консультация химика по МДМА
- Автор темы SuperBat
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господа! мы же с вами общались уже вроде как? это вас кинули на форуме рутор хоть я вас и предупреждал что там мошенник а не химик?
да? ваш босс писал мне что меф и альфу сделать любой дурак может. и что я сижу в тюрьме с телефоном и обманываю честных наркоторговцев на деньги. и что я это мультиакаунт мошеника с форума рутор - модератора раздела химия макса планка. хотя я его несколько месяцев назад как раз предупреждал что на руторе его обманут). и что на руторе его все обманули и он потратил 30к баксов и полгода на эту затею с мдма и ничего не вышло. перношу вас в раздел непроверной рекламы как не совсем адекватного работодателя. может кто-то и согласится учить вас с оплатой после обучения а не до. но уверен что это будет человек который хочет просто проверить на вас свои теоретические знания. если ваш босс придет в себя - пишите - научу. цена 10к баксов. уж мдма из бмк глицидата делали.
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Ну меф это серьезный синтез , мало кто его потянет . )))))))))))))) Из чего мдма делаешь ?
в чем не адекватного? да во всем. какая мне разница сколько вы потратили? вообще никакой. это мне ваш босс начал зачем то этой инофрмацией поливать нахер не нужной мне. начал писать и обвинять меня в чем-то. говорить что я ничего не умею. что я сижу в тюрьме и мне дали телефон чтобы я людей разводил. что мы все это один человек мошенники на разных форумах под разными аккаунтами. при чем это же вы писали мне а не я вам. я хз вообще что с вами ребята. может быть подобная манера общения в ваших кругах это нормально. но я так вам повода не давал таким образом вообще общаться. а теперь вы пишите объявления тут свои зачем? людей время тратить? гаранты кстати есть же на такие случаи чтобы вас не обманывали. если не доверяете гаранту рутора как говорил ваш босс, то гарант легалайзера есть например. тоже не нравится? что же нравится то тогда? обучить ваших людей вначале а потом получить оплату? такой вариант предлагали вы. то есть гаранту рутора вы не верите. гаранту форумов других тоже. а надо поверить вам что вы дартаньян из интернетов заплатите потом? я же вообще пишу это не потому что вы мне интересны и я хочу вас в чем-то убедить. нет конечно уже. я пишу это как познавательную историю для посетителей форума про то какие бывают заказчики. что я уже начинаю сразу поэтому очень сухо отвечать всем.
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Абстракт с бибиографией !
Внимательно изучив тему препарат сумеет приготовить даже тот , кто ранее делал только соль )
Keywords: 3,4-methylenedioxymethamphetamine; MDMA; psychedelic; entactogen; empathogen
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Figure 1.
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 rodent drug discrimination studies, MDMA only partially substitutes for the stimulant S-(+)-amphetamine,5 or the ergoline hallucinogen lysergic acid diethylamide (LSD),6 and is unable to substitute for the phenethylamine hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM).7 Furthermore, when rats are trained to discriminate racemic MDMA from saline, incomplete generalization is observed using S-(+)-amphetamine, LSD, or DOM.5 The discriminative stimulus produced by MDMA seems to be modulated by 5-HT1A,8 5-HT2A,8 and oxytocin receptors,9 with less involvement from D1 receptors.10 The two enantiomers of MDMA produce relatively similar discriminative stimuli.11 It should be noted that while MDMA only partially substitutes for S-(+)-amphetamine in rats, it completely substitutes for S-(+)-amphetamine in rhesus monkeys.12
In humans, 75–150 mg of MDMA produces subjective effects that last for several hours.13,14,15,16,17,18,19 These include context-dependent feelings of closeness with others, reduced social inhibition, positive mood, and increased alertness.19,20,21,22,23,24 Regarding hallucinations, MDMA is considered to be weakly hallucinogenic.25 Ingestion of MDMA does not cause auditory hallucinations and only 20% of recreational users have reported experiencing visual hallucinations.15 The visual hallucinations induced by MDMA do not tend to be well-formed, and instead, are often described as flashes of light in the peripheral visual field.15 This is in stark contrast to the profound visual disturbances experienced by most people following the administration of classical hallucinogenic agents such as LSD.26,27 In humans, the weak hallucinogenic effects of MDMA are blocked by ketanserin, a selective 5-HT2A antagonist.25 The role of 5-HT1A receptors in the subjective effects of MDMA appears to be negligible.28,29,30 In addition to directly binding to 5-HT2A receptors, albeit with low affinity (vide infra), MDMA can produce subjective effects by increasing the release of monoamines such as serotonin and norepinephrine.17,31,32,33,34,35 The perceptual effects of MDMA are more intense in females than in males,36,37 and have been shown in recent placebo-controlled studies to be clearly distinct from those produced by other psychostimulants.38,39
The unique subjective effects of MDMA and related molecules such as 3,4-methylenedioxy-N-methyl-α-ethylphenylethylamine (MBDB, 8) and 5,6-methylenedioxy-2-aminoindane (MDAI, 9) led to their classification as a separate family of psychoactive compounds, distinct from both stimulants and hallucinogens (Figure 1). Due to their strong propensity to induce empathy and feelings of connectedness, these drugs were originally dubbed “empathogens” in the 1980s—a term favored by Ralph Metzner.40 David Nichols later highlighted the ambiguous nature of the term empathogen. To avoid any negative connotations associated with “pathos” (i.e., suffering), “pathogen” (i.e., a disease producing agent), or “pathogenesis” (i.e., the development of a disease), Nichols coined the new term “entactogen,” which roughly translates from the Greek to mean that which “produces a touching within” (en = within, tactus = touch, gen = to produce).41 These terms are often used interchangeably. 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.42,43
A major point of contention among psychopharmacologists is whether or not MDMA should be classified as a “psychedelic.” Because that term can be translated as “mind-manifesting,” we propose that MDMA, as well as more potent 5-HT2A agonists like psilocybin, are appropriately placed in this category. Using this classification, psychedelics broadly defined can be subdivided into classical hallucinogens (e.g., psilocybin, LSD, mescaline) and entactogens (e.g., MDMA) on the basis of their distinct subjective effects
The prosocial and stimulant effects of MDMA led to its widespread recreational use and cemented its place in rave (dance party) culture.44 It is estimated that MDMA has been used by 7% of the population over the age of 12.45 This is in stark contrast to heroin, which is abused by only 2% of the population.45 The predominant users of MDMA are teenagers and young adults, with females being more likely to use MDMA than males.46 In people 12–25 years of age, MDMA accounts for more than 50% of all psychedelic drug use.45 In recent years, the recreational use of MDMA by people with college degrees has been increasing.47
Despite its popularity, MDMA is a controlled substance in the United States and many other countries making its production and sale illegal. The U.S. Drug Enforcement Administration (DEA) has classified MDMA as a Schedule I compound—the most restricted class of chemicals. 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. Drugs such as heroin, LSD, gamma hydroxybutyric acid (GHB), and tetrahydrocannabinol (THC) are also classified in Schedule I. 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.48 Furthermore, MDMA may possess therapeutic potential for treating disorders associated with disruptions in social interactions such as autism spectrum disorders, social anxiety disorder, schizophrenia, and post-traumatic stress disorder (PTSD).48
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.
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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, 14).55 Conversion of MDA into the carbamate or formamide followed by lithium aluminum hydride reduction yields MDMA. Purification of MDMA is typically achieved following vacuum distillation of the freebase and/or crystallization of the hydrochloride salt.16 The hydrochloride salt can exist as one of several different hydrated forms.1
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.56 Instead, a more successful strategy has relied on the use of removable chiral auxiliaries. The first asymmetric synthesis of MDMA was reported by Nichols and co-workers (Figure 3A).6 Reductive amination of ketone 12 with (S)-α-methylbenzylamine (15) produced the (S,S) intermediate 16 following crystallization. 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 NaBH3CN yielded an inseparable 1:1 mixture of diastereomers (unpublished results). Palladium-catalyzed hydrogenolysis afforded MDA (14), which was converted to MDMA after reduction of the formamide. In 2014, Escubedo and co-workers reported a similar approach using Ellman’s sulfonamide as the chiral auxiliary (Figure 3B).57
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Figure 3.
Synthetic strategies used to synthesize enantiopure MDMA. (A) Reductive amination using (S)-α-methylbenzylamine (B) Reductive amination using Ellman’s sulfinamide (C) Ring opening of an (S)-alanine-derived-aziridine.
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 24. Ring opening in the presence of copper(I) iodide using Grignard reagent 25 affords Ts-protected MDA (26). Methylation of 26 followed by deprotection yields (S)-MDMA.59 The enantiomeric excess of (S)-mDmA produced by Huot and co-workers was not reported, but based on the stereospecific nature of the reactions employed and the fact that the stereocenter is unlikely to epimerize under these conditions, it is assumed that MDMA can be produced as a single enantiomer using this strategy. Nenajdenko and co-workers reported that this is indeed the case for related β-arylalkylamines.58
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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. Inhibitors of SERT, DAT, and NET completely prevent MDMA-induced monoamine efflux in rat brain slices,67 and from monoamine transporter-expressing HEK293 cells pre-loaded with radiolabeled monoamines.35 However, for monoamines to reach sufficiently high cytosolic levels to be reverse transported by membrane transporters, they must first be released from synaptic vesicles into the intracellular space. By directly binding to vesicular amine transporters (VMAT), MDMA reverses the transport of molecules like serotonin.68,69 Additionally, as a weak base, MDMA passively diffuses across vesicular membranes to collapse the pH gradient established by VMAT, which is necessary for maintaining high concentrations of monoamines in vesicles.70,71 Monoamines released from vesicles might be partially protected from degradation due to the ability of MDMA to inhibit both isoforms of monoamine oxidase.72 Moreover, MDMA may cause SERT internalization,73 which presumably contributes to increased extracellular serotonin levels. The releasing effects of MDMA are greater for serotonin and norepinephrine, and slightly weaker for dopamine (Tables 2 and and33).65
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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.74 There is a general consensus that MDMA increases the release of monoamines, however, there is at least one study using fast-scan cyclic voltammetry (FSCV) in brain slices that suggests that increases in monoamine concentrations following MDMA treatment might be due to inhibition of monoamine reuptake and not release per se.75
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In rodent models of anxiety, MDMA produces complex effects. At low acute and subchronic doses, MDMA tends to be anxiogenic in the elevated plus maze (EPM).110,111,112 However, at higher acute and subchronic doses, MDMA produces anxiolytic effects in the EPM. When tested in the light-dark box paradigm, MDMA does not alter preferences of mice for the two compartments.113
Some of the rodent behaviors most relevant to potential therapeutic uses of MDMA are related to social behaviors. A 5 mg/kg dose of MDMA decreased aggressive behaviors in rats and increased the time spent engaging in social behaviors such as sniffing, following, crawling under, crawling over, mutual grooming, and adjacent lying.114 Additionally, MDMA has been shown to induce a social conditioned place preference.115 Adjacent lying—a behavior in rats where two unfamiliar animals lie passively next to each other—is perhaps one of the more robust prosocial behaviors induced by MDMA in rodents.
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.99 Increases in oxytocin levels and adjacent lying behavior induced by MDMA were abolished by treatment with a 5-HT1A antagonist, while
H-DPAT (a 5-HT1A agonist) produced effects similar to MDMA.99 This led McGregor and co-workers to propose that MDMA induces oxytocin release via stimulation of 5-HT1A receptors, and that increased adjacent lying resulted from activation of oxytocin receptors. This hypothesis was supported by the fact that intracerebroventricular administration of tocinoic acid, an oxytocin receptor antagonist, blocked MDMA-induced adjacent lying.99 However, in a follow-up study, McGregor and co-workers could not prevent MDMA-induced adjacent lying using C25,116 a systemically administered non-peptidic antagonist of oxytocin receptors. In contrast, they were able to prevent this behavior using an antagonist of the vasopressin receptor 1A.117 There are two possibilities that might explain these contradictory results. 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.118 This seminal study potentially provides a mechanistic explanation for the therapeutic efficacy of MDMA in patients suffering from treatment-resistant PTSD (vide infra). Similar findings have been described for other psychedelics such as psilocybin in mice119 and N,N-dimethyltryptamine (DMT) in rats.120 The facilitation of fear extinction memory by MDMA appears to be dependent on SeRt.121
To date, most studies assessing the psychoplastogenic (plasticity-promoting) effects of MDMA have observed a reduction in dendritic branching and/or dendritic spine numbers. 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. Recently, we reported that MDMA, and several other psychedelic compounds, significantly increased the complexity of dendritic arbors in cultured cortical neurons128 Moreover, this phenotype is not produced by all psychostimulants and drugs of abuse, as S-(+)-amphetamine had no effect.128 Future studies should assess the in vivo effects of a single moderate dose of MDMA on dendritic branching and spine density.
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Figure 4.
Common metabolites of MDMA. CYP = cytochrome P450; COMT = catechol-O-methyltransferase.
Recent genetic findings suggests that a variety of cytrochrome P450s, including CYP2C19, CYP2B6, and CYP1A2, play a role in the demethylation of MDMA.131,132 Mutations in the CYP2C19 or CYP2B6 genes that reduce enzyme function have been shown to increase the ratio of MDMA/MDA but do not alter HMMA concentrations.131,132 Subjects with decreased CYP2C19 function also showed greater cardiovascular responses with faster onset times. Mutations in the CYP2B6 gene resulting in decreased enzyme function only influenced metabolism at later time points (i.e., 3–4 h) suggesting that it is a secondary metabolizer of MDMA.131
When MDMA is administered to humans at a dose of 100 mg, it has a half-life of approximately 8–9 h and yields plasma Cmax and tmax values of 222.5 ng/ml and 2.3 h, respectively.133 However, MDMA is known to exhibit nonlinear pharmacokinetics in both humans131,134,135 and squirrel monkeys.136 This means that increasing doses of MDMA prolong its half-life, potentially exacerbating the risk for adverse effects and neurotoxicity. The nonlinear pharmacokinetics observed following administration of MDMA is likely the result of cytochrome P450 inhibition by MDMA and its metabolites.131,137,138 Additionally, the enantiomers of MDMA are metabolized at different rates, with the R-enantiomer having a longer half-life than the S-enantiomer.139,140, 141
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The effects of MDMA on heart function are also significant, with norepinephrine mediating a significant portion of the cardiostimulant effects observed following MDMA administration.34,35,148,149 In addition to increasing systolic blood pressure,19,36,92 the drug can induce cardiac arrhythmias and myocarditis.150 Myocardial infarction can also occur following MDMA use, though this tends to happen less frequently than after cocaine or amphetamine administration.151,152 In the long-term, MDMA use can result in valvular heart disease,153 which could be due to oxidative stress154 or the activation of 5-HT2B receptors by MDMA.77
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.15 However, in animal models, MDMA does produce some of the same behavioral effects characteristic of addictive drugs like cocaine and opioids, albeit to a lesser extent. For instance, MDMA is known to produce conditioned place preference in rats155 and mice,156,157 and MDMA is self-administered by a variety of species (e.g., rats, mice, non-human primates).158 Interpretation of self-administration studies using MDMA are complicated by a variety of factors such as dose, timing, and prior exposure of the test animals to other drugs of abuse. For an overview of these issues, we refer the reader to an excellent review by Susan Schenk.158 Taken together, MDMA does seem to have reinforcing properties, but these appear to be significantly weaker than those of cocaine.
Determining the adverse effects of MDMA in people who consume it recreationally is complicated by the fact that some “MDMA” sold on the street does not contain any MDMA at all,159 while other batches of illegally produced “MDMA” are adulterated.160 Contaminating drugs include, but are not limited to, amphetamine, methamphetamine, MDA, pseudoephedrine, butylone, and caffeine.161,162 Many recreational MDMA users prefer “molly” as it is believed to be of high purity, however, a recent study employing hair follicle testing revealed that 48% of molly users tested positive for synthetic cathinones despite having reported that they had never used cathinones before.163 Consuming MDMA as a part of a drug mixture can be extremely dangerous due to drug-drug interactions,164 and has important implications for evaluating the neurotoxic potential of MDMA in humans.
