Low-Dose Naltrexone: An Emerging Treatment for Long COVID - LDN Functional Medicine Perspective Long Covid

A Clinical Perspective from Two Decades of LDN Practice

Yoon Hang Kim, MD, MPH, FAAMA

Direct Integrative Care & Functional Medicine via Telemedicine

Serving IA, IL, MO, GA, FL, TX

www.directintegrativecare.com

Introduction

Long COVID, formally known as post-acute sequelae of SARS-CoV-2 infection (PASC), continues to challenge healthcare systems globally. Millions of patients experience persistent symptoms including fatigue, cognitive impairment, pain, and sleep disturbances that can persist for months or years after initial infection. As a physician who has prescribed low-dose naltrexone (LDN) for over two decades and presented at multiple LDN Research Trust conferences, I have witnessed firsthand how this therapy can benefit patients with complex chronic conditions. The emerging evidence for LDN in Long COVID represents a natural extension of its established applications in fibromyalgia, chronic fatigue syndrome, and autoimmune disorders.

This article synthesizes current evidence, mechanisms, and clinical applications of LDN for Long COVID, drawing from both published research and clinical experience. While LDN remains an off-label intervention, the growing body of preliminary evidence warrants serious consideration by clinicians seeking options for their patients with post-COVID symptoms.

Understanding Low-Dose Naltrexone

Naltrexone is an opioid antagonist conventionally administered at doses exceeding 50 mg for managing opioid and alcohol dependence. However, at low doses (typically 0.5–4.5 mg), LDN operates through fundamentally different pathways. Rather than serving as a direct opioid blocker, LDN functions primarily as an anti-inflammatory agent and immune modulator (Younger et al., 2014).

This mechanistic shift is crucial to understanding LDN’s therapeutic potential. At low doses, naltrexone acts as a TLR4 antagonist, mitigating microglial activation and reducing neuroinflammation. Additionally, transient opioid receptor blockade triggers a rebound increase in endogenous endorphin production, which modulates immune function (Toljan & Vrooman, 2018). These mechanisms make LDN particularly relevant for conditions characterized by neuroinflammation and immune dysregulation—hallmarks of Long COVID.

LDN Functional Medicine Perspective Long Covid - Current Research Status

Observational Studies and Pilot Data

Multiple observational studies have reported improvements in fatigue, pain, sleep, cognition, and daily functioning after one to three months of LDN therapy, with response rates of 50–60%. A landmark study from Dublin tracked 38 Long COVID patients and documented gains in energy levels, pain reduction, concentration, sleep quality, and overall recovery perception after two months of treatment (O’Kelly et al., 2022).

A 2022 pilot study involving 36 patients with post-COVID fatigue demonstrated enhanced fatigue scores and quality of life when LDN (4.5 mg/day) was combined with transdermal NAD⁺ (Campagnolo et al., 2024). While this study lacked a control group, the magnitude of improvement was notable. A 2025 systematic review reinforced these findings, suggesting LDN improves fatigue, cognition, sleep, pain, and functioning, with 73.9% of patients reporting positive responses. A November 2025 meta-analysis further demonstrated statistically significant reductions in fatigue, brain fog, and headaches (Darkoh et al., 2025).

Patient-Reported Outcomes

A landmark 2025 study published in Proceedings of the National Academy of Sciences analyzed patient-reported outcomes from over 3,900 individuals with ME/CFS and Long COVID (Eckey et al., 2025). LDN achieved a net approval score of 49.4%, with patients reporting improvements in fatigue (41.5%), post-exertional malaise (33.2%), and brain fog (42.3%). Notably, LDN was among the most effective treatments with one of the lowest instances of side effects.

Ongoing Clinical Trials

Several randomized controlled trials are advancing to clarify LDN’s efficacy. The British Columbia trial (NCT05430152), a double-blind, placebo-controlled study assessing LDN’s impact on fatigue and inflammatory markers in post-COVID fatigue syndrome, has completed enrollment (Naik et al., 2024). The NIH RECOVER-TLC pediatric/young adult LDN trial targets fatigue reduction in ages 6–25. The LIFT trial (NCT06366724) at Brigham and Women’s Hospital combines LDN with pyridostigmine for ME/CFS and Long COVID with orthostatic intolerance.

