LDN and Gut Health: Mast Cell Activation Syndrome (2023)

By Leonard B. Weinstock, MD, FACG

The following excerpt is from The LDN Book, Volume 2: The Latest Research on How Low Dose Naltrexone Could Revolutionize Treatment for PTSD, PAIN, IBD, Lyme Disease, Dermatologic Conditions, and More (Chelsea Green Publishing, October 2020), edited by Linda Elsegood and is reprinted with permission from the publisher.

There are several gastrointestinal (GI) diseases and disorders for which low dose naltrexone has been applied as a therapeutic agent. The pathological factors that allow for the use of LDN in gut disorders and diseases include uncontrolled inflammation, abnormal immunity, increased intestinal permeability, increased visceral hypersensitivity, abnormal motility, and unregulated cellular growth.

The potential use of LDN or endorphins to treat motility disorders is not well known by clinicians. If LDN does lead to improved motility, then it could be used to treat constipation, abnormal small intestinal motility, small intestinal bacterial overgrowth, and gastroparesis. Reducing the overactive immune system by reducing T cells can help Mast Cell Activation Syndrome (MCAS), sarcoidosis, and mesenteric panniculitis. Direct toll-like receptor blockade by naltrexone could help reduce neuroinflammatory processes such as visceral hypersensitivity in IBS.

The following is a review of the medical literature that illustrates the effect of LDN on Mast Cell Activation Syndrome.

Mast Cell Activation Syndrome (MCAS)

Mast cell activation syndrome is a common disorder involving uncontrolled mast cell (MC) activation with multisystemic inflammatory and allergic symptoms.⁴⁶ A study of a German control group estimated the prevalence of MCAS in this population to be 17 percent.⁴⁷ Of the patients in the study, 74 percent reported similar symptoms in one or more first-degree relatives. The indirect prevalence estimate for MCAS in Americans is 1 percent.⁴⁸ Although MCAS is technically an immune disorder with a mutation in the MC control gene, the GI tract is a common site of MC deposition, and activation of these cells produces symptoms both in the gut and systemically. The most common symptoms reported by 50 percent or more of the 413 patients were fatigue, myalgia, conjunctivitis, rhinitis, tinnitus, hives, itching, nausea, heartburn, dyspnea, near syncope, headache, chills, and edema.⁴⁹ Virtually all organ systems can be involved in MCAS.⁵⁰

GI symptoms are commonly reported by MCAS patients and often mistaken by physicians for symptoms of functional syndromes, especially in the cases where the term IBS is assigned to the patient.⁵¹ In IBS patients, local and systemic effects of mediators released by MCs can account for constipation, diarrhea, and pain.⁵² In a study of IBS patients’ colon tissue, histamine and tryptase levels were shown to correlate with pain, as was proximity of the MCs to the submucosal nerves.⁵³ Interestingly, constipation has been linked to the local release of MC mediators near glial cells and filaments.⁵⁴ Thus, MC-induced neuropathy may explain reduced peristalsis of the large intestine. GI symptoms can include tingling or burning, aphthous ulcers, globus, heartburn, dysphagia, chest pain, nausea, altered bowels, bloating, and abdominal pain.⁵⁵ Dyspepsia may be due to mediator-induced nociception.⁵⁶ Gastritis, in the absence of Helicobacter pylori and/ or non-steroidal anti-inflammatory medications, could be explained by MC-mediator-induced inflammation.⁵⁷ Chronic and acute peritoneal pain has been reported in the setting of epiploic appendagitis, where local increased MC deposition was identified.⁵⁸ Studies that demonstrate success with MC-directed therapy in some patients who were labeled with an IBS diagnosis are suggestive of a pathophysiological role of the aberrant MC.⁵⁹ SIBO was recently shown to be common in MCAS.⁶⁰ Bacterial overgrowth, as determined by an abnormal breath test, was present in 30.9 percent of 139 MCAS subjects versus 10.0 percent of 30 controls.

