DrugFacts: MDMA (Ecstasy) Revised December 2012 MDMA (3,4-methylenedioxymethamphetamine) is a synthetic, psychoactive drug that is chemically similar to the

stimulant methamphetamine and the hallucinogen mescaline. MDMA produces feelings of increased energy, euphoria, emotional warmth, and distortions in time, perception, and tactile experiences. How Is MDMA Abused? MDMA is taken orally, usually as a capsule or tablet. It was initially popular among Caucasian adolescents and young adults in the nightclub scene or at weekend-long dance parties known as raves. More recently, the profile of the typical MDMA user has changed, with the drug now affecting a broader range of ethnic groups. MDMA is also popular among urban gay malessome report using MDMA as part of a multiple-drug experience that includes marijuana, cocaine, methamphetamine, ketamine, sildenafil (Viagra), and other legal and illegal substances. How Does MDMA Affect the Brain? MDMA exerts its primary effects in the brain on neurons that use the chemical (or neurotransmitter) serotonin to communicate with other neurons. The serotonin system plays an important role in regulating mood, aggression, sexual activity, sleep, and sensitivity to pain. MDMA binds to the serotonin transporter, which is responsible for removing serotonin from the synapse (or space between adjacent neurons) to terminate the signal between neurons; thus MDMA increases and prolongs the serotonin signal. MDMA also enters the serotonergic neurons via the transporter (because MDMA resembles serotonin in chemical structure) where it causes excessive release of serotonin from the neurons. MDMA has similar effects on another neurotransmitternorepinephrine, which can cause increases in heart rate and blood pressure. MDMA also releases dopamine, but to a much lesser extent.

MDMA can produce confusion, depression, sleep problems, drug craving, and severe anxiety. These problems can occur soon after taking the drug or, sometimes, even days or weeks after taking MDMA. In addition, chronic users of MDMA perform more poorly than nonusers on certain types of cognitive or memory tasks, although some of these effects may be due to the use of other drugs in combination with MDMA. Research in animals indicates that MDMA can be harmful to the brainone study in nonhuman primates showed that exposure to MDMA for only 4 days caused damage to serotonin nerve terminals that was still evident 6 to 7 years later. 1 Although similar neurotoxicity has not been shown definitively in humans, the wealth of animal research indicating MDMAs damaging properties strongly suggests that MDMA is not a safe drug for human consumption. The adverse psychological effects of MDMA

A review of adverse reactions due to ecstasy has been presented by McCann et al. (1996). As noted in the introduction, current research evidence is sparse and retrospective, generally uncontrolled, generally lacks toxicological confirmation of the drugs taken, lacks data on course and outcome, rarely relates mental state to toxicological results, and depends heavily on single case studies but nevertheless frequently concludes cause and effect relationships from what may be chance associations, although it is also possible that the cause and effect relationship is true. Psychotic phenomena With respect to serious mental illness such as prolonged psychosis, there is currently a dearth of accurate statistics. Ecstasy may rarely produce a state of intoxication which mimics a psychosis, such as paranoia,4,41 but this does not usually last for more than a few days, and appears to be relatively rare. Although ecstasy is not a hallucinogen in most people, it can cause hallucinations on occasion, especially in higher doses. I have myself seen a person in a state of toxic delirium after taking no more than 200mg of pure MDMA and no other drugs (toxicologically confirmed). She was completely disoriented, had marked difficulty walking (she collapsed several times injuring herself), and spent several hours trying to pick up nonexistent objects from the floor and talking to people who were not present. There was no history of psychosis, although her mother had suffered from depersonalisation disorder (see below). She was an experienced ecstasy user with no previous phenomena of this nature. She experienced depersonalisation on a single dose of fluoxetine ('Prozac').

