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March 21, 2001

America at Risk: The Ecstasy Threat


 

Dr. Bill Jacobs
Medical Director
Gateway Community Services

Introduction

Interest in the drug Ecstasy has grown considerably in recent times. The interest actually comes from both sides of the spectrum. Researchers continue to study the effects of 3,4-methylenedioxymethamphetamine (MDMA), the original, pure compound from which Ecstasy was named. Believing or wishing that MDMA is safe, adolescents and young adults throughout the United States and other western countries continue to increase their use of the drug. As a consequence of this increased illicit use, drug abuse researchers are now reporting on the toxic effects of MDMA.

The most popular setting for Ecstasy use continues to be ‘raves,’ i.e. parties that last at least all night and sometimes even two or three days. The location of a rave is generally fairly inconspicuous until the time of the event. The typical music at raves is of the "techno," "pulse" or "trance" genre. This music is conducive to nonstop dancing, which is compatible with the effects of Ecstasy and other drugs consumed at raves. Raves have become popular among the youth of our society. Of increasing concern is the rampant drug selling and use invariably found at such events. This concern has been reflected in news coverage on television and extended into mainstream media. In June of this year (2000), Time magazine featured an article on "The Lure of Ecstasy" and its potential dangers. In August of this year (2000), "60 Minutes" produced a segment on the rising popularity and concern of recreational use of Ecstasy. In November 2000, both "48 Hours" and MTV broadcasted 1-hour programs on Ecstasy.

Along with the increased focus of the media on MDMA use, researchers have also expanded their interest in the drug, how it works and its potential deleterious effects. Clinicians have started to see consequences of MDMA use among their patients as physicians two decades ago saw consequences of the last "safe" drug, cocaine, in their emergency rooms and offices. I hope to provide an updated review of Ecstasy: its history, epidemiology, pharmacology, acute effects, delayed effects, potential for long-lasting effects and drug testing issues. I will describe MDMA-precipitated psychiatric diseases, which last far longer than the presence of MDMA in the body.

History

The German division of the Merck Company first synthesized and patented MDMA in 1914. There are conflicting beliefs on the original purpose of creating this compound. It has been erroneously reported that MDMA was developed for appetite control, however, it was actually created as an experimental compound. The patent expired before MDMA became of commercial interest and thus never reached the public market. Psychotherapists first began using it on the West Coast in 1976 and quickly spread to the East Coast. Therapists thought that it could enhance the psychotherapeutic process by inducing the patient to be more open and to feel more connected to the therapist. Often the therapists and the patients took MDMA together as part of this so-called therapy.

Throughout the early eighties until its ban in 1985, a small but vocal group of insight-oriented therapists used MDMA extensively in their practices. Recreational use of MDMA first appeared in 1968 in the United States. At that time it was most popular among young partygoers and "New Age" seekers, i.e. self-described freethinkers who particularly like the ability of MDMA to induce feelings of wellbeing and connection. On July 1, 1985, after preliminary reports from Johns Hopkins researchers became known, the United States Department of Justice’s Drug Enforcement Agency placed MDMA on Schedule I status on emergency basis. Interestingly, some therapists and clergymen displayed significant support for MDMA being placed on a less restrictive status. However, after several hearings the substance was placed permanently on Schedule I status since MDMA was demonstrated to have significant potential for neurotoxicity in lab animals.

Despite its current illegal status, MDMA production and use continues to flourish. Unlike other ‘party drugs’ like Rohypnol (Roofies), GHB, and Special K or Ketamine, the drug is no longer manufactured by a pharmaceutical company. Sterile precautions, quality control, and FDA-like supervision are not part of the MDMA process. Production of MDMA occurs in basements and throughout Europe. Pure or pharmaceutical MDMA is non-existent and basement chemists have from time to time made bad versions of MDMA. Production has been accompanied by production of several knock-offs, that is, compounds that resemble the original structure yet may have a ring substitution here or there. Some of these chemically related compounds are even more dangerous than MDMA. For example, PMA (paramethoxyamphetamine) has been detected as a substance being sold as Ecstasy in the United States, Denmark, Germany and Australia. Consumption of this drug has been linked to multiple fatalities. Between July and September of 2000, in Florida, six deaths were attributed to variants of MDMA

Epidemiology

Illicit or recreational MDMA use has been steadily increasing over the past decade. Most of the use is among teens and young adults. It is most commonly used at Raves, nightclubs and parties. Although it is perceived as a middle-class, suburban drug, one study found no association between MDMA use and residential area or parents’ social class. Initiation of Ecstasy use is likely to be preceded by use of tobacco, alcohol, marijuana and other amphetamines. Ecstasy users are likely to use other drugs. Strong associations were found between MDMA use and certain music preferences and party going.

The National Institute of Drug Abuse Monitoring the Future Study reported this year life-time use of Ecstasy (see figure 1),. In 12th graders, 5.6% used Ecstasy within the past twelve months in 1999. In 1998 the figure was 3.6%. The Monitoring the Future Study also reported MDMA use in 12th graders within the past 30 days. In 1999, it was 2.5% and in 1998 it was 1.5%. Forty percent of high school seniors reported that Ecstasy would be easy to get if wanted. This is a dramatic increase of over 20% from one decade ago. Another survey of teens, sponsored by the Partnership for a Drug Free America, found that while marijuana use is decreasing, ecstasy use continues to increase . Between 1998 and 1999, trial use of Ecstasy increased from 7% to 10 %, and use has doubled since 1995 when only 5% had reported ever using the drug.