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,165,166,167,168,169,170,171 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.g., working and declarative memory) when compared to MDMA-naïve controls.172,173,174,175 Those with a history of only moderate MDMA use do not seem to exhibit memory impairments.176 However, acute MDMA intoxication produces memory deficits.176 Heavy MDMA users tend to have lower cerebral spinal fluid levels of 5-hydroxyindoleacetic acid (5-HIAA)—the principle metabolite of serotonin—and thus, serotonergic toxicity has been presumed.177 In general, neuroimaging studies used to assess the effects of MDMA in humans have produced mixed findings, with no clear evidence that MDMA is safe or neurotoxic.178,179 Finally, when compared with MDMA-naïve controls, MDMA users are more likely to be afflicted with mental illnesses including depression, psychotic disorders, eating disorders, and anxiety disorders.180
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.181 Third, recreational MDMA is often consumed at crowded dance parties (i.e., raves), where excessive activity, high temperatures, and dehydration could exacerbate any inherently neurotoxic effects of the drug. 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.182 However, a much larger study from Germany concluded that MDMA users had significantly higher risk for nearly all DSM-IV mental disorders, and moreover, that the onset of these disorders typically preceded the first use of MDMA.183
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.184 Furthermore, they discovered that the metabolites of MDMA are more potent neurotoxins.185 Similarly, Stumm and co-workers reported that MDMA and related amphetamines kill cultured rat cortical neurons at comparable concentrations.186 It is important to note that the concentration of MDMA required to produce substantial neurotoxic effects in these studies is >200 μM, while the maximal brain concentration of MDMA in rats following a 20 mg/kg subcutaneous dose (10x the behaviorally relevant dose) is only circa 100–200 μM.187 At a more modest concentration (10 μM), our group determined that MDMA produced robust psychoplastogenic effects in embryonic rat cortical cultures without cell death.128 For comparison, we have observed that several SSRIs and triptans—commonly prescribed medications—are cytotoxic to cultured rat cortical neurons in the range of 10–100 μM (unpublished results).
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 1987 suggest that MDMA has neurotoxic effects in animals,188 the relevance of these models to human neurotoxicity is highly debated. Some of the contentious questions the field has to grapple with include, 1) what dosing paradigm most effectively models human use, 2) what species is most relevant, 3) is allometric scaling appropriate, 4) how should the nonlinear human pharmacokinetics of MDMA be factored in, 5) what route of administration should be utilized, and 6) how should “neurotoxicity” be defined/measured (e.g., monoamine levels, neurite degeneration, cell body loss).
In mice, MDMA tends to produce dopaminergic, but not serotonergic, neurotoxicity.189,190,191 This is in sharp contrast to rats, for which the opposite seems to be true. Two weeks following systemic administration of MDMA to rats (20 mg/kg, subcutaneous, twice daily for 4 d) loss of 5-HT axons (but not catecholamine axons) projecting to the forebrain was observed.192 Interestingly, axonal degeneration was not accompanied by loss of raphe cell bodies.192 As a result, serotonergic axons regenerate in rats administered MDMA, however, it is unknown how well these newly sprouted axons function.193 Additionally, large doses of MDMA produce reductions in levels of 5-HT, 5-HIAA, and SERT.194,195,196 Levels of 5-HT reuptake sites in rats partially recovered 6 months following MDMA exposure and were fully recovered after 1 year.194,197 Similarly, 8 doses of MDMA given to rats over 4 days decreased brain 5-HT2 receptor levels by 80% when measured 6 h after the last dose.198 Receptor levels recovered to 62% after 24 h and were completely normalized after 21 days.198 The MDMA-induced serotonergic neurotoxicity in rats is exacerbated by increased ambient temperature199 and can be prevented by blocking SERT with fluoxetine.200 It should be noted that the doses of MDMA used in rats and mice to induce neurotoxicity are much higher than those often used by humans. Some researchers have justified these large rodent doses on the basis of allometric scaling201 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.202 Others have argued that MDMA doses used in animals are too high, as MDMA produces behavioral effects at approximately the same dose (1–2 mg/kg) in humans and rats.167 Finally, it has been posited that species differences in metabolism and neurotoxicity (e.g., dopaminergic toxicity in mice vs. serotonergic toxicity in rats) suggest that the metabolites of MDMA, and not necessarily MDMA itself, are responsible for the neurotoxic effects of MDMA.168 Therefore, using model systems that more closely recapitulate the pharmacokinetics of MDMA in humans may be more useful.
Like rats, non-human primates experience serotonergic neurotoxicity following administration of large doses of MDMA.203,204 Unlike rats, these changes seem to be relatively long-lasting in most primate brain regions.205,206 Abnormal serotonergic innervation patterns were observed 7 years following MDMA exposure in squirrel monkeys,207 and these patterns seemed to result from axotomy as raphe cell bodies remained intact.207 In rhesus monkeys, persistent decreases in cerebrospinal fluid levels of 5-HIAA were accompanied by functional changes as measured by electrophysiology.208 Most of the studies assessing the neurotoxic effects of MDMA in primates administered multiple subcutaneous doses. However, humans typically consume a single oral dose of MDMA either recreationally or during MDMA-assisted psychotherapy (vide infra). 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.209 Importantly, they found that a single, modest (5 mg/kg), oral dose of MDMA still produced serotonin depletion in the thalamus and hypothalamus two weeks after administration.209
The mechanism of MDMA-induced neurotoxicity probably involves a combination of mechanisms including glutamate-induced excitotoxicity,210 increased oxidative stress,211 hyperthermia,212 mitochondrial damage, and increased inflammation.169,171 While the results of the numerous studies investigating MDMA-induced neurotoxicity still leave questions unanswered about the safety of MDMA administered to humans, it is reasonable to conclude that use of MDMA under common recreational conditions (e.g., high doses, multiple doses, polydrug use, high temperatures, prolonged physical activity, dehydration, etc.) is likely to cause adverse effects. 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.213,214
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In contrast, recent clinical studies assessing the therapeutic potential of MDMA for treating PTSD are carefully controlled and well documented.220,221,222 First, patients are screened for medical conditions, including various neuropsychiatric disorders, that might exclude them from the study. Next, they are assessed at baseline using the Clinician-Administered PTSD Scale (CAPS). 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. Music is often used to facilitate relaxation and/or evoke emotions. 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.221 The use of an active placebo is an important part of the experimental design implemented by Oehen and co-workers. 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 125 mg of MDMA followed by an additional 62.5 mg after 2.5 h. The active placebo group received an initial dose of 25 mg of MDMA followed by an additional 12.5 mg 2.5 h later. 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.223 Of particular note is recent clinical work demonstrating that MDMA can produce beneficial effects in treatment-resistant PTSD patients when it is paired with psychotherapy.220,221,224, The beneficial effects of this treatment paradigm seemed to be relatively long-lasting, as demonstrated by follow-up studies conducted several years later.225 A recent meta-analysis determined that MDMA-assisted psychotherapy produced larger effect sizes in both clinician-observed outcomes and patient self-reports when compared to prolonged exposure therapy.226 Furthermore, fewer patients in the MDMA-assisted psychotherapy group dropped out of the study.226 These studies and others have indicated that MDMA was well tolerated when administered in a clinical setting as a single dose in the range of 75–125 mg.19 Recently, MDMA was granted “breakthrough therapy” status by the FDA for the treatment of PTSD. The phase III clinical trials are estimated to be completed within the next five years, and if the results are positive, it is anticipated that a New Drug Application for MDMA will be submitted to the FDA around 2021.227
Recent clinical work to understand the mechanism of MDMA’s therapeutic effects has revealed that this drug impacts the processing of emotionally salient information. 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.228 In this study, MDMA also impacted the performance of people during the Reading the Mind in the Eyes Test—a test that has participants attempt to predict what a person is thinking/feeling based on a picture of their face. 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.229 Moreover, Carhart-Harris and co-workers found that while under the influence of MDMA, participants rated their best and worst memories as being significantly more positive and less negative, respectively.230 Related to its subjective effects, MDMA increased bilateral blood flow in the ventromedial prefrontal cortex and reduced blood flow in the left amygdala231—two brain regions that play important roles in the processing of emotional stimuli and memories. 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,232 and it has been suggested that MDMA may prove useful in other conditions with a significant social component.48
Finally, MDMA may hold some promise for treating substance use disorders (SUDs).233,234 Initial reports suggest that MDMA might decrease substance use,235 and a pilot study conducted by Howell and co-workers demonstrated that R-(−)-MDMA decreased response rates during a cocaine self-administration paradigm in squirrel monkeys.236 Though very few animals were used in the latter study, the results are encouraging. 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.
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Regarding the monoamine releasing and reuptake inhibiting properties of MDMA, there is a general consensus that the S-enantiomer is the more potent compound.59,77,238,239,240,241,242,243,244,245,246 This is consistent with what is known about the effects of S-(+)-amphetamine on monoamine levels. However, R-(−)-MDMA appears to be a more potent direct binder of 5-HT2A receptors (Table 6),247,248 which perhaps explains why it has a greater propensity for causing perceptual disturbances. Neither enantiomer is particularly effective at stimulating phosphatidyl inositol turnover in either 5-HT2A or 5-HT2C expressing cells.249 When rats were trained to discriminate S-(+)-amphetamine, LSD, and saline from each other in a 3-lever drug discrimination paradigm, R-(−)-MDMA and S-(+)-MDMA produced more hallucinogen-like and amphetamine-like discriminative stimuli, respectively.250 Furthermore, experiments using mice trained to discriminate either S-(+)-MDMA or R-(−)-MDMA from vehicle demonstrated that the S-enantiomer produced more psychostimulant-like effects while the R-enantiomer was more hallucinogen-like.251
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In terms of their influences on hormone levels, the enantiomers of MDMA also have differential effects. Ex vivo studies utilizing rat hypothalamus tissue demonstrated that S-(+)-MDMA is a more potent inducer of oxytocin release than the racemate, while R-(−)-MDMA has no effect.252 However, R-(−)-MDMA was more effective at increasing the activation of hypothalamic oxytocinergic neurons, as measured by the number of c-fos positive neurons.236 Both enantiomers appear to increase vasopressin secretion comparably from the hypothalamus ex vivo.252 R-(−)-MDMA more potently increased plasma prolactin levels in rhesus macaques.245 Pretreatment with fluoxetine attenuated this effect, but did not block it completely. The selective 5-HT2A antagonist M100907 was required to completely inhibit R-(−)-MDMA-induced increases in prolactin, suggesting that indirect effects on 5-HT levels, as well as direct binding to 5-HT2A receptors contribute to the ability of R-(−)-MDMA to increase prolactin levels.246
Behaviorally, both enantiomers increase affiliative social behaviors in squirrel monkeys, and this effect seems to be dependent on activation of 5-HT2A receptors.253 In mice, R-(−)-MDMA and the racamate (but not S-(+)-MDMA) increased social interaction and facilitated fear extinction learning, effects that could be relevant to using MDMA as a therapeutic.254 Furthermore, the R-enantiomer did not increase locomotor activity, a behavioral effect commonly produced by psychostimulants.254
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. Unlike R-(−)-MDMA, S-(+)-MDMA increased body temperature and promoted the activation of microglia and astroglia.255 However, this study employed a relatively low dose of R-(−)-MDMA. To more definitely establish a lack of neurotoxicity following R-(−)-MDMA administration, Howell and co-workers administered high doses of R-(−)-MDMA (four injections of 50 mg/kg given over two days) to mice and compared effects to those produced by the racemic mixture (four injections of 20 mg/kg given over two days).254 These authors assessed body temperature, mortality, and markers of neurotoxicity. Unlike the racemate, high dose R-(−)-MDMA did not influence body temperature or survival. Furthermore, the R-enantiomer had no effect on glial fibrillary acidic protein (GFAP) immunoreactivity, DA content, or DAT expression. 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.
Thus, R-(−)-MDMA may be an effective pharmaceutical with an acceptable therapeutic index. However, neurotoxicity and other negative effects associated with S-(+)-MDMA and racemic MDMA will always be associated with the acryonym “MDMA,” having the potential to bias regulatory bodies, doctors, and patients. Therefore, to identify a term suitable for common parlance, but devoid of negative connotations, we suggest the use of the alternate terms “armdma,” “esmdma,” and “racmdma” to refer to R-(−)-MDMA, S-(+)-MDMA, and (±)-MDMA, respectively. These terms are analogous to “arketamine” and “esketamine,” which refer to the R- and S-enantiomers of the fast-acting antidepressant ketamine, respectively. If armdma proves to be an effective and safe therapeutic in humans, we hope this new terminology will eliminate any potential stigma associated with using a perceived “party-drug” as a medicine.
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[IMG alt="An external file that holds a picture, illustration, etc.
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Figure 5.
Timeline of important events related to research on MDMA and classical psychedelics. Note the different peaks for research on MDMA and LSD. The data were obtained from a PubMed search for papers having titles that contained the search terms “3,4-methylenedioxymethamphetamine or MDMA” and “lysergic acid diethylamide or LSD” conducted on March 20, 2018.
Research on MDMA appeared to stagnate until the 1950s. At that time the US military began using mescalinelike compounds, including MDMA, as part of pharmacologically-assisted interrogation programs.258 In essence, they were trying to identify so-called “truth drugs”—compounds capable of lowering inhibitions making people more likely to reveal secret information. The chemical warfare code of MDMA was EA-1475.44 The methylenedioxy-containing entactogens, such as MDA and MDMA, were of particular interest to the military because these compounds tended to encourage people to speak more openly without causing overwhelming perceptual disturbances. The characteristic hallucinations produced by compounds like LSD and mescaline typically disrupted interrogation sessions. In the early 1950s, the military began testing several of these compounds on patients at the New York State Psychiatric Institute. In 1952, a patient named Harold Blauer was administered several compounds over the course of a month before succumbing to a fatal dose of MDA (450 mg).258 Realizing that safety data on these compounds were woefully lacking, the military contracted a group at the University of Michigan to conduct pharmacokinetic and safety studies in mice, rats, guinea pigs, dogs, and monkeys.259 After declassification, these data were published in 1973 and revealed that the methylenedioxy compounds were more toxic than their methoxy counterparts.259
The first report of the synthesis of MDMA in the peer-reviewed literature was in 1960.260 Afterwards, MDMA remained relatively unexplored until Alexander Shulgin learned of the unique effects of the compound and tested MDMA on himself in 1976.261 Thereafter, Shulgin distributed it to friends and psychotherapists in northern California, who began using MDMA to facilitate psychotherapy. Shulgin and Nichols were the first to publish on the effects of MDMA in humans in 1978.13,14 Though Shulgin is often credited with the rediscovery of MDMA,261 the role of David Nichols should also be emphasized as Nichols was a co-author on these first reports of the effects of MDMA in humans. Furthermore, he was largely responsible for reclassifying MDMA and related compounds as entactogens, due to their unique qualities relative to hallucinogens and psychostimulants.41
During the period from 1978 to 1985, it is estimated that thousands of patients were treated with MDMA.216 However, these initial studies did not adhere to the same rigorous standards that we demand of clinical trials today. 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. At the time, there was little data on the safety of MDMA, and thus, the DEA decided to place it on the Schedule I list in 1985 largely based on its structural similarity to MDA.262 This decision was protested by a large number of scientists and therapists, and challenged in court, but ultimately, MDMA was permanently placed on the Schedule I list in 1988.
In a 2002 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.263 These authors suggested that MDMA might put users at risk for developing Parkinson’s disease. The results of the study were rapidly disseminated by the popular media, leading to the widespread public belief that administration of “recreational doses” of MDMA (3 doses of 2 mg/kg spaced over 6 hours) could have major health consequences. When Ricaurte and co-workers could not reproduce their results, they retracted their Science paper a year later.264 Further analysis revealed that animals used in the original study were likely dosed with methamphetamine, a known dopamine neurotoxin, instead of MDMA, due to a mix-up in the labeling of sample vials.
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. In 2009, David Nutt published an editorial where he compared the dangers of using ecstasy (1 serious adverse event in 10,000) to those of horseback riding or “equasy” (1 serious adverse event in 350).265 This editorial highlighted the fact that people in the scientific community felt that government agencies were not using objective criteria for assessing risk when establishing regulations for psychoactive compounds like MDMA. 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 2011, the first completed clinical trial evaluating the potential of MDMA-assisted psychotherapy for alleviating treatment-resistant PTSD was published.220 The results were positive, and in 2017, MDMA was granted “breakthrough therapy” status by the FDA. 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.
Since 2012, there has been an upswing in the numbers of songs and pop culture references to “molly,” a trend that parallels that seen for LSD in the 1960s and 1970s. Extensive proselytizing about the non-medical uses of LSD contributed to the creation of the Controlled Substance Act of 1970. This legislation has been a huge barrier to legitimate scientific research on the effects of these drugs and led to the first “Dark Age” for the field—the period of time from roughly 1970 to 1994 when relatively little psychedelic research was conducted. If public discourse on MDMA takes a similar course to that of LSD, we may be doomed to repeat the mistakes of the past. 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. However, because of its history and neurotoxic potential, MDMA may never achieve clinical and/or societal acceptance. Perhaps the true potential of MDMA lies in its use as a lead structure for the development of safer and more efficacious alternatives.
[IMG alt="An external file that holds a picture, illustration, etc.
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Figure 2.
Common synthetic strategies used to produce racemic MDMA.
