Headaches: a Review of the Role of Dietary Factors

Abstract

Dietary triggers are commonly reported by patients with a variety of headaches, particularly those with migraines. The presence of any specific dietary trigger in migraine patients varies from 10 to 64 % depending on study population and methodology. Some foods trigger headache within an hour while others develop within 12 h post ingestion. Alcohol (especially red wine and beer), chocolate, caffeine, dairy products such as aged cheese, food preservatives with nitrates and nitrites, monosodium glutamate (MSG), and artificial sweeteners such as aspartame have all been studied as migraine triggers in the past. This review focuses the evidence linking these compounds to headache and examines the prevalence of these triggers from prior population-based studies. Recent literature surrounding headache related to fasting and weight loss as well as elimination diets based on serum food antibody testing will also be summarized to help physicians recommend low-risk, non-pharmacological adjunctive therapies for patients with debilitating headaches.

Full text

HEADACHE (RB HALKER, SECTION EDITOR)
Headaches: a Review of the Role of Dietary Factors
Zoya Zaeem
1
&Lily Zhou
1
&Esma Dilli
1
Published online: 6 October 2016
#Springer Science+Business Media New York 2016
Abstract Dietary triggers are commonly reported by patients
with a variety of headaches, particularly those with migraines.
The presence of any specific dietary trigger in migraine pa-
tients varies from 10 to 64 % depending on study population
and methodology. Some foods trigger headache within an
hour while others develop within 12 h post ingestion.
Alcohol (especially red wine and beer), chocolate, caffeine,
dairy products such as aged cheese, food preservatives with
nitrates and nitrites, monosodium glutamate (MSG), and arti-
ficial sweeteners such as aspartame have all been studied as
migraine triggers in the past. This review focuses the evidence
linking these compounds to headache and examines the prev-
alence of these triggers from prior population-based studies.
Recent literature surrounding headache related to fasting and
weight loss as well as elimination diets based on serum food
antibody testing will also be summarized to help physicians
recommend low-risk, non-pharmacological adjunctive thera-
pies for patients with debilitating headaches.
Keywords Headaches .Migraines .Dietary triggers .
Caffeine .Elimination diets .Biogenic amines
Introduction
Headache is a common presenting complaint to primary care
providers, emergency room physicians, and neurologists alike
with a lifetime prevalence of above 90 % [1]. Although less
prevalent than tension-type headaches, migraines are associ-
ated with significantly higher morbidity. It has a prevalence of
15 % and is the seventh highest cause of disability inthe world
[2]. In the USA, it was associated with a healthcare spending
exceeding $11 billion dollars in the year 2004 alone [3].
While there are many established pharmacological treat-
ments for common primary headaches, both for headache pre-
vention (prophylactic therapy) and headache termination (abor-
tive therapy), these are all associated with a variety of side
effects. Additionally, the overuse of abortive medications can
increase headache frequency. Because of these reasons, it is
important to explore dietary factors for headache prevention.
The role of dietary supplements (also known as
nutraceuticals) has been reviewed recently and found to show
promise in the treatment of migraines [4,5••]. Currently, the
American Academy of Neurology concludes that there is
moderate (level B) evidence for the use of riboflavin, fever-
few, and magnesium and some lower quality evidence (level
C) for the use of coenzyme Q10 in migraine prevention [5••].
Through this review, we hope to consolidate the current
literature regarding food, food additives, and dietary patterns
that trigger headaches, with a focus on migraines, and the
implications of this for clinical practice.
Dietary Triggers
The definition of what qualifies as a food trigger is variable
between studies and often based on patient self-report. A pop-
ular definition proposed previously included foods or bever-
ages that precede an attack by less than 48 h [6]. Estimates of
the prevalence of specific dietary triggers among migraine
patients vary widely between 10 and 64 % in recent studies
(Table 1).
This article is part of the Topical Collection on Headache
*Esma Dilli
esma.dilli@vch.ca
1
Division of Neurology, University of British Columbia, 8219-2775
Laurel Street, Vancouver, BC V5Z 1M9, Canada
Curr Neurol Neurosci Rep (2016) 16: 101
DOI 10.1007/s11910-016-0702-1

