MDMA Editorial

Evaluation of hyponatremia associated with use of Methylenedioxymethylamphetamine (MDMA)

Robert Zenenberg, D.O.
Fellow in Nephrology,
New York University Medical Center

David S. Goldfarb, M.D.
Associate Professor of Clinical Medicine and Urology,
New York University School of Medicine

Int J Med Toxicol 2000; 3(5): 30
See also Case Presentation

These case conferences are supported by an unrestricted educational grant from Orphan Medical, Inc.
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Address for Correspondence:
David S. Goldfarb
Nephrology Section/111G
New York DVAMC
423 E. 23 St.
New York, N.Y. 10010
Telephone: 212-686-7500, x 3877

Ecstasy (MDMA) is an amphetamine analog with psychedelic effects, which is commonly used by young people, particularly at dance parties called "raves". This issue of the journal reports a case of MDMA-associated hyponatremia, a known complication of this drug. The authors attribute the hyponatremia to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In this editorial, we will review the basic pathophysiology and diagnostic evaluation of hyponatremia while commenting on this patient’s presentation.

Anti-diuretic hormone (ADH) is produced in the hypothalamus and stored in the posterior pituitary gland. Anti-diuretic hormone release and suppression, as well as thirst, are important factors in the daily regulation of plasma tonicity. Normally, Anti-diuretic hormone is released when hypothalamic osmoreceptors sense very small increases in plasma tonicity. The presence of anti-diuretic hormone in the circulation leads to water reabsorption by the kidney. Conversely, anti-diuretic hormone is suppressed and water is excreted when small decreases in plasma tonicity are sensed by the hypothalamus.

The collecting duct, at the distal end of the nephron, is normally impermeable to water in the absence of anti-diuretic hormone. When released by the pituitary, anti-diuretic hormone acts at the collecting duct to express water channels called aquaporins on the apical (luminal) membrane of this segment. Aquaporins are freely permeable to water, and in response to the hypertonic renal medullary interstitium, water will be reabsorbed when these channels appear at the apical membrane. A concentrated urine will then be excreted. If anti-diuretic hormone is not present, water channels are not expressed on the collecting duct apical membrane, and water will be excreted. A dilute urine will result.

Anti-diuretic hormone release can also be elicited by non-osmotic stimuli via baroreceptor stimulation. An example of a strong stimulus for non-osmotic anti-diuretic hormone release is extracellular fluid volume (ECFV) depletion. Hypovolemic hyponatremia can occur with salt and water losses of both extrarenal (diarrhea, severe sweating) and renal (diuretics, glycosuria) origin. In such cases, extracellular fluid volume depletion can override the normal osmotic-mediated anti-diuretic hormone regulation. Since anti-diuretic hormone stimulates sodium reabsorption and has pressor effects, it has a role as a hormone maintaining extracellular fluid volume. The priority of maintaining extracellular fluid volume (by reabsorbing salt and water) overrides the maintenance of plasma osmolarity. States of extracellular fluid volume overload such as heart failure and cirrhosis are also associated with anti-diuretic hormone release. Despite volume expansion, these are states of decreased "effective arterial blood volume" in which renal reabsorption of sodium and water are stimulated and lead to edema and hyponatremia.

The syndrome of syndrome of inappropriate antidiuretic hormone secretion produces euvolemic hyponatremia. It occurs as the result of non-osmotic, non- extracellular fluid volume-mediated factors. These include nausea and pain; most pulmonary diseases such as pneumonia or tuberculosis; CNS processes such as increased intracranial pressure; many malignancies, especially lung cancer; and numerous drugs such as carbemazepine, morphine, cyclophosphamide and the selective serotonin reuptake inhibitor class of drugs such as fluoxetine. MDMA stimulates central nervous system release of serotonin and inhibits serotonin reuptake thus increasing serotonin levels acutely. In animal models serotonin stimulates the release of anti-diuretic hormone. Additionally, a controlled study in humans also demonstrated that acute MDMA administration caused anti-diuretic hormone release. These data strongly suggest that MDMA can indeed cause syndrome of inappropriate antidiuretic hormone secretion.

