Spanish version

Researching and Innovating in
Functional biology, nutrition and Genomics

Migraine & Headaches

Migraine is a complex, recurrent and disabling disease. The most common and characteristic clinical symptom of this type of headache is often unilateral throbbing associated with photo and phonophobia, nausea and vomiting. For decades numerous clinical, histochemical, molecular and genetic approaches have been developed, generating a wide array of hypotheses on the origin of migraine, but none have been able to completely elucidate its etiopathogeny.

Most therapeutic approaches to the acute treatment of migraine include drugs that interact with vascular receptors. The prophylaxis of this disease frequently includes agonists and also calcium channel blockers and beta-adrenergic receptor antagonists.

In spite of this therapeutic arsenal, it is a well-known fact that the treatment of the disease is not sufficiently or completely satisfactory and drug abuse may even lead to chronification of the disease. For this reason we are studying new alternatives that have an effect on the biochemical mediators involved.

One of these mediators, and probably the most significant, is histamine, which has selective H3 receptor affinity and an inhibiting effect of the neurogenic response involved in the physiopathology of migraine.

What is histamine?

Histamine is a substance of great biological interest that is widely distributed in the different tissues of the human body, where it performs important physiological activities. It is a mediator in the response of immediate hypersensitivity and in allergies, it intervenes in smooth muscle function of the bronchial tubes and blood vessels, in the regulation of gastric secretions and as a neurotransmitter in the central nervous system, amongst others.

Histamine is also a biogenic amine that can be found in many normal foods. High levels of it are found especially in foods that have been frequently reported to be migraine triggers in susceptible people.

The relationship between diet and migraine is old and controversial and was based on the connection, reported in surveys, between the consumption of certain foods and the onset of migraine pain. Many of the foods involved were potentially rich in biologically active amines: histamine, tyramine and others. In spite of this association, the relationship between diet and migraine presents a few weaknesses, such as:

The presence of amines in foods is not constant, even within the same product type, which may explain certain apparent contradictions, such as the fact that not always do the foods involved trigger the disease.
Not all foods related with the onset of migraine are histamine rich, but may release endogenous histamine.
In the field of biogenic amines, histamine is the predominant molecule in migraine triggering. Recently García-Martín et al. (2008) cited a series of arguments that further support the relationship between histamine and migraine, amongst which the following should be noted:

The frequency of migraine is higher in patients with allergic diseases.
The serum concentration of histamine is higher in people afflicted by migraine, both during pain episodes and during migraine-free periods.
Higher levels of histidine (a precursor amino acid of histamine) are found in the blood serum and cerebrospinal fluid of migraine patients than in that of control subjects.
Intravenous administration of high doses of histamine (0.5 µg/Kg) to migraine patients immediately produces headache and later a migraine attack.
In healthy people, and under normal conditions, histamine is metabolized primarily via two different routes, methylation and disamination, at an intestinal and hepatic level.

The disproportion between the amount of histamine ingested or released from the cells that store it in the body and the body’s capacity to metabolize it leads to an accumulation of histamine in serum, triggering the onset of adverse effects. Diamine Oxidase, or DAO, is one of the most important enzymes in the metabolism of histamine, so when its activity decreases the risk of suffering the adverse effects of histamine, one of which is migraine, is increased.

The endogenous accumulation of histamine can occur for several reasons:

Excess ingestion
Endogenous release
Reduced metabolic capacity
Reduced metabolic capacity is the origin of histamine intolerance or dietary histaminosis due to incorrect functioning of histamine metabolism systems, primarily because of reduced DAO activity.

There are at least three possible origins of this enzymatic deficiency:

Genetic origin; genetic polymorphisms with different enzymatic activity have been identified. This explains why migraine runs in families.
Pathological origin; DAO deficiency seems to be more prevalent in populations with intestinal inflammatory diseases (ulcerative colitis, Crohn’s disease)
Pharmacological origin; due to DAO blocking or inhibition by several drugs. This risk seems relatively important given that 90 drugs, some of which are frequently used, have been proven to inhibit the activity of DAO. (See article “Histamine and Drugs”)
The signs of blood serum accumulation of histamine are similar to those of allergy. However, in dietary histaminosis the onset of symptoms is not associated with the consumption of any specific product, but with a wide variety of foods with varying and even low histamine content.

Preventive treatment of migraine

When migraine is a result of histamine intolerance, certain dietary recommendations have been proposed, including reduced or zero alcohol consumption and the exclusion of potentially triggering foods (see article “Low histamine diet”). An alternative preventive and innovative treatment for migraine is adding exogenous DAO to the diet, in the form of a dietary supplement.

Scientific background


The Spanish Association of Patients with Heachache (AEPAC) and the DR Healthcare laboratory presented the pioneer study that suggests Diamine Oxidase enzyme (DAO) deficiency as a possible migraine trigger due to its role in the metabolism of histamine, a molecule that is found in all daily diet foods. An excess of histamine would increase the risk of suffering migraine.

The conclusions of this research, led by Dr. Carmen Vidal, Professor of Nutrition and Bromatology at the University of Barcelona, were presented in the Spanish House of Representatives in May 2010, within the framework of the International Conference on Awareness of Migraine and Other Vascular headaches, inaugurated by Gaspar Llamazares, chair of the Congress Health Committee.

The MigraDAO study correlated a low blood DAO activity in the migraine population when compared with the non-migraine control group (see article)

The study consisted of determining the concentration of the Diamine Oxidase enzyme (DAO) in migraine patients who met the criteria established by the International Headache Society (IHS). The results obtained indicate that 96% of people who suffer from migraine have a low (49% with values between 40 ? 80 hdu/ml ? histamine degrading units) or very low (47% with values below 40 hdu/ml) level of DAO. This means that these people do not metabolize histamine as well as healthy people, due to reduced activity of Diamine Oxidase (DAO), the enzyme most involved in the metabolism of ingested histamine. Therefore, reduced DAO activity produces an excess of histamine, which leads to increased risk of migraine.

The study also indicates that other clinical pictures such as osteopathic pain, atopic skin or irritable colon syndromes could be related with a low level of the Diamine Oxidase (DAO) enzyme given that 41.3% of patients with migraine experience 3 or 4 additional symptoms.

These statistically significant results evidence a reduced DAO activity in the population that suffers from migraine. Patients with migraine who participated in the MigraDAO study, with a mean age of 37 years, presented a moderate intensity of perceived pain of 7.7 in the VAS scale during migraine episodes. The most frequently reported value was 8, in 38% of patients, 10 representing unbearable pain.

The DR Healthcare laboratory has promoted this study with the aim of scientifically corroborating its hypothesis that one the main causes of migraine can be found in diet as a result of a Diamine Oxidase enzyme (DAO) deficiency.