Three Reason for Using LDN in an Integrative, Functional, and Metabolism LDN Clinic.
Three Reasons I include LDN in My Practice of Medicine
By Yoon Hang Kim, MD, MPH
After more than two decades of prescribing low-dose naltrexone, I still find myself genuinely excited about this medication. Not because it's a magic bullet—I learned a long time ago that those don't exist—but because LDN offers something increasingly rare in medicine: a safe, affordable intervention that works through elegant biological mechanisms to address root causes rather than just mask symptoms.
When I see a new patient struggling with autoimmune disease, chronic pain, or the complex symptom clusters we're now seeing in conditions like Long COVID and mast cell activation syndrome, LDN is often part of my treatment strategy. Not always the first thing I reach for, and certainly not the only thing, but it's earned a permanent place in my integrative toolkit.
Here are the three core mechanisms that explain why.
1. Immune Modulation: Restoring Balance in Autoimmunity
The immune system isn't meant to be suppressed—it's meant to be balanced. This is where LDN shines, and it's fundamentally different from conventional immunosuppressive therapies.
The Science
LDN exerts its immunoregulatory effects by binding to opioid receptors present on immune cells themselves. Research published in the International Immunopharmacology journal confirms that LDN modulates T regulatory cell function—the Tregs that act as our immune system's "traffic controllers," deciding when to ramp inflammation up and when to dial it down.
In autoimmune conditions, this regulatory system has gone haywire. The immune system is stuck in overdrive, attacking healthy tissue. LDN appears to help restore that balance without the immunosuppression that leaves patients vulnerable to infections.
What I See in Practice
I've watched patients with Hashimoto's thyroiditis, rheumatoid arthritis, lupus, and inflammatory bowel disease experience meaningful improvements on LDN. Not everyone responds—I'm transparent with my patients that approximately one-third won't see significant benefit from standard protocols—but for the responders, the changes can be profound.
The key lies in understanding that LDN supports the body's own regulatory mechanisms rather than overriding them. When someone's endorphin reserves are adequate and their disease is primarily driven by immune dysregulation, LDN can act as sufficient therapy. For more complex cases—mold toxicity, CIRS, chronic Lyme—LDN becomes one critical component of a multimodal approach, calming the immune system enough to make deeper treatments more tolerable and effective.
2. Anti-Inflammatory Action: Beyond Traditional NSAIDs
When we talk about inflammation, most people think of the obvious signs—redness, swelling, pain. But the chronic, low-grade inflammation driving conditions like fibromyalgia, metabolic syndrome, and autoimmune disorders operates differently. It's a smoldering fire that conventional anti-inflammatories barely touch.
The TLR4 Connection
This is where the research gets fascinating. At low doses, naltrexone acts as an antagonist to Toll-like receptor 4 (TLR4)—a receptor found on macrophages, mast cells, and microglial cells throughout the body. This mechanism is entirely independent of LDN's opioid receptor effects.
When TLR4 is chronically activated, it triggers a cascade of pro-inflammatory cytokines. A study in the Journal of Biological Chemistry demonstrated that LDN maintains SIRT1 protein expression and prevents NF-κB nuclear translocation—essentially interrupting the inflammatory signaling cascade at a fundamental level.
The result? Decreased production of inflammatory cytokines like IL-6 and TNF-α. Research published in Frontiers in Immunology confirmed that naltrexone inhibits production of these inflammatory mediators in human immune cells following stimulation with various toll-like receptor ligands.
Clinical Implications
For patients with conditions involving systemic inflammation—fibromyalgia, MCAS, chronic pain syndromes—this anti-inflammatory mechanism offers something different from traditional approaches. Unlike NSAIDs, which come with gastrointestinal and cardiovascular risks, LDN's safety profile is remarkably clean.
I particularly appreciate this mechanism in my patients with mast cell activation syndrome, where we're dealing with overactive inflammatory responses on multiple fronts. LDN's TLR4 antagonism provides anti-inflammatory support while we address the mast cell dysregulation through other means—ketotifen, cromolyn, and targeted metabolic interventions.
3. Neuro-Inflammatory Modulation: Calming the Brain's Immune System
Perhaps the most elegant mechanism of LDN involves its effects on neuroinflammation—specifically its ability to modulate microglial cells, the immune cells of the central nervous system.
Understanding Microglia
Microglia serve as the brain's first line of defense, but when they become chronically activated, they produce a toxic cascade of inflammatory mediators, cytokines, and excitatory substances. This neuroinflammatory state has been implicated in fibromyalgia, chronic fatigue syndrome, Long COVID brain fog, and numerous other conditions characterized by fatigue, cognitive dysfunction, and centralized pain.
