Low-Dose Naltrexone in the Management of Sjögren's Syndrome -LDN Sjogren

By Yoon Hang "John" Kim, MD, MPH

About the Author: Dr. Yoon Hang "John" Kim is a board-certified integrative medicine physician with over 20 years of clinical experience. He completed his integrative medicine fellowship at the University of Arizona under Dr. Andrew Weil and holds certifications in preventive medicine, medical acupuncture, and integrative/holistic medicine. Dr. Kim is a recognized expert in low-dose naltrexone (LDN) therapy, having authored three books and more than 20 articles on the subject. He founded and moderates the LDN Support Group with over 7,000 members and has presented at multiple LDN Research Trust conferences. His clinical practice, Direct Integrative Care, serves patients across multiple states with a focus on autoimmune conditions, chronic pain, and complex chronic illness.

Low-Dose Naltrexone in the Management of Sjögren's Syndrome -LDN Sjogren

Sjögren's syndrome is one of those conditions that can quietly steal quality of life. It's a systemic autoimmune disease that primarily attacks moisture-producing glands, leaving patients with chronically dry eyes and mouth—but often so much more. Fatigue, joint pain, brain fog, and involvement of various organ systems can make daily life a real struggle.

Low-dose naltrexone (LDN) has emerged as a promising option for these patients. At doses typically ranging from 0.5 to 4.5 mg per day, LDN behaves very differently from standard-dose naltrexone (50–100 mg) used in addiction medicine. Instead of blocking opioid receptors around the clock, LDN creates a brief, transient blockade that actually upregulates the body's endorphin system and modulates immune function. While the published evidence remains limited to case reports, what we're seeing clinically is encouraging.

Understanding Sjögren's Syndrome

Sjögren's syndrome is a chronic autoimmune disorder where the immune system mistakenly attacks the lacrimal (tear) and salivary glands. The hallmark symptoms—dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia)—are what most people think of, but that's often just the tip of the iceberg.

Many patients experience what I call "non-classic" or systemic Sjögren's: debilitating fatigue, widespread joint and muscle pain, peripheral neuropathies, cognitive difficulties, and involvement of the lungs, kidneys, skin, or nervous system. Some patients have minimal sicca symptoms but profound systemic manifestations. This heterogeneity is important to recognize because treatment approaches may differ.

The disease predominantly affects women (approximately 9:1 ratio compared to men) and typically presents between ages 40 and 60, though it can occur at any age. Diagnosis involves clinical evaluation, serological tests (anti-SSA/Ro and anti-SSB/La antibodies), and sometimes minor salivary gland biopsy. Standard treatments focus on symptom management—artificial tears, saliva substitutes, and immunosuppressive agents like hydroxychloroquine—but no cure exists, and many patients remain symptomatic despite conventional therapy.

How Does Low-Dose Naltrexone Work?

LDN's mechanism is fascinating and counterintuitive. By briefly blocking opioid receptors (typically for just a few hours when taken at bedtime), LDN triggers a compensatory upregulation of endogenous endorphin production and enhances receptor sensitivity. This creates a "rebound" effect that persists throughout the day.

Perhaps more importantly for autoimmune conditions, LDN antagonizes Toll-like receptor 4 (TLR4) on microglia and macrophages. This reduces pro-inflammatory cytokine release and calms neuroinflammation—a mechanism that may explain why patients often report improvements in fatigue, pain, and brain fog.

The safety profile is remarkably favorable. The most common side effects are vivid dreams or mild sleep disturbance, which typically resolve within the first few weeks or can be managed by adjusting the timing of the dose. LDN must be obtained from compounding pharmacies since it's not commercially available in low-dose formulations.

What Does the Published Evidence Show?

The published evidence for LDN in Sjögren's syndrome consists primarily of case reports, but the results are consistent and encouraging.

Dr. Scott Zashin, a rheumatologist at UT Southwestern, published the initial case report in 2019 describing a 47-year-old woman with suspected Sjögren's who had failed standard therapy. After initiating LDN, she experienced significant clinical improvement with reduction of inflammatory markers.

In a 2020 follow-up publication, Zashin reported two additional cases. A 66-year-old woman with documented Sjögren's who had discontinued hydroxychloroquine due to concerns about retinal toxicity experienced recurrence of joint pain and elevated inflammatory markers. After starting LDN at 1 mg and titrating to 2 mg daily, her pain resolved and her ESR and CRP normalized. A 24-year-old woman with documented Sjögren's presenting with chronic widespread pain, fatigue, headaches, and markedly elevated inflammatory markers (ESR 90 mm/h, CRP 14.2 mg/L) showed progressive improvement after LDN titration, ultimately achieving normal inflammatory markers at one-year follow-up on 8.5 mg daily.

A 2023 review in the Mediterranean Journal of Rheumatology by de Carvalho and Skare examined LDN across rheumatological conditions and concluded that while data is limited, LDN appears to be a promising and safe option for pain management in Sjögren's syndrome.

Notably, the published cases consistently show improvement in systemic symptoms—pain, fatigue, and inflammatory markers—rather than the sicca symptoms themselves. This makes sense given LDN's immunomodulatory mechanisms.

