Effects of MDMA on the human body



The effects of MDMA (or ecstasy) on the human brain and body are complex. The biochemical effects induced include serotonin, dopamine, and norepinephrine release, and can act directly on a number of receptors, including α2-adrenergic (adrenaline) and 5-HT2A (serotonin) receptors. (DHEA), and the antidiuretic hormone vasopressin (which may be important in its occasional production of water intoxication or hyponatremia).

It is not understood how the chemical effects of MDMA induce its psychoactive effects. Most explanations focus on serotonin release. MDMA causes serotonin vesicles in the neurons to release quantities of serotonin into the synapses. Studies using pretreatment with an SSRI to block the ability of MDMA to release serotonin in volunteers suggest serotonin release is necessary for most psychoactive effects of MDMA in humans. Released serotonin stimulates several receptors that are believed to contribute to the experiential effects of MDMA. Laboratory rodent experiments have shown MDMA to activate oxytocin-containing neurons in the hypothalamus by stimulating 5-HT1A receptors. This appears to contribute to some of the social effects of MDMA: upon administering a drug that blocked brain receptors for oxytocin, the effects of the drug on social behavior were reduced. A second serotonin receptor, 5-HT2A receptors (which are important for the effects of hallucinogens), makes mild contributions to MDMA effects. When the receptor was blocked, volunteers given MDMA reported decreases in MDMA-induced perceptual changes, emotional excitation, and acute adverse responses. In contrast, blocking these 5-HT2A receptors had little effect on MDMA-induced positive mood, well-being, extroversion, and most short-term sequelae. One possible explanation for some of these 5-HTA-mediated effects is that 5-HT2A stimulation inhibits dopamine release.

Although serotonin is important to the effects of MDMA, other drugs that release serotonin, such as fenfluramine, do not have effects like MDMA. This indicates that other neurochemical systems must be important for the MDMA experience. In addition to serotonin, dopamine and noradrenaline may play important roles in producing MDMA effects. The dopaminergic D2 receptor antagonist haloperidol selectively reduced the euphoric effects of MDMA in volunteers while increasing feelings of anxiety. Although not yet examined in humans, several studies in rodents indicate the noradrenergic mechanisms contribute to the stimulating effects of MDMA. Like many substituted amphetamines, MDMA is a TAAR1 agonist, which is the receptor responsible for the effect of amphetamines and trace amines on monoamine transporter reuptake inhibition.

The effects of MDMA on regional cerebral blood flow (CBF) have been studied in humans using [H215O]-Positron Emission Tomography (PET) MDMA was found to produce alteration of brain activity in cortical, limbic, and paralimbic structures. The dose of MDMA, 1.7 mg/kg, was psychoactive and participants reported heightened mood, increased extroversion, feelings of altered reality, and mild perceptual alterations. Feelings of "extroversion" correlated with CBF in the temporal cortex, amygdala, and orbitofrontal cortex.

Subjective effects


Short-term experiential effects, which tend to last less than 4 hours, include:
 * Mental and physical euphoria
 * A sense of general well-being and contentedness
 * Decreased negative emotion and behavior such as stress, anxiety, fear, and paranoia
 * Increased sociability and feelings of communication being easy or simple
 * Increased urge to communicate with others
 * Increased empathy and feelings of closeness or connection with others
 * Reduced insecurity, defensiveness, and fear of emotional injury
 * Decreased irritability, aggression, anger, and jealousy
 * A sense of increased insightfulness and introspection
 * Mild psychedelia (colors and sounds are enhanced, mild closed-eye visuals, improved pattern recognition, etc.)
 * Enhanced tactile sensations (touching, hugging, and sex)

Effects beginning after the main effects of MDMA have ended, which can last several days, include:
 * Lowered mood or even depression (comedown) after the effects have worn off
 * Increased anxiety, stress, and other negative emotions
 * Residual feelings of empathy, emotional sensitivity, and a sense of closeness to others (afterglow)

Other short-term effects
Acute physiological effects include:


 * Increased heart rate and blood pressure
 * Increased body temperature
 * Increased perspiration and sweating
 * Impaired Speech
 * Pupil dilation
 * Blurred vision
 * Nystagmus (rapid involuntary eye movements and jittering)
 * Trismus (difficulty opening the mouth widely) and bruxism (grinding and clenching of the teeth)
 * Difficulty sleeping
 * Loss of appetite
 * Nausea and emesis
 * Urinary retention
 * In males, possible erectile dysfunction

Adverse effects
Also, serious adverse events in MDMA users may be an interaction of the drug with a preexisting medical condition. Risk of adverse event after MDMA consumption is thought to be increased by preexisting cardiovascular problems, such as cardiomyopathy, hypertension, viral myocarditis, and congenital cardiac conduction abnormalities (such as Wolff–Parkinson–White, Romano–Ward, Brugada, and Jervell and Lange–Nielsen Syndromes).