According to one longitudinal survey of college students in Florida, the percentage of students who have used methamphetamines like MDMA is also increasing. In 1994, 9.2% percent had ever used methamphetamines. Over the next five years that figure gradually increased to 16% in 1999. Past year and current use also increased during that time to 10.6% of students had used within the past 12 months and 4.3% reported current use in 1999. Another indicator of increased MDMA use is emergency department reports. According to the most recent data available from the Drug Abuse Warning Network (DAWN), there were significant increases in MDMA mentions between 1994 and 1999 (see figure 2). The estimated number of MDMA mentions in Emergency Department visits more than doubled between 1998 and 1999 to 2,850.

Statistics from drug testing in the military also indicate a growing problem. Drug Testing Advisory Board (DTAB) statistics revealed 93 total positives for MDMA in fiscal year 1998, 432 total positives in 1999, and 1,070 in 2000.

Chemical Structure

The structure of the 3,4-methylenedioxymethamphetamine and chemically related compounds are presented below:

Pharmacology

The pharmacology of MDMA in humans has been fairly extensively studied; five studies on its metabolism and pharmacokinetics are present in the literature. MDMA metabolism has been described as follows: MDMA is either N-demethylated to 3,4-methylenedioxyamphetamine (MDA) or O-demethylenated to 3,4-dihydroxymethamphetamine (HHMA). MDA is O-demethylenated to 3,4-dihydroxyamphetamine (HHA). HHMA and HHA are O-methylated to 4-hydroxy-3-methoxy-methamphetamine (HMMA) and 4-hydroxy-3-methoxy-amphetamine (HMA), respectively. After glucuronide or sulphate conjugation, HHMA, HHA, HMMA and HMA are excreted in urine. N-demethylation is regulated by cytochrome P450 3A4. O-demethylenation is regulated by cytochrome P450 2D6, an enzyme that is genetically deficient in about 10% of Caucasians. As this enzyme displays genetic polymorphism, variable metabolism for MDMA is likely. O-methylation is performed by catechol-O-methyltransferase.

Plasma concentration over time after MDMA administration has been studied. The time to maximum concentration (Tmax) has been found to be two hours in several studies. However, one study found Tmax to be four hours. Elimination half-life was found to be between eight and nine hours.

Subjective effects of Ecstasy emerge 20 to 40 minutes after intake. Often there is a "rush" similar to that experienced with amphetamines and then the effects plateau. Duration of action is about four hours .

The pharmacokinetics of MDMA has also been studied. A recent study xii found that MDMA metabolism shows nonlinear pharmacokinetics. As the dose of MDMA is increased, MDMA concentrations do not rise proportionally. Similar results have been found in previous studies as well 15 . Variations in the cytochrome P450 system among individuals can result in non-linearity of some drugs; however, studies have ruled this out in the case of MDMA. Higher MDMA concentrations relative to dose increases may be due to saturation of metabolic enzymes. However, the cause of non-linearity may be more complex. For example, interactions between MDMA metabolites and various steps in the metabolic pathway may also be involved. HMMA has been shown to inhibit the O-demethylation step, which could in turn hinder subsequently administered parent compound . Furthermore, MDMA may act as an inhibitor of cytochrome P450 2D6 in addition to it being a substrate of the enzyme.

Acute Effects of Ecstasy

 

Acute Subjective Effects

Subjective effects of MDMA have been obtained using a variety of methods. One of the earlier reports used semi-structured interviews with psychiatrists who had taken MDMA. The two most common acute reinforcing subjective effects of Ecstasy use reported are an intense feeling of attachment and connection to others and highly increased energy. Although the name did not become popular, Ecstasy was initially named ‘Empathy’ due to its ability to make users feel like they understand and share the emotions of others and thus feel closer to others. Ecstasy makes one feel physically energetic or even restless. Thus, it enables users to dance all night or even for days at a time depending on the amount and frequency ingested. One study, comparing short-term administration of MDMA to amphetamines and placebo in subjects pre-exposed to MDMA, associated MDMA with changes in body perceptions and marked euphoria. Other ‘pleasurable’ acute effects may be peacefulness, euphoria, altered time perception, heightened sensory perception, intensified feelings and increased desire for sex. This desire often may not be fulfilled as Ecstasy also can inhibit the ability to become aroused and/or reach orgasm. Difficulty concentrating and lack of appetite have also been reported Ecstasy is not thought of as a hallucinogenic; it has been described as a hybrid of mescaline and amphetamine. Studies have concluded that visual auditory or tactile hallucinations occur only twenty percent of the time .

 

Use of MDMA can also have the indirect effect of increased risk of sexually transmitted diseases. Users may be more likely to engage in unplanned/unprotected or otherwise riskier sexual behaviors. In a sample of gay and bisexual men, MDMA abuse was strongly associated with high-risk sexual behavior even when alcohol, other drug use and age were controlled.

Acute Neuropsychiatric Effects

Several short-term neuropsychiatric effects have been reported. These effects are included in the table below.

