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MDMA (Ecstasy):

Does It Play A Causal Role In Nephropathy?

A Review

John Podraza, Department of Biological Sciences, Hartwick College, Oneonta, New York


The increasing recreational use of MDMA (methylenedioxymethamphetamine) and its presumed toxic effects have alarmed many forensic and emergency medical personnel (Fineschi and Masti, 1996). Numerous cases have been reported in the literature proposing ecstasy-induced renal damage. A focus will be given to forty-three cases where ecstasy ingestion has resulted in medical intervention. The nephrotoxic potential of MDMA in both the animal and the human will be reviewed with a focus on the drug’s mechanism of action.


The drug MDMA is classified as an entactogen by Merck (1996) and chemically resembles a hybrid of amphetamine and mescaline (Hardman et al., 1973). There are two separate and distinct groups associated with the use of the drug. First is the medical discipline involved with psychotherapy where MDMA is used as an adjunct to treat the "physical pain and emotional stress associated with severe medical illness, post-traumatic stress disorders, depression, phobias, addictions, psychosomatic disorders and relationship (marital) problems" (Grob and Poland, 1997).

Recreational users compose the second group and a number of reported complications have been associated with use of the drug in this context. Complications include hepatotoxicity (Andreu et al., 1998; Dykhuizen et al., 1995; Fidler et al., 1996; Henry et al., 1992; Jones et al., 1994; Pereira et al., 1997; Roques et al., 1998), inflammatory CNS disease (Bitsch et al., 1996), intracranial hemorrhage (Harries and DeSilva, 1992; Hughes et al., 1993; McEvoy et al., 1998), cardiac abnormalities (Brody et al., 1998; Massari et al., 1995; Suarez and Riemersma, 1988), pneumomediastinum (Levine et al., 1993), aplastic anemia (Marsh et al., 1994), and finally nephrotoxicity (see table I). A neurotoxic effect has also been proposed and has consumed the majority of MDMA’s research attention (Green and Goodwin, 1996; Huether et al., 1997; McCann and Ricaurte, 1991; McCann et al., 1994; McCann et al., 1998; Ricaurte and McCann, 1994-1995; Simantov and Tauber, 1997). An important observation is that none of these complications have ever been attributed to the use of MDMA in the psychotherapy setting.

MDMA vs. Ecstasy

While many researchers have hypothesized to why there is such a broad difference in observed toxic effects, the primary dispute is one of nomenclature. The term ecstasy is not automatically interchangeable with MDMA. While medical research is conducted using pure MDMA, ecstasy tablets sold on the street frequently contain other substances. The clandestine manufacture of ecstasy often leads to the intentional, as well as accidental, introduction of contaminants into the tablets (Ziporyn, 1986). An ecstasy tablet can range anywhere from having no hallucinogenic or stimulant substances what so ever, to being, although rarely so, pure methylenedioxymethamphetamine. Contaminants include chalk, paracetamol, lysergic acid (LSD), amphetamines (speed), heroin (smack) (Day, 1996), caffeine, methamphetamine (ice), methylenedioxyamphetamine (MDA; love), ketamine (special K) (Wolff et al., 1995), N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), methylenedioxyethamphetamine (MDEA; Eve), 4-bromo-2,5-dimethoxyphenylethylamine (2C-B; Venus) (Giroud et al., 1998), ephedrine, pseudoephedrine, and triprolidine (Milroy et al., 1996). Medical clinicians often hypothesize that the reported adverse reactions associated with ecstasy consumption can be attributable to one or more of these contaminants.

Various catastrophes have been reported with regards to ecstasy's applied terminology and interaction with other substances. Tillman et al. (1997) described a case where several persons ingested what they thought to be MDA, a psychoactive substance similar in effect to MDMA. Unfortunately this MDA was methylene dianiline p,p’- diaminodiphenylmethane, an hepatotoxic material used in the preparation of polyurethane foams. Similar misconceptions have been reported with the use of ‘liquid ecstasy’ (GHB; gamma-hydroxybutyrate) a highly toxic substance (Thomas et al., 1997), and ‘herbal ecstasy’, an all natural alternative. In 1996 Deb Josefson, a physician journalist, reported that "fifteen deaths among young people in the US have been attributable to the herbal stimulant ephedra...marketed as a safe and legal alternative to street drugs under names such as Herbal Ecstasy..." The recreational use of ecstasy also has the potential for disastrous effects in patients who fail to disclose previous drug use on medical history forms. Henry and Hill (1998) noted that ecstasy can have a fatal interaction with prescription drugs including ritonavir, an HIV medication, and Nencini et al. (1988) indicated that MDMA can enhance the analgesic properties of morphine injections.

