Why this poison is interesting

Lithium is the simplest poison in this library and the hardest to reason about from a number. Every kinetic parameter is favourable: it is an ion, so there is no metabolism; it does not bind plasma proteins; its volume of distribution is 0.7–0.9 L/kg, roughly total body water; and more than 95% leaves unchanged in the urine.¹ A poison with that profile is the textbook case for extracorporeal removal, and EXTRIP duly concluded that lithium is dialysable at level of evidence A — the strongest grade the workgroup awards for anything.⁴

And then every recommendation about when to actually dialyse is graded D.⁴ The systematic review behind them found 166 articles, mostly case reports, yielding a very low quality of evidence for all recommendations, from 418 patients of whom 228 allowed patient-level data extraction.⁴ We are certain the treatment removes the poison and uncertain that removing it helps. That gap is the intellectual centre of this page, and it recurs across Band B — the same structure appears in digoxin, where Fab binds the drug exactly as designed and the ATOM studies could not show a mortality benefit.

The second reason lithium is interesting is that the same number means three different things. A concentration of 2.5 mmol/L in a young person who has swallowed a bottle, in an elderly patient whose diuretic was changed a fortnight ago, and in a lithium-treated patient who has taken an extra week's supply on top of steady-state therapy, describe three different diseases with three different trajectories. The Priadel label states the acute case bluntly: a single acute overdose usually carries low risk and patients tend to show mild symptoms only, irrespective of their serum lithium concentration.¹

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

The toxic principle

Lithium is the lightest metal and, in the body, a monovalent cation of similar size to sodium and potassium. That resemblance is the whole of its pharmacology: it enters cells through sodium channels because they cannot distinguish it well, and it is then exported poorly, because Na⁺/K⁺-ATPase handles it far less efficiently than it handles sodium. The consequence is a slow accumulation inside cells that lags the plasma concentration by hours.

What lithium then does inside the cell is, remarkably, not known with any confidence — and this deserves stating plainly rather than glossing. Two mechanisms are usually offered for its therapeutic action: inhibition of inositol monophosphatase, depleting the inositol available for phosphatidylinositol signalling; and inhibition of glycogen synthase kinase-3. Neither has been shown to be the mechanism of its neurotoxicity, and the relationship between the therapeutic mechanism and the toxic one is unestablished.

An honest gap, stated rather than papered over

For most of this library, the mechanism of toxicity is either the therapeutic mechanism taken too far — as in sotalol's QT prolongation — or a distinct pathway that only opens in overdose, as with paracetamol's NAPQI. Lithium fits neither, because the therapeutic mechanism itself is uncertain. Both UK labels say so outright — Priadel that the exact mechanism of action of lithium in the treatment of bipolar disorders is not known¹, Camcolit that the precise mechanism of action of lithium as a mood-stabilising agent remains unknown² — so the inositol-depletion and GSK-3 accounts are taught as mechanism against the explicit position of the licensed labelling. A mechanism-first site should say so: what is well established is where lithium goes, how it is handled and what it does clinically; what is not established is the molecular event that makes a Purkinje cell malfunction. Traditional teaching

The renal handling, by contrast, is well understood and is where most lithium toxicity actually comes from.

Why chronic lithium toxicity is a sodium story

Lithium filtered at the glomerulusFreely filtered — no protein binding to prevent it¹
Proximal tubule, reabsorbed in competition with sodiumThe critical step, and the one sodium depletion subverts¹
Volume depletion, hyponatraemia, diuretic, NSAID, ACE inhibitorKidney conserves sodium — and therefore conserves lithium. The label names thiazides and NSAIDs as the commonest interacting drugs¹
Normal volume and sodium intakeLithium excreted; steady state maintained
Nephrogenic diabetes insipidusPolyuria and polydipsia, both listed among the label's renal effects² — and the polyuria causes the volume depletion that closes the loop above