The use of ecstasy may sometimes alter the clinical picture in a pre-existing psychosis such as schizophrenia. This is referred to as a pathoplastic effect. Some people with schizophrenia or manicdepression will also take ecstasy, especially as the peak age of onset of schizophrenia is 20-30. It has not been clearly established whether or not ecstasy can specifically induce a relapse of preexisting schizophrenia or manic-depression, beyond the increased risk of relapse attached to any substantial emotional stressor. Ecstasy experiences are typically emotional events, and for this reason alone one would expect to see an association with increased risk of relapse in serious mental illness. Ecstasy releases dopamine in a similar manner to amphetamine and cocaine 13 and as such might be expected to increase the risk of psychotic illness in a similar manner to other psychostimulants, although possibly not to the same extent. Some investigators report that they have repeatedly observed clear links between the onset of psychotic symptoms and the use of ecstasy.42 This latter study is based on two cases, other substances were involved, and there was no toxicological confirmation of pill content. However, there are several other reports41,43,44,45,46 and taken together the evidence is indicative of a risk. The size of that risk is unknown at the present time, but is likely to be relatively small. Can ecstasy cause a true 'drug-induced psychosis'? As distinct from the categories above, Poole and Brabbins (1996) have argued that this term should be restricted to psychotic symptoms arising in the context of drug intoxication but persisting beyond elimination of the drug and its metabolites from the body. Such a psychosis should only recur on re-exposure to the drug, and must have a different course and outcome from the major functional psychoses (i.e. schizophrenia, manic-depression et al.). The drugs for which there is at least some scientific evidence of such a syndrome are amphetamines, cocaine and cannabis. Ecstasy may eventually be included in this group. Anxiety disorders and panic attacks As stated previously, we are currently limited to a handful of case reports.1,3,4,38,47,48,49 However, the majority of communications from persons who have suffered adverse effects in association with taking ecstasy suggests that the leading theme may be anxiety disorders rather than depression, and this impression is confirmed by the published clinical reports in which forms of anxiety disorder appear to be more common than depression. It is possible that the serotonergic terminals involved in anxiety control are a distinct subset from those principally involved in mood control, and that ecstasy may preferentially affect the former. However, it is more likely that the real explanation lies in the psychological effects of ecstasy in terms of impairing psychic defences against anxiety generating material in the unconscious as discussed previously.

Depersonalisation and derealisation

Depersonalisation refers to the feeling that one is not 'real', and that one is detached and unable to feel emotion.40 It is very unpleasant. Sufferers may feel that they are separated from the world by a glass wall. Derealisation is where the environment appears to be unreal and devoid of the usual emotional component. People may be described as 'cardboard-like'. Although these phenomena have been reported in association with ecstasy use,30 they may be due to fatigue and may be seen as symptoms in a wide range of disorders, including depression, anxiety, schizophrenia and temporal lobe epilepsy. Depersonalisation and derealisation disorder may also occur spontaneously, so once again care is necessary in drawing a cause and effect conclusion from an association which may be accidental. Depression A brief period of low mood associated with the 'come-down' is common, although experienced users will tend to avoid this by taking other drugs. Chronic ecstasy use is also sometimes followed by a longer lasting depression.50 However, it is unclear whether the chronic use of ecstasy might not have been a form of self-medication of a pre-existing depression, or latent depression, rather than actually causative of depression. Depression may be predicted on theoretical grounds due to links between mood and serotonin. However, rats and monkeys with extensively damaged cortical serotonergic nerve terminals generally show little difference, or only very modest differences, in their behaviour relative to control animals. It is possible that this is because ecstasy appears to preferentially alter one type of serotonin terminal, and not those of a second system in the brain.10 One conclusion from the data so far is that it is probably this second system which controls mood, appetite, sleep, and sex drive. Serotonin levels are low for a week in this second system, but the structural changes are generally not seen.10 This matches the weekly cycle of what has actually been observed in humans. It is clear that further studies are required. Cognitive deficits (Impaired memory, attention and concentration) Research into drug-induced cognitive deficits is difficult to do well. The number of possible confounding variables is high. For example, it is essential to control for the use of other drugs,

particularly regular cannabis smoking, and for the effects of any mood disorder upon cognition. If subjects have been told to abstain from all drugs for several weeks, a withdrawal syndrome may result which could confound tests conducted during this period. All claims of cognitive deficits should be accompanied by evidence that the urine tests of the subjects were clear of drugs and their metabolites, particularly cannabis metabolites which can take at least 4 weeks to disappear from urine. Reports of subtle memory deficits which not accompanied by urine test data may be due to cannabis use. A report of subtle memory deficits in association with ecstasy use has been made by Krystal and Price, 1992. Sleep disturbance