Numerous other factors can be attributable to the adverse reactions from ecstasy not seen in the psychotherapy setting. These include high ambient temperatures, aggregation (crowding), elevated activity levels (dancing/sex), dehydration, and pre-existing medical conditions. Genetic susceptibility has also been proposed by Tucker et al. (1994). They conducted a study showing that the debrisoquine hydroxylase enzyme (CYP2D6) in the liver is responsible for the demethylation of MDMA. Because approximately 5-9% of the Caucasian population is deficient in the p450 family of enzymes, of which CYP2D6 is a member, this could lead to an increased toxic risk to those individuals. Several reports have shown extreme levels of MDMA present in the body without severe complications (Henry et al., 1992; Ramcharan et al., 1998). This is further evidence for a difference in metabolism of the drug among individuals. Multiple drug use also poses a problem, but medical reports showing MDMA present in the blood regularly attribute the negative outcome to ecstasy. Crifasi and Long (1996) reported the case of a 29 year old male who operated a motor vehicle inappropriately while under the influence of MDMA. They stated that unlike other reports, their case was uncomplicated by other drugs. However, later on in the report Crifasi and Long stated that the operator’s urine screen tested positive for amphetamines and cannabinoids.

Therapeutic Use vs. Recreational Use

It is important to make several main distinctions between the controlled use of MDMA in psychotherapy and the patterns observed in the recreational use of ecstasy. The preferred psychotherapeutic dose of MDMA is in the 100-150 mg range with dosing in clinical experiments conducted up to a maximum of 2.5 mg/kg (R. Doblin, pers. comm.). In 1996 however, McCann et al. reported that "in the setting of raves, it is not uncommon for an individual to take up to 8 MDMA tablets or capsules [approximately 800 mg] in one night, once a week." McCann et al. completed another study in 1998 focusing on 14 exceptionally heavy recreational users and showed that the average dose and time course of MDMA was 386 mg, 6 times a month. Another important distinction is the setting in which the use of MDMA takes place. While therapists administer MDMA in a controlled clinical setting, recreational users taking MDMA at raves and nightclubs are frequently exposed to hot, poorly ventilated conditions which are often further compounded by limited water availability and the consumption of alcohol. The realization of these poor recreational conditions has influenced some event organizers to provide chill out rooms where MDMA users can go to cool off. Despite these efforts, the immense differences still prevalent in dose, time course, and setting of recreational MDMA usage versus that seen in psychotherapy may also be responsible for the observed toxic effects.


MDMA has often been erroneously reported in the literature to have been synthesized in 1912 as an appetite suppressant by Merck Laboratories, Germany. In truth, MDMA was an unplanned side reaction that occurred while Merck was trying to synthesize Hydrastinin, a vasoconstrictor (Gamma, 1998). MDMA was subsequently patented in 1914 (Merck, 1914), but with the outbreak of World War I received little investigational attention into the drug’s potential applications (Shulgin and Shulgin, 1991). Grob and Poland (1997) tell of how MDMA came on the scene in the US in the early 1950’s and was tested by the US Army in animals. Alexander Shulgin, a Berkeley biochemist, is believed to have introduced the drug to the psychotherapeutic scene after self-administering the drug and testifying to MDMA’s rehabilitative potential (Shulgin and Shulgin, 1991; Shulgin and Nichols, 1978). After several years of responsible and controlled use by psychiatrists (Greer, 1985; Greer and Tolbert, 1986; Greer and Strassman, 1985), abuse patterns began to develop by recreational users (Grob and Poland, 1997). The drug quickly gained in popularity and before long received the attention of the media and the US Drug Enforcement Agency (DEA). Concerns over the safety of MDMA grew after Ricaurte et al. (1985) published a report stating that MDA (methylenedioxyamphet-amine), a precursor to MDMA, damaged serotonin brain cells in animals. Despite a very controversial and hotly debated battle in court, in 1986 the DEA classified MDMA as a Schedule I substance, making the drug off limits to both practitioners and recreational users alike (Young, 1985; Young, 1986; Lawn, 1986).

Since that time, MDMA has grown in popularity as a recreational drug, especially on the college and rave scenes (Henry et al., 1992; Randall, 1992; Gerada and Ashworth, 1997; Roberts et al., 1997; Nielsen et al., 1995; Schuster et al., 1998; Schwartz and Miller, 1997; Webb et al., 1996; Wright and Pearl, 1995). The National Household Survey on Drug Abuse (NHSDA), conducted by the Substance Abuse and Mental Health Services Administration (SAMHSA) in conjunction with the National Institute for Drug Abuse (NIDA), estimated that in 1995 and 1996 over 6.5 million people in the US age 12 and higher were lifetime users of ecstasy. In 1997 of the 216 million people represented, 1.5% were lifetime users; the highest percentages coming from the 18 to 25 year old age bracket.

