red. Compounds are classified as psychostimulants, hallucinogens, or entactogens based on the behavioral responses they produce in experimental animals and their subjective effects in humans. In humans, 75— mg of MDMA produces subjective effects that last for several hours. We will use the latter term as it more adequately captures the unique ability of these drugs to promote introspective states—a property that has been proposed to be useful in the context of psychotherapy vide infra. Though the subjective effects of MDMA appear to be unique compared to those of LSD, both compounds tend to increase openness, promote trust, and enhance emotional empathy. Using this classification, psychedelics broadly defined can be subdivided into classical hallucinogens e. The prosocial and stimulant effects of MDMA led to its widespread recreational use and cemented its place in rave dance party culture. Despite its popularity, MDMA is a controlled substance in the United States and many other countries making its production and sale illegal. The U. Schedule I drugs are those deemed to have high abuse potential, do not have an accepted medical use, and lack accepted safety for use under medical supervision. Unfortunately, the legal, financial, and political hurdles that accompany Schedule I classification significantly hinder scientific research into the effects of MDMA. As it is one of the few compounds known to reliably produce a prosocial state, MDMA may possess potential as a neurochemical tool for elucidating the mechanisms of social behaviors and the neural underpinnings of empathy and social bonding. Despite its relatively simple structure, MDMA elicits robust behavioral responses by binding with high affinity to a number of neuroreceptors and transporters. Below, we discuss the synthesis of MDMA and its pharmacology, metabolism, and adverse effects. Additionally, we review the prosocial and psychoplastogenic plasticity-promoting properties of MDMA, the differences between its enantiomers, and its potential use in medicine. Finally, we provide brief historical context for the development of MDMA and conclude by emphasizing the important role that MDMA is expected to play in determining the trajectory of future psychedelic research. Racemic MDMA—the form used recreationally and in clinical trials—is typically synthesized from safrole 10 or piperonal Displacement of the bromide with methylamine produces MDMA. The synthesis of MDMA from piperonal 13 is also common, and begins with a Henry reaction between 13 and nitroethane. The key nitrostyrene intermediate formed can then be partially reduced and hydrolyzed to produce ketone 12 , or fully reduced using lithium aluminum hydride to afford 3,4-methylenedioxyamphetamine MDA, While the racemate is the most commonly administered form of MDMA, recent research suggests that there are distinct differences in the pharmacology of the two enantiomers. Hence, the development of efficient asymmetric strategies for producing enantiopure MDMA is incredibly important. Traditional resolution via selective crystallization of diastereomeric salt forms has not proven the most effective route for synthesizing MDMA in high enantiomeric excess. The use of Raney nickel at 50 psi appears to be crucial for the selectivity of this reaction. In our hands, Raney nickel catalyzed hydrogenation did not proceed under atmospheric conditions, and the use of hydride reducing agents such as NaBH 3 CN yielded an inseparable mixture of diastereomers unpublished results. Synthetic strategies used to synthesize enantiopure MDMA. The chiral pool has also been exploited to produce enantiopure MDMA. Using a method developed by Nenajdenko and co-workers, 58 S -alaninol 23 can be protected and converted to the aziridine The most well characterized effect of MDMA is its ability to increase brain levels of monoamines such as serotonin, dopamine, and norepinephrine, which is accomplished via complex mechanisms. Effects of MDMA on monoamine reuptake using synaptosomes prepared from rat brains. In addition to being a monoamine uptake inhibitor, MDMA is a potent releaser of these neurochemicals, and again, MDMA accomplishes this via several mechanisms. At the cellular membrane, MDMA reverses the flux of monoamines through their transporters, expelling intracellular serotonin, dopamine, and norepinephrine into the extracellular space. The releasing effects of MDMA are greater for serotonin and norepinephrine, and slightly weaker for dopamine Tables 2 and 3. Effects of MDMA on monoamine release using synaptosomes prepared from rat brains. While much of the work elucidating the monoamine-releasing properties of MDMA have employed in vitro and ex vivo models, recently, the DA and 5-HT releasing effects of MDMA have been observed in vivo using microdialysis in the striatum and frontal cortex of rats. In addition to directly interacting with monoamine transporters, MDMA has been shown to bind with modest affinities to a variety of neuroreceptors including adrenergic, serotonergic, histaminergic, and muscarinic receptors. The low micromolar affinities observed support the notion that MDMA induces most of its effects indirectly by modulating monoamine levels. Therefore, it is possible that the binding affinity of MDMA for many receptors has been underestimated. For example, it is now well established that MDMA binds directly to 5-HT2A receptors, albeit with micromolar affinity, though binding assays performed with 3 H-ketanserin do not capture this interaction. Furthermore, MDMA is unable to displace radiolabeled monoamine transporter inhibitors despite exhibiting nM potency in functional assays Tables 1 — 4 , which is consistent with its proposed role as a monoamine releaser rather than a competitive uptake inhibitor. However, to the best of our knowledge, this