Why this poison is interesting

The amphetamines and cocaine produce a toxidrome that looks the same at the bedside and is generated by mechanisms that are not merely different but opposite in structure. Cocaine blocks the monoamine transporters, so serotonin, dopamine and noradrenaline that have already been released cannot be cleared. Amphetamines reverse them, so the transporter that normally carries transmitter into the neurone carries it out instead. One prevents clearance; the other empties the store.

That structural difference has a consequence worth stating carefully. Reuptake blockade is saturable in a clinically meaningful way — once every transporter is occupied, more drug adds nothing to that mechanism. Reverse transport is not limited in the same way, because its ceiling is the amount of transmitter available rather than the number of transporters. It is the same argument that separates a monoamine oxidase inhibitor from an SSRI on the serotonin toxicity page, applied one step further along the synapse.

The third reason this page exists is that the amphetamines kill by two routes that are not cardiac, which is where the clinical attention usually goes. The first is hyperthermia, which is a muscular and thermoregulatory problem rather than a drug effect on any organ. The second is hyponatraemia, which is an endocrine one, is specific to MDMA in practice, and has been demonstrated in human volunteers.¹

A poison is a drug whose kinetics have escaped its pharmacology.

The toxic principle

An amphetamine is a substrate at the monoamine transporter, not merely a ligand. Being transported into the neurone is the first step of its mechanism rather than the end of its action, and everything that follows is a consequence of a molecule being in the wrong compartment.

The selectivity between drugs in this family is a matter of which transporter each prefers. Methamphetamine and dexamfetamine act most strongly at the dopamine and noradrenaline transporters, producing the classical stimulant picture — euphoria, alertness, tachycardia, hypertension, psychosis. MDMA is comparatively serotonin-selective, which is why it produces the empathogenic subjective effect it is taken for and why it, rather than methamphetamine, is the member of this family that regularly produces frank serotonin toxicity.

MDMA-associated hyponatraemia is the second lethal mechanism and the more specific one. Fallon and colleagues gave 40 mg of MDMA to eight healthy drug-free male volunteers and found that plasma arginine vasopressin concentrations increased significantly at 1, 2 and 4 hours.¹ That is a human demonstration, at a low dose, in people who were not unwell — which makes it a much stronger foundation than the case reports the association is usually built on.

Fallon's study went further and tested the metabolites. In an isolated rat hypothalamus preparation, MDMA and five of its metabolites all increased vasopressin release, with 4-hydroxy-3-methoxymethamphetamine (HMMA), the major metabolite, the most potent and 3,4-dihydroxymethamphetamine the least.¹ The human part of that study is human and the metabolite ranking is not — the authors themselves conclude that further work will demonstrate whether it is also true in vivo¹, and this page keeps that boundary visible.

Toxicokinetics

As with cocaine, there is no UK product label for a recreational amphetamine preparation, so the table below is qualitative where a label would give a figure — and says so. What the kinetics establish is a much longer exposure than cocaine's, which is the reason the two drugs' timelines look nothing alike.

