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Hyponatremia Associated with 3,4-Methylenedioxymethylamphetamine (“Ecstasy”) Abuse

      ABSTRACT

      We present a case of acute, symptomatic hyponatremia in a young woman that developed after use of 3,4-methylenedioxymethylamphetamine (MDMA), more commonly known as “ecstasy.” The patient was treated with 5% saline and had complete recovery. The pathogenesis of MDMA-associated hyponatremia involves excessive water intake and inappropriately elevated antidiuretic hormone (ADH) levels. It seems that young, premenopausal women are at particularly high risk for the development of severe, symptomatic hyponatremia after use of this drug. Review of the literature revealed 4 fatal outcomes from MDMA-associated hyponatremia. All were women and all died from cerebellar tonsillar herniation. We suggest that acute hyponatremia that develops after MDMA use may be a life-threatening condition. Recent recommendation that MDMA users should drink large volumes of water may not be appropriate.

      KEY INDEXING TERMS

      Recreational use of 3,4-methylenedioxymethylamphetamine (MDMA), better known as “ecstasy,” has gained increasing popularity among young people.
      • Vastag B.
      Ecstasy experts want realistic messages.
      • O’Connor B.
      Hazards associated with the recreational drug ‘ecstasy’.
      It is commonly abused at “rave” parties, usually with intense dancing in a relatively hot environment. Serious short- and long-term complications, including death, have been reported with use of this agent.
      • O’Connor B.
      Hazards associated with the recreational drug ‘ecstasy’.
      • Burgess C.
      • O’Donohoe A.
      • Gill M.
      Agony and ecstasy: a review of MDMA effects and toxicity.
      • Brown C.
      • Osterloh J.
      Multiple severe complications from recreational ingestion of MDMA (‘ecstasy’).
      Although first described by Maxwell in 1993, the association of MDMA with hyponatremia is not widely appreciated.
      • Maxwell D.L.
      • Polkey M.I.
      • Henry J.A.
      Hyponatraemia and catatonic stupor after taking “ecstasy”.
      We present a case of acute, symptomatic hyponatremia in a young woman that developed after ingestion of this drug. Given the seriousness of hyponatremia that may be seen after MDMA use and the potentially devastating consequences of inappropriate treatment, we have included a review of published cases of hyponatremia associated with MDMA abuse.

