Effects of MDMA on the human body

This article discusses the effects of MDMA (3,4-methylenedioxy-N-methylamphetamine, commonly known as "Ecstasy") on the human brain and body. More general information on MDMA, such as history and legal status, can be found in the main entry for MDMA.MDMA has complex effects, interacting with several neurochemical systems. It induces serotonin, dopamine, norepinephrine, and acetylcholine release, and can act directly on a number of receptors, including a2-adrenergic (adrenaline) and 5HT_2A(serotonin) receptors [de la Torre R, Farré M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Camí J. [http://www.ncbi.nlm.nih.gov/pubmed/15228154 "Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition"] . "Ther Drug Monit." 2004 Apr;26(2):137–44.] . MDMA promotes the release of several hormones including prolactin, oxytocin, ACTH, dehydroepiandrosterone (DHEA), and the antidiuretic hormone vasopressin (which may be important in its occasional production of water intoxication or hyponatremia).

It is not fully understood why MDMA induces these unusual psychoactive effects. Most explanations focus on serotonin release. MDMA causes serotonin vesicles in the neurons to release quantities of serotonin into the synapses. From studies using pretreatment with an SSRI to block the ability of MDMA to release serotonin in volunteers, we know that serotonin release is necessary for most effects of MDMA in humans. [Liechti ME, Vollenweider FX. [http://www.ncbi.nlm.nih.gov/pubmed/12404538 "Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies"] . "Hum Psychopharmacol." 2001 Dec;16(8):589–598] Released serotonin is believed to stimulate several receptors that 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. [Morley KC, Arnold JC, McGregor IS. [http://www.ncbi.nlm.nih.gov/pubmed/15908091 "Serotonin (1A) receptor involvement in acute 3,4-methylenedioxymethamphetamine (MDMA) facilitation of social interaction in the rat"] . "Prog Neuropsychopharmacol Biol Psychiatry". 2005 Jun;29(5):648–57.] 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. [cite news |url=http://www.newscientist.com/article.ns?id=dn11530&feedId=online-news_rss20 |title=Ecstasy really does unleash the love hormone |author=Emma Young |date=April 4, 2007 |work=New Scientist] 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 [ [http://www.ncbi.nlm.nih.gov/pubmed/10989266 Liechti ME, Saur MR, Gamma A, Hell D, Vollenweider FX. "Psychological and physiological effects of MDMA ("Ecstasy") after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans" Neuropsychopharmacology. 2000 Oct;23(4):396-404.] ] . 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 induces 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. [ [http://www.ncbi.nlm.nih.gov/pubmed/1102234 A comparison of fenfluramine and amphetamine in ma... [Clin Pharmacol Ther. 1975 - PubMed Result ] ] 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. [ [http://www.ncbi.nlm.nih.gov/pubmed/10871712 Liechti ME, Vollenweider FX. Acute psychological and physiological effects of MDMA ("Ecstasy") after haloperidol pretreatment in healthy humans" Eur Neuropsychopharmacol. 2000 Jul;10(4):289-95.] ] Although not yet examined in humans, several studies in rodents, indicate the noradrenergic mechanisms contribute to the stimulating effects of MDMA. [ [http://www.ncbi.nlm.nih.gov/pubmed/17363047 Alpha1-adrenergic receptors mediate the locomotor ... [Pharmacol Biochem Behav. 2007 - PubMed Result ] ] Finally, currently unexplored effects of MDMA may turn out to be important, such as trace amine receptors. [ [http://www.ncbi.nlm.nih.gov/pubmed/11723224 Amphetamine, 3,4-methylenedioxymethamphetamine, ly... [Mol Pharmacol. 2001 - PubMed Result ] ]

