The exact mechanisms by which foods trigger headaches are not yet fully understood, so the possible mechanisms by which dairy products, including milk, act as triggers remain uncertain. Several potential mechanisms have been considered in previous reports. One of these mechanisms is thought to be the impact of tyramine. Tyramine is an endogenous biogenic monoamine originating from the amino acid tyrosine. The potential link between biogenic monoamines such as tyramine and migraine attacks has been postulated based on their association with milk and dairy products [15].

Tyramine is present in certain cheeses, dairy products, and certain alcoholic beverages. Similar to 5- hydroxytryptamine, dopamine, and epinephrine, it undergoes oxidative deamination in the body, facilitated by the enzyme monoamine oxidase. Tyramine induces the release of endogenous aromatic amines such as noradrenaline from sympathetic nerves [16]. Blackwell and Mabbitt observed that patients taking monoamine oxidase inhibitors developed sometimes severe headaches following the consumption of cheeses and dairy products. It has been shown that the occurrence of headaches is related to the inhibition of monoamine oxidase, which is responsible for the absorption of tyramine and its breakdown in the intestine [17]. In an earlier randomized controlled trial (RCT) conducted in 1971, migraine patients had a significantly greater increase in free plasma tyramine and a decrease in conjugated tyramine compared with controls. This finding raised the question of whether there is an enzyme deficiency in tyramine conjugation in migraine [17]. Recent studies over the past 20 years have suggested that biogenic amines like tyramine, and tryptamine, contribute to the pathogenesis of migraine [18].

Abnormalities in tyrosine-related metabolites have been demonstrated in chronic migraine patients. Although the mechanism is not fully understood, one hypothesis is that abnormalities in tyrosine metabolites activate the pain matrix [19]. The pathological interplay of reduced energy reserves and altered tyrosine metabolism, including elevated levels of neuromodulators and an imbalance of neurotransmitters in platelets and plasma, observed in individuals with migraines, might reflect similar biochemical irregularities within the synaptic gaps of the pain network, forming the pathological biochemical changes underlying migraine attacks (Fig. 1) [19].

Schematic representation of neurotransmitters and enigmatic amines in the pathophysiology of migraine. (ANS: Antinociceptive system, DA: Dopamine, NE: Norepinephrine 5-HT: Serotonin TRY: Tyrosine TRYPT: Tryptophan OCT: Octopamine), created with Biorender

In a study exploring tyrosine metabolism in the pathogenesis of chronic migraine, the plasma levels of dopamine and noradrenaline were several times higher in the patients with chronic migraine in comparison to the control group [20]. Food additives may also play a role in the occurrence of headaches. Whipping cream and heavy cream are mainly used in ready-to-eat products and contain numerous food additives such as emulsifying salts, potassium sorbate, carrageenan, and others. In a recent study investigating the role of food triggers in migraine and MOH, dairy products, particularly those found in processed foods containing additives such as carrageenan and calcium isosorbate, were shown to be potential headache triggers. Food additives and preservatives as well, had a significant inducing effect on headache attacks as well as specific foods. In the same study, foods such as milk, cream cheese, whipped cream, cream cheese, and milk powder were found to be common food triggers for both migraine and IBS, and patients with MOH and IBS avoided consuming milk, cream cheese, and cream [1, 5].

Another question that remains to be answered is whether many migraine sufferers have a food-based inflammation at varying severities. Current knowledge about the association between migraine and dairy favors a complex relationship with various aspects among these two entities. Neurogenic inflammation is well known to have a role in the pathophysiology of both migraine and IBS. Increased permeability of the intestinal barrier and the subsequent inflammation have been linked to increased occurrence of migraine. Leaky gut syndrome has been more frequently observed in chronic migraine patients with medication overuse and its pathogenesis has been demonstrated to involve increased inflammatory markers such as LPS, VE-Cadherin, HMGB-1and HIF-1alpha (Fig. 2) [21].) It seems reasonable to suggest that a wide spectrum of food-based inflammation may precipitate migraine attacks.

The potential contribution of increased intestinal permeability to neuroinflammation: metabolism of dairy products along with the increased fermentation in the colon, poor absorption in the small intestine, intestinal dysbiosis, and permeability individuals leading to the production of particular microbiota profiles that are more prone to trigger headaches., in addition to the epigenetic changes triggered by diet [13, 21]. Figure 2 created with Biorender

Dietary compounds can affect all major elements of the cellular epigenetic profile: DNA methylation, histone modification, and the effects of non-coding RNAs (ncRNAs), resulting in changes in transcription and/or translation [22]. It has been hypothesized that this phenomenon could be explained by allergic reactions to dairy proteins. These allergic reactions activate the immune system, leading to neuroinflammation through antibodies such as IgE and IgG, which may result in cerebral vasodilation and trigger migraine headaches. Another hypothesis is a possible involvement of food intolerance associated with the brain-gut axis [23].

The neurotransmitter-based hypothesis is as follows; dairy products such as ice cream, and yogurt which contain high levels of tyrosine are also rich in histamine and several authors suggested that histamine-rich foods may trigger migraines. Histamine intolerance is a condition characterized by the imbalance in histamine homeostasis, primarily due to impaired intestinal degradation of this amine often due to a deficiency of the enzyme diamine oxidase (DAO). Headache is a prominent symptom among the many histamine-related manifestations. Current clinical strategies for the management of symptoms associated with this disorder involve the exclusion of histamine-rich foods or other bioactive amines, coupled with exogenous DAO supplementation [24]. However, the lack of efficacy of histamine antagonists in preventing headache attacks suggests that histamine alone may not be the only substance involved in the mechanism [25].

Foods rich in tyrosine are also considered dopaminergic foods since tyrosine is an essential amino acid converted to dopamine. Dairy products such as milk, cheese, and yogurt are among the foods rich in the amino acid tyrosine. The relationship between dietary habits and inflammation has therefore been the subject of long-standing research. Furthermore, the consumption of high-fat cheeses and cream sauces has been shown to increase inflammatory parameters in humans, especially IL-6 [26]. A survey study mentioned earlier showed that the food triggers for MOH patients were mainly dopaminergic foods, including milk, cream, and cream cheese [5].