Toxicokinetics

Lithium — every parameter favours dialysis, and none of them predicts recovery
Parameter	Therapeutic	In overdose	Why it changes
Absorption	Rapidly absorbed from the gastrointestinal tract; prolonged-release Priadel reaches peak serum concentration at about 2 h with approximately 90% bioavailability¹	Delayed. Peak effects may not occur for as long as 24 hours, especially in patients not on chronic therapy or after a sustained-release preparation¹	The gap between a 2-hour peak concentration and a 24-hour peak effect is the intracellular distribution lag made visible. A single early concentration in an acute overdose describes the plasma, not the patient.
Protein binding	None. Lithium is not bound to plasma proteins¹	None	One of the two numbers that make lithium dialysable. Everything in the plasma is available to the dialyser; there is no bound reservoir to re-equilibrate.
Volume of distribution	0.7–0.9 L/kg — approximately total body water¹	Unchanged, but the distribution into that volume is slow	The second number. Compare digoxin's 510 litres, or amlodipine's 21 L/kg: a poison in a small volume is a poison the plasma compartment can actually be used to remove. The slowness of intracellular equilibration is what nonetheless limits how fast the patient improves.
Metabolism	None. Lithium is not metabolised in the liver¹	None	No bioactivation, no active metabolite, no cytochrome interactions, no hepatic route into toxicity. Almost unique in this library.
Elimination	>95% renal, unchanged¹. Reabsorbed proximally in competition with sodium	Unchanged mechanism — but reabsorption rises whenever sodium reabsorption rises	This is the mechanism of virtually all chronic lithium toxicity. Dehydration, intercurrent illness, a new thiazide or an NSAID, or declining renal function, each raise the concentration without any change in dose.¹
Half-life	18–36 h¹	Prolonged in the elderly and in renal impairment¹	Long enough that a patient who stops absorbing does not rapidly clear. EXTRIP's suggestion to dialyse when the expected time to obtain a concentration below 1.0 mmol/L with optimal management is more than 36 hours is a direct arithmetic consequence of this figure.³⁴
Charcoal	—	Activated charcoal does not adsorb lithium¹	Charcoal binds organic molecules by adsorption to a carbon surface. A small hydrated monovalent cation is not adsorbed. This is one of the few poisonings where charcoal is not merely unhelpful but mechanistically irrelevant.
Gastric lavage	—	Slow-release tablets do not disintegrate in the stomach and most are too large to pass up a lavage tube¹	A formulation-level obstacle rather than a pharmacological one. The label also notes gut decontamination is not useful for chronic accumulation¹ — where the lithium is already in the tissues, there is nothing in the gut to remove.
Dialysability	—	Yes — EXTRIP concluded lithium is dialysable at level of evidence A, and recommends intermittent haemodialysis as the preferred modality, with continuous renal replacement an acceptable alternative if it is not available³⁴	Unbound, unmetabolised, small volume of distribution, renally cleared: every property points the same way. The certainty is about the removal, not about the benefit — the same 2015 review that graded dialysability A graded every clinical recommendation D.⁴

Metabolism and the metabolites

There are none. Lithium is an element; it is absorbed as an ion, distributed as an ion, and excreted as an ion. It is not metabolised in the liver.¹ This section exists in the spine of every monograph on this site, and here its emptiness is informative rather than an omission.

The corollary is that the entire interaction profile of lithium is renal and haemodynamic rather than metabolic. The label names the commonest culprits: thiazide diuretics and non-steroidal anti-inflammatory drugs.¹ Both act by increasing proximal sodium — and therefore lithium — reabsorption. A patient started on a thiazide for hypertension has had their lithium dose effectively increased without anyone prescribing more lithium.

Elimination and accumulation

Three presentations, one ion, and the distinction between them determines almost everything about what the concentration means.

Acute overdose in a lithium-naive person: The label is explicit: a single acute overdose usually carries low risk and patients tend to show mild symptoms only, irrespective of their serum lithium concentration.¹ The tissue compartment is empty and takes hours to fill; much of the ingested lithium is excreted before it ever gets into a neuron. A high concentration in this setting is the least alarming of the three. Established
Acute-on-chronic overdose: If an acute overdose has been taken by a patient on chronic lithium therapy, this can lead to serious toxicity occurring even after a modest overdose as the extravascular tissues are already saturated with lithium.¹ The new dose has nowhere to distribute into. The most dangerous of the three, and the one where the concentration understates the problem. Established
Chronic accumulation: No overdose at all. Dehydration, intercurrent illness, deteriorating renal function, or a new thiazide or NSAID.¹ Tissue and plasma are in equilibrium, so a modest concentration accompanies genuine neurotoxicity. These are the patients in whom the neurological signs are most prominent and most likely to persist. Established

The Camcolit label adds a second gradient that is easy to miss: the target range is 0.4–0.8 mmol/L for prophylaxis, and 0.4–0.7 mmol/L in the elderly, in whom toxic symptoms are likely with plasma concentrations above 1.0 mmol/L and are more likely at lower concentrations than in the general population.² The threshold at which a number becomes worrying is patient-specific and moves downward with age.