The effects of MDMA on regional cerebral blood flow (CBF) have been studied in humans using [H215O] -Positron Emission Tomography (PET) [Vollenweider FX, Geyer M, Greer G. [http://www.heffter.org/review/Review2/chap3.pdf "Acute Psychological and Neurophysiological Effects of MDMA In Humans"] . "The Heffter Review of Psychedelic Research", Volume 2, 2001.] 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 "extraversion" 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:
* increased positive emotion and decreased negative emotion
* increased sense of well-being
* decreased anxiety, although some individuals feel increases
* increased sociability and feelings of closeness or connection with other peoplecite journal
title = Subjective Reports of the Effects of MDMA in a Clinical Setting
author = G. Greer, R. Tolbert
journal = Journal of Psychoactive Drugs
year = 1986
volume = 18
issue = 4
pages = 319
url = http://www.maps.org/w3pb/new/1986/1986_greer_628_1.pdf]
* reduced defensiveness and fear of emotional injury cite journal
title = Psychological and Cardiovascular Effects and Short-Term Sequelae of MDMA ("Ecstasy") in MDMA-Naïve Healthy Volunteers
author = F. X. Vollenweider, A. Gamma, M. Liechti, T. Huber
journal = Neuropsychopharmacology
year = 1998
volume = 19
issue = 4
pages = 241–251
doi = 10.1038/sj.npp.1395197
url = http://www.nature.com/npp/journal/v19/n4/pdf/1395197a.pdf]
* a sense of increased insightfulness and introspective ability [ [http://www.psychedelic-library.org/enhance.htm Can Drugs Be Used to Enhance the Psychotherapeutic Process? ] ]
* visual distortions, such as simple patterns, distorted objects, and flashes of light
* increased desire to talk and feeling that communication is easy

Effects beginning after the main effects of MDMA have ended, which can last several days, include:
* Decreased mood or even depression (Scat/Come down) after the effects have worn off
* Feelings of decreased ability to concentrate
* Residual feelings of empathy, emotional sensitivity, and a sense of closeness to others

Other short-term effects

Acute physiological effects include [The Psychological and Physiological Effects of MDMA on Normal Volunteers, by Joseph Downing, from Journal of Psychoactive Drugs, Vol. 18/4 1986.] :
* Increased heart rate and blood pressure
* 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
* Trisma (jaw-clenching) and bruxia (grinding of the teeth).
* Sensitivity to temperature, possibly due to thermoconstriction

Acute toxic/dangerous effects

The rate of serious adverse events in MDMA users appears to be low. 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.Science and Technology Committee Report (page 176), 2006). [http://news.bbc.co.uk/1/shared/bsp/hi/pdfs/31_07_06_drugsreport.pdf] ] In terms of deaths, 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. [ [http://thedea.org/statistics.html TheDEA.org: Ecstasy Statistics ] ] [ [http://www.canedintotnes.co.uk/content/view/3/2/ Caned In Totnes - Clubbers Guide to Ecstasy (MDMA) ] ] 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. [ [http://www.statistics.gov.uk/statbase/ssdataset.asp?vlnk=7892 Deaths related to drug poisoning, England and Wales ] ] 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. [ Drugs – facts The report of the Royal Society of Arts Commission on Illegal Drugs, Communities and Public Policy. March 2007 ] This is approximately the same risk of death as is associated with adverse drug reactions to estrogen-containing (combined) forms of hormonal contraception. [ Jick H. Oral contraceptives and Myocardial Infarction: how strong is the link? Journal of Cardiovascular Medicine. 1982 May 15;7(5):481, 484-5. ]

In some cases, 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). [ [http://www.ncbi.nlm.nih.gov/pubmed/16595612 Hall AP, Henry JA. Acute toxic effects of 'Ecstasy' (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth. 2006 Jun;96(6):678-85.] ] Serious neurological complications, such as subarachnoid hemorrhage, intracranial bleeding, cerebral infarction due to MDMA-induced increases in blood pressure may occur in people with preexisting congenital arteriovenous malformations or cerebral angiomas. Lack of the enzyme cytochrome p450 isozyme 2D6 is no longer thought to be a significant risk factor for MDMA-related adverse event.

Serious adverse events in MDMA users may also be caused by drugs sold as "ecstasy" [ Tanner-Smith EE. Pharmacological content of tablets sold as "ecstasy". "Drug and Alcohol Dependence" 2006. 83:247–254.] , but which are not actually MDMA. Dangerous overheating, sometimes fatal, is associated with drugs such as PMA [ Kraner JC, McCoy DJ, Evans MA, Evans LE, Sweeney BJ. Fatalities caused by the MDMA-related drug paramethoxyamphetamine (PMA). "Journal of Analytical Toxicology". 2001 Oct;25(7):645–8.] or 4-MTA. [ De Letter EA, Coopman VA, Cordonnier JA, Piette MH. One fatal and seven non-fatal cases of 4-methylthioamphetamine (4-MTA) intoxication: clinico-pathological findings. "International Journal of Legal Medicine". 2001;114(6):352–6. ]