Table 1

Neuropsychiatric Effects of MDMA

Anxiety Depression Mental fatigue ‘Emotional inflation’ Fear Paranoia Racing thoughts Confusion ‘Negative self talk’ Irritability Defensiveness Decreased libido Inability to complete the sexual response cycle Decreased desire to perform physical or mental tasks Increased obsessiveness Motor tics Decreased ability to interact or be open with others Altered time perception Panic attacks Psychosis Irrational or impulsive behavior

Severe psychosis is the most likely reason for one to seek psychiatric care in the acute phase of drug intoxication.

Acute Medical Effects

Ecstasy may produce several non-fatal unpleasant side effects during the acute phase of intoxication. Unpleasant effects often worsen with increasing dose and frequency of drug use. The most common of these side effects are presented in table 2. These effects may cause a user to discontinue use of the drug; or alternatively, find methods to manage them. Sucking on a baby pacifier has become a trendy method of relieving bruxism. Sometimes other drugs are used in an attempt to counteract these effects. Insomnia and motor restlessness are often managed by dancing and partying until they subside.

Table 2

Common Acute Medical Effects of MDMA

Nausea Vomiting Trismus Bruxism Hypertension Palpitations Headache Hyperreflexia Difficulty walking Urinary urgency Diaphoresis Anorexia Muscle aches Muscle tension Hot flashes Cold flashes Nystagmus Insomnia.

More serious acute medical complications of Ecstasy use have also been reported as blurred vision, illusions, visual hallucinations, motor tics, dry mouth, corneal erosions, urinary retention, paresthesias, fainting and decreased respiratory rate.

Fatal and Potentially Fatal Acute Effects Associated with Ecstasy

Although Ecstasy has been touted as a "safe" drug by many, there have been numerous fatal or near fatal occurrences associated with its use. Due to concentration difficulties and delayed reaction time, the risk of fatal accidents, most commonly car accidents, is increased during Ecstasy intoxication. Numerous cases of reckless driving have been reported over the past 2 decades . Further investigation is needed to determine the magnitude of such risks during Ecstasy intoxication.

Much more complex and only partially understood are the deadly physiologic changes that can occur with Ecstasy use. Potentially fatal complications include pneumomediastinum, severe chest pain, seizures, status epilepticus, syndrome of inappropriate anti-diuretic hormone (SIADH) , cardiac arrhythmias, asystole, subarachnoid hemorrhage, cerebral venous sinus thrombosis, hyperpyrexia and multi-organ system failure. McEvoy et al. reports that drugs like ecstasy may increase the risk of intracerebral hemorrhage, especially in people with underlying vascular malformation. Severe headaches or altered consciousness following drug use may due to stroke. CT scans and drug testing are recommended

Liver Damage

One area of great concern is acute liver damage following Ecstasy ingestion. In a review of patients admitted from 1994 through 1996 to an intensive care unit for acute liver failure, eight percent (5/62) were related to Ecstasy use, without evidence of other possible etiologies. Of all cases related to drug ingestion, 31 percent were due to Ecstasy. In patients under 25 year of age, Ecstasy was the second leading cause of liver failure. The clinical presentations of these cases were fairly typical. A prodromal period lasting a few days preceded the more telling signs and symptoms of jaundice, abdominal pain and elevated serum aminotransaminase levels. Hypoglycemia and prolonged prothrombin time quickly followed. None of the patients experienced hepatic encephalopathy. All patients fully recovered within three to twelve months. Histopathology studies revealed hepatocellular necrosis and edematous portal tracts. Eosinophils were common in the inflammatory infiltrate of the portal tracts. The delay between Ecstasy use and onset of symptoms was somewhat more variable. In most cases, the delays was only a few days, however, some cases had a delay of up to three weeks. The total amount of the drug ingested and the frequency of use varied considerably; no correlation could be made between such variables and incidence or extent of damage.

An earlier report described eight cases of acute liver damage related to Ecstasy ingestion All patients revealed a history of recent MDMA use and all tests for other etiologies were negative. The eight cases were divided in three characteristic groups according to clinical findings: (1) severe hepatic damage with hyperthermia (2) severe hepatic damage without hyperthermia and (3) mild hepatotoxicity. The first group consisted of two patients that both collapsed within six hours of Ecstasy ingestion. Common symptoms of heatstroke such as hypotension, coagulopathy, renal impairment, and severe hepatotoxicity were present. Both patients progressively worsened. They experienced seizures, DIC, severe coagulopathy, rhabdomyolysis, myoglobinuria, renal failure and encephalopathy. Both required mechanical ventilation. One patient developed diffuse cerebral edema. This patient eventually required liver transplantation, yet died of sepsis 13 days postoperatively. Pathologic examination of the original liver showed microvesicular fatty infiltration. The other patient improved gradually after treatment with aggressive fluid resuscitation, dantrolene and supportive care. He was able to go home 15 days after admission. It is unclear if liver damage in these cases was due to direct effects of Ecstasy, due to hyperthermic injury or both. Four patients incurred acute liver failure without hyperthermia. Common clinical findings included malaise, nausea, vomiting, hyperbilirubinemia, coagulopathy, encephalopathy and sepsis. All four patients met requirements for liver transplantation. One died due to severe cerebral edema while awaiting a donor. Two were transplanted, yet died of sepsis within four weeks postoperatively. Histopathology revealed sub-massive lobular collapse. One patient was successfully transplanted and discharged from the hospital. The final two patients incurred relatively less severe hepatic damage. Onset of symptoms was generally slower. Liver biopsy revealed lobular hepatitis with cholestasis. They both recovered spontaneously within three weeks. In all of these cases, no correlation existed between the amount or frequency of Ecstasy consumed and the severity of illness.