Research from Dr. Jarrod Younger at UAB's Neuroinflammation, Pain and Fatigue Laboratory has been particularly illuminating. His work demonstrates that LDN crosses the blood-brain barrier and directly modulates microglial inflammation—going beyond its endorphin effects to act on the receptors that activate the inflammatory process in these cells.
The Clinical Picture
When microglia are stuck in an activated state, patients experience what researchers call "sickness behavior": widespread pain, profound fatigue, cognitive difficulties (the dreaded "brain fog"), sleep disruption, and mood disturbances. Sound familiar? These are exactly the symptoms that bring so many patients to my practice.
Brain imaging studies have confirmed increased microglial activation in fibromyalgia patients compared to healthy controls—providing objective evidence for what these patients have long known: their symptoms are real, and they're rooted in measurable biological changes.
By reducing neuroinflammation, LDN addresses the central sensitization that amplifies pain signals and perpetuates the fatigue-pain cycle. It's working at the level of the central nervous system, which helps explain why patients often report improvements not just in pain, but in energy, cognition, and overall quality of life.
Putting It Together: The Art of LDN Prescribing
Understanding these three mechanisms—immune modulation, anti-inflammatory action, and neuro-inflammatory modulation—informs how I approach LDN therapy in my practice.
For the standard patient with moderate illness and adequate functional capacity, I typically start at 1.5 mg and titrate to 4.5 mg over 2-4 weeks. But the "standard patient" represents only a portion of my practice.
For severely ill patients with depleted endorphin reserves—those who can barely function, who've been sick for years—I start much lower, sometimes at microgram doses. The hormesis principle suggests that at very low concentrations, substances that act as inhibitors at higher doses may actually function as stimulators. I've seen this play out clinically in my most sensitive patients.
For treatment-resistant cases, I don't give up. Some patients need higher doses (up to 25-45 mg) combined with ketosis support for neuropathic conditions. Others need LDN stacked with ketotifen and methylene blue for MCAS. The key is individualization.
The Bottom Line
LDN isn't for everyone, and it's not a standalone cure for complex chronic conditions. But its ability to modulate immunity, reduce inflammation, and calm neuroinflammation makes it a valuable tool in the integrative medicine arsenal.
What I appreciate most is that LDN works with the body's own regulatory systems rather than against them. In a medical landscape dominated by interventions that suppress and override, there's something deeply satisfying about a treatment that restores balance.
If you're struggling with autoimmune disease, chronic pain, or inflammatory conditions, LDN may be worth discussing with a knowledgeable provider. The research continues to grow, and my two decades of clinical experience have only deepened my appreciation for this remarkable medication.
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.
Through his telemedicine practice, Dr. Kim specializes in LDN (Low Dose Naltrexone) for the treatment of autoimmune conditions, chronic pain, integrative oncology, and complex conditions, including fibromyalgia, chronic fatigue, MCAS, and mold toxicity. He has been an international speaker at multiple LDN Research Trust conferences and is the author of three books and more than 20 articles. Dr. Kim has helped establish integrative medicine programs at institutions nationwide.
Consulting, Professional Education, Speaking/Writing Engagement: www.yoonhangkim.com
99-Person Membership-Based Integrative Funtional Medicine & Metabolism and LDN Telemedicine:
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Resources:
- LDN Research Trust: ldnresearchtrust.org
- LDN Support Group: ldnsupportgroup.org
References:
- Li Z, et al. Low-dose naltrexone (LDN): A promising treatment in immune-related diseases and cancer therapy. Int Immunopharmacol. 2018;61:178-184.
- Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014;33:451-459.
- Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization. Med Sci. 2018;6(4):82.
- Yang J, et al. The safety and efficacy of low-dose naltrexone in patients with fibromyalgia: A systematic review. J Pain Res. 2023;16:1017-1023.
- Cant R, Dalgleish AG, Allen RL. Naltrexone Inhibits IL-6 and TNFα Production in Human Immune Cell Subsets following Stimulation with Ligands for Intracellular Toll-Like Receptors. Front Immunol. 2017;8:809.
- Patten DK, et al. The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn's Disease, and Other Chronic Pain Disorders. Pharmacotherapy. 2018;38(3):382-389.
- Hutchinson MR, et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). Eur J Neurosci. 2008;28:20-29.
Disclaimer: This article is for educational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider before starting any new treatment.
