Low-Dose Naltrexone and Apixaban Interaction: What Clinicians and Patients Need to Know

Is there a known interaction between LDN and apixaban?

We found no published pharmacokinetic study that gave naltrexone with apixaban and measured apixaban levels, clotting or bleeding. That is an evidence gap, not a clean result.

The one direct interaction statement comes from the naltrexone side. The 50 mg tablet label says that studies to evaluate possible interactions between naltrexone and drugs other than opioids have not been performed, and that caution is advised if naltrexone is given with other drugs [1].

What the naltrexone label covers

The label's non-opioid interactions are short. Safety and efficacy of combining naltrexone with disulfiram are unknown, and the label says using two potentially hepatotoxic drugs together is not ordinarily recommended. Lethargy and somnolence have been reported with thioridazine. Naltrexone also blocks opioid-containing medicines, including some cough, cold and antidiarrheal products, and the label lists people receiving opioid analgesics as a contraindication [1]. The naltrexone labels were written for the 50 mg tablet and the 380 mg monthly injection and give no guidance on LDN doses [1][6].

What the apixaban label treats as an interaction

Apixaban is an oral direct factor Xa inhibitor [7]. Its label addresses combined P-gp and strong CYP3A4 inducers and inhibitors:

• Combined P-gp and strong CYP3A4 inducers such as rifampin, carbamazepine, phenytoin and St. John's wort: the label says to avoid concomitant use. In 20 healthy participants, rifampin 600 mg daily cut oral apixaban AUC by 54% and reduced oral bioavailability from 49% to 39% [3].
• Combined P-gp and strong CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir: the label says to cut the apixaban dose by 50% for patients taking 5 mg or 10 mg twice daily, and to avoid the combination in patients already on 2.5 mg twice daily. In 18 healthy subjects, ketoconazole raised apixaban AUC by 99% and peak concentration by 62% [2].

Naltrexone was not part of those studies, so there is no figure for the pair.

Does LDN increase bleeding risk?

The effect of LDN on apixaban levels, clotting or bleeding has not been measured. A meta-analysis of four randomized fibromyalgia trials found no significant difference in serious adverse events between LDN and placebo, while vivid dreams and nausea were more common with LDN [8]. Those trials did not involve apixaban.

Apixaban has an established bleeding risk of its own. In ARISTOTLE, major bleeding occurred at 2.13% per year on apixaban versus 3.09% per year on warfarin in 18,201 patients with atrial fibrillation [4].

Why LDN is a different question from 50 mg naltrexone

LDN is not an FDA-approved product or indication. It means naltrexone at doses well below the approved 50 mg tablet, typically 0.5 to 6 mg a day and most often 4.5 mg, used off-label and supplied mainly through compounding pharmacies [5][9]. A 2026 review of 105 studies, 15 of them randomized trials, concluded that current evidence does not support routine clinical use and described the 4.5 mg dose as empirically derived rather than evidence-based [5]. Compounded drugs are not FDA-approved, and FDA does not verify their safety, effectiveness or quality before marketing [10]. The proposed LDN mechanisms remain largely theoretical [5].