Lithium Toxicity


Practice Essentials

Lithium is commonly used as maintenance treatment of bipolar disorder. Lithium poisoning occurs frequently, since it is used in a population at high risk for overdose. Furthermore, lithium has a relatively narrow therapeutic index that predisposes patients on lithium maintenance treatment to poisoning with relatively minor changes in medications or health status.[1]

Clinically, the three main categories of lithium poisoning are as follows (see Presentation):

Lithium levels should be measured in symptomatic patients. However, levels may not correlate with clinical symptoms due to the kinetic profile of lithium. Multiple measurements may be indicated to evaluate the effects of treatment and in patients who have taken sustained-release tablets (see Workup).

Supportive therapy is the mainstay of treatment of lithium toxicity. Airway protection is crucial due to emesis and risk of aspiration. Seizures can be controlled with benzodiazepines, phenobarbital, or propofol. See Treatment.




Lithium has been used in medicine since the 1870s. Lithium was initially used to treat depression, gout, and neutropenia, and for cluster headache prophylaxis, but it fell out of favor because of its side effects. The US Food and Drug Administration (FDA) banned the use of lithium in the 1940s because of fatalities but lifted the ban in 1970.



The central nervous system (CNS) is the major organ system affected, although the renal, gastrointestinal (GI), endocrine, and cardiovascular (CV) systems also may be involved.

Lithium is available only for oral administration. It is almost completely absorbed from the GI tract. Peak levels occur 2-4 hours postingestion, although absorption can be much slower in massive overdose or with ingestion of sustained-release preparations.

Lithium dosing

Lithium is minimally protein bound (< 10%) and has an apparent volume of distribution of 0.6-1 L/kg. The therapeutic dose is 300-2700 mg/d with desired serum levels of 0.6-1.2 mEq/L.

Lithium clearance is predominantly through the kidneys. Because it is minimally protein bound, lithium is freely filtered at a rate that depends on the glomerular filtration rate (GFR). Consequently, dosing must be adjusted on the basis of renal function. Individuals with chronic renal insufficiency must be closely monitored if placed on lithium therapy.

Most filtered lithium is reabsorbed in the proximal tubule; thus, drugs known to inhibit proximal tubular reabsorption, such as carbonic anhydrase inhibitors and aminophylline, may increase excretion. Diuretics acting distally to the proximal tubule, such as thiazides and spironolactone, do not directly affect the fractional excretion of lithium (although they may affect serum lithium levels indirectly through their effects on volume status). Reabsorption of lithium is increased and toxicity is more likely in patients who are hyponatremic or volume depleted, both of which are possible consequences of diuretic therapy.

Lithium half-life

The plasma elimination half-life of a single dose of lithium is from 12-27 hours (varies with age). The half-life increases to approximately 36 hours in elderly persons (secondary to decreased GFR). Additionally, half-life may be considerably longer with chronic lithium use.



United States

The American Association of Poison Control Centers’ National Poison Data System reported 6901 case mentions and 3715 single exposures to lithium in 2016.[2] The figures are similar to those reported in the preceding 5 years.[3]


In the 3715 single exposures to lithium reported to the American Association of Poison Control Centers’ National Poison Data System in 2016, outcomes were moderate in 1341 cases and major in 157 cases, with two deaths.[2] Lethal outcomes in lithium toxicity are generally secondary to severe CNS effects with subsequent cardiovascular collapse. Renal, gastrointestinal, and endocrine morbidity may also occur.


In 2016, of the 3715 single exposures to lithium reported to the American Association of Poison Control Centers’ National Poison Data System, 2962 (80%) were in patients aged 20 years or older; 431 (12%) were in patients 13 to 19 years old, and 132 (4%) were in children younger than 6 years.[2]


As with all toxic ingestions, it is important to determine the amount, time, co-ingestants, and reason for ingestion. Toxicity does not often correlate with the measured lithium level since clinical toxicity is affected by the type of the poisoning.

Clinical features

Three main categories of lithium poisoning are as follows: acute, acute-on-chronic, and chronic.

Acute poisoning

These patients usually do not have a tissue body burden. SIgns and symptoms are predominantly gastrointestinal (GI), including nausea, vomiting, cramping, and sometimes diarrhea. Progression of acute toxicity can involve neuromuscular signs such as tremulousness, dystonia, hyperreflexia, and ataxia. Cardiac dysrhythmias have been reported but rarely occur. The most common electrocardiographic finding is T-wave flattening.