Serious adverse events in MDMA users may also be caused by drugs sold as "ecstasy", but which are not actually MDMA. Dangerous overheating, sometimes fatal, is associated with drugs such as PMA or 4-MTA. To help mitigate risks associated with the consumption of MDMA, certain organizations have created screening test kits to prevent the consumption of more harmful substances such as PMA, Methamphetamine, 2C analogs, BZP and TFMPP.

Hyponatremia
An important cause of death following MDMA use is hyponatremia, low blood sodium levels as a result of drinking too much water. 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). 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. 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). 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).

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. MDMA-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, which can lead into lethal hyperthermia if it becomes too severe. It has been suggested that hyperthyroidism may also increase risk of MDMA-related hyperthermia.

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; MDMA 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. Treatment is most effective the sooner it is given, as with all adverse drug reactions. Hyperthermia is a particular concern if MDMA use is combined with other substances, such as 5HTP, or if additional stimulants are involved, such as methamphetamine or cocaine. MDMA is also implicated in affecting the mechanism of uncoupling protein (UCP), more specifically UCP3 in mitochondria which can lead to the abnormal thermogenic response.

In animal studies, a combination of prazosin (α1 adrenergic antagonist) and pindolol (5-HT1A antagonist/beta blocker) quickly and completely terminates drug-induced hyperthermia. Another drug, the migraine medicine pizotyline has also been shown to be useful in treating MDMA overdose in animals. However, neither of these treatments are approved for use in humans.

MDMA appears to decrease heat loss in the body by causing constriction of blood vessels near the skin. In addition, it can increase heat production by muscles and the brain. These effects may be amplified in people who become dehydrated and are therefore unable to cool by sweating. On top of this, MDMA can mask the body's normal thirst and exhaustion responses, particularly if a user is dancing or is otherwise physically active for long periods of time without hydration. Because of these effects, MDMA can temporarily reduce the body's ability to regulate its core temperature so that high-temperature surroundings (e.g. clubs) combined with physical exertion may lead to hyperpyrexia if precautions are not taken to remain cool. Sustained hyperpyrexia may lead to rhabdomyolysis, which in turn can cause renal failure and death. Depending on the initial cause of rhabdomyolysis, it may be successfully treated with dantrolene if diagnosed early enough, but often the characteristic symptoms may not be apparent until the condition is already severe.

Treatment
MDMA-induced hyperthermia may be treated with dantrolene.

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.

The standard treatment for MDMA overdose given in hospitals includes a range of drugs such as cyproheptadine or chlorpromazine but these are often of limited efficacy. MDMA overdose mainly results in hyperthermia and hyponatremia, which leads onto convulsions from the hyponatremia and rhabdomyolysis (toxic muscle breakdown) from the hyperthermia. These complications can be treated; benzodiazepines such as diazepam or lorazepam are used to control convulsions and dantrolene blocks rhabdomyolysis.

It's been argued that "the seriousness of the effects can be dependent on environmental factors other than the drug concentration", as blood concentrations of the drug spanned a large range in cases of death in MDMA users. This not-with-standing, "most of the cases of serious toxicity or fatality have involved blood levels... up to 40 times higher than the usual recreational range."

Quoted from Dr. Julie Holland: "Not only are MDMA related cases a small percentage of all drug-related emergency room visits, but a large percentage of MDMA cases are not life-threatening. In a recent study conducted by the physicians in the Emergency Department of Bellevue, (Rella, Int J Med Toxicol 2000; 3(5): 28) regional hospital ecstasy cases phoned into the New York City poison control center were analyzed. There were 191 cases reported during the years 1993 to 1999 inclusive. This is a rate of fewer than thirty cases per year. 139 cases (73%) were mild and experienced minor or no toxicity. The most commonly reported symptoms were increased heart rate (22%), agitation (19%), and nausea and vomiting (12%). In these seven years, only one ecstasy-related death was reported, which was due to hyperthermia, or overheating.