hypothesis has not been directly tested. Radioligand binding studies have shown that MDMA binds to both sigma-1 and sigma-2 receptors with K i values in the low micromolar range, which are comparable to the affinities of MDMA for monoamine transporters. Administration of MDMA to humans leads to robust increases in plasma levels of cortisol, prolactin, dehydroepiandrosterone DHEA , vasopressin, and oxytocin. Dumont and co-workers were the first to demonstrate in a controlled laboratory setting that MDMA increases oxytocin levels. While numerous other studies have replicated the finding that MDMA elevates oxytocin levels, they have all failed to reproduce a correlation between oxytocin levels and prosocial feelings, calling into question the relevance of this hormone for the prosocial effects of MDMA. Like other serotonergic psychedelics, MDMA produces behavioral effects consistent with serotonin syndrome such as flat body posture, hind limb abduction, and forepaw treading. Both of these effects are enhanced following repeated administration of MDMA, demonstrating that MDMA is capable of producing behavioral sensitization. Unlike amphetamine, selective serotonin reuptake inhibitors block MDMA-induced increases in locomotion. In rodent models of anxiety, MDMA produces complex effects. When tested in the light-dark box paradigm, MDMA does not alter preferences of mice for the two compartments. Some of the rodent behaviors most relevant to potential therapeutic uses of MDMA are related to social behaviors. In terms of mechanism, systemic MDMA increases plasma levels of oxytocin in rats and activates oxytocinergic neurons in the hypothalamus, as measured by Fos immunohistochemistry. This hypothesis was supported by the fact that intracerebroventricular administration of tocinoic acid, an oxytocin receptor antagonist, blocked MDMA-induced adjacent lying. In contrast, they were able to prevent this behavior using an antagonist of the vasopressin receptor 1A. First, tocinoic acid could have non-selective antagonistic effects at the vasopressin receptor 1A. Alternatively, C25 might not have been able to cross the blood-brain barrier. In addition to its prosocial effects, MDMA has been shown by Howell and co-workers to promote fear extinction learning in mice. Similar findings have been described for other psychedelics such as psilocybin in mice and N,N -dimethyltryptamine DMT in rats. Like most psychostimulants, MDMA causes robust changes in gene expression and protein levels associated with neural plasticity. The latter study also observed a reduced number of dendritic spines in the hippocampus of rats. Finally, MDMA was observed to inhibit neurite outgrowth in PC12 cells, though the relevance of this cell line to studies on neural plasticity is debatable. However, these studies are often conducted using extremely high doses of MDMA administered over extended periods of time, and probably more accurately reflect neurotoxicity resulting from overstimulation of psychoplastogenic receptors. More modest doses would likely yield increases, as opposed to decreases, in dendritic branching and spine density. The primary routes for metabolism of MDMA are N -demethylation and loss of the methylene bridge connecting the catechol Figure 4 , both of which are mediated by various cytochrome Ps. Mutations in the CYP2B6 gene resulting in decreased enzyme function only influenced metabolism at later time points i. When MDMA is administered to humans at a dose of mg, it has a half-life of approximately 8—9 h and yields plasma C max and t max values of Similar to other amphetamines, MDMA produces a number of adverse effects including trismus, tachycardia, bruxism, dry mouth, palpitations, diaphoresis, and insomnia. In Long-Evans rats, slight increases in ambient temperature resulted in excessive brain hyperthermia leading to death at an MDMA dose that is significantly lower than the LD 50 in rats at room temperature. The effects of MDMA on heart function are also significant, with norepinephrine mediating a significant portion of the cardiostimulant effects observed following MDMA administration. In terms of the addictive potential of MDMA, the data are mixed. Several people have argued that MDMA has lower abuse potential because recreational users have reported that its pleasurable effects diminish with repeated use, but its side effects increase. For instance, MDMA is known to produce conditioned place preference in rats and mice, , and MDMA is self-administered by a variety of species e. For an overview of these issues, we refer the reader to an excellent review by Susan Schenk. Certainly, the most controversial aspect of MDMA pharmacology is its potential to induce neurotoxicity. The neurotoxic effects of MDMA have been extensively reviewed by others, , , , , , , and thus, we will focus only on the key studies. Additionally, we will attempt to highlight why this is such a contentious area and why the controversy is not likely to be resolved soon. People who consume MDMA particularly those who do so regularly, and in high doses perform poorly on various tests related to attention, learning, and memory e. While retrospective studies on MDMA-using populations are certainly important, there are several confounding factors that limit the interpretability of these data. First, MDMA produced by clandestine laboratories is often contaminated with other drugs of abuse and neurotoxic compounds such as methamphetamine. Second, recreational MDMA users are typically polydrug users. Together, these facts make it difficult, if not impossible, to distinguish the neurotoxic effects induced by MDMA itself versus those caused by impurities, drug-drug interactions, or drug-environment interactions. Furthermore, due to the retrospective nature of many human studies regarding