      Case Reports

      A previously well, 18-year-old woman was admitted to the ICU because of altered mental status. At 11 pm the night before, she took 1 tablet of “ecstasy” with several beers. On arriving home early in the morning, she experienced excessive thirst and consumed “a lot” of water. Over next several hours, she became anxious, remorseful, and mildly agitated with visual hallucinations. She vomited several times and by 10 am had become lethargic and unresponsive. At the time of admission to the ICU 3 hours later, the patient did not respond to instructions and her arms were postured in a flexor position. She was intermittently agitated and exhibited pronounced bruxism. Temperature was 95.2°F (35.1°C), pulse was 68 beats/min and regular, respiratory rate was 14 breaths/min, blood pressure was 141/89 mm Hg, and weight was 65 kg. Pupils were dilated at 8 to 9 mm in diameter with sluggish response to light. Remaining findings on physical examination were unremarkable.
      Laboratory data included serum sodium of 124 mmol/L, serum urea nitrogen of 8 mg/dL, creatinine of 0.4 mg/dL, glucose of 107 mg/dL, albumin of 4.0 g/dL, calcium of 7.9 mg/dL, phosphorus of 3.2 mg/dL, creatinine kinase of 580 IU/L (reference range, 30–135), aspartate aminotransferase of 55 IU/L (reference range, 14–36), and alanine aminotransferase of 28 IU/L (reference range, 9–52). Arterial blood gas analysis revealed pH 7.37, pco2 of 37 mm Hg, and HCO3 of 21.5 mmol/L. Measured serum osmolality was 250 mOsm/kg. Other electrolytes, as well as total bilirubin, alkaline phosphatase, thyroid-stimulating hormone, and coagulation tests, were normal. Urinary sodium and osmolality were 185 mmol/L and 761 mOsm/kg, respectively. Urine drug screen was positive for amphetamine and negative for opiates, cocaine, or cannabinoids.
      The clinical course and management of the patient is depicted in Figure 1. She was given 1 L of normal saline over 8 hours without improvement in mental status and deteriorating serum sodium to 120 mmol/L. Over the next several hours, her corrected serum sodium decreased to 118 mmol/L. (Measured sodium was reported to be 114 mmol/L; however, glucose in that sample was 349 mg/dL.) Nephrology consultation was requested, and she was given 480 mL of 5% saline i.v. over the ensuing 6 hours. During infusion of hypertonic saline, the patient excreted 1600 mL of urine with initial urine sodium concentration of 183 mmol/L. This approach resulted in improvement in serum sodium to 128 mmol/L. Over the next 24 hours, she excreted 4500 mL of urine with normalization of serum sodium. Serum toxicological testing performed more than 24 hours after ingestion failed to detect MDMA, and the level of methylenedioxyamphetamine (MDMA metabolite) was 18 ng/mL. Although lagging behind the improvement in laboratory parameters, her mental status recovered slowly. She was discharged from the hospital without any obvious clinical or laboratory abnormality. Neuropsychological testing 1 month after MDMA ingestion showed minimal abnormalities; these disappeared by 3 months. Two years after the event, she is performing at a high academic level at a prestigious university.
      Figure thumbnail gr1
      Figure 1Serum sodium (▵) and ADH (○) in patient with MDMA-induced hyponatremia. The ADH levels were inappropriately elevated, with values of 4.7, 7.2, and 1.7 pg/mL. Treatment with 5% saline resulted in improvement of hyponatremia.

