Yoon Hang Kim, MD, MPH

Board-Certified in Preventive Medicine | Integrative & Functional Medicine Physician

Osher Fellow, Andrew Weil Center for Integrative Medicine, University of Arizona

www.directintegrativecare.com

Last updated: August 2026

Abstract

Amlexanox is an anti-allergic, anti-inflammatory compound developed in Japan and approved by the FDA in the United States only as a 5% topical paste for recurrent aphthous ulcers. Interest has grown among integrative and functional medicine clinicians in compounded oral amlexanox for mast cell activation syndrome (MCAS) and long COVID, driven by a plausible mechanistic rationale: amlexanox raises intracellular cyclic AMP in mast cells through phosphodiesterase inhibition, suppressing mediator release, and separately inhibits the non-canonical kinases TBK1 and IKKε.

This review examines the distance between that mechanistic rationale and the clinical evidence. The mechanistic literature is genuinely substantial: amlexanox inhibits histamine and leukotriene release from sensitized human lung tissue and leukocytes, binds Hsp90, and — in activated macrophages — directly targets PDE4B. The clinical literature is not. The best-characterized modern controlled study of systemic oral amlexanox is a 42-patient placebo-controlled trial in obesity and type 2 diabetes, which found an approximately 0.5 percentage-point greater HbA1c reduction versus placebo, with benefit concentrated in a responder subset characterized by higher baseline adipose inflammation. That trial studied a different population through a different inflammatory pathway than the one relevant to mast cell stabilization.

MCAS-specific clinical evidence consists of a single three-patient case report collection published in the inaugural issue of a journal without PubMed indexing. No randomized controlled trial or dedicated prospective study of amlexanox for long COVID has been identified. The premise underlying long COVID use — that mast cell activation drives post-COVID pathology — is itself contested, with biomarker studies reporting both positive and null findings. No validated MCAS dosing regimen exists, and long-term safety data for chronic compounded oral use in these populations are absent.

The conclusion is deliberately modest. Amlexanox is mechanistically interesting and may warrant formal study, but it remains investigational for MCAS and long COVID. It should be considered only under close physician supervision, after better-studied agents have been appropriately trialed, and with expectations calibrated to the current evidence rather than to mechanistic promise.

Amlexanox is an older anti-allergy and anti-inflammatory medication that has attracted growing interest among integrative and functional medicine practitioners for its potential role in mast cell activation syndrome (MCAS) and long COVID. Originally developed in Japan as an anti-allergic agent and FDA-approved in the United States as a topical treatment for canker sores (aphthous ulcers), amlexanox is now being explored in compounded oral and topical formulations for conditions far beyond its original indications.

The interest is understandable. Patients with MCAS and long COVID need additional therapeutic options, and amlexanox has a biologically plausible mechanism. But as with any off-label, early-stage therapeutic, the gap between mechanistic promise and clinical proof must be stated clearly. This article reviews what we actually know — and what we do not yet know — about amlexanox for these conditions.

How Does Amlexanox Work at the Cellular Level?

Amlexanox raises intracellular cyclic AMP (cAMP) in mast cells, in part through phosphodiesterase inhibition, which suppresses the release of histamine and other inflammatory mediators. It also inhibits the kinases TBK1 and IKKε — a separate pathway that relates mainly to metabolic inflammation rather than mast cell activity.

Amlexanox operates through multiple pharmacological mechanisms, which is part of what makes it theoretically attractive — and part of what makes its clinical effects difficult to predict.

The mechanism most relevant to mast cell biology is phosphodiesterase (PDE) inhibition. Phosphodiesterases degrade cyclic AMP (cAMP) inside cells; when they are inhibited, intracellular cAMP levels rise. In mast cells, elevated cAMP activates protein kinase A (PKA), which phosphorylates downstream targets that suppress degranulation signaling. The net effect is reduced release of histamine, leukotrienes, and other inflammatory mediators. This mechanism was characterized by Makino and colleagues in 1987, who demonstrated that amlexanox accelerated cAMP generation and inhibited phosphodiesterase activity in rat mast cells, leading to reduced histamine release (Makino et al., 1987). More recent work has identified PDE4B as a direct molecular target of amlexanox in activated macrophages, though the specific PDE subtype responsible for its effect in mast cells was not defined in the original mast cell studies (Han et al., 2020).

