MDMA (“Ecstasy”)

MDMA (“Ecstasy”)

3,4-methylenedioxymethamphetamine (MDMA, commonly known as “ecstasy,” and chemically N-methyl-1-[3,4- methylene-dioxyphenyl]-2-aminopropane) is a synthetic amphetamine ana-logue that is also similar to mescaline. During the ‘psychedelic’ 1970s, recreational use of MDMA took root due to its psychologi-cal effects and the fact that it was available legally. Recreational use was partially fueled by reports of the use of MDMA as a psychotherapeutic adjunct.

The publicity that followed the scheduling of MDMA only served to increase its popularity, particularly on college cam-puses. Recently, the use of MDMA has increased and its pat-tern of use has changed. These factors have heightened public awareness of the drug and paradoxically led to an increase in use and adverse consequences. Emerging evidence supports the hy-pothesis that MDMA is a neurotoxin in humans with long-lived sequelae on cognition, memory and emotions.

Epidemiology

Despite its existence for nearly 90 years, the recreational use of MDMA appears to have had its origins in the 1960s (Pope et al., 2001). Initial drug use centered around college campuses (Pope et al., 2001; Peroutka et al., 1988). At that time, use of MDMA was generally in small groups in private places (Peroutka et al., 1988). Accurate epidemiologic data are not available for the 1960s. However, by 1977 about 2.8% of US college students used MDMA (Strote et al., 2002). College is the first time that people are likely to begin use of MDMA (Cuomo et al., 1994; Randell, 1992). Nonetheless, use in high school students has also increased, so that in 1998, 4.4% of 10th graders and 5.6% of high school seniors had tried MDMA (Johnston et al., 1999). In a survey of 14 000 college students at 119 American colleges by the Harvard School of Public Health College Alcohol Study, there was a 69% increase in use between 1997 and 1999 (from 2.8 to 4.7%) (Strote et al., 2002). At 10 high use schools with a 1997 rate of 4.7%, the rate increased to 10.6% by the year 2000 (Strote et al., 2002). Over the same time the use of marijuana did not significantly change (38.5% in 1997 and 37.6% in 2000) (Strote et al., 2002). MDMA is the only illicit drug to see continued increase in use. In surveys of a large New England college performed in 1969, 1978, 1989 and 1999, all drug use peaked in 1978 and dropped there-after but MDMA use has continued to increase. The increasing popularity of MDMA is not just an American phenomenon, but is seen in both Europe (Cregg and Traqcey, 1993; Christophersen, 2000) and Australia (Topp et al., 1999).

In addition to increased popularity of MDMA, the pattern of use appears to have changed. Initial use was in small groups at doses ranging from 75 to 150 mg with an occasional booster of 50 to 100 mg (Peroutka et al., 1988; Downing, 1986; Siegel, 1986; Liester, 1992). The 1990s saw the onset of the rave phenomenon. These are generally large gatherings in warehouses or dance clubs. Dosage utilized in raves are much more variable ranging from 100 to 750 mg and as high as 1 250 mg/night (Brown et al., 1995; Forsyth, 1996). Concomitant drug use is also more common in raves (Strote et al., 2002; Gervin et al., 2001; Gerhard, 2001). These include alcohol, marijuana and opiates. Furthermore, the term “ecstasy”, which was originally used to refer specifically to MDMA, has grown to refer to other related compounds such as 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedix-oyethylamphetamine (MDE or Eve) (Gerhard, 2001). The com-bination of these variables increases the risks of adverse conse-quences associated with MDMA use (see later).

MDMA users generally limit the frequency of use of the drug. Most report limiting use of MDMA to twice per month or less. Fridays and Saturdays are the most common days of use be-cause users say they need 1 day to recover after use (Peroutka et al., 1988; Liester et al., 1992). More frequent use is associated with a loss of the desired effect of the drug (Gerhard et al., 2001).

Prior to its placement on Schedule 1 by the DEA, MDMA was considered as an adjunct to psychotherapy (Shulgin and Nichols, 1978; Greer and Tolbert, 1986, 1998). In this setting, a dosage of 50 to 200 mg (with modal doses ranging from 100 to 150 mg), with a booster of 50 to 75 mg several hours later, was used. There are no controlled studies of the use of MDMA in psychotherapy. However, there is one open study of 29 subjects in which the dosage used was 75 to 150 mg after a 6-hour fast with an offered second dose of 50 to 75 mg. All subjects reported posi-tive attitudinal and emotional changes. Twenty-two felt that their insight into their own psychopathology was enhanced. Twenty-one subjects in couples treatment reported increased closeness and communication with their partner (Greer and Tolbert, 1986). All subjects reported adverse consequences similar to those re-ported by recreational drug users. While the use of MDMA as a psychotherapeutic adjunct appears to have advocates (Greer and Tolbert, 1998), the documentation of neurotoxicity in humans (Reneman et al., 2002; McCann et al., 1998; Semple et al., 1999) makes such use dubious.