Other adverse effects
MDMA users almost always experience bruxism (teeth grinding) and trismus (jaw clenching) as a short-term effect from the drug. Many users of MDMA alleviate this by using chewing gum, or chewing on improvised mouth guards (such as a small plastic glow stick or pacifier). Temporary jaw ache often results from jaw clenching or excessive chewing. Some users consume supplemental magnesium tablets to relax the jaw muscles and relieve clenching, although this practice has not been formally studied. In extreme cases, MDMA use has been associated with excessive wear of teeth and resulting dental problems.

Liver damage, which may have an immunological cause, has been seen in a small number of users. It is not clear to what extent liver toxicity is caused by MDMA or other compounds found in ecstasy tablets. Animal studies suggest MDMA can cause liver damage and that the risk and extent of liver damage is increased by high body temperature.

While there has been an urban legend that having an allergy to penicillin or related antibiotics means one is allergic to MDMA, this myth is baseless, as the two drugs are far too different for an allergy to one to translate into an allergy to the other.

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.

While users sometimes report increased sexual desire, there are many reports of difficulty achieving both erection and orgasm while on the drug. It has been said that, "[MDMA] is a love drug but not a sex drug for most people." This is the rationale behind the use of sextasy (combining MDMA with Viagra).

The combination of MDMA and low doses of viagra has been shown to prevent MDMA related serotonin depletion in rats. It even has a preventative effect 24 hours later by increasing resistance to MDMA-related oxidative stress.

Long-term adverse effects
Research on possible long-term adverse effects of MDMA have mainly focused on two areas. The first area is possible serotonergic neurotoxicity. The second area is psychiatric and behavioral problems that might result from MDMA use. These possible adverse effects may be independent. Studies finding serotonergic changes do not always find cognitive-behavioral changes and studies finding cognitive-behavioral changes do not always find serotonergic changes.

In addition to these main areas of research, there have been a number of animal studies suggesting MDMA can cause other possible neurological changes, including apoptosis, non-serotonergic neurotoxicity in the somatosensory cortex, and increased expression and altered processing of amyloid precursor protein.

Serotonergic changes
Experiments indicate that both moderate and high doses of MDMA 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.

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, 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's 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; ), 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). 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.

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. 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.

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. )

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. Earlier scientists have suggested that dopamine might be important for initiating the cascade of oxidative stress. However, it needs to be a chemical which is not produced in the brain, but produced systemically, so this seems to rule out dopamine. More recent scientists suggest an MDMA metabolite (such as 3,4-dihydroxy-methamphetamine) may be responsible.

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.

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.

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.

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.

There are problems in trying to translate studies of neuroprotection with antioxidants from animal studies to humans. The effective doses of antioxidants given to these animals are much higher than humans would ever take both in its method of administration (injected vs. oral) and in its dosage. Both the neurotoxic and neuroprotective effects may be maximized in these animal studies, and it is not possible to know what doses or patterns of use (if any) would produce the same effects in people.

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 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.

More significant risks occur if MDMA is taken with some other prescription drugs, including antidepressants that act as monoamine oxidase inhibitor. This can lead to serotonin syndrome and the possibility of life-threatening hypertension.

Many users also attempt to replenish the hypothesized deficit of serotonin that is thought to follow the use of MDMA by administering 5-HTP, in an attempt to reduce the depressed mood and unpleasant symptoms in the days following MDMA usage (including the immediate "come-down" and what is known as "suicide Tuesday" or "mid-week blues"). The serotonin precursor 5-HTP, which is commercially available as a dietary supplement, supplies the user with more of the raw materials to synthesize the neurotransmitter, theoretically reducing the negative psychological effects of depleted serotonin. (Note that normal dietary sources of serotonin precursors may have less than normal effects if tryptophan hydroxylase levels have been reduced by MDMA.) Varied reports indicate that the perceived impact of pre-loading is dependent upon a number of factors and while it has not been shown to reliably increase the subjective effects of MDMA, your mileage may vary.

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 MDMA 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 MDMA 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 do not permit conclusions regarding the long-term effects of MDMA exposure".

