Hyponatremia

An important cause of death following MDMA use is hyponatremia, low blood sodium levels as a result of drinking too much water.^[20] While it is important to avoid becoming dehydrated, especially when out dancing in a hot environment, there have been a number of users suffering from water intoxication and associated hyponatremia (dilution of the blood that can cause swelling of the brain).^[21] Although many cases of this clearly involved individuals drinking large amounts of water, there are cases where there is no evidence of excessive water consumption. Their cases may be caused by MDMA inducing release of the antidiuretic hormone vasopressin by the pituitary gland.^[22] The action of vasopressin on the renal tubules leads to the retention of water, resulting in users producing less urine. (This is unrelated to having difficulty passing urine, a phenomenon known colloquially as E-wee).^[23] Hyponatremia also affects marathon runners and bodybuilders, who have been known to die from similar causes, as a result of drinking too much water and sweating out too much salt. It affects women more than men.

Hyponatremia is preventable by drinking fluid containing sodium, such as that contained in sports drinks (typically ~20mM NaCl).^[24]

[edit] Hyperthermia

The primary acute risks of taking MDMA resemble those of other stimulant amphetamines. The second most important cause of death from MDMA use is hyperthermia, core body temperature rising too high until the major organs shut down at about 42°C. This is comparatively more problematic than blood salt imbalance, harder to treat and to avoid. Ecstasy-related hyperthermia may occur as a symptom of serotonin syndrome, which is where too much serotonin is released into the brain. This can occur with MDMA if too much 5HTP or other serotonergic drugs are consumed together. 50–200 mg of 5HTP is believed by some users to make MDMA work better and last longer, but anecdotally more than 300 mg 5HTP may increase risk of serotonin syndrome^{[citation needed]}, which can lead into lethal hyperthermia if it becomes too severe. It has been suggested that hyperthyroidism may also increase risk of ecstasy-related hyperthermia.^[25]

Note that this is different from normal hyperthermia. Dance parties are an obvious hyperthermia risk environment, the venue often being hot and crowded, and the attending public dancing whilst on stimulant drugs. Ideally the temperature inside the dance rooms should be maintained in the range 24–27°C; ecstasy affects the body’s ability to regulate temperature and it is easy to become either too hot or too cold if the temperature is outside of this range.

Mild hyperthermia and/or dehydration can occur from dancing too long, and users may recover with administration of fluids and rest in a cooler environment. However, if the user expresses concern about how hot they feel, or if their body temperature is still rising even when they have stopped dancing and are in a cooler environment, and their skin is hot and dry to the touch, then they may be developing more dangerous drug-induced hyperthermia, and these cases should be taken to and handled by a medical professional immediately.

Overdose

Due to the difference between the recreational dose and the lethality dose, it is extremely rare for a death to be accredited just to the consumption of MDMA. While a typical recreational dose is roughly 100–150 mg (often being measured by eye and dealt with as fractions of a gram), this dose is often then repeated but remains well below the lethal dose. Consumption of the drug can be self-reinforcing while under the influence, and overdoses can occur. People who are grossly obese, or who have diabetes, high blood pressure or heart conditions have a greater risk of overdose death from any stimulant, and should generally avoid MDMA and similar drugs.In very rare cases, MDMA has been associated with serious neurological problems such as subarachnoid hemorrhage, intracranial bleeding, or cerebral infarction. Similar problems have been noted with amphetamines. The mechanisms are thought to involve the short-term hypertension leading to damage of cerebral blood vessels, especially in patients with pre-existing conditions such as arteriovenous malformations or cerebral angiomas.

Serotonergic changes

Experiments indicate that both moderate and high dose or rapidly repeated MDMA exposure may lead to long-lasting changes in neurons that make serotonin. Serotonergic changes have been demonstrated experimentally in the brains of all mammalian species studied, with most studies involving rats. In these studies, the brains of animals who are given high or repeated doses of MDMA show long-term decreases in all measures of serotonergic functioning, including concentrations of serotonin, tryptophan hydroxylase, and binding of the serotonin transporter protein. Although measures of serotonin are decreased, there are no decreases in the number of cells in the dorsal raphe, which indicates that the serotonin neurons have not died. Limited studies attempting to stain and photograph serotonergic axons shortly after high-dose MDMA exposure have reported that axons appear swollen and misshapen, as if they might be degenerating. However, few studies have attempted to stain and examine axons and with the measures commonly used in MDMA studies it is difficult or impossible to distinguish axon loss from decreases in production of markers of serotonin.^[41][42]

Animal studies show that there is recovery of serotonergic markers. However, if axons are actually regrowing, there is no assurance that they will reform their original connections. While rats show extensive recovery that sometimes appears complete ^[43][44], some primate studies show evidence of lasting alterations in serotonergic measures. Human studies, discussed below, show recovery, but these studies use indirect measures that may lack sensitivity for detecting subtle changes.

