Since the '90s, popularity of the designer drug Ecstasy (MDMA) has soared, successfully securing a place in almost everyone's recreational drug vocabulary. Millions of high school and college students worldwide have tried the drug. Much of Ecstasy’s popularity lies in its unique profile; instead of leaving the user stoned or drunk, MDMA can increase clarity of thought while instilling a sense of empathy for others and a positive view of oneself. Sound like the perfect drug? Not quite. Evidence of neurotoxicity is abundant and discourages many users from taking the drug on a regular basis. Because of this, MDMA probably has little relevance to physique enhancement. Nonetheless, it remains a fascinating drug, albeit disguised by myths and propaganda. But as usual, Chemically Correct is here to help astute minds sort out the real data.
History
Unlike the subjects of my previous articles (bupropion and nicotine), the history of MDMA hasn't been lost in the nameless world of the pharmaceutical industry, nor does it date back to the beginning of time. David Pearce has compiled an in-depth compilation of MDMA history and pharmacology at mdma.net, and I’m indebted to him for the brief history (as well as much of the other information) I’m about to provide here. The German pharmaceutical company Merck first synthesized MDMA in the early 1900’s. They created the compound as an intermediate during the synthesis of a vasoconstrictor. The CIA showed a brief interest in MDMA during the 1950s, but it never reached human testing and was quickly abandoned. The true revival of MDMA from pharmaceutical obscurity occurred in the late 1970s when psychedelic chemist Alexander Shulgin not only synthesized MDMA, but tried it as well. His account of his synthesis and experience with MDMA (as well as many of his other creations) can be found in his book, PiHKAL (Phenylethylamines I Have Known and Loved). He wrote of his experience, “I have never felt so great, or believed this to be possible…I am overcome with the profundity of the experience…” His enthusiasm for MDMA is especially noteworthy, considering his immense experience with other drugs. Shulgin quickly introduced the drug to several of his psychotherapist friends. His friends were equally awed, and MDMA’s potential as an adjunct to therapy was quickly realized and implemented. During the ‘80s, a small but substantial number of therapists around the country were using MDMA on their patients.
As word spread of the amazing drug, people began to explore its potential use recreationally. During the early 1980s, MDMA was readily available for purchase via 1-800 numbers, convenience stores, and of course, at bars and clubs. Inevitably, the DEA became aware of the situation, and succeeded in making MDMA a Schedule 1 substance, as it remains classified to this today.
But this has far from decreased MDMA’s popularity. The Israeli underground as well as other international organizations control MDMA production and trafficking, and ensure that adequate supplies are available for black market distribution. Despite DEA efforts, and even the occasional bust, the popularity and availability of MDMA is unlikely to die anytime soon. Probably the most unfortunate effect of scheduling is the red tape it puts in front of researchers who wish to investigate MDMA.
Chemistry
3,4-methylenedioxymethamphetamine is a ring-substituted phenylethylamine (PEA). As the chemical name suggests, MDMA consists of a methamphetamine backbone. Despite having some stimulant properties, MDMA produces remarkably different effects than its parent compound. Methamphetamine lacks MDMA’s potent serotonergic effects. This means that adding an ether group to the ring of a PEA at least somewhat determines whether the drug will be serotonergic in nature. Other serotonergic PEA’s, such as mescaline and even the antidepressant venlafaxine (Effexor), both have ether groups around the ring. I mentioned that ether groups “somewhat determine” serotonergic nature because in MDMA, stereochemistry seems to play a big role as well. The (+) enantiomer is more dopaminergic (crossing over with amphetamine) while the (-) enantiomer is more serotonergic (crossing over with mescaline) (1).
Pharmacology
Due to the nature of each enantiomer, MDMA has been described as a cross between a stimulant and a hallucinogen. But the Ecstacy experience would rarely be characterized as “seeing cool shit on speed.” Such a label leaves much to be desired, so Dr. David Nichols (one of Shulgin’s close friends) coined the term “entactogen” to classify MDMA, which means, “to touch within” (2). David Pearce has more aptly characterized MDMA as an entactogen-empathogen, referring to both its ability to allow the user to get in touch with himself as well as its ability to increase the empathy one feels for others (3).
While the psychological effects of MDMA are often complex and difficult to characterize clinically, most users report euphoria, increases in energy, self-confidence, extroversion, sexual arousal, and intensity of sensory perception (53, 68).