Hyponatremia

An important cause of death following MDMA use is hyponatremia, low blood sodium levels as a result of drinking too much water. [ Budisavljevic MN, Stewart L, Sahn SA, Ploth DW. Hyponatremia associated with 3,4-methylenedioxymethylamphetamine ("Ecstasy") abuse. "American Journal of Medical Sciences". 2003 Aug;326(2):89–93. ] 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). [ Ben-Abraham R, Szold O, Rudick V, Weinbroum AA. 'Ecstasy' intoxication: life-threatening manifestations and resuscitative measures in the intensive care setting. European Journal of Emergency Medicine. 2003 Dec;10(4):309-13. ] 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. [ Wolff K, Tsapakis EM, Winstock AR, Hartley D, Holt D, Forsling ML, Aitchison KJ. Vasopressin and oxytocin secretion in response to the consumption of ecstasy in a clubbing population. "Journal of Psychopharmacology". 2006 May;20(3):400–10. ] 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"). [ [http://www.askmen.com/sports/health_60/80c_mens_health.html AskMen.com - Ecstacy pill ] ] 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.

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 a bit 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. 50–200mg of 5HTP is believed by some users to make MDMA work better and last longer, but anecdotally more than 300mg 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 ecstasy-related hyperthermia. [ [http://www.ncbi.nlm.nih.gov/pubmed/17524054 Does hyperthyroidism increase risk of death due to... [J Forensic Sci. 2007 - PubMed Result ] ]

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. 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.

In animal studies, a combination of prazosin and pindolol (5HT1A antagonist/beta blocker) quickly and completely terminates drug-induced hyperthermia. [ Sprague JE, Banks ML, Cook VJ, Mills EM. Hypothalamic-pituitary-thyroid axis and sympathetic nervous system involvement in hyperthermia induced by 3,4-methylenedioxymethamphetamine (Ecstasy). "Journal of Pharmacology and Experimental Therapeutics". 2003 Apr;305(1):159–66.] Another drug, the migraine medicine pizotyline has also been shown to be useful in treating MDMA overdose in animals. [Young R, Khorana N, Bondareva T, Glennon RA. Pizotyline effectively attenuates the stimulus effects of N-methyl-3,4-methylenedioxyamphetamine (MDMA). "Pharmacology Biochemistry and Behavior". 2005 Oct;82(2):404–10.] 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.

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. [Duffy MR, Swart M. Severe Ecstasy poisoning in a toddler. "Anaesthesia". 2026 May;61(5):498–501.]

The standard treatment for ecstasy overdose given in hospitals includes a range of drugs such as cyproheptadine or chlorpromazine [Rusyniak DE, Sprague JE. Toxin-induced hyperthermic syndromes. "Medical Clinics of North America". 2005 Nov;89(6):1277–96.] 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. [Duffy MR, Ferguson C. Role of dantrolene in treatment of heat stroke associated with Ecstasy ingestion. "British Journal of Anaesthesia". 2027 Jan;98(1):148–9.]

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." [Kalant, H. [http://www.cmaj.ca/cgi/content/full/165/7/917 The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs] . "Canadian Medical Association Journal" 165(7):917.]

Adverse drug interactions

Overdose on MDMA alone is unlikely under normal usage conditions, but some drug combinations greatly increase the danger.

Many drugs having risk of adverse interaction with MDMA are ones that affect serotonin by inhibiting monoamine oxidase (MAO). A recent qualitative review by Silins and colleagues described the following drugs as having particularly high risk when taken with MDMA: monoamine oxidase inhibitor (MAOI) antidepressants (such as phenelzine and tranylcypromine), other MAOIs (such as, iproniazid, isoniazid, nialamide, clorgyline), and the antidepressant moclobemide. Some MAOIs (such as phenelezine and tranylcypromine) have very long lasting effects and might still have adverse interactions with MDMA up to 2 weeks after they were last taken. [ [http://www.maps.org/w3pb/new/2007/2007_Silins_22923_1.pdf Silins E, Copeland J, Dillon P. Qualitative review of serotonin syndrome, ecstasy (MDMA) and the use of other serotonergic substances: hierarchy of risk. Aust N Z J Psychiatry. 2007 Aug;41(8):649-55.] ] In addition to drugs affecting MAO, drugs that are substrates for the enzymes CYP1A2, CYP2B6, CYP3A4, and CYP2D6 may have metabolic interactions with MDMA, causing either MDMA or the other drug to achieve higher concentrations in the body than normal. MDMA inhibits CYP2D6 for perhaps a week or more, possibly decreasing metabolism of some drugs in the week after use, which may increase risks of these drugs. Deaths have occurred in people taking MDMA and the antiviral drug ritonavir together. [ [http://www.ncbi.nlm.nih.gov/pubmed/15765827 Wynn GH, Cozza KL, Zapor MJ, Wortmann GW, Armstrong SC. Med-psych drug-drug interactions update. Antiretrovirals, part III: antiretrovirals and drugs of abuse. Psychosomatics. 2005 Jan-Feb;46(1):79-87.] ] [ [http://www.maps.org/w3pb/new/1998/1998_henry_242_1.pdf Henry JA, Hill IR. Fatal interaction between ritonavir and MDMA. Lancet. 1998 Nov 28;352(9142):1751-2.] ]

