Using Low-Dose Naltrexone (LDN) for Long COVID

Long COVID, also known as Post-Acute Sequelae of SARS-CoV-2 infection (PASC), affects millions worldwide. Common symptoms—fatigue, brain fog, pain, and post-exertional malaise—can persist for months after the initial infection. As of 2025, no FDA-approved treatments specifically target Long COVID, prompting patients and providers to explore alternative and off-label therapies.

One such option gaining attention is low-dose naltrexone (LDN), a medication originally approved for opioid and alcohol dependence. When taken at much lower doses (1–4.5 mg/day), LDN has shown promise in modulating the immune system, reducing inflammation, and improving quality of life in patients with complex chronic conditions—including Long COVID.

What Is Low-Dose Naltrexone (LDN)?

Naltrexone is a non-selective opioid receptor antagonist approved in standard doses (50–150 mg/day) for substance use disorders. At low doses, however, LDN exhibits unique pharmacological properties:

• Analgesic

• Anti-inflammatory

• Immunomodulatory

LDN has been used off-label for fibromyalgia, multiple sclerosis, Crohn’s disease, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—a condition with notable overlap with Long COVID. Its potential benefits in Long COVID stem from its ability to dampen chronic inflammation and rebalance immune system activity.

How LDN May Help with Long COVID

Long COVID is believed to be driven by persistent immune activation, chronic inflammation, and possible autonomic dysfunction. Here’s how LDN may address these issues:

🧠 Immune Modulation

LDN temporarily blocks opioid receptors, prompting a rebound increase in the body’s natural opioids (endorphins). This has downstream effects on immune regulation, including:

• Reduced microglial activation in the brain (linked to brain fog and fatigue)

• Suppressed T- and B-cell proliferation

• Improved neuroimmune balance

⚡ Ion Channel Restoration

A study by Griffith University’s National Centre for Neuroimmunology and Emerging Diseases (NCNED) found that Long COVID patients exhibit dysfunctional TRPM3 ion channels in natural killer (NK) cells. These ion channels are crucial for cellular signaling and energy. LDN appears to restore TRPM3 activity, potentially improving:

• Fatigue

• Mental clarity

• Cellular immune responses

🔥 Anti-Inflammatory Effects

LDN blocks Toll-like receptor 4 (TLR4) pathways, reducing the production of pro-inflammatory cytokines. This mechanism may help relieve:

• Muscle/joint pain

• Post-exertional malaise

• Systemic inflammation

💤 Symptom Relief

Many patients report improvements in:

• Fatigue

• Brain fog

• Sleep quality

• Overall function

What Does the Research Say?

Although larger randomized trials are still underway, preliminary findings and patient reports support LDN’s use for Long COVID:

• Griffith University (2025):Published in Frontiers in Immunology, this study showed LDN restored TRPM3 function in NK cells, bringing cellular responses closer to normal.

• Miami VA Cohort (2023):In a study of 108 Long COVID patients, those using LDN had a fivefold higher likelihood of symptom improvement compared to those receiving physical therapy alone.

• Pilot Study (2022):A single-center investigation of 38 patients found LDN (1–3 mg/day) improved energy, concentration, and pain after 8 weeks. Only 2 participants discontinued due to mild side effects (fatigue and diarrhea).

• LDN + NAD+ Study (2024):Combining LDN with NAD+ iontophoresis patches led to improvements in fatigue (Chalder Fatigue Scale) and quality of life (SF-36) scores. However, this small observational study lacked a control group.

• Patient Experiences:On platforms like X (formerly Twitter), patients describe substantial improvements. One user reported a friend feeling “70% recovered” after six months of LDN use.

Ongoing Trials

Larger randomized controlled trials (RCTs) are in progress:

• Australia (Griffith University): Testing LDN in 100 Long COVID patients to measure symptom improvement over 3 months.

• Canada & U.S.: Additional trials are exploring LDN’s impact on fatigue, immune markers, and neurocognitive symptoms.

Is LDN Safe?

✅ Generally Well-Tolerated

Across studies, LDN has demonstrated a high safety profile. Side effects are usually mild and transient:

• Vivid dreams

• Headache

• Nausea or gastrointestinal upset

In a 2022 pilot, only 5.3% discontinued due to side effects.

⚠️ Important Considerations

• Off-label status: LDN is not FDA-approved for Long COVID or ME/CFS. Physicians unfamiliar with its use may hesitate to prescribe it.

• Access: In the U.S., LDN can be obtained via compounding pharmacies but may not be covered by insurance. In the UK, it's usually only available privately.

• Dosing: Most patients begin at 1 mg/day, increasing gradually to 3–4.5 mg/day. Some require lower doses due to sensitivity or side effects.

Future Directions and Challenges

LDN’s potential lies in its ability to address neuroinflammation, immune dysregulation, and cellular energy dysfunction—core features of Long COVID. However, challenges remain:

Key Research Needs:

• Large-scale RCTs to confirm efficacy and optimal dosing

• Mechanistic studies to understand its effects on TRPM3, microglia, and cytokines

• Combination trials pairing LDN with physical therapy, dietary changes, or mitochondrial support (e.g., NAD+, CoQ10)

Personalized Treatment:

LDN may be particularly beneficial for patients with:

• ME/CFS-like features

• Post-exertional malaise

• Cognitive dysfunction linked to neuroinflammation

Conclusion

Low-dose naltrexone is a low-risk, affordable, and accessible therapy that holds potential for easing some of the most disabling symptoms of Long COVID. While the current evidence base is still evolving, LDN has shown enough promise to warrant further study—and for many, it already offers a glimmer of hope.

If you’re considering LDN, consult with a healthcare provider experienced in its off-label use. As clinical trials progress, we may soon have more definitive answers on where LDN fits in the broader landscape of Long COVID treatment.

📌 Learn More:

• Search trials: ClinicalTrials.gov

• Explore LDN groups: Facebook, Reddit, and X communities for support and shared experiences

• Check resources: The ME Association, Frontiers in Immunology, BMJ Open

Yoon Hang Kim MD

www.yoonhangkim.com