Effects of MDMA on the human body



This article discusses the pharmacokinetics (what the body does to MDMA) and the pharmacodynamics (what MDMA does to the body) of MDMA. More general information on MDMA can be found in the main entry for MDMA.

Pharmacokinetics
MDMA reaches maximal concentrations in the blood between 1.5 and 3 hours after ingestion. It is then slowly metabolized and excreted, with levels decreasing to half their peak concentration over approximately 8 hrs. Metabolites of MDMA that have been identified in humans include 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxy-methamphetamine (HMMA), 4-hydroxy-3-methoxyamphetamine (HMA), 3,4-dihydroxyamphetamine (DHA, also called alpha-methyldopamine), 3,4-methylenedioxyphenylacetone (MDP2P), and N-hydroxy-3,4-methylenedioxyamphetamine (MDOH). The contributions of these metabolites to the psychoactive and toxic effects of MDMA are an area of active research.

MDMA is known to be metabolized via three pathways. One such pathway proceeds via N-demethylation; byproducts of which include several active metabolites, including MDA. The metabolism may be primarily by the cytochrome P450 enzymes CYP2D6 (in humans, but CYP2D1 in mice), and CYP3A4. Complex, nonlinear pharmacokinetics arise via autoinhibition of CYP2D6 and CYP2D8, resulting in zeroth order kinetics at higher doses. It is thought that this can result in sustained and higher drug concentrations if the user takes consecutive doses of the drug. 65% of MDMA is excreted unchanged in the urine (additionally 7% is metabolised into MDA) during 24 hours after usage.

MDMA is a chiral compound and has been almost exclusively administered as a racemate. However, an early uncontrolled report suggests that the S-enantiomer is significantly more potent in humans than the R-enantiomer (Anderson et al. 1978). Studies in humans indicate that the disposition of MDMA is stereoselective, with the S-enantiomer having a shorter elimination half-life and greater excretion than the R-enantiomer. For example, Fallon et al. reported that the area under the plasma concentration versus time curve (AUC) was two to four times higher for the R-enantiomer than the S-enantiomer after a 40 mg oral dose in human volunteers. Similarly, the plasma half-life of (R)-MDMA was significantly longer than that of the S-enantiomer ((5.8 ± 2.2 hours) vs 3.6 ± 0.9 hours). However, because MDMA has dose dependent kinetics, it is likely that these half lives would be higher at more typical doses (100 mg is sometimes considered a typical dose). Given as the racemate, MDMA has a half-life of around 8 hours.

Short-term neurochemical effects
Serotonin is a neurotransmitter believed to play a role in the regulation of mood and pleasure. MDMA causes serotonin vesicles in the neurons to release quantities of serotonin into the synapses. Although popular press accounts focus on the role of serotonin release, the mechanism by which MDMA causes its unusual psychoactivity is largely unknown. In vitro and nonhuman animal studies have established that MDMA also induces dopamine, norepinephrine, and acetylcholine release, and can act directly on a number of receptors, including a2-adrenergic (adrenaline) and 5HT2A(serotonin) receptors. MDMA promotes the release of several hormones including prolactin and the antidiuretic hormone vasopressin, which may be important in its occasional production of water intoxication or hyponatremia. Laboratory rodent experiments have also shown MDMA to activate oxytocin-containing neurons in the hypothalamus. Upon administering a drug that blocked brain receptors for oxytocin, the effects of the drug on social behavior were reduced.

Subjective effects
Effects desired by users include:
 * increased positive emotion and decreased negative emotion
 * increased sense of well-being
 * increased sociability and feelings of closeness or connection with other people
 * reduced defensiveness and fear of emotional injury
 * a sense of increased insightfulness and introspective ability

MDMA, particularly with larger doses, is sometimes reported to cause visual distortions. In a review of studies in which 1.5 to 1.7 mg/kg oral MDMA was administered in their laboratory to 74 people, Vollenweider et al. reported that scenic hallucinations were reported only once, while simple patterns, distorted objects, and flashes of light were commonly reported