Target organs — and why those

Cerebellum

TargetNot a defined molecular target — the cerebellum is where the clinical damage concentrates

Why hereThis is the honest entry on this page. Lithium's neurotoxicity is disproportionately cerebellar — ataxia, coarse tremor, dysarthria, nystagmus — and Purkinje cells are the population most often implicated in persistent sequelae. Why these cells is not established. Candidate explanations include their high metabolic rate and their dependence on precisely tuned calcium handling, neither demonstrated as the cause in poisoned humans. Adityanjee and colleagues, reviewing 90 published cases of persistent lithium neurotoxicity, state that the biologic mechanism remains unclear and advance a competing account — demyelination at multiple sites in the nervous system, the cerebellum among them — rather than a Purkinje-specific one.⁵ A card that cannot answer 'why here' should normally not be a card; this one is kept because the organ selectivity is real, well described and unexplained, and pretending otherwise would be worse. Traditional teaching

At the bedsideCerebellar syndrome with ataxia, incoordination, coarse tremor, dysarthria and nystagmus, listed among the label's nervous system disorders.¹ These are the features most likely to persist after the lithium has gone.

Cerebral cortex and brainstem

TargetNeuronal excitability, by a mechanism not established

Why hereLithium enters neurons through sodium channels and is cleared from them slowly, so the intracellular concentration lags plasma by hours in both directions. That accounts for the timing of the neurological syndrome without accounting for its content. Inferred

At the bedsideA graded progression: fine resting tremor, drowsiness and muscular weakness at the mild end; confusion, fasciculation, brisk reflexes, myoclonic jerks, choreoathetoid movements and stupor at the moderate; coma and convulsions at the severe.¹ The gradation is clinically more useful than the concentration, and EXTRIP's indications reflect that — decreased consciousness, seizures or life-threatening dysrhythmias justify treatment irrespective of the concentration.³

Kidney — collecting duct

TargetPrincipal cells; aquaporin-2-mediated water reabsorption

Why hereLithium enters principal cells through the epithelial sodium channel and impairs the vasopressin-driven aquaporin-2 response, producing a nephrogenic diabetes insipidus that is resistant to vasopressin because the defect is downstream of the receptor. The label lists symptoms of nephrogenic diabetes insipidus, polyuria and polydipsia among lithium's renal effects.² Established That the resulting volume depletion then increases proximal lithium reabsorption, closing the loop, is a deduction from two separately established steps rather than a demonstrated sequence. Inferred

At the bedsidePolyuria and polydipsia — and, at concentrations above 2–3 mmol/L, a large output of dilute urine and renal insufficiency.¹ Long-term use is associated with impairment of renal function, interstitial fibrosis and permanent changes.²

Thyroid and parathyroid

TargetThyroid hormone release; calcium-sensing set point

Why hereA chronic-therapy effect rather than an acute poisoning one, included because it changes the assessment of the toxic patient. Lithium interferes with thyroid hormone release, and the label lists goitre, hypothyroidism and hyperthyroidism, together with hypercalcaemia as a very frequent effect and hyperparathyroidism.² Hypothyroidism is a contraindication to starting lithium if untreated.² Established

At the bedsideA confused, slow, tremulous lithium patient may be hypothyroid rather than — or as well as — lithium-toxic. The label directs that thyroid function be assessed before starting and re-assessed periodically.²

Heart

TargetRepolarisation; sinoatrial node

Why hereThe Camcolit label records that lithium can cause an increase in the QTc interval, particularly at higher blood levels, and advises avoiding it in congenital long QT syndrome and with other QT-prolonging drugs.² Established The usual explanation — that lithium substitutes imperfectly for potassium in cardiac cells and so prolongs repolarisation — is textbook teaching rather than a label finding, and neither cited label offers it. Inferred

At the bedsideFlat or inverted T waves, QT prolongation, AV block, sinoatrial block and junctional bradycardia in severe poisoning.¹ Risk factors the label names include bradycardia, thyroid disease and hypokalaemia, hypomagnesaemia and hypocalcaemia — several of which lithium itself contributes to.

