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 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.


  • 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.


  1. Lawrence B. Afrin et al., “Characterization of Mast Cell Activation Syndrome,” American Journal of the Medical Sciences 353, no. 3 (March 2017): 207–15, https:// doi.org/10.1016/j.amjms.2016.12.013.
  2. Gerhart J. Molderings et al., “Familial Occurrence of Systemic Mast Cell Activation Disease,” PLOS One 8, no. 9 (September 30, 2013): e76241, https://doi.org/10.1371/journal.pone.0076241.
  3. Cash and Chey, “Diagnosis of Irritable Bowel Syndrome.”
  4. Mark Pimentel et al., “Normalization of Lactulose Breath Testing Correlates with Symptom Improvement in Irritable Bowel Syndrome: A Double-Blind, Randomized, Placebo-Controlled Study,” American Journal of Gastroenterology 98, no. 2 (February 2003): 412–19.
  5. Lawrence B. Afrin and Gerhard J. Molderings, “A Concise, Practical Guide to Diagnostic Assessment for Mast Cell Activation Disease,” World Journal of Hematology 3, no. 1 (February 6, 2014): 1–17.
  6. Leonard B. Weinstock et al., “The Significance of Mast Cell Activation in the Era of Precision Medicine,” American Journal of Gastroenterology 113, no. 11 (November 2018): 1725–26, https://doi.org/10.1038/s41395-018-0257-7.
  7. Giovanni Barbara et al.,“Activated Mast Cells in Proximity to Colonic Nerves Correlate with Abdominal Pain in Irritable Bowel Syndrome,” Gastroenterology 126, no. 3 (March 2004): 693–702, https://doi.org/10.1053/j.gastro.2003.11.055; Giovanni Barbara et al., “Mast Cell-Dependent Excitation of Visceral-Nociceptive Sensory Neurons in Irritable Bowel Syndrome,” Gastroenterology 132, no. 1 (January 2007): 26–37, https://doi.org/10.1053/j.gastro.2006.11.039; Stefan Wirz and Gerhard J. Molderings, “A Practical Guide for Treatment of Pain in Patients with Systemic Mast Cell Activation Disease,” Pain Physician 20, no. 6 (September 2017): E849–E861.
  8. Rezaie et al., “Lactulose Breath Testing as a Predictor of Response to Rifaximin.”
  9. Gabrio Bassotti et al., “Increase of Colonic Mast Cells in Obstructed Defecation and Their Relationship with Enteric Glia,” Digestive Diseases and Sciences 57, no. 1 (January 2012): 65–71, https://doi.org/10.1007/s10620-011-1848-y.
  10. Cash and Chey, “Diagnosis of Irritable Bowel Syndrome”; Mark J. Hamilton, “Nonclonal Mast Cell Activation Syndrome: A Growing Body of Evidence,” Immunology and Allergy Clinics of North America 38, no. 3 (August 2018): 469–81; Fred H. Hsieh, “Gastrointestinal Involvement in Mast Cell Activation Disorders,” Immunology and Allergy Clinics of North America 38, no. 3 (August 2018): 429–41.
  11. Anupam Aich et al., “Mast Cell-Mediated Mechanisms of Nociception,” International Journal of Molecular Sciences 16, no. 12 (December 2015) 29069–92, https://doi.org/10.3390/ijms161226151.
  12. Harissios Vliagoftis et al., “Mast Cells at Mucosal Frontiers,” Current Molecular Medicine 5, no. 6 (October 2005): 573–89, https://doi.org/10.2174/1566524 054863915.
  13. Leonard B. Weinstock et al., “Mast Cell Deposition and Activation May Be a New Explanation for Epiploic Appendagitis,” British Medical Journal Case Report 2018, bcr–2018–224689, http://doi.org/10.1136/bcr-2018-224689.