So what neurochemical activity occurs to produce this so-called entactogen-empathogen effect? Simply stated, MDMA induces the synaptic release of serotonin and dopamine (4,5). Not satisfied? Good—didn’t think you would be. As usual, we’ll go into the details of MDMA’s action on each monoamine and their respective receptor subtypes.
Serotonin
MDMA enters serotonergic neurones via the serotonin re-uptake pump, and reverses the normal direction of monoamine travel, inducing serotonin release (6). MDMA can also block the re-uptake pump, much like an SSRI (7). Recently, it has been shown that up-take inhibition by MDMA contributes to greater increases in 5-HT than direct release (9). Synthesis of 5-HT increases 6-fold upon administration, but falls below baseline shortly thereafter (20). MDMA also inhibits MAO-A, potentiating increases in serotonin (8).
MDMA relies upon indirect stimulation of 5-HT (1B) and 5-HT (2A) receptors to produce its stimulant effects (13). Antagonism of 5-HT (2C) receptors can potentiate MDMA’s dopamine release, but even without 5-HT (2C) antagonism, dopamine release is robust (13).
Probably in response to massive serotonin overflow, a decrease in tryptophan hydroxylase activity is observed following MDMA administration, which explains the reduced synthesis of 5-HT (10). MDMA also inhibits the firing of serotonergic neurons by indirect stimulation of 5-HT (1A) autoreceptors (11,12).
Dopamine
The concentrations of MDMA that are required to induce 5-HT release are 10 times lower than those need to induce dopamine release (21). However, once proper concentrations are achieved, dopamine release is actually greater than 5-HT (22). MDMA-induced increased in dopamine are due to several distinct mechanisms. First, MDMA produces dopamine release and uptake inhibition via the dopamine transporter, independent of any actions by 5-HT (7,14). Second, stimulation of 5-HT (2A) receptors by serotonin increases dopamine synthesis and release (15); when MDMA is administered with a 5-HT (2A) antagonist, dopamine release is attenuated (16). Third, MDMA elicits the release of dopamine from noradrenergic neurons via the NA uptake pump (23). Finally, MAO-B inhibition by MDMA prevents metabolism of dopamine (8).
Noradrenaline
Effects of MDMA on noradrenaline are similar to that of dopamine, except more potent (22,24): there is NA release that is facilitated by the increase in serotonin (17) and independent of serotonin increase (18). Furthermore, MDMA causes desensitization of a2-adrenoceptors, enhancing noradrenergic transmission (19). MDMA has modest affinity for the a2-adrenoceptor (25), but it is more likely that NA, rather than MDMA, causes the desensitization by acting as a direct agonist (19).
Acetylcholine
Part of MDMA’s stimulant effects might be due to the release of acetylcholine in the prefrontal cortex and the dorsal striatum, an effect that can be eliminated by the administration of an H1-antagonist (26, 27).
Hormonal Effects
MDMA acutely increases levels of corticosterone, cortisol, prolactin, oxytocin, vasopressin and DHEA (24,64). Corticosterone in particular works very intimately with the 5-HT system, and may modulate many of MDMA’s changes to 5-HT receptors, and even 5-HT neurotoxicity (65).
An interesting observation is that females seem to be much more sensitive to the subjective and neurotoxic effects of MDMA (66). This too is probably related to hormones. Estrogen has a substantial activating effect on 5-HT neurotransmission, upregulating tryptophan hydoxylase, decreasing both 5-HT transporter mRNA and the sensitivity of 5-HT (1A) autoreceptors (67).
For those interested, I intend on exploring the psychoactive and neuromodulatory effects of hormones as well as their implications in gender differences and psychiatric diseases in subsequent edition of Chemically Correct.
Pharmacokinetics
MDMA’s half-life is approximately 2.5 hours for the (-) enantiomer and 2.2 hours for the (+) enantiomer (28). Because MDMA has non-linear pharmacokinetics (29), hardcore users who insist upon taking back-to-back doses will experience disproportionately high plasma levels. 50% of MDMA ingested by humans can be recovered unchanged in the urine (29). The other half is metabolized mainly by cytochrome P450 enzyme CPY2D6 to 3,4-methylenedioxyamphetamine (MDA) and 3,4-dihydroxymethamphetamine (HHMA), as well as other minor metabolites (30).