The controversial use of ecstasy is not a problem limited to the United States, many other countries have struggled with the same dilemma. In Europe as of 1997, MDMA was number two on the list of most commonly used illicit drugs (United Nations, 1997).

Since the scheduling of MDMA, many psychotherapists have struggled to regain use of the drug in therapy. Dr. Charles Grob and Dr. Russell Poland, both of the Harbor-UCLA Medical Center, have been granted permission to undergo human research into the psychobiologic effects of MDMA (Dr. Grob, pers. comm.). The FDA has also approved the psychotherapeutic use of MDMA in cancer patients (R. Doblin, pers. comm.). Dr. Franz Vollenweider of Switzerland has likewise persevered for the right to study MDMA in his country (R. Doblin, pers. comm.). Most recently, the Multidisciplinary Association for Psychedelic Studies (MAPS) has planned a conference in Israel for late August 1999, in order to facilitate possible MDMA research in the treatment of post-traumatic stress disorder (PTSD) at Ben-Gurion University of the Negev. Similar research with MDMA in PTSD treatment has been proposed by Jose Bouso, Ph.D. candidate of the Psychiatric Hospital of Madrid, Spain, and is currently being reviewed for approval (R. Doblin, pers. comm.).

Toxicity in Animals

One of the arguments for the scheduling of MDMA was the lack of toxicology data on the substance (Lawn, 1986). Since then, researchers have scrambled to evaluate the possible toxicity of MDMA in humans. However, with MDMA being a schedule I narcotic, obtaining approval for such studies has been rather difficult. While several important human studies have been conducted, the majority of MDMA research has been in animals where government approval has been more easily obtained.

Hardman et al. (1973) conducted one of the first toxicology studies of MDMA in the 1950’s in order to determine the drug’s LD50 (lethal dose) in 5 different mammalian species. Aside from various behavioral observations, the authors made no reference to MDMA’s toxicity to the kidneys. In 1987, Frith et al. conducted an important and more extensive toxicological evaluation of MDMA on the dog and the rat, meeting the FDA’s pre- clinical research require-ments necessary before phase 1 and phase 2 human studies could begin (R. Doblin, pers. comm.). Alterations in blood urea nitrogen (BUN) and creatinine were observed with varying dose, both indicators of impaired renal function (see table I). The authors also noted that there was a decreased kidney weight in the male rats but an increased kidney weight to body weight ratio for both sexes of rat. Frith et al. further noted a list of histopathologic lesions in the rat including mineralization, hydronephrosis, calculi, infarct, inflammation, and chronic progressive nephropathy of the kidneys. However, the authors state, "these lesions are considered to represent the normal spectrum of spontaneous lesions in rats. No treatment-related microscopic lesions were evident."

Other studies have shown that MDMA can elevate the core body temperature of the laboratory rat (Dafters, 1995; Schmidt et al., 1990; Gordon et al., 1991; Nash et al., 1988), and many suspect that this induced hyperthermia is responsible when altered renal status is observed. Lalich (1947) showed how dehydration, secondary to hyperthermia, can be a causal factor in the induced renal failure of animals. Burger and Fuhrman (1964) showed how animal tissues, including the renal cortex, are susceptible to thermally-induced damage.

Researchers have struggled to evaluate whether the induced hyperthermia from MDMA is intensified by various stimuli. Dafters’ (1995) study indicated that water consumption and ambient temperature had a direct capacity to enhance or attenuate the hyperthermic reaction. When MDMA was administered at 11° C, the hyperthermia was negligible. However, water deprivation in conjunction with an ambient temperature of 30° C significantly increased the hyperthermia. In a very interesting study, Malberg and Seiden (1998) showed that a high ambient temperature has a greater effect on raising the core body temperature of rats administered MDMA over those receiving saline only.

A study by Gordon and Fogelson (1994) implicated that the cage design for animals in MDMA studies may be responsible for the hyperthermia observed. The authors report how MDMA, at 30mg/kg, increased the core body temperature of rats by greater than 2.0° C when kept in acrylic cages but had no effect in wire-screen cages. Despite these results, hyperthermia in association with MDMA administration is still a concern for many clinicians.

One important study by Burns et al. (1996) showed that MDMA administered to rats activated the renin-angiotensin-aldosterone system. This system is controlled primarily by the juxtaglomerular cells of the kidney, but the lungs, liver, and adrenal cortex also play important roles. The implications for this study will be discussed later on, as the renin-angiotensin-aldosterone system has a consequential position in the etiology of human toxicity to MDMA.