Amphetamines and MDMA — long enough for the consequences to accumulate
Parameter	Therapeutic	In overdose	Why it changes
Absorption	Oral: over tens of minutes to a couple of hours. Smoked, insufflated or injected: minutes	Redosing during a night out produces a stepped rather than a single exposure	The oral route dominates for MDMA and matters clinically, because a patient who has taken further tablets after judging the first ineffective has an exposure still rising when they present.
Duration of effect	Hours, not minutes — several hours for MDMA and considerably longer for methamphetamine	Longer still with redosing	This is the single most important kinetic contrast with cocaine. Cocaine's danger is concentrated into about an hour; the amphetamines sustain the drive for many hours, which is exactly what is required for hyperthermia and for water loading to develop.
Metabolism	Hepatic, with a substantial contribution from CYP2D6 for MDMA	HMMA is the major MDMA metabolite and was the most potent releaser of vasopressin in an isolated rat hypothalamus¹	A metabolite implicated in the mechanism that kills, though the demonstration is ex vivo and in rat tissue.¹ The CYP2D6 dependence also means MDMA shares a polymorphic activation step with tramadol and codeine, from a very different direction.
Urinary pH dependence	Amphetamine is a weak base; its renal excretion increases in acidic urine	Theoretically exploitable and not exploited	The one place in this library where a real ion-trapping mechanism is deliberately not used. Acidifying the urine of a patient who is hyperthermic, rhabdomyolysing and at risk of myoglobinuric renal failure is the opposite of what the kidney needs. A mechanism can be correct and still be the wrong thing to do, which is a useful counterweight to the alkalinisation argument on the salicylate page.
Purity and identity	—	Unknown at the bedside. Tablets sold as MDMA vary widely in content, and the substituted cathinones are sold interchangeably	The dose axis is unmeasurable, which is why no threshold appears on this page. It also means a presentation that does not fit MDMA may be a cathinone, a different amphetamine, or a mixture.
Co-ingestants	—	GHB/GBL was co-used in 54.2% of 850 central London methamphetamine presentations, and that group had a higher Poisoning Severity Score and greater need for level 2/3 care²	A co-ingestant that changes the outcome, not merely the picture. The same series found GHB/GBL appeared to attenuate the neuropsychiatric features² — a sedative masking a stimulant, in a combination associated with more intensive care rather than less. See GHB and GBL.
Dialysability	—	Never assessed. EXTRIP has published no recommendation covering the amphetamines or MDMA³	The absence is genuine rather than dismissible: these are moderately sized, moderately bound molecules and nobody has put the question. But the lethal problems here — heat and sodium — are not solved by removing drug, which is the better reason not to pursue it.

Metabolism and the metabolites

The pathway below is drawn at the synapse rather than in the liver, because that is where the mechanism is — with one hepatic branch, which is the branch Fallon's work implicates in the hyponatraemia.

Amphetamines — the transporter run backwards, and the metabolite that raises vasopressin

Amphetamine, methamphetamine or MDMAA substrate at the monoamine transporter, not merely a blocker of it
Cytoplasmic drugThe first step of the mechanism is uptake — the opposite of cocaine, which binds the transporter without being carried through it
Reversed concentration gradientThe carrier now moves transmitter outwards. Release becomes independent of nerve firing
Dopamine and noradrenaline released — methamphetamine, dexamfetamineSympathomimetic toxidrome and psychosisAgitation (41.5%), anxiety (35.2%), hallucinations (16.5%) and psychosis (14.8%) in 850 London presentations²
Serotonin released — MDMA preferentiallySerotonin toxicityExamine for clonus — see SSRIs and serotonin toxicity
HMMA and other metabolitesHMMA was the most potent of the metabolites tested at releasing vasopressin from isolated rat hypothalamus¹
Water retentionCombined with drinking free water: hyponatraemia, cerebral oedema, seizure

Elimination and accumulation

Nothing accumulates pharmacologically in a way that changes management. What accumulates is heat, and water. Both are stated here as elimination problems because that is genuinely what they are — the body's capacity to eliminate heat and to eliminate free water are the two clearances that fail in this poisoning, and neither has anything to do with the liver or the kidney's handling of the drug.

These two lethal mechanisms pull in opposite directions therapeutically, which is the awkward heart of this poisoning. Hyperthermia and rhabdomyolysis argue for volume; hyponatraemia argues against free water. The resolution is that the two are distinguished by measurement rather than by clinical impression — which is why the sodium is not an optional test here — and that the specifics of fluid choice and correction rate belong to TOXBASE and NPIS, not to this page.

Target organs — and why those

Skeletal muscle and thermoregulation

TargetSustained contraction plus impaired cutaneous heat loss

Why hereThe organ system that kills, and it is not usually thought of as an organ. Muscle supplies the heat; vasoconstriction removes the means of losing it; the environment supplies the rest. Above about 40 °C the injury becomes self-sustaining and multi-organ. The reason this card sits first is that it outranks the cardiac effects in importance, which is the opposite of clinical intuition for a stimulant. Inferred

At the bedsideHyperthermia, rigidity, rhabdomyolysis, acute kidney injury, coagulopathy. Measure the temperature properly and early. Sedation is part of cooling because it removes the heat source; antipyretics do nothing because the set point is not raised.