      Discussion

      The ingestion of MDMA is associated with serious complications, including hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, liver failure, cardiac arrhythmias, cerebral infarction, and psychiatric disturbances.
      • O’Connor B.
      Hazards associated with the recreational drug ‘ecstasy’.
      • Burgess C.
      • O’Donohoe A.
      • Gill M.
      Agony and ecstasy: a review of MDMA effects and toxicity.
      • Brown C.
      • Osterloh J.
      Multiple severe complications from recreational ingestion of MDMA (‘ecstasy’).
      Although in our patient creatinine kinase was mildly elevated, with peak value of 1381 IU/L, she had no signs of frank rhabdomyolysis. She developed acute symptomatic hyponatremia that resolved after treatment with hypertonic saline. Measured serum osmolality at 250 mOsm/kg with an osmolar gap of less than 10 mOsm/kg excluded the possibility of translocational or pseudohyponatremia. Furthermore, no signs of volume depletion were evident on physical examination, and her hyponatremia did not improve after treatment with normal saline. She had no thyroid, adrenal, cardiac, liver, or kidney disease. Urinary sodium concentration (185 mmol/L) that was greater than serum sodium concentration (120 mmol/L) indicated that the patient was in a state of negative free water clearance.
      • Halterman R.K.
      • Berl T.
      Therapy of dysnatremic disorders.
      • Furst H.
      • Hallows K.R.
      • Post J.
      The urine/plasma electrolyte ratio.
      Based on weight and serum sodium concentration, positive water balance was estimated to be 4.5 L (Appendix A). However, the reason for the decrease in serum sodium to 118 mmol/L after admission to the hospital was not immediately obvious. Hospital records revealed that no free water was administered and she was unable to drink. No significant hypokalemia was present; unfortunately, however, urinary potassium excretion was not measured. She was given 1 L of normal saline; based on urine volume and urine sodium concentration, the change in serum sodium after this intervention should have been less than 2 mmol/L (Appendix B). A possible explanation for greater decrease in serum sodium could be unmeasured urinary potassium excretion. Furthermore, before admission to the hospital, she drank large quantities of water, and delayed absorption of some water could also have contributed to additional decrease in serum sodium. Assuming some contribution of the urinary potassium excretion, delayed absorption of approximately 500 mL of water could explain a calculated serum sodium that is very close to the measured value (Appendix B).
      It seems that both excess water intake and the inappropriate presence of ADH are involved in the pathogenesis of MDMA-associated hyponatremia.
      • Holden R.
      • Jackson M.A.
      Near-fatal hyponatraemic coma due to vasopressin over-secretion after “ecstasy” (3,4-MDMA) [letter].
      Our patient, like many patients with MDMA-induced hyponatremia (Table 1), reported increased intake of electrolyte-free water. This is of particular concern because intake of large volumes of water is common in MDMA users to counteract hyperthermia. In addition to excessive water intake, the measurement of ADH in our case (Figure 1) supports the role of inappropriately increased levels of ADH in the pathogenesis of MDMA-induced hyponatremia. The ability of MDMA to directly stimulate ADH secretion has been demonstrated in normal volunteers.
      • Henry J.A.
      • Fallon J.K.
      • Kicman A.T.
      Low-dose MDMA (“ecstasy”) induces vasopressin secretion [letter].
      However, under this experimental condition, the rise in ADH was accompanied by small fall in plasma sodium concentration, and study subjects remained asymptomatic. This implies that additional water intake is necessary for the development of symptoms. It is possible that in patients who develop hyponatremia after MDMA use, additional stimuli of ADH release, such as nausea, vomiting, or anxiety, lead to higher ADH levels than those seen in healthy volunteers. Finally, it is also possible that in some cases of MDMA-associated hyponatremia, sodium loss and subsequent volume depletion caused by excessive sweating could contribute to the development of hyponatremia. Recently, the involvement of the gastrointestinal tract in the development of hyponatremia after MDMA use was proposed by Cherney et al.
      • Cherney D.Z.I.
      • Davids M.R.
      • Halperin M.L.
      Acute hyponatremia and “ecstasy”: insights from a quantitative and integrative analysis.
      The authors speculate that initial secretion of sodium in the intestinal lumen is followed by absorption of electrolyte-free water. However, they provided no clinical, laboratory, or experimental evidence to substantiate their hypothesis. Furthermore, in the discussion of this hypothesis, they failed to consider contributions of urinary volume and sodium and potassium excretion. For these reasons, this hypothesis remains unconfirmed.
      Table 1Clinical Characteristics and Outcome of Patients with MDMA-Associated Hyponatremia
