What Causes Canker Sores? — Mechanisms, Not Just Triggers

TL;DR

Canker sores are not caused by a virus. They result from the immune system mistakenly attacking the lining of the mouth. Multiple triggers can set this off in people who are genetically susceptible to it. The most evidence-backed triggers are: nutritional deficiencies (B12, iron, folate, zinc), SLS in toothpaste, psychological stress, oral trauma, and hormonal fluctuations. This page breaks down the mechanism behind each.

The Core Mechanism: Immune Dysregulation

Before listing triggers, it's important to understand why triggers cause ulcers — because the same trigger (e.g., stress) can affect everyone differently. In canker sore sufferers, the immune system overreacts to minor irritation in the mouth that most people's bodies would simply ignore.

Current evidence points to:

1. Inflammatory proteins spike at the ulcer site: TNF-α, a protein that signals inflammation and tissue destruction, is found at higher levels in canker sore tissue, and it appears to be a key driver of the damage (Natah et al., 2000 — PMID: 10678712; Natah et al., 2004 — PMID: 15287304).

2. Immune cells attack the mouth lining: Early ulcers show one type of immune cell (CD4+ T-cells) flooding the area; established ulcers show a different, more destructive type (CD8+ cytotoxic T-cells) taking over. This is the same kind of cell-mediated attack the immune system uses against viruses — but here it's targeting healthy tissue.

3. The immune system's "off switch" isn't working: Healthy immune responses have a built-in brake — regulatory T-cells that call off the attack once a threat is resolved. In chronic canker sore sufferers, these brakes are less effective, so the inflammatory response keeps going longer than it should.

4. Early warning cells fire before the ulcer appears: Immune cells called mast cells activate and release inflammatory chemicals 1–2 days before the ulcer becomes visible — which is why you often feel a burning or tingling sensation before anything shows up.

This is not a simple infection or a textbook autoimmune disease. It's a misfiring immune response that, so far, has no single identified cause.

Nutritional Deficiencies

This is the most useful category to investigate first — deficiencies show up on a standard blood test and can be corrected.

Vitamin B12 Deficiency

Vitamin B12 deficiency is significantly overrepresented in RAS patients. A 2024 meta-analysis found people with canker sores had about three times the odds of B12 deficiency (Mousavi et al., 2024 — BMC Oral Health), and a placebo-controlled trial found B12 supplements reduced outbreaks (Volkov et al., 2009 — PMID: 19124628). The mechanism likely involves B12's role in maintaining the mucosal epithelium and modulating immune function — B12 deficiency impairs DNA synthesis in rapidly dividing epithelial cells, increasing mucosal fragility.

More compelling: supplementation works. An RCT (Volkov et al., 2009 — PMID: 19124628) found that 1000mcg sublingual B12 nightly reduced ulcer frequency significantly versus placebo, regardless of baseline serum B12 levels. This is one of the stronger RCTs in this space.

Worth knowing: B12 deficiency is often an absorption problem, not a dietary one. If you eat animal products but your B12 stays low, the culprit may be pernicious anemia or another absorption problem. A sore, smooth, red tongue alongside your canker sores is a reason to ask for testing.

B12 is the one supplement with a placebo-controlled trial for canker sores behind it, and the trial used 1,000 mcg a day:

Iron Deficiency

Iron deficiency disrupts mucosal integrity via impaired oxidative metabolism in epithelial cells. A meta-analysis of nine studies found people with canker sores had about 2.6 times the odds of low ferritin (Chen et al., 2015 — PMID: 25720915). Iron deficiency anemia should be screened with ferritin, not just hemoglobin — ferritin depletion precedes anemia.

Only take iron if a ferritin test shows you're low. If it does, iron bisglycinate is usually easier on the stomach than ferrous sulfate:

Folate Deficiency

Folate (vitamin B9) is required for DNA synthesis and cell proliferation. Mucosal cells turn over rapidly; folate deficiency creates a vulnerability. Associated with canker sores in controlled studies (Wray et al., 1975 — PMID: 1148667), particularly in patients with celiac disease (which impairs folate absorption) and Crohn's disease (where sulfasalazine depletes folate). Folic acid and methylfolate both correct a deficiency; a common MTHFR gene variant slows folate processing somewhat but doesn't stop folic acid from working (see the folate article for details).