Kidney and the sodium — MDMA specifically

TargetVasopressin-mediated free water retention

Why hereDemonstrated rather than inferred: plasma arginine vasopressin rose significantly at 1, 2 and 4 hours in eight healthy male volunteers given 40 mg of MDMA.¹ The metabolite contribution — HMMA most potent of those tested — comes from isolated rat hypothalamus and the authors state that further work is needed to show whether it holds in vivo.¹ The human vasopressin finding is established; the metabolite ranking is not. Established

At the bedsideHeadache, vomiting, confusion, seizure or coma in a young person with a normal-looking presentation and a sodium in the 120s. Check the sodium in every MDMA presentation with any neurological feature.

Brain — dopaminergic and serotonergic pathways

TargetMassive non-vesicular release at both transporters

Why hereThe euphoria, the psychosis and the serotonergic syndrome are the same mechanism read at three intensities and two transporters. Methamphetamine's dopaminergic dominance produces a psychosis clinically indistinguishable from a primary psychotic illness; MDMA's serotonergic selectivity produces the syndrome the SSRI page describes. In 850 central London methamphetamine presentations the commonest features were neuropsychiatric: agitation 41.5%, anxiety 35.2%, hallucinations 16.5% and psychosis 14.8%.² Established

At the bedsideAgitation, paranoia, hallucinations. For MDMA, examine for clonus — the Hunter criteria's key finding applies here exactly as it does to a drug interaction.

Heart and vasculature

TargetExcess noradrenaline at adrenergic receptors

Why hereReal, and deliberately placed below the thermal and electrolyte cards rather than above them. Tachycardia, hypertension, increased myocardial oxygen demand and vasoconstriction all follow directly from noradrenaline release. Unlike cocaine, the amphetamines are not sodium-channel blockers, so the wide-QRS problem does not belong here — which is a genuine and useful difference between two drugs that look identical at the bedside. Established

At the bedsideTachycardia, hypertension, chest pain, and in severe cases myocardial ischaemia, dissection or intracranial haemorrhage from the hypertensive surge. A wide QRS in a stimulant presentation should prompt a search for cocaine or another sodium-channel blocker rather than being attributed to the amphetamine.

Liver

TargetSecondary injury from hyperthermia, plus idiosyncratic hepatotoxicity

Why hereTwo separate mechanisms sharing one organ. Most MDMA-associated liver injury is a consequence of hyperthermia — the same heat-mediated cellular injury that damages muscle and kidney. A separate, rarer idiosyncratic hepatitis is described and is not temperature-dependent; its mechanism is not established, which is why this card is inferred. Inferred

At the bedsideTransaminitis in the acute presentation, usually with hyperthermia. Fulminant hepatic failure is described and is rare; the distinction from the heat-mediated injury is made by whether the patient was ever hot.

Serotonergic neurones — the chronic question

TargetLong-term serotonergic function after repeated MDMA exposure

Why hereThis card is included to mark a question rather than to answer one. Persistent reductions in serotonergic markers after MDMA have been reported in animals, and neuropsychological and imaging findings have been described in heavy human users. Translating animal neurotoxicity doses to human recreational exposure is contested, and human studies are confounded by polydrug use and by the difficulty of establishing a pre-exposure baseline. No number appears on this card because the honest answer is that the magnitude is disputed. Inferred

At the bedsideNot an acute finding, and not something to counsel about with false precision in an emergency department. It belongs on this page because omitting it would imply the question is settled in the other direction.