Toxicity in Humans

Numerous cases have been reported in the literature proclaiming that ecstasy is toxic to the kidneys. A compilation of renal function indicators (see table II) was used to review forty-three cases (see table I) where the recreational use of ecstasy led to some form of medical intervention. A majority of these cases showed several signs of impaired renal function. The major clinical signs observed included: hyperthermia, hyperkalemia, hyponatremia, hypo-calcemia, elevated blood urea nitrogen (BUN) and creatinine (not shown), elevated creatinine kinase, rhabdomyolysis, myoglobinuria, disseminated intravascular coagulation (DIC), oliguria, acidosis, and acute renal failure (ARF). Interestingly, all of the previously described signs and symptoms correspond directly to complications associated with heat stress and exercise (Shrier et al., 1967). However, hyperthermia was not observed in all cases but this may simply be due to a prolonged time frame between the onset of illness and the seeking of medical attention. In 1996, Hall et al. stated, "the cases reported in the literature with a full complement of these features [hyperthermia, rhabdomyolysis, DIC, ARF] mainly have a fatal outcome." Fortunately, only thirteen of the forty-three cases reviewed here were fatal, the cause of death frequently being complicated by varying treatment strategies.

Several cases of amphetamine abuse have also been included in table II showing the close comparisons with ecstasy ingestion. Urinary tract retention (case 1) is a complication similar in pathogenesis to that of intravenous amphetamine abuse (Bakir and Dunea, 1996). Rhabdomyolysis is also associated with the use of amphetamines (Scandling and Spital, 1982; Kendrick et al., 1977) and is diagnosed in the presence of an elevated creatinine kinase (CK), serum potassium, uric acid, calcium, abnormal serum glutamic- oxalacetic transaminase (SGOT), and the presence of myoglobinuria (Knochel, 1981; Koeffler et al., 1976; Grossman et al., 1974).


Unfortunately when the recreational use of ecstasy is associated with complications like DIC and oliguria secondary to heat stress and exercise, potentially dangerous procedures such as a biopsy are often contraindicated (Ginsberg et al., 1970; Schrier et al., 1967). However, a few biopsies/autopsies were performed and have provided valuable information into the similarities between ecstasy-induced versus heat stress and/or amphetamine-induced renal tissue damage.

Biopsies were performed in cases 2, 6, and 12 and autopsies were conducted in cases 6, 8, 9, and 11. The results of the biopsies showed a range of histopathological damage to the kidneys including: extensive tubular degeneration and necrosis, interstitial edema and hemorrhage, small vessel occlusion, and the infiltration of leukocytes in the renal medulla. The glomeruli appeared to receive the most damage exhibiting either partial or complete infarction, loss of epithelial cell foot processes, denudation of the basement membrane, disarray of cellular organelles, vacuolization of the cytoplasm, and degeneration of the luminal microvilli. It should be noted however, that atypical changes in the human glomeruli are frequently observed in the healthy state (Osawa et al., 1966; Jorgensen, 1966) and often not observed after exposure to thermal stress (Shrier et al., 1967; Malamud et al., 1946; Vertel and Knochel, 1967; Baxter and Teschan, 1958; Knochel et al., 1961). The autopsies undertaken showed macroscopically normal kidneys but some exhibited healed arteritis and the presence of myoglobin in the renal vessels. Several reports also noted DIC-induced damage to other organs. Thrombi were observed occluding vessels of the heart and lungs (Bingham et al., 1998; Fineschi and Masti, 1996) and type II muscle fiber atrophy was noted (Chadwick et al., 1991).

The renal tissue damage reported above closely resembles tissue damage caused by accelerated hypertension (Woodrow et al., 1995), abuse of amphetamines, heroin, and cocaine (Bakir and Dunea, 1996; Bingham et al., 1998; Citron et al., 1970; Dar and McBrien, 1996; Rajs and Falconer, 1992; Karch and Billingham, 1986), and most importantly heat stroke (Sobel et al., 1963; Kew et al., 1967).

Mechanism of Action

An overwhelming similarity observed in most cases of MDMA-induced renal failure is the onset of hyperthermia. In amphetamine and methamphetamine abuse, we know that it is heat injury that plays the causal role in associated renal failure and coagulopathy (Gary and Saidi, 1979). It has also been shown that heat injury from any source can cause rhabdomyolysis, coagulopathy, and multiple organ failure (Dar and McBrien, 1996). Therefore it would seem reasonable to postulate that the hyperthermia induced by MDMA is responsible for the resultant renal damage especially when one observes the striking resemblance in the etiology of these cases to that of heatstroke (Schrier et al., 1967; Malamud et al., 1946; Gore and Isaacson, 1949; Kew et al., 1969; Kew et al., 1970; Bianchi et al., 1972; Chao et al., 1981; Rubel and Ishak, 1983).

