LDN and Your Liver: Separating Myth from Evidence
Why the FDA’s Black Box Warning Doesn’t Apply to Low-Dose Naltrexone
Yoon Hang Kim, MD, MPH
Board Certified in Preventive Medicine | Fellowship Trained Integrative Medicine Physician | Institute of Functional Medicine Scholarship Recipient
Direct Integrative Care | www.directintegrativecare.com
If you’ve ever Googled naltrexone and liver safety, you’ve probably run into a wall of scary language. “Black box warning.” “Hepatic injury.” “Contraindicated in liver disease.” I get it—these phrases would make anyone pause. And if your doctor handed you a prescription for Low-Dose Naltrexone (LDN) and you went home and searched the internet, you might have talked yourself out of filling it by bedtime.
But here’s what the internet isn’t great at telling you: context matters. The liver warning on naltrexone comes from a very specific set of circumstances that has almost nothing to do with the way we use LDN in clinical practice. Let me walk you through what the evidence actually says.
Where the Liver Warning Actually Comes From
The FDA placed a hepatotoxicity warning on naltrexone based on studies using extremely high doses—around 300 mg per day—in a subset of obese patients. At those doses, some participants developed significant elevations in liver enzymes called transaminases (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK], 2020). That’s a dose roughly 60 to 600 times higher than what we prescribe in LDN therapy.
To put this in perspective: the standard addiction-treatment dose of naltrexone is 50 mg per day. LDN doses typically range from 0.5 to 4.5 mg per day. We’re talking about a fraction—sometimes one-tenth, sometimes one-sixtieth—of the standard dose, and an even smaller fraction of the dose that triggered the original warning (Skip’s Pharmacy, n.d.). The systemic exposure at LDN doses is far below the threshold where liver toxicity has ever been observed.
What the Clinical Data Actually Shows
When we look at naltrexone at its FDA-approved dose of 50 mg, multiple clinical trials demonstrate a low rate of liver enzyme elevation and very rare instances of clinically apparent liver injury. LiverTox, the authoritative NIH drug-induced liver injury database, notes that naltrexone has been associated with low rates of enzyme elevations during therapy and only rare instances of clinically significant liver injury (NIDDK, 2020).
One particularly informative study followed 74 alcohol-dependent patients treated with 25–50 mg of naltrexone daily for 12 weeks. Not only did the researchers find no clinically relevant liver function abnormalities, they actually observed statistically significant decreases in ALT and AST—the two primary markers of liver inflammation (Yen et al., 2006). The liver enzymes got better, not worse.
More recently, Ayyala et al. (2022) published a retrospective study of 160 patients prescribed naltrexone for alcohol use disorder, 63% of whom had underlying liver disease and nearly half of those had cirrhosis. Across all groups—including the cirrhosis group—mean AST and ALT levels were significantly lower after naltrexone treatment compared to before. The authors concluded that naltrexone is safe in patients with underlying liver disease, including those with compensated cirrhosis.
Extrapolating to LDN: A Wide Safety Margin
Here’s where clinical reasoning meets common sense. If hepatotoxicity has been observed primarily at 300 mg per day, and not at 50 mg per day, then the safety margin for a 0.5–4.5 mg dose is enormous. Professional reviews have concluded that naltrexone does not appear to be hepatotoxic at recommended doses (Singh & Saadabadi, 2023). When you drop the dose to LDN range, we’re operating with an exceptionally wide therapeutic margin.
The LDN Research Trust, a leading international resource on LDN therapy, reports that there is no evidence LDN causes liver stress. In fact, some prescribers have noted improvements in liver enzymes during LDN therapy, though this remains largely anecdotal and has not been confirmed through large randomized controlled trials (LDN Research Trust, n.d.).
In my own clinical practice spanning two decades of LDN prescribing, I have not encountered a case of liver injury attributable to LDN at standard dosing. That’s not proof—it’s one clinician’s experience—but it aligns consistently with the published literature.
What About Patients Who Already Have Liver Disease?
This is a question I hear frequently, and it’s a fair one. The answer, based on current evidence, is nuanced but encouraging.
For standard-dose naltrexone (50 mg), expert guidance indicates that mild-to-moderate chronic liver disease—classified as Child-Pugh A or B—does not require dose adjustment. Long-acting naltrexone has been tolerated in these patients, with enzyme changes largely attributed to the underlying liver condition rather than the medication itself (Providers’ Clinical Support System, 2014). The medication is contraindicated in acute hepatitis or overt liver failure, and that’s a bright line we respect (NIDDK, 2020).
If standard-dose naltrexone is considered safe in patients with compensated liver disease, it follows logically that LDN—at one-tenth to one-hundredth of that dose—carries even less hepatic risk. The key is proper patient selection, appropriate monitoring, and clinical vigilance.
Practical Monitoring: What I Recommend
While some guidelines suggest that baseline liver function tests are not strictly required before starting naltrexone for addiction treatment (Singh & Saadabadi, 2023), Below is optimized for safety for someone with existing liver conditions.