Timeline of effects

MDMA and the amphetamines — long enough for heat and water to do their work

Time

What you seeWhat is happening

0–60 minOnset
What you seeEuphoria, alertness, tachycardia, hypertension, mydriasis, bruxism, sweating.
What is happeningReverse transport begins as the drug is taken up into presynaptic neurones and displaces vesicular stores. Oral onset over tens of minutes; smoked or injected within minutes.
1–4 hPeak, and the vasopressin window
What you seeFull sympathomimetic effect. Nothing yet suggests the sodium is falling.
What is happeningPlasma vasopressin was significantly raised at 1, 2 and 4 hours in eight healthy volunteers given 40 mg of MDMA.¹ Free water retention is under way while the patient is drinking and sweating.
1–6 hRedosing
What you seeEscalating agitation; the exposure is still rising when the patient presents.
What is happeningA stepped rather than single exposure. Purity is unknown, so the patient's own estimate of dose carries little information.
2–8 hHyperthermia builds
What you seeRigidity, agitation, rising temperature. Above about 40 °C the injury becomes multi-organ.
What is happeningHeat production from sustained muscle activity exceeds heat loss reduced by cutaneous vasoconstriction, in a hot environment. This is a balance failing over hours, which is why cocaine — gone within one — does not do it.
4–12 hHyponatraemia declares itself
What you seeThe gap drawn here is the sodium falling silently. Then headache, vomiting, confusion, seizure or coma, often in someone who otherwise looks to be coming down.
What is happeningVasopressin-driven water retention¹ plus free water intake plus sodium loss in sweat. Nothing about the earlier presentation predicts it, and the diagnosis is made by a blood test rather than by examination.
6–24 h+Offset, and the sequelae
What you seeSympathomimetic effects settle. Rhabdomyolysis, renal injury and hepatic injury do not.
What is happeningHepatic metabolism and renal excretion clear the drug. As on the cocaine page, clearance does not equal recovery — the damage from heat is already done.
DaysThe comedown
What you seeLow mood, fatigue, poor concentration.
What is happeningDepletion of the monoamine stores the drug forced out, and receptor adaptation to the preceding excess. Not a poisoning, and the reason for the redosing pattern that generates the next one.

A latent phase produced by an endocrine effect

Amphetamines and MDMA — a hormone acting normally on a kidney behaving normally, while the patient supplies the water

The other 26 kinds of latent phase in this library

Antipsychotics — a physical object in the stomach — extended-release quetiapine forming a pharmacobezoar
Arsenic — a tissue declaring on its own timetable rather than the poison's — the arsenic is excreted within days, but the nail that was growing while it circulated does not show its white transverse line for several weeks
Arsine and stibine — a red cell mass haemolysing faster than a kidney can cope with — the exposure is over, the haemolysis is silent until the urine changes colour, and the renal failure that follows is the cause of death
Beta-blockers — a repolarisation lesion waiting for an ectopic beat to fall inside it — sotalol prolongs the QT and then, for hours, nothing happens
Calcium-channel blockers — a tablet that has not yet dissolved
Carbon monoxide — an inflammatory process continuing after the poison itself has gone
Chlorine and ammonia — paraquat's cause at its shortest — the time an injured alveolar epithelium takes to leak
Cocaine — a package that has not yet failed — the calcium-channel blocker's cause moved outside the tablet, where wrapping integrity cannot be measured
Digoxin — distribution of the drug to its target — which that page argues is not a latent phase in the paracetamol sense at all
Ethylene glycol — paracetamol's cause with a different enzyme — glycolate accumulating behind glycolate oxidase while the patient looks merely drunk
GHB and GBL — not the poisoning but its withdrawal — a half-life under an hour means admission for any reason interrupts round-the-clock redosing
Hydrofluoric acid — an ion diffusing far enough to reach a nerve ending — and the thinner the solution, the further it travels before anybody feels it
Iron — a true remission — the corrosive injury settling while absorbed iron moves into the cells it will poison, so the patient improves on their way to the dangerous phase
Ketamine — nitrous oxide's cause on a longer clock — urothelial damage accumulating over months to years of repeated exposure
Lead — bone giving lead back — a store with a half-life of 10 to 30 years releasing its contents when pregnancy, lactation, menopause or osteoporosis resorbs it, so the blood concentration rises after the exposure has ended
Lithium — transport across cell membranes
Mercury — distribution on two clocks — tissue concentrations peaking within 24 hours everywhere except the brain, which is not reached until 2 to 3 days, and which then cannot let the poison out again
Methaemoglobin inducers — paracetamol's cause at its shortest — one to four hours manufacturing the toxic species
Methanol — paracetamol's cause again — formate accumulating behind a folate-dependent disposal step that primates perform poorly
Nitrous oxide — damage accumulating to a threshold
Opioids — an antidote wearing off before the poison does — renarcotisation, the only gap in this set that treatment creates rather than reveals
Organophosphate insecticides — a fat store emptying — and, separately, a second and unexplained lesion declaring itself at a neuromuscular junction the first phase had already left
Paracetamol — time spent manufacturing a toxic metabolite
Paraquat — the body responding to an injury that is already complete
Sodium-channel blockade — a gap that cannot be shortened
Thallium — hair on its own clock rather than the poison's — sensory symptoms come first and the alopecia that makes the diagnosis obvious follows them, well after the interval in which treatment is recommended