Acute-on-chronic poisoning

These patients take lithium regularly and have taken a larger dose recently. These patients may display both GI and neurologic symptoms, and serum levels can be difficult to interpret. Patients should be treated according to their clinical manifestations.

Chronic poisoning

These patients typically have a large body burden of lithium and may be difficult to treat. Chronic lithium toxicity is usually precipitated by introduction of a new medication that may impair renal function/excretion or cause a hypovolemic state. Symptoms are primarily neurologic. Mental status is often altered and can progress to coma and seizures if the diagnosis is unrecognized. Many severely poisoned patients can develop a syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) such as cognitive impairment, sensorimotor peripheral neuropathy, and cerebellar dysfunction.

Drug interactions

The following three major drug classes have been identified as potential precipitants of lithium toxicity:

Systemic effects

Renal toxicity is common with chronic lithium therapy, and may take any of the following forms:

NDI is the most severe manifestation. Lithium inhibits the action of antidiuretic hormone (ADH) on the distal renal tubule, impairing sodium and water reabsorption. Following a cross-sectional study showing that use of statins is associated with lower NDI risk, an international group has initiated a randomized controlled study in lithium users who have indicators of NDI, to determine whether atorvastatin improves urine osmolality and aquaporin excretion.[4]

The most common endocrine disorder secondary to chronic toxicity is hypothyroidism. Lithium is taken up avidly by thyroid cells and blocks thyroid hormone release from thyroglobulin, which inhibits adenylate cyclase and prevents thyroid-stimulating hormone (TSH) from activating thyroid cells via the TSH receptor.[5] It may also affect thyroid hormone synthesis. Myxedema coma has been reported as a complication of toxicity.

Acute exposure to lithium can cause leukocytosis, whereas chronic exposure can produce aplastic anemia.

Patients who are on long-term lithium therapy can develop localized edema, dermatitis, and skin ulcers.


Neurologic effects of lithium toxicity include the following:

Gastrointestinal effects of lithium toxicity include the following:

Mild-to-moderate lithium toxicity is characterized by tremor, weakness, and mild confusion. Moderate-to-severe lithium toxicity is characterized by the following:

Laboratory Studies

Therapeutic drug monitoring is readily available in most settings, and symptomatic patients should have their lithium levels measured. However, levels may not correlate with clinical symptoms due to the kinetic profile of lithium. A repeat level should be checked several hours later after intravenous hydration to disclose any trend. Serial levels may be warranted in cases of sustained-release tablets. The sample must be sent in a lithium-free tube; falsely elevated levels have been obtained in plasma samples from tubes with speckled green tops that contained lithium heparin as an anticoagulant.[6]

Urinalysis, electrolyte levels, and renal function should also be sent. A low anion gap (see the Anion Gap calculator) or a low urine specific gravity may suggest lithium toxicity due to sodium loss. A thyroid function panel may also be considered in patients presenting with symptoms suggestive of hypothyroidism.

Co-ingestants should also be considered in cases of intentional overdose. An acetaminophen level should be obtained in every patient suspected of intentional overdose.

Lumbar puncture should be considered in patients with altered mental status and suspicion of central nervous system infection.

Imaging Studies

Consider a computed tomography (CT) scan of the head in individuals with severe movement disorders, seizures, stupor, or coma. CT scan may be needed to rule out other etiologies and to examine for trauma secondary to intoxication.


Chronic lithium toxicity is frequently associated with nonspecific and diffuse depressed ST segments and T-wave inversion unassociated with symptoms or significant sequelae. A retrospective study in 76 patients receiving lithium therapy found that corrected QT interval >440 ms and diffuse T wave inversion were significantly more common in the 11 patients with serum lithium levels >1.2 mEq/L.[7]

Lithium intoxication may result in dysrhythmias, including complete heart block. Serious cardiac toxicity is uncommon and generally only occurs in individuals with underlying heart disease.

Prehospital Care

Emergency medical services (EMS) personnel should do the following:

Emergency Department Care

Supportive therapy is the mainstay of treatment of lithium toxicity. Airway protection is crucial due to emesis and risk of aspiration. Seizures can be controlled with benzodiazepines, phenobarbital, or propofol.

GI decontamination

Gastric lavage may be attempted if the patient presents within one hour of ingestion.