The mechanism of liver injury following Ecstasy administration is unclear. That the amount of Ecstasy consumed is independent of hepatic sequelae points to an idiosyncratic reaction. Cases of liver damage following ingestion of a single Ecstasy tablet have been reported . A metabolite or a contaminant in the preparation may be the toxic agent. The presence of eosinophils in multiple cases leads to speculation of a hypersensivity reaction occurring in some individuals. In cases in which hyperthermia is involved an ischemic process such as that which occurs in heatstroke may be involved. Alternatively, phenotypic variations in the enzyme cytochrome P450 2D6 may result in varied vulnerability to the drug.

Other Serious Effects

A potentially fatal syndrome of mental status changes, convulsions, autonomic instability, hyperthermia, tachycardia, mydriasis, muscle rigidity, coagulopathy and rhabdomyolysis has been described in several cases following Ecstasy ingestion. Less common features were acute renal failure and SIADH. The syndrome has features of neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS). Clinical characteristics resembling NMS found in Ecstasy-related cases include mental status changes, hyperthermia, elevated creatinine kinase, and autonomic dysfunction. Those resembling SS included mental status changes, restlessness, hyperthermia, diaphoresis, hyperreflexia, diarrhea, mild extrapyramidal symptoms, hyperreflexia, and myoclonic movements. NMS tends to have its onset 3-9 days after drug administration, whereas onset of SS is usually within hours. The latter is more typically the Ecstasy- induced syndrome, with the typical onset being between fifteen minutes and six hours of drug administration. Similar to the cases of hepatic injury, amount did not correlate with severity of symptoms.

Cardiovascular Effects

One case of aortic dissection following Ecstasy use has been described. The patient in this case was a previously healthy 29-year-old man who ingested ecstasy at a rave. The only other substance he consumed during the rave was alcohol. Absence of other drugs was confirmed by toxicology screening. The patient returned home after the party, slept that night and collapsed the next day about two hours after waking. The patient was subsequently evaluated at an emergency room, which was about six hours after he had taken the ecstasy. The patient had shortness of breath, abdominal pain, diarrhea and vomiting. He was afebrile and normotensive. The only positive lab finding was an elevated white blood cell count of 17.8. In the ER, he had a loose, bloody stool. He refused further evaluation at that point. He was diagnosed with gastroenteritis and discharged home. Eight hours later, he returned to the ER hypertensive (180/105) and febrile at 39°C. His condition deteriorated quickly; he died about five hours after this presentation, about 48 hours after ecstasy ingestion. Aortic dissection extending from the root to the bifurcation was found at autopsy. The dissection caused cardiac tamponade; 300 ml of blood was found in the pericardial sac. Dissection intruding into the inferior and superior mesenteric arteries resulted in bowel ischemia. Septicemia was also evident. Histology revealed a small amount of cystic medial necrosis; this was the only pathology found that may have predisposed the patient to aortic dissection. MDMA- induced hypertension may have been the crucial factor leading to dissection.

There have been several reports of MDMA related cardiovascular toxicity. New research suggests that like other amphetamine analogs, MDMA may be able to produce cardiac and/or cardiovascular toxicities. Changes in cardiovascular reflex function were found in rats that were treated with neurotoxic doses of MDMA. Increased risk of cerebrovascular events is thought to be related to MDMA related changes to the serotonin neurotransmission system.

Although rare, there have reports of hyponatraemia related to ecstasy use. In order to reduce the risk of hyperthermia many ecstasy users will drink large quantities of fluids. Sometimes water intake greatly exceeded fluid lost through physical exertion leading to acute illness and a small number of deaths. It appears that in ecstasy- associated cases; hyponatraemia is more likely the result of a large intake of fluids in a short amount of time rather than the result of inappropriate secretion of antidiuretic hormone (SIADH).

Etiologies of Short-term Effects

Etiologies of acute effects are often multifactorial. For example, hyperpyrexia may result from a combination of factors including surroundings (hot clubs), activities (continuous dancing) and serotonergic dysregulation in the thermoregulatory center of the brain.

It has been reported that individuals with Wolff-Parkinson-White are at greater risk for sudden cardiac risk following MDMA use30. Researchers continue to study the neurobiology that underlies MDMA’s effects. Animal studies have laid the groundwork; human studies are increasingly emerging as well. Acute neuropsychiatric effects of MDMA administration appear to be mediated by an acute release of serotonin and a simultaneous blockade of its reuptake in the brain 27 .

Delayed and Long-term Effects of MDMA

Some unpleasant effects, medical complications and neuropsychiatric changes may develop some time after using MDMA and/or they may persist chronically. Conditions such as temporomandibular joint syndrome, dental erosion, myofacial pain, aplastic anemia and hepatoxicity have been reported32.