Proposed Mechanisms of Action

LDN’s potential in Long COVID stems from several hypothesized mechanisms:

Glial Modulation and Neuroinflammation Reduction: LDN acts as a TLR4 antagonist, mitigating microglial activation in the brain. This mechanism may address the persistent neuroinflammation contributing to fatigue, pain, and cognitive dysfunction in Long COVID (Younger et al., 2014).

Restoration of Ion Channel Function: Groundbreaking 2025 research from Griffith University demonstrated that LDN (3–4.5 mg/day) restores TRPM3 ion channel function in natural killer cells from Long COVID patients. This finding addresses immune dysregulation—a proposed biomarker in Long COVID—and correlates with quality-of-life improvements (Sasso et al., 2025).

Endorphin Upregulation: Transient opioid receptor blockade boosts endogenous endorphin production, modulating immune function and pain perception—mechanisms paralleling those observed in ME/CFS and fibromyalgia.

Clinical Approach: Lessons from Two Decades of Practice

Drawing from my experience prescribing LDN across conditions including fibromyalgia, autoimmune disorders, and chronic pain, I have observed that approximately one-third of patients do not respond to standard LDN protocols. This clinical reality has shaped my approach to Long COVID.

Assessing Endorphin Reserve

Before initiating LDN, I assess each patient’s endorphin reserve by evaluating functional capacity. Key questions include: How long have they been symptomatic? Do they achieve restorative sleep? What is their baseline energy? How quickly do they recover from setbacks? Patients with severely depleted reserves require different dosing strategies than those with moderate illness.

Dosing Strategies

Standard protocols typically initiate oral LDN at 0.5–1.5 mg nightly, titrating to 3–4.5 mg/day over weeks, with treatment durations of 2–6+ months. However, for severely ill patients or those with low functional capacity, I recommend starting at microgram doses (ultra-low-dose naltrexone) and titrating very slowly—sometimes over months rather than weeks. The LDN Research Trust recognizes three dosing categories: ultra-low dose (microgram dosing), very-low dose (0.1–0.5 mg daily), and low dose (1–4.5 mg, sometimes up to 10 mg).

Safety Profile

LDN demonstrates a favorable safety profile with low discontinuation rates across chronic conditions. Common initial side effects include vivid dreams, insomnia, nausea, dizziness, fatigue, and mood alterations—typically resolving with dose adjustments. In the Dublin study, only 5.3% of patients discontinued due to adverse effects (O’Kelly et al., 2022). Important contraindications include concurrent opioid use, and LDN lacks formal guideline endorsement for Long COVID pending additional RCT data.

Clinical Summary

Common Dose: 0.5–4.5 mg daily (titrated slowly over weeks)

Primary Mechanisms: TLR4 antagonism, glial modulation, TRPM3 restoration, endorphin upregulation

Symptoms Targeted: Fatigue, brain fog, chronic pain, sleep disturbances, post-exertional malaise

Key Evidence: Multiple pilot studies positive; RCTs in progress (NCT05430152, NCT06366724)

Regulatory Status: Off-label; not FDA-approved specifically for Long COVID

Limitations of Current Evidence

Despite promising signals, current evidence is constrained by small sample sizes (typically <100 participants), lack of randomization in observational studies, and potential biases including spontaneous recovery. Phenotypic heterogeneity in Long COVID, variable infection-to-treatment intervals, and concurrent therapies limit generalizability. Systematic reviews appropriately classify LDN as “promising but low-certainty,” emphasizing the need for well-designed RCTs.

