Methanol Toxicity

Etiology

Methanol toxicity can occur via ingestion, dermal absorption, and inhalation. Most reported ingestions are linked to drinking windshield wiper fluid as part of a suicide attempt. Accidental ingestion can occur via exploratory behavior in children. Methanol has also been abused as a substitute for ethanol, with agents including food-warming fuel. Carburetor cleaner can be a source of abuse via inhalation.[4]

Epidemiology

People at risk include toddlers and young children exploring their environment, as well as individuals with alcohol use disorder or suicidal behavior. Most cases are isolated incidents. However, epidemics have occurred secondary to ethanol contamination or improper distillation.[5] While estimating the incidence of methanol poisoning is challenging, fomepizole was used in approximately 3,000 United States Poison Center cases in 2023, and methanol poisoning contributed to the death of 24 individuals in the same year.[6]

Pathophysiology

When ingested, methanol is absorbed rapidly via the gastrointestinal tract, but its exact bioavailability is unknown. The alcohol is absorbed directly into the total body water compartment with a volume of distribution of approximately 0.7 L/kg. Serum concentrations peak rapidly after absorption. Elimination of methanol is complex and likely dose-dependent, with higher doses undergoing zero-order elimination, similar to ethanol. A large percentage of methanol is excreted unchanged by the respiratory tract, but this process is inefficient.

Metabolism occurs mainly in the liver through serial oxidation via alcohol dehydrogenase and aldehyde dehydrogenase. However, the process begins with alcohol dehydrogenase present in the gastric mucosa. Alcohol dehydrogenase oxidizes methanol to formaldehyde, and aldehyde dehydrogenase subsequently oxidizes formaldehyde to formic acid. Each oxidation step involves the conversion of nicotinamide adenine dinucleotide (NAD) into its reduced form (NADH). This enzymatic metabolism provides a zero-order elimination rate of about 8 to 9 mg/dL/h when methanol concentration is between 100 and 200 mg/dL.

Formic acid is not easily eliminated and mostly accumulates, while a small amount of its unprotonated form, formate, interacts with folate to yield carbon dioxide and water for exhalation. Unmetabolized methanol, such as in cases where the patient is treated with an alcohol dehydrogenase inhibitor, is insufficiently cleared through the kidneys or lungs and can result in an estimated effective half-life of 30 to 85 hours by 1st-order elimination.[7]

Methanol's metabolites account for its toxicity. Formic acid, the product of methanol's serial oxidation, directly damages multiple organ systems, most notably the central nervous system. Formic acid is responsible for the elevated anion gap metabolic acidosis observed late in methanol poisoning. The retina appears to be particularly sensitive to this organic substance due to reasons that are not well understood. Similarly, the basal ganglia are particularly sensitive to formic acid, and bilateral basal ganglia necrosis with or without hemorrhage is the feared but characteristic finding of methanol poisoning. Acute kidney injury and pancreatitis are also frequently reported in methanol poisoning.[8][9]

Toxicokinetics

A methanol dose of approximately 1 g/kg of body weight is potentially lethal. A density of approximately 0.8 g/mL of pure methanol equates to about 1 to 2 mL of pure methanol per kg of body weight. The dose required to cause permanent visual damage remains controversial. In a study of a large methanol poisoning outbreak, no visual changes were observed in individuals with blood methanol concentrations below 52 mg/dL.[10] However, most experts agree that blood methanol concentrations exceeding 25 mg/dL warrant treatment.

Methanol is less inebriating than other alcohols, likely due to its lower molecular weight. Methanol increases serum osmolality, while its primary toxic metabolite, formic acid, is responsible for the anion gap metabolic acidosis and end-organ damage. As methanol is metabolized, the osmolar gap narrows while the anion gap widens. The development of anion gap metabolic acidosis from formate accumulation is multifactorial, driven by the buildup of poorly eliminated organic acids (eg, formic acid and formate) and disruption of oxidative phosphorylation due to formate’s inhibition of cytochrome oxidase.

Formate’s inhibition of mitochondrial respiration may contribute to lactic acidosis, enhancing its capacity to cross the blood-brain barrier as formic acid. Elevated lactate also results from increased shunting of pyruvate to lactate due to the higher NADH/NAD ratio associated with alcohol metabolism. End-organ damage and retinal toxicity are primarily attributed to oxidative stress induced by formic acid.

