By Yoon Hang Kim, MD, MPH | Board-Certified Preventive Medicine | Integrative & Functional Medicine

When patients ask me about low-dose naltrexone, I tell them the truth: it works remarkably well for about two-thirds of people who try it. The other third? Not so much. That's honest medicine—acknowledging both the promise and the limitations of any therapy.

After more than twenty years of prescribing LDN and presenting at multiple LDN Research Trust conferences, I've developed a deep appreciation for why this therapy works when it does. And increasingly, the answer points to one mechanism that doesn't get nearly enough attention: neuroinflammation.

What Is Neuroinflammation, and Why Should You Care?

Your brain has its own immune system, and at the center of it are cells called microglia. Think of them as the brain's resident macrophages—immune cells that normally lie dormant but spring into action when they sense injury, infection, or systemic inflammation. When activated, microglia release pro-inflammatory cytokines that contribute to pain, fatigue, and cognitive dysfunction (Younger et al., 2014).

Here's the problem: in many chronic conditions, microglia get stuck in an activated state. Long after the original insult has resolved, these cells keep pumping out inflammatory signals. The result is chronic neuroinflammation—a low-grade fire in the central nervous system that amplifies pain, disrupts sleep, and contributes to the persistent symptoms we see in conditions like fibromyalgia, chronic fatigue syndrome, and Long COVID.

How LDN Calms the Brain's Immune System

For years, we attributed LDN's benefits primarily to its effects on endorphins. The theory goes like this: LDN temporarily blocks opioid receptors at night, prompting the brain to increase production of endorphins and enkephalins—our natural painkillers and mood stabilizers. Over time, this helps modulate how the nervous system processes pain.

But that's only part of the story. We now understand that LDN also works through a completely different pathway: it dampens neuroinflammation by inhibiting Toll-like receptor 4 (TLR4) on glial cells in the central nervous system (Younger & Mackey, 2014). This matters enormously for patients with chronic pain, because blocking TLR4 prevents the overactivation of microglia and reduces the release of inflammatory substances that amplify pain signals.

In practical terms, LDN appears to work through two main pathways:

• Indirectly: by increasing endorphins and enkephalins, leading to reduced inflammation and better immune balance
• Directly: by blocking inflammatory signaling in the CNS via TLR4 and microglial cells

This dual-action model helps explain why LDN benefits such a wide range of conditions—and why it's particularly effective for patients whose symptoms seem driven by central sensitization or neuroinflammation.

The Clinical Evidence: What the Research Shows

The most compelling research on LDN and neuroinflammation comes from fibromyalgia studies. In a randomized, double-blind, placebo-controlled trial, Dr. Jarred Younger found that LDN reduced pain by 28.8% compared to 18% with placebo—a statistically significant difference that many patients experience as life-changing (Younger et al., 2013). Importantly, these benefits were accompanied by improvements in mood and overall quality of life.

A retrospective analysis from Mayo Clinic adds to this picture: 65% of patients taking LDN for chronic pain reported perceived benefit (Toljan & Vrooman, 2023). That tracks closely with my own clinical experience—roughly two-thirds of patients respond well, while about one-third don't see meaningful improvement with standard protocols.

LDN has also shown effectiveness in reducing symptoms in various autoimmune and inflammatory conditions, including Crohn's disease, multiple sclerosis, and pruritus associated with systemic sclerosis (Kim & West, 2019). The common thread? These conditions all involve some degree of immune dysregulation and neuroinflammation.

Why Some Patients Don't Respond—And What to Do About It

Understanding why LDN fails is just as important as understanding why it works. In my clinical experience, non-responders often fall into specific categories:

• Severely depleted endorphin reserves: Patients who are very ill or have very low functional capacity may not have the baseline endorphin activity for LDN to modulate
• Genetic variations: Individual differences in opioid receptor function can affect response
• Conditions not primarily mediated by LDN's pathways: If the root cause isn't neuroinflammation or immune dysregulation, LDN may not be the right tool
• Co-existing factors: Mold toxicity, chronic infections, or other drivers that override LDN's mechanisms

For these patients, I've developed what I call an "endorphin reserve assessment"—evaluating functional capacity in everyday life to estimate how much baseline endorphin activity remains. Patients with severely depleted reserves often need to start at microgram doses rather than the standard 1.5-4.5 mg range. Some highly sensitive patients require nanogram dosing initially, with titration intervals measured in months rather than weeks.

