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Migraine headaches in humans have been documented for 6,000 years; the condition is complex and often chronic.¹ Today, migraine is the third most prevalent disease in the world and the second leading cause of disability,² affecting up to one billion people worldwide,³ following depression.⁴ This painful neurovascular condition is characterized by a unilateral, pulsing headache that lasts for hours to days and is often associated with a variety of symptoms such as nausea, vomiting, and sensitivity to light, sound, or odors.²

A challenge in migraine research lies in its complex multifactorial pathogenesis; headaches may result from genetic, endocrine, metabolic, and/or environmental factors.^2,5 But while the exact pathophysiology of migraine remains unclear, there is evidence that neuroinflammation plays a role, and food has been identified as a triggering factor.² To this end, continued research into mast cells and their release of histamine, an inflammatory trigger, plays a fundamental part in migraine pathophysiology and management.^1-2,6 What is the role of mast cells and histamine in migraine etiology? How might an understanding of neuroinflammation inform migraine therapies like diet modification?

It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system, which leads to the release of several proinflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses, including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation.² Evidence suggests that neuroinflammation in the meninges is the key element resulting in the sensitization of trigeminal nociceptors.¹ The successive events such as neuropeptide release, vasodilation, plasma protein extravasation, and mast cell degranulation that form the basic characteristics of the inflammation are believed to occur in this persistent pain state.¹

Mast cells have been shown to be involved in the pathophysiology of migraines; meningeal mast cells are in close association with neurons, which then can be activated and degranulated.² This causes the release of mediators, including neuropeptides and bio-organic amines like histamine and serotonin, which can selectively result in the release of pro-inflammatory cytokines, such as TNF-?, IL-1, and IL-6, further promoting a cascade of associated inflammatory events.²

Histamine in Migraine

Histamine is described as an ancient “tissue amine” preceding multicellular organisms.⁶ Its cells originate in the central nervous system from the tuberomammillary nucleus and travel throughout the brain, with the responsibility of ensuring wakefulness, energy homeostasis, and memory consolidation. In migraine, histamine plays a crucial role in sustaining the neurogenic inflammation pathway and modulating nociceptive sensitization.⁶

Histamine is fundamental for inducing allergic inflammation in eczema, which is associated with increased headaches in childhood, especially in patients with severe disease accompanied by atopy, fatigue, and sleep disturbance.⁶ Higher migraine prevalence is also found in patients with allergic rhinitis.⁶ Sleep deprivation increases CSF histamine (derived from brain mast cells) and exacerbates migraine.⁶ Studies suggest that migraineurs have increased plasma histamine levels and are more sensitive to it,^6-8 thus making them more susceptible to external triggers of histamine like food.⁹

Histamine Food Triggers: Clinical Considerations

Histamine intolerance (HIT), also referred to as food histaminosis or hypersensitivity to food histamine, arises from the failure of the gastrointestinal enzyme diamine oxidase (DAO) to degrade dietary histamine at the intestinal level.¹⁰ DAO deficit results in an increase in systemic histamine concentrations and the subsequent onset of symptoms, including gastrointestinal and extraintestinal manifestations like migraine.^3,10,11-12 Dietary interventions may be powerful tools in the identification and treatment of HIT and migraine.⁸

Identifying the triggers and perpetuators of migraine and establishing any potential antecedents is an important preliminary functional medicine assessment approach. The response of a headache patient to any given dietary trigger may depend on several factors, including the amount and/or timing of the exposure.⁸ Furthermore, each headache patient may have a unique set of triggers; food diaries, specific serological testing, and elimination diets are used to identify triggers in individual patients.⁸

Following an elimination diet or, if HIT is suspected, a low-histamine diet, may help to reduce HIT-related symptoms.¹³ A low-histamine diet is currently the most advised strategy to prevent the symptomatology of histamine intolerance.¹⁰ A disproportionate amount of histamine in the body is suspected to result from the consumption of histamine-containing foods or drinks and the reduced ability of enzymes to digest and degrade histamine.¹³ In foods, the manufacturing process, the cleanliness of materials, the microbial composition, and the fermentation influence the amount of histamine contained.¹³

As well, foods that normally may be low in histamine will have increasing amounts of histamine as they age or ripen (i.e., a green tomato vs. a ripe tomato), especially those with higher protein content (i.e., leftover beef).¹⁴ To decrease histamine load, patients may be advised to eat foods that have been freshly prepared and refrigerate or freeze leftovers immediately.¹⁵

A functional medicine clinician, perhaps with the help of a functional dietician, may design an individually tailored low-histamine diet for patients. This may positively influence the pathophysiologic process, including inflammation, and accomplish symptom reduction.¹³ Some foods commonly associated with histamine reaction include, but are not limited to:^14,16-19

• Cheeses: Gouda, cheddar, Danish bleu, Swiss cheese
• Seafood: Herring, smoked mackerel, canned sardines, tuna, anchovy
• Meats: Sausage, pork, smoked meats
• Other proteins: Egg whites, tamari, tempeh, miso
• Nuts: All varieties
• Fats & oils: Avocado, coconut, nut oils
• Vegetables: Eggplant, spinach, sauerkraut, tomatoes
• Fruits: Citrus, papaya, strawberries, pineapple, bananas
• Beverages: Coffee, tea, beer, red wine
• Other: Chocolate, licorice

Although no consensus exists in the medical literature as to the efficacy of a low-histamine dietary intervention for migraine due to a lack of comprehensive and high-quality large randomized controlled studies, the available data are promising in the support of this diet as a disease-modifying agent for some migraine patients.^20,21 The effectiveness of a low-histamine diet has been demonstrated in small clinical studies, which report favorable results in terms of improvement or total remission of symptoms frequently associated with histamine intolerance and DAO defciency, including:¹¹

• In a prospective study, 28 patients with chronic headache (and 17 with other dermatological and respiratory symptoms) followed a four-week intervention of the low-histamine diet. The patients with chronic headache saw a 68% reduction in symptoms.¹¹
• Another small study also focused on headache symptoms reported a gastrointestinal enzyme diamine oxidase deficiency in 23 of 27 patients (85%). (DAO deficit results in an increase in systemic histamine concentrations and the subsequent onset of symptoms). The researchers found a significant increase in DAO activity after patients followed a low-histamine diet for four weeks, along with a remission or reduction in frequency of headaches in almost 90% of individuals.¹¹

A low-histamine diet is considered by some as the gold standard for patients diagnosed with HIT^11,22 and may be a part of the larger picture of assessing migraine triggers. For functional medicine clinicians, information about histamine in foods is available in the form of a printable PDF for patients in the IFM Toolkit. For a more comprehensive food and nutrient list and to read in depth about the impact of histamine-reduced diets and the enzyme diamine oxidase, please read IFM’s article Fight Inflammation and Stabilize Mast Cells Naturally. Learn more about the functional medicine approach to immune health and clinical tools that help to enhance resilience at IFM’s upcoming Immune Advanced Practice Module (APM).

Related Articles

Treating the Underlying Causes of Chronic Migraine

Decreasing Migraine Frequency With Nutrition

Functional Medicine Matrix: Organizing Clinical Imbalances

References

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