A second mechanism involves inhibition of two non-canonical IκB kinases: TBK1 (TANK-binding kinase 1) and IKKε (inhibitor of nuclear factor kappa-B kinase subunit epsilon). Reilly and colleagues at the University of Michigan demonstrated in 2013 that amlexanox selectively inhibits these kinases, which are upregulated in obesity and drive metabolic inflammation through NF-κB signaling. In obese mouse models, amlexanox treatment elevated energy expenditure, produced weight loss, improved insulin sensitivity, and reduced hepatic steatosis (Reilly et al., 2013).

An important nuance frequently lost in clinical discussions: these two mechanisms operate through different inflammatory pathways. Han and colleagues (2020) demonstrated that amlexanox's anti-inflammatory effect in classically activated macrophages operates through PDE4B inhibition and is independent of TBK1/IKKε. The TBK1/IKKε pathway is more relevant to the chronic, low-grade metabolic inflammation associated with obesity and insulin resistance (Han et al., 2020). Clinicians and patients should not assume that amlexanox's metabolic effects and its mast cell effects share the same mechanism; they likely do not.

Amlexanox has also been shown to bind Hsp90 and inhibit its C-terminal chaperone activity (Okada et al., 2003). Separately, older pharmacological studies established that amlexanox inhibits the release of histamine and leukotrienes from sensitized human lung tissue and atopic human leukocytes (Kohno et al., 1989), and modulates the activation of human neutrophils (Taniguchi et al., 1990).

What Does the Clinical Evidence Actually Show?

There are no randomized controlled trials of amlexanox in MCAS or long COVID. The strongest human data come from a placebo-controlled trial in obesity and type 2 diabetes, while MCAS-specific evidence is limited to a single three-patient case series in a non-indexed journal.

This is where intellectual honesty matters most. The clinical evidence for amlexanox in MCAS and long COVID is, at present, extremely limited. Here is what exists, stratified by evidence quality.

The Best-Characterized Modern Trial: Obesity and Type 2 Diabetes

The best-characterized modern placebo-controlled study of systemic oral amlexanox was conducted by Oral and colleagues at the University of Michigan and published in Cell Metabolism in 2017. This was a placebo-controlled randomized trial of 42 patients with obesity and type 2 diabetes. Participants in the treatment arm received oral amlexanox at 50 mg three times daily for 12 weeks. After 12 weeks, patients on amlexanox showed approximately a 0.5 percentage-point greater reduction in hemoglobin A1c compared with placebo, a statistically significant difference. Importantly, the metabolic response was not uniform: only a subset of treated patients showed the fuller metabolic benefit, including improved insulin sensitivity and reduced liver fat. These responders were characterized by higher baseline levels of adipose tissue inflammation — suggesting that amlexanox may be most effective in patients with a specific inflammatory phenotype (Oral et al., 2017).

Earlier double-blind, placebo-controlled work with oral amlexanox exists in the asthma literature: a small randomized, double-blind study of 15 adult asthmatics found an acute bronchodilator effect of orally administered amlexanox (Imokawa et al., 1993). The drug also has a longer history of clinical and research use in Japan for allergic conditions. However, the 2017 metabolic trial represents the best-characterized modern rigorous evaluation of oral amlexanox in a Western clinical trial setting.

This trial is important, but its direct applicability to MCAS and long COVID is limited: it was conducted in patients with metabolic disease, using an inflammatory mechanism (TBK1/IKKε) that is distinct from the phosphodiesterase-mediated cAMP mechanism most relevant to mast cell stabilization. The patient population, target biology, and clinical endpoints are fundamentally different from those in MCAS management.

The MCAS Case Series: Three Patients

The only published clinical report specifically addressing amlexanox in MCAS is a three-patient case report collection by Saleeby and Gregory (2025), published in the Journal of Independent Medicine. The authors describe integration of compounded oral amlexanox into the treatment regimens of three patients with MCAS, asthma, and autoimmune conditions, some with post-COVID-related diagnoses. Patient outcomes were self-reported and included enhanced symptom management and reduced corticosteroid reliance.

