Does Modafinil Cause Elevated ALT?
Yes, modafinil can cause elevated alanine aminotransferase (ALT) levels, although this is an uncommon adverse effect that occurs in approximately 2% of patients taking the medication.
Evidence for Modafinil's Effect on Liver Enzymes
The FDA drug label for modafinil specifically mentions liver function abnormalities as a potential adverse reaction 1. According to the official drug information:
- Abnormal liver function was reported in 2% of modafinil-treated patients compared to 1% in placebo-treated patients in controlled clinical trials
- Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of modafinil
- These elevations appeared to increase with time in the population treated with modafinil in placebo-controlled trials
Importantly, the FDA label notes that "no differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin" between modafinil and placebo groups 1. However, the fact that "abnormal liver function" is listed as an adverse reaction occurring in 2% of patients (versus 1% in placebo) suggests that ALT elevations can occur in some individuals.
Clinical Significance and Monitoring
The liver enzyme elevations associated with modafinil appear to be:
- Generally mild and not clinically significant in most patients
- Not associated with symptoms of liver injury in the majority of cases
- Not requiring specific monitoring in patients without pre-existing liver disease
Unlike some medications that carry black box warnings for hepatotoxicity, modafinil is not known to cause severe liver injury. For comparison, medications like lomitapide and mipomersen carry black box warnings for hepatotoxicity with specific monitoring requirements 2.
Special Populations and Risk Factors
Certain patient populations may be at higher risk for developing liver enzyme elevations with modafinil:
- Patients with pre-existing liver disease
- Patients taking other hepatotoxic medications
- Patients with alcohol use disorder
In a study examining modafinil use in patients with primary biliary cirrhosis, the medication was generally well-tolerated without significant worsening of liver function, suggesting it may be safe even in some patients with pre-existing liver disease 3.
Recommendations for Clinical Practice
For patients being prescribed modafinil:
- Baseline liver function tests may be considered, especially in patients with pre-existing liver disease
- Routine monitoring of liver enzymes is not specifically required by the FDA label for modafinil
- If a patient develops symptoms suggestive of liver dysfunction (jaundice, right upper quadrant pain, fatigue, nausea), liver function tests should be obtained
- If significant ALT elevations occur (>3x upper limit of normal), consider dose reduction or discontinuation
Conclusion
While modafinil can cause elevated ALT levels in approximately 2% of patients, this effect appears to be mild and generally not clinically significant. The benefit of modafinil for approved indications typically outweighs this potential risk in most patients without pre-existing liver disease.