MCAS is often associated with hypermobile Ehlers-Danlos syndrome (hEDS) and postural orthostatic tachycardia syndrome (POTS), both of which also have extensive GI system involvement.⁶¹ MCAS, both alone and in association with these other disorders, results in significant GI morbidity.⁶² MCAS patients pose considerable management challenges due to their pathophysiologic heterogeneity, numerous systemic symptoms and triggers, comorbid conditions, and varied response to therapy. Triggers for MC activation include stress, food, alcohol, excipients in medications, infections, altered microbiome, environmental stimuli (including heat, chemicals, atmospheric changes, electrical changes, and odors), and mold exposure.⁶³

The first publication to demonstrate the efficacy of LDN in MCAS looked at a patient who also had POTS and SIBO. In addition to receiving antibiotic therapy for SIBO, the patient received LDN and immunotherapy with intravenous immunoglobulin (IVIg). A dramatic and sustained response in more than 40 severe symptoms of POTS, MCAS, and SIBO was documented. The utility of IVIg in autoimmune neuromuscular diseases has been established, but clinical experience with POTS is relatively unreported, and data on IVIg in POTS and MCAS had not been previously reported. In this case study the patient found significant benefit from IVIg and rifaximin, but it was not until she escalated the dose of LDN from 2 mg to 4.5 mg that she attained complete improvement. Other early experience in our clinic was also discussed in this publication. We looked at 27 patients with POTS, 11 of whom were administered LDN. Seven of the 11 experienced improvement in GI symptoms, and five experienced improvements in MCAS and POTS. Out of 15 patients who were administered antibiotics for SIBO, this therapy helped GI symptoms in 10 and POTS symptoms in four. We did not use an improvement scale.⁶⁴ This has been observed in additional POTS patients in our clinic as well.

Owing to the numerous MC mediators and receptors, no single medication currently available will control all symptoms of MCAS. It is a common approach to offer first-line therapy with efforts to identify and avoid triggers and then to prescribe antihistamines, vitamin C, vitamin D, and montelukast. A number of MCAS physicians have seen that LDN helped some of their patients. In a review of a cohort of my own MCAS patients, I found clinical evidence of LDN’s efficacy in treating the condition. Out of the 116 MCAS patients who were given daily 4.5 mg LDN, 60 percent reported improvements, 28 percent saw no benefit, and 22 percent had to stop LDN owing to side effects.

SYMPTOMS RELIEVED IN MCAS PATIENTS TAKING LDN

(Video) LDN and the leaky gut - Dr Leonard Weinstock

• Depression
• Brain fog
• Anxiety
• Nausea
• Insomnia
• Hives
• Rash
• Itch
• Allergies
• Dyspnea
• Edema
• Erythromelalgia
• Fatigue
• Headache
• Dizziness
• Abdominal pain
• Diarrhea
• Constipation
• Bloating
• Pain (joint, nerve, and muscle)

Although worthy, it would be difficult to have this data accepted for publication given that the patients involved simultaneously altered their diets and used several medications. Patients in this series could tell that the LDN treatment was effective due to the clinical response they noted as they increased their doses to 4.5 mg. Others noticed the therapeutic impact when they ran out of LDN, or after they had stopped and then restarted the medication.

LDN has the potential to restore gut health in several GI disorders and diseases, including inflammatory bowel disease, constipation, gastroparesis, irritable bowel syndrome (IBS), MCAS, sarcoidosis, and mesenteric panniculitis. High-quality research using randomized, double-blind, placebo-controlled studies is the ideal. However, until funding is available for such trials, continued clinical use and reports of case series will benefit many patients.

References

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Dr. Leonard B. Weinstock is board-certified in gastroenterology and internal medicine. He is president of Specialists in Gastroenterology and the Advanced Endoscopy Center. He is an associate professor of clinical medicine and surgery at Washington University School of Medicine. A complete CV is available at www.gidoctor.net.