This case series provides preliminary clinical observations, but several limitations must be acknowledged. It involves only three patients, uses self-reported outcomes without blinding or control conditions, and was published in the inaugural issue of a new journal without PubMed indexing or an established impact factor. The Journal of Independent Medicine is published by the Independent Medical Alliance, formerly the FLCCC Alliance — an organization whose evidence standards have been the subject of significant debate in the medical community. None of this means the clinical observations are wrong, but it does mean they cannot be treated as established evidence. Replication in larger, controlled studies is essential before these observations can guide standard clinical decision-making (Saleeby & Gregory, 2025).

Long COVID: No Dedicated Clinical Trials

No randomized controlled trial or dedicated prospective clinical study of amlexanox for long COVID has been identified as of August 2026. The 2025 Saleeby & Gregory case collection includes some patients with post-COVID-related diagnoses, but no dedicated long COVID clinical evaluation of amlexanox has been published. A major 2024 living systematic review of long COVID interventions by Zeraatkar and colleagues — which searched databases through December 2023 — did not include amlexanox among the interventions assessed, reflecting how early-stage this proposed use remains (Zeraatkar et al., 2024).

The rationale for long COVID use rests on mechanistic inference: if mast cell involvement contributes to long COVID pathology in a subset of patients — a hypothesis proposed early in the pandemic (Afrin et al., 2020) — and if amlexanox stabilizes mast cells, then amlexanox might benefit long COVID patients with MCAS features. The biomarker evidence for mast cell involvement in long COVID is genuinely mixed. Some studies support it — Wechsler and colleagues (2022) found elevated mast-cell-derived proteases (active tryptase and CPA3) and inflammatory cytokines in patients with post-acute COVID-19 syndrome. Others do not — Lenning and colleagues (2024) found no significant difference in mast-cell-specific proteases between long COVID patients and matched post-infection controls in a case-control study. This inconsistency means the logic is reasonable but unproven, and clinicians should not assume that every long COVID patient has a mast cell phenotype amenable to this approach.

How Does Amlexanox Compare to Established MCAS Treatments?

Patients and clinicians often ask whether amlexanox offers something that existing MCAS treatments do not. The honest answer is: it might, but we do not yet know.

The MCAS treatment landscape is stratified by evidence quality, and it is important not to flatten that stratification. Well-established conventional agents include H1 and H2 antihistamines, cromolyn sodium, and leukotriene modifiers such as montelukast — all with regulatory approval for related indications, decades of clinical experience, and endorsement in the AAAAI Mast Cell Disorders Committee work group report on MCAS diagnosis and management (Weiler et al., 2019). Ketotifen occupies an intermediate position: it has controlled trial evidence in irritable bowel syndrome with visceral hypersensitivity (Klooker et al., 2010) and long-standing clinical use for chronic urticaria, but MCAS-specific trial data are limited, and its use for MCAS rests substantially on case-level experience and inference from adjacent conditions. Quercetin, luteolin, and low-dose naltrexone (LDN) have thinner MCAS-specific clinical evidence, resting primarily on preclinical mechanistic work, case reports, and clinical experience rather than randomized controlled trials.

Amlexanox's theoretical distinction is its dual mechanism: phosphodiesterase-mediated cAMP elevation (mast cell stabilization) combined with TBK1/IKKε inhibition (broader anti-inflammatory and potentially metabolic effects). No other agent in common MCAS use is known to combine these two targets. Whether this mechanistic profile translates into superior clinical outcomes — or whether it simply provides an alternative for patients who have not responded to first-line agents — remains unknown.

For readers interested in the broader MCAS treatment landscape, my comprehensive review covers established and emerging therapies in detail: MCAS: A New Epidemic in Plain Sight.

What Are the Safety Concerns?