      Age SexNo. of PillsWater IntakeTemperature (°C)SerumSodium (mmol/L)Osmolality (mOsm/kg)TreatmentOutcomeRef.
      SerumUrineSerumUrine
      18 F3na“normal”120186242562HS, Fr, WRRecovery
      • Gomez-Balaguer M.
      • Pefia H.
      • Morillas C.
      Syndrome of inappropriate antidiuretic hormone secretion and “designer drugs” (Ecstasy).
      27 F2“copious amounts”na124na267naFrDeath
      • O’Connor A.
      • Cluroe A.
      • Couch R.
      Death from hyponatraemia-induced cerebral oedema associated with MDMA (“Ecstasy”) use.
      26 M1“large volume”na101na248naFr, NSRecovery
      • Holmes S.B.
      • Banerjee A.K.
      • Alexander W.D.
      Hyponatraemia and seizures after ecstasy use.
      17 F1“several liters”37.511510256577NSRecovery
      • Magee C.
      • Staunton H.
      • Tormey W.
      Hyponatraemia, seizures and stupor associated with ecstasy ingestion in a female.
      19 FNAna35.9115162253522HS, FrRecovery
      • Ajaelo I.
      • Koenig K.
      • Snoey E.
      Severe hyponatremia and inappropriate antidiuretic hormone secretion following ecstasy use.
      24 FNAnana113153240639WRRecovery
      • Watson I.D.
      • Serlin M.
      • Moncur P.
      Acute hyponatraemia.
      20 F1/2na“normal”119145263491WR, NSRecovery
      • Nuvials X.
      • Masclans J.R.
      • Peracaula R.
      Hyponatraemic coma after ecstasy ingestion [letter].
      30 F1“large quantities”341171na38nana
      • Box S.A.
      • Prescott L.F.
      • Freestone S.
      Hyponatraemia at a rave.
      15 Fna“large quantities”32.8125nananaNS, WR, FrDeath
      • Parr M.J.
      • Low H.M.
      • Botterill P.
      Hyponatraemia and death after “ecstasy” ingestion.
      20 F1“large quantity”“normal”112112238256MannitolRecovery
      • Holden R.
      • Jackson M.A.
      Near-fatal hyponatraemic coma due to vasopressin over-secretion after “ecstasy” (3,4-MDMA) [letter].
      15 Fna“large volumes”“apyrexial”1196256655WRRecovery
      • Matthai S.M.
      • Davidson D.C.
      • Sills J.A.
      Cerebral oedema after ingestion of MDMA (“ecstasy”) and unrestricted intake of water [letter].
      16 Fnanana11299242184WRRecovery
      • Matthai S.M.
      • Davidson D.C.
      • Sills J.A.
      Cerebral oedema after ingestion of MDMA (“ecstasy”) and unrestricted intake of water [letter].
      24 F1na3812068258365HSRecovery
      • Satchell S.C.
      • Connaughton M.
      Inappropriate antidiuretic hormone secretion and extreme rises in serum creatinine kinase following MDMA ingestion.
      23 F1/2na“no fever”123nananaObservationRecovery
      • Kessel B.
      Hyponatraemia after ingestion of “ecstasy”[letter].
      17 F1 1/2na37.5130nanananaRecovery
      • Maxwell D.L.
      • Polkey M.I.
      • Henry J.A.
      Hyponatraemia and catatonic stupor after taking “ecstasy”.
      17 F1“5 liters”“afebrile”118na247970ConservativeRecovery
      • Maxwell D.L.
      • Polkey M.I.
      • Henry J.A.
      Hyponatraemia and catatonic stupor after taking “ecstasy”.
      23 F1“10 liters”34.1115246nanaNS, glucoseDeath
      • Balmelli C.
      • Kupferschmidt H.
      • Rentsch K.
      Fatal brain oedema after ingestion of ecstasy and benzylpiperazine.
      19 F1Unknown35121111242485HSRecovery
      • Traub S.J.
      • Hoffman R.S.
      • Nelson L.S.
      The “Ecstasy” hangover: hyponatremia due to 3,4-methylenedioxymethamphetamine.
      F, female; M, male, NA, not available; HS, hypertonic saline; NS, normal saline; Fr, furosemide; WR, water restriction.
      Although urinary sodium excretion was substantial in some cases (including ours), we do not believe that the pathogenesis of MDMA-associated hyponatremia includes the syndrome of cerebral salt wasting.
      • Maesaka J.K.
      • Gupta S.
      • Fishbane S.
      Cerebral salt-wasting syndrome: does it exist?.
      In this syndrome, hyponatremia usually develops over 7 to 10 days, and ADH is elevated but only to levels appropriate for the level of volume depletion.
      • Palmer B.F.
      Hyponatremia in neurosurgical patient: syndrome of inappropriate antidiuretic hormone secretion versus cerebral salt wasting.
      As discussed previously, volume depletion in our case was not present, and treatment with normal saline did not improve hyponatremia or decrease ADH levels (Figure 1). However, we did not evaluate fractional excretion of urate, which has been suggested to be of diagnostic value in this setting.
      • Maesaka J.K.
      • Fishbane S.
      Regulation of renal urate excretion: a critical review.
      Review of the literature identified 18 additional cases of hyponatremia associated with MDMA abuse (Table 1). Seventeen were young women 15 to 30 years old (median age, 19.5 years). The majority of them admitted taking only 1 pill (50–150 mg) of MDMA, usually with large quantities of fluid. All cases presented with severely altered mental status, and the interval from drug ingestion until onset of symptoms was short, between 4 and 24 hours. The serum sodium concentrations ranged from 101 to 130 mmol/L (median, 118 mmol/L). The median serum and urine osmolalities were 248 (range, 238–267 mOsm/kg) and 506 mOsm/kg (range, 38–970 mOsm/kg), respectively. A few cases had low urinary sodium and clinical signs of volume depletion that might have contributed to the development of hyponatremia.