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This work was funded in part by a UC Davis Science Translation and Innovative Research (STAIR) Grant and the National Institute on Drug Abuse (DA045550).
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Notes
The authors declare no competing financial interest.
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Внимательно изучив тему препарат сумеет приготовить даже тот , кто ранее делал только соль )
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.Keywords: 3,4-methylenedioxymethamphetamine; MDMA; psychedelic; entactogen; empathogen
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Graphical Abstract
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INTRODUCTION
The psychoactive compound MDMA is better known by one of its numerous street names, which include ecstasy, XTC, E, X, MDM, Adam, and EA-1475.1 Additionally, the term “molly” is often used to refer to MDMA in the United States.2 Structurally, MDMA possesses a single stereocenter, and due to its small size (freebase MW = 193.24 g/mol) and hydrophobic nature (logP = 2.050),3 MDMA readily crosses the blood-brain barrier (BBB).4 Chemically, MDMA is related to amphetamine (2), and contains the phenethylamine core structure common to this class of psychostimulants, which also includes methamphetamine (3), and methylphenidate (4) (Figure 1). The hallucinogens 2,5-dimethoxy-4-iodoamphetamine (DOI, 5), 2,5-dimethoxy-4-bromophenethylamine (2C-B, 6), and mescaline (7) are also structurally related to MDMA. As such, it is not surprising that MDMA produces effects reminiscent of both psychostimulants and hallucinogens. However, the interoceptive effects of MDMA (i.e., sense of the body’s internal state) are distinct from those produced by either of these well-known classes of psychoactive compounds.[IMG alt="An external file that holds a picture, illustration, etc.
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Figure 1.
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 rodent drug discrimination studies, MDMA only partially substitutes for the stimulant S-(+)-amphetamine,5 or the ergoline hallucinogen lysergic acid diethylamide (LSD),6 and is unable to substitute for the phenethylamine hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM).7 Furthermore, when rats are trained to discriminate racemic MDMA from saline, incomplete generalization is observed using S-(+)-amphetamine, LSD, or DOM.5 The discriminative stimulus produced by MDMA seems to be modulated by 5-HT1A,8 5-HT2A,8 and oxytocin receptors,9 with less involvement from D1 receptors.10 The two enantiomers of MDMA produce relatively similar discriminative stimuli.11 It should be noted that while MDMA only partially substitutes for S-(+)-amphetamine in rats, it completely substitutes for S-(+)-amphetamine in rhesus monkeys.12
In humans, 75–150 mg of MDMA produces subjective effects that last for several hours.13,14,15,16,17,18,19 These include context-dependent feelings of closeness with others, reduced social inhibition, positive mood, and increased alertness.19,20,21,22,23,24 Regarding hallucinations, MDMA is considered to be weakly hallucinogenic.25 Ingestion of MDMA does not cause auditory hallucinations and only 20% of recreational users have reported experiencing visual hallucinations.15 The visual hallucinations induced by MDMA do not tend to be well-formed, and instead, are often described as flashes of light in the peripheral visual field.15 This is in stark contrast to the profound visual disturbances experienced by most people following the administration of classical hallucinogenic agents such as LSD.26,27 In humans, the weak hallucinogenic effects of MDMA are blocked by ketanserin, a selective 5-HT2A antagonist.25 The role of 5-HT1A receptors in the subjective effects of MDMA appears to be negligible.28,29,30 In addition to directly binding to 5-HT2A receptors, albeit with low affinity (vide infra), MDMA can produce subjective effects by increasing the release of monoamines such as serotonin and norepinephrine.17,31,32,33,34,35 The perceptual effects of MDMA are more intense in females than in males,36,37 and have been shown in recent placebo-controlled studies to be clearly distinct from those produced by other psychostimulants.38,39
The unique subjective effects of MDMA and related molecules such as 3,4-methylenedioxy-N-methyl-α-ethylphenylethylamine (MBDB, 8) and 5,6-methylenedioxy-2-aminoindane (MDAI, 9) led to their classification as a separate family of psychoactive compounds, distinct from both stimulants and hallucinogens (Figure 1). Due to their strong propensity to induce empathy and feelings of connectedness, these drugs were originally dubbed “empathogens” in the 1980s—a term favored by Ralph Metzner.40 David Nichols later highlighted the ambiguous nature of the term empathogen. To avoid any negative connotations associated with “pathos” (i.e., suffering), “pathogen” (i.e., a disease producing agent), or “pathogenesis” (i.e., the development of a disease), Nichols coined the new term “entactogen,” which roughly translates from the Greek to mean that which “produces a touching within” (en = within, tactus = touch, gen = to produce).41 These terms are often used interchangeably. 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.42,43
A major point of contention among psychopharmacologists is whether or not MDMA should be classified as a “psychedelic.” Because that term can be translated as “mind-manifesting,” we propose that MDMA, as well as more potent 5-HT2A agonists like psilocybin, are appropriately placed in this category. Using this classification, psychedelics broadly defined can be subdivided into classical hallucinogens (e.g., psilocybin, LSD, mescaline) and entactogens (e.g., MDMA) on the basis of their distinct subjective effects
The prosocial and stimulant effects of MDMA led to its widespread recreational use and cemented its place in rave (dance party) culture.44 It is estimated that MDMA has been used by 7% of the population over the age of 12.45 This is in stark contrast to heroin, which is abused by only 2% of the population.45 The predominant users of MDMA are teenagers and young adults, with females being more likely to use MDMA than males.46 In people 12–25 years of age, MDMA accounts for more than 50% of all psychedelic drug use.45 In recent years, the recreational use of MDMA by people with college degrees has been increasing.47
Despite its popularity, MDMA is a controlled substance in the United States and many other countries making its production and sale illegal. The U.S. Drug Enforcement Administration (DEA) has classified MDMA as a Schedule I compound—the most restricted class of chemicals. 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. Drugs such as heroin, LSD, gamma hydroxybutyric acid (GHB), and tetrahydrocannabinol (THC) are also classified in Schedule I. 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.48 Furthermore, MDMA may possess therapeutic potential for treating disorders associated with disruptions in social interactions such as autism spectrum disorders, social anxiety disorder, schizophrenia, and post-traumatic stress disorder (PTSD).48
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.
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SYNTHESIS
Racemic MDMA—the form used recreationally and in clinical trials—is typically synthesized from safrole (10) or piperonal (13). The German chemist Anton Köllisch was the first to synthesize MDMA in 1912.49 His synthetic route began with the hydrobromination of 10 to produce 11. Displacement of the bromide with methylamine produces MDMA.50 A similar route was described in the peer-reviewed literature for the first time by Polish chemists Biniecki and Krajewski.51 Alternatively, MDMA can be synthesized from 10 by Wacker oxidation followed by reductive amination of 12 with methylamine and sodium cyanoborohydride. 52,53 Compound 12 can also be accessed from 10, following olefin isomerization to produce isosafrole, peracid oxidation to the epoxide, and acid-catalyzed epoxide isomerization to the ketone.54The 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, 14).55 Conversion of MDA into the carbamate or formamide followed by lithium aluminum hydride reduction yields MDMA. Purification of MDMA is typically achieved following vacuum distillation of the freebase and/or crystallization of the hydrochloride salt.16 The hydrochloride salt can exist as one of several different hydrated forms.1
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.56 Instead, a more successful strategy has relied on the use of removable chiral auxiliaries. The first asymmetric synthesis of MDMA was reported by Nichols and co-workers (Figure 3A).6 Reductive amination of ketone 12 with (S)-α-methylbenzylamine (15) produced the (S,S) intermediate 16 following crystallization. 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 NaBH3CN yielded an inseparable 1:1 mixture of diastereomers (unpublished results). Palladium-catalyzed hydrogenolysis afforded MDA (14), which was converted to MDMA after reduction of the formamide. In 2014, Escubedo and co-workers reported a similar approach using Ellman’s sulfonamide as the chiral auxiliary (Figure 3B).57
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Figure 3.
Synthetic strategies used to synthesize enantiopure MDMA. (A) Reductive amination using (S)-α-methylbenzylamine (B) Reductive amination using Ellman’s sulfinamide (C) Ring opening of an (S)-alanine-derived-aziridine.
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 24. Ring opening in the presence of copper(I) iodide using Grignard reagent 25 affords Ts-protected MDA (26). Methylation of 26 followed by deprotection yields (S)-MDMA.59 The enantiomeric excess of (S)-mDmA produced by Huot and co-workers was not reported, but based on the stereospecific nature of the reactions employed and the fact that the stereocenter is unlikely to epimerize under these conditions, it is assumed that MDMA can be produced as a single enantiomer using this strategy. Nenajdenko and co-workers reported that this is indeed the case for related β-arylalkylamines.58
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PHARMACODYNAMICS
Effects on Monoamines.
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. First, MDMA binds to and inhibits the serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET), inhibiting monoamine reuptake and leading to increased extracellular levels of these amines.35,60,61,62,63 Electrophysiology experiments suggest that this inhibition results from MDMA serving as a substrate, rather than a blocker, of these transporters.64 In contrast to (S)-amphetamine, racemic MDMA is a more potent inhibitor of SERT than either DAT or NET (Tables 1 and and22).65 In addition to inhibiting the uptake of extracellular monoamines, MDMA also prevents transport of monoamines into vesicles. While, MDMA has been shown to inhibit the uptake of serotonin and dopamine into both synaptosomes and vesicles, it does not affect the cellular uptake and/or vesicular packaging of either γ-aminobutyric acid (GABA) or glutamate.66Table 1.
Effects of MDMA on monoamine reuptake using synaptosomes prepared from rat brains. Values for Ki (nM) are reported ± standard deviations.65 NE = norepinephrine; DA = dopamine; 5-HT = serotonin.Compound | NE Uptake | DA Uptake | 5-HT Uptake |
|---|---|---|---|
S-(+)-Amph | 38.9 ± 1.8 | 34 ± 6 | 3,830 ± 170 |
(±)-MDMA | 462 ± 18 | 1,572 ± 59 | 238 ± 13 |
Table 2.
Effects of MDMA on monoamine transport inhibtion using HEK293 cells stably expressing human monoamine transporters. Values for IC50 (μM) are reported with 95% confidence intervals in parentheses.62 NE = norepinephrine; DA = dopamine; 5-HT = serotonin.Compound | NE Uptake | DA Uptake | 5-HT Uptake |
|---|---|---|---|
S-(+)-Amph | 0.094 (0.06–0.14) | 1.30 (0.83–2.0) | >10 |
(±)-MDMA | 0.447 (0.33–0.60) | 17 (12–24) | 1.36 (1.0–2.0) |
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. Inhibitors of SERT, DAT, and NET completely prevent MDMA-induced monoamine efflux in rat brain slices,67 and from monoamine transporter-expressing HEK293 cells pre-loaded with radiolabeled monoamines.35 However, for monoamines to reach sufficiently high cytosolic levels to be reverse transported by membrane transporters, they must first be released from synaptic vesicles into the intracellular space. By directly binding to vesicular amine transporters (VMAT), MDMA reverses the transport of molecules like serotonin.68,69 Additionally, as a weak base, MDMA passively diffuses across vesicular membranes to collapse the pH gradient established by VMAT, which is necessary for maintaining high concentrations of monoamines in vesicles.70,71 Monoamines released from vesicles might be partially protected from degradation due to the ability of MDMA to inhibit both isoforms of monoamine oxidase.72 Moreover, MDMA may cause SERT internalization,73 which presumably contributes to increased extracellular serotonin levels. The releasing effects of MDMA are greater for serotonin and norepinephrine, and slightly weaker for dopamine (Tables 2 and and33).65
Table 3.
Effects of MDMA on monoamine release using synaptosomes prepared from rat brains. Values for EC50 (nM) are reported ± standard deviations.65 NE = norepinephrine; DA = dopamine; 5-HT = serotonin.Compound | NE Release | DA Release | 5-HT Release |
|---|---|---|---|
S-(+)-Amph | 7.07 ± 0.95 | 24.8 ± 3.5 | 1,765 ± 94 |
(±)-MDMA | 77.4 ± 3.4 | 376 ± 16 | 56.6 ± 2.1 |
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.74 There is a general consensus that MDMA increases the release of monoamines, however, there is at least one study using fast-scan cyclic voltammetry (FSCV) in brain slices that suggests that increases in monoamine concentrations following MDMA treatment might be due to inhibition of monoamine reuptake and not release per se.75
Direct Effects on Receptors.
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.76,77,62 The binding profile of MDMA across much of the recepterome is shown in Table 5. The low micromolar affinities observed support the notion that MDMA induces most of its effects indirectly by modulating monoamine levels. The 5-HT2B receptor is one of the few receptors that MDMA binds to with submicromolar affinity (Ki = 500 nM), though the role of this receptor in the effects of MDMA is unclear. For example, MDMA failed to produce a response in a 5-HT2B functional assay using HEK293 cells.78 However, it is believed that 5-HT2B agonism is at least partly responsible for the 5-HT releasing effects of MDMA, as pharmacological inhibition or genetic deletion of 5-HT2B receptors block MDMA-induced release of 5-HT.79 Binding of MDMA to 5-HT2B receptors was studied using a radiolabeled agonist, while many of the other receptor binding assays (e.g., 5-HT2A ad 5-HT2C) utilized radiolabeled antagonists. 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 3H-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.Table 4.
Effects of MDMA on monoamine release using monoamine-preloaded HEK293 cells stably expressing human monoamine transporters. Values for EC50 (μM) are reported with 95% confidence intervals in parentheses.62 NE = norepinephrine; DA = dopamine; 5-HT = serotonin.Compound | DA Release | 5-HT Release |
|---|---|---|
S-(+)-Amph | 1.76 (1.1–2.9) | >33 |
(±)-MDMA | 22 (8.9–53) | 5.63 (3.5–9.2) |
Table 5.
Binding affinity profile for (±)-MDMA with values for Ki reported in nM. Radioligand binding assays were performed using stably or transiently expressing cell lines (HEK, HEKT, or CHO) unless noted otherwise.Receptor | Radiolabeled Ligand | Ligand Classification | Species | Ki (nM) | Reference |
|---|---|---|---|---|---|
5-HT1A | 3H- H-DPAT | Agonist | Human | >10,000 | 77 |
5-HT1A | 3H- H-DPAT | Agonist | Human | 12,200 | 62 |
5-HT 1B | 3H-GR-125743 | Antagonist | Human | >10,000 | 77 |
5-HT 1D | 3H-GR-125743 | Antagonist | Human | >10,000 | 77 |
5-HT 1E | 3H-5-HT | Agonist | Human | >10,000 | 77 |
5-HT2A | 3H-Ketanserin | Antagonist | Rat | >10,000 | 77 |
5-HT2A | 3H-Ketanserin | Antagonist | Human | 7,800 | 62 |
5-HT2B | 3H-LSD | Agonist | Human | 500 | 77 |
5-HT2C | 3H-Mesulergine | Antagonist | Rat | >10,000 | 77 |
5-HT2C | 3H-Mesulergine | Antagonist | Human | >13,000 | 62 |
5-HT3 | 3H-Zacopride | Antagonist | Human | >10,000 | 77 |
5-HT5 | 3H-LSD | Agonist | Human | >10,000 | 77 |
5-HT6 | 3H-LSD | Agonist | Human | >10,000 | 77 |
5-HT7 | 3H-LSD | Agonist | Human | >10,000 | 77 |
Alpha1A | 125I-HEAT | Antagonist | Human | >10,000 | 77 |
Alpha1A | 3H-Prazosin | Inverse Agonist | Human | >6,000 | 62 |
Alpha1B | 125I-HEAT | Antagonist | Human | >10,000 | 77 |
Alpha2A | 3H-Clonidine | Agonist | Human | 2,532 | 77 |
Alpha2A | 3H- Rauwolscine | Antagonist | Human | 15,000 | 62 |
Alpha2B | 3H-Clonidine | Agonist | Human | 1,785 | 77 |
Alpha2C | 3H-Clonidine | Agonist | Human | 1,123 | 77 |
Beta1 | 125I-Pindolol | Partial Agonist | Rat | >10,000 | 77 |
Beta2 | 125I-Pindolol | Partial Agonist | Rat | >10,000 | 77 |
CB1 | 3H-CP-55940 | Agonist | Rat (brain) | >10,000 | 77 |
M1 | 3H-QNB | Antagonist | Human | >10,000 | 77 |
M2 | 3H-QNB | Antagonist | Human | >10,000 | 77 |
M3 | 3H-QNB | Antagonist | Human | 1,851 | 77 |
M4 | 3H-QNB | Antagonist | Human | 8,245 | 77 |
M5 | 3H-QNB | Antagonist | Human | 6,339 | 77 |
Nicotinic Alpha1Beta2 | 3H-Epibatidine | Agonist | Human | >10,000 | 77 |
Nicotinic Alpha2Beta2 | 3H-Epibatidine | Agonist | Human | >10,000 | 77 |
Nicotinic Alpha2Beta4 | 3H-Epibatidine | Agonist | Human | >10,000 | 77 |
Nicotinic Alpha3Beta2 | 3H-Epibatidine | Agonist | Human | >10,000 | 77 |
Nicotinic Alpha3Beta4 | 3H-Epibatidine | Agonist | Human | >10,000 | 77 |
Nicotinic Alpha7 | 3H-Epibatidine | Agonist | Human | >10,000 | 77 |
D1 | 3H-SCH23390 | Antagonist | Human | >10,000 | 77 |
D1 | 3H-SCH23390 | Antagonist | Human | >13,600 | 62 |
D2 | 3H-NMSP | Antagonist | Human | >10,000 | 77 |
D2 | 3H-Spiperone | Antagonist | Human | 25,200 | 62 |
D3 | 3H-NMSP | Antagonist | Human | >10,000 | 77 |
D3 | 3H-Spiperone | Antagonist | Human | >17,700 | 62 |
D4 | 3H-NMSP | Antagonist | Rat | >10,000 | 77 |
D5 | 3H-SCH23390 | Antagonist | Human | >10,000 | 77 |
GABA A | 3H-Muscimol | Agonist | Rat (forebrain) | >10,000 | 77 |
GABA B | 3H-Baclofen | Agonist | Rat (forebrain) | >10,000 | 77 |
NMDA | 3H-MK-801 | Antagonist | Rat (forebrain) | >10,000 | 77 |
H1 | 3H-Pyrilamine | Antagonist | Human | 2,138 | 77 |
H1 | 3H-Pyrilamine | Antagonist | Human | >14,400 | 62 |
H2 | 3H-Pyrilamine | Antagonist | Human | >10,000 | 77 |
Prostaglandin EP3 | 3H-PGE2 | Agonist | Human | >10,000 | 77 |
Prostaglandin EP4 | 3H-PGE2 | Agonist | Human | >10,000 | 77 |
NET | 3H-Nisoxetine | Inhibitor | Human | >10,000 | 77 |
NET | 3H-Nisoxetine | Inhibitor | Human | 30,500 | 62 |
DAT | 3H-GBR 12935 | Inhibitor | Human | >10,000 | 77 |
DAT | 3H-WIN35,428 | Inhibitor | Human | 6,500 | 62 |
SERT | 3H-Citalopram | Inhibitor | Human | >10,000 | 77 |
SERT | 3H-Citalopram | Inhibitor | Human | 13,300 | 62 |
TAAR1 | 3H-RO5166017 | Agonist | Rat | 370 | 62 |
TAAR1 | 3H-RO5166017 | Agonist | Mouse | 2,400 | 62 |
Trace Amine-Associated Receptor 1 (TAAR1).