The International Classification of Headache Disorders III
(ICHD III-beta) also set out specific criteria for related sec-
ondary headaches induced by food and/or additives [24].
These definitions are more stringent and describe headaches
related to foods or additives containing one or more specific
substances, which may not be identified but is capable of
causing headache in a sensitive patient. By ICHD III criteria,
the headache must have developed within 12 h of ingestion,
resolve within 72 h after ingestion, and have one of the fol-
lowing features: bilateral, mild to moderate, pulsatile, and/or
aggravated by physical activity.
Chocolate
Chocolate is a processed food that originates from the culti-
vation of cacao plants in Mesoamerica and contains vasoac-
tive compounds including biogenic amines, flavonoid phe-
nols, and caffeine (to be discussed separately below) [25].
It is commonly found to be a trigger among survey data
from migraine patients in Caucasian and Hispanics popula-
tions though frequencies vary widely, with 1.4 [26]to
22.5 % [27] of patients being affected (Table 2). Conversely,
not a single patient among a Japanese survey including more
Table 1 Dietary effects among
migraine patients Paper Prevalence
(%)
Any specific dietary
trigger
Rasmussen [7](Denmark,n= 119, not specified) 10
Rasmussen [8](Denmark,n=96,notspecified) 10.4
Kelman [9](USA,n=1009, withandwithoutaura) 10.6
Zivadinov [10] (Croatia, n=720, with and without aura) 12.5
Cologno [11](Italy,n= 77, with aura) 15.6
Andress-Rothrock [12] (USA, n= 200, not specified) 18
Turner [13] (USA/Mexican Americans, n=132,withand
without aura)
21.2
Kelman 2007 (USA, n= 1750, with and without aura) 26.9
Robbins [14] (USA, n= 494, with and without aura) 30
Deniz [15](Turkey,n= 185, with and without aura) 32.9
Constantinides [16] (Greece, n=51, withandwithoutaura) 33.3
Karli [17] (Turkey=56, with and without aura) 33.9
Chabriat [18] (France, n= 385, not specified) 36
Mollaoğlu [19](Turkey,n=126,withandwithoutaura) 43.6
Van den Bergh 1987 (Belgium, n= 217, not specified) 44.7
Ierusalimschy [20] (Brazil, n= 100, without aura) 46
Spierings [21](USA,n= 38, not specified) 58
Fukui 2008 (Brazil, n= 200, not specified) 64
Hunger/fasting Takeshima 2004 (Japan, n= 244, with and without aura) 0.8
Kelman 2006 (USA, n= 1009, with and without aura) 27.2
Chakravarty [22](India,n=200, without aura, pediatric) 31.5
Andress-Rothrock 2010 (USA, n= 200, not specified) 39
Robbins 1994 (USA, n= 494, with and without aura) 40
Deniz 2004 (Turkey, n= 185, with and without aura) 41.6
Scharff 1995 (USA, n= 172, without aura) 44.9
Yad av [23](India,n= 182, without aura) 46.3
Ierusalimschy 2002 (Brazil, n=100,without aura) 48
Bánk 2000 (Hungary, n= 78, with and without aura) 52
Mollaoğlu 2013 (Turkey, n= 126, with and without aura) 53.9
Turner 1995 (USA/Mexican Americans, n=132,withand
without aura)
54.5
Kelman 2007 (USA, n= 1750, with and without aura) 57.3
Fukui 2008 (Brazil, n= 200, not specified) 63.5
Karli 2005 (Turkey=56, with and without aura) 73.2
Spierings 2001 (USA, n= 38, not specified) 82
101 Page 2 of 11 Curr Neurol Neurosci Rep (2016) 16: 101

