Rare but relevant: MDMA and hyponatraemia

Abstract

Conventionally used for its stimulant, empathogenic and entactogenic effects, 3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) is one of the most commonly used psychoactive drugs, specifically among young adults and in nightlife and recreational party contexts. Often perceived as a safe drug, MDMA can display an array of toxic effects on multiple organs, with hyponatraemia (a low blood sodium concentration that can cause an altered mental state) being increasingly reported. Although hyponatraemia per se is among the most common electrolyte disorders encountered in clinical care, acute MDMA‐induced hyponatraemia was first described in 1993 and constitutes a life‐threatening condition if left untreated, particularly among women, who present higher incidence rates and increased odds of developing severe clinical effects. The present review outlines the main clinical manifestations and prevalence of MDMA‐induced hyponatraemia, its pathophysiological mechanisms and the therapeutical approaches to correct this electrolyte imbalance.

INTRODUCTION

Diagnosed once plasma sodium concentration falls below the normal threshold of 135 mmol/L, hyponatraemia is one of the most common electrolyte disorders, associated with increased morbidity and mortality [1, 2, 3, 4, 5]. With several possible aetiological causes, including syndrome of inappropriate antidiuresis (SIAD), adrenal insufficiency, polydipsia, salt‐losing nephropathy and medication‐induced causes, among others, hyponatraemia has also been linked to drug use [6, 7], namely amphetamines and structurally related substances [2]. Among these, 3,4‐methylenedioxymethamphetamine (MDMA, commonly known as Molly or ecstasy) has received particular attention. This synthetic drug is widely used for its empathogenic, entactogenic and euphoriant effects, which have contributed to its widespread popularity in nightlife and recreational settings [8, 9, 10]. Classified in 1985 by the US Drug Enforcement Agency (DEA) as a Schedule I substance [11], MDMA use peaked throughout the late 1980s and 1990s [12]. Even though a decline was noted in the early 2000s, since 2010 there has been a resurgence with increased availability of MDMA products on the global drug market [12], with the latest report from the European Union Drugs Agency (EUDA) indicating MDMA as the second most commonly used illicit stimulant in the European Union, after cocaine [8].

Typically sold in capsules or tablets, with different shapes, logos and colours to gain the curiosity of users, MDMA products often vary in chemical composition and are frequently adulterated with other drugs, including amphetamine‐like substances, in addition to by‐products of the synthetic process, altogether contributing to the diverse effects and adverse consequences experienced by consumers [6].

Besides its psychostimulant effects, adverse effects of MDMA include agitation, liver failure, rhabdomyolysis, dysrhythmias, myocardial infarction, disseminated intravascular coagulation, hyperthermia and hyponatraemia, with the latter condition not infrequently progressing to seizures, coma, cerebral oedema and ultimately death [13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26].

Although its use is still mainly associated with recreational settings, in recent years MDMA has also been considered as a possible therapeutic strategy for the treatment of post‐traumatic stress disorder and alcohol use disorder [27, 28, 29]. As such, this possibility further emphasises the importance of acknowledging and understanding the full toxicological profile of MDMA, particularly its influence upon electrolyte balance.

CLINICAL PRESENTATION

Although frequently asymptomatic [2], in more severe scenarios hyponatraemia can progress suddenly and quickly, with the onset of clinical manifestations depending on several factors, including its duration and severity [30].

Hyponatraemic patients may experience a variety of symptoms, usually non‐specific, and ranging from mild to severe. In mild cases, irritability, restlessness, headaches, impaired concentration and fatigue may occur, typically when plasma sodium levels range from 130 to <135 mmol/L [2, 7, 31]. In contrast, in acute and moderate or severe hyponatraemia (when plasma sodium levels range from 125 to <130 mmol/L or fall below 125 mmol/L, respectively) patients may present with confusion, nausea, vomiting, gait ataxia, seizures, decreased consciousness, cardiorespiratory distress, and ultimately brain oedema and herniation [2, 7, 30, 31]. Considering the rigidity of the skull, this latter condition can culminate in permanent brain damage or even death, owing to intracranial hypertension and reduced cerebral blood flow [30]. Non‐cardiogenic pulmonary oedema might also be observed upon MDMA‐induced hyponatraemia, as a consequence of acute water intoxication during MDMA intoxication [30].