      MDMA abuse is associated with mortality ranging from 0.2 to 5.3 cases per 10,000 users in the United Kingdom.
      • Gore S.M.
      Fatal uncertainty: death-rate from use of ecstasy or heroin.
      According to the literature, the majority of deaths were caused by hyperthermia with disseminated intravascular coagulation.
      • Mueller P.D.
      • Korey W.S.
      Death by “ecstasy”: the serotonin syndrome?.
      • Milroy C.M.
      • Clark J.C.
      • Forrest A.R.W.
      Pathology of deaths associated with “ecstasy” and “eve” misuse.
      • Dowling P.
      • McDonough E.T.
      • Bost R.O.
      ‘Eve’ and ‘Ecstasy’. A report of five deaths associated with the use of MDEA and MDMA.
      • Henry J.A.
      • Jeffreys K.J.
      • Dawling S.
      Toxicity and deaths from 3,4 methylenedioxymethamphetamine (“ecstasy”).
      • Walubo A.
      • Seger D.
      Fatal multi-organ failure after suicidal overdose with MDMA, ‘Ecstasy’: case report and review of the literature.
      However, it has been suggested that the majority of patients who present with hyponatremia after MDMA use do not have elevated body temperature.
      • Walubo A.
      • Seger D.
      Fatal multi-organ failure after suicidal overdose with MDMA, ‘Ecstasy’: case report and review of the literature.
      The review of patients presented in Table 1, as well as a report by Milroy,
      • Milroy C.M.
      • Clark J.C.
      • Forrest A.R.W.
      Pathology of deaths associated with “ecstasy” and “eve” misuse.
      support such an argument. Only 1 of the reviewed patients had mildly elevated body temperature.
      • Satchell S.C.
      • Connaughton M.
      Inappropriate antidiuretic hormone secretion and extreme rises in serum creatinine kinase following MDMA ingestion.
      Three (17%) of the 18 reported patients with MDMA associated hyponatremia died (Table 1), and all were women.
      Treatment of MDMA-associated hyponatremia deserves particular attention. In all reported cases, hyponatremia developed within 24 hours. As suggested by a number of different lines of evidence, acute, symptomatic hyponatremia, particularly in young women, is a serious condition with significant morbidity and mortality.
      • Arieff A.I.
      Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective sur-gery in healthy women.
      • Fraser C.L.
      • Arieff A.I.
      Epidemiology, pathophysiology, and management of hyponatremic encephalopathy.
      • Lauriat S.M.
      • Berl T.
      The hyponatremic patient: practi-cal focus on therapy.
      There were no deaths in the reported cases of MDMA-associated hyponatremia who received treatment with hypertonic saline. However, 3 patients presented in Table 1 and an additional case of an 18-year-old woman reported by Hartung et al
      • Hartung T.K.
      • Schofield E.
      • Short A.I.
      Hypo-natremic states following 3,4-methylenedioxymethamphet-amine (MDMA, “ecstasy”) ingestion.
      who died were treated with furosemide,
      • O’Connor A.
      • Cluroe A.
      • Couch R.
      Death from hyponatraemia-induced cerebral oedema associated with MDMA (“Ecstasy”) use.
      • Parr M.J.
      • Low H.M.
      • Botterill P.
      Hyponatraemia and death after “ecstasy” ingestion.
      • Hartung T.K.
      • Schofield E.
      • Short A.I.
      Hypo-natremic states following 3,4-methylenedioxymethamphet-amine (MDMA, “ecstasy”) ingestion.
      normal saline,
      • Parr M.J.
      • Low H.M.
      • Botterill P.
      Hyponatraemia and death after “ecstasy” ingestion.
      • Hartung T.K.
      • Schofield E.
      • Short A.I.
      Hypo-natremic states following 3,4-methylenedioxymethamphet-amine (MDMA, “ecstasy”) ingestion.
      water restriction,
      • Parr M.J.
      • Low H.M.
      • Botterill P.
      Hyponatraemia and death after “ecstasy” ingestion.
      or other fluids.
      • Balmelli C.
      • Kupferschmidt H.
      • Rentsch K.
      Fatal brain oedema after ingestion of ecstasy and benzylpiperazine.
      All had cerebral edema and 3 had cerebellar tonsillar herniation at autopsy.
      We strongly advocate treatment with hypertonic saline in symptomatic patients with MDMA-associated hyponatremia to reverse acute cerebral edema. Water restriction with or without loop diuretics may be employed in less severe cases but is inadequate treatment for symptomatic patients. Our case, as well as others reported in the literature, raises concern about the recommendation recently suggested for “providing plenty of water at rave parties.”
      • Vastag B.
      Ecstasy experts want realistic messages.
      In summary, we describe a case of severe acute hyponatremia after ingestion of MDMA that was associated with elevated levels of ADH. The patient responded to treatment with hypertonic saline with full functional recovery. We strongly suggest that serum sodium always be measured in symptomatic premenopausal women suspected of using ecstasy before management is undertaken.