Baseline assessment. I obtain liver function tests before starting LDN, not because I expect problems, but because having a baseline gives us context if any questions arise later.
Periodic monitoring. I check LFTs at 3–6 month intervals during the first year, and then annually if everything looks stable. For patients with known liver disease, I monitor more frequently.
Red flag awareness. I educate every patient about warning signs that warrant immediate contact: new jaundice (yellowing of skin or eyes), dark urine, right upper quadrant abdominal pain, unexplained marked fatigue, or ALT/AST rising to 3–5 times the upper limit of normal (Gaviria et al., 2016). These are stop-and-evaluate signals regardless of what medication a patient is taking.
The Bottom Line
The FDA’s black box warning on naltrexone is a relic of a specific high-dose study that has very little relevance to LDN therapy. At doses of 0.5–4.5 mg per day, the hepatic risk appears to be exceptionally low. Multiple studies—including those in patients with existing liver disease—have failed to demonstrate meaningful liver toxicity at standard doses, let alone at the micro-fractions we use in LDN practice.
Does that mean we should be cavalier about liver safety? Absolutely not. It means we should be proportionate in our concern. We monitor. We assess. We watch for red flags. But we don’t withhold a potentially beneficial therapy from patients based on a warning that was generated at doses 60 to 600 times higher than what we prescribe.
If your doctor has recommended LDN and you’ve been hesitant because of what you’ve read about naltrexone and the liver, I hope this gives you a more complete picture. As always, discuss your specific situation with your prescribing physician—especially if you have a history of liver disease. But don’t let a misapplied warning keep you from a treatment that might help.
Disclaimer: This article is for educational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider before starting or modifying any treatment regimen.
Yoon Hang Kim, MD, MPH is a board-certified preventive medicine physician specializing in integrative and functional medicine. A graduate of Dr. Andrew Weil’s Integrative Medicine Fellowship at the University of Arizona and a recipient of the Institute of Functional Medicine scholarship, Dr. Kim has been practicing integrative medicine since 1999. He is recognized internationally as an expert in Low-Dose Naltrexone therapy, having authored two books on LDN—including Low Dose Naltrexone: Two Decades of Clinical Observation and Review of Current Research—and published articles on chronic pain management. Dr. Kim has presented at multiple LDN Research Trust conferences and is a frequent guest on podcasts covering LDN and integrative medicine topics. He currently practices telemedicine through Direct Integrative Care (www.directintegrativecare.com), serving patients in Iowa, Illinois, Missouri, Georgia, Florida, and Texas. Educational resources and additional content are available at www.yoonhangkim.com.
References
Ayyala, D., Bottyan, T., Tien, C., Pimienta, M., Yoo, J., Stager, K., Gonzalez, J. L., Stolz, A., Dodge, J. L., Terrault, N. A., & Han, H. (2022). Naltrexone for alcohol use disorder: Hepatic safety in patients with and without liver disease. Hepatology Communications, 6(12), 3433–3442. https://doi.org/10.1002/hep4.2080
Gaviria, M., Karpyak, V. M., & Choi, D.-S. (2016). Liver toxicity of naltrexone: A case study and review of literature. Journal of Liver Research, Disorders & Therapy, 2(3), 73–77. https://doi.org/10.15406/jlrdt.2016.02.00030
LDN Research Trust. (n.d.). Are there any drawbacks to long-term use of low dose naltrexone (LDN)? https://ldnresearchtrust.org/are-there-any-drawbacks-long-term-use-low-dose-naltrexone-ldn
McDonough, M., & Crowley, P. (2015). Naltrexone and liver disease. Australian Prescriber, 38(5), 151. https://doi.org/10.18773/austprescr.2015.063
National Institute of Diabetes and Digestive and Kidney Diseases. (2020). Naltrexone. In LiverTox: Clinical and research information on drug-induced liver injury. National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK548583/
Providers’ Clinical Support System. (2014). Naltrexone and liver safety guideline. https://pcssnow.org/wp-content/uploads/2014/10/PCSS-MAT-NTX-Liver-Safety-Guideline1.pdf
Singh, D., & Saadabadi, A. (2023). Naltrexone. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK534811/
Skip’s Pharmacy. (n.d.). Low dose naltrexone – Can it hurt the liver? https://www.skipspharmacy.com/pharmacy-news/low-dose-naltrexone-can-it-hurt-the-liver/
The Sinclair Method. (n.d.). Naltrexone black box warning. https://www.sinclairmethod.org/naltrexone-black-box-warning/
Yen, M. H., Ko, H. C., Tang, F. I., Lu, R. B., & Hong, J. S. (2006). Study of hepatotoxicity of naltrexone in the treatment of alcoholism. Alcohol, 38(2), 117–120. https://doi.org/10.1016/j.alcohol.2006.05.003