Safety data for compounded oral amlexanox specifically in the MCAS and long COVID context are essentially absent. The following concerns are based on general pharmacological principles and available data:

Long-term safety data specifically for compounded oral amlexanox in MCAS and long COVID are lacking. Systemic oral amlexanox has a history of clinical use in Japan for allergic conditions, including asthma, dating to at least the late 1980s (Imokawa et al., 1993). That prior experience means the drug is not entirely without systemic human exposure — but it does not establish the safety or efficacy of chronic compounded oral use in the MCAS or long COVID populations, which represent different patient groups, different comorbidity profiles, and different regulatory contexts. Chronic use in MCAS, as would be anticipated in ongoing management, has not been formally studied in any controlled setting.

No safety data are available for pregnancy or pediatric use in the compounded oral formulation used for MCAS.

Rare hypersensitivity reactions to amlexanox itself have been documented in the topical paste literature. This is worth noting because MCAS patients are, by definition, a population with heightened immune reactivity, potentially increasing the risk of medication hypersensitivity.

Compounding quality variability is an inherent concern. Because oral amlexanox for MCAS is not commercially available in the United States and must be compounded, potency and purity can vary between pharmacies. Patients should use reputable compounding pharmacies that are PCAB-accredited and appropriately licensed by the relevant state board(s) of pharmacy.

What Dose Is Typically Used?

No validated dosing regimen for MCAS exists. Published case reports have used initial doses in the range of approximately 40 mg per day, with individualized titration in some patients up to 40 mg two or three times daily (Saleeby & Gregory, 2025). The 2017 metabolic trial used 50 mg three times daily for 12 weeks, following a preliminary open-label phase that started at 25 mg three times daily for two weeks before titrating up (Oral et al., 2017). These regimens should not be interpreted as established MCAS dosing — they represent limited case-level experience and a metabolic study in a different patient population. As with all medications in MCAS patients — who are often exquisitely sensitive to new agents — the principle of "start low, go slow" applies rigorously, and dose selection should be individualized by the prescribing physician.

What Questions Should You Discuss With Your Doctor?

If you are considering amlexanox for MCAS or long COVID symptoms, the following questions provide a framework for an informed shared decision-making conversation:

• Is amlexanox appropriate given my specific symptoms, diagnoses, and current medications?
• Have I tried better-studied alternatives first — including H1/H2 antihistamines, cromolyn sodium, montelukast, and ketotifen — and if so, why have they been insufficient?
• What dose and formulation (oral vs. topical) is being recommended, and what is the rationale?
• How will we monitor for benefit — and for side effects — over time?
• What is the plan if I do not see improvement, or if I have a reaction?
• Is the compounding pharmacy being used accredited, and is the formulation quality-assured?

What Is the Bottom Line?

Amlexanox has a biologically plausible mechanism of action for mast cell stabilization, involving PDE-mediated cAMP elevation, and it has demonstrated anti-inflammatory and metabolic effects in preclinical models and a placebo-controlled human trial in obesity and type 2 diabetes. Some integrative practitioners report clinical benefit in MCAS patients based on small, uncontrolled case observations.

However, amlexanox is not an evidence-proven treatment for MCAS or long COVID. No randomized controlled trials have been conducted in these populations. The published MCAS-specific clinical data amount to three patients in a single case series in a new, non-indexed journal. Long-term safety data specifically for the compounded oral formulation in MCAS and long COVID populations are lacking, and no validated dosing regimen exists.

This is a drug worth watching — and potentially worth studying rigorously. But it should be approached as an investigational option, used under close physician supervision, after better-studied alternatives have been appropriately trialed, and with realistic expectations grounded in the current state of evidence.

Frequently Asked Questions

Is amlexanox FDA-approved for MCAS?

No. Amlexanox is FDA-approved only as a 5% topical paste (Aphthasol) for the treatment of recurrent aphthous ulcers (canker sores). Its use for MCAS and long COVID is entirely off-label and investigational. The oral compounded formulation used by some integrative practitioners has not undergone FDA review for this indication.

How is amlexanox different from cromolyn sodium or ketotifen?