Insomnia for several days after taking ecstasy is relatively common, but in a few cases this has persisted for months with excessive dreaming and sometimes nightmares.1 A persistent reduction in stage 2 sleep has been verified in a sleep laboratory, although the subjects in this investigation were not considered to be suffering from sleep disorders.56 Addictive Potential For some people, MDMA can be addictive.2 A survey of young adult and adolescent MDMA users found that 43 percent of those who reported ecstasy use met the accepted diagnostic criteria for dependence, as evidenced by continued use despite knowledge of physical or psychological harm, withdrawal effects, and tolerance (or diminished response). 3 These results are consistent with those from similar studies in other countries that suggest a high rate of MDMA dependence among users. 4 MDMA abstinence-associated withdrawal symptoms include fatigue, loss of appetite, depressed feelings, and trouble concentrating.2 What Other Adverse Effects Does MDMA Have on Health? MDMA can also be dangerous to overall health and, on rare occasions, lethal. MDMA can have many of the same physical effects as other stimulants, such as cocaine and amphetamines. These include increases in heart rate and blood pressurewhich present risks of particular concern for people with circulatory problems or heart diseaseand other symptoms such as muscle tension, involuntary teeth clenching, nausea, blurred vision, faintness, and chills or sweating.

In high doses, MDMA can interfere with the bodys ability to regulate temperature. On rare but unpredictable occasions, this can lead to a sharp increase in body temperature (hyperthermia), which can result in liver, kidney, cardiovascular system failure, or death. MDMA can interfere with its own metabolism (breakdown within the body); therefore, potentially harmful levels can be reached by repeated MDMA administration within short periods of time. Other drugs that are chemically similar to MDMA, such as MDA (methylenedioxyamphetamine, the parent drug of MDMA) and PMA (paramethoxyamphetamine, associated with fatalities in the United States and Australia), 5 are sometimes sold as ecstasy. These drugs can be neurotoxic or create additional health risks to the user. Furthermore, ecstasy tablets may contain other substances, such as ephedrine (a stimulant); dextromethorphan (DXM, a cough suppressant); ketamine (an anesthetic used mostly by veterinarians); caffeine; cocaine; and methamphetamine. Although the combination of MDMA with one or more of these drugs may be inherently dangerous, users who also combine these with additional substances such as marijuana and alcohol may be putting themselves at even higher risk for adverse health effects. What Treatment Options Exist? Treatment of psychological and psychiatric adverse effects multi-levelled, individually tailored, dogma-free approach is generally the best, ombining biological, psychological and social methods. There is virtually no literature which specifically deals with the treatment of psychological and psychiatric adverse effects due to ecstasy.29 Accordingly, many of the references are to methods originally developed for amphetamine and cocaine dependence. Nevertheless, the principles are similar across the 'psychostimulant group'. An initial assessment is followed by a decision about which of the available services is most suitable.66 Apart from those with severe psychiatric and physical complications, ecstasy users are most likely to remain in the community. The management of disorders which can be classified and treated as would be normal were they not drug-induced will not be considered further here. The reader is referred to standard works on adult general psychiatry (e.g. Gelder, Gath & Mayou 1995). When carrying out an assessment, it is important to bear in mind that a 'drug induced psychosis' should not be diagnosed simply because a patient with a psychosis has also been using drugs. Incorrect attribution of psychotic symptoms to the use of ecstasy may result in persons with schizophrenia or affective disorder not receiving proper care and education about their illness. They are not prescribed

depot medications or lithium, are not adequately engaged with services, and their families are not appropriately educated. The result is a very high relapse rate. It is thus important to take a careful history, speak with relatives, and avoid jumping to hasty conclusions to ensure that there is not an underlying psychiatric disorder which is associated with drug use by chance. Urinanalysis is essential when psychotic symptoms occur in association with drug use. It is also important to note that the overwhelming majority of ecstasy users are polydrug consumers, and care must be taken not to attribute symptoms to the wrong drug. Counselling, psychotherapy and cognitive/behavioural therapy