The trace-amine associated receptor (TAAR1) has also been suggested as a key target mediating the effects of MDMA. Bunzow and co-workers demonstrated that MDMA acts as an agonist at rat TAAR1 receptors to increase cAMP production in a TAAR1-expressing HEK293 cell line.80 Like MDMA, several other hallucinogens and psychostimulants have been shown to bind to and activate TAAR1 to a greater extent than neurotransmitters such as serotonin, dopamine or norepinephrine.80,81,82 Due to the known modulatory influence of TAAR1 on monoamine transporter function,83 it is likely that TAAR1 activation contributes to the effects of MDMA on extracellular monoamine levels. Interestingly, 4-hydroxyamphetamine proved to be a particularly potent agonist of TAAR1 (EC50 = 51 nM). As MdMa is metabolized into 4-hydroxy-substituted compounds, there is the distinct possibility that metabolites of MDMA may potently activate TAAR1. However, to the best of our knowledge, this hypothesis has not been directly tested. Finally, it is unclear if TAAR1 plays any role in the effects of MDMA in humans, as MDMA does not activate human TAAR1 in cellular assays like it does mouse and rat TAAR1.84Sigma-1 Receptor.
Radioligand binding studies have shown that MDMA binds to both sigma-1 and sigma-2 receptors with Ki values in the low micromolar range, which are comparable to the affinities of MDMA for monoamine transporters.85 Moreover, treatment with BD1063, a selective sigma-1 antagonist, blocked the effects of MDMA on rodent locomotion.85 The sigma-1 receptor has been proposed to be a novel target for the treatment of depression and anxiety,86,87,88,89,90 and it is reasonable to hypothesize that this receptor plays some role in the behavioral and clinical effects of MDMA.Hormonal Effects.
Administration of MDMA to humans leads to robust increases in plasma levels of cortisol, prolactin, dehydroepiandrosterone (DHEA), vasopressin, and oxytocin.18,38,91,92,93,94,95,96 It is possible that some of these hormonal changes are the result of serotonergic activity,97,98,99 and it is likely that they modulate some of the effects of MDMA.100 For example, the rise in plasma DHEA levels was significantly correlated with feelings of euphoria.18 Furthermore, the effects of MDMA on oxytocin levels are often invoked to explain the drug’s prosocial effects. Dumont and co-workers were the first to demonstrate in a controlled laboratory setting that MDMA increases oxytocin levels.93 They also found that increases in blood oxytocin levels were correlated with the subjective prosocial feelings induced by MDMA more so than blood levels of the drug itself. 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.100,101 As such, the role of oxytocin in the effects of MDMA is currently controversial.Behavioral Effects in Rodents.
Like other serotonergic psychedelics, MDMA produces behavioral effects consistent with serotonin syndrome such as flat body posture, hind limb abduction, and forepaw treading.102 At lower doses, MDMA produces “amphetamine-like” hyperactivity in the open field. Both of these effects are enhanced following repeated administration of MDMA, demonstrating that MDMA is capable of producing behavioral sensitization.103 Behavioral sensitization is correlated with the enhanced ability of MDMA to increase monoamine levels (measured via microdialysis) following repeated dosing. 104 The locomotor effects of MDMA are perhaps the best-studied behavioral responses in rodents, and they are modulated by a variety of neuroreceptors including 5-HT1B,105 5-HT2A,106 D1,107 and D2107 receptors. Unlike amphetamine, selective serotonin reuptake inhibitors block MDMA-induced increases in locomotion.108 Furthermore, MDMA does not produce this behavioral effect in mice genetically lacking SERT, further implicating this monoamine transporter in the hyperlocomotive effects of MDMA.109In rodent models of anxiety, MDMA produces complex effects. At low acute and subchronic doses, MDMA tends to be anxiogenic in the elevated plus maze (EPM).110,111,112 However, at higher acute and subchronic doses, MDMA produces anxiolytic effects in the EPM. When tested in the light-dark box paradigm, MDMA does not alter preferences of mice for the two compartments.113
Some of the rodent behaviors most relevant to potential therapeutic uses of MDMA are related to social behaviors. A 5 mg/kg dose of MDMA decreased aggressive behaviors in rats and increased the time spent engaging in social behaviors such as sniffing, following, crawling under, crawling over, mutual grooming, and adjacent lying.114 Additionally, MDMA has been shown to induce a social conditioned place preference.115 Adjacent lying—a behavior in rats where two unfamiliar animals lie passively next to each other—is perhaps one of the more robust prosocial behaviors induced by MDMA in rodents.
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.99 Increases in oxytocin levels and adjacent lying behavior induced by MDMA were abolished by treatment with a 5-HT1A antagonist, while
H-DPAT (a 5-HT1A agonist) produced effects similar to MDMA.99 This led McGregor and co-workers to propose that MDMA induces oxytocin release via stimulation of 5-HT1A receptors, and that increased adjacent lying resulted from activation of oxytocin receptors. This hypothesis was supported by the fact that intracerebroventricular administration of tocinoic acid, an oxytocin receptor antagonist, blocked MDMA-induced adjacent lying.99 However, in a follow-up study, McGregor and co-workers could not prevent MDMA-induced adjacent lying using C25,116 a systemically administered non-peptidic antagonist of oxytocin receptors. In contrast, they were able to prevent this behavior using an antagonist of the vasopressin receptor 1A.117 There are two possibilities that might explain these contradictory results. 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.118 This seminal study potentially provides a mechanistic explanation for the therapeutic efficacy of MDMA in patients suffering from treatment-resistant PTSD (vide infra). Similar findings have been described for other psychedelics such as psilocybin in mice119 and N,N-dimethyltryptamine (DMT) in rats.120 The facilitation of fear extinction memory by MDMA appears to be dependent on SeRt.121
Plasticity-Promoting Effects.
Like most psychostimulants, MDMA causes robust changes in gene expression and protein levels associated with neural plasticity.122 Acute treatment with MDMA (10 mg/kg) causes differential gene expression of BDNF in the frontal cortex and hippocampus of rats, with BDNF levels increasing in the former brain region and decreasing in the latter.123 The administration of 4 doses over a period of 6 h to rats led to robust increases in BDNF transcript levels in several cortical regions both 1 h and 7 h following dosing.124 The largest effects were seen in the prefrontal cortex with increases in TrkB expression observed in that region 24 h after dosing.124 Here, MDMA produced weaker effects on NT3 and TrkC gene expression.124 Chronic treatment with MDMA in mice125 and subchronic administration of large doses (20 mg/kg) in rats126 led to increases in BDNF transcription and translation in the hippocampus. 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,127 though the relevance of this cell line to studies on neural plasticity is debatable.To date, most studies assessing the psychoplastogenic (plasticity-promoting) effects of MDMA have observed a reduction in dendritic branching and/or dendritic spine numbers. 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. Recently, we reported that MDMA, and several other psychedelic compounds, significantly increased the complexity of dendritic arbors in cultured cortical neurons128 Moreover, this phenotype is not produced by all psychostimulants and drugs of abuse, as S-(+)-amphetamine had no effect.128 Future studies should assess the in vivo effects of a single moderate dose of MDMA on dendritic branching and spine density.
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METABOLISM AND PHARMACOKINETICS
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 P450s.129 The common metabolites of MDMA (1) include MDA (14), 3,4-dihydroxymethamphetamine (HHMA, 28), 3,4-dihydroxyamphetamine (HHA, 29), 4-hydroxy-3-methoxy-methamphetamine (HMMA, 30), and 4-hydroxy-3-methoxy-amphetamine (HMA, 31). The major metabolite of MDMA in humans is HMMA, which is mainly excreted as the glucuronic acid conjugate.130[IMG alt="An external file that holds a picture, illustration, etc.
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Figure 4.
Common metabolites of MDMA. CYP = cytochrome P450; COMT = catechol-O-methyltransferase.
Recent genetic findings suggests that a variety of cytrochrome P450s, including CYP2C19, CYP2B6, and CYP1A2, play a role in the demethylation of MDMA.131,132 Mutations in the CYP2C19 or CYP2B6 genes that reduce enzyme function have been shown to increase the ratio of MDMA/MDA but do not alter HMMA concentrations.131,132 Subjects with decreased CYP2C19 function also showed greater cardiovascular responses with faster onset times. Mutations in the CYP2B6 gene resulting in decreased enzyme function only influenced metabolism at later time points (i.e., 3–4 h) suggesting that it is a secondary metabolizer of MDMA.131
When MDMA is administered to humans at a dose of 100 mg, it has a half-life of approximately 8–9 h and yields plasma Cmax and tmax values of 222.5 ng/ml and 2.3 h, respectively.133 However, MDMA is known to exhibit nonlinear pharmacokinetics in both humans131,134,135 and squirrel monkeys.136 This means that increasing doses of MDMA prolong its half-life, potentially exacerbating the risk for adverse effects and neurotoxicity. The nonlinear pharmacokinetics observed following administration of MDMA is likely the result of cytochrome P450 inhibition by MDMA and its metabolites.131,137,138 Additionally, the enantiomers of MDMA are metabolized at different rates, with the R-enantiomer having a longer half-life than the S-enantiomer.139,140, 141
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ADVERSE EFFECTS
Similar to other amphetamines, MDMA produces a number of adverse effects including trismus, tachycardia, bruxism, dry mouth, palpitations, diaphoresis, and insomnia.15,19,36,142 Rhabdomyolysis, cardiac arrhythmias, hyperthermia, hyponatremia, and acute renal failure are the more severe side-effects and are common causes of death following MDMA intoxication.143,144 The more severe adverse effects of MDMA are potentially exacerbated by the intense exercise and hot environment characteristic of raves. 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 LD50 in rats at room temperature.145 Similarly, Fantegrossi and co-workers found that MDMA lethality was increased when NIH Swiss mice were housed at high densities (>6 mice per cage), which reduces the ability to dissipate body heat.146 Risk for serotonin syndrome—a collection of symptoms that include high body temperature, sweating, and tremor (among others)—increases with higher doses of MDMA.147The effects of MDMA on heart function are also significant, with norepinephrine mediating a significant portion of the cardiostimulant effects observed following MDMA administration.34,35,148,149 In addition to increasing systolic blood pressure,19,36,92 the drug can induce cardiac arrhythmias and myocarditis.150 Myocardial infarction can also occur following MDMA use, though this tends to happen less frequently than after cocaine or amphetamine administration.151,152 In the long-term, MDMA use can result in valvular heart disease,153 which could be due to oxidative stress154 or the activation of 5-HT2B receptors by MDMA.77
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.15 However, in animal models, MDMA does produce some of the same behavioral effects characteristic of addictive drugs like cocaine and opioids, albeit to a lesser extent. For instance, MDMA is known to produce conditioned place preference in rats155 and mice,156,157 and MDMA is self-administered by a variety of species (e.g., rats, mice, non-human primates).158 Interpretation of self-administration studies using MDMA are complicated by a variety of factors such as dose, timing, and prior exposure of the test animals to other drugs of abuse. For an overview of these issues, we refer the reader to an excellent review by Susan Schenk.158 Taken together, MDMA does seem to have reinforcing properties, but these appear to be significantly weaker than those of cocaine.
Determining the adverse effects of MDMA in people who consume it recreationally is complicated by the fact that some “MDMA” sold on the street does not contain any MDMA at all,159 while other batches of illegally produced “MDMA” are adulterated.160 Contaminating drugs include, but are not limited to, amphetamine, methamphetamine, MDA, pseudoephedrine, butylone, and caffeine.161,162 Many recreational MDMA users prefer “molly” as it is believed to be of high purity, however, a recent study employing hair follicle testing revealed that 48% of molly users tested positive for synthetic cathinones despite having reported that they had never used cathinones before.163 Consuming MDMA as a part of a drug mixture can be extremely dangerous due to drug-drug interactions,164 and has important implications for evaluating the neurotoxic potential of MDMA in humans.
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,165,166,167,168,169,170,171 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.g., working and declarative memory) when compared to MDMA-naïve controls.172,173,174,175 Those with a history of only moderate MDMA use do not seem to exhibit memory impairments.176 However, acute MDMA intoxication produces memory deficits.176 Heavy MDMA users tend to have lower cerebral spinal fluid levels of 5-hydroxyindoleacetic acid (5-HIAA)—the principle metabolite of serotonin—and thus, serotonergic toxicity has been presumed.177 In general, neuroimaging studies used to assess the effects of MDMA in humans have produced mixed findings, with no clear evidence that MDMA is safe or neurotoxic.178,179 Finally, when compared with MDMA-naïve controls, MDMA users are more likely to be afflicted with mental illnesses including depression, psychotic disorders, eating disorders, and anxiety disorders.180
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.181 Third, recreational MDMA is often consumed at crowded dance parties (i.e., raves), where excessive activity, high temperatures, and dehydration could exacerbate any inherently neurotoxic effects of the drug. 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.182 However, a much larger study from Germany concluded that MDMA users had significantly higher risk for nearly all DSM-IV mental disorders, and moreover, that the onset of these disorders typically preceded the first use of MDMA.183
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.184 Furthermore, they discovered that the metabolites of MDMA are more potent neurotoxins.185 Similarly, Stumm and co-workers reported that MDMA and related amphetamines kill cultured rat cortical neurons at comparable concentrations.186 It is important to note that the concentration of MDMA required to produce substantial neurotoxic effects in these studies is >200 μM, while the maximal brain concentration of MDMA in rats following a 20 mg/kg subcutaneous dose (10x the behaviorally relevant dose) is only circa 100–200 μM.187 At a more modest concentration (10 μM), our group determined that MDMA produced robust psychoplastogenic effects in embryonic rat cortical cultures without cell death.128 For comparison, we have observed that several SSRIs and triptans—commonly prescribed medications—are cytotoxic to cultured rat cortical neurons in the range of 10–100 μM (unpublished results).