It is not known what dose(s) of MDMA would produce similar toxic effects in humans. This is because there are some difficulties in translating animal MDMA toxicity studies to humans. Firstly, it is difficult to equate rat doses to human doses, because rats metabolize MDMA twice as fast as humans and often larger doses or multiple doses are administered to simulate human plasma levels. Second, if the neurotoxicity of MDMA depends on its metabolites (Jones 2004;^[45]), it may be difficult or impossible to translate an MDMA dose between species since different species metabolize MDMA to different extents. Therefore, it is difficult to say what dose in humans would produce the effects seen in animals.

Keeping these limitations in mind, comparisons of MDMA exposures can be made between animal neurotoxicity studies and human clinical studies. One (uncertain) estimate suggests that the neurotoxic dose may be only moderately higher than amounts given in clinical studies (1.5 or 1.7 mg/kg, about 100 or 120 mg).^[46] That published comparison was made based on data from rats.

Further comparisons can be made using monkey data. In a recent study by Mechan et al. (2006), the lowest repeated dose regimen that produced serotonergic effects, detectable after 2 weeks, in squirrel monkeys was 2.4 mg/kg given orally three times in a row (every 3 hours). The peak plasma MDMA concentrations seen after that dose was 787 ± 129 ng/ml (mean ± SEM, range: 654 to 1046 ng/ml) and the area-under-the-concentration-vs-time-curve (AUC, a measure of overall drug exposure) was 3451 ± 103 hr*ng/ml. In comparison, 1.6 mg/kg oral (112 mg in a 70 kg / person) in humans produces peak MDMA concentrations of 291.8 ± 76.5 ng/ml (range: 190 – 465 ng/ml) and an AUC of 3485.3 ± 760.1 hr*ng/ml (Kolbrich et al. 2008). Thus, a typical human dose produces peak MDMA concentrations that are about 37% of a known neurotoxic dose and has a very similar AUC. Because MDMA has nonlinear kinetics, it is likely that fewer than three of these doses would be needed to produce an exposure in humans greater than the dose schedule that produced decreased brain serotonin and decreased serotonin transporter binding in monkeys.

[edit] Mechanisms of serotonergic changes

The mechanism proposed for this apparent neurotoxicity involves the induction of oxidative stress. This stress results from an increase in free radicals and a decrease in antioxidants in the brain. (Shankaran, 2001) Oxidation is part of the normal metabolic processes of the body. As the cell goes about its life, by-products called oxidative radicals are formed, also called free radicals. These molecules have an unpaired electron that makes them highly reactive. They pull strongly on the electrons of neighboring molecules and destabilize the electrical balance of those molecules, sometimes causing those molecules to fall apart. This can become a chain reaction.

In normal functioning, there are antioxidants in the system that act as free radical scavengers. These are molecules with an extra electron that they are willing to give up to the free radicals, making both the free radical and the antioxidant more stable. MDMA rapidly increases the levels of free radicals in the system, which is thought to overwhelm the reserves of scavengers. The radicals then damage cell walls, reduce the flexibility of blood vessels, destroy enzymes, and cause other molecular damage in the neurological pathways. (Erowid, 2001) It has been shown that MDMA’s neurotoxic effects in rodents are increased by a hyperthermic environment and decreased by a hypothermic one. (Yeh, 1997)

Studies have suggested that the neurotoxic molecules are not hydroxyl free radicals, but superoxide free radicals. When rats are injected with salicylate, a molecule that scavenges hydroxyl free radicals, the neurotoxic effects of MDMA are not attenuated, but actually potentiated. Further evidence of this superoxide theory comes from the observation that CuZn-superoxide dismutase transgenic mice (mice with excess human antioxidant enzyme) demonstrate neuroprotective mechanisms that protect the mice from MDMA-induced depletion of 5-HT (serotonin) and 5-HIAA and lethal effects. (Baggott, 2001 and Yeh, 1997)

MDMA itself does not seem to be neurotoxic as infusing it into an animal’s brain does not produce long-term serotonergic changes. This suggests that another molecule may be triggering the oxidative stress. Different scientists have suggested that either a dopamine or an MDMA metabolite (such as 3,4-dihydroxy-methamphetamine) might be important for initiating the cascade of oxidative stress. However, no consensus has emerged as of yet.

[edit] Possible neuroprotective strategies

There are a number of factors that have been shown to protect animals from long-term MDMA-induced serotonin changes. These include dose, temperature, antioxidants, and SSRIs. Some MDMA users have attempted to use analogous strategies to decrease their risks of long-term serotonin changes, although there is uncertainty as to how well this works in people^{[citation needed]}.

The most obvious strategy is reducing dose. Long-term serotonergic changes are dose dependent in animals. Taking higher or repeated doses of MDMA is therefore likely to increase chances of similar changes in people. Although the threshold dose to cause toxicity is unknown in humans, lower doses are almost certainly less risky^{[citation needed]}.