Delayed Neuropsychiatric Effects

MDMA is neurotoxic to both animals and humans. Researchers from a variety of disciplines have documented several neuropsychiatric consequences that appear to be the result of MDMA. MDMA related neuropsychiatric changes may persist or new ones may emerge. Such chronic symptoms have been reported as panic disorder, psychosis, aggressive outbursts, flashbacks, major depressive disorder, suicidal thinking, memory deficits, cognitive disturbances, anxiety and panic attacks and carbohydrate or chocolate cravings 32. Sleeping disorders, anorexia and other eating disorders and long-term fears have also been observed. Parrott et al. reported increased impulsiveness in heavy MDMA users. These users were significantly more likely than light users and controls to have higher scores of several psychiatric symptoms (see table 3). The most common reasons for which individuals seek treatment in the chronic phase are depression, anxiety and panic attacks. It appears MDMA can exacerbate existing conditions, contribute to relapse or actually be responsible for changes that lead to a new condition. Some MDMA related changes in the brain appear to be permanent.

Table 3

Psychiatric Symptoms of MDMA Use

Depression Paranoid ideation Somatisation Psychoticism Anxiety Obsessionality Hostility Insomnia Restless sleep Altered appetite Phobic anxiety

Long-Lasting Cognitive and Behavioral Changes

Evidence of long- lasting cognitive- behavioral changes in MDMA users is also accumulating. Parrott summarizes such changes in three major categories: memory, higher executive functioning and impulsiveness. Verbal and visual memory deficits were first described. Studies used various tests and found immediate and delayed recall repeatedly disrupted in drug-free MDMA users . A 1999 report by McCann et al. described results of a controlled study on cognitive performance. Results showed that compared to non-users, drug-free MDMA users had deficits on specific tasks involving sustained attention, complex attention, combined incidental learning, short-term memory and semantic recognition combined with verbal reasoning. In this study cerebrospinal 5-HIAA was measured for each subject and found to be decreased, however, the positive correlation with memory deficits described in a prior study by Bolla et al. was not found. Higher executive functioning as assessed by various tasks, e.g. the Wisconsin Card Sort, the Tower of London, random generation letter task, has been shown to be impaired in multiple studies . Impulsivity is now known to be at least partially related to brain serotonin deficiency. Views on the correlation between impulsivity and MDMA use have evolved over the past decade. Initially, McCann and colleagues found impulsiveness to be lower in MDMA users68. However, based on further research, the current thought is that impulsiveness is higher in MDMA users. Additionally, McCann has described new data not yet published that finds MDMA users with higher impulsiveness ratings.

Etiology of Delayed and Long-lasting MDMA Effects

Many of the chronic effects of MDMA use have been linked to long lasting changes in the brain’s serotonergic system. Evidence of MDMA-related serotonergic changes in animals and humans is well documented. Brain imaging studies have been useful in further describing these changes. Changes in cerebral blood flow and the effects of MDMA when using a pretreatment of a 5-HT 2 neurotoxin have also been studied and are described below.

Decreased Levels of Serotonin in Animal Studies

Numerous studies have been performed in MDMA- treated rats, guinea pigs and monkeys that show long-lasting decreases in levels of serotonin in the brain and in levels of 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of serotonin, in the brain and CSF. Studies have found that serotonin transporter density is reduced in these animals as well. Additionally, activity of tryptophan hydroxylase is also reduced in pretreated animals. This enzyme catalyzes the first step in the synthesis of serotonin from tryptophan. 5-HT axon terminal markers are reduced after an animal is exposed to MDMA. The most recent research shows that anterograde transport of labeled material in ascending 5-HT pathways from raphe nuclei to the forebrain is reduced in rats treated with MDMA two weeks prior. The same results are obtained when rats were pretreated with a documented 5-HT neurotoxin, dihydroxytryptamine. Thus, one may conclude that MDMA itself is also a 5-HT neurotoxin.

Serotonin Axon Recovery in Animals

There is also evidence that 5-HT axons try to recover after MDMA administration ceases. In studies with monkeys and squirrels, 5-HT axons regenerated, however, in an altered pattern. Fischer’s study with monkeys found that axons did not seem to regenerate to distal areas they originally projected and regrowth appeared to occur in more proximal regions. Hatzidimitriou et al. studied monkeys over a seven-year period and found that brain 5-HT abnormalities persisted. Recovery was noted in some regions; however, in other areas recovery did not occur or was only partial. Distance of damage from cell bodies was also examined and was found to correlate partially with recovery. However, damage did persist in some proximal regions, thus distance was not found to be the only factor. A study using positron emission tomography (PET) to assess the brains of MDMA- treated baboons provided further evidence of short and long-term neuroanatomical changes induced by MDMA. Radioligands of the 5-HT transporter tracked changes after MDMA administration. PET scans at 13, 19 and 40 days after MDMA was administered showed a reduction in 5-HT transporters in all areas of the brain. Nine to 13 months later, specific regions of the brain, the hypothalamus and midbrain showed recovery of transporter density, however, production over baseline also occurred, indicating abnormal recovery.

