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Table 15.1 Vasoactive amines and headache-triggering agents in chocolate.

Chemical Amount typically found in chocolate

Table 15.1 Vasoactive amines and headache-triggering agents in chocolate.

Chemical Amount typically found in chocolate

Phenylethylamine (BPEA)

0.46.6 ^g/g

(14);

0.386.4 ^g/g

(15)

Theobromine

Average 2 mg/g

(16);

1.365.65 mg/g

(17)

Caffeine

Average 0.2 mg/g

(16);

0.1160.617 mg/g

(17)

Tyramine

3.812 ^g/g

(14)

Spermine

1.63 ^g/g

(18)

A variety of studies have investigated the role of ingested tyramine as a trigger for headache. All of the studies supporting a causal relationship between tyramine and migraine were generated from a single laboratory (Hanington et al. (11, 19, 20, 23)), and one series of their research reports describe updates of an ongoing study, with each subsequent report including subjects and data from previous reports.

These researchers included a 'dietary headache' group comprised of only migraine sufferers who avoided specific foods because of a recognized connection between eating those foods and migraine activity. Subjects in this dietary headache group (n = 11 in the last report of this study) were compared to a non-dietary headache group (n = 9) and a group of headache patients in which the relationship between food and headache was unclear (n = 7). Subjects were orally administered either 100 mg of tyramine (equivalent to 3 1/2 oz of cheese with a high tyramine content) or a lactose placebo on a varying number of occasions. The dietary headache group was more likely to report headaches after ingesting the tyramine that after ingesting the lactose, and this group was also significantly more likely to report a headache after tyramine than subjects in either of the other two groups. In a later study (23), the same researchers reported that 35 dietary migraine sufferers were more likely to develop headaches after 125 mg of tyramine in comparison to lactose and a non-dietary control group of 27 migraine sufferers.

Other controlled studies of tyramine and headache have failed to replicate the findings of Hanington et al., even when the same subject selection criteria of food sensitivity and avoidance were applied (8, 21, 22, 26, 27). Shaw et al. (22) reported that none of the nine dietary migraine subjects in their study experienced a headache after ingestion of 200 mg of tyramine. Moffett et al. (21) reported no differences in headache occurrence in a group of dietary headache sufferers and non-dietary headache sufferers after ingestion of 125 mg of tyramine or placebo.

Although there is some evidence that BPEA and tyramine contribute to migraine headache in some patients, there is some dispute concerning the contribution of dietary as opposed to endogenously produced BPEA. Karoum et al. (26) measured BPEA and tyramine in human blood, cerebrospinal fluid and urine, as well as in rat brains before and after ingestion of foods including chocolate, and found no alteration of either BPEA or tyramine. The authors con-

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cluded that the dietary contribution of these amines did not directly contribute in a significant way to their quantity in the body, but rather that these amines are produced from endogenous sources. This failure of ingested foods to alter physiological levels of BPEA and tyramine may explain why some studies fail to demonstrate changes in headache after food ingestion.

Chemicals found in chocolate other than BPEA and tyramine have also been implicated as causing headaches, although not as frequently. Caffeine has also been linked to headache, and theobromine a caffeine metabolite is typically present in chocolate and cocoa products (27). It is the theobromine rather than the caffeine content in chocolate that is postulated as a headache trigger (28). Recently, another vasoactive amine present in chocolate, spermine, has been identified as an important transmitter of pain (29). The role of spermine specifically as a trigger for headache is unknown.

Headache As an Expression of Food Allergy

The proposed relationship between food allergy and headache is controversial. Some researchers have asserted that migraine itself may be an expression of food allergy (30, 31). The majority of researchers investigating this possible link, however, have dismissed the possibility that the vast majority of food-induced migraines are caused by food allergies (7, 32).

One common link between allergy and food-induced migraine is that vasoactive amines (most notably histamine) are released during an allergy attack, and increased levels of plasma histamine have been identified during migraine episodes (33), as well as in migraine patients when they ingest implicated trigger foods (34). Studies that have examined RAST or skin prick tests of allergies in comparison to identified food triggers of migraine, however, have rarely identified any link between positive allergy findings and food-induced headache. Schuller et al. (35) have reviewed the research literature regarding this subject, and found that studies supporting the association between food allergy and migraine are far outnumbered by studies that have not supported this association. If there were indeed a link between positive food allergy findings and clinical symptoms such as headache, chocolate would indeed demonstrate this association. One study found that 67% of a group of allergy patients tested positive for chocolate allergy, and the vast majority of these patients regularly ate chocolate (36).

Restrictive Diet Studies

Anecdotally, dietary restriction is associated with headache improvement in one-third to two-thirds of migraineurs. Several studies have attempted to investigate

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