All three agents can influence mast cell activity, but through different mechanisms. Cromolyn sodium works primarily through mast cell membrane stabilization with minimal systemic absorption, making it well-suited for GI-dominant MCAS. Ketotifen combines H1 antihistamine activity with partial mast cell stabilization. Amlexanox raises intracellular cAMP in mast cells through phosphodiesterase inhibition, and additionally inhibits the TBK1/IKKε kinases involved in broader inflammatory signaling. Whether this distinct mechanistic profile produces clinically meaningful advantages over established agents remains unproven.

Can I take amlexanox with LDN?

This combination has not been formally studied. There is no established direct pharmacological interaction between amlexanox and LDN, but both agents modulate immune and inflammatory signaling, and combined effects are unpredictable. This decision should be made in close consultation with your prescribing physician, with careful monitoring for side effects. For more information on LDN in MCAS, see my comprehensive discussion in The LDN Primer: 2026 Edition.

Is amlexanox safe for long-term use?

Long-term safety data specifically for compounded oral amlexanox in MCAS or long COVID have not been established through controlled study. The 12-week obesity trial by Oral et al. (2017) represents the longest modern controlled human exposure in a Western clinical trial. Amlexanox does have a longer history of systemic clinical use in Japan for allergic conditions, but this broader experience does not directly transfer to MCAS or long COVID use. Patients using amlexanox chronically should be monitored closely with regular clinical reassessment.

Where can I get amlexanox?

Oral amlexanox for MCAS is not available at standard retail pharmacies in the United States. It must be obtained from a compounding pharmacy with a physician's prescription. Patients should use compounding pharmacies that are PCAB-accredited and appropriately licensed by the relevant state board(s) of pharmacy, to support quality and potency consistency.

Summary

What amlexanox is. An older anti-allergic and anti-inflammatory compound, developed in Japan and FDA-approved in the United States only as a topical paste for canker sores. Oral use for MCAS and long COVID is off-label and requires compounding.

What the mechanism supports. The preclinical and pharmacological case is real. Amlexanox raises intracellular cAMP in mast cells via phosphodiesterase inhibition, reducing degranulation and mediator release; it inhibits histamine and leukotriene release from human lung tissue and leukocytes; it binds Hsp90; and it inhibits TBK1 and IKKε. Two important caveats: PDE4B was identified as a direct target in macrophages, not mast cells, and the TBK1/IKKε pathway drives metabolic inflammation rather than mast cell activity. These are separate mechanisms and should not be conflated.

What the clinical evidence supports. Considerably less. One 42-patient placebo-controlled trial in obesity and type 2 diabetes — a different population, a different pathway. One three-patient MCAS case series in a non-indexed inaugural journal issue. One small randomized asthma study from 1993. That is the extent of controlled and published clinical data relevant to this use.

What remains unknown. Whether amlexanox helps MCAS. Whether it helps long COVID — where even the underlying mast cell premise is contested by conflicting biomarker studies. What dose to use. Whether chronic use is safe in these populations. Whether it offers any advantage over cromolyn, ketotifen, antihistamines, or leukotriene modifiers.

How to hold it clinically. As investigational, not established. Better-studied agents come first. If amlexanox is used, it belongs in a shared decision-making conversation with explicit acknowledgment of the evidence gap, a defined monitoring plan, a defined stopping point, and a quality-assured compounding source. Mechanistic plausibility is a reason to study a drug rigorously. It is not, by itself, a reason to expect it to work.

#amlexanox #MCAS #MastCellActivationSyndrome #LongCOVID #MastCellStabilizer #IntegrativeMedicine #FunctionalMedicine #CompoundedMedications #OffLabelUse #EvidenceBasedMedicine #DrKim

References

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2. Kohno S, Shimizu T, Mizuta J, et al. [Inhibitory effect of amlexanox (AA-673) on the immunological and non-immunological release of histamine or leukotrienes]. Arerugi. 1989;38(11):1236-1245. PMID: 2483310.

3. Taniguchi K, Masuda Y, Takanaka K. Action sites of antiallergic drugs on human neutrophils. Jpn J Pharmacol. 1990;52(1):101-108. doi:10.1254/jjp.52.101. PMID: 2155337.