When the MDMA-induced hyperthermia is further compounded by the extreme environmental factors associated with its use recreationally, a life threatening situation quickly develops. Cunningham (1997) suggests that ecstasy induces rhabdomyolysis secondary to hyperpyrexia and possibly extreme oxygen/energy consumption (from dancing) and crush injury (due to lying unconscious for several hours). Rhabdomyolysis is a hypercatabolic state where the massive breakdown of muscle is characterized by muscle pain, weakness, and brown urine. Muscle cells contain a variety of proteins, enzymes, and electrolytes including: glycogen (for energy), myoglobin (for oxidation), creatinine kinase, potassium, and phosphate (Saladin, 1998). When a muscle cell is damaged, sodium, calcium, and water from the extracellular fluid (ECF) enter the cell while myoglobin, creatinine kinase, and potassium leak out (Davies, 1995). It is this exchange of enzymes, protein, and electrolytes across the cell membrane that gives rise to the hyperkalemia, hyponatremia, hypocalcemia, and elevated creatinine kinase levels seen in cases of MDMA ingestion.

Rhabdomyolysis also causes myoglobinuria. When myoglobin is released from a muscle cell, it is subsequently picked up by the kidneys and excreted in the urine turning it brown, hence myoglobinuria. In the healthy state, the human body has a constant, yet minimal, outflow of myoglobin in the urine. However, when the urinary pH is less than 5.6, as with metabolic acidosis, the myoglobin protein becomes toxic to the kidneys by forming a precipitate (myoglobin cast) that consequently occludes the renal tubules (Davies, 1995). However, as seen in table I, myoglobinuria is very transient and often not observed even in the presence of rhabdomyolysis (Cadier and Clarke, 1993; Fahal et al., 1992). Also, myoglobinuria has been associated with exercise in the absence of substantial heat injury or renal failure (Schrier et al., 1967). Therefore, a presumptive diagnosis of renal impairment should not be made in the presence of myoglobinuria alone.

Metabolic acidosis related to ecstasy ingestion may be responsible for various symptoms cited in the literature and is probably caused by multiple events. Saladin (1998) describes how acidosis can depress the central nervous system causing confusion, disorientation, and even coma. The increased number of potassium ions in the ECF (hyperkalemia), from muscle cell degradation, begins to acidify the blood. Interestingly, potassium ions can then diffuse into other cells, displacing hydrogen ions, thus lowering the pH even further. In many cases of ecstasy toxicity, the acidosis is further compounded when an elevated activity level increases the production of lactic acid. Also, when dysentery is present, alkaline bases are excreted and the acidosis can quickly become difficult to control.

Hyperkalemia itself is a dangerous state in the human body and can also be challenging to manage with ecstasy consumption. Elevated serum potassium levels have the potential to cause fatal cardiac arrhythmias. Also, if renal tubule necrosis develops, hyperkalemia becomes even more pronounced as the tubules fail to excrete appropriate levels of potassium and blood potassium rises further (Cunningham, 1997). This can lead to a dangerous positive feedback loop as an acidic state can aggrandize the hyperkalemia when the kidneys preferentially excrete acidic protons over potassium ions.

The combination of hyperpyrexia and the resulting rhabdomyolysis can then lead to disseminated intravascular coagulation (DIC) (Fineshi and Masti, 1996; Screaton et al., 1992; Larner, 1992; Henry et al., 1992; Ferrara et al., 1995; Cimbura, 1972; Reed et al., 1972; Poklis et al., 1979; Lukaszewski, 1979; Nichols et al., 1990; Forrest et al., 1994; Fahal et al., 1992). A mechanism for the temperature-induced DIC was suggested by Ginsberg et al (1970) after examining a case of amphetamine intoxication. The authors noticed that platelet counts did not reach their lowest levels until several days after thermic insult. Because platelets have a life-span of 3-4 days, this observation suggested hyperthermically-induced damage to the megakaryocyte, the platelet mother cell. DIC is diagnosed when a platelet count below 100,000/mm3, fibrinogen below 40mg/100ml (Ginsberg et al., 1970), and a prothrombin time less than 12.5 sec. is observed (see table I). DIC can lead to microvascular obstruction as fibrin- platelet complexes form on the inside walls of blood vessels. This obstruction could potentially effect any organ including the kidney, in which case it would cause ischemia and eventually necrosis (Fahal et al., 1992). It may also cause a lesion similar to that seen in thrombotic thrombocytopenic purpura (Eknoyan and Riggs, 1986).