History and Physical

History is often challenging to acquire in cases of self-harm, criminal poisoning, and substance abuse. Physical examination findings are often unremarkable in early ingestions. Patients may be embarrassed or may not want to admit to their actions. These individuals also frequently underestimate the magnitude and severity of their ingestion. Accidental ingestions, however, are often self-reported or witnessed. A diagnostic dilemma often arises, leaving the clinician to consider toxic alcohol exposure as a potential cause of findings such as metabolic acidosis with an elevated anion gap.

Patients may appear normal or mildly inebriated within the first 12 to 24 hours after ingestion, a phase known as the latent period. Nausea, vomiting, and abdominal pain often follow, progressing to central nervous system depression and hyperventilation as metabolic acidosis develops. Ocular symptoms from retinal toxicity typically include blurry vision, decreased visual acuity, photophobia, and a “halo vision,” with funduscopic findings that include papilledema, optic disc hyperemia, or pupillary defects. Symptoms of basal ganglia toxicity may be initially masked by altered mental status and the severity of illness. Without treatment, patients risk progression to coma, respiratory or circulatory failure, and death.

Evaluation

Patients who have ingested methanol can present along a spectrum, ranging from asymptomatic with an increased osmolar gap to critically ill with end-organ toxicity and anion gap metabolic acidosis. The evaluation of methanol toxicity should follow a structured diagnostic approach incorporating historical details and objective findings.

Essential investigations for any toxicology patient with suspected self-harm include an electrocardiogram, basic metabolic panel, and acetaminophen and salicylate concentrations. Additional tests to consider when self-harm is a concern include a complete blood count, transaminases, lipase, pregnancy status, serum or urine ketones, lactate, and ethanol concentration. Measuring ethanol concentration is crucial in toxic alcohol ingestion, as ethanol competitively inhibits methanol metabolism due to its higher affinity for alcohol dehydrogenase.

Toxic alcohol concentrations, measured by gas chromatography, provide confirmatory results but are often unavailable in many healthcare facilities. These concentrations are reported in mg/dL and typically peak shortly after absorption, decreasing by zero-order kinetics as previously described. The timing of ingestion is crucial, as toxic alcohol concentrations may not accurately reflect toxicity if metabolism has progressed, given that the metabolites are primarily responsible for the toxic effects.

In methanol toxicity, formate concentration can be assessed to correlate with acidosis or clinical signs of end-organ damage, though this measurement is also rarely available in most settings. Toxic alcohol concentrations often require sending a serum sample to an external facility, leading to delays of hours to days, while a diagnosis is typically required sooner.

A systematic approach to diagnosis involves monitoring the patient for anticipated toxic effects. Since anion gap acidosis occurs later, patients presenting with a normal acid-base status early after ingestion should be observed for at least 16 to 24 hours. Serial basic metabolic panels every 2 to 4 hours are recommended to detect the onset of metabolic acidosis and an elevated anion gap. This observation period should only begin after confirming that the patient’s ethanol concentration is undetectable, as ethanol delays methanol metabolism.

Many clinicians prefer using the osmolar gap for risk stratification in patients presenting early after ingestion. A mildly elevated osmolar gap is nonspecific and indicates the presence of any osmotically active substance, such as an alcohol. The osmolar gap is typically elevated shortly after alcohol ingestion and decreases as anion gap metabolic acidosis develops. The initial increase in osmolality results from the osmotically active parent compound, while acidosis arises from the production of toxic metabolites. Accounting for ethanol is essential when calculating the osmolar gap, as it is also osmotically active. The equation for calculating the osmolar gap is as follows:

Serum osmolality = [(2 times the sodium concentration) + (blood urea nitrogen divided by 1.6) + (glucose concentration divided by 18) + (ethanol concentration divided by 4.6)]

The osmolar gap cannot entirely rule out toxic alcohol poisoning but can guide treatment decisions when it exceeds 25 mOsm/kg H2O. However, some references suggest using a threshold of 50 mOsm/kg H2O.[11] An osmolar gap above 50 mOsm/kg H2O strongly suggests toxic alcohol poisoning. Using the formula for calculating the osmolar gap, a toxic alcohol concentration can theoretically be extrapolated based on the molar mass of methanol (32 g/mol) or ethylene glycol (62 g/mol). Baseline osmolar gaps typically range from -10 to 10 mOsm/kg H2O, so this variability should be considered to avoid missing a diagnosis. For example, a measured gap of +10 in a patient with a baseline of -10 may fail to alert clinicians to toxic alcohol poisoning. However, serial serum osmolality measurements and osmolar gap calculations are rarely used in clinical evaluations.