The gap is not pharmacological at all — it is the time an electrolyte takes to move.

What the mechanism predicts at the bedside

Measure the temperature properly, early, and again. Hyperthermia is the classical cause of death here and it develops over hours rather than announcing itself.
Check the sodium in any MDMA presentation with a neurological feature. The vasopressin effect is demonstrated in human volunteers¹ and the seizure it causes is treated entirely differently from a drug-induced one.
Sedation is part of cooling, because the muscles are the heat source. Antipyretics have nothing to lower.
Examine for clonus if MDMA is involved — it is a serotonin releaser, and the Hunter findings apply as they do to any serotonergic agent.
A wide QRS points away from an amphetamine and towards cocaine or another sodium-channel blocker. The amphetamines are not local anaesthetics.
Ask about GHB/GBL specifically. It was co-used in 54.2% of 850 central London methamphetamine presentations, and that group had higher severity scores and greater need for level 2/3 care.²
Do not acidify the urine. The ion-trapping mechanism is real and the patient is at risk of myoglobinuric renal failure, which is precisely the situation in which acid urine is harmful.
Check creatine kinase and renal function in any agitated or hyperthermic presentation.
Purity is unknown and the patient's dose estimate carries little information. A presentation that does not fit may be a substituted cathinone or a different drug entirely.
Dialysis has no role and has never been assessed³, and would not address either of the two mechanisms that kill.

The antidote, from the poison's side

There is no antidote, and unusually for this library there is no serious candidate for one. The reason is structural: you cannot antagonise release. A receptor antagonist would have to block every receptor for three transmitters simultaneously; a transporter blocker would prevent the drug entering the neurone but would itself be cocaine.

Benzodiazepines: The first-line intervention and the closest to mechanism-directed. They reduce agitation, reduce muscle activity and therefore heat production, reduce sympathetic outflow, and raise the seizure threshold. Four problems addressed upstream of all of them, exactly as on the cocaine page.
Active cooling: The intervention that most directly addresses the mechanism that kills. Its effectiveness depends on stopping the heat production, which is why it is inseparable from sedation and, in severe cases, from paralysis.
Cyproheptadine: For the serotonergic component of MDMA toxicity, with the same weak evidential footing set out on the SSRI page: the receptor rationale is sound, the demonstration that the drug changes outcome is not. Traditional teaching
Correcting the sodium: Not an antidote but the definitive treatment of the second lethal mechanism. The rate of correction is itself a source of harm, and this page deliberately gives no figures — that is a TOXBASE, NPIS and critical-care decision.
Antipsychotics: Superficially attractive for the agitation and psychosis, and conventionally avoided as first-line in a hyperthermic stimulant presentation: they impair thermoregulation, lower the seizure threshold and can prolong the QT, which are three of this patient's existing problems. See the antipsychotics page for why heat is a hazard of that class in its own right.
Extracorporeal removal: Never assessed³, and it would not address heat or sodium.