Hyperthermia also has the potential to induce a state of dehydration especially when combined with elevated activity levels, inefficient fluid replacement, and the consumption of alcohol. A low blood pressure and high blood osmolarity subsequently develop and in conjunction with hyponatremia activates the renin-angiotensin mechanism (Saladin, 1998). The main focus of this mechanism is to stabilize glomerular filtration rate allowing for a steady excretion of toxic nitrogenous wastes from the body. Interestingly, the use of MDMA has been shown in rats to further enhance the activation of this system (Burns et al., 1996). In the renin-angiotensin mechanism, the JG cells of the kidney release the enzyme renin and through a series of metabolic steps, the hormone angiotensin II is produced. Angiotensin II then stimulates vasoconstriction which restricts renal blood flow. In the healthy state this restriction should not effect waste excretion. Although in the case of MDMA, elevated serum levels of urea nitrogen and creatinine are observed suggesting impaired glomerular blood flow possibly due to coagulopathy. Angiotensin II also produces an increased re-absorption of water which can lead to an oliguric state (urine output of less then 500ml/day). Prolonged oliguria is an additional cause of azotemia, the buildup of toxic nitrogenous wastes in the blood, and may also be the result of necrotizing glomerulonephritis, renal vascular breakdown, or excretory obstruction (Loughridge et al., 1960). Furthermore, Angiotensin II, in conjunction with hyperkalemia and hyponatremia, stimulates the adrenal cortex to secrete aldosterone. Aldosterone consequently enhances the re-absorption of sodium (and therefore water) and excretion of potassium at the distal convoluted tubule and collecting duct of the kidney thus elevating blood pressure.

Angiotensin II also creates a feeling of thirst in an attempt to stimulate the body towards re-hydration. However, due to the psychoactivity of MDMA, this feeling may be dangerously enhanced or attenuated. When excessive water intake is observed, a severe acute hyponatremic state frequently develops (Bingham et al., 1998; Maxwell et al., 1993; Satchell and Connaughton, 1994; Williams and Unwin, 1997; Matthai et al., 1996). Sjoblom et al. (1997) argue that water intoxication should not cause hyponatremia unless renal function is impaired or an increase in anti-diuretic hormone (ADH) secretion is observed. In 1998, Henry et al. conducted a study in humans showing that a single dose of 47.5mg of MDMA did in fact increase the baseline arginine vasopressin (AVP; ADH) concentration which saw a consequent reduction in sodium concentration. In 1993, Maxwell et al. diagnosed a woman with syndrome of inappropriate anti-diuretic hormone secretion (SIADH) after MDMA consumption but were beleaguered by the fact that she drank five liters of water, developed dilutional hyponatremia, but then did not respond by diuresis. This appears rational as MDMA has been shown to cause massive releases of serotonin in the brain and we know ADH secretion is regulated by serotonin (Iovino and Steardo, 1985). The protocol for the diagnosis of SIADH is an elevated urine osmolality and sodium excretion with a low blood osmalility and sodium content (Satchell and Connaughton, 1994).

The Serotonin Syndrome

A number of articles reporting on the adverse reactions associated with the use of ecstasy in the recreational setting have implicated the serotonin syndrome. Sternbach (1991) and Bodner et al. (1995) tell us that the syndrome is diagnosed when a known central serotonergic agent is administered resulting in at least three of the following complications: "mental status or behavioral change (confusion, agitation, hypomania, coma), alteration in muscle tone or neuromuscular activity (incoordination, shivering, tremor, hyperreflexia, myoclonus, rigidity), autonomic instability (diaphoresis, tachycardia, hypertension, hypotension), hyperpyrexia, and diarrhea." They also state that when the serotonin syndrome can be diagnosed in the presence of elevated temperature possible complications include DIC, rhabdomyolysis, cardiac dysrhythmias, renal failure, seizures, coma, and death. The syndrome has been specifically diagnosed in several cases reported here (Dar and McBrien, 1996; Green et al., 1995; Huether et al., 1997), and appears to be an accurate deduction considering that MDMA is a known central serotonergic agent.


After careful and critical evaluation of all available data, and in the absence of a definitive study focusing specifically on the kidneys, one can only deduce that MDMA is not a direct nephrotoxin. While the drug does play ‘a’ causal role, MDMA does not play ‘the’ causal role in nephropathy. In fact, when impaired renal function is observed after the ingestion of ecstasy, multiple factors are to blame. The only true causal role that MDMA plays is to induce a hyperpyrexic state. If the developing hyperthermia is further compounded by predisposing conditions (Hall, 1997), high ambient temperatures, crowding (aggregation), loud noise, alcohol/multi-drug use, inefficient fluid replacement, and elevated activity levels only then might the kidneys respond via ineffective functioning. Of course, these conditions only increase the possibility for impaired renal performance and may in fact lead to other complications or even no adverse reaction what-so-ever (Logan et al., 1993). We must also remind ourselves however, that genetic susceptibility and the ever abounding impurities in the street drug may increase the observed toxicity although MDMA is not to blame.