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 1987 suggest that MDMA has neurotoxic effects in animals,188 the relevance of these models to human neurotoxicity is highly debated. Some of the contentious questions the field has to grapple with include, 1) what dosing paradigm most effectively models human use, 2) what species is most relevant, 3) is allometric scaling appropriate, 4) how should the nonlinear human pharmacokinetics of MDMA be factored in, 5) what route of administration should be utilized, and 6) how should “neurotoxicity” be defined/measured (e.g., monoamine levels, neurite degeneration, cell body loss).
In mice, MDMA tends to produce dopaminergic, but not serotonergic, neurotoxicity.189,190,191 This is in sharp contrast to rats, for which the opposite seems to be true. Two weeks following systemic administration of MDMA to rats (20 mg/kg, subcutaneous, twice daily for 4 d) loss of 5-HT axons (but not catecholamine axons) projecting to the forebrain was observed.192 Interestingly, axonal degeneration was not accompanied by loss of raphe cell bodies.192 As a result, serotonergic axons regenerate in rats administered MDMA, however, it is unknown how well these newly sprouted axons function.193 Additionally, large doses of MDMA produce reductions in levels of 5-HT, 5-HIAA, and SERT.194,195,196 Levels of 5-HT reuptake sites in rats partially recovered 6 months following MDMA exposure and were fully recovered after 1 year.194,197 Similarly, 8 doses of MDMA given to rats over 4 days decreased brain 5-HT2 receptor levels by 80% when measured 6 h after the last dose.198 Receptor levels recovered to 62% after 24 h and were completely normalized after 21 days.198 The MDMA-induced serotonergic neurotoxicity in rats is exacerbated by increased ambient temperature199 and can be prevented by blocking SERT with fluoxetine.200 It should be noted that the doses of MDMA used in rats and mice to induce neurotoxicity are much higher than those often used by humans. Some researchers have justified these large rodent doses on the basis of allometric scaling201 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.202 Others have argued that MDMA doses used in animals are too high, as MDMA produces behavioral effects at approximately the same dose (1–2 mg/kg) in humans and rats.167 Finally, it has been posited that species differences in metabolism and neurotoxicity (e.g., dopaminergic toxicity in mice vs. serotonergic toxicity in rats) suggest that the metabolites of MDMA, and not necessarily MDMA itself, are responsible for the neurotoxic effects of MDMA.168 Therefore, using model systems that more closely recapitulate the pharmacokinetics of MDMA in humans may be more useful.
Like rats, non-human primates experience serotonergic neurotoxicity following administration of large doses of MDMA.203,204 Unlike rats, these changes seem to be relatively long-lasting in most primate brain regions.205,206 Abnormal serotonergic innervation patterns were observed 7 years following MDMA exposure in squirrel monkeys,207 and these patterns seemed to result from axotomy as raphe cell bodies remained intact.207 In rhesus monkeys, persistent decreases in cerebrospinal fluid levels of 5-HIAA were accompanied by functional changes as measured by electrophysiology.208 Most of the studies assessing the neurotoxic effects of MDMA in primates administered multiple subcutaneous doses. However, humans typically consume a single oral dose of MDMA either recreationally or during MDMA-assisted psychotherapy (vide infra). 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.209 Importantly, they found that a single, modest (5 mg/kg), oral dose of MDMA still produced serotonin depletion in the thalamus and hypothalamus two weeks after administration.209
The mechanism of MDMA-induced neurotoxicity probably involves a combination of mechanisms including glutamate-induced excitotoxicity,210 increased oxidative stress,211 hyperthermia,212 mitochondrial damage, and increased inflammation.169,171 While the results of the numerous studies investigating MDMA-induced neurotoxicity still leave questions unanswered about the safety of MDMA administered to humans, it is reasonable to conclude that use of MDMA under common recreational conditions (e.g., high doses, multiple doses, polydrug use, high temperatures, prolonged physical activity, dehydration, etc.) is likely to cause adverse effects. 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.213,214
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POTENTIAL USE IN MEDICINE
In recent years there has been renewed interest in using psychedelic compounds like psilocybin and MDMA to treat neuropsychiatric disorders.215,216,217 This should not be surprising because before MDMA was placed on the Schedule I list, it was widely used by some psychiatrists to assist in treating a variety of disorders including anxiety disorders and depression. 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.218,219 However, most of the work conducted during this period yielded only anecdotal reports, and there were no placebo-controlled clinical trials conducted that adhered to current rigorous standards.In contrast, recent clinical studies assessing the therapeutic potential of MDMA for treating PTSD are carefully controlled and well documented.220,221,222 First, patients are screened for medical conditions, including various neuropsychiatric disorders, that might exclude them from the study. Next, they are assessed at baseline using the Clinician-Administered PTSD Scale (CAPS). 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. Music is often used to facilitate relaxation and/or evoke emotions. 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.221 The use of an active placebo is an important part of the experimental design implemented by Oehen and co-workers. 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 125 mg of MDMA followed by an additional 62.5 mg after 2.5 h. The active placebo group received an initial dose of 25 mg of MDMA followed by an additional 12.5 mg 2.5 h later. 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.223 Of particular note is recent clinical work demonstrating that MDMA can produce beneficial effects in treatment-resistant PTSD patients when it is paired with psychotherapy.220,221,224, The beneficial effects of this treatment paradigm seemed to be relatively long-lasting, as demonstrated by follow-up studies conducted several years later.225 A recent meta-analysis determined that MDMA-assisted psychotherapy produced larger effect sizes in both clinician-observed outcomes and patient self-reports when compared to prolonged exposure therapy.226 Furthermore, fewer patients in the MDMA-assisted psychotherapy group dropped out of the study.226 These studies and others have indicated that MDMA was well tolerated when administered in a clinical setting as a single dose in the range of 75–125 mg.19 Recently, MDMA was granted “breakthrough therapy” status by the FDA for the treatment of PTSD. The phase III clinical trials are estimated to be completed within the next five years, and if the results are positive, it is anticipated that a New Drug Application for MDMA will be submitted to the FDA around 2021.227
Recent clinical work to understand the mechanism of MDMA’s therapeutic effects has revealed that this drug impacts the processing of emotionally salient information. 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.228 In this study, MDMA also impacted the performance of people during the Reading the Mind in the Eyes Test—a test that has participants attempt to predict what a person is thinking/feeling based on a picture of their face. 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.229 Moreover, Carhart-Harris and co-workers found that while under the influence of MDMA, participants rated their best and worst memories as being significantly more positive and less negative, respectively.230 Related to its subjective effects, MDMA increased bilateral blood flow in the ventromedial prefrontal cortex and reduced blood flow in the left amygdala231—two brain regions that play important roles in the processing of emotional stimuli and memories. 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,232 and it has been suggested that MDMA may prove useful in other conditions with a significant social component.48
Finally, MDMA may hold some promise for treating substance use disorders (SUDs).233,234 Initial reports suggest that MDMA might decrease substance use,235 and a pilot study conducted by Howell and co-workers demonstrated that R-(−)-MDMA decreased response rates during a cocaine self-administration paradigm in squirrel monkeys.236 Though very few animals were used in the latter study, the results are encouraging. 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.
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S-(+)-MDMA VS R-(−)-MDMA
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.237 The R- and S-enantiomers are sometimes referred to as the l- and d-enantiomers, respectively. An excellent review on this subject was published recently by Howell and coworkers,236 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.59,77,238,239,240,241,242,243,244,245,246 This is consistent with what is known about the effects of S-(+)-amphetamine on monoamine levels. However, R-(−)-MDMA appears to be a more potent direct binder of 5-HT2A receptors (Table 6),247,248 which perhaps explains why it has a greater propensity for causing perceptual disturbances. Neither enantiomer is particularly effective at stimulating phosphatidyl inositol turnover in either 5-HT2A or 5-HT2C expressing cells.249 When rats were trained to discriminate S-(+)-amphetamine, LSD, and saline from each other in a 3-lever drug discrimination paradigm, R-(−)-MDMA and S-(+)-MDMA produced more hallucinogen-like and amphetamine-like discriminative stimuli, respectively.250 Furthermore, experiments using mice trained to discriminate either S-(+)-MDMA or R-(−)-MDMA from vehicle demonstrated that the S-enantiomer produced more psychostimulant-like effects while the R-enantiomer was more hallucinogen-like.251
Table 6.
Binding affinity profile for (±)-MDMA, R-(−)-MDMA, and S-(+)-MDMA with values for Ki reported in nM ± SEM.247Receptor | Hot Ligand | Hot Ligand Activity | (±)-MDMA | R-(−)-MDMA | S-(+)-MDMA |
|---|---|---|---|---|---|
5-HT 1 | 3H-5-HT | Agonist | 6,850 ± 1,300 | 4,200 ± 500 | >10,000 |
5-HT2 | 3H-Ketanserin | Antagonist | 8,300 ± 1,100 | 3,310 ± 140 | >10,000 |
D2 | 3H-NMSP | Antagonist | >10,000 | >10,000 | >10,000 |
In terms of their influences on hormone levels, the enantiomers of MDMA also have differential effects. Ex vivo studies utilizing rat hypothalamus tissue demonstrated that S-(+)-MDMA is a more potent inducer of oxytocin release than the racemate, while R-(−)-MDMA has no effect.252 However, R-(−)-MDMA was more effective at increasing the activation of hypothalamic oxytocinergic neurons, as measured by the number of c-fos positive neurons.236 Both enantiomers appear to increase vasopressin secretion comparably from the hypothalamus ex vivo.252 R-(−)-MDMA more potently increased plasma prolactin levels in rhesus macaques.245 Pretreatment with fluoxetine attenuated this effect, but did not block it completely. The selective 5-HT2A antagonist M100907 was required to completely inhibit R-(−)-MDMA-induced increases in prolactin, suggesting that indirect effects on 5-HT levels, as well as direct binding to 5-HT2A receptors contribute to the ability of R-(−)-MDMA to increase prolactin levels.246
Behaviorally, both enantiomers increase affiliative social behaviors in squirrel monkeys, and this effect seems to be dependent on activation of 5-HT2A receptors.253 In mice, R-(−)-MDMA and the racamate (but not S-(+)-MDMA) increased social interaction and facilitated fear extinction learning, effects that could be relevant to using MDMA as a therapeutic.254 Furthermore, the R-enantiomer did not increase locomotor activity, a behavioral effect commonly produced by psychostimulants.254
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. Unlike R-(−)-MDMA, S-(+)-MDMA increased body temperature and promoted the activation of microglia and astroglia.255 However, this study employed a relatively low dose of R-(−)-MDMA. To more definitely establish a lack of neurotoxicity following R-(−)-MDMA administration, Howell and co-workers administered high doses of R-(−)-MDMA (four injections of 50 mg/kg given over two days) to mice and compared effects to those produced by the racemic mixture (four injections of 20 mg/kg given over two days).254 These authors assessed body temperature, mortality, and markers of neurotoxicity. Unlike the racemate, high dose R-(−)-MDMA did not influence body temperature or survival. Furthermore, the R-enantiomer had no effect on glial fibrillary acidic protein (GFAP) immunoreactivity, DA content, or DAT expression. 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.
Thus, R-(−)-MDMA may be an effective pharmaceutical with an acceptable therapeutic index. However, neurotoxicity and other negative effects associated with S-(+)-MDMA and racemic MDMA will always be associated with the acryonym “MDMA,” having the potential to bias regulatory bodies, doctors, and patients. Therefore, to identify a term suitable for common parlance, but devoid of negative connotations, we suggest the use of the alternate terms “armdma,” “esmdma,” and “racmdma” to refer to R-(−)-MDMA, S-(+)-MDMA, and (±)-MDMA, respectively. These terms are analogous to “arketamine” and “esketamine,” which refer to the R- and S-enantiomers of the fast-acting antidepressant ketamine, respectively. If armdma proves to be an effective and safe therapeutic in humans, we hope this new terminology will eliminate any potential stigma associated with using a perceived “party-drug” as a medicine.
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HISTORY AND IMPORTANCE IN NEUROSCIENCE
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,44,49,256,257 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. Instead, MDMA originated from a campaign by Merck to sidestep a patent on the hemostatic drug hydrastinine held by Bayer, one of Merck’s top rivals. In fact, MDMA was first synthesized in 1912 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.256[IMG alt="An external file that holds a picture, illustration, etc.
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Figure 5.
Timeline of important events related to research on MDMA and classical psychedelics. Note the different peaks for research on MDMA and LSD. The data were obtained from a PubMed search for papers having titles that contained the search terms “3,4-methylenedioxymethamphetamine or MDMA” and “lysergic acid diethylamide or LSD” conducted on March 20, 2018.
Research on MDMA appeared to stagnate until the 1950s. At that time the US military began using mescalinelike compounds, including MDMA, as part of pharmacologically-assisted interrogation programs.258 In essence, they were trying to identify so-called “truth drugs”—compounds capable of lowering inhibitions making people more likely to reveal secret information. The chemical warfare code of MDMA was EA-1475.44 The methylenedioxy-containing entactogens, such as MDA and MDMA, were of particular interest to the military because these compounds tended to encourage people to speak more openly without causing overwhelming perceptual disturbances. The characteristic hallucinations produced by compounds like LSD and mescaline typically disrupted interrogation sessions. In the early 1950s, the military began testing several of these compounds on patients at the New York State Psychiatric Institute. In 1952, a patient named Harold Blauer was administered several compounds over the course of a month before succumbing to a fatal dose of MDA (450 mg).258 Realizing that safety data on these compounds were woefully lacking, the military contracted a group at the University of Michigan to conduct pharmacokinetic and safety studies in mice, rats, guinea pigs, dogs, and monkeys.259 After declassification, these data were published in 1973 and revealed that the methylenedioxy compounds were more toxic than their methoxy counterparts.259
The first report of the synthesis of MDMA in the peer-reviewed literature was in 1960.260 Afterwards, MDMA remained relatively unexplored until Alexander Shulgin learned of the unique effects of the compound and tested MDMA on himself in 1976.261 Thereafter, Shulgin distributed it to friends and psychotherapists in northern California, who began using MDMA to facilitate psychotherapy. Shulgin and Nichols were the first to publish on the effects of MDMA in humans in 1978.13,14 Though Shulgin is often credited with the rediscovery of MDMA,261 the role of David Nichols should also be emphasized as Nichols was a co-author on these first reports of the effects of MDMA in humans. Furthermore, he was largely responsible for reclassifying MDMA and related compounds as entactogens, due to their unique qualities relative to hallucinogens and psychostimulants.41
During the period from 1978 to 1985, it is estimated that thousands of patients were treated with MDMA.216 However, these initial studies did not adhere to the same rigorous standards that we demand of clinical trials today. 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. At the time, there was little data on the safety of MDMA, and thus, the DEA decided to place it on the Schedule I list in 1985 largely based on its structural similarity to MDA.262 This decision was protested by a large number of scientists and therapists, and challenged in court, but ultimately, MDMA was permanently placed on the Schedule I list in 1988.
In a 2002 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.263 These authors suggested that MDMA might put users at risk for developing Parkinson’s disease. The results of the study were rapidly disseminated by the popular media, leading to the widespread public belief that administration of “recreational doses” of MDMA (3 doses of 2 mg/kg spaced over 6 hours) could have major health consequences. When Ricaurte and co-workers could not reproduce their results, they retracted their Science paper a year later.264 Further analysis revealed that animals used in the original study were likely dosed with methamphetamine, a known dopamine neurotoxin, instead of MDMA, due to a mix-up in the labeling of sample vials.
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. In 2009, David Nutt published an editorial where he compared the dangers of using ecstasy (1 serious adverse event in 10,000) to those of horseback riding or “equasy” (1 serious adverse event in 350).265 This editorial highlighted the fact that people in the scientific community felt that government agencies were not using objective criteria for assessing risk when establishing regulations for psychoactive compounds like MDMA. 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 2011, the first completed clinical trial evaluating the potential of MDMA-assisted psychotherapy for alleviating treatment-resistant PTSD was published.220 The results were positive, and in 2017, MDMA was granted “breakthrough therapy” status by the FDA. 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.
Since 2012, there has been an upswing in the numbers of songs and pop culture references to “molly,” a trend that parallels that seen for LSD in the 1960s and 1970s. Extensive proselytizing about the non-medical uses of LSD contributed to the creation of the Controlled Substance Act of 1970. This legislation has been a huge barrier to legitimate scientific research on the effects of these drugs and led to the first “Dark Age” for the field—the period of time from roughly 1970 to 1994 when relatively little psychedelic research was conducted. If public discourse on MDMA takes a similar course to that of LSD, we may be doomed to repeat the mistakes of the past. 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. However, because of its history and neurotoxic potential, MDMA may never achieve clinical and/or societal acceptance. Perhaps the true potential of MDMA lies in its use as a lead structure for the development of safer and more efficacious alternatives.
[IMG alt="An external file that holds a picture, illustration, etc.
Object name is nihms-982919-f0002.jpg"]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197894/bin/nihms-982919-f0002.jpg[/IMG]
Figure 2.