Comparing Treatment Approaches

Feature	Standard Treatment	LDN ± Ketosis
Primary Goal	Manage dryness; suppress immune activity	Modulate immune response; reduce inflammation; support metabolic health
Best For	Sicca symptoms; preventing organ damage	Fatigue, chronic pain, brain fog, neuropathy
Availability	Standard pharmacies; often insurance-covered	Compounded LDN (not typically covered); ketosis via dietary modification
Evidence Level	High (established standard of care)	Low to moderate (case reports, clinical experience)

LDN should be viewed as an adjunct therapy, not a replacement for appropriate rheumatological care. Patients with Sjögren's syndrome benefit from a team approach—rheumatology, ophthalmology, dentistry, and, when appropriate, integrative medicine.

My Clinical Experience: LDN + Ketosis

In my own practice, I've had the opportunity to work with numerous Sjögren's patients—both those with classic presentations (predominant dry eyes and dry mouth) and those with non-classic, systemic manifestations (fatigue, widespread pain, neuropathy, brain fog). What I've observed has been genuinely exciting.

Patients who combine LDN with nutritional ketosis have shown excellent responses. The rationale for this combination makes physiological sense: ketosis itself has well-documented anti-inflammatory and neuroprotective effects, and ketones serve as an alternative fuel source that may support mitochondrial function in the setting of chronic inflammation. When paired with LDN's immunomodulatory properties, the synergy appears meaningful.

I've seen patients experience significant reductions in fatigue and pain, clearing of brain fog, and improvements in overall quality of life. Some patients with classic sicca symptoms have even reported modest improvements in dryness, though as the literature suggests, systemic symptoms tend to respond more robustly than glandular dysfunction.

This combination—LDN plus therapeutic ketosis—represents the kind of integrative approach I find most valuable: addressing the underlying inflammatory and metabolic terrain rather than simply suppressing symptoms. It's low-risk, well-tolerated, and puts patients in an active role in their own healing.

Of course, my clinical observations aren't controlled trials, and individual responses vary. But when conventional options have been exhausted or are poorly tolerated, this approach offers real hope.

The Bottom Line

Sjögren's syndrome remains challenging to treat, particularly for patients whose primary complaints are fatigue, pain, and cognitive difficulties rather than (or in addition to) dryness. Low-dose naltrexone offers a mechanistically plausible, low-risk option that has shown consistent benefits in published case reports and in clinical practice.

For patients interested in optimizing their response, combining LDN with nutritional ketosis represents a promising integrative strategy. While we await larger controlled trials, the favorable safety profile and clinical observations to date make this an approach worth considering—ideally in partnership with healthcare providers who understand both the potential and the limitations of this therapy.

Low-Dose Naltrexone LDN in the Management of Sjögren's Syndrome

At www.directinegrativecare.com Dr. Kim is dedicated to guiding you on your path to wellness through a deeply personalized and supportive approach. We focus on integrative medicine, looking beyond symptoms to uncover the root causes of chronic conditions and develop a treatment plan tailored specifically to your unique health journey. By combining compassionate care with innovative therapies, our goal is to empower you with the knowledge and tools needed to achieve lasting health. We invite you to explore our website to learn more about how our patient-centered practice can help you find balance and vitality. 

Yoon Hang Kim MD

Integrative & Functional Medicine Physician

Virtual Practice Serving IA, IL, MO, FL, GA, and TX

www.directintegrativecare.com

References

Carsons, S. E., & Blum, M. A. (2025). Sjogren syndrome. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK431049/

Cleveland Clinic. (n.d.). Sjogren's syndrome. https://my.clevelandclinic.org/health/diseases/4929-sjogrens-syndrome

de Carvalho, J. F., & Skare, T. (2023). Low-dose naltrexone in rheumatological diseases. Mediterranean Journal of Rheumatology, 34(1), 1–6. https://doi.org/10.31138/mjr.34.1.1

LDN Research Trust. (n.d.-a). How low dose naltrexone works. https://ldnresearchtrust.org/how-low-dose-naltrexone-works

LDN Research Trust. (n.d.-b). Low dose naltrexone (LDN) and Sjogren's syndrome. https://ldnresearchtrust.org/low-dose-naltrexone-ldn-and-sjogren%E2%80%99s-syndrome-dr-pamela-smith

Mayo Clinic. (n.d.). Sjogren's syndrome: Symptoms and causes. https://www.mayoclinic.org/diseases-conditions/sjogrens-syndrome/symptoms-causes/syc-20353216

National Health Service. (n.d.). Sjögren's syndrome. https://www.nhs.uk/conditions/sjogrens-syndrome/

Sjogren's Foundation. (n.d.). Understanding Sjogren's. https://sjogrens.org/understanding-sjogrens

The American College of Rheumatology. (n.d.). Sjogren's disease. https://rheumatology.org/patients/sjogrens-disease

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

Zashin, S. (2019). Sjogren's syndrome: Clinical benefits of low-dose naltrexone therapy. Cureus, 11(3), e4225. https://doi.org/10.7759/cureus.4225

Zashin, S. (2020). Sjogren's syndrome and clinical benefits of low-dose naltrexone therapy: Additional case reports. Cureus, 12(7), e8948. https://doi.org/10.7759/cureus.8948