A non-judgmental attitude may be helpful at the outset to create a trusting relationship, as some of the clients have difficulties with authority figures.67,68,69 However, Rogerian-style unconditional positive regard and empathy are typical effects of ecstasy, and it is reasonable to suppose that some users may occasionally respond better to firm limit setting and reality orientation. Denial is an important defence mechanism: 'Everyone knows E's and Whiz aren't addictive, I can stop anytime'. Denial can be dealt with using facts from the person's life rather than research findings, e.g. 'Lets examine the effect that taking 10 E's every weekend is having on your studies... on your finances... on the way you feel by Wednesday afternoon... on your life in general now that you have been arrested and charged with intent to supply because you bought a big bag of pills to save money... on your having a relationship with a violent nightclub bouncer... on your increasing tendency to smoke "brown" (heroin) for the comedown...' This approach may be more effective than discussions about serotonergic terminals. There is a general account of problems which may be encountered in Zweben, 1989.

The cognitive-behavioural approach focuses on problem behaviours, as distinct from nondirective therapies which concentrate on feelings and relationships. Cognitive aspects include explaining the causes of relapse and the conditioning mechanisms which lead to the sudden appearance of craving in some situations. The place, people and objects associated with the primary "reward" can become conditioned stimuli for drug use by classical conditioning. Therapy may attempt to change the "behaviour eliciting" properties of key stimuli.70,71

Motivational interviewing can be a very valuable technique (see Miller & Rollnick, 1991), and relapse prevention is important.72,73 Psychodynamic psychotherapy

This approach may be suitable for persons whose symptoms have a strongly neurotic character, and who are not too seriously impaired. The approach involves a gradual exploration of the unconscious, and a 'working through' of difficult material. The focus is not usually upon the drug taking behaviour itself. Persons with a clear history of childhood trauma may do well. There is a valuable account of psychodynamic, 'object relations' based approaches to treating the stimulant dependent in Wallace, 1991.74,75,76 Meditation, relaxation and martial arts Relaxation exercises may be useful for persons with anxiety problems. Tapes are widely available. Meditation involves learning to attend to a single stimulus without allowing the attention to wander. This is useful for a range of disorders, particularly 'busy head syndrome'. Some people are deterred from meditation by the association of this discipline with quasi-religious groups. It is not necessary to join a group to meditate effectively, nor is teaching required or any form of religious affiliation. Lawrence LeShan's brief account 'How to Meditate' 77 is all that is required. See also Gorski, 1990. Martial arts are also useful for strengthening the 'signal over noise' ratio, and improving attention and concentration. They are demanding, and require a complete change of lifestyle from weekend long raving. They can also meet high stimulus needs, provide an 'endorphin rush', and encourage selfcontrol. Okinawan Goju-Ryu karate is particularly suitable, providing high intensity, little physical contact, high stimulation training environments. In fact, most forms of physical exercise and gym work can be valuable in persons who wish to stop the regular use of psychostimulants. Medication The client may be self-medicating an underlying disorder which should be treated separately, such as depression, an anxiety disorder, a personality disorder or an incipient psychosis. If such a condition is identified or suspected, treatment should be as for the underlying condition (antidepressants, antipsychotics, lithium, carbamazepine etc.)

Antidepressants Antidepressants such as fluoxetine ('Prozac') may be useful. Serotonin reuptake inhibitors such as fluoxetine will prevent the neurotoxicity of MDMA in animal studies if taken within 3 hours of the MDMA dose. 50% of the depletion is blocked at 6 hours, but there is no protective effect at 12 hours.5 However, these studies generally involve massive doses of fluoxetine. Fluoxetine after MDMA has been reported as able to reduce sleep disorders and restlessness. Antioxidants and Food Supplements: Tryptophan and Tyrosine Some ecstasy users also take high doses of antioxidants such as vitamin C and vitamin E. There is some evidence that free radicals may be involved in the neurotoxicity process. Tyrosine and tryptophan may elevate levels of serotonin,78 but the use of tryptophan is severely restricted in the UK and other countries due to a contaminated batch. It may only be prescribed by a medical practitioner on a named patient basis. Bananas and chocolate are rich sources of tryptophan, and it is a valid suggestion that persons taking ecstasy may profit by eating these foods. It is also possible to obtain a product called '5HTP Serotonic'. 5-HT is another term for serotonin, and 5-HTP is actually one step closer to serotonin in the biochemical pathway than tryptophan. This product may be obtained from Life Enhancement Products, P.O. Box 751390, Petaluma, California CA 94975-1390. Benzodiazepines (Lorazepam, Temazepam, Diazepam ('Valium') Insomnia may be treated with a short course of temazepam. Panic attacks are often treated with lorazepam. Severe chronic anxiety may be treated with intermittent courses of diazepam. All of these drugs are potentially addictive. Accordingly, they are best not used for more than a few weeks at a time. Antidepressants such as fluoxetine and sertraline are also useful for treating anxiety. If the person can not tolerate these, clomipramine is a good alternative. The brain's anxiety mechanisms may play a specific role in the neurobiology of stimulants, which suggests that benzodiazepines may be useful in the early stages of withdrawal.79,80 Haloperidol and other antipsychotics