Studies in rats also find that environments or activities that increase the animals’ body temperature increase serotonergic changes. However, this finding has not been replicated in primates, possibly because rodents are less able to regulate body temperature than primates. Nonetheless, it is possible that higher body temperature also increases serotonergic changes in people^{[citation needed]}.

Antioxidants may decrease possible MDMA-induced serotonergic changes. Studies in rats have shown that injections of ascorbic acid, alpha lipoic acid, or some other radical scavengers are effective in reducing oxidative stress caused by MDMA. (Erowid, 2001) It has been speculated that humans may be able to similarly achieve protection using a combination of antioxidants, such as Vitamin A, C, and E or multivitamins including selenium, riboflavin, zinc, carotenoids, etc. may help reduce oxidative damage. No published studies have confirmed that this works. In addition, many of these vitamins, though, are water soluble, and are quickly excreted from the body. The typical MDMA user is psychoactive for 4–6 hours and may not have an appetite from the time of taking until the following sleep cycle or many hours later. Damage occurs in the absence of these antioxidants.Selective serotonin reuptake inhibitors (SSRIs) have been shown to decrease or block MDMA neurotoxicity in rodents, even if they are given several hours after MDMA. Because of this, some MDMA users administer an SSRI while, or shortly after taking MDMA, in an attempt to prevent possible neurotoxicity. These SSRIs are typically antidepressants such as fluoxetine or sertraline. The theory of some scientists^[who?] is that SSRIs prevent dopamine or a neurotoxic MDMA metabolite from entering through the serotonin reuptake transporter, where it is theorized that it may contribute to formation of reactive oxygen species, including hydrogen peroxide. There are several concerns with taking SSRIs with MDMA. On a practical level, administration of SSRIs will block the desired effects of the drug if taken too early. This blocking effect can last several weeks, depending on the half-life of the SSRI. In addition, MDMA and the SSRI will often mutually reduce each other’s metabolism, causing them to last longer in the body. Theoretically, this might increase risk of overdosing on the SSRI, leading to serotonin syndrome. Although this appears to occur rarely (if ever), it is considered a theoretical possibility.

Evidence for serotonergic changes in humans

Studies have used positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging methods to estimate brain serotonin transporter levels in ecstasy users. These studies have found reduced levels of the transporter in recently abstinent MDMA users as well as evidence of partial or full recovery with prolonged abstinence. However, the sensitivity of these methods is unknown and changes may not have been detected. Three studies of 5-HT2A receptors in human MDMA users have been published by one group of researchers (Reneman and colleagues). Together, these studies find possibly reduced receptor binding during active MDMA use and increased receptor binding in longer-abstinent subjects. The authors argue that long-lasting reductions in 5-HT release may have caused compensatory up-regulation of 5-HT2A receptors. Other studies have measured cerebrospinal fluid concentrations of the serotonin metabolite 5HIAA. Three of four published studies have reported concentrations to be lower in ecstasy users than non-users.

One difficulty in interpreting these studies is that it is difficult to know if serotonergic differences predated MDMA use. In addition, none of these studies can address whether any changes are neurotoxicity proper or neuroadaptation. A recent review concluded that “the current state of neuroimaging in human MDMA users does not permit conclusions regarding the long-term effects of MDMA exposure”.^[49]In addition, mood is sometimes found to be worse and impulsivity greater in ecstasy users. At least two meta-analyses of these studies have been completed (Morgan 2000; Sumnall & Cole 2005). Morgan’s analysis of 17 studies showed that ecstasy users had a slight tendency to be more impulsive and have lower mood than controls. Sumnall and Cole’s analysis showed a slight increase in the prevalence of depressive symptoms in ecstasy users over controls. (Mood measured in these studies does not indicate clinical levels of depression, which has not been associated with MDMA use.) Of course, studies like these raise a cause-consequence question: did these impulsive and depressed people use ecstasy to self-medicate or did otherwise normal people become depressed and impulsive after using ecstasy?^[52][53][54]A recent important study (the NeXT Netherlands XTC toxicity study) prospectively examined 25 people before and after their first episode of ecstasy use (mean 2.0 ± 1.4 ecstasy pills, on average 11.1 ± 12.9 weeks since last ecstasy use). The study measured working memory, selective attention, and associative memory using fMRI. No significant effects were found of the reportedly modest dose(s) of ecstasy on any of these measures, suggesting that the first few exposures to ecstasy typically do not cause significant residual toxicity.[55] Thus, if ecstasy does cause cognitive-behavioral changes, it would likely require repeated use for these changes to occur (or become detectable). Contrary to this another recent report has shown that a single exposure to MDMA can result in cognitive-behavioral changes.

Addiction and tolerance

The potential of MDMA to produce addiction is controversial. Some studies indicate that many users may be addicted, but this depends on the definition of addiction; while many ecstasy users may take the drug regularly and develop significant tolerance to its effects, relatively few users exhibit cravings or physical symptoms of dependence, or find it difficult to stop using the drug when they decide to do so