  14. T. Frieling, “Evidence for Mast Cell Activation in Patients with Therapy- Resistant Irritable Bowel Syndrome,” Zeitschrift für Gastroenterologie 49, no. 2 (February 2011): 191–94, http://doi.org/10.1055/s-0029-1245707; Lei Zhang et al., “Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside,” Neurogastroenterology and Motility 22, no. 2 (April 2016): 181–92, http://doi.org/10.5056/jnm15137; Beatriz Lobo et al., “Downregulation of Mucosal Mast Cell Activation and Immune Response in Diarrhoea-Irritable Bowel Syndrome by Oral Disodium Cromoglycate: A Pilot Study,” United European Gastroenterology Journal 5, no. 6 (October 2017): 887–97, http:// doi.org/10.1177/2050640617691690; Tamira K. Klooker et al., “The Mast Cell Stabiliser Ketotifen Decreases Visceral Hypersensitivity and Improves Intestinal Symptoms in Patients with Irritable Bowel Syndrome,” Gut 59, no. 9 (September 2010): 1213–21, http://doi.org/10.1136/gut.2010.213108.
  15. Leonard B. Weinstock et al., “Small Intestinal Bacterial Overgrowth Is Common in Mast Cell Activation Syndrome,” American Journal of Gastroenterology 114, no. 2019 ACG Annual Meeting Abstracts (October 2019).
  16. Anneleen B. Beckers et al., “Gastrointestinal Disorders in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type: A Review for the Gastroenterologist,” Neurogastroenterology & Motility 29, no. 8 (August 2017): e13013, https://doi.org/10.1111/nmo.13013; John K. DiBaise, “Postural Tachycardia Syndrome (POTS) and the GI Tract: A Primer for the Gastroenterologist,” American Journal of Gastroenterology 113, no. 10 (October 2018): 1458–67, https://doi.org/10.1038/s41395-018-0215-4
  17. Suranjith L. Seneviratne et al., “Mast Cell Disorders in Ehlers-Danlos Syndrome,” American Journal of Medical Genetics Part C: Seminars in Medical Genetics 175, no. 1 (March 2017): 226–36, https://doi.org/10.1002/ajmg.c.31555; Emily M. Garland, “Postural Tachycardia Syndrome: Beyond Orthostatic Intolerance,” Current Neurology and Neuroscience Reports 15, no. 60 (July 2015), https://doi.org/10.1007 /s11910-015-0583-8; Taylor A. Doherty et al., “Postural Orthostatic Tachycardia Syndrome and the Potential Role of Mast Cell Activation,” Autonomic Neuroscience 215 (December 2018): 83–88, https://doi.org/10.1016/j.autneu.2018.05.001.
  18. Pimenteletal.,“NormalizationofLactuloseBreathTestingCorrelateswithSymptom Improvement”; Susan V. Jennings et al., “The Mastocytosis Society Survey on Mast Cell Disorders: Patient Experiences and Perceptions,” Journal of Allergy and Clinical Immunology 2, no. 1 (January–February 2014): 70–76, https://doi.org /10.1016/j.jaip.2013.09.004; Jill Schofield and Lawrence B. Afrin, “Recognition and Management of Medication Excipient Reactivity in Patients with Mast Cell Activation Syndrome,” American Journal of the Medical Sciences 357, no. 6 (June 2019): 507–11, https://doi.org/10.1016/j.amjms.2019.03.005; Lawrence B. Afrin et al., “Mast Cell Activation Disease and Microbiotic Interactions,” Clinical Therapeutics 37, no. 5 (February 2015): 941–53, http://doi.org/10.1016/j .clinthera.2015.02.008; Aarane M. Ratnaseelan et al., “Effects of Mycotoxins on Neuropsychiatric Symptoms and Immune Processes,” Clinical Therapeutics 40, no. 6 (June 2018):903–17, https://doi.org/10.1016/j.clinthera.2018.05.004.
  19. Leonard B. Weinstock et al., “Successful Treatment of Postural Orthostatic Tachycardia and Mast Cell Activation Syndromes Using Naltrexone, Immunoglobulin and Antibiotic Treatment,” British Medical Journal Case Reports 2018 (January 2018): bcr-2017-221405, https://doi.org/10.1136/bcr-2017-221405.

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.

Linda Elsegood is the founder of the LDN Research Trust, which was set up in the U.K. as a registered charity in 2004, and is the editor of The LDN Book, Volume 1 and 2. Diagnosed with multiple sclerosis in August of 2000, she started LDN therapy in December of 2003, and now has a better quality of life and hope for the future. Through the Trust, she has connected thousands of patients, doctors, and pharmacists around the world with information, articles, and patient stories about LDN, and helped organize conferences, seminars, and the Trust’s LDN Radio Show.