Although they are often studied in the same people or animals, possible serotonergic changes may have different risk, mechanisms, and recovery compared to possible cognitive and behavioral enhancing changes occurring during MDMA exposure. Studies in animals and mankind have generally failed to correlate these two domains.

Psychiatric and behavioral changes
Some studies find that repeated MDMA use may lead to subtle changes in learning, memory, attention, executive function, mood, and decision making. Considerable research has been done into these possible cognitive-behavioral deficits but studies are inconclusive. Most are retrospective, that is, they study people after they started using MDMA. This makes it difficult to know if differences between users and non-users were preexisting.

There does not seem to be a single type of cognitive task that is consistently altered in the different studies. Tasks that have shown differences include ones measuring attention, learning, memory, and executive function. Many of the findings, which are more commonly reported in people with more extensive MDMA use histories (or even abuse diagnoses), may simply reflect preexisting differences between people who are drawn to use drugs like MDMA frequently and those who do not.

In addition, mood is sometimes found to be worse and impulsivity greater in MDMA users. At least two meta-analyses of these studies have been completed. Morgan's analysis of 17 studies showed that MDMA 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 MDMA 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 MDMA to self-medicate or did otherwise normal people become depressed and impulsive after using MDMA. This question has not been conclusively answered and both possibilities may be true in individual cases.

There are a growing number of longitudinal or prospective studies, looking at users and nonusers at several points in time. Published prospective studies tend to report subtle difference between users and nonusers with performance within normal range. These difference tend to persist or increase across time; While persisting differences are consistent with differences predating MDMA use, increases may indicate worsening due to drug exposure.

A recent study (the NeXT Netherlands XTC toxicity study) prospectively examined 25 people before and after their first episode of MDMA use (mean 2.0 ± 1.4 ecstasy pills, on average 11.1 ± 12.9 weeks since last MDMA 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 MDMA on any of these measures, suggesting that the first few exposures to MDMA typically do not cause significant residual toxicity. Thus, the authors conclude, if MDMA does cause cognitive-behavioral changes, it would likely require repeated use for these changes to occur (or become detectable). Authors of a large prospective field study, screening participants' hair samples to evaluate their drug use and selecting control group participants from within the raver subculture, reached similar conclusions and suggested that the regular sleep deprivation and dehydration that all ravers experience may be the cause of some of the cognitive-behavioural differences previously recorded in MDMA users. Contrary to this another recent report has shown that a single exposure to MDMA can result in cognitive-behavioral changes. The study took a group of people who have never used MDMA and had them perform cognitive tests. The participants were then exposed to a low dose of MDMA and underwent the same cognitive tests three years later. It was found that scores on immediate and delayed verbal recall and verbal recognition were significantly lower in the group of incident MDMA users compared with persistent MDMA-naive subjects. The authors recognize there were limitations to their study but believe that they have demonstrated that MDMA most likely does cause cognitive-behavioral effects after one exposure.

In addition to concerns about neurotoxicity, several published reports have described hallucinogen persisting perception disorder in MDMA users. This appears to be very rare and published cases have been complicated by use of other drugs, in concurrence with MDMA use.

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 MDMA 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. Cottler et al. (2001) interviewed 52 users and found that 43% met standard criteria for dependence. Tolerance and after effects ("withdrawal" effects) are symptoms of dependence for many drugs, but seem to occur in some MDMA users who are actually not dependent. For example, studies in Switzerland in which MDMA was given to people who had never used it before documented after effects. When people are classified as addicted to MDMA, it is not clear if that indicates a difficulty in quitting the drug. In a prospective study in Germany, many who were initially categorized as addicted, spontaneously 'improved' without any treatment for the alleged addiction. Given the complexities in classifying MDMA users as addicted, conclusions about the addictive potential of MDMA are less reliable than those about nicotine addiction.

Retracted article on MDMA-induced dopamine neurotoxicity in primates
In a retracted article on toxicity of MDMA on dopamine cells, a research team led by Dr. George A. Ricaurte at Johns Hopkins University implicated MDMA as a cause of Parkinson's-like brain abnormalities in monkeys, suggesting that a single use of MDMA caused permanent and serious damage to dopamine neurons. This controversial finding was subsequently retracted with the researchers stating that they had inadvertently injected their experimental animals with methamphetamine instead of MDMA.