Research In Progress

A study is currently in progress by the author focusing closely on the effects of MDMA administration and its influence on kidney function in the rat. MDMA is being administered at 2.5 & 5.0 mg/kg p.o. once weekly for 7 weeks in an environmentally controlled atmosphere. The main purpose of the study is to examine whether changes in renal clearance, renal vasculature, and renal tissue integrity are observed with MDMA administration in the absence of the environmental factors frequently associated with the adverse reactions seen recreationally in humans.

Acknowledgments: This work was funded by a research grant from the Multidisciplinary Association for Psychedelic Studies, Inc. Special thanks is given to Mr. Rick Doblin for his expert critique on this manuscript. Appreciation is also given to Dr. Allen Crooker for his inspiration, and Prof. Mary Whitlock & Ms. Alison Whitlock for their administrative assistance.

Address inquiries to:

John Podraza
Hartwick College
888 Hartwick Dr.
Oneonta, NY 13820


Table I: Toxicity in Humans



Dose & Environment


Blood MDMA





15 tablets of E in 36 h.

urinary tract retention



Bryden et al., 1995


37 M

E at rave

­ BP, apyrexial, Ol, R, DIC, ARF


hemodialysis dependent

Woodrow et al., 1995


23 M

1 tablet of E, some amph.

T. 40C, NBP, DIC, R, ARF, Ol, no Mu, Ac


& Amph.


hemofiltration for 21 days, RTN

Barrett and Taylor, 1993


18 M

3 tablets of E at concert

T. 42C, DIC, R



Campkin and Davies, 1992


32 F

100 - 150mg of E

T. 41.6C, DIC, ¯ BP, Ol, R



Brown and Osterloh, 1987


30 M

10 days after taking E at party

BP 190/100, ARF, apyrexial, fluid overload, ­ K+


hemodialysis died of cardiac arrest

Bingham et al., 1998


19 M

several tablets of E & amph. at rave

T. 40C, ARF, R, burn patient


hemodialysis, RTN

Cadier and Clarke, 1993


16 F

1 tablet of E

T. 42C, ¯ BP, DIC, no R, Ac

0.424mg/l stomach 28.0mg/l

hemofiltration, deceased

Chadwick et al., 1991


17 M

10 tablets of E and alcohol at club

T. 42C, ¯ BP, DIC, ­ K+, Ac, Ol



Dar and McBrien, 1996


23 M

3 tablets of E at rave

T. 40C, DIC, Ol, ARF, NBP, no Mu,

0.2mg/l & Amph.

Hemofiltration for 20 days

Fahal et al., 1992


20 M

several tablets of E at club

T. 40C, Mu, DIC & R

0.185ug/ml & MDEA


Fineschi and Masti, 1996


32 M

regular use of amphetamines

T. 37C, ARF, no DIC, no R, ­ K+


hemodialysis, RTN

Foley et al., 1984


21 M

2g of amphetamine

  1. 42C, ARF, Ol, DIC



Ginsberg et al., 1970


26 M paraplegic

1 tablet of E

T. 41C, ¯ BP, DIC, Ol, ARF, CK 555,000



Hall et al., 1996


23 M

4 tablets of E and amphetamines at club

T. 42C, Ac, DIC, no Mu, CK 7,540



Logan et al., 1993


17 F

1.5 tablets of E

apyrexial, incontinent, dehydrated, ¯ Na+



Maxwell et al., 1993


17 F

1 tablet of E

apyrexial, drank 5 liters of water, incontinent, ¯ Na+, SIADH

0.05 mg/l


Maxwell et al., 1993


24 M

200mg of E

T. 40.2C, CK 96,550 R



Singarajah and Lavies, 1992


13 mo. M

1 tablet of E




Bedford Russell et al., 1992


19 F





Nimmo et al., 1993


20 M

18 tablets of E




Roberts et al., 1993


20 F

2 tablets of E

T. 42C, ¯ BP, ­ K+



Mueller and Korey, 1998


21 M

7 tablets of E, some amph. and alcohol at club

T. 42C, ¯ BP, Ac, Mu, DIC, ¯ Ca+, Ol, ARF, CK 122,34



hemodialysis for 45 days, RTN

Murthy et al., 1997


30 M

50 tablets of E, oxazepam, & alcohol

T. 38.7C, ¯ Ca+, ­ CPK

stomach 2800mg


Ramcharan et al., 1998


18 M

3 tablets of E at club

T. 41.8C, ¯ BP



Henry et al., 1992


17 M

2 tablets of E at party

T. 41C, DIC



Henry et al., 1992


18 M

5 tablets of E at party

T. 42.1C



Henry et al., 1992


21 F

several tablets of E at party

T. 41C, DIC, R, ARF


died after liver transplant

Henry et al., 1992


20 M


T. 40C, ¯ BP, DIC, R, ARF


& MDA & Amph.