The Bigger Picture: Neuroinflammation as a Unifying Framework

What excites me most about the neuroinflammation model is how it connects seemingly disparate conditions. Fibromyalgia, chronic fatigue syndrome, Long COVID, mast cell activation syndrome, autoimmune thyroiditis—these conditions share more in common than their diagnostic labels suggest.

In each case, we're often dealing with an immune system that's lost its ability to self-regulate, microglia that are stuck in overdrive, and a central nervous system that has become hypersensitive to normal stimuli. LDN doesn't cure these conditions, but by calming neuroinflammation, it can create the conditions for deeper healing.

I've seen this play out clinically time and again. A patient with multiple sclerosis who couldn't walk without assistance now hikes mountains. A patient with post-herpetic neuralgia who was considering early retirement experienced 50% improvement and continued working. A patient with severe insomnia and tinnitus saw both normalize—and when we discontinued LDN, the improvements held, suggesting the therapy had helped reset his system rather than just masking symptoms.

Practical Considerations for Clinicians and Patients

Options for reducing inflammation in the central nervous system are limited. Among the tools I find most consistently helpful are LDN, alpha-lipoic acid, and high-quality fish oil (EPA/DHA). I also consider cannabidiol (CBD) and acetylglutathione for patients who need additional support.

For standard patients with moderate illness, I typically start at 0.1 mg to 1.5 mg and titrate to 4.5 mg over 2-4 weeks. For severely ill patients or those with low functional capacity, I start at 0.5 mg or lower and titrate every 2-4 weeks. The most sensitive patients may need 3-month intervals between dose adjustments.

The most common side effects are vivid dreams or temporary insomnia in the early weeks. Vivid dreams are usually well tolerated, except in patients with PTSD, who may experience nightmares and re-experience trauma. For most patients, these effects are transient and resolve with continued therapy.

The Bottom Line

LDN won't fix everything. But for patients struggling with chronic pain, autoimmune conditions, or neuroinflammatory syndromes, it offers something rare in medicine: a therapy that works with the body's own regulatory systems rather than against them.

By calming neuroinflammation, boosting endorphin levels, and modulating immune function, LDN can help the nervous system learn to stop screaming. And for patients who have been dismissed, gaslit, or told "there's nothing more we can do," that represents something far more powerful than another prescription: it offers hope that doesn't come with the price tag of dependency or systemic harm.

The key is individualization. There is no one-size-fits-all approach to LDN therapy. Whether it means starting at microgram doses for the severely depleted patient or pushing to higher doses for refractory neuropathy, the clinician must be willing to think beyond standard protocols while remaining grounded in the science.

That's honest medicine. That's integrative medicine done right.

References

Kim, Y. H., & West, K. (2019). Treating chronic pain with low dose naltrexone and ultralow dose naltrexone: A review paper. Journal of Pain Management and Therapy, 3(1), 1-5.

Toljan, K., & Vrooman, B. (2023). Efficacy of low-dose naltrexone and predictors of treatment success or discontinuation in fibromyalgia and other chronic pain conditions. Biomedicines, 11(4), 1087. https://doi.org/10.3390/biomedicines11041087

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, bcr2017221405. https://doi.org/10.1136/bcr-2017-221405

Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). Low-dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial. Arthritis & Rheumatism, 65(2), 529-538. https://doi.org/10.1002/art.37734

Younger, J., & Mackey, S. (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

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 is a board-certified physician specializing in integrative and functional medicine. A graduate of Dr. Andrew Weil's Integrative Medicine Fellowship at the University of Arizona, Dr. Kim has been practicing integrative medicine since 1999. He is recognized internationally as an expert in LDN therapy, having authored two books on LDN and published articles on chronic pain management. Dr. Kim has presented at multiple LDN Research Trust conferences and has established integrative oncology programs at Miami Cancer Institute, University of Kansas Medical Center, and Memorial Hospital.

Dr. Kim practices telemedicine through Direct Integrative Care, serving patients in Iowa, Illinois, Missouri, Georgia, Florida, and Texas.

Website: www.directintegrativecare.com

YouTube: @YoonHangKimMD

LDN Support Group: www.ldnsupportgroup.org

Disclaimer: This publication is for educational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider before starting or modifying any treatment regimen.