Common synthetic strategies used to produce racemic MDMA.
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Acknowledgments
FundingThis work was funded in part by a UC Davis Science Translation and Innovative Research (STAIR) Grant and the National Institute on Drug Abuse (DA045550).
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Footnotes
Notes
The authors declare no competing financial interest.
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MDMA is increasingly used in clinical research, but no cGMP process has yet been reported. We describe here the first fully validated cGMP synthesis of up to 5 kg (≈30 000 patient doses) of MDMA in a four-step process beginning with a noncontrolled starting material. The overall yield was acceptable (41–53%, over four steps), and the chemical purity of the final product was excellent, exceeding 99.9% of the peak area by HPLC in each of the four validation trials. The availability of cGMP-compliant MDMA will facilitate ongoing clinical trials and provide for future therapeutic use, if encouraging results lead to FDA approval.
This publication is licensed under
CC-BY-NC-ND 4.0.
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Interest in the clinical utility of psychedelic compounds has increased dramatically in recent years. Although medical usage of these substances, in tandem with psychotherapy, was briefly─and controversially (1)─explored, in the 1950s and 1960s, (2) increased regulatory oversight and social disapprobation effectively eliminated such research until the late 1990s, when tentative efforts to revive it commenced. (3) Promising early results very slowly stimulated additional engagement, both experimentally and culturally, provoking recent regulatory shifts that have further stimulated engagement by making research chemicals more accessible and expanding the permissible scope of clinical studies. (4)
This second wave of so-called psychedelic studies more expansively includes compounds like entactogen 3,4-methylenedioxymethamphetamine (MDMA). Like traditional psychedelics, MDMA had previously enjoyed a brief period of encouraging early-stage exploration, in the 1970s and 1980s, which was similarly curtailed by social and regulatory backlash. In contrast to psychedelics like LSD and psilocybin, however, the addition of MDMA to the U.S. Drug Enforcement Administration’s (DEA) Schedule I appeared to be largely related to MDMA’s popularity as an illicit “party drug,” (5) rather than to significant concerns regarding either contemporary research efforts or its therapeutic utility. (6) Indeed, in clinical trials conducted since the U.S. Food and Drug Administration (FDA) and DEA first granted research approval, in 2004, (7) MDMA has shown promise as a psychotherapeutic aid for patients suffering from PTSD, (8) autism-related social anxiety, (9) and alcoholism. (10)
As the research environment grows steadily more supportive of clinical exploration, and as successful clinical trials open the door for fully approved treatments, the need for pharmaceutically acceptable MDMA continues to expand. To ensure that patients receive safe, effective drugs, the manufacture of pharmaceutical substances is closely regulated by the FDA, under a structure called Current Good Manufacturing Practice (cGMP). (11) These rules delineate standards for every aspect of the manufacturing process, including facility design, establishment and documentation of operating procedures, process monitoring, and chemical analysis. Because only small samples of each pharmaceutical batch are submitted for (destructive) quality control testing, a well-controlled manufacturing process is the best-known way to ensure that all drugs distributed to consumers are of predictably high quality, consistency, and efficacy. cGMP-compliant synthetic processes are typically developed for drug candidates in tandem with progressing clinical trials. (12)
Unlike many drug candidates, MDMA (1) enjoyed a robust synthetic history prior to receiving any serious consideration as a pharmaceutical substance. MDMA was first synthesized by Merck, in 1912, as an intermediate to the styptic compound methylhydrastitine. (13) Scientists periodically explored its pharmacological effects over the intervening half-century, both at Merck and in the United States Army, (14) but MDMA does not appear in either the patent or the chemical literature again until 1960, when Biniecki and Krajewski published a synthesis identical to Merck’s in Poloniae Pharmaceutica (15) (it is unlikely that they were aware of the Merck patent). This synthetic route proceeded via hydrobromination of the natural product safrole (2), yielding the Markovnikov adduct 3, which was then converted to MDMA using methylamine in methanol. A variety of synthetic approaches from methyl piperonyl ketone (4), which was commercially available at the time, and which can be easily prepared either from safrole─typically via Wacker oxidation─or piperonal (5)─typically by reducing its nitroalkene derivative 6 with iron in hydrochloric acid─were summarized by Shulgin, in 1986. (16) A novel approach from piperonal, via Curtius rearrangement, was reported by Schulze, in 2010, (17) and a handful of asymmetric syntheses of (S)-MDMA, some relying on alternate starting materials, have also appeared in the literature (Scheme 1). (18)
Scheme 1. Common Synthetic Approaches to MDMA
Clandestine chemists preparing MDMA for the black market have additionally developed a number of synthetic routes from readily available starting materials like catechol (7), (19) eugenol (8), (19) isosafrole (9), (20) and piperine (10), (21) though most still approach MDMA through a safrole (22) or (less frequently) piperonal (21) intermediate. These synthetic methods often rely on chemicals readily available to ordinary consumers, in an effort to circumvent controlled substance precursor regulations. Most of these clandestine syntheses are well-documented, both by anonymous chemists, in online forums, and by forensic scientists, who often identify clandestine production methods by their distinct impurity profiles. (20)
To date, none of the synthetic explorations into MDMA appear to have considered cGMPs. While intended for pharmaceutical production, Merck’s early investigations occurred less than a decade after the FDA was founded, and well before its cGMP rules were developed. Some clandestine labs reliably produce large quantities of high-quality MDMA; (23) however, these facilities necessarily operate outside of regulatory frameworks and certainly do not report or document cGMP-compliant procedures. Most other synthetic explorations of MDMA have been geared toward the production of MDMA as a research chemical, usually for small-scale studies in animals or for forensic analysis (Figure 1).
Figure 1. Less-used MDMA precursors.
Indeed, prior to a recently completed Phase 3 trial for PTSD, (8) it is likely that few even contemplated a need for cGMP-compliant MDMA. As a Schedule I substance, it officially had no recognized medical utility up until now. As a well-known compound with a lengthy history in the public domain and a short treatment regimen, it also had little apparent commercial value. (24)
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We report here the first cGMP synthesis of MDMA and its hydrochloride salt (MDMA·HCl), which is used in pharmaceutical formulations. In this fully validated, four-stage process, up to 5 kg of MDMA·HCl was reproducibly synthesized, with an overall yield of 41.8–54.6% and a minimum purity of 99.4% (w/w) by HPLC assay. Over a minimum of four consecutive trials, for each stage, the established targets for yields and impurity profiles were achieved─and, in most cases, exceeded. Chemical impurities in the final product (MDMA·HCl) averaged 0.04% of the total peak area, by HPLC, and no single impurity ever exceeded 0.03% of the total peak area. Of all of the organic solvents used in the production process, only isopropanol (Class 3, 409–509 ppm), tetrahydrofuran (Class 2, <7 ppm), methanol (Class 2, <6 ppm), and n-heptane (Class 3, <67 ppm) were detected in the final product─all in concentrations well below the permitted daily exposure (PDE) per FDA guidance. (25) The scale and reliability of this cGMP process will improve access to MDMA for ongoing and future clinical trials─and potentially for licensed therapeutic use, pending FDA approval.
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Increased demand for pharmaceutical-grade MDMA encouraged us to develop a cGMP-compliant production process, both to supply our own Phase III clinical trials, for PTSD, and to ameliorate existing supply constraints for the broader research community. While large-scale clandestine production is common, to the best of our knowledge, no multi-kilogram synthesis of pharmaceutical-grade MDMA has yet been reported in the literature. We therefore needed to develop a practicable synthetic route while simultaneously addressing cGMP requirements.
MDMA is not a particularly complex molecule, and many synthetic pathways have been reported. Most begin from either safrole or piperonal, which are highly regulated and consequently difficult to obtain; for the sake of convenience and efficiency, we elected to avoid these. We identified 5-bromo-1,3-benzodioxole (11), which does not appear on any geopolitical entity’s list of controlled substance precursors, as a useful starting material for our synthesis. The 1,3-benzodioxole moiety appears in a variety of natural products, including oils, (26) spices, (27) and traditional plant-based medicines. (28) Many compounds containing this structural feature are known to interact with cytochrome P450 enzymes in mammals, producing a range of clinically notable effects, both pharmacologically useful and neurotoxic. (29) Compound 11 is synthesized via the bromination of benzodioxole with NBS; analysis of multiple batches, from a range of suppliers, indicated that the only significant impurities present in the batch are 5,6-dibromo-1,3-benzodioxole and succinimide, which is insoluble in Compound 11 and consequently present in only very trace amounts. We additionally screen for the presence of 4-bromo-1,3-benzodioxole, which would likely present separation challenges during production, but we have never observed this isomer in the starting material. At the levels observed, neither of the two significant impurities interfered with the downstream chemistry.
Compound 11 has been previously used in at least two (reported) approaches to MDMA: as a starting material in the asymmetric synthesis of (S)-MDMA, through a protected aziridine intermediate, (30) and as a precursor to safrole, via Grignard reaction with allyl bromide (Scheme 2). (19,31)
Scheme 2. Synthesis of cGMP MDMA·HCl
Instead of approaching MDMA conventionally, via safrole, we elected to generate a 2-propanol substituent via ring-opening addition between the same aryl Grignard reagent used to synthesize safrole, above, and 1,2-propylene oxide (12), which is both inexpensive and readily available. Reactions of Grignard reagents and epoxides are well-known, (32) but─to the best of our knowledge─this particular synthetic pathway has not previously been used to produce MDMA. Our familiarity with this type of reaction made us optimistic that scale-up would proceed smoothly─and it did. Although Grignard formation is slow, the bulk reaction can be expedited via initiation with a small amount of previously prepared Grignard reagent. The 5,6-dibromo-1,3-benzodioxole impurity present in the starting material does not undergo Grignard formation and is removed during workup as part of the organic layer. The workup at this stage was quite efficient, and distillation via a wiped-film evaporator (two to three passes) yielded 1-(3,4-methylenedioxy-phenyl)-2-propanol (13) in excess of 96% chemical purity by HPLC. The adjusted yield, based on HPLC assay, was 79.22–87.39% (w/w) over five trials.
The next three steps relied on well-known synthetic transformations. 13 was oxidized to methyl piperonyl ketone (4) with a biphasic (DCM/H2O) TEMPO/KBr/bleach reagent system, which was followed by aqueous workup and filtration to remove remaining solids. The solvent was removed via a rotatory evaporator, and the crude product was of sufficient purity to proceed to the next process stage, without an additional purification step (100.2–108.2% yield over four trials; 84.98–90.01% w/w by HPLC assay). Stage 3, reductive amination of 4, was accomplished with aqueous methylamine and NaOH/NaBH4. Workup was somewhat complex, using an acid/base treatment to remove the vast majority of impurities, followed by acidification with HCl in isopropanol which yielded 71.6–75.8% MDMA·HCl (14), over eight trials, with chemical purity exceeding 99.26% of peak area, by HPLC. Recrystallization in isopropanol (Stage 4) yielded 85.5–86.2% of a white, crystalline solid, with a minimum purity of 99.95% by HPLC and a minimum assay of 99.40% (w/w), also by HPLC (Table 1).
Table 1. Results from Stage 4 Validation Trials for the Synthesis of cGMP MDMA·HCl
MDMA·HCl was previously known to form one major crystal form (Form I) and at least four hydrates that incorporate 0.25–1 waters of hydration. (16) Our polymorphic screening process identified two new anhydrous crystal forms (Forms II and III) and established Form I as the most stable of the three. Form II can be reproducibly produced from a variety of alcoholic solvents, as well as in the presence of ethyl acetate and an ethereal antisolvent. Unlike Form III, which spontaneously converted to Form I after 2.5 weeks at ambient conditions, and could not be reproduced, Form II is shelf-stable, though it will convert to Form I under competitive equilibration conditions. Interestingly, both Form I and Form II reversibly convert into the known monohydrate; upon dehydration, the monohydrate formed from Form I will revert back to Form I, and the monohydrate formed from Form II will revert back to Form II. If crystallized from a concentrated aqueous solution with no form memory, the monohydrate will thermally dehydrate exclusively into Form I. X-ray powder diffraction spectra for all three forms are shown in Figure 2.
Figure 2. XRPD spectra for MDMA·HCl forms I–III and MDMA·HCl monohydrate.
To maintain compliance with cGMP regulations, all reagents were visually inspected and tested, prior to use. Conformance to established specification(s) was documented, reagents were labeled with identifying raw material numbers, and these identifying numbers were recorded whenever a reagent was used, in-process. Organic reagents were typically confirmed by FT-IR, as well as by other methods specific to their chemical identity and various process needs (e.g., Karl–Fischer titration to establish water content, etc.), in accordance with established procedures. Inorganic reagents were confirmed by appropriate chemical identification tests. Reagents that failed to meet all established specifications were not used at any stage of the process.
Another concern for cGMP manufacturing is the presence of residual solvents, which must be below solvent-specific concentration thresholds defined in USP <467>. The limits set for residual solvent concentrations are based on anticipated daily exposure to a pharmaceutical product. In clinical use, MDMA is never recommended for daily─or even regular─consumption; instead, it is ingested during a small number of therapy sessions, spread over weeks or months. Nevertheless, our monograph utilizes the USP <467> PDE limits as acceptance criteria─and our process yielded residual solvent concentrations significantly below these limits, over four consecutive validation trials (Table 2). The limit of detection for all tested solvents was 1 ppm; solvents detected in concentrations below the quantitation limit were reported as such.
Table 2. Residual Solvent Profile of cGMP MDMA·HCl
In addition to meeting residual solvent concentration limits, cGMP pharmaceuticals must have acceptable impurity profiles. Any single impurity exceeding 0.1% must be both characterized and quantified. Over four trials, our process yielded MDMA·HCl with chemical purity in excess of 99.9% of peak area by HPLC; no single impurity ever exceeded 0.05% of the total peak area. While impurity characterization was consequently not required, we routinely screened for two known impurities (Figure 3), both of which were generated via low-level electrophilic addition during the Stage 2 oxidation of 13. Chlorination was only significant when the bleach was overcharged, and the reaction conditions used in Stage 2 prevent this. Bromination, which also increased with excess bleach, was a more significant side reaction, but it was successfully minimized using KBr in catalytic, rather than stoichiometric, quantities. Neither impurity was ever found in excess of 0.03% of the total peak area, by HPLC, in any of the four Stage 4 validation trials.
Figure 3. Known impurities in MDMA·HCl.
Heavy metal impurities in finished pharmaceutical products are also an area of potential concern. As with residual solvents, cGMP-compliant limits are established with the assumption that a medication will be consumed on a daily basis, a usage pattern that we do not anticipate will ever be in effect for clinically administered MDMA. Nevertheless, we used the oral daily dose PDEs from USP ⟨232⟩ when determining acceptability parameters. As shown in Table 3, the greatest quantifiable amount of any heavy metal impurity was 97% less than the permissible daily intake limit─and most were well below that level.
Table 3. Heavy Metal Impurities found in cGMP MDMA·HCl
To validate this cGMP process, each stage was successfully completed at the 8 kg scale (based on the starting charge of benzodioxole) at least four consecutive times, in accordance with the documented procedures. All reagents, products, intermediates, common impurities, and (as required) reaction end points were validated using cGMP-compliant analytical methods, some of which were specifically developed for this synthetic process. Any deviations from the documented procedures or parameters were noted, and the anticipated impact on the final product─if any─was characterized. No documented deviation appeared to affect either the final product or the outcome of the Stage 4 recrystallization step, which yielded remarkably consistent results throughout the validation process (Table 1). We are confident that our cGMP protocols are sufficient to reliably produce enough pharmaceutically acceptable MDMA to meet expanding research and therapeutic needs.
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Into a separate 50 L reaction vessel was charged 1.06 kg of magnesium turnings (44 mol; 1.1 equiv) and 32 L of THF. The suspension was stirred and then heated to a gentle reflux. To the reaction vessel was then added 400.0 g of 5-bromo-1,3-benxodioxole (2.0 mol), followed by 400 mL of the small-batch Grignard solution described above. Reflux was maintained. After 5 min, a significant increase in the reflux rate was observed in the glass condenser, indicating initiation. While maintaining reflux, 7.6 kg of 5-bromo-1,3-benxodioxole (38 mol) was then added to the reaction vessel, using a dropping funnel, and the batch was stirred at a gentle reflux for 40 min.