To the best of our knowledge, the clinical report describing the lowest serum sodium level following MDMA ingestion concerns a 26‐year‐old female who presented with severe hyponatraemia, seizures and pulmonary oedema. Despite a sodium concentration of 101 mmol/L and the presence of severe clinical manifestations [32], the patient recovered, in contrast to several other reports on patients with higher serum sodium levels who experienced fatal outcomes likely related to hyponatraemia [26, 33, 34]. This case highlights the variability in clinical outcomes.

Furthermore, special attention should be given to women, patients with chronic kidney disease and those with hypoxemia, as they are at higher risk of developing severe symptoms or hyponatraemic encephalopathy [7, 30].

HOW COMMON IS IT?

Up to the present day, epidemiological studies exploring the association between hyponatraemia and MDMA use remain scarce. Yet, some studies have attempted to estimate the incidence of MDMA‐induced hyponatraemia among festival attendees. According to Dijken et al. [9], in a sample of 107 individuals surveyed in festival ‘chill out’ spaces (63 under the influence of MDMA and 44 controls), plasma sodium decreases meeting their definition of hyponatraemia (Na⁺ < 136 mmol/L) were observed in 14.3% of MDMA users. Regarding gender differences, the authors noted that women were the most affected group, with an incidence of 26.7% (i.e. among women who consumed MDMA, approximately one in four developed hyponatraemia, with the lowest plasma sodium concentration recorded being 133 mmol/L), in contrast to 3% in men. On the other hand, among the 30 female ecstasy users, MDMA‐induced hyponatraemia seemed independent of body mass index, fluid ingestion and number of pills consumed [9]. Similar results were reported by Rosenson et al. [35] in a retrospective analysis of ecstasy intoxications recorded by the California Poison Control System over a 5‐year period. According to the authors, among the 38.8% of cases with hyponatraemia (defined in their study as plasma sodium concentrations below 130 mmol/L) reported between January 2000 and October 2005, 75.3% occurred in women. Furthermore, women with hyponatraemia showed a fourfold increased odds of developing seizures and coma, whereas men presented a twofold increased odds for seizures only. Of note, four deaths were reported following MDMA‐induced hyponatraemia, three being women, with all four cases having previously required pressors for hypotension and later presenting with cerebral oedema [35]. Moreover, when analysing the clinical course of MDMA intoxication in patients admitted to an intensive care unit in Amsterdam, between 2010 and 2020, around 23% were reported to have MDMA‐induced hyponatraemia. The majority (14 patients, 82%) presented with severe clinical manifestations, with seven patients experiencing convulsions and two patients experiencing brain oedema, from which one patient ultimately died, whereas the other recovered following hypertonic saline administration and fluid restriction [14]. Atila and colleagues conducted a secondary analysis of four randomised clinical trials carried out at the University Hospital Basel, between 2017 and 2022, involving 96 participants. Their results showed a 31% incidence of acute hyponatraemia following the administration of a single MDMA dose, with a mean plasma sodium concentration of 133 mEq/L. In addition, the authors observed that hyponatraemia occurred only among the participants with unrestricted fluid intake [36].

PATHOPHYSIOLOGICAL MECHANISM

Contrasting with most drugs, the severity of MDMA toxicity seems to be poorly correlated with dose or blood concentrations. Indeed, MDMA‐intoxicated patients frequently display wide inter‐individual variability, with some asymptomatic individuals presenting higher plasma concentrations than symptomatic or even severely intoxicated cases. Although not yet fully elucidated, current evidence suggests a multi‐factorial process, with contributing factors including the environmental conditions of consumption (e.g. poorly ventilated settings, crowded and overheated venues), patient behaviour (e.g. excessive dancing), toxicokinetics and genetic variability (e.g. cytochrome P450 polymorphisms) and drug interactions (e.g. pill adulterants and polydrug use), to name a few [10, 14]. Among these, environmental factors are particularly relevant, as rave parties are often held in enclosed, overheated venues, where consumers engage in excessive physical activity through prolonged, stereotyped dance movements. This, alongside the ability of MDMA to rapidly increase body temperature, promotes diaphoresis with associated dehydration and electrolyte loss, further contributing to plasma sodium depletion [19, 35, 37] (Figure 1). In response, MDMA consumers often intentionally or unintentionally increase their water intake, either because of polydipsia or as a strategy to prevent hyperthermia (where the body temperature may rise to 43°C), which in turn can result in hyponatraemia and subsequent water intoxication [2, 6, 13]. Acute hyponatraemia results in intracellular oedema associated with the osmotic movement of free water into cells. In chronic or prolonged cases (ranging from hours to days), an adaptive response occurs through the extrusion of electrolytes (Na⁺, K⁺, Cl⁻) and, subsequently, organic osmolytes (e.g. myo‐inositol, taurine, glutamine), thereby reducing intracellular water content and limiting cerebral oedema [7].