Other adverse effects

MDMA users sometimes experience bruxism (teeth grinding) and trismus (jaw clenching) as a short-term effect from the drug. [ [http://www.ravesafe.org/research/e-research_Toothwear-1999.htm RaveSafe Information on Toothwear/E Research ] ] Many users of MDMA alleviate this by using chewing gum, [ [http://www.cesar.umd.edu/cesar/drugs/ecstasy.asp Ecstasy |CESAR ] ] 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, although this practice has not been formally studied. [ [http://www.bluelight.ru/vb/showthread.php?s=&threadid=79027 MDMA: Essential Guide v1.00 - Bluelight ] ] In extreme cases, ecstasy 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 but significant number of users. [ Nunez O, Banares R, Barrio J, Menchen L, Diego A, Salinero E, Clemente G. Variability of the clinical expression of Ecstasy-induced hepatotoxicity. Gastroenterologia y Hepatologia. 2002 Oct;25(8):497-500. (Spanish). ] 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. [ Carvalho M, Carvalho F, Remiao F, de Lourdes Pereira M, Pires-das-Neves R, de Lourdes Bastos M. "Effect of 3,4-methylenedioxymethamphetamine ('ecstasy') on body temperature and liver antioxidant status in mice: influence of ambient temperature". "Archives of Toxicology". 2002 Apr;76(3):166–72. ] Aside from this, reports of allergic reactions are extremely rare. However, 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.

In 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.

Although MDMA is typically known for increasing friendliness, published reports suggest that violent and aggressive behavior can sometimes be a rare effect of using MDMA. Reduced inhibitions can sometimes result in inappropriate behavior and aggression in people taking MDMA, especially inexperienced users. [ Hoaken PN, Stewart SH. "Drugs of abuse and the elicitation of human aggressive behavior". "Addictive Behaviors". 2003 Dec;28(9):1533–54.] This is hypothesized to be due to MDMA action on monoaminergic pathways and adrenal function, although this theory has not been formally tested. MDMA is however much less likely to cause aggression and random violence than other commonly used recreational drugs such as alcohol and cocaine. [ Hendrickson JC, Gerstein DR. "Criminal involvement among young male ecstasy users". "Substance Use and Misuse". 2005;40(9–10):1557–75. ]

While users sometimes report increased sexual desire, there are many reports of difficulty achieving both erection and orgasm while on the drug. [ [http://www.soc.ucsb.edu/sexinfo/?article=Influence&refid=001#X UCSB's SexInfo ] ] It has been said that, " [MDMA] is a love drug but not a sex drug for most people." [ [http://www.idmu.co.uk/esex.htm Ecstasy & Sex ] ] [ [http://www.erowid.org/chemicals/mdma/mdma_effects.shtml Erowid MDMA Vault : Effects ] ] This is the rationale behind the use of sextasy (combining MDMA with Viagra).

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 and neurotoxicity. 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.

Long-term adverse effects

Research on possible long-term adverse effects of MDMA has mainly 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 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 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. [cite journal|author=Baumann MH, Wang X, Rothman RB.|title=3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings|year=2006|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16541247&query_hl=1&itool=pubmed_docsum|pmid=16541247|journal=Psychopharmacology|doi=10.1007/s00213-006-0322-6|volume=189|pages=407] [cite web|title=Interviews with two foremost researchers into neurotoxicity who hold opposing views|author=Saunders, Nicholas|year=1995|url=http://ecstasy.org/info/interviews.html]