Neurotoxicity
The big question on everyone’s mind might be, “Just how bad is MDMA for your brain?” But before we can answer that question, we need to address some preliminaries.
Definition of Neurotoxicity
The Kleven-Seiden criteria for neurotoxicity of amphetamine analogues has four requirements: 1) long-lasting depletions of 5-HT or dopamine; 2) a decrease in high affinity uptake sites for 5-HT or dopamine; 3) decreased activity of synthetic enzymes for 5-HT or dopamine (i.e. tryptophan or tyrosine hydroxylase); and 4) alterations in neuronal morphology (31).
Evidence of Neurotoxicity
A single 10mg/kg dose to rats produces two waves of 5-HT depletion, one within 3-6 hours after administration with levels returning to normal within a day, and another depletion 1 week after MDMA administration (5). This second wave is also accompanied by a decrease in 5-HT transporters (5). Acute administration in rats also decreases tryptophan hydroxylase (32). Rats taking 80mg/kg twice a day for two days experience degeneration of axon terminals (33). Thus, MDMA fulfills all the requirements for inducing neurotoxicity in rats, albeit at varying dosages.
Full criteria for neurotoxicity is also met in nonhuman primates such as baboons and monkeys, who appear to be much more sensitive to MDMA. Dosages as little as 2.5mg/kg can cause long lasting reductions in 5-HT levels (34).
As for humans, former MDMA users have reduced levels of the major serotonin metabolite 5-HIAA in their cerebrospinal fluid, suggesting 5-HT depletion (35). It has also been demonstrated that human MDMA users have decreased 5-HT uptake site binding compared to controls (36). Such observations would indicate that MDMA users suffer from 5-HT neurotoxicity. But before we say that MDMA is neurotoxic to humans, we should look at the conditions within the studies. The “users” in both studies were extremely experienced, having used MDMA around 200 times, multiple times a month for several years.
Whether the more “typical” user of MDMA (single doses, a few times a year) experiences neurotoxicity remains to be answered definitively.
Mechanisms of Neurotoxicity
Probably unknown to most “Just Say No” zealots is that MDMA by itself is not neurotoxic. When administered directly into the brain, MDMA will induce 5-HT release without any 5-HT neurotoxicity (37). This means that MDMA damage to the 5-HT system requires at least some systemic metabolism. Where, when, and how things go wrong is up for debate, but MDMA metabolites, monoamine metabolites, nitric oxide and hyperthermia probably all play a role. While the major metabolites of MDMA (MDA, HHMA) fail to produce neurotoxicity (38), HHMA can be further metabolized to form quinone-like free radicals, which can produce oxidative stress and membrane damage (39). Such minor toxic metabolites can also irreversibly inhibit tryptophan hydroxylase, which can take up to 2 weeks to recover activity (34,40).
Further oxidative stress on the 5-HT system might be due to dopamine. Blocking MDMA-induced dopamine release will prevent neurotoxic markers such as decreases in tryptophan hydroxylase activity and loss of 5-HT uptake sites (41). Conversely, augmenting dopamine release with L-Dopa will increase neurotoxicity (42). Researchers theorize that high concentrations of dopamine near depleted 5-HT neurons causes a decrease in uptake selectivity, allowing dopamine to enter through the 5-HT transporter. It’s possible that dopamine by itself could act as a foreign toxin to 5-HT neurons, but more likely, MAO-B metabolism of dopamine within the cell produces toxic by-products, including hydrogen peroxide, which increases oxidative stress (43).
MDMA also causes increases in nitric oxide synthase (NOS) in the frontal and parietal cortex (44). Nitric oxide (NO) generates oxidative stress by decreasing glutathione concentrations (45) and producing toxic free radicals via reaction with superoxide (46). Inhibiting NOS with N-nitro-L-arginine prevents MDMA’s neurotoxic effect, but only in the two regions of the brain where NOS is upregulated (44). The role of NO could be related to the toxic effects of dopamine metabolism, as nitric oxide can increase the synthesis of dopamine (47). However, inhibition of NO had no effect on MDMA induced dopamine increases, making it likely that NO has a more direct role in MDMA neurotoxicity (44).