Lithium is a monovalent cation that does not bind to charcoal; therefore, activated charcoal has no role. However, activated charcoal might be considered in the case of exposure to co-ingestants. The clinician also has to be aware that acute lithium toxicity can produce vomiting and precipitate aspiration of activated charcoal.

Whole-bowel irrigation with polyethylene glycol lavage can be effective in preventing absorption from extended-release lithium.

Because of its similarity to potassium, the use of sodium polystyrene sulfonate has been proposed as a method of eliminating lithium.[8] However, hypokalemia has been reported and studies have still not shown definite evidence of benefit. One retrospective review showed a possible decrease in lithium half-life with administration of sodium polystyrene sulfonate in patients presenting with chronic lithium toxicity.[9] However, it is unknown if this was clinically relevant or if patient outcome was improved.

The benefit of early decontamination of the digestive tract with sodium polystyrene sulfonate, whole bowel irrigation, or both was demonstrated in a retrospective study of 59 cases of acute lithium poisoning in patients on long-term therapy. Compared with the 44 patients in whom decontamination was delayed more than 12 hours or not performed, the 15 patients who underwent early decontamination had a significantly lower risk of severe poisoning (odds ratio, 0.21; P = 0.049), regardless of the lithium dose ingested or the serum lithium level.[10]

Enhanced elimination

The mainstay of treatment is fluid therapy. The goal of saline administration is to restore glomerular filtration rate (GFR), normalize urine output, and enhance lithium clearance.

Lithium is readily dialyzed because of water solubility, low volume of distribution, and lack of protein binding.

Hemodialysis is indicated for patients who have renal failure and are unable to eliminate lithium. It is also indicated in patients who cannot tolerate hydration, such as those with congestive heart failure (CHF) or liver disease, and should be considered in patients who develop severe signs of neurotoxicity, such as profound altered mental status and seizures. An absolute level of 4 mEq/L in acute toxicity and a level of 2.5 mEq/L in chronic toxicity in patients with symptoms should also be considered for hemodialysis, although guidelines for hemodialysis based on levels alone are controversial.

The Extracorporeal Treatments in Poisoning Workgroup recommends extracorporeal treatment in severe lithium poisoning. The group recommends performing extracorporeal treatment in patients with the following[11] :

Extracorporeal treatment should be continued until clinical improvement is seen or levels fall to < 1.0 mEq/L. If levels are not readily measurable, extracorporeal treatments should be continued for a minimum of 6 hours.

Because postdialysis rebound elevations in lithium levels have been documented, continuous venovenous hemofiltration (CVVH) has been advocated.[12, 13]

Patients who are already on peritoneal dialysis should continue with it while awaiting hemodialysis or CVVH.


Consider the following consults:


Medication Summary

The goal of therapy is to remove or reduce the excess amounts of lithium resulting from an overdose.

Polyethylene glycol bowel prep (GoLYTELY, Colyte)

Clinical Context:  Laxative with strong electrolytic and osmotic effects that has cathartic actions in the GI tract.

Further Outpatient Care

Discharge planning varies, depending on whether the overdose was unintentional or intentional. In unintentional overdose, asymptomatic patients and patients with serum lithium concentrations in the therapeutic range and minor toxicity may be discharged with scheduled follow-up in 1-2 days. In intentional overdose, coordinate care with mental health care providers before discharging the patient from the hospital.

Further Inpatient Care

Indications for hospital admission are as follows:


Transfer may be indicated if hemodialysis facilities are not available locally.


Complications of lithium toxicity may include the following:


Most cases of lithium poisoning result in a favorable outcome; however, up to 10% of individuals with severe lithium toxicity develop chronic neurologic sequelae.


David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

Disclosure: Nothing to disclose.


Amit Gupta, MD, Department of Emergency Medicine, Staten Island University Hospital

Disclosure: Nothing to disclose.

Specialty Editors

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

Disclosure: Nothing to disclose.

John G Benitez, MD, MPH, Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

Disclosure: Nothing to disclose.

Chief Editor

Michael A Miller, MD, Clinical Professor of Emergency Medicine, Medical Toxicologist, Department of Emergency Medicine, Texas A&M Health Sciences Center; CHRISTUS Spohn Emergency Medicine Residency Program

Disclosure: Nothing to disclose.

Additional Contributors

Mark S Slabinski, MD, FACEP, FAAEM, Vice President, USACS Central

Disclosure: Nothing to disclose.


The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, James G Linakis, PhD, MD, to the development and writing of this article.


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