Conclusion

LDN represents a low-risk, accessible option for managing Long COVID symptoms, supported by growing preliminary evidence and compelling mechanistic insights. As randomized controlled trials mature in 2026, clearer efficacy data will emerge. In the meantime, clinicians should weigh individual patient profiles, assess endorphin reserve, titrate doses appropriately, and monitor for side effects. For patients struggling with persistent post-COVID symptoms and limited treatment options, LDN merits consideration as part of a comprehensive management strategy.

As the quote often attributed to W. Edwards Deming reminds us: “A bad system will beat a good person every time.” For Long COVID patients navigating a healthcare system with limited approved treatments, LDN offers hope—not as a panacea, but as one promising tool in an evolving therapeutic landscape.

Low-Dose Naltrexone: An Emerging Treatment for Long COVID

References

Campagnolo, N., Johnston, S., Collatz, A., Staines, D., & Marshall-Gradisnik, S. (2024). Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19. Brain, Behavior, & Immunity – Health, 36, 100733. https://doi.org/10.1016/j.bbih.2024.100733

Darkoh, A., Ngwa, A. D. K., Akinbile, A. G., Ogunleye, A. E., & Osondu, C. (2025). Does low-dose oral naltrexone alleviate symptoms of Long COVID? A systematic review and meta-analysis. COVID, 5(12), 198. https://doi.org/10.3390/covid5120198

Eckey, M., Li, P., Morrison, B., Bergquist, J., Davis, R. W., & Xiao, W. (2025). Patient-reported treatment outcomes in ME/CFS and long COVID. Proceedings of the National Academy of Sciences, 122(28), e2426874122. https://doi.org/10.1073/pnas.2426874122

Naik, H., Cooke, E., Boulter, T., Dyer, R., Bone, J. N., Tsai, M., Cristobal, J., McKay, R. J., Song, X., & Nacul, L. (2024). Low-dose naltrexone for post-COVID fatigue syndrome: A study protocol for a double-blind, randomised trial in British Columbia. BMJ Open, 14(5), e085272. https://doi.org/10.1136/bmjopen-2024-085272

O’Kelly, B., Vidal, L., McHugh, T., Woo, J., Avramovic, G., & Lambert, J. S. (2022). Safety and efficacy of low dose naltrexone in a long covid cohort: An interventional pre-post study. Brain, Behavior, & Immunity – Health, 24, 100485. https://doi.org/10.1016/j.bbih.2022.100485

Sasso, E. M., Eaton-Fitch, N., Smith, P., Muraki, K., & Marshall-Gradisnik, S. (2025). Low-dose naltrexone restored TRPM3 ion channel function in natural killer cells from long COVID patients. Frontiers in Molecular Biosciences, 12, 1582967. https://doi.org/10.3389/fmolb.2025.1582967

Toljan, K., & Vrooman, B. (2018). Low-dose naltrexone (LDN)—Review of therapeutic utilization. Medical Sciences, 6(4), 82. https://doi.org/10.3390/medsci6040082

Weinstock, L. B., Brook, J. B., Myers, T. L., & Goodman, B. (2018). Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment. BMJ Case Reports, 2018, bcr2017221405. https://doi.org/10.1136/bcr-2017-221405

Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology, 33(4), 451–459. https://doi.org/10.1007/s10067-014-2517-2

About the Author

Yoon Hang Kim, MD, MPH, FAAMA is a board-certified preventive medicine physician with an integrative medicine fellowship from the University of Arizona. He has been prescribing LDN for over two decades and has presented at multiple LDN Research Trust conferences internationally. Dr. Kim established integrative oncology programs at Miami Cancer Institute and the University of Kansas Medical Center. He currently practices functional medicine via telemedicine through Direct Integrative Care (www.directintegrativecare.com), serving patients in Iowa, Illinois, Missouri, Georgia, Florida, and Texas. He is the author of Low Dose Naltrexone Therapy: An Evidence-Based Review and Case Histories and the LDN Primer clinical guide.

Disclosure: The author reports no conflicts of interest. LDN is an off-label treatment and patients should consult with qualified healthcare providers before initiating therapy.