Histamine Intolerance in ME/CFS, Long COVID, and Fibromyalgia: A Hidden Link in Chronic Illness

Histamine intolerance (HIT) is emerging as a key factor in the complex symptom profile of chronic illnesses such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Long COVID, and fibromyalgia. While historically under recognised, new research suggests that disrupted histamine metabolism may contribute significantly to the persistent fatigue, pain, gastrointestinal dysfunction, and neurological symptoms observed in these conditions. This blog post explores the biological basis of histamine intolerance, its prevalence in both the general and chronically ill populations, and the dietary and lifestyle interventions that may offer symptom relief.

What is Histamine Intolerance?

Histamine intolerance occurs when the body cannot adequately break down histamine — a compound involved in immune response, digestion, and neurotransmission. Unlike allergies, which involve the immune system's overreaction to specific antigens, histamine intolerance is typically caused by an imbalance between accumulated histamine and the body’s ability to degrade it, especially by the enzyme diamine oxidase (DAO).

What is Mast Cell Activation Syndrome?

Mast Cell Activation Syndrome (MCAS) is an overlapping but distinct disorder to histamine intolerance. It is a chronic disorder characterised by inappropriate and excessive activation of mast cells—immune cells that normally defend against pathogens and mediate allergic responses. In MCAS, mast cells release histamine, prostaglandins, tryptase, and other chemical mediators without a clear allergen trigger, leading to a wide array of recurrent, multisystem symptoms including fatigue, flushing, abdominal pain, brain fog, tachycardia, and skin reactions. Read our blog post on MCAS.

Signs and Symptoms of Histamine Intolerance

Histamine intolerance manifests in a variety of multisystem symptoms, often mimicking allergic reactions:

• Dermatological: Hives, itching, flushing

• Gastrointestinal: Bloating, diarrhoea, acid reflux

• Neurological: Headaches, brain fog, anxiety

• Cardiovascular: Dizziness, hypotension, tachycardia

• Respiratory: Nasal congestion, wheezing

• Gynaecological: Premenstrual syndrome, dysmenorrhoea

  
  

These symptoms are often non-specific, contributing to delayed or missed diagnoses.

Prevalence in the General Population vs. ME/CFS, Long Covid and Fibromyalgia

In the general population, histamine intolerance is estimated to affect 1–3%, though it is likely underdiagnosed (1). However, this prevalence is markedly higher in individuals with ME/CFS, Long COVID, and fibromyalgia, where systemic inflammation and gut dysfunction are common.

ME/CFS

Mast cell activation syndrome (MCAS) and, to a lesser extent, histamine intolerance (HIT) have been increasingly associated with chronic fatigue syndrome (ME/CFS) in emerging research. While the mechanisms remain under investigation, multiple studies highlight a substantial overlap in symptomatology, immune dysregulation, and neuroinflammation.

Histamine Intolerance (HIT) and ME/CFS:

While fewer direct studies link HIT (a metabolic deficiency in histamine breakdown) with ME/CFS, it's suspected that many ME/CFS patients who show improvement on low-histamine diets or DAO supplements may be experiencing unrecognised HIT.

• Dechene (1993) hypothesised that histamine, influenced by hormones and electrolytes, might exacerbate chronic fatigue symptoms (2)

  
  

Long Covid

Current research strongly suggests an association between histamine intolerance and long COVID, though the exact nature of the relationship is still under investigation. Multiple studies have observed that a significant number of long COVID patients report symptoms overlapping with histamine intolerance, including flushing, gastrointestinal distress, brain fog, orthostatic intolerance, and rashes.

• Chambers (2023) found that many long COVID patients exhibited histamine-related symptoms potentially due to impaired methylation (affecting histamine breakdown) and suggested that DAO enzyme deficiency may contribute to symptoms (3)

  
  

Fibromyalgia

Histamine intolerance (HIT) is increasingly associated with fibromyalgia, particularly in women, and emerging evidence suggests a significant pathophysiological and symptomatic overlap between the two conditions.

• High Prevalence of DAO Deficiency in Fibromyalgia Patients: A 2023 study found that approximately 74.5% of Spanish women with fibromyalgia had a genetic deficiency in diamine oxidase (DAO), the primary enzyme responsible for breaking down histamine in the gut (4)

• DAO Supplementation Shows Symptom Relief: A randomised double-blind placebo-controlled trial in 2023 demonstrated that exogenous DAO enzyme supplementation led to statistically significant reductions in fibromyalgia symptoms, including fatigue and pain (5)

  
  

Causes and Mechanism of Histamine Intolerance

1. Enzymatic Deficiency: Low levels of DAO (in the gut) or histamine-N-methyltransferase (HNMT, in the liver and CNS) impair histamine breakdown.

2. Genetic Factors: Mutations in the DAO or MTHFR genes reduce enzyme efficiency and methylation capacity.

3. Gut Barrier Dysfunction: Common in ME/CFS and Long Covid, "leaky gut" increases histamine absorption and systemic inflammation (6).

   
   

Managing Histamine Intolerance through Diet and Lifestyle

Effective management of HIT in chronic illness often involves a multipronged approach targeting both reduction of histamine intake and support of histamine degradation:

Dietary Changes

• Low-Histamine Diet: Avoid aged cheeses, fermented foods, alcohol, processed meats, and leftovers — all of which are high in histamine.

• Support DAO Production: Nutrients such as vitamin B6, vitamin C, zinc, and copper may support DAO activity.

• Avoid DAO Blockers: Medications like NSAIDs, antidepressants, and some diuretics can inhibit DAO.

  
  

  

  
  

Supplements

• DAO Enzyme Supplements: Help break down histamine from food, particularly when taken before meals.

• Quercetin and Luteolin: Bioflavonoids with mast cell-stabilising and antihistamine effects.

• Methylation Support: Folate (as methyl folate), B12, and betaine support histamine degradation in those with MTHFR mutations.

  
  

Lifestyle Interventions

• Stress Management: Chronic stress can trigger mast cell degranulation.

• Sleep Optimization: Poor sleep increases inflammation and sensitises histamine pathways.

• Environmental Controls: Reduce exposure to dust, mould, and chemical irritants.

  
  

Conclusion

Histamine intolerance is an under recognised yet increasingly validated contributor to the debilitating symptoms of ME/CFS, Long COVID, and fibromyalgia. Its overlap with these conditions suggests that a subset of patients may benefit significantly from targeted interventions that reduce histamine burden and support histamine metabolism. As research evolves, histamine regulation may become a central focus in the broader management of post-viral and chronic inflammatory syndromes.