FIGURE 1.

Proposed mechanisms underlying 3,4‐methylenedioxymethamphetamine (MDMA)‐induced hyponatraemia. MDMA consumption promotes hyperthermia and diaphoresis with significant sodium loss, accompanied by excessive water intake arising from polydipsia and attempts to prevent hyperthermia. In parallel, MDMA and the main metabolites stimulate vasopressin (antidiuretic hormone, ADH) release from the neurohypophysis (posterior pituitary), leading to renal water retention. The combined effect of water overload, sodium loss and inappropriate vasopressin release results in hyponatraemia, which may progress to cerebral oedema. The clinical consequences are often unpredictable owing to inter‐individual genetic polymorphisms. 5‐HT, serotonin; HHA, 3,4‐dihydroxyamphetamine; HHMA, 3,4‐dihydroxymethamphetamine.

Another broadly accepted mechanism involves the serotonin‐mediated stimulation of antidiuretic hormone (ADH) release from the posterior pituitary gland (neurohypophysis), resulting in SIAD [2, 6, 19]. Once ingested, MDMA is mainly metabolised in the liver by the cytochrome P450 isoenzyme CYP2D6, through N‐dealkylation, deamination and oxidation reactions, forming 3,4‐dihydroxymethamphetamine (HHMA) and 3,4‐dihydroxyamphetamine (HHA), which are subsequently methylated by catechol‐O‐methyltransferase (COMT) [2, 38]. As CYP2D6 displays genetic polymorphisms, certain populations may be more predisposed to the toxic effects of MDMA [2, 38]. Structurally similar to serotonin, MDMA and its main metabolites (HMMA and HHA) have been reported to increase serotonin levels within the central nervous system, stimulating the hypothalamus and, consequently, the posterior pituitary, thus promoting the release of ADH, which in turn contributes to SIAD and water retention [6, 13]. Furthermore, stress, physical activity and nicotine, all often present in MDMA consumption scenarios, seem to increase ADH release, aggravating this condition [6]. Beyond these ADH‐dependent pathways, further mechanisms have also been proposed, including a direct effect of MDMA on aquaporin‐2 channels, in the inner medullary collecting duct of the kidney, leading to increased water reabsorption independently of ADH levels [19].

In addition to ADH, MDMA can also increase the release of cortisol and oxytocin, both of which are suggested to contribute to MDMA‐mediated hyponatraemia. Following ingestion of MDMA, particularly under conditions of high ambient temperature and physical activity (e.g. dancing), cortisol levels have been reported to increase by approximately 800%, peaking 2–4 hours post‐ingestion, indirectly contributing to the heightened sense of energy [11]. Regarding oxytocin, besides contributing to the empathogenic effects of MDMA, this hormone is structurally similar to vasopressin. Atila et al. [36] suggested a vasopressin‐like effect on the kidneys owing to structural homology, as MDMA‐induced hyponatraemia was associated with an acute and marked increase in oxytocin but not in copeptin, the C‐terminal fragment of the ADH prohormone that is commonly used as an indirect biomarker of ADH release [36].

As previously stated, women appear to be more susceptible to hyponatraemia following MDMA ingestion, with the literature proposing oestrogens as key contributors to these sex differences. Oestrogens have been reported to influence brain cell volume regulation, stimulate ADH release and decrease Na⁺/K⁺‐ATPase pump activity. Additionally, women present a higher density and greater sensitivity of ADH receptors in the kidney, making them more prone to the development of hyponatraemia [6, 10, 13].

PROGNOSIS AND TREATMENT

Given the potential for sudden progression, early diagnosis and prompt correction of plasma sodium levels in patients with acute hyponatraemia is of foremost importance to prevent complications and poor outcomes. Close monitoring of electrolyte levels is also recommended to optimise resolution and avoid the overcorrection of sodium levels.

Once diagnosed, the treatment regimen varies according to the severity of hyponatraemia. The main goal is to correct sodium levels and restore water balance, while also managing other MDMA‐induced adverse effects [2], particularly cerebral oedema and neurological symptoms, if present [39]. As such, strategies already used in other contexts of hyponatraemia are most frequently adopted [11], including fluid restriction, hypertonic or isotonic saline, and, in selected cases, loop diuretics (e.g. furosemide), urea or vasopressin receptor antagonists (e.g. tolvaptan, conivaptan). Nevertheless, treatment guidelines should be consulted, bearing in mind that recommendations from the US Expert Panel and the European Clinical Practice Guideline may differ slightly (Table 1) [39].