Critical appraisal

The vasopressin finding is human, and small. Eight healthy drug-free male volunteers, 40 mg of MDMA, plasma AVP significantly raised at 1, 2 and 4 hours.¹ All male, all healthy, one low dose. It establishes that MDMA raises vasopressin in humans; it does not establish the magnitude of the effect at recreational doses or in women — which matters, because the clinical hyponatraemia literature has long noted a female preponderance that this study cannot address.
The metabolite ranking is not human. HMMA being the most potent releaser was shown in isolated rat hypothalamus, and the authors conclude that further work will demonstrate whether this is also true in vivo.¹ This page states that boundary in the toxic-principle section, the pathway note and the organ card, because describing an ex vivo rat finding in human terms is the exact error the library's earlier audits caught.
The reverse-transport mechanism is badged as inferred, not established. It is the standard and near-universally accepted account of amphetamine action, supported by a large in vitro and animal literature; the specific causal chain in poisoned humans has not been demonstrated, and the badge marks that honestly rather than implying the mechanism is doubted.
The hyperthermia mechanism is inference from physiology. That heat is generated by muscle and retained by vasoconstriction is a reconstruction from known effects rather than a measurement made in amphetamine-poisoned patients. The clinical corollaries — that antipyretics do not work and that sedation is part of cooling — follow from it and are widely accepted.
The London series is a retrospective database study from two EDs in one city.² Its figures — the rise from 4 presentations in 2005 to 294 in 2018, the 850-case series, 94.9% male, agitation 41.5%, GHB/GBL co-use 54.2% — are quoted exactly and describe that population. They are not UK incidence and do not generalise to a district general hospital, and the authors themselves conclude that further work is required.
The 'releasers have no ceiling' argument is a pharmacological argument, not an experimental result. It is internally consistent and explains the clinical differences from cocaine well; it has not been demonstrated by measuring synaptic transmitter in poisoned humans, and it should be read as a good explanation rather than as a finding.
The chronic serotonergic neurotoxicity card deliberately carries no numbers. The animal-to-human dose translation is contested and the human studies are confounded by polydrug use; printing a figure would give false precision to a genuinely open question in either direction.
No dose, threshold, tablet-content or lethality figure appears anywhere on this page. For substances of unknown purity sold under interchangeable names, any such number would be misleading as well as out of scope.
EXTRIP's silence is a genuine absence here rather than a moot one³ — unlike cocaine, where the half-life settles it. It is recorded as unassessed, and the better argument against pursuing it is that neither lethal mechanism is a drug-concentration problem.

References

1
Fallon JK, Shah D, Kicman AT, et al. Action of MDMA (ecstasy) and its metabolites on arginine vasopressin release. Annals of the New York Academy of Sciences 2002 Jun;965:399–409. PMID 12105115. (Eight healthy drug-free male volunteers given 40 mg of (R,S)-MDMA; plasma arginine vasopressin increased significantly at 1, 2 and 4 hours. In isolated rat hypothalamus, MDMA and five metabolites all increased AVP release, with HMMA the most potent and DHMA the least; the authors state that further work will demonstrate whether this is also true in vivo.)
2
Harnett JT, Dargan PI, Dines AM, et al. Increasing emergency department attendances in central London with methamphetamine toxicity and associated harms. Emergency Medicine Journal 2022 Jun;39(6):463–66. PMID 34649939. doi:10.1136/emermed-2020-209550. (Retrospective database study, two central London EDs, 2005–2018; 1244 methamphetamine presentations, rising from 4 in 2005 to 294 in 2018; 850-case series 2014–2018, 94.9% male, median age 35.1; agitation 41.5%, anxiety 35.2%, hallucinations 16.5%, psychosis 14.8%; GHB/GBL co-used in 54.2%, associated with a higher Poisoning Severity Score and requirement for level 2/3 care.)
3
EXTRIP Workgroup — published recommendations index. Extracorporeal Treatments in Poisoning Workgroup. Cited for the absence of any recommendation covering the amphetamines or MDMA. extrip-workgroup.org/recommendations

Amphetamines and MDMA

At a glance