Clinical bottom line
Low-dose naltrexone (LDN) is a putative adjunctive therapy under investigation for symptom management in patients with chronic Lyme disease, a condition characterized by persistent symptoms following standard antibiotic treatment. Current evidence supporting LDN’s use in this context is limited and largely extrapolated from studies on chronic pain and immune modulation. While some mechanistic rationale and preliminary clinical observations suggest potential benefits, robust clinical trials specifically evaluating LDN in chronic Lyme disease are lacking. Clinicians should approach LDN use cautiously, considering the uncertain efficacy and the need for further validation.
What the evidence shows
Chronic Lyme disease (CLD), also referred to as post-treatment Lyme disease syndrome, involves ongoing symptoms such as fatigue, musculoskeletal pain, and cognitive difficulties despite appropriate antibiotic therapy (Marques et al., 2018; Marques et al., 2025). The pathophysiology is incompletely understood but may involve immune dysregulation and neuroinflammation.
Low-dose naltrexone, typically administered at doses of 1–5 mg daily, is hypothesized to exert immunomodulatory effects by transiently blocking opioid receptors, which may upregulate endogenous endorphin production and modulate microglial activation (Bostick et al., 2019; Radi et al., 2023). These mechanisms have prompted investigation of LDN in various chronic pain and inflammatory conditions.
Evidence for LDN in chronic pain syndromes, including fibromyalgia and complex regional pain syndrome, suggests modest symptom improvement and a favorable safety profile (Spargo et al., 2025; Pain Physician, 2021). However, these findings cannot be directly extrapolated to CLD without dedicated studies.
Marques et al. (2025) provide an updated evidence-based overview of CLD, noting that while symptom management remains challenging, no high-quality randomized controlled trials have yet evaluated LDN specifically for CLD. The existing literature primarily consists of case reports, small observational studies, or extrapolations from related conditions.
Caveats and uncertainty
The primary limitation is the absence of rigorous clinical trials assessing LDN’s efficacy and safety in chronic Lyme disease. Most available data derive from chronic pain populations with different underlying pathologies, limiting generalizability.
The heterogeneity of CLD presentations and the lack of standardized diagnostic criteria complicate clinical trial design and interpretation. Additionally, the placebo effect in symptom-driven conditions is notable and must be carefully controlled.
Potential side effects of LDN are generally mild but include sleep disturbances and gastrointestinal symptoms (Bostick et al., 2019). Drug interactions and contraindications should be considered on a case-by-case basis.
Given these uncertainties, LDN should not replace established therapies or delay appropriate diagnostic evaluation. Its use remains off-label and experimental in CLD.
How this may change practice
Clinicians managing patients with chronic Lyme disease may encounter interest in LDN as an adjunctive option for symptom relief. Awareness of the current evidence landscape is essential to provide balanced counseling.
LDN might be considered on a case-by-case basis for patients with refractory symptoms after thorough evaluation and standard treatment, ideally within a research or registry framework to contribute to evidence generation.
Ongoing and future clinical trials are needed to clarify LDN’s role, optimal dosing, and long-term safety in CLD. Until then, clinicians should prioritize evidence-based symptom management strategies and multidisciplinary care.