Timeline of effects

Acute lithium overdose — the concentration peaks long before the patient does

Time

What you seeWhat is happening

0–2 hAbsorption
What you seeNausea, diarrhoea, perhaps nothing. Usually well.
What is happeningRapid gastrointestinal absorption; prolonged-release Priadel peaks at about 2 h with ~90% bioavailability.¹ The plasma concentration may already be alarming.
2–24 hDistribution into cells
What you seeThe gap. Mild symptoms, or none, while the concentration is high — and the label says explicitly that acute overdose tends to produce mild symptoms irrespective of serum concentration.¹
What is happeningLithium entering cells through sodium channels and leaving them poorly. Peak effects may not occur for as long as 24 hours, particularly in patients not on chronic therapy or after a sustained-release preparation.¹ The poison is in the body but not yet where it acts.
12–48 hNeurological syndrome
What you seeThe graded progression: tremor and weakness, then confusion, fasciculation, myoclonus and choreoathetosis, then in severe cases coma, convulsions and cerebellar signs.¹
What is happeningIntracellular concentration now approaching equilibrium with a plasma concentration that may already be falling. Plasma and patient are moving in opposite directions.
During treatmentThe two curves separate
What you seeConcentration falls quickly; the patient does not.
What is happeningClinical improvement generally takes longer than reduction of serum lithium concentrations regardless of the method used.¹ Dialysis clears the compartment that is not causing the symptoms first.
After stopping dialysisRebound
What you seeConcentration rises again with no new ingestion.
What is happeningDelayed diffusion out of tissues.¹ EXTRIP obtains serial concentrations over 12 hours after interruption to decide on further sessions³; the label advises monitoring for at least a week.¹
Weeks to permanentSILENT
What you seePersistent neurological deficit, characteristically cerebellar, after the lithium has been cleared.
What is happeningThe syndrome of irreversible lithium-effectuated neurotoxicity, described as a distinct entity by Adityanjee and colleagues.⁵ The reason the timeline does not end when the concentration does.

Another kind of latent phase again

Lithium — transport across cell membranes

The other 26 kinds of latent phase in this library

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

Superficially identical gaps between a well patient and a poisoned one, with entirely unrelated causes — which is why this site draws them rather than describing them in a sentence.

What the mechanism predicts at the bedside

Ask how the patient got to this concentration before interpreting it. Acute, chronic and acute-on-chronic are three diseases; the label's own risk assessment differs for each.¹
A high concentration after an acute overdose in a lithium-naive patient is the least alarming version of a high concentration — and a modest one in an acute-on-chronic presentation is the most.¹
A concentration drawn outside the 12-hour convention is not comparable to the therapeutic range.²
Charcoal is pointless — lithium is not adsorbed.¹ So is lavage for most slow-release preparations, on the mechanical grounds the label gives.¹
Do not give a diuretic. The label says so directly.¹ Volume depletion increases lithium reabsorption.
Look for the precipitant in chronic toxicity, because it is usually a new drug or a lost fluid. Thiazides and NSAIDs are the commonest named interactions¹; vomiting and diarrhoea do the same thing without a prescription.
A neurological picture out of proportion to the concentration should not be discounted. EXTRIP treats decreased consciousness, seizures and life-threatening dysrhythmias as indications irrespective of the concentration.³
Expect the concentration to rebound after dialysis, and expect the patient to lag it in both directions.¹³
Check the thyroid. A slow, tremulous, confused patient on long-term lithium has two plausible explanations and the label requires periodic thyroid monitoring for exactly this reason.²
Neurological recovery may be incomplete. SILENT is described precisely because some deficits, particularly cerebellar, persist after the ion has gone.⁵

The antidote, from the poison's side

There is no antidote to lithium and there could not be one. The Priadel label states it plainly: there is no specific antidote to lithium.¹ An antidote must either block a receptor, replace a depleted cofactor, prevent a bioactivation, or bind the poison. Lithium has no receptor to block, depletes no cofactor, undergoes no bioactivation, and is a bare monovalent cation with nothing to bind that would not also bind sodium and potassium.

What lithium has instead is the best claim to extracorporeal removal in Band B, and it is worth seeing why every property points the same way.