The evaluation of a patient with hyponatremia must include determination of extracellular fluid volume. The history and physical examination are often, though not always, sufficient to determine the patient’s extracellular fluid volume status. In cases of hyponatremia of obscure origin, measurement of the central venous pressure, or the pulmonary capillary wedge pressure may be indicated. The urine osmolarity has little utility to discriminate syndrome of inappropriate antidiuretic hormone secretion from states of extracellular fluid volume depletion or excess. Almost all causes of hyponatremia (except for psychogenic polydipsia) are associated with anti-diuretic hormone release, and will thus be associated with an elevation in urine osmolarity, regardless of the patient’s extracellular fluid volume status.

There are several reports of participants at raves who were hyponatremic after taking MDMA and engaging in vigorous dancing. Folklore at such parties includes the advice that MDMA users should drink fluid to counteract adverse effects of the drug. Whether users of the drug have increased anti-diuretic hormone secretion in response to hypovolemia or due to the direct effect of the drug on anti-diuretic hormone secretion, or both, ingestion of solute-free water will lead to hyponatremia if anti-diuretic hormone secretion is not suppressed. The relative contributions of these two mechanisms in causing anti-diuretic hormone secretion and resultant hyponatremia in cases of MDMA use have yet to be resolved.

The patient in this case report was vomiting for several hours, and it is possible that she became extracellular fluid volume-depleted as a result. The physical examination described does not clearly define her extracellular fluid volume status. Unfortunately, signs of orthostasis were not elicited and no measurement of central venous pressure is reported. Other case reports have this flaw as well. There are therapeutic implications to distinguishing these two mechanisms. Extracellular fluid volume-depletion should be treated with administration of normal saline, leading to suppression of anti-diuretic hormone and excretion of solute-free water. Treatment of syndrome of inappropriate antidiuretic hormone secretion with saline infusion can lead to worsening of hyponatremia, since the administered salt can be excreted in a concentrated urine, while solute-free water is retained. The result would be a lowering of serum sodium concentration. Syndrome of inappropriate antidiuretic hormone secretion is best treated with restriction of water administration. If symptoms of hyponatremia are present, solute-free water will be excreted in response to furosemide. Hypertonic saline administration will also lead to a rise in serum sodium concentration, since its osmolality is greater than that of the urine in response to anti-diuretic hormone.

She also had severe nausea and headache for several hours prior to her presentation. It is difficult to tell if the hyponatremia (and associated cerebral edema) caused the nausea and headache, or if the nausea and headache (pain), perhaps effects of the drug, caused anti-diuretic hormone release and subsequent hyponatremia. Nausea is an extremely potent stimulus for anti-diuretic hormone release.

Finally, we need to make some points about the utility of urine sodium measurements in the diagnosis of hyponatremia. Eextracellular fluid volume depletion, and states of extracellular fluid volume overload such as congestive heart failure and cirrhosis may be associated with low urine sodium concentrations (<10 mEq/L), while syndrome of inappropriate antidiuretic hormone secretion, a state of sodium balance, should yield higher values (>20 meq/L). However, the most accurate assessment of the extracellular fluid volume status of the patient is via the history and physical examination. Urine sodium concentrations can be misleading in many instances. For example, the urinary excretion of non-reabsorbable anions such as certain antibiotics, ketoanions, and bicarbonate augments the urinary excretion of sodium and other cations. A patient with metabolic alkalosis from vomiting can excrete bicarbonate in the urine and have high urinary sodium concentrations despite being extracellular fluid volume-depleted. Achieving a minimally low urine sodium concentration also requires as much as 24 hours and may not be evident in the emergency department only hours after an acute ingestion or other event. Other situations where urine sodium concentrations may be elevated despite Eextracellular fluid volume-depletion is with diuretic use, with glycosuria, and in cases of renal insufficiency where delayed tubular adaptation is always present.

In summary, there is reasonable evidence that MDMA use may lead to syndrome of inappropriate antidiuretic hormone secretion and hyponatremia. The possibility that extracellular fluid volume-depletion is also a factor in this and other such cases should be considered. The optimal therapeutic regimen depends on the distinction.


Int J Med Toxicol 2000; 3(5): 30
See also Case Presentation

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