The batch was then divided into two 20.4 L portions for workup. For each portion, 5.45 L of a 10% (w/w) sodium chloride solution, followed by 1.37 L of acetic acid, was added to the 50 L reaction vessel while maintaining the temperature at 10–25 °C. The half-batch portion was then transferred from carboy into the reaction vessel while ensuring that the temperature remained below 40 °C. Following this addition, the half-batch portion was stirred at 30–40 °C for 45 min; then, the pH was adjusted to <5 by sequential addition of three 200 mL of aliquots of acetic acid. The batch was allowed to settle, and the aqueous layer was removed. 8.2 L of n-heptane were then charged into the 50 L reaction vessel, followed by an additional 8 L of the sodium chloride solution. The batch was stirred and allowed to settle, and the aqueous layer was again removed. The dark brown organic layer was filtered over a vacuum, using a plate filter with a 11 μm filter mesh. Following workup, the two half-batches were combined, and the solvent was removed in a 20 L rotatory evaporator. The crude yield was 7442.7 g and analysis by 1H NMR revealed 2.5% residual THF (n-heptane not detected; target limit is ≤10% total amount of both solvents).
The crude product was charged with 1488.5 g of PEG400 (0.2 equiv w/w) and mixed to ensure homogeneity. This mixture was then distilled at 150–185 °C and 0.1–1.5 mbar, using a wiped-film evaporator. Two passes yielded 6293.2 g of a pale yellow oil (94.2% yield; 96.44% area, 89.78% w/w by HPLC).
For workup, the organic layer was cooled to 0 °C, and 4890 mL of a 12% (w/w) solution of aqueous sodium hydrosulfite was added while maintaining the temperature at 0–10 °C. The reaction mixture was then warmed to 19.5 °C and stirred for 15 min. The layers were separated, and the organic layer was returned to the 50 L reaction vessel. Then, 4900 mL of freshly prepared 0.5 M aqueous NaOH was added, and the reaction mixture was stirred for 15 min. The layers were separated, and the brown organic layer was returned to the 50 L reaction vessel. To this were added 4900 mL of 11% (w/w) aqueous NaCl, followed by 98 mL of concentrated HCl 36% w/w aqueous solution. After stirring for 15 min at 18.5 °C, the layers were separated, and the organic layer was returned to the reaction vessel. Two more washes─the first with another 4900 mL of the 11% NaCl solution, the second with 4900 mL of a saturated NaCl solution─were completed, following the same procedure. The organic layer was filtered over a Buchner funnel fitted with a filter cloth rinsing with 500 mL of DCM and then transferred to a 20 L rotatory evaporator. The solvent was removed under vacuum, yielding 2442.1 g of a yellow-to-brown oil (101.0% crude yield; 94.52% peak area, 89.80 w/w by HPLC).
The crude product was returned to the 50 L reaction vessel and then stirred with 12 100 mL TBME for 15 min at 18.6 °C. The layers were then separated, and the aqueous layer was washed with an additional 2400 mL of TBME. The organic layers were then combined in the 50 L reaction vessel; 12 000 mL of 2.0 M HCl was added portionwise, and the mixture was stirred for 20 min at 15–30 °C. At this point, the pH was 1 (target is 1–2), and layers were again separated. The lower, aqueous layer was returned to the 50 L flask, washed with 12000 mL of TBME and then stirred for 15 min with 6000 mL of 5.4 M aqueous NaOH. Another 12 000 mL of TBME was then added, along with 1589.6 g of Rochelle Salt, and the mixture was stirred for 120 min. The pale brown/orange organic layer was separated from the aqueous layer, and the aqueous layer was washed again with 12 000 mL of TBME. The organic layers were combined, and the solvent was removed, in batches, with a 20 L rotatory and evaporator. Two thousand four hundred milliliters of isopropanol were added to the residue, then removed by a rotatory evaporator. The crude weight of the product (MDMA-free base) was 2524.0 g (94.57% peak area by HPLC).
The crude MDMA was then returned to the 50 L flask, along with 20 280 mL of 2-propanol. Stirring was initiated, and 2435 mL 5.4 M HCl in 2-propanol (13.1 mol) was added, dropwise, over 120 min. The mixture was then stirred for an additional 30 min, at room temperature. The white precipitate was captured via vacuum filtration, on a plate filter fitted with a filter cloth. The filter cake was washed twice with 2-propanol (2500 mL) and then dried under vacuum (100 mbar) for 18 h at 57.3 °C. After drying, 2280.4 g of crude MDMA·HCl remained (73.4% unadjusted yield, 99.26% peak area by HPLC).
The batch was then transferred through a 1.2 μm in-line filter capsule, using positive pressure, to a clean, 50 L reaction vessel, fitted with a jacket that had been preheated to 66.1 °C. In this new reaction vessel, the batch was cooled to 55.3 °C, over the course of 90 min. Then, 41.1 g of MDMA·HCl Form 1 seed crystal (0.18 mol, 0.008 equiv) was added, and the batch was stirred at the same temperature for 30 min. The batch was cooled to 15.2 °C at a rate of 3 °C/h and then stirred at this temperature for an additional 10 h.
The white suspension was removed from the mother liquor via vacuum filtration over a filter plate fitted with a filter cloth and then washed with 8220 mL of 2-propanol. The filter cake was transferred to a drying oven and dried under vacuum (140 mbar) for 19 h at 56.6 °C. The collected MDMA·HCl was a white solid weighing 3548.3 g (85.5% yield; 99.95% peak area, 99.64% w/w by HPLC). No single impurity exceeded 0.02% of the peak area by HPLC, and residual solvents (methanol, <6 ppm; 2-propanol, 490 ppm) were found to be within the target range.
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The authors would like to thank MAPS staff and donors for fundraising and financial support. The authors would also like to thank Heather Clouting for her contribution and leadership in initiating the seminal CMC Department at MAPS PBC.
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This article references 32 other publications.
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Abstract
MDMA is increasingly used in clinical research, but no cGMP process has yet been reported. We describe here the first fully validated cGMP synthesis of up to 5 kg (≈30 000 patient doses) of MDMA in a four-step process beginning with a noncontrolled starting material. The overall yield was acceptable (41–53%, over four steps), and the chemical purity of the final product was excellent, exceeding 99.9% of the peak area by HPLC in each of the four validation trials. The availability of cGMP-compliant MDMA will facilitate ongoing clinical trials and provide for future therapeutic use, if encouraging results lead to FDA approval.
This publication is licensed under
CC-BY-NC-ND 4.0.
Introduction
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Interest in the clinical utility of psychedelic compounds has increased dramatically in recent years. Although medical usage of these substances, in tandem with psychotherapy, was briefly─and controversially (1)─explored, in the 1950s and 1960s, (2) increased regulatory oversight and social disapprobation effectively eliminated such research until the late 1990s, when tentative efforts to revive it commenced. (3) Promising early results very slowly stimulated additional engagement, both experimentally and culturally, provoking recent regulatory shifts that have further stimulated engagement by making research chemicals more accessible and expanding the permissible scope of clinical studies. (4)
This second wave of so-called psychedelic studies more expansively includes compounds like entactogen 3,4-methylenedioxymethamphetamine (MDMA). Like traditional psychedelics, MDMA had previously enjoyed a brief period of encouraging early-stage exploration, in the 1970s and 1980s, which was similarly curtailed by social and regulatory backlash. In contrast to psychedelics like LSD and psilocybin, however, the addition of MDMA to the U.S. Drug Enforcement Administration’s (DEA) Schedule I appeared to be largely related to MDMA’s popularity as an illicit “party drug,” (5) rather than to significant concerns regarding either contemporary research efforts or its therapeutic utility. (6) Indeed, in clinical trials conducted since the U.S. Food and Drug Administration (FDA) and DEA first granted research approval, in 2004, (7) MDMA has shown promise as a psychotherapeutic aid for patients suffering from PTSD, (8) autism-related social anxiety, (9) and alcoholism. (10)
As the research environment grows steadily more supportive of clinical exploration, and as successful clinical trials open the door for fully approved treatments, the need for pharmaceutically acceptable MDMA continues to expand. To ensure that patients receive safe, effective drugs, the manufacture of pharmaceutical substances is closely regulated by the FDA, under a structure called Current Good Manufacturing Practice (cGMP). (11) These rules delineate standards for every aspect of the manufacturing process, including facility design, establishment and documentation of operating procedures, process monitoring, and chemical analysis. Because only small samples of each pharmaceutical batch are submitted for (destructive) quality control testing, a well-controlled manufacturing process is the best-known way to ensure that all drugs distributed to consumers are of predictably high quality, consistency, and efficacy. cGMP-compliant synthetic processes are typically developed for drug candidates in tandem with progressing clinical trials. (12)
Unlike many drug candidates, MDMA (1) enjoyed a robust synthetic history prior to receiving any serious consideration as a pharmaceutical substance. MDMA was first synthesized by Merck, in 1912, as an intermediate to the styptic compound methylhydrastitine. (13) Scientists periodically explored its pharmacological effects over the intervening half-century, both at Merck and in the United States Army, (14) but MDMA does not appear in either the patent or the chemical literature again until 1960, when Biniecki and Krajewski published a synthesis identical to Merck’s in Poloniae Pharmaceutica (15) (it is unlikely that they were aware of the Merck patent). This synthetic route proceeded via hydrobromination of the natural product safrole (2), yielding the Markovnikov adduct 3, which was then converted to MDMA using methylamine in methanol. A variety of synthetic approaches from methyl piperonyl ketone (4), which was commercially available at the time, and which can be easily prepared either from safrole─typically via Wacker oxidation─or piperonal (5)─typically by reducing its nitroalkene derivative 6 with iron in hydrochloric acid─were summarized by Shulgin, in 1986. (16) A novel approach from piperonal, via Curtius rearrangement, was reported by Schulze, in 2010, (17) and a handful of asymmetric syntheses of (S)-MDMA, some relying on alternate starting materials, have also appeared in the literature (Scheme 1). (18)
Scheme 1
Scheme 1. Common Synthetic Approaches to MDMA
Clandestine chemists preparing MDMA for the black market have additionally developed a number of synthetic routes from readily available starting materials like catechol (7), (19) eugenol (8), (19) isosafrole (9), (20) and piperine (10), (21) though most still approach MDMA through a safrole (22) or (less frequently) piperonal (21) intermediate. These synthetic methods often rely on chemicals readily available to ordinary consumers, in an effort to circumvent controlled substance precursor regulations. Most of these clandestine syntheses are well-documented, both by anonymous chemists, in online forums, and by forensic scientists, who often identify clandestine production methods by their distinct impurity profiles. (20)
To date, none of the synthetic explorations into MDMA appear to have considered cGMPs. While intended for pharmaceutical production, Merck’s early investigations occurred less than a decade after the FDA was founded, and well before its cGMP rules were developed. Some clandestine labs reliably produce large quantities of high-quality MDMA; (23) however, these facilities necessarily operate outside of regulatory frameworks and certainly do not report or document cGMP-compliant procedures. Most other synthetic explorations of MDMA have been geared toward the production of MDMA as a research chemical, usually for small-scale studies in animals or for forensic analysis (Figure 1).
Figure 1
Figure 1. Less-used MDMA precursors.
Indeed, prior to a recently completed Phase 3 trial for PTSD, (8) it is likely that few even contemplated a need for cGMP-compliant MDMA. As a Schedule I substance, it officially had no recognized medical utility up until now. As a well-known compound with a lengthy history in the public domain and a short treatment regimen, it also had little apparent commercial value. (24)
Results
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We report here the first cGMP synthesis of MDMA and its hydrochloride salt (MDMA·HCl), which is used in pharmaceutical formulations. In this fully validated, four-stage process, up to 5 kg of MDMA·HCl was reproducibly synthesized, with an overall yield of 41.8–54.6% and a minimum purity of 99.4% (w/w) by HPLC assay. Over a minimum of four consecutive trials, for each stage, the established targets for yields and impurity profiles were achieved─and, in most cases, exceeded. Chemical impurities in the final product (MDMA·HCl) averaged 0.04% of the total peak area, by HPLC, and no single impurity ever exceeded 0.03% of the total peak area. Of all of the organic solvents used in the production process, only isopropanol (Class 3, 409–509 ppm), tetrahydrofuran (Class 2, <7 ppm), methanol (Class 2, <6 ppm), and n-heptane (Class 3, <67 ppm) were detected in the final product─all in concentrations well below the permitted daily exposure (PDE) per FDA guidance. (25) The scale and reliability of this cGMP process will improve access to MDMA for ongoing and future clinical trials─and potentially for licensed therapeutic use, pending FDA approval.
Discussion
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Increased demand for pharmaceutical-grade MDMA encouraged us to develop a cGMP-compliant production process, both to supply our own Phase III clinical trials, for PTSD, and to ameliorate existing supply constraints for the broader research community. While large-scale clandestine production is common, to the best of our knowledge, no multi-kilogram synthesis of pharmaceutical-grade MDMA has yet been reported in the literature. We therefore needed to develop a practicable synthetic route while simultaneously addressing cGMP requirements.
MDMA is not a particularly complex molecule, and many synthetic pathways have been reported. Most begin from either safrole or piperonal, which are highly regulated and consequently difficult to obtain; for the sake of convenience and efficiency, we elected to avoid these. We identified 5-bromo-1,3-benzodioxole (11), which does not appear on any geopolitical entity’s list of controlled substance precursors, as a useful starting material for our synthesis. The 1,3-benzodioxole moiety appears in a variety of natural products, including oils, (26) spices, (27) and traditional plant-based medicines. (28) Many compounds containing this structural feature are known to interact with cytochrome P450 enzymes in mammals, producing a range of clinically notable effects, both pharmacologically useful and neurotoxic. (29) Compound 11 is synthesized via the bromination of benzodioxole with NBS; analysis of multiple batches, from a range of suppliers, indicated that the only significant impurities present in the batch are 5,6-dibromo-1,3-benzodioxole and succinimide, which is insoluble in Compound 11 and consequently present in only very trace amounts. We additionally screen for the presence of 4-bromo-1,3-benzodioxole, which would likely present separation challenges during production, but we have never observed this isomer in the starting material. At the levels observed, neither of the two significant impurities interfered with the downstream chemistry.
Compound 11 has been previously used in at least two (reported) approaches to MDMA: as a starting material in the asymmetric synthesis of (S)-MDMA, through a protected aziridine intermediate, (30) and as a precursor to safrole, via Grignard reaction with allyl bromide (Scheme 2). (19,31)
Scheme 2
Scheme 2. Synthesis of cGMP MDMA·HCl
Instead of approaching MDMA conventionally, via safrole, we elected to generate a 2-propanol substituent via ring-opening addition between the same aryl Grignard reagent used to synthesize safrole, above, and 1,2-propylene oxide (12), which is both inexpensive and readily available. Reactions of Grignard reagents and epoxides are well-known, (32) but─to the best of our knowledge─this particular synthetic pathway has not previously been used to produce MDMA. Our familiarity with this type of reaction made us optimistic that scale-up would proceed smoothly─and it did. Although Grignard formation is slow, the bulk reaction can be expedited via initiation with a small amount of previously prepared Grignard reagent. The 5,6-dibromo-1,3-benzodioxole impurity present in the starting material does not undergo Grignard formation and is removed during workup as part of the organic layer. The workup at this stage was quite efficient, and distillation via a wiped-film evaporator (two to three passes) yielded 1-(3,4-methylenedioxy-phenyl)-2-propanol (13) in excess of 96% chemical purity by HPLC. The adjusted yield, based on HPLC assay, was 79.22–87.39% (w/w) over five trials.
The next three steps relied on well-known synthetic transformations. 13 was oxidized to methyl piperonyl ketone (4) with a biphasic (DCM/H2O) TEMPO/KBr/bleach reagent system, which was followed by aqueous workup and filtration to remove remaining solids. The solvent was removed via a rotatory evaporator, and the crude product was of sufficient purity to proceed to the next process stage, without an additional purification step (100.2–108.2% yield over four trials; 84.98–90.01% w/w by HPLC assay). Stage 3, reductive amination of 4, was accomplished with aqueous methylamine and NaOH/NaBH4. Workup was somewhat complex, using an acid/base treatment to remove the vast majority of impurities, followed by acidification with HCl in isopropanol which yielded 71.6–75.8% MDMA·HCl (14), over eight trials, with chemical purity exceeding 99.26% of peak area, by HPLC. Recrystallization in isopropanol (Stage 4) yielded 85.5–86.2% of a white, crystalline solid, with a minimum purity of 99.95% by HPLC and a minimum assay of 99.40% (w/w), also by HPLC (Table 1).
Table 1. Results from Stage 4 Validation Trials for the Synthesis of cGMP MDMA·HCl
trial | yield (%) | purity (% peak area by HPLC) | assay (% w/w by HPLC) |
|---|---|---|---|
1 | 85.5 | 99.95 | 99.64 |
2 | 85.9 | 99.96 | 99.40 |
3 | 86.2 | 99.99 | 99.77 |
4 | 86.1 | 99.95 | 99.76 |
Figure 2
Figure 2. XRPD spectra for MDMA·HCl forms I–III and MDMA·HCl monohydrate.