4. Imokawa S, Satou A, Taniguchi M, et al. [Amlexanox has an acute bronchodilator effect in patients with aspirin-induced asthma (AIA)]. Nihon Kyobu Shikkan Gakkai Zasshi. 1993;31(8):976-982. PMID: 8230896.

5. Okada M, Itoh H, Hatakeyama T, Tokumitsu H, Kobayashi R. Hsp90 is a direct target of the anti-allergic drugs disodium cromoglycate and amlexanox. Biochem J. 2003;374(Pt 2):433-441. doi:10.1042/BJ20030351. PMID: 12803546.

6. Reilly SM, Chiang SH, Decker SJ, et al. An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice. Nat Med. 2013;19(3):313-321. doi:10.1038/nm.3082. PMID: 23396211.

7. Han Y, Hou R, Zhang X, Liu H, Gao Y, Li X, Qi R, Cai R, Qi Y. Amlexanox exerts anti-inflammatory actions by targeting phosphodiesterase 4B in lipopolysaccharide-activated macrophages. Biochim Biophys Acta Mol Cell Res. 2020;1867(10):118766. doi:10.1016/j.bbamcr.2020.118766. PMID: 32504661.

8. Oral EA, Reilly SM, Gomez AV, et al. Inhibition of IKKε and TBK1 improves glucose control in a subset of patients with type 2 diabetes. Cell Metab. 2017;26(1):157-170.e7. doi:10.1016/j.cmet.2017.06.006. PMID: 28683283.

9. Saleeby Y, Gregory B. Amlexanox: a promising alternative to steroid and antihistamine dependence in patients with mast cell activation syndrome, allergies, asthma, and autoimmunity — a case report collection. J Indep Med. 2025;1(1):71-78. doi:10.71189/JIM/2025/V01N01A06.

10. Wechsler JB, Butuci M, Wong A, Kamboj AP, Youngblood BA. Mast cell activation is associated with post-acute COVID-19 syndrome. Allergy. 2022;77(4):1288-1291. doi:10.1111/all.15188. PMID: 34820848.

11. Lenning OB, Jonsson G, Grimstad T, et al. No signs of mast cell involvement in long-COVID: a case-control study. Scand J Immunol. 2024;100(5):e13407. doi:10.1111/sji.13407. PMID: 39285602.

12. Zeraatkar D, Ling M, Kirsh S, et al. Interventions for the management of long covid (post-covid condition): living systematic review. BMJ. 2024;387:e081318. doi:10.1136/bmj-2024-081318. PMID: 39603702.

13. Afrin LB, Weinstock LB, Molderings GJ. Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. Int J Infect Dis. 2020;100:327-332. doi:10.1016/j.ijid.2020.09.016. PMID: 32920235.

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15. Klooker TK, Braak B, Koopman KE, et al. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut. 2010;59(9):1213-1221. doi:10.1136/gut.2010.213108. PMID: 20650926.

About Dr. Kim

Dr. Yoon Hang "John" Kim is a board-certified Preventive Medicine physician with over 20 years of experience in integrative and functional medicine. He completed fellowship training at the University of Arizona Center for Integrative Medicine under Dr. Andrew Weil and holds certifications in medical acupuncture (UCLA), integrative medicine, and holistic medicine. Dr. Kim specializes in low dose naltrexone (LDN), autoimmune conditions, chronic pain, integrative oncology, fibromyalgia, chronic fatigue syndrome, mast cell activation syndrome, and mold toxicity. He is the author of three books — including The LDN Primer: 2026 Edition — and more than 20 peer-reviewed articles, and has established integrative medicine programs at major academic medical centers. He is the founder of the LDN Support Group with over 9,000 members.

Professional: www.yoonhangkim.com

Clinical: www.directintegrativecare.com

YouTube: @YoonHangKimMD

Related Reading

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• The COMT Gene and Mast Cell Activation Syndrome — How COMT variants may influence MCAS symptom expression through catecholamine, estrogen, and methylation pathways.
• Heart Health Supplements: What Does the Evidence Actually Show? — A companion evidence-review article demonstrating our editorial approach to supplement and medication evidence evaluation.

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