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 [ [http://jpet.aspetjournals.org/cgi/content/abstract/276/2/846 Sabol KE, Lew R, Richards JB, Vosmer GL, and Seiden LS (1996) Methylenedioxymethamphetamine-induced serotonin deficits are followed by partial recovery over a 52-week period. Part I: synaptosomal uptake and tissue concentrations. J Pharmacol Exp Ther 276: 846-854.] ] [ [http://jpet.aspetjournals.org/cgi/content/abstract/264/3/1484 Scanzello CR, Hatzidimitriou G, Martello AL, Katz JL, and Ricaurte GA (1993) Serotonergic recovery after (±)3,4-(methylenedioxy) methamphetamine injury: observations in rats. J Pharmacol Exp Ther 264: 1484-1491.] ] , 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; [http://www.erowid.org/references/refs_view.php?A=ShowDocPartFrame&ID=6440&DocPartID=5981 de la Torre & Farré (2004) Neurotoxicity of MDMA (ecstasy): the limitations ofscaling from animals to humans] ), 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). [ [http://www.maps.org/w3pb/new/2001/2001_vollenweider_1137_1.pdf Vollenweider FX, Jones RT, Baggott MJ (2001): Caveat Emptor: Editors Beware, Neuropsychopharmacology, 24: 461-463. 29] ] 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. (2008), the lowest repeated dose regimen that produced long-term serotonergic effects 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. 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 toxic one 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. (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 have emerged as of yet.

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. These vitamins flush through the system in 3-4 hoursFact|date=February 2007. 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) Fact|date=February 2007 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 [cite journal| author = R. H. Schwartz, N. S. Miller| title = MDMA (Ecstasy) and the Rave: A Review
year = 1997
journal = Pediatrics
volume = 100
issue = 4
pages = 705–708
url=http://pediatrics.aappublications.org/cgi/content/full/100/4/705| doi = 10.1542/peds.100.4.705| pmid = 9310529] by administering 5-HTP, in an attempt to reduce the depressed mood and unpleasant symptoms in the days following MDMA usage [ [http://www.bluelight.ru/vb/showthread.php?s=&threadid=80280 Bluelight 5-HTP FAQ] ] (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.) Pre-loading with 5-HTP has not been shown to reliably increase the subjective effects of MDMA. Instead, some users reporting a moderate muting of the MDMA effect when 5-HTP is consumed within 24 hours prior to MDMA use. [ [http://www.erowid.org/ask/ask.cgi?A=Show&QID=1750 MDMA and 5-HTP information and advice] ]

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". [Cowan R. [http://www.ncbi.nlm.nih.gov/pubmed/16847678 "Neuroimaging research in human MDMA users: a review "] . "Psychopharmacology" (Berl). 2007 Jan;189(4):539–56. Epub 2006 Jul 18.]

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 changes occurring after MDMA exposure. Studies in animals and humans have generally failed to correlate these two domains.

Psychiatric and behavioral changes

Some studies find that repeated ecstasy use may lead to subtle decreases in learning, memory, attention, executive function, mood, and decision making.fact|date=September 2008 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 ecstasy. This makes it difficult to know if differences between users and non-users were preexisting.fact|date=September 2008

There does not seem to be a single type of cognitive task that is consistent altered in the different studies. Tasks that have shown differences include ones measuring attention, learning, memory, and executive function [Kalechstein AD, De La Garza R 2nd, Mahoney JJ 3rd, Fantegrossi WE, Newton TF. [http://www.ncbi.nlm.nih.gov/pubmed/17082969 "MDMA use and neurocognition: a meta-analytic review"] . "Psychopharmacology" (Berl). 2007 Jan;189(4):531–7.] . Many of the findings, which are more commonly reported in people with more extensive ecstasy use histories (or even abuse diagnoses), may simply reflect preexisting differences between people who are drawn to use drugs like ecstasy frequently and those who do not.

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 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? [Hanson KL, Luciana M, Sullwold K. [http://www.ncbi.nlm.nih.gov/pubmed/18384979 "Reward-related decision-making deficits and elevated impulsivity among MDMA and other drug users"] . "Drug Alcohol Depend." 2008 Jul 1;96(1-2):99–110.] [Alati R, Kinner SA, Hayatbakhsh MR, Mamun AA, Najman JM, Williams GM. [http://www.ncbi.nlm.nih.gov/pubmed/17850992 "Pathways to ecstasy use in young adults: anxiety, depression or behavioural deviance?"] "Drug Alcohol Depend." 2008 Jan 1;92(1–3):108–15.] [Lieb R, Schuetz CG, Pfister H, von Sydow K, Wittchen H. [http://www.ncbi.nlm.nih.gov/pubmed/12234649 "Mental disorders in ecstasy users: a prospective-longitudinal investigation"] . "Drug Alcohol Depend." 2002 Oct 1;68(2):195–207.] 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 (Reneman et al. 2006; Gouzoulis-Mayfrank et al. 2005; Thomasius et al. 2006) or increase across time (Zakzanis and Young 2001; Zakzanis and Campbell 2006). While persisting differences are consistent with differences predating ecstasy use, increases may indicate worsening due to drug exposure.