TABLE 1.

Key recommendations from European versus US guidelines on hyponatraemia management.

	Guidelines
	Europe (3)	USA (5)
Definition and cut‐offs	Defines hyponatraemia as Na+ < 135 mmol/L
	When guiding therapeutic decisions, places greater emphasis on the onset time (acute <48 h versus chronic >48 h)	Focuses more on the severity of symptoms rather than on chronology
Use of hypertonic saline solution (3% NaCl)	Recommends a 150 mL bolus of 3% NaCl over 20 min, repeatable, for acute and severe cases (e.g. seizures, coma)	Recommends a 100 mL bolus of 3% saline infused over 10 min, and repeated twice more, if needed In moderate or mild cases, with low risk of brain herniation, a continuous infusion of 3% NaCl (0.5–2 mL/kg/h) is recommended, adjusted according to clinical response
Correction rate	Warns about the risk of osmotic demyelination
	Maximum correction of 10 mmol/L in the first 24 h and 8 mmol/L for each subsequent 24 h	Similar to European recommendation, but more cautious in high‐risk patients (alcoholism, malnutrition, liver disease; in these patients, correction should not exceed 8 mmol/L within 24 hours)
Additional pharmacotherapeutic interventions	Places greater emphasis on the use of urea and vaptans (vasopressin receptor antagonists, such as tolvaptan), although the latter are recommended with considerable caution	More restrictive regarding vaptans, recommending their use only in very specific contexts a

^a Vaptans are only considered in chronic SIADH (syndrome of inappropriate antidiuretic hormone secretion), and only when fluid restriction has failed and the patient is not hypovolaemic, as vaptans may worsen hypovolaemia. They should never be used in acute severe symptomatic hyponatraemia, where treatment with hypertonic saline (3% NaCl) is required.

If the patient is asymptomatic or presents with mild to moderate symptoms, fluid restriction is the first‐line treatment and may resolve the hyponatraemia, as ADH levels decrease and kidney function returns to normal with spontaneous diuresis [6, 38, 39]. Nevertheless, urine output, serum and urine sodium, and urine osmolality should be closely monitored, given that a 3% hypertonic saline solution may be required in more refractory patients [2]. If negative free water clearance and elevated urine osmolality are detected, 3% hypertonic saline should also be administered at a rate of 0.5–2 mL/Kg/h [1, 40].

Hypertonic saline (3% NaCl) is indicated in severe cases or when neurological symptoms such as seizures, coma or cerebral oedema are present, and can be administered either as boluses or continuous infusions. According to US consensus guidelines, an increment of serum sodium by 4–6 mmol/L, over a 4‐hour infusion, can significantly reverse the clinical signs of herniation and reduce intracranial pressure by almost 50% [1, 39]. In contrast, the European Society for Endocrinology guidelines recommend the administration of a 150 mL bolus of hypertonic saline over a period of 20 minutes, repeatable until achieving a 5 mmol/L increase in serum sodium within the first hour of treatment [1, 39]. Isotonic saline (0.9% NaCl) is primarily used in hypovolaemic hyponatraemia, for instance in cases of gastrointestinal or renal losses.

CONCLUSION

Associated with increased morbidity and mortality if not promptly recognised and treated, MDMA‐induced hyponatraemia is a relatively common yet often underappreciated complication that requires urgent intervention and close monitoring. Efforts should therefore focus on raising awareness among healthcare professionals to promptly identify these cases and provide timely and adequate management to prevent potentially severe sequelae. Furthermore, given the rising popularity of MDMA use, particularly among young individuals, consumers should also be educated on the potential risks of MDMA ingestion and the behaviours and measures that may help prevent the development of hyponatraemia and its clinical consequences.

AUTHOR CONTRIBUTIONS

Maria Rita Garcia: Data curation (lead); writing—original draft. Nelson G. M. Gomes: Data curation (supporting); supervision (supporting); writing—review and editing. Diana Dias‐da‐Silva: Conceptualization; data curation (supporting); supervision (lead); writing—review and editing.

DECLARATION OF INTERESTS

None.

Garcia MR, Gomes NGM, Dias‐da‐Silva D. Rare but relevant: MDMA and hyponatraemia. Addiction. 2026;121(3):713–718. 10.1111/add.70255

DATA AVAILABILITY STATEMENT

No new data were collected for this study. The work is based on a review of published literature, and therefore data sharing is not applicable.