Long-Lasting 5-HT Changes in the Human Brain

Human studies provide further evidence of long lasting 5-HT alterations. In a controlled inpatient study, McCann et al. found that abstinent MDMA users had significantly lower cerebrospinal fluid levels of the major serotonin metabolite, 5-HIAA. In contrast, levels of the major dopamine metabolite, homovanillic acid (HVA), and the major norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), did not show significant changes, indicating that MDMA affects serotonergic system most predominantly. PET studies compared MDMA users to nonusers. MDMA users had abstained from the drug for at least three weeks prior to participating in the study. Results showed significantly decreased brain 5-HT transporter sites in MDMA users. The extent of this decrease correlated positively with the amount and frequency of use reported by the subjects. Further evidence of serotonergic neurotoxicity was demonstrated when serotonin binding in long term MDMA users was measured by single photon emission computed tomography (SPECT). A cortical reduction of SERT binding was found, especially in the sensory-motor cortex. Another study using SPECT reported a correlation between memory impairment and MDMA related serotonin neoronal injury. Auditory evoked potentials (AEP) provide another method of measuring serotonergic activity in the brain. Low serotonergic neurotransmission correlates with increased activity in certain AEP domains. Recreational Ecstasy users were found to have increased activity of this domain compared to two control groups.

In another study using positron emission tomography, Obrocki et al. focussed on correlations between MDMA use and glucose metabolism. Glucose metabolism as measured by PET scans was significantly disrupted in MDMA users. The glucose metabolic rate was reduced in particular brain regions: the hippocampus, the amygdala and the cingulate bilaterally. It was elevated in other areas: Brodmann’s areas 10 and 11, the putamen and the caudate bilaterally. The most significant metabolic rate changes were found in the hippocampus and Brodmann’s area 11.

Changes in Cerebral Blood Flow

Cerebral blood flow (CBF) also appears to be affected by MDMA use. The vascular system is partially regulated by serotonin, with serotonin having vasoconstrictive effects. Thus, a correlation between MDMA use and CBF has been investigated. In subjects with normal brain MRIs, regional CBF was found to be lower in users compared to controls. Regions most affected were the parietal and dorsolateral frontal areas. These areas are related to the serotonergic system as 5-HT neurons project and terminate in the fronto-parietal cortex. Larger decreases in CBF were found in users who had used Ecstasy more recently and in users who had taken higher doses. After periods of abstinence, CBF is thought to potentially recover. Due to postulated aberrantly located or excessive regrowth of serotonergic terminals, CBF may even increase over baseline. In one study published this year, Reneman et al. investigated MDMA’s effects on brain 5-HT2A receptor density and subsequently the relationship of these effects to regional cerebral blood vessel volumes. SPECT was used to measure receptor density and dynamic magnetic resonance imaging assessed cerebral blood volumes. Current MDMA users were found to have significantly lower mean cortical receptor binding compared to the former MDMA-user group and the non-user group. This implies down-regulation of 5-HT2A receptors may occur as a compensatory mechanism following massive serotonin release induced by MDMA. The MDMA user group data showed a significant positive correlation between 5-HT2A receptor binding and rCBV in the globus pallidus and occipital cortex; lower receptor densities were associated with lower blood vessel volumes, which may be considered equivalent to vasoconstriction. Interestingly, former MDMA users were found to have higher receptor densities in this study. This may be due to upregulation of receptors caused by serotonergic depletion after repeated use of MDMA. Furthermore, rCBV was higher in former users, indicating vasodilation. This data provides evidence that MDMA impacts 5-HT2A receptors and, in turn, cerebral blood vessel volumes 45.

Another study published this year found MDMA related changes in cerebral blood flow in several areas on the brain. PET scans showed increased blood flow was found in the cerebellum, occipital cortex, ventromedial frontal, and inferior temporal lobe; and decreases were found in the thalamus, insula, temporal lobe, cingulate cortex and the motor and somatosensory cortex 27.

Effects of MDMA when Pretreatments are used

Further evidence of 5-HT2A receptor involvement was obtained by Liechti et al. The acute effects of MDMA were evaluated with pretreatment of the 5-HT2 antagonist ketanserin. Compared to pretreatment of MDMA administration with placebo, ketanserin attenuated several common effects of MDMA such as perceptual changes, emotional excitation, and acute adverse responses. Perceptual changes included a moderate intensification of visual, acoustic and tactile perception and a changed experience of the environment; there were no hallucinations. Ketanserin’s effect on emotional excitability is particularly significant when reviewing other data showing that a D2 antagonist (haloperidol) and a serotonin reuptake inhibitor (citalopram) did not produce similar changes. Ketanserin did not appear to have a significant effect on positive mood, well- being and extroversion commonly induced by MDMA . When given as a pretreatment to MDMA administration, citalopram did however reduce several acute psychological effects by about 60%. These included positive mood, derealization, depersonalization, thought disorder and loss of thought and body control. Thus, the serotonin reuptake site appears to have a significant role in the mechanism of action of MDMA .

Autopsy Findings

Brain autopsy findings of an MDMA user were described in one report. Blood and brain tissue analysis revealed the presence of MDMA, indicating the subject had used MDMA just prior to death; forensic hair analysis revealed that the subject had also used the drug chronically. In the striatum, concentrations of serotonin and its major metabolite, 5-HIAA, were decreased 50-80% compared to controls. Dopamine and its metabolites were also measured throughout the brain: dopamine was found to be about 47% reduced in the nucleus accumbens and homovanillic acid, a major dopamine metabolite, was increased by 45% in the putamen.