When methanol toxicity with anion gap metabolic acidosis is suspected, the patient should be screened for associated symptoms and undergo a funduscopic examination. The osmolar gap may not be significantly elevated once the patient becomes acidotic, as the parent compound will have metabolized to some extent.

If the patient presents later in the clinical course, the osmolar gap may be normal. An observation period is unnecessary if the patient is already acidotic. However, if the patient is stable, serum or urine ketones should be checked, and treatment should include 1 to 2 L of isotonic, dextrose-containing intravenous fluids along with thiamine supplementation. Many patients at risk for toxic alcohol poisoning may also have alcoholic ketoacidosis or starvation ketosis. If improvement occurs, as evidenced by a decrease in acidosis and the anion gap, toxic alcohol ingestion becomes less likely, and other potential causes should be considered.

A serum alcohol concentration may also be estimated, though the term "alcohol" refers to more than just ethanol. This approach can be helpful in risk stratification for small, inadvertent ingestions with clear, accurate histories. The estimation is based on the dose or amount ingested in mL, the percentage concentration of the ingested alcohol, bioavailability, the volume of distribution in L/kg, and the patient's weight in kg. This method is particularly useful when assessing toxicity in cases of small, accidental ingestions, usually in children. The equation is as follows:

Serum concentration = [(dose times bioavailability) / (volume of distribution times patient weight)]

The process begins by determining the percent concentration of the ingested agent, with 1% equaling 1 g/100 mL, assuming the product's contents are listed in weight per volume. Products using volume per volume to measure concentration require additional calculation steps. The amount ingested is then calculated by multiplying the percent concentration by the volume ingested. This result is multiplied by bioavailability, which is conservatively assumed to be 100%. The product is then divided by the product of the volume of distribution (0.7 L/kg) and the patient’s weight in kg.

The result, expressed in g/L, should be converted to mg/dL by multiplying by 100. This serum concentration assumes that the entire ingestion occurred instantaneously with complete absorption. For small mouthfuls, an adult’s mouthful is approximately 30 mL. A toddler’s mouthful is around 10 mL (see associated practice question).

Toxic alcohol exposure is confirmed when a serum concentration is detected through gas chromatography. The condition should be suspected in patients developing metabolic acidosis with an elevated anion gap, preceded by an osmolar gap, and presenting with the associated symptoms described above. Lactate and ketones may be detectable but are nonspecific.[12]

Treatment / Management

Treatment options for methanol toxicity include supportive care, fomepizole (Antizole, 4-methylpyrazole, or 4MP), ethanol, dialysis, and, theoretically, folate. Fomepizole is the antidote of choice for patients who present early after toxic alcohol exposure. This agent inhibits alcohol dehydrogenase. Ethanol may also be used therapeutically to inhibit alcohol dehydrogenase when fomepizole is unavailable, with a target continuous serum ethanol concentration of at least 100 mg/dL to prevent the metabolism of toxic alcohols.

Both treatments have advantages and disadvantages. Fomepizole is easier to dose, does not induce inebriation, and strongly inhibits alcohol dehydrogenase, but it is relatively expensive. Ethanol, while less costly, is more difficult to dose accurately, requires close monitoring of serum ethanol levels, and induces inebriation, which may necessitate intensive care monitoring.

Indications for treatment include an elevated methanol concentration, suspicion of early presentation after exposure, and severe or progressing acidosis despite resuscitation, along with clinical suspicion of methanol ingestion. Recommendations for starting treatment vary based on methanol concentration. The most conservative recommendation is to begin treatment if the methanol concentration exceeds 20 to 25 mg/dL. However, if metabolic acidosis is mild or absent, and no evidence of end-organ toxicity is present, treatment could be considered starting at a methanol concentration of 32 mg/dL, as molar calculations suggest that this value corresponds to a maximum of 10 mmol/L of the toxic metabolite (formate). This concentration should not result in more than a 10 mmol/L base deficit or a toxic amount of metabolite.

Note that the molar-based treatment cutoff for ethylene glycol is 62 mg/dL. See StatPearls' companion activity on ethylene glycol toxicity.

When the methanol concentration is not readily available, indications for treatment with an alcohol dehydrogenase inhibitor, such as fomepizole, are less clear. If methanol ingestion is strongly suspected based on history, immediate treatment with fomepizole is reasonable while awaiting confirmation. Methanol metabolism is inhibited for 12 hours after initial treatment with fomepizole, providing time for further diagnostics or preparation for hemodialysis.