Other short-term effects
Acute physiological effects include :
 * Pupil dilation with attendant photosensitivity and color perception
 * Impaired vision
 * Nystagmus, rapid involuntary rhythmic eye movement, with the eyes moving quickly in one direction (quick phase), and then slowly in the other (slow phase).
 * General restlessness
 * Loss of appetite
 * Increased heart rate and blood pressure
 * Dehydration
 * Depression (Skag/Come down) after the effects have worn off
 * Trisma (jaw-clenching) and bruxia (grinding of the teeth).
 * Stimulated senses

Acute toxic/dangerous effects
Figures in the United States show that fewer than 10 people per year die with only MDMA in their system, and fewer than 100 per year with MDMA and other drugs. In England and Wales, in the five years between 2001 and 2005, there were an average 27 deaths per year attributed to MDMA alone. In the same period, the average deaths for heroin (including morphine), methadone, temazepam, and cocaine alone were 575, 99, 61, and 45 respectively. An average of 132 deaths resulted from the use of paracetamol alone. Comparison of the number of ecstasy pills estimated to be consumed in England and Wales per year compared to the number of deaths resulting from ecstasy use, suggests that the risk of death from taking ecstasy is around 1 death per 100,000 users per year. This is approximately the same risk of death as is associated with adverse drug reactions to estrogen-containing (combined) forms of hormonal contraception.

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 maintain fluid intake, especially when out dancing in a hot environment, too much fluid can also be dangerous. Marathon runners and bodybuilders have been known to die from similar causes, as a result of drinking too much water and sweating out too much salt.

While dehydration is undesirable, there also 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 antiduretic 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, which is probably not related to having difficulty passing urine (a phenomenon known colloquially as E-wee).

Hyperthermia
In addition to the potential dangers from other drugs sold as 'ecstasy', the primary acute risks of taking MDMA resemble those of other stimulant amphetamines. The second most important cause of death from MDMA use is malignant hyperthermia, core body temperature rising too high until the major organs shut down at about 42°C. This is a bit more problematic than blood salt imbalance, harder to treat and to avoid. Malignant hyperthermia is more often seen when people have taken dangerous ecstasy analogues such as PMA or 4-MTA. It usually happens as a secondary consequence of serotonin syndrome, which is where too much serotonin is released into the brain. This can occur with MDMA if too much 5HTP is consumed alongside, as this can overload the brain with serotonin once the 5HTP gets converted. As a guideline, 50-200mg of 5HTP will make MDMA work better and last longer, but with more than 300mg 5HTP, the user can start to become confused, red-faced, hot and dry to the touch; this is serotonin syndrome, which can lead into lethal malignant hyperthermia if it becomes too severe.

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 bodies 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 malignant 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. Malignant 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.

In animal studies, a combination of prazosin and pindolol (5HT1A antagonist/beta blocker) quickly and completely terminates drug-induced malignant 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. Rhabdomyolysis can generally be successfully treated with dantrolene if diagnosed early enough, but often the characteristic symptoms may not be apparent until the condition is already severe.

Overdose
The third most prominent cause of death from MDMA is acute overdose. While the typical recreational dose (100-150 mg) is well below the lethal dose, consumption of the drug can be self-reinforcing while under the influence, and overdoses can occur. Small children, however, can easily die from overdose with just a single adult dose. 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. However, most fatal ecstasy overdoses are in children who find their parent’s pills.

The standard treatment for ecstasy overdose given in hospitals includes a range of drugs such as cyproheptadine or chlorpromazine but these are often of limited efficiency. 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.

Overdose on MDMA alone is however unlikely under normal usage conditions, but some drug combinations can make it more dangerous. Two particularly dangerous combinations should be noted, which block enzymes that normally break down MDMA in the body. People who take MDMA whilst also taking these drugs have greatly increased drug effect, but also increased side effects, which can lead to lethal overdose at normal doses. These combinations have killed people. First the anti-ulcer drug cimetidine, which blocks a liver enzyme CYP2D6, and second the MAOI series of drugs, which block monoamine oxidase (e.g. moclobemide, tranylcypromine, iproniazid). These drugs are no longer widely prescribed but if you are taking them, do not take MDMA at all.

It has 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 notwithstanding, "most of the cases of serious toxicity or fatality have involved blood levels... up to 40 times higher than the usual recreational range."