Pharmacology

MDMA is toxic to serotonergic neurons. Serotonergic loss is evident through several markers which include reduced brain serotonin, 5-hydroxyindoleacetic acid (5-HIAA), and the sero-tonin transporter. Immunocytochemical studies suggest that serotonergic neurons are damaged, but the cell bodies are pre-served. Recovery from MDMA-induced serotonergic damage can occur. In monkeys the damage persists at least 7 years. In hu-mans, serotonergic damage after repeated MDMA use is evident through several different types of studies. CSF 5-HIAA levels are reduced in MDMA users, an effect that is more pronounced in women than in men.

Diagnosis

A typical MDMA user is a college student. In a survey of 14 000 college students in 119 American colleges, MDMA users were more likely to use marijuana, smoke cigarettes and engage in binge alcohol consumption (Strote et al., 2002). They were also more likely to have multiple sex partners (Strote et al., 2002). They considered art and parties important, but they were not aca-demic underachievers.

Acute Positive Psychological Effects

Unlike many drugs of abuse which are frequently used alone, MDMA is almost always used in the company of others. Most MDMA users report positive mood and emotional effects as they relate to others. Experienced MDMA users report a greater ca-pacity for empathy, communication and understanding. Users also report increased self-esteem, high energy, relaxation, sen-sual awareness, euphoria and dissociation.

Physical Consequences of MDMA Use

Humans exhibit complications that are related to both the sym-pathomimetic and serotonergic properties of MDMA. These include nausea, vomiting, anorexia, hypertension, palpitations, diaphoresis, headaches, difficulty walking, muscle aches and ten-sion, hot and cold flashes, urinary urgency, nystagmus, blurred vision, insomnia and dry mouth. The common complaints of tris-mus and bruxism may reflect MDMA enhancement of serotonin activation of the 5HT_1B receptors of the trigeminal motor nuclei (Tancer and Johanson, 2001).

At least two MDMA-related deaths have been associated with automobiles (Hooft et al., 1994; Cifasi and Long, 1996).

Clinical Manifestations of Long-term of MDMA Neurotoxicity

Former chronic ecstasy users (an average of 527 tablets) have higher self-reported depression. The predictors of developing this depressive syndrome are maximum quantity of pills con-sumed over a 12-hour period and mild, frequent life stress. Heavy MDMA use has also been associated with higher rates of psychopathology including obsessive and compulsive be-haviors, anxiety, somatization and loss of libido. The relation-ship between MDMA use and these syndromes is unclear, but since these syndromes involve serotonergic mechanisms, additional investigation into these potential long-term sequelae is warranted. MDMA users have been noted to have problems with memory, attention, reasoning, impulse control and sleep abnormalities.

MDMA Somatic Toxicity

MDMA has been associated with a wide range of somatic toxic events. These include thrombotic or hemorrhagic strokes, leu-koencephalopathy, myocardial infarction, arrhythymias and pneumothorax. The wide range of manifestations suggests that most of these cases are either idiosyncratic or related to impu-rities remaining from the synthetic process. Since much of the MDMA supply is synthesized in small “basement” laboratories, the quality control of the manufacturing process may not be ad-equate. Cases of severe medical illness or death due to electrolyte and fluid are more likely due to MDMA use. These complica-tions may be related to the specific environment in raves. In raves people are exposed to hot, crowded environments. In association with the increased body temperature caused by MDMA dehy-dration and its consequences are likely. MDMA may also cause serotonergic hyperstimulation and produce a fatal serotonin syndrome-like (illness).

Treatment

There have been no studies examining the treatment of MDMA use. The issue of how a practitioner may help his/her patient dis-continue MDMA use is never addressed in the literature. This may be due to the rarity of presentation of subjects seeking treat-ment for MDMA addiction. Serotonin reuptake inhibiting antide-pressants may offer a possible treatment for subjects who present with an MDMA addiction.