If testing shows you're low on folate, get B12 checked too, since high-dose folate can hide a B12 deficiency:

Vitamin D Deficiency

Vitamin D deficiency is found at elevated rates in RAS patients across multiple independent studies — pooled data show levels about 10 ng/mL lower in people with canker sores than in controls (Al-Maweri et al., 2020 — PMID: 31493304). One uncontrolled study found fewer, shorter attacks after a year of high-dose vitamin D in deficient patients, but no controlled trial has tested it yet. The mechanism is direct: the Vitamin D receptor (VDR) on T-lymphocytes suppresses Th1 immune activity — the same IFN-γ and TNF-α pathway that drives mucosal destruction in aphthous ulcers. Deficiency removes this brake. Vitamin D also upregulates cathelicidin, an antimicrobial peptide supporting mucosal barrier integrity. Deficiency is common (~41% of US adults below the 20 ng/mL threshold); testing and correcting it is a low-threshold intervention.

If your level comes back low:

Zinc Deficiency

Zinc is essential for epithelial repair and T-cell immune regulation. Zinc deficiency both weakens the mucosal barrier and dysregulates the immune response — a dual mechanism. A meta-analysis of 19 studies found lower blood zinc in people with canker sores (Al-Maweri et al., 2021 — Clin Oral Investig), and a placebo-controlled trial found zinc reduced ulcers (Orbak et al., 2003 — PMID: 12790293). Zinc for everyone doesn't seem to work, so test first and keep your total under 40 mg a day.

See the full supplement guide: Best Supplements for Canker Sore Prevention →

Sodium Lauryl Sulfate (SLS) in Toothpaste

SLS is a detergent used in most commercial toothpastes. It disrupts the oral mucin layer — the protective protein film over the epithelium. Without this layer, the mucosa is more vulnerable to physical trauma and immune-mediated damage.

The evidence is reasonably consistent:

• Herlofson & Barkvoll (1994 — PMID: 7825393): Switching from SLS-containing to SLS-free toothpaste cut ulcers by about two-thirds in a small 10-person study; a larger 2012 trial found it mainly reduced pain rather than the number of sores.
• The evidence is small but points the same way, and the switch costs nothing.

Verdict: Worth doing. If you use SLS toothpaste and get canker sores, switching to SLS-free is cheap, low-risk, and one of the better-supported changes you can make. See Best Toothpaste for Canker Sores and Do Home Remedies for Canker Sores Actually Work?

Psychological Stress

Stress is one of the most commonly reported triggers, and there's real evidence behind it. In a study that followed 160 people with recurring canker sores for up to a year, a stressful event raised the odds of a new ulcer about 2.7 times (Huling et al., 2012 — J Oral Pathol Med).

How stress does it isn't pinned down. The explanation on most health sites, that stress lowers a protective antibody (secretory IgA) in saliva, doesn't have good evidence behind it. Stress hormones do affect immune cells throughout the body, and stress also changes behavior: worse sleep, more cheek biting, different eating.

Multiple studies have confirmed the stress-canker sore association, though it's not perfectly predictable — stress seems to lower the threshold for an outbreak rather than directly cause one. High stress doesn't guarantee a sore, but it makes one more likely.

Oral Trauma

Minor trauma — biting the cheek, dental procedures, ill-fitting dentures, sharp food edges — is a well-established trigger, particularly in susceptible individuals. In people who don't have RAS, the same trauma heals without ulceration. In RAS sufferers, trauma can initiate the immune cascade that produces ulcers.

This likely explains why ulcers preferentially form at specific sites: the movable mucosa (inner cheeks, tongue), which is subject to more mechanical stress.

Two of the most common trauma triggers have dedicated guides: Canker Sores From Braces and Canker Sores After Dental Work. A bite can also turn into two sores side by side; see the bite, swell, bite cycle in Multiple Canker Sores at Once.

Two cheap ways to cut down on trauma: a soft toothbrush, which is gentler on the lining of your mouth, and a barrier patch over a fresh sore so you don't keep catching it with your teeth.

If you wear braces, wax over the bracket that rubs does the same job.

Hormonal Fluctuations

Many women report canker sores in the premenstrual phase. Progesterone fluctuations are thought to affect mucosal immune function. Many women link their outbreaks to the hormonal cycle, and some report fewer sores during pregnancy, but a review of the evidence found that a link with the menstrual cycle, pregnancy, or menopause hadn't been established by well-designed studies (McCartan & Sullivan, 1992 — PMID: 1495706).