Other
MDMA users have also been recorded to demonstrate 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, however this can result in temporary mouth ulcers through inadvertent biting of the mouth lining. 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.

While users sometimes report increased sexual desire, there are many reports of difficulty achieving both erection and orgasm while on the drug. "[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).

Reported allergic reactions are extremely rare, but some very rare cases have been reported of people dying from anaphylactic shock after taking MDMA, i.e. they were allergic to MDMA, the same way some people are allergic to peanuts. Liver damage, which may have an immunological cause, has been seen in a small number of users. Animal studies suggest risk and extent of liver damage is increased by high body temperature.

A UK parliamentary committee commissioned report found the use of "Ecstasy" to be less dangerous than tobacco and alcohol in social harms, physical harm and addiction.

Studies suggest that violent and aggressive behavior can also sometimes be an effect of using MDMA. Reduced inhibitions can sometimes result in inappropriate behavior and aggression in people taking MDMA, especially inexperienced users. This is in large part due to MDMA action on monoaminergic pathways and adrenal function. MDMA is however much less likely to cause aggression and random violence than other commonly used recreational drugs such as alcohol and cocaine.

While most MDMA is taken orally or snorted, some users resort to drug injection to achieve a faster, more intense effect. This entails the risks associated with injection of many illicit drugs, including the transmission of blood-borne viruses, bacterial infections, vein damage, and increased chance of overdose. Injecting crushed up pills is particularly dangerous with ecstasy as the pills are not manufactured in a sterile controlled environment as are pharmaceutical pills, and the filler used to bulk out the pills could contain a wide variety of substances which might be insoluble and thus very hazardous to inject.

Some people can overdose more readily from MDMA because they have Gilbert syndrome, a genetic condition where the liver's glucuronidation system is impaired, inihibiting excretion of MDMA.

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. Cottler et al. (2001) interviewed 52 users and found that 43% met standard criteria for dependence. However, some of these people may have been inappropriately diagnosed with dependence because they reported tolerance or after effects from MDMA. 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 nicotine addiction. Cases have been reported of addictive personality types abusing MDMA as they would with alcohol, tobacco, or other drugs, taking excessively high doses against the natural recommendations, and taking it too frequently and even daily, against recommendations. However they typically end up abandoning MDMA for drugs more suitable to addictive behavior after a period of time, and the tolerance issues of MDMA make it naturally antagonistic to long term daily addiction. An article published in the Lancet found it to be less of a threat in terms of addiction and physical harm than tobacco and alcohol.

Two men in Denver, Colorado claim they had been using cocaine excessivly (15 grams shared between the two each month for a period of 9 months) until taking 4 pills of MDMA each in one night. After this dose all physical and phycological cravings for cocaine disapeared. They claim to have never tried cocaine since and attribute this to the experience they had with MDMA. They also claim they did not adopt a new habitual habit of taking MDMA as replacement for the cocaine.

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

Serotonergic changes
Some experiments indicate that high dose or rapidly repeated MDMA exposure may lead to the synaptic terminals of serotonin neurons being damaged. The precise mechanism of this effect is unclear, but is thought to involve (Jones 2004; Miller 1997; Monks et al. 2004) reactive oxygen species (ROS), chemicals known to cause oxidative cell damage. These ROS may be partly formed by excessive activity of serotonin neurons, reactive MDMA metabolites, and/or reactive dopamine metabolites. Once formed, ROS can cause damage directly to neurons and they may also impair mitochonridial respiration, a crucial function for cells.

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, it is difficult to distinguish axon loss from decreases in production of markers of serotonin.

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)

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, the neurotoxicity of MDMA may be dependent on its metabolites (Jones 2004; de la Torre & Farré 2004). Since different species metabolize MDMA to different extents, it may be difficult or impossible to translate an MDMA dose between species. Therefore, it is difficult to say what dose in humans would produce the effects seen in animals.

There are a number of factors that have been shown to protect animals from neurotoxicity. Studies in rats have shown that injections of ascorbic acid, alpha lipoic acid, l-cysteine, 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. These vitamins flush through the system in 3-4 hours. 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.