To maintain compliance with cGMP regulations, all reagents were visually inspected and tested, prior to use. Conformance to established specification(s) was documented, reagents were labeled with identifying raw material numbers, and these identifying numbers were recorded whenever a reagent was used, in-process. Organic reagents were typically confirmed by FT-IR, as well as by other methods specific to their chemical identity and various process needs (e.g., Karl–Fischer titration to establish water content, etc.), in accordance with established procedures. Inorganic reagents were confirmed by appropriate chemical identification tests. Reagents that failed to meet all established specifications were not used at any stage of the process.
Another concern for cGMP manufacturing is the presence of residual solvents, which must be below solvent-specific concentration thresholds defined in USP <467>. The limits set for residual solvent concentrations are based on anticipated daily exposure to a pharmaceutical product. In clinical use, MDMA is never recommended for daily─or even regular─consumption; instead, it is ingested during a small number of therapy sessions, spread over weeks or months. Nevertheless, our monograph utilizes the USP <467> PDE limits as acceptance criteria─and our process yielded residual solvent concentrations significantly below these limits, over four consecutive validation trials (Table 2). The limit of detection for all tested solvents was 1 ppm; solvents detected in concentrations below the quantitation limit were reported as such.
Table 2. Residual Solvent Profile of cGMP MDMA·HCl
solvent | acceptance criteria (ppm) | highest level found (ppm) |
|---|---|---|
THF | 720 | <7 |
tert-Butyl methyl ether (TBME) | 5000 | not detected |
n-Heptane | 5000 | <67 |
methanol | 3000 | <6 |
2-propanol | 5000 | 509 |
dichloromethane (DCM) | 600 | not detected |
Figure 3
Figure 3. Known impurities in MDMA·HCl.
Heavy metal impurities in finished pharmaceutical products are also an area of potential concern. As with residual solvents, cGMP-compliant limits are established with the assumption that a medication will be consumed on a daily basis, a usage pattern that we do not anticipate will ever be in effect for clinically administered MDMA. Nevertheless, we used the oral daily dose PDEs from USP ⟨232⟩ when determining acceptability parameters. As shown in Table 3, the greatest quantifiable amount of any heavy metal impurity was 97% less than the permissible daily intake limit─and most were well below that level.
Table 3. Heavy Metal Impurities found in cGMP MDMA·HCl
element | concentration limit (μg/g) | highest value found in product (μg/g) |
|---|---|---|
cadmium | 5 | <0.1 |
lead | 5 | <0.1 |
arsenic | 15 | <0.1 |
mercury | 30 | 0.7 |
cobalt | 50 | <0.1 |
vanadium | 100 | 0.2 |
nickel | 200 | 1.1 |
copper | 3000 | 3.3 |
Experimental Section
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General
Reactions were performed using commercially available raw materials and solvents. Unless otherwise stated, all commercially obtained reagents were qualified prior to use and then used as received. Reactions were conducted in a 50 L reaction vessel. The small-scale production of the Grignard reagent, used to initiate the bulk reaction, was conducted in a 2 L reactor fitted with a reflux condenser. A Huber Unistat was used for temperature control and logging. In-process analysis was conducted by HPLC, with supplemental 1H NMR analysis used to quantify residual solvent content during evaporation steps. A wiped-film evaporator was used for distillation. All processes were conducted under nitrogen (target: <5% O2). Residual solvent testing was performed on an Agilent J&W DB-624 HRGC column (60 m × 0.32 mm, 1.80 μm film thickness).Stage 1─Synthesis of 1-(3,4-Methylenedioxyphenyl)-2-propanol
Grignard Formation
Into a 2 L vessel was charged 16.6 g of magnesium turnings (0.68 mol, 1.1 equiv), followed by 500 mL of THF (181 ppm H2O by KF titration) at 20 °C. Stirring was initiated after the introduction of THF, and the vessel was heated to a gentle reflux. To the vessel was then charged 125 g of 5-bromo-1,3-benzodioxole (0.62 mol, 1 equivalent chemical purity >98.70% by HPLC) in two unequal portions. The first portion weighed 6.3 g and was stirred for 12 h at a gentle reflux until an exotherm was observed. Following this initiation step, the remaining 118.4 g was added, dropwise, to the reaction vessel, and the resultant Grignard solution was stirred at reflux for 40 min and then cooled to 25 °C.Into a separate 50 L reaction vessel was charged 1.06 kg of magnesium turnings (44 mol; 1.1 equiv) and 32 L of THF. The suspension was stirred and then heated to a gentle reflux. To the reaction vessel was then added 400.0 g of 5-bromo-1,3-benxodioxole (2.0 mol), followed by 400 mL of the small-batch Grignard solution described above. Reflux was maintained. After 5 min, a significant increase in the reflux rate was observed in the glass condenser, indicating initiation. While maintaining reflux, 7.6 kg of 5-bromo-1,3-benxodioxole (38 mol) was then added to the reaction vessel, using a dropping funnel, and the batch was stirred at a gentle reflux for 40 min.
Addition to Propylene Oxide
The bulk Grignard solution was cooled to 10 °C, and 128.8 g of copper iodide (1.5 mol, 0.4 equiv) was added to the 50 L vessel. A solution of 2.5 L (±)-propylene oxide (37 mol, 0.93 equiv) in 2.5 L of THF was then added to the reaction vessel while maintaining the temperature at 0–10 °C. The container and dropping funnel were rinsed with an additional 800 mL of THF, which was then added to the 50 L reaction vessel. The batch was stirred for 40 min at 5–20 °C, forming a dark brown solution and a crystalline suspension. Completion analysis performed by HPLC confirmed the reaction end point (0.30% 5-bromo-1,3-benzodioxole; target limit was ≤1%).The batch was then divided into two 20.4 L portions for workup. For each portion, 5.45 L of a 10% (w/w) sodium chloride solution, followed by 1.37 L of acetic acid, was added to the 50 L reaction vessel while maintaining the temperature at 10–25 °C. The half-batch portion was then transferred from carboy into the reaction vessel while ensuring that the temperature remained below 40 °C. Following this addition, the half-batch portion was stirred at 30–40 °C for 45 min; then, the pH was adjusted to <5 by sequential addition of three 200 mL of aliquots of acetic acid. The batch was allowed to settle, and the aqueous layer was removed. 8.2 L of n-heptane were then charged into the 50 L reaction vessel, followed by an additional 8 L of the sodium chloride solution. The batch was stirred and allowed to settle, and the aqueous layer was again removed. The dark brown organic layer was filtered over a vacuum, using a plate filter with a 11 μm filter mesh. Following workup, the two half-batches were combined, and the solvent was removed in a 20 L rotatory evaporator. The crude yield was 7442.7 g and analysis by 1H NMR revealed 2.5% residual THF (n-heptane not detected; target limit is ≤10% total amount of both solvents).
The crude product was charged with 1488.5 g of PEG400 (0.2 equiv w/w) and mixed to ensure homogeneity. This mixture was then distilled at 150–185 °C and 0.1–1.5 mbar, using a wiped-film evaporator. Two passes yielded 6293.2 g of a pale yellow oil (94.2% yield; 96.44% area, 89.78% w/w by HPLC).
Stage 2─Oxidation to 1-(3,4-Methylenedioxyphenyl)-propan-2-one
A 50 L reaction vessel was charged with 2760.1 g of crude 1-(3,4-methylenedioxyphenyl)-2-propanol from Stage 1 (88.56% w/w by HPLC assay; active charge is 2444.3 g, 13.6 mol, 1 equivalent) and 9780 mL of dichloromethane at 10–25 °C. Stirring was initiated, and 178.5 g of potassium bromide was added, followed by 233.2 g of TEMPO (0.11 equiv). The batch was cooled to 0 °C, and 7280 mL (60%) of a solution of sodium hydrogen carbonate (0.25 equiv) in 12120 mL of bleach (1.6 equiv, diluted to 12.5% w/v) was added, dropwise, while stirring efficiently and maintaining the temperature at −10 to 10 °C. A 1 mL of sample was then removed, for analysis by HPLC, and four additional 610 mL (5%) of aliquots of the NaHCO3/bleach solution were then added, dropwise, to the reaction vessel. A sample was collected after each addition, and HPLC analysis was used to monitor the reaction progress. After the fourth aliquot was added, 1.61% of Stage 1 starting material remained (target limit is ≤5%). Stirring was halted, and the layers were allowed to settle. The layers were separated, and the organic layer was returned to the 50 L vessel.For workup, the organic layer was cooled to 0 °C, and 4890 mL of a 12% (w/w) solution of aqueous sodium hydrosulfite was added while maintaining the temperature at 0–10 °C. The reaction mixture was then warmed to 19.5 °C and stirred for 15 min. The layers were separated, and the organic layer was returned to the 50 L reaction vessel. Then, 4900 mL of freshly prepared 0.5 M aqueous NaOH was added, and the reaction mixture was stirred for 15 min. The layers were separated, and the brown organic layer was returned to the 50 L reaction vessel. To this were added 4900 mL of 11% (w/w) aqueous NaCl, followed by 98 mL of concentrated HCl 36% w/w aqueous solution. After stirring for 15 min at 18.5 °C, the layers were separated, and the organic layer was returned to the reaction vessel. Two more washes─the first with another 4900 mL of the 11% NaCl solution, the second with 4900 mL of a saturated NaCl solution─were completed, following the same procedure. The organic layer was filtered over a Buchner funnel fitted with a filter cloth rinsing with 500 mL of DCM and then transferred to a 20 L rotatory evaporator. The solvent was removed under vacuum, yielding 2442.1 g of a yellow-to-brown oil (101.0% crude yield; 94.52% peak area, 89.80 w/w by HPLC).
Stage 3─Reductive Amination to MDMA·HCl
Next, 2963.9 g of crude 1-(3,4-methylenedioxyphenyl)-propan-2-one from Step 2 (13.7 mol, 81.26% w/w by HPLC) was added to a 50 L reaction vessel with 31170 mL of methanol (Kimia, confirmed by FT-IR), and the temperature was lowered to 5 °C. Then, 3520 mL of 40% (w/w) aqueous methylamine (102 mol, 7.5 equiv) was added, dropwise, and the batch was then cooled to −10 °C. To the reaction vessel was added 40.4 g of NaOH (1 mol) and 286.4 g of NaBH4 (7.6 mol, 0.5 equiv) in 630 mL of purified water, over the course of 120 min. The clear brown solution was then warmed to 3.9 °C and stirred for 25 min. A sample was removed and submitted for completion analysis by HPLC; the peak area for the product was 81.04%, and the starting material was undetected, which met the completion threshold of ≤1%. Then, 9640 mL of purified water was added to the reaction vessel, portionwise, while maintaining the temperature at 0–10 °C. The mixture was transferred to a 20 L rotatory evaporator, and methanol was removed, under vacuum. A sample was submitted for analysis, and 1H NMR indicated ≤10% residual methanol, which met the specification.The crude product was returned to the 50 L reaction vessel and then stirred with 12 100 mL TBME for 15 min at 18.6 °C. The layers were then separated, and the aqueous layer was washed with an additional 2400 mL of TBME. The organic layers were then combined in the 50 L reaction vessel; 12 000 mL of 2.0 M HCl was added portionwise, and the mixture was stirred for 20 min at 15–30 °C. At this point, the pH was 1 (target is 1–2), and layers were again separated. The lower, aqueous layer was returned to the 50 L flask, washed with 12000 mL of TBME and then stirred for 15 min with 6000 mL of 5.4 M aqueous NaOH. Another 12 000 mL of TBME was then added, along with 1589.6 g of Rochelle Salt, and the mixture was stirred for 120 min. The pale brown/orange organic layer was separated from the aqueous layer, and the aqueous layer was washed again with 12 000 mL of TBME. The organic layers were combined, and the solvent was removed, in batches, with a 20 L rotatory and evaporator. Two thousand four hundred milliliters of isopropanol were added to the residue, then removed by a rotatory evaporator. The crude weight of the product (MDMA-free base) was 2524.0 g (94.57% peak area by HPLC).
The crude MDMA was then returned to the 50 L flask, along with 20 280 mL of 2-propanol. Stirring was initiated, and 2435 mL 5.4 M HCl in 2-propanol (13.1 mol) was added, dropwise, over 120 min. The mixture was then stirred for an additional 30 min, at room temperature. The white precipitate was captured via vacuum filtration, on a plate filter fitted with a filter cloth. The filter cake was washed twice with 2-propanol (2500 mL) and then dried under vacuum (100 mbar) for 18 h at 57.3 °C. After drying, 2280.4 g of crude MDMA·HCl remained (73.4% unadjusted yield, 99.26% peak area by HPLC).
Stage 4─Recrystallization of MDMA·HCl
To a 50 L reaction vessel was added 4107.3 g of crude MDMA·HCl and 41 000 mL of 2-propanol. The batch temperature was increased to 67.2 °C, while stirring, and the mixture was then stirred for 30 min at 67.2 °C until all of the solids dissolved. Stress tests had demonstrated stability for 72 h at 70–80 °C proving the thermal stability of MDMA·HCl.The batch was then transferred through a 1.2 μm in-line filter capsule, using positive pressure, to a clean, 50 L reaction vessel, fitted with a jacket that had been preheated to 66.1 °C. In this new reaction vessel, the batch was cooled to 55.3 °C, over the course of 90 min. Then, 41.1 g of MDMA·HCl Form 1 seed crystal (0.18 mol, 0.008 equiv) was added, and the batch was stirred at the same temperature for 30 min. The batch was cooled to 15.2 °C at a rate of 3 °C/h and then stirred at this temperature for an additional 10 h.
The white suspension was removed from the mother liquor via vacuum filtration over a filter plate fitted with a filter cloth and then washed with 8220 mL of 2-propanol. The filter cake was transferred to a drying oven and dried under vacuum (140 mbar) for 19 h at 56.6 °C. The collected MDMA·HCl was a white solid weighing 3548.3 g (85.5% yield; 99.95% peak area, 99.64% w/w by HPLC). No single impurity exceeded 0.02% of the peak area by HPLC, and residual solvents (methanol, <6 ppm; 2-propanol, 490 ppm) were found to be within the target range.
Author Information
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- Corresponding Author
- Jay B. Nair - MAPS Public Benefit Corporation (MAPS PBC), 3141 Stevens Creek Blvd #40547, San Jose, California 95117, United States;
https://orcid.org/0000-0002-4873-4690; Email: [email protected]
- Jay B. Nair - MAPS Public Benefit Corporation (MAPS PBC), 3141 Stevens Creek Blvd #40547, San Jose, California 95117, United States;
- Authors
- Linda Hakes - Independent Consultant for MAPS Public Benefit Corporation, 3141 Stevens Creek Blvd #40547, San Jose, California 95117, United States
- Berra Yazar-Klosinski - Multidisciplinary Association for Psychedelic Studies (MAPS), 3141 Stevens Creek Blvd #40563, San Jose, California 95117, United States
- Kathryn Paisner - KP2 LLC, 2510 14th Ave., Oakland, California 94606, United States
- Author Contributions
L.H. and B.Y.-K. provided oversight on behalf of MAPS. K.P. and J.B.N. drafted the manuscript. All authors contributed to the critical review and final version of the manuscript. All authors have given approval to the final version of the manuscript. - Funding
This research was sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS), a 501(c)(3) nonprofit organization. MAPS funded this study using private and foundation donations. MAPS Public Benefit Corporation (MAPS PBC), wholly owned by MAPS, was the trial organizer. - Notes
All information in this article is provided for academic and scientific purposes only.
The authors declare no competing financial interest.
Acknowledgments
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The authors would like to thank MAPS staff and donors for fundraising and financial support. The authors would also like to thank Heather Clouting for her contribution and leadership in initiating the seminal CMC Department at MAPS PBC.
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- Alexander M. Sherwood, Elise K. Burkhartzmeyer, Samuel E. Williamson, Michael T. Faley. Swim in the Chiral Pool: MDMA and MDA Enantiomers from Alanine-Derived Precursors. ACS Omega 2023, 8 (24) , 22132-22137. https://doi.org/10.1021/acsomega.3c02358
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ты вот на будущее если такую простынь скидываешь - то делай просто фаул пдф или текстовый и прикрепляй его к сообщению. так удобней будет - кому надо скачают
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Не скачают )))
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так мы с вами не захотели иметь дело, в чем проблема ? ищем другие варианты или это запрещено ?
конечно не запрещено - было бы запрщено удалил бы вашу тему и всё. у нас на форуме свобода слова +-. просто не забывайте сразу в объявлении соем указывать что вы платить хотите потсле а не до и что работу с гарантом вы не приемлите. чтобы не тратить чужое время. а так отказ от гаранта на любой площадке будет восприниматься как попытка скама.
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Ну так бы и я хотел , мне феньку а деньги потом ))))))