Poly-substance Abuse

Many people who use Ecstasy use other drugs of abuse like alcohol, tobacco, marijuana, inhalants and/or other "club drugs." Sometimes it is not clear whether the effects are the result of MDMA, another drug, a combination of drugs or pre-existing differences among users49. One study found subjects who had used ecstasy heavily or marijuana heavily with MDMA had more cognitive performance deficits than those who only used marijuana and non-users. The authors suggest that marijuana use in addition to ecstasy may contribute to these cognitive deficits. However, long-term impairments were also found in light ecstasy users. Since both marijuana use and MDMA use have been associated with memory impairment, another study compared subjects in these two groups to controls with no history of illicit substance use. Increased verbal memory impairment was found for both groups of drug users, but Ecstasy users were found to have impaired delayed memory significantly more than the other groups. Another study, comparing light and heavy Ecstasy users to non-Ecstasy users, reported that Ecstasy users were more likely than controls to smoke cigarettes and to use cocaine, amphetamines and LSD.

MDMA Detection

Various procedures have been developed to detect MDMA in urine, blood, sweat, saliva, hair and nails. The most common routine drug screening procedure involves an immunoassay of a urine sample. Routine drug screening will detect stimulant use easily. These tests can be performed rapidly and is thus useful in emergency settings. Unchanged MDMA and the metabolite MDA can be detected in the blood from ½ to 1 day. In urine it can be detected for 2 to 3 days after ingestion. Immunoassay techniques work by using competitive binding of labeled drugs for specific drug antibodies. Abbott Laboratories manufacture the most common immunoassay used for emergency room urine toxicology screens. Another patented immunoassay, EMIT-dau amphetamine class assay, manufactured by the Syva Company is commonly used in athletic drug testing and in substance abuse rehabilitation centers. It allows for low detection limits. Other companies, such as Lifepoint are developing instant quantitative saliva testing systems for MDMA. Another immunoassay, Drugwipe, has been developed for on-site qualitative determination using saliva and sweat. Results can be obtained in two minutes without having to use a laboratory. Given these characteristics, police officers may be able to perform the test on duty, similar to the breath test for alcohol.

Gas chromatography/ mass spectrometry (GC/MS) is considered the gold standard for detecting MDMA, as it is the most specific technique. Positive urine immunoassays should be confirmed using this method to avoid false positive results. The National Institute of Drug Abuse requires GC/MS in its programs. GC/MS can be performed on blood and urine. National Medical Services, currently tests blood and urine for MDMA utilizing a gas chromatography screen with gas chromatography/mass spectrometry confirmation at 10 ng/ml (blood) and 200 ng/ml (urine). The company reports a detection time of up to 4 hours (blood) and up to 24 hours (urine).

Hair analysis is becoming increasingly popular. Ease of sample collection and longer duration substance presence make it attractive. GC/MS was first used to detect MDMA in hair in 1993. Since then investigators have been refining techniques of hair analysis to make them more accurate, more rapid and easier to perform. On July 16, 2000, Psychemedics Corporation began testing for the presence of MDMA in all hair samples it receives from corporations and individuals. Ecstasy testing will also be included in their high school testing programs. In addition, the company offers Ecstasy testing of hair samples with a kit available in drugstores and over the internet at www.drugfreeteenagers.com.

MDMA and similar substances are now listed in proposed new guidelines for workplace drug testing. At the June 6, 2000 meeting of the Drug Testing Advisory Board (DTAB), an initial draft of the revised Mandatory Guidelines for Workplace Drug Testing Programs was released. The draft guidelines include MDMA in the drugs to be tested for as a part of the test for amphetamines. In addition, cutoff levels that have been developed for hair, sweat and oral fluid specimens are listed below.

Hair

               Initial Test Cutoff Concentration (pg/mg)

Marijuana metabolites............ 1.0

Cocaine metabolites............... 500

Opiate metabolites1................. 200

Phencyclidine......................... 300

Amphetamines2...................... 500

1 Labs are permitted to initial test all specimens for 6-AM at a 200 pg/mg cutoff in addition to the opiates test kit

2 Target analyte must be d-methamphetamine and test kit must significantly cross-react with MDMA, MDA, and MDEA (~ 50 to150% cross-reactivity)

 

            Confirmatory Test Cutoff Concentration (pg/mg)

Marijuana metabolite1............... 0.05

Cocaine metabolite2.................. 100

Cocaine parent drug................. 1000

Opiates

Morphine............................... 200

Codeine................................. 200

6-acetylmorphine ................. 200

Hair 6-AM rule (TO BE DETERMINED)

Phencyclidine.......................... 300

Amphetamines

Amphetamine....................... 300

Methamphetamine 3.............. 300

MDMA............................... 300

MDA................................... 300

MDEA................................ 300

1 Delta-9-tetrahydrocannabinol-9-carboxylic acid

2 Benzoylecgonine (BE/Cocaine ratio >= 0.1)

3 Specimen must also contain Amphetamine at a concentration > 50 pg/mg

 

Oral Fluid

                   Initial Test Cutoff Concentration (ng/mL)

THC Parent drug and metabolite.... 4

Cocaine metabolites............... 20

Opiate metabolites1................ 40

Phencyclidine......................... 4

Amphetamines 2..................... 160

1 Labs are permitted to initial test all specimens for 6-AM at a 4 ng/mL cutoff

2 Target analyte must be d-methamphetamine and test kit must significantly cross-react with MDMA, MDA, and MDEA (~ 50 to150% cross-reactivity)