the effects of MDMA, 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. Prospective studies are incredibly important for answering these questions. One prospective study from The Netherlands found that sensation-seeking, impulsivity, and depression did not predict future MDMA use. Because of the many factors that can confound human studies, researchers have turned to well controlled model systems in the laboratory to investigate MDMA neurotoxicity. However, the relevance of these models to human neurotoxicity is often questioned. Capela and co-workers found that MDMA can induce apoptotic cell death in embryonic rat cortical neurons via a 5-HT2A-dependent mechanism. In addition to studies using cultured neurons, in vivo animal models are frequently used to test the neurotoxic potential of MDMA. While findings dating back to suggest that MDMA has neurotoxic effects in animals, the relevance of these models to human neurotoxicity is highly debated. In mice, MDMA tends to produce dopaminergic, but not serotonergic, neurotoxicity. Some researchers have justified these large rodent doses on the basis of allometric scaling and the fact that experienced recreational users of MDMA often develop tolerance, leading them to ingest multiple doses in a short period of time to achieve the desired subjective effects of the drug. Like rats, non-human primates experience serotonergic neurotoxicity following administration of large doses of MDMA. To address this discrepancy, Ricaurte and co-workers compared both dose frequency and route of administration in squirrel monkeys. They found that repeated dosing and subcutaneous administration produces greater neurotoxic effects than oral dosing. The mechanism of MDMA-induced neurotoxicity probably involves a combination of mechanisms including glutamate-induced excitotoxicity, increased oxidative stress, hyperthermia, mitochondrial damage, and increased inflammation. However, in controlled studies in the clinic using low doses to assist psychotherapy, MDMA may be safe and well tolerated, as discussed below. When a variety of factors were considered, including physical, social, and economic factors, MDMA consistently ranked as being less harmful than illegal drugs such as heroin, cocaine, and methamphetamine, as well as legal drugs such as alcohol and nicotine. In recent years there has been renewed interest in using psychedelic compounds like psilocybin and MDMA to treat neuropsychiatric disorders. The benefits of MDMA were believed to result from increased introspection, a decrease in fear response upon accessing painful memories, and the promotion of trust between patients and their therapists. Patients then receive training sessions to establish rapport with an experienced clinician. The environment is carefully controlled so that it is aesthetically pleasing and resembles a living space rather than a medical facility. Both a male and a female therapist are present for the duration of the treatment session. After the drug is administered, there is limited verbal communication between the therapists and the patient. Instead, the patient is encouraged to explore any feelings that the experience might evoke. The therapists provide nurturing physical contact whenever necessary to help ease tension or distress. After the MDMA-session, the patient receives additional non-drug psychotherapy sessions. An effective dosing paradigm was established by Oehen and co-workers utilizing low dose MDMA as an active placebo. Inactive placebos, such as lactose, fail to produce physiological and psychological responses noticeable to trained clinicians or experienced MDMA users. This raises the question as to whether or not studies utilizing inactive placebos can truly be considered double-blind experiments. Patients in the experimental treatment group received an initial dose of mg of MDMA followed by an additional The active placebo group received an initial dose of 25 mg of MDMA followed by an additional The dose of MDMA used for the active placebo group was chosen to stimulant mild but detectable psychological effects. The most common use for MDMA in medicine is as an adjunct to psychotherapy for treating anxiety disorders. Using functional magnetic resonance imaging fMRI , de Wit and co-workers found that MDMA attenuated the blood-oxygen-level dependent BOLD response to angry faces in the amygdala, while also enhancing the activation of the ventral striatum in response to happy faces. Specifically, MDMA improved scores when the stimulus had a positive emotional valence. However, when the face had a negative emotional valence, MDMA-treated individuals performed poorly. Due to its general tendencies to reduce responses to threatening stimuli while enhancing responses to positive social cues, MDMA is being investigated for treating social anxiety in autistic adults, and it has been suggested that MDMA may prove useful in other conditions with a significant social component. While other psychedelic compounds such as LSD, psilocybin, and ibogaine have been more extensively studied than MDMA with respect to their abilities to treat SUDs, the minimal perceptual disturbances caused by MDMA may offer a distinct advantage over the classical hallucinogens. While racemic MDMA is the form used both recreationally and in clinical trials, preclinical work and some human data suggest that there are distinct differences between the R - and S -enantiomers of MDMA—the non-superposable mirror images of each other. An excellent review on this subject was published recently by Howell and coworkers, so we will only cover the highlights here. Regarding the monoamine releasing and reuptake inhibiting properties of MDMA, there is a general consensus that the S -enantiomer is the more potent compound. Neither enantiomer is particularly effective at