This is not universal, but the pattern is notable enough to track if you menstruate.

Genetic Predisposition

RAS has a strong familial component. If both parents have RAS, their offspring have a ~90% chance of developing it — a pattern that confirms strong genetic predisposition. HLA typing studies have identified several associated alleles, though no single HLA type is necessary or sufficient.

Genetics establishes the susceptibility — environmental triggers determine whether and when ulcers occur. This is why identical twins with the same HLA profile can differ in outbreak frequency.

Celiac Disease and IBD

Celiac disease and inflammatory bowel disease (Crohn's and ulcerative colitis) are both significantly associated with RAS. The association is likely multifactorial:

• Malabsorption of B12, iron, folate, and zinc → nutritional deficiency mechanism
• Systemic immune dysregulation → generalized mucosal vulnerability
• In Crohn's disease specifically: oral manifestations including aphthous ulcers are a recognized feature

If you have frequent, severe, or atypical RAS that doesn't respond to nutritional interventions, screening for celiac and IBD is clinically indicated. For a deeper look at the gluten connection — and the critical reason to get tested before going gluten-free — see Does a Gluten-Free Diet Help Canker Sores?

NSAIDs as a Canker Sore Trigger

NSAIDs — ibuprofen (Advil, Motrin), naproxen (Aleve), and aspirin — are documented canker sore triggers in a subset of susceptible patients. This is not a well-publicized connection, which is part of why chronic sufferers who take NSAIDs regularly often don't identify them as a cause.

Mechanism: NSAIDs inhibit the COX-1 and COX-2 enzymes, blocking prostaglandin synthesis. Prostaglandins — particularly PGE2 — play a mucosal protective role: they stimulate mucus production, maintain mucosal blood flow, and support epithelial barrier integrity. COX-1 inhibition specifically disrupts mucosal defense; this is the same mechanism responsible for NSAID-induced gastric ulcers. The oral mucosa shares this prostaglandin-dependent protective mechanism. When NSAID use depletes mucosal PGE2, the oral epithelium becomes more vulnerable to the immune-mediated attack that produces aphthous ulcers in susceptible individuals.

NSAID hypersensitivity: Some patients appear to have a heightened mucosal sensitivity to NSAIDs that is distinct from classic aspirin allergy (IgE-mediated). This NSAID hypersensitivity manifests variably — oral ulcers, urticaria, or asthma exacerbation — depending on the individual's immune phenotype. The shared mechanism is prostaglandin pathway disruption in individuals whose mucosal tolerance for it is lower than average.

The 2-day lag pattern: NSAID-triggered canker sores typically appear 1–3 days after NSAID exposure rather than immediately. This delay is consistent with the timeline for the mucosal immune cascade to build and produce a visible ulcer — and it's the primary reason patients don't connect NSAID use to subsequent outbreaks. A headache on Monday followed by a canker sore on Wednesday doesn't feel like cause and effect.

Practical implication: If you take NSAIDs regularly — for headaches, arthritis, menstrual pain — and have unexplained canker sore outbreaks, a trial substitution with acetaminophen (Tylenol) is a reasonable, low-risk intervention. Acetaminophen does not inhibit COX enzymes and does not share this mucosal mechanism. If outbreaks decrease during the substitution period, you have your answer.

Scope: Not all NSAID users develop canker sores — this is a susceptibility effect, not a universal response. The prostaglandin depletion theory is mechanistically well-grounded, but direct RCT evidence is limited to case series and observational data. The connection is most relevant for people who already have RAS and take NSAIDs frequently.

What Does NOT Cause Canker Sores

• Herpes simplex virus: Despite the common confusion with cold sores, HSV is not involved in RAS. They are mechanistically distinct.
• Poor dental hygiene: No evidence supports this. Some antiseptic mouthwashes may actually irritate the mucosa and worsen outbreaks.
• Citrus / acidic foods: These are irritants that worsen existing ulcers, not causes of new ones. For the full breakdown of which foods genuinely trigger outbreaks vs. which just aggravate active ulcers, see Foods That Cause Canker Sores.

Next: Best Supplements for Canker Sore Prevention →