The hyperthermic effect of MDMA is possibly the most acute risk that users face, as it can quickly lead to dehydration or even heat stroke. The extent of hyperthermia depends greatly upon the environmental temperature as well as water intake (48). A less noticeable effect of hyperthermia to the user is depletion of antioxidants in the liver (49). Preventing MDMA-induced hyperthermia with the use of a D1 antagonist blocked neurotoxic changes (50, 34).
MDMA Neuroprotection
A simple and sure way to prevent neurotoxicity is to take an SSRI either before or with MDMA. SSRI’s with long half-lives and active metabolites, such as fluoxetine (Prozac), can provide protection even if MDMA is administered a week after the last SSRI dose (51). Because SSRI’s are neuroprotectant, this implies that entrance of MDMA (or dopamine) via the serotonin re-uptake pump is required to produce neurotoxicity. Further evidence that dopamine is the toxic culprit, and not MDMA itself, lies in the observation that SSRI’s can provide some neuroprotection up to an hour after MDMA administration (52). Such a time frame would coincide more with MDMA’s delayed dopamine release, rather than its immediate penetration of the re-uptake pump.
The only downside to taking an SSRI before or with MDMA is that it largely nullifies the “ecstasy” of the experience (53). No MDMA uptake through the 5-HT transporter equates to no MDMA magic (i.e. serotonin and dopamine release). So unless you’re paranoid about some frat boy slipping MDMA into your drink, SSRI’s probably aren’t the best option for MDMA users looking to have a good time.
The serotonin precursors, 5-HTP and L-tryptophan, are also effective neuroprotectants against MDMA toxicity (62). Unlike the SSRI’s however, 5-HT precursors can actually augment the MDMA experience (63).
Another interesting option is use of the MAO-B inhibitor L-deprenyl. The premise behind this should make sense since we’ve already discussed the role of MAO-B deamination in neurotoxicity. Pretreatment with deprenyl in rats prevents lipid peroxidation as well as deficits in 5-HT, 5-HT transporters and tryptophan hydroxylase (54). For humans, a dose of 5-10mg before MDMA use should be sufficient, although longer use of low-dose deprenyl might be prudent, since it has additional antioxidant effects (55).
While there might be many distinct factors in MDMA neurotoxicity, what ties them together is that they all cause an increase in oxidative stress. Thus, a diverse and complete regimen of antioxidants (possibly even double dosing before and after taking MDMA) wouldn’t be a bad idea. Positive research exists for selenium (56), vitamin C (57), vitamin E (58), zinc (59), alpha lipoic acid (60), and L-cysteine (61). But getting creative and adding other antioxidants like green tea, vitamin A, and grape seed extract would probably help as well.
Other simple precautions, like minimizing exposure to overly hot environments, staying hydrated, and maintaining a good diet could go a long way in preventing toxicity, but are often underrated and ignored
Conclusions
MDMA can be a very life-enriching experience for many, especially when it’s used with intimate friends in a comfortable environment, maximizing the potential for positive self-insight and communication. During its brief popularity in the psychotherapy circle, patients often found that it allowed them to be more honest with themselves and their doctors, confronting issues in a couple of hours which often took years to work up to. For other people, it provides a less than healthy means of escape and self-medication. But for the majority of users, MDMA is just plain fun. But despite all the glowing reviews, MDMA is still a very flawed drug. Even if one is successful in preventing neurotoxicity, the rapid tolerance that one develops minimizes MDMA’s potential for any sort of continued use beyond a handful of times. MDMA does not induce a cocaine-like tolerance, in which users will take more and more to get the same effect. Rather, people just find that MDMA eventually loses its magic, and they stop using the drug.
The real benefits of MDMA won’t be derived from individual use, but rather from continued research on the drug. The amount we can learn from MDMA is far from being realized; MDMA research stands to elucidate many aspects of neuroadaptation and toxicity; the 5-HT and dopaminergic systems, and their involvement in mood and psychopathology. MDMA could even influence the development of future pharmaceuticals for mood disorders. Imagine a non-neurotoxic drug that implemented MDMA’s powerful and fast acting effects on 5-HT and dopamine. It would place Prozac and Ritalin into the realms of castor oil and bloodletting. But such a future isn’t here yet. So until then, take your antioxidants, stay hydrated, and “roll” safely.
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