SSRIs have been shown to decrease or block MDMA neurotoxicity in rodents. 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. This is done to prevent dopamine or a neurotoxic MDMA metabolite from entering through the serotonin reuptake mechanism, where it is theorized that it may contribute to formation of reactive oxygen species, including hydrogen peroxide. However, administration of SSRIs before using MDMA is known to block the euphoric high from the drug, due to the regulation of serotonin. This blocking effect can last several weeks, depending on the half-life of the SSRI. The same effects are seen with recent cocaine use, which itself is an DARI (Dopamine reuptake inhibitor).

However, MDMA use in conjunction with a different class of antidepressants, namely Monoamine oxidase inhibitors, is strongly contra-indicated due to danger of serotonin syndrome and the possibility of life-threatening hypertension. The safety of this practice has not been systematically evaluated.

Many users also attempt to replenish the deficit of serotonin which follows the use of MDMA by administering 5-HTP, in an attempt to alleviate to a degree the depression and overall mental unsettlement 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, reportedly supplies the user with more of the raw materials to synthesize the neurotransmitter, reducing the negative psychological effects of depleted serotonin. Pre-loading with 5-HTP has not been shown to increase the subjective effects of MDMA. Anecdotal reports seem to indicate this is largely placebo with some users reporting a moderate muting of the MDMA effect when 5-HTP is consumed within 24 hours prior to MDMA use.

Psychiatric and behavioral changes
Considerable research has been done into possible cognitive-behavioral deficits among ecstasy users but data have been largely inconclusive. 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 depressed than controls. Sumnall and Cole's analysis showed a slight increase in the prevalence of depressive symptoms in ecstasy users over controls. Of course, studies like these raise a chicken-or-egg question: did these impulsive and depressed people use ecstasy to self-medicate or did otherwise normal people become depressed and impulsive after using ecstasy? This question has not been answered.

A three year study showed that low doses of MDMA over an extended period of time resulted in a decrease in verbal memory functioning. The authors of the study suggested the main factor of this decrease to be a depletion of serotonin due to neurotoxicity of MDMA, a depletion that "might be irreversible". However, a large study in 2002 (Strote et al.) showed that ecstasy users in 4-year colleges have GPAs which do not differ significantly from those of non-users.

In addition to concerns about neurotoxicity, several published reports have described hallucinogen persisting perception disorder in MDMA users. This appears to be very rare.

Retracted article on MDMA-induced dopamine neurotoxicity in primates
In a now-retracted study, 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 brain damage. These claims were hotly disputed by physicians, therapists, and other experts in the field, including a team of scientists at New York University. Criticisms of the study included its use of injection rather than oral administration; that this type and scale of damage (>20% mortality) would translate to hundreds of thousands or millions of deaths which had not materialized in the real world amidst extremely broad global MDMA usage; and, most importantly, that other research teams could not duplicate the study's findings.

On September 6, 2003, Dr. George A. Ricaurte and his team announced that they were retracting all results of their commonly cited and controversial study. The researchers said that the labels on the drugs had been somehow switched, and they had inadvertently injected their experimental monkeys and baboons with extremely high doses of methamphetamine instead of MDMA. The chemical supplier, Research Triangle Institute, has publicly claimed that the proper drug was supplied, and Ricaurte has yet to pursue them for their alleged error.

Ricaurte had also come under fire for supplying PET scans to the U.S. Office of National Drug Control Policy that were used in anti-drug literature (Plain Brain/Brain After Ecstasy) that seemed to suggest MDMA created holes in human brains, an implication that critics called misleading. Ricaurte later asked the Agency to change the literature, citing the "poor quality" of the images. These images are still circulating in educational systems across the U.S., however, and the myth that ecstasy users develop "holes in their brains" remains quite popular and government funded.

Although one of the most visible researchers in the media, Ricaurte is just one of many studying neurotoxicity of MDMA and related drugs. The overall findings of the field (that is, changes of markers of serotonergic function with high or repeated MDMA doses in most mammalian species studied) have been confirmed on multiple occasions by multiple groups. Thus, the overall concerns about MDMA neurotoxicity may not be lessened by the discovery that some of Ricaurte's work is unreliable.