stimulating phosphatidyl inositol turnover in either 5-HT2A or 5-HT2C expressing cells. In terms of their influences on hormone levels, the enantiomers of MDMA also have differential effects. Behaviorally, both enantiomers increase affiliative social behaviors in squirrel monkeys, and this effect seems to be dependent on activation of 5-HT2A receptors. As discussed, the primary concern for using MDMA in the clinic is its potential neurotoxicity. Most neurotoxicity studies were performed using the racemate, however, there is some evidence to suggest that the neurotoxic effects of MDMA stem from the S -enantiomer, with the R -enantiomer being relatively benign. The racemate significantly increased astrogliosis while decreasing both DA content and DAT expression. This study provides compelling evidence that at least in mice, 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. Urban legend, rumor, and myth have clouded the true history of MDMA. Several excellent historical accounts of the discovery and development of MDMA have been reported previously, 44 , 49 , , and thus, we only discuss the highlights here Figure 5. First, it is a common misconception that MDMA was originally designed to be an appetite suppressor or a weight loss drug. In fact, MDMA was first synthesized in and subsequently patented, but as it was only intended to be an intermediate en route to the desired compound, its biological activity was not assessed. It was not until 15 years after its initial synthesis that MDMA was actually tested in animal models. Merck was interested in identifying compounds that mimicked the effects of epinephrine, 49 and MDMA was one candidate tested owing to its structural similarities. Unfortunately, the results of these tests could not be found in the Merck archive. Timeline of important events related to research on MDMA and classical psychedelics. Research on MDMA appeared to stagnate until the s. At that time the US military began using mescalinelike compounds, including MDMA, as part of pharmacologically-assisted interrogation programs. The characteristic hallucinations produced by compounds like LSD and mescaline typically disrupted interrogation sessions. In the early s, the military began testing several of these compounds on patients at the New York State Psychiatric Institute. In , a patient named Harold Blauer was administered several compounds over the course of a month before succumbing to a fatal dose of MDA mg. The first report of the synthesis of MDMA in the peer-reviewed literature was in Furthermore, he was largely responsible for reclassifying MDMA and related compounds as entactogens, due to their unique qualities relative to hallucinogens and psychostimulants. During the period from to , it is estimated that thousands of patients were treated with MDMA. As a result, the true therapeutic potential of MDMA was not captured in the scientific literature. Furthermore, the properties of MDMA that made it an effective aid to psychotherapy also led to its widespread use in social situations. During this period of time, recreational use of MDMA increased dramatically, and mounting evidence suggested that MDA, a structurally related compound, was neurotoxic. In a paper published in Science , Ricaurte and co-workers described experiments performed in nonhuman primates demonstrating severe dopaminergic and to a lesser extent serotonergic neurotoxicity of MDMA. When Ricaurte and co-workers could not reproduce their results, they retracted their Science paper a year later. Despite its retraction, the Ricaurte study had dealt a serious blow to the credibility of MDMA as a safe therapeutic. Heated public debate ensued about the potential dangers of the drug and its government regulation. Since the retraction of the Ricaurte study, there have been multiple clinical trials investigating the effects of MDMA, and thus far, all data suggest that MDMA can be administered safely under these conditions. In , the first completed clinical trial evaluating the potential of MDMA-assisted psychotherapy for alleviating treatment-resistant PTSD was published. This designation helps to expedite the review and potential approval process for promising therapeutics. Phase III clinical trials are currently being planned, and if the results of those trials warrant approval by the FDA, a bona fide accepted medical use for MDMA will have been established. This would necessitate the removal of MDMA from the Schedule I list, a regulatory change that could have profound implications for the field of psychedelic medicine. Schedule I status has severely hampered access to psychedelics for research purposes. In sum, this trajectory is perhaps why MDMA is the most influential compound for the future of psychedelic research. However, MDMA is also a highly divisive compound having the potential to swing public opinion against general use of psychedelics in medicine. Extensive proselytizing about the non-medical uses of LSD contributed to the creation of the Controlled Substance Act of This would be unfortunate as MDMA is an important neurochemical tool for elucidating the neural mechanisms of social behaviors and empathy, and it has the potential to offer real relief to people suffering from PTSD and other anxiety disorders. Perhaps the true potential of MDMA lies in its use as a lead structure for the development of safer and more efficacious alternatives. As a library, NLM provides access to scientific literature. ACS Chem Neurosci. Find articles by Lee E Dunlap. Find articles by Anne M Andrews. Find articles by David E Olson. Author Contributions D. Issue date Oct PMC Copyright notice. Open in a new tab. Notes The authors declare no competing financial interest. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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