Fomepizole and ethanol inhibit alcohol dehydrogenase, preventing the conversion of methanol into its toxic metabolites, formic acid and formate. By inhibiting alcohol dehydrogenase, methanol clearance is prolonged from approximately 8.5 mg/dL/hr to an effective half-life of 45 to 90 hours. Fomepizole is administered intravenously, starting with a loading dose of 15 mg/kg, followed by maintenance doses of 10 mg/kg every 12 hours until the methanol concentration falls below 25 mg/dL and normal acid-base status is restored.

If more than 4 maintenance doses are needed, the dose increases to 15 mg/kg every 12 hours due to autoinduction and increased metabolism. During hemodialysis, fomepizole should be given either every 4 hours or timed immediately after dialysis. Importantly, fomepizole only reduces the risk of end-organ damage before acidosis develops while the parent compound is still present and minimal amounts of toxic metabolites have formed.

Ethanol dosing is more complex, is harder to monitor, and carries the risk of inebriation. This alcohol may be administered intravenously or orally, with the goal therapeutic serum concentration ranging from 80 to 120 mg/dL. The intravenous ethanol formulation is typically 10%, and the loading dose is calculated using the following formula:

Loading dose = Goal plasma concentration (100 mg/dL) × volume of distribution of ethanol (0.6 L/kg) × patient weight

Maintenance dosing is then based on the estimated zero-order elimination rate. Empirically, 10% intravenous ethanol may be given with a loading dose of 8 mL/kg over 30 to 60 minutes, followed by maintenance doses of 1 to 2 mL/kg per hour. Maintenance dosing is doubled during hemodialysis. Oral dosing may be calculated using the same equation, with a target serum concentration of 100 mg/dL and solving for the amount to be ingested. Empirically, 50% (100 proof) oral ethanol may be given with a loading dose of 2 mL/kg, followed by maintenance dosing of 0.2 to 0.4 mL/kg per hour, also doubled during hemodialysis.

Patients with toxic methanol ingestion often require hemodialysis, even when fomepizole is administered. Intermittent hemodialysis is preferred over continuous renal replacement therapy (CRRT), as it is much more efficient at clearing toxic substances like methanol. Due to methanol's low volume of distribution, low molecular weight, and lack of protein binding, both methanol and its toxic metabolites are effectively dialyzed. Hemodialysis is beneficial even in early methanol toxicity after fomepizole treatment, as it can reduce the patient's length of stay and mitigate the risk of formate toxicity caused by insufficient alcohol dehydrogenase inhibition.

Hemodialysis should be considered for methanol poisoning in cases of severe acidosis, coma, seizures, new visual deficits, or elevated anion gap, though these conditions are not the only criteria for initiation. This decision should be made in consultation with a medical toxicologist, poison control center, or nephrologist.[13] Some patients may require multiple hemodialysis sessions to reduce methanol to nontoxic levels.(A1)

Additional treatment strategies for methanol toxicity include folate supplementation, which may enhance the metabolism of formate to carbon dioxide and water, though its benefits are primarily theoretical. Admission to the intensive care unit is indicated for severe symptoms, significant metabolic derangements, cases requiring hemodialysis, and instances when ethanol is used as an antidote.[14](B2)

Differential Diagnosis

The differential diagnosis of methanol ingestion includes other metabolic acidosis etiologies and poisoning from other toxic alcohols. Important toxicological considerations for metabolic acidosis include poisoning by salicylates, acetaminophen, iron, toluene, carbon monoxide, cyanide, alcoholic ketoacidosis, and other toxic alcohols, such as ethylene glycol, diethylene glycol, isopropyl alcohol, and propylene glycol. Nontoxicological considerations should include diabetic ketoacidosis, alcoholic ketoacidosis, starvation ketosis, lactic acidosis, and uremia.

Prognosis

Patients who present early in the course of methanol poisoning and receive prompt treatment before toxic metabolites form are likely to have a good prognosis. Retinal and basal ganglia toxicity may result in permanent visual impairment, neurologic deficits, or Parkinsonian features. Significant morbidity and mortality can occur when patients present late, or the diagnosis is not recognized in a timely fashion.

Complications

The complications of methanol poisoning include the following:

• Metabolic acidosis
• Permanent visual deficits 
• Parkinson-like disease
• Coma
• Respiratory failure
• Circulatory failure 
• Complications associated with hemodialysis 
• Death

Early intervention is crucial to prevent significant morbidity and mortality.