No protein binding — the entire plasma content is available to the dialyser.¹
Volume of distribution 0.7–0.9 L/kg — the plasma compartment is a meaningful fraction of the total, unlike digoxin's 510 litres.¹
No metabolism — nothing is being generated to replace what is removed.¹
Small, hydrated, monovalent — it crosses a dialysis membrane readily.
Renally cleared, in a patient whose kidney is often the reason they are poisoned — so the natural route of elimination is frequently the one that has failed.¹

The EXTRIP criteria, and the logic inside them

The workgroup's general recommendation is that extracorporeal treatment is recommended in severe lithium poisoning (1D). Beneath it: recommended where kidney function is impaired and the concentration exceeds 4.0 mmol/L, or in the presence of decreased consciousness, seizures or life-threatening dysrhythmias irrespective of the concentration (both 1D). Suggested where the concentration exceeds 5.0 mmol/L, where confusion is present, or where the expected time to reach below 1.0 mmol/L with optimal management exceeds 36 hours (all 2D). Cessation when the concentration falls below 1.0 mmol/L or clinical improvement is apparent, or after a minimum of 6 hours if a concentration is not readily available (1D), with serial concentrations over 12 hours afterwards to decide about further sessions.³⁴

Read as a set, these criteria are unusually transparent about their own reasoning. Two of them are clinical and override the number entirely, which is a formal acknowledgement that the plasma concentration is not the thing being treated. One is a kinetic prediction rather than a measurement — the 36-hour criterion asks whether the kidney can finish the job in a reasonable time, which is the correct question for a poison whose only natural exit is renal. And the cessation criterion is clinical improvement or a concentration below 1.0 mmol/L — a genuine disjunction, either sufficing.

Critical appraisal

The mechanism of lithium's therapeutic action, and of its neurotoxicity, carries a traditional-teaching badge. Inositol monophosphatase inhibition and GSK-3 inhibition are widely taught as the mechanism. Neither has been established as the cause of the clinical neurotoxicity, and the relationship between therapeutic and toxic mechanisms is unresolved. The badge marks a claim that is repeated confidently and has not been demonstrated — which is what the tier is for.
The cerebellar selectivity is real and unexplained. The organ card above keeps its place on the strength of the clinical description, not of a mechanism, and it says so. Explanations invoking Purkinje cell metabolic rate or calcium handling are plausible and unevidenced in poisoned humans, and the one review to address the question directly calls the biologic mechanism unclear and proposes demyelination instead.⁵
SILENT is a described syndrome, not a quantified risk. Adityanjee and colleagues characterised it as an entity⁵; this page does not state how often it follows severe poisoning, because that figure would need a denominator the literature does not provide.
The autocatalytic loop — nephrogenic diabetes insipidus causing the volume depletion that increases lithium reabsorption — is inference. Each step is separately established; the loop as a driver of clinical deterioration is a reasonable deduction rather than a demonstrated sequence.
EXTRIP's thresholds are consensus numbers with a D grade, and the 4.0 and 5.0 mmol/L figures should not be read as though they were derived from outcome data.³⁴ The workgroup's own quantification of disagreement, and its two-round Delphi process, are the honest part of the method — not a substitute for trials.
The 'acute overdose carries low risk' statement is a label generalisation and should not be used to discharge anyone.¹ It describes a tendency in a population, is explicitly qualified by the caveat that severe symptoms may occur after a delay where elimination is reduced or a slow-release preparation has been taken, and says nothing about the individual in front of you.
Nothing here quantifies how much dialysis shortens the neurological syndrome, which is the outcome patients care about. Given the lag between concentration and clinical state, it is entirely possible for a treatment to clear the ion rapidly and change recovery time very little — and that possibility has not been excluded.

References

1
Priadel 400 mg prolonged-release tablets (lithium carbonate) — Summary of Product Characteristics. electronic medicines compendium, product 13163. Sections 4.9 (Overdose) and 5.2 (Pharmacokinetic properties). medicines.org.uk/emc/product/13163
2
Camcolit 400 mg controlled-release lithium carbonate — Summary of Product Characteristics. electronic medicines compendium, product 10829. Sections 4.2 (Posology — therapeutic ranges and the 12-hour sampling convention), 4.4, 4.5 and 4.8. medicines.org.uk/emc/product/10829
3
EXTRIP Workgroup. Lithium — recommendations. Extracorporeal Treatments in Poisoning Workgroup. extrip-workgroup.org/lithium
4
Decker BS, Goldfarb DS, Dargan PI, et al; EXTRIP Workgroup. Extracorporeal Treatment for Lithium Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup. Clinical Journal of the American Society of Nephrology 2015 May 7;10(5):875–87. PMID 25583292.
5
Adityanjee, Munshi KR, Thampy A. The syndrome of irreversible lithium-effectuated neurotoxicity. Clinical Neuropharmacology 2005 Jan–Feb;28(1):38–49. PMID 15714160.

Lithium

At a glance