Antipsychotic drugs such as haloperidol and chlorpromazine are not a good first choice in ecstasy-

associated anxiety and psychosis. In general, such symptoms associated with ecstasy use are shortlived. It is thus better practice to administer benzodiazepines for at least the first few days, as the antipsychotic effect of dopamine antagonists such as haloperidol usually takes several weeks to become manifest, by which time symptoms will have resolved in most cases. Haloperidol and chlorpromazine have numerous serious and unpleasant side-effects, and the neuroleptic malignant syndrome may be linked to the hyperthermic syndromes associated with several ecstasy-related deaths.81 How Widespread Is MDMA Abuse? Monitoring the Future Survey* After sharp declines in ecstasy use since its peak in 2000/2001, current and past-year use of MDMA has risen among 8th and 10th graders. This follows several years of decreases in the perceived risk and disapproval of using MDMA. MDMA Use by Students Monitoring the Future Survey, 2012 8th Grade 10th Grade 12th Grade Lifetime** 3.3% 6.4% 7.3% Past Year 2.4 4.7 4.5 Past Month 1.1 1.9 1.4 National Survey on Drug Use and Health (NSDUH)*** In 2009, an estimated 760,000 people (0.3 percent of the population) in the United States aged 12 or older used MDMA in the month prior to being surveyed. Lifetime use increased significantly among individuals aged 12 years or older, from 4.3 percent (10.2 million) in 2002 to 5.7 percent (14.2 million) in 2009; however, past-year use of ecstasy decreased from 1.3 percent to 1.1 percent during the same period. Approximately 1.1 million Americans used ecstasy for the first time in 2009, which is a significant increase from the 894,000 first-time users reported in 2008. Other Information Sources For more information on MDMA, please visit www.clubdrugs.gov and www.teens.drugabuse.gov. Data Sources

* These data are from the 2010 Monitoring the Future survey, funded by the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, and conducted annually by the University of Michigans Institute for Social Research. The survey has tracked 12thgraders illicit drug use and related attitudes since 1975; in 1991, 8th- and 10th-graders were added to the study. ** Lifetime refers to use at least once during a respondents lifetime. Past year refers to use at least once during the year preceding an individuals response to the survey. Past month refers to use at least once during the 30 days preceding an individuals response to the survey. *** NSDUH (formerly known as the National Household Survey on Drug Abuse) is an annual survey of Americans aged 12 and older conducted by the Substance Abuse and Mental Health Services Administration, Department of Health and Human Services. This survey is available on line at www.samhsa.gov and can be ordered by phone from NIDA at 8776432644. References 1. Ricaurte GA and McCann UD. Experimental studies on 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and its potential to damage brain serotonin neurons. Neurotox Res 3(1):85 99, 2001. 2. Stone AL, Storr CL, and Anthony JC. Evidence for a hallucinogen dependence syndrome developing soon after onset of hallucinogen use during adolescence. Int J Methods Psychiatr Res 15:116130, 2006. 3. Cottler LB, Womack SB, Compton WM, Ben-Abdallah A. Ecstasy abuse and dependence among adolescents and young adults: Applicability and reliability of DSM-IV criteria. Human Psychopharmacol 16:599606, 2001. 4. Leung KS, Cottler LB. Ecstasy and other club drugs: A review of recent epidemiological studies. Curr Opin Psychiatry 21:234241, 2008. 5. Kraner JC, McCoy DJ, Evans MA, Evans LE, Sweeney BJ. Fatalities caused by the MDMArelated drug paramethoxyamphetamine (PMA). J Anal Toxicol 25(7):645648, 2001.