Table 2 Food triggers in
migraine patients Triggers Paper Prevalence
(%)
Wine Takeshima 2004 (Japan, n= 244, with and without aura) 1.4
Alcohol Karli 2005 (Turkey = 56, with and without aura) 3.6
Mollaoğlu 2013 (Turkey, n= 126, with and without aura) 3.9
Ulrich [28] (Denmark, n= 169, with aura) 9
Rasmussen 1992 (Denmark, n= 96, not specified) 19.8
Kelman 2006 (USA, n= 1009, with and without aura) 20
Rasmussen 1993 (Denmark, n= 119, not specified) 20.2
Andress-Rothrock 2010 (USA, n= 200, not specified) 20.5
Henry [29] (France, n= 880, with and without aura) 23
Constantinides 2015 (Greece, n= 51, 49 responses, with and
without aura)
26.5
Ierusalimschy 2002 (Brazil, n= 100, without aura) 28
Peatfield 1995 (UK, n= 429, not specified) 28
a
Peatfield [30](UK,n= 500, with and without aura) 29
Bánk 2000 (Hungary, n= 78, with and without aura) 30
Fukui 2008 (Brazil, n= 200, not specified) 34
b
Scharff 1995 (USA, n= 172, without aura) 35.3
Kelman 2007 (USA, n= 1207, with and without aura) 37.8
Spierings 2001 (USA, n= 38, not specified) 42
Van den Bergh 1987 (Belgium, n= 217, not specified) 51.6
Beer or spirits Russell [31] (Denmark, n= 333, with and without aura) 9.3
Red wine or cheese Russell 1996 (Denmark, n= 333, with and without aura) 26.1
Cheese Yadav 2010 (India, n=182,withoutaura) 0
Bánk 2000 (Hungary, n= 78, with and without aura) 0
Constantinides 2015 (Greece, n= 51, 49 responses, with and
without aura)
4.1
Fukui 2008 (Brazil, n= 200, not specified) 8.5
Scharff 1995 (USA, n= 172, without aura) 9.1
Peatfield 1995 (UK, n= 429, not specified) 16.5
Peatfield 1984 (UK, n= 500, with and without aura) 18.2
Cheese and dairy Van den Bergh 1987 (Belgium, n= 217, not specified) 18.5
Milk and cheese Mollaoğlu 2013 (Turkey, n= 126, with and without aura) 10.3
Milk Van den Bergh 1987 (Belgium, n= 217, not specified) 2.3
Fukui 2008 (Brazil, n= 200, not specified) 2.5
Ice cream Takeshima 2004 (Japan, n= 244, with and without aura) 1.2
Fukui 2008 (Brazil, n= 200, not specified) 3.0
Van den Bergh 1987 (Belgium, n= 217, not specified) 4.6
Chocolate Yadav 2010 (India, n=182,withoutaura) 0.0
Takeshima 2004 (Japan, n= 244, with and without aura) 0.0
Bánk 2000 (Hungary, n= 78, with and without aura) 1.4
Chakravarty 2009 (India, n= 200, without aura, pediatric) 1.5
c
Russell 1996 (Denmark, n= 333, with and without aura) 6.9
Constantinides 2015 (Greece, n= 51, 49 responses, with and
without aura)
10.2
Peatfield 1995 (UK, n= 429, not specified) 16.5
Mollaoğlu 2013 (Turkey, n= 126, with and without aura) 18.3
Peatfield 1984 (UK, n= 500, with and without aura) 19.2
Fukui 2008 (Brazil, n= 200, not specified) 20.5
Scharff 1995 (USA, n= 172, without aura) 22.1
Van den Bergh 1987 (Belgium, n= 217, not specified) 22.5
Curr Neurol Neurosci Rep (2016) 16: 101 Page 3 of 11 101

than 240 migraine patients identified it as a trigger [32]sug-
gesting possible geographic variations in frequency.
Evidence from small double-blind studies among patients
who identified chocolate as a consistent migraine trigger have
yielded mixed results with two studies finding no difference
between chocolate and placebo as a provocative factor for
headaches [33,34] and the other finding chocolate causing
more headaches than placebo (5/12 vs. 0/8) in patients with
self-reported chocolate-triggered migraines [25].
Caffeine
Caffeine is a plant-based methylxanthine class stimulant.
It is estimated that 87 % of Americans consume caffeine
on a daily basis, with a mean estimated average dietary
intake of 193 mg/day per consumer [35]. It is even more
popular in Scandinavian countries where the average daily
exceeding 400 mg per person [36].
Caffeine acts as a competitive antagonist at adenosine A1
and A2A G-protein-coupled receptor subtypes [36]. Purines
including adenosine are linked to cerebral vessel vasodilation.
It is known that plasma adenosine increases during migraine
attacks [37] and that migraine can be triggered by exogenous
adenosine administration [38]. Additionally, central nervous
system adenosine levels are elevated during extended periods
of wakefulness and decrease with sleep, an effective migraine
remedy for many patients [39]. Because of this reason, caf-
feine is a common additive to abortive medications for both
tension- and migraine-type headaches with good evidence of
improved efficacy [40].
Caffeine is also a well-studied therapy for the treatment of
post-dural puncture headaches (PDPH). A 2015 Cochrane
meta-analysis concluded that compare to placebo Bcaffeine
shows a significant decrease in the proportion of participants
with post-dural puncture headache persistence and in those
needing supplementary interventions^[41]. The meta-
analysis reviewed five randomized controlled trials (RCTs)
involving the use of caffeine in this context [42–46]. Two of
these trials compared caffeine directly to placebo in the treat-
ment of PDPH, and both oral [39] and IV [40]administrations
of caffeine were found to be effective. There is mixed evi-
dence that caffeine may also be effective for PDPH prophy-
laxis with one trial finding benefit with intravenous adminis-
tration [47] during surgeries under spinal anesthesia and an-
other two studies showing no benefit with oral caffeine alone
[48] or in conjunction with acetaminophen [49].
Caffeine and caffeine-containing analgesics are also cur-
rent first-line treatments in the termination of hypnic head-
aches—the so called Balarm-clock^headaches that wake pa-
tients from a night’s sleep at a consistent time, usually in the
early mornings [50]. There are several case series to support
the use of caffeine in the treatment of hypnic headaches
[51–54], and due to the rarity of the condition, there is unlikely
to be higher quality evidence.
Tonic caffeