An Evidence-Based Guide to LDN, Ketotifen, and Integrative Therapies

Yoon Hang Kim, MD, MPH

Mast Cell Activation Syndrome (MCAS) is a complex and often underdiagnosed condition in which mast cells—an essential part of the immune system—become dysregulated and release mediators like histamine, prostaglandins, and cytokines inappropriately. This can result in a wide array of symptoms ranging from fatigue and brain fog to skin reactions, gastrointestinal issues, and even anaphylaxis-like responses.

While conventional medicine typically focuses on antihistamines and mast cell stabilizers, functional medicine seeks to address the root causes and restore balance to the immune system. This approach is increasingly supported by clinical evidence and utilized by MCAS specialists including Dr. Lawrence Afrin, Dr. Tania Dempsey, and Dr. Leonard Weinstock.

Below are key tools used in a functional medicine approach to MCAS: Low Dose Naltrexone (LDN), Ketotifen, Cromolyn Sodium, and an Anti-Inflammatory Diet.

1. Low Dose Naltrexone (LDN): Calming the Overactive Immune Response

Low Dose Naltrexone (LDN) is a compounded medication that works by transiently blocking opioid receptors, which paradoxically results in an upregulation of the body’s natural endorphins and enkephalins. These molecules don’t just influence mood and pain—they also have immunomodulatory effects.

In MCAS, where the immune system is inappropriately reactive, LDN appears to help through several mechanisms:

TLR4 Inhibition: LDN blocks Toll-like receptor 4, dampening the NF-κB inflammatory pathway

Reducing Pro-inflammatory Cytokines: Decreases IL-6 and TNF-α while increasing regulatory cytokines like IL-10

Modulating T-cell Activity: T-cell microparticles activate mast cells; LDN reduces excessive T-cell dysfunction

Stabilizing Mast Cells Indirectly: Through immune system recalibration rather than direct mast cell action

Improving Resilience to Triggers: Better tolerance to stress, infection, or allergens

The Evidence

The landmark 2018 BMJ Case Report by Weinstock et al. documented a patient with severe POTS and MCAS who achieved a 43% decrease in MCAS severity with LDN combined with IVIg therapy. Data from the LDN Research Trust involving 116 MCAS patients showed that 60% reported improvements in various symptoms. A 2025 study published in ScienceDirect found MCAS patients rated LDN benefit at 5.6/10 mean score for overall health status.

LDN is not a cure, but many patients report significant improvement in fatigue, brain fog, and inflammatory symptoms over time. Doses typically range from 0.5 mg to 4.5 mg, individualized to patient tolerance. The “rebound” effect is primarily why it is dosed nightly.

2. Ketotifen: Stabilizing the Mast Cells

Ketotifen is a powerful mast cell stabilizer and H1 antihistamine, typically available through compounding pharmacies in the U.S. Unlike common over-the-counter antihistamines, ketotifen has dual action:

Prevents Mast Cell Degranulation: Reduces the release of histamine, tryptase, and various prostaglandins by stabilizing calcium permeability in mast cell membranes

Blocks Histamine Receptors: Reduces downstream symptoms like flushing, hives, or gastrointestinal distress

In functional medicine, ketotifen is often used as a bridge therapy to help control symptoms while deeper root causes—like gut dysbiosis, mold exposure, or chronic infections—are addressed. It is preferred for systemic, skin, and respiratory symptoms due to its H1-receptor antagonism.

Common starting doses are 0.5–1 mg at bedtime, with titration based on response and side effects. Some patients may experience drowsiness initially. Maximum therapeutic effect typically requires 6–12 weeks of consistent use.

3. Cromolyn Sodium: The GI Specialist

Cromolyn sodium is the gold standard for GI-dominant MCAS symptoms because of its negligible systemic absorption (<1%). It works by inhibiting both immediate and late-phase mast cell mediator release.

Unlike ketotifen, cromolyn doesn’t have antihistamine properties—it is purely a mast cell stabilizer. This makes it particularly effective for abdominal pain, nausea, bloating, diarrhea, and food-related reactions.

Cromolyn is available as an oral solution (Gastrocrom®) or can be compounded into capsules for individuals sensitive to liquid formulations.

4. Anti-Inflammatory Diet: Lowering the Baseline Fire

Food is medicine—or it’s fuel for the fire. An anti-inflammatory diet is foundational in managing MCAS. Because mast cell activation can be triggered by inflammatory foods and gut permeability (leaky gut), removing dietary triggers is crucial.