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. [ [http://www.ncbi.nlm.nih.gov/pubmed/17476480 Jager G, de Win MM, Vervaeke HK, Schilt T, Kahn RS, van den Brink W, van Ree JM, Ramsey NF. "Incidental use of ecstasy: no evidence for harmful effects on cognitive brain function in a prospective fMRI study". "Psychopharmacology" (Berl). 2007 Aug;193(3):403–14.] ] Thus, if ecstasy does cause cognitive-behavioral changes, it seems to require repeated use for these changes to occur (or become detectable).

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, such as cannabis.

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) [cite journal
title = Ecstasy abuse and dependence among adolescents and young adults: applicability and reliability of DSM-IV criteria
author = L. B. Cottler, S. B. Womack, W. M. Compton, A. Ben-Abdallah
journal = Human Psychopharmacology: Clinical and Experimental
volume = 16
issue = 8
pages = 599–606
doi = 10.1002/hup.343
url = http://www.maps.org/w3pb/new/2001/2001_cottler_1292_1.pdf
year = 2001|format=PDF] 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. [cite journal
title = Use, abuse and dependence of ecstasy and related drugs in adolescents and young adults—a transient phenomenon? Results from a longitudinal community study
author = K. von Sydow, R. Lieb, H. Pfister , M. Höfler, H.-U. Wittchen
journal = Drug and Alcohol Dependence
volume = 66
year = 2002
pages = 147–159
url = http://www.maps.org/w3pb/new/2002/2002_von_sydow_1341_1.pdf
doi = 10.1016/S0376-8716(01)00195-8 |format=PDF] Given the complexities in classifying MDMA users as addicted, conclusions about the addictive potential of MDMA are less reliable than nicotine addiction. [cite web
url = http://www.nida.nih.gov/researchreports/nicotine/Nicotine.html
title = Nicotine Research Report
author = NIH] 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. ["The Lancet" 2007; 369:972 [http://www.thelancet.com/journals/lancet/article/PIIS0140673607604711/abstract] ] [ Graphical display of the results of "The Lancet" article [http://en.wikipedia.org/wiki/

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] ]

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. [cite journal | title = Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA ("ecstasy")
author = Ricaurte GA, Yuan J, Hatzidimitriou G, Cord BJ, McCann UD
journal = Science
year = 2002
volume = 297
issue = 5590
pages =2260–3
url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12351788
pmid = : 12351788 | doi = 10.1126/science.1074501] This controversial finding was subsequently retracted with the researchers stating that they had inadvertently injected their experimental animals with methamphetamine instead of MDMA. [cite journal | title = Retraction of Ricaurte et al., Science 297 (5590) 2260-2263
journal = Science
year = 2003
volume = 301
issue = 5639
pages = 1479
url = http://www.sciencemag.org/cgi/content/full/301/5639/1479b
pmid = 12970544 | doi = 10.1126/science.301.5639.1479b | author = Ricaurte, G. A.] 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. [cite journal | title = Causes and Consequences of Methamphetamine and MDMA Toxicity
author = Quinton MS, Yamamoto BK
journal = AAPS Journal
year = 2006
volume = 8
issue = 2
pages =E337–E347
url = http://www.aapsj.org/view.asp?art=aapsj080238
doi = 10.1208/aapsj080238] Thus, the overall concerns about MDMA neurotoxicity may not be lessened by the discovery that some of Ricaurte's work has been unreliable.

External links

* [http://www.erowid.org/chemicals/mdma/mdma.shtml Erowid Vaults: MDMA]
* [http://www.maps.org/sys/w3pb.pl WWW Psychedelic Bibliography] - A searchable database with full text of many scientific articles on psychedelics
* [http://www.acde.org/common/ecstasy.htm American Council for Drug Education factsheet on Ecstasy]

Footnotes