Henry et al., 1992


20 M

3 tablets of E at club

T. 40C, DIC, R, ARF

0.24 mg/l MDA, MDEA, & Amph.


Henry et al., 1992


24 F

1 tablet of E at rave

T. 38C, ¯ Na+, CK 45,000, no Mu, SIADH

0.05mg/l Amph.


Satchell and Connaughton, 1994


19 M

MDMA at club

T. 43.3C, DIC, R, Mu, CK 44,500

MDMA & Amph.


Screaton et al., 1992


19 M

MDMA at club

T. 41C, DIC, R, CK 29,700, creatinine 250umol/l



Screaton et al., 1992


19 M

3 tablets of E at club

T. 40C, DIC, R, CK 3,940



Screaton et al., 1992


33 F

65mg of E

T. 41.6C, R, ARF



Hayner and McKinney, 1986


20 M

2 tablets of E & amph. at club

T. 40.2C, CK 59,700 ¯ BP, DIC, Ol, Ac, ­ K+, ¯ Ca+, no Mu

MDEA & Amph.


Tehan et al., 1993


33 M

0.25 tablet of E & alcohol at party

afebrile, ¯ Na+, CK 112,000



Williams and Unwin, 1997


25 F

1 tablet of E & alcohol at party

T. 41.9C, hypoglycemic, DIC, CK 99,700



Williams and Unwin, 1997



amph. & cannabis at disco

T. 41C, ¯ BP, R, DIC, ARF, CK 33,000

amph. & pseudo-ephedrine

liver damage

Jones et al., 1994



amph., ecstasy, & alcohol at rave

T. 42C, R, DIC, CK 50,000, ­ creatinine

MDA & amph.

liver damage

Jones et al., 1994



3 tablets of E

T. 41.9C, R, DIC, hypoglycemic



Montgomery and Myerson, 1997

Ac = acidosis, Amph. = amphetamine, ARF = acute renal failure, BP = blood pressure, Ca+ = calcium, CK = creatinine kinase (IU/L), DIC = disseminated intravascular coagulation, E = ecstasy, K+ = potassium, MDEA = methylenedioxyethamphetamine, Mu = myoglobinuria, Na+ = sodium, NBP = normal blood pressure, Ol = oliguria, R = rhabdomyolysis, RTN = returned to normal, SIADH = syndrome of inefficient anti-diuretic hormone secretion, T = temperature,

*Authors specifically state that renal function was unaffected.

**Fahal et al. (1992) suggest that a blood MDMA level ³ 0.2mg/l is definitive of serious toxicity. Bost (1995) supports this conclusion stating a fatal range of 0.95 to 2.0mg/l.



Table II: Renal Function Indicators Adapted from Saladin (1998) and Marieb (1995).



Normal Range




15-120m g/dl; 12-65m mol/l

renal failure



7-26mg/dl; 2.5-9.3mmol/l

renal disease, dehydration, urinary obstruction



0.5-1.2mg/dl; 44-97m mol/l

renal disease



285-295mOsm/kg H20

kidney disease, hypernatremia, dehydration

SIADH, hyponatremia, overhydration


2.5-4.5mg/dl; 0.8-1.5mmol/l

renal failure, hypocalcemia



3.5-5.1mEq/l; 3.5-5.1mmol/l

renal disease


Total Protein

6.0-8.0g/dl; 60-80g/l


diarrhea, renal failure


136-145mEq/l; 136-145mmol/l


SIADH, diarrhea, overhydration


Uric Acid








impaired renal function














renal disease

Partial Thromboplastin Time(PTT)*


Activated (APTT)



early DIC

Platelet Count*




Prothrombin Time (PT)*






not present


renal disease



50-1400mOsm/kg H20

hypernatremia, SIADH, acidosis

renal tubular necrosis


80-90% reabsorbed

renal disease



25-120mEq/24 hr

renal disease

acute renal failure, SIADH



nephrotic syndrome



40-220mEq/24 hr


renal failure

Uric Acid

0.4-1.0g/24 hr

1.5-4.0mmol/24 hr


renal disease


yellow, amber

(darker) dehydration

(lighter) overhydration

Specific Gravity



SIADH, decreased

renal blood flow

renal disease


1000-2000ml/24 hr

renal disease

SIADH, renal disease


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