Core Principles

Eliminate High-Histamine Foods: Fermented foods, aged cheeses, alcohol, and leftovers can exacerbate symptoms

Avoid Common Allergens: Gluten, dairy, soy, and artificial additives can be mast cell irritants

Focus on Whole, Nutrient-Dense Foods: Fresh, organic vegetables and fruits (especially low-histamine options like blueberries, zucchini, and leafy greens); wild-caught fish rich in omega-3s; healthy fats (olive oil, avocado, coconut oil); clean protein (pasture-raised meats, collagen peptides)

Supportive Supplements

Quercetin: A bioflavonoid that inhibits the release of histamine, tryptase, and pro-inflammatory cytokines from mast cells. While most mechanistic studies are preclinical, clinical use is widespread due to its favorable safety profile. Typical doses range from 500–1,000 mg daily.

Vitamin C: Enhances Diamine Oxidase (DAO) enzyme activity and has been shown to decrease circulating histamine levels. Typical doses range from 500–2,000 mg daily.

DAO Enzymes: Support histamine breakdown from dietary sources. Most effective supplements are derived from pig kidney extract. Taken before meals containing histamine.

Clinical Algorithm: Matching Treatment to Patient Phenotype

Not all MCAS patients present the same way. The table below categorizes therapeutic agents by predominant symptom pattern:

Final Thoughts

Managing MCAS requires more than simply suppressing symptoms. The functional medicine model offers a systems-based approach, aiming to rebalance the immune system, identify root triggers, and restore resilience.

While these treatments lack massive Phase III trials, they are widely utilized by MCAS specialists due to their biological plausibility and favorable safety profiles. The 2025 MedCrave publication on LDN and hydroxycarbamide for mast cell disorders highlights the ongoing shift toward immunomodulatory combinations in this emerging field.

As always, work with a knowledgeable healthcare provider to tailor any treatment to your specific needs—especially when using compounded medications or navigating complex immune conditions.

References

Primary Clinical Trials & Case Reports

Bonamichi-Santos, R., Castells, M., & Galvão, L. (2018). Non-clonal mast cell activation: A growing body of evidence. Frontiers in Immunology, 9, 2373. https://doi.org/10.3389/fimmu.2018.02373

Molderings, G. J., Haenisch, B., Bogdanow, M., Fimmers, R., & Afrin, L. B. (2016). Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Archives of Pharmacology, 389(7), 671–694. https://doi.org/10.1007/s00210-016-1247-1

Theoharides, T. C., Tsilioni, I., & Bawazeer, M. (2019). Mast cells, neuroinflammation and pain in fibromyalgia syndrome. Frontiers in Cellular Neuroscience, 13, 353. https://doi.org/10.3389/fncel.2019.00353

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

Weinstock, L. B., & Afrin, L. B. (2025). Use of low dose naltrexone and hydroxycarbamide for mast cell disorders (ISM, MCAS, HaT). Journal of Cancer Prevention & Current Research, 16(1), 12–15. MedCrave Online.

Mechanistic & Expert Reviews

Afrin, L. B., & Weinstock, L. B. (2014). Oral cromolyn sodium therapy for mast cell activation syndrome. American Journal of the Medical Sciences, 347(6), 500–502. https://doi.org/10.1097/MAJ.0b013e31828f4f9c

Dempsey, T. (2024). Methylene blue: A look at its surprising health benefits and mast cell stabilization. Dr. Tania Dempsey Integrative Medicine. https://drtaniadempsey.com/what-is-methylene-blue

Hamidian Panehkhaneh, S., & Ghafouri-Fard, S. (2021). Cytokine storm syndrome in SARS-CoV-2 infections: A functional role of mast cells. Frontiers in Immunology, 12, 671340. https://doi.org/10.3389/fimmu.2021.671340

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

Interested in personalized care for MCAS or other immune-related conditions? Schedule a consultation at Direct Integrative Care to explore functional medicine solutions tailored to you.

Dr. Yoon Hang Kim is a board-certified preventive medicine physician specializing in integrative & functional medicine and LDN therapy. He has presented at multiple LDN Research Trust conferences and practices telemedicine through www.directintegrativecare.com serving patients in Iowa, Illinois, Missouri, Georgia, Florida, and Texas.

Keywords: MCAS, Mast Cell Activation Syndrome, functional medicine, LDN, low dose naltrexone, ketotifen, cromolyn sodium, mast cell stabilizer, histamine intolerance, anti-inflammatory diet, integrative medicine, POTS, dysautonomia, quercetin, DAO enzyme