      Appendix A

      Free Water Gain

      Patient presented to the hospital with serum sodium of 124 mmol/L. Her weight was 65 kg.
      Total body water=65 kg×0.6=39 L
      (124 mmol/L ÷ 140 mmol/L)×39 L=34.5 L
      39 L − 34.5 L=4.5 L
      Water excess=4.5 L

      Appendix B

      Deterioration of Hyponatremia

      Patient received 1 L of normal saline and excreted 1.5 L of urine with initial sodium concentration of 185 mmol/L. Expected decrease in serum sodium after this intervention should be less than 2 mmol/L:
      124 mmol/L×39 L=4836 mmol/39 L
      4836 mmol/39 L + 154 mmol + 1L=4990 mmol/40 L
      4990 mmol/40 L − 278 mmol (urinary sodium) − 1.5 L (urine volume)=4712 mmol/38.5 L
      4712 mmol/38.5 L=122.4 mmol/L
      However, the patient’s serum sodium dropped to 118 mmol/L. If we speculate that the patient had delayed absorption of 500 mL of water and excreted 52 mmol of potassium in addition to the recorded 278 mmol of sodium in 1.5 L of urine, calculated serum sodium reaches a value very near the measured one:
      4836 mmol/39 L + 154 mmol + 1 L + 0.5 L (delayed absorption)=4990 mmol/40.5 L
      4990 mmol/40.5 L − 330 mmol (Urinary Na+K) − 1.5 L (urine volume)=4660 mmol/39 L
      4660 mmol/39 L=119 mmol/L

      Appendix C

      Correction of Hyponatremia

      Patient was given 480 mL of 5% saline and she excreted 1.6 L of urine with initial sodium concentration of 183 mmol/L. Serum sodium rose to 128 mmol/L.
      118 mmol/L×39 L=4602 mmol/39 L
      4602 mmol/39 L + 411 mmol (sodium in 5% saline) + 0.480 L (volume of 5% saline)=5013 mmol/39.48 L
      5013 mmol/39.48 L − 293 mmol (urinary Na) − 1.6 L (urine volume)=4720 mmol/37.88 L
      4720 mmol/37.88 L=125 mmol/L
      The discrepancy between calculated and measured serum sodium (125 versus 128 mmol/L) is most likely explained by progressive decrease in urinary sodium concentration during 5% saline infusion with excretion of less than 293 mmol of sodium. In fact, urinary sodium was 14 mmol/L 3 hours later.

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