 

           Confirmatory Test Cutoff Concentration (ng/mL)

THC Parent drug............... 2

Cocaine metabolite2.................. 8

Opiates

Morphine............................... 40

Codeine................................. 40

6-acetylmorphine ................. 4

Phencyclidine.......................... 2

Amphetamines

Amphetamine....................... 160

Methamphetamine3............... 160

MDMA................................. 160

MDA..................................... 160

MDEA.................................. 160

2 Benzoylecgonine

3 Specimen must also contain Amphetamine at a concentration > (TO BE DETERMINED) ng/mL

 

Sweat

              Initial Test Cutoff Concentration (ng/2.5 mL eluate)

Marijuana metabolites............ 1.5

Cocaine metabolites............... 10

Opiate metabolites1................ 10

Phencyclidine........................ 7.5

Amphetamines2...................... 10

1 Labs are permitted to initial test all specimens for 6-AM at a 10 ng/2.5 mL eluate cutoff

2 Target analyte must be d-methamphetamine and test kit must significantly cross-react with MDMA, MDA, and MDEA (~ 50 to150% cross-reactivity)

 

         Confirmatory Test Cutoff Concentration (ng/2.5 mL eluate)

THC parent drug.......................... 0.5

Cocaine parent drug................... 10

Cocaine metabolite2.................. 10

Opiates

Morphine............................... 10

Codeine................................. 10

6-acetylmorphine ................. 10

Phencyclidine.......................... 7.5

Amphetamines

Amphetamine........................ 10

Methamphetamine3................ 10

MDMA................................. 10

MDA..................................... 10

MDEA.................................. 10

2 Benzoylecgonine

3 Specimen must also contain Amphetamine at a concentration > (TO BE DETERMINED) ng/mL

 

Urine

Initial Test Cutoff Concentration (ng/mL)

Marijuana metabolites........... 50

Cocaine metabolites.............. 150

Opiate metabolites 1.............. 2000

Phencyclidine........................ 25

Amphetamines 2.................... 500

1 Labs are permitted to initial test all specimens for 6-AM at a 10 ng/mL cutoff

2 Target analyte must be d-methamphetamine and test kit must significantly cross-react with MDMA, MDA, and MDEA (~ 50 to150% cross-reactivity)

 

Confirmatory Test Cutoff Concentration (ng/mL)

Marijuana metabolite1............... 15

Cocaine metabolite2.................. 100

Opiates

Morphine............................... 2000

Codeine................................. 2000

6-acetylmorphine 4................. 10

Phencyclidine.......................... 25

Amphetamines

Amphetamine..................... 250

Methamphetamine3............ 250

MDMA.......................... 250

MDA.................................. 250

MDEA................................ 250

1 Delta-9-tetrahydrocannabinol-9-carboxylic acid

2 Benzoylecgonine

3 Specimen must also contain d-Amphetamine at aconcentration > 100 ng/mL

4 If a laboratory uses both initial test kits to screen a specimen concurrently, it may report 6-AM alone

 

Other New Research

Researchers are developing in vitro models and using PET scans to describe and explain drug-induced dopamine neurotoxicity . Burrows et al. recently reported that MDMA may disrupt mitochondrial function by inducing a decrease in cytochrome oxidase activity in dopamine-rich areas of the brain. Other researchers are now reporting that MDMA may alter egr-1 mRNA expression in several areas of the brain in rats. In vitro studies are now suggesting that MDMA use could increase the risk of immune system-related diseases. Natural killer cell activity, macrophage function, cytotoxic T-lymphocyte activity and T-cell regulatory function were some of the immune functions that appeared to be modulated by MDMA. Oxygen-based radicals may play a role in MDMA neurotoxicity. Jayanthi et al. suggest that free radicals produced by MDMA may agitate antioxidant enzymes. New studies are suggesting that ascorbic acid may prevent MDMA-related brain damage in rats. It is not know whether ascorbic acid will have the same protective effects in humans. Recently, temperature was shown to affect methamphetamine induced dopamine nuerotoxicity. Hyperthermia in now believed to exacerbate and hypothermia attenuates dopamine neurotoxic effects. One study presented at the November 2000 Society for Endocrinolgy Meeting in London suggests ecstasy may be more dangerous for young women because of high estrogen levels.

Conclusion

MDMA is increasingly becoming recognized as a dangerous drug of abuse. It is clear that MDMA has a multitude of acute, delayed and sometimes permanent adverse effects. MDMA can produce major psychiatric disorders, which persists and may become life-long diseases in their own right. While acute toxicity is medical and can include emergency room visits and medical crisis, different problems emerge over time. Problems sleeping through the night, anorexia, fears and phobias, depression, and problems thinking and remembering new material can appear after use and persist. These maleffects can occur during the intoxication phase or may evolve over months following use. Cases of persistent depression, memory and learning dysfunction, sleep disorders, anxiety and panic and eating disorders may be linked in the near future to MDMA related brain serotonin damage. MDMA was viewed as safe for many years, but now we are seeing, as we did with cocaine, that it can be extremely harmful. We still do not know what all of the potential long-term effects might be for current and former users. We do not understand variables that relate to neurotoxic risk but it does appear that female gender is one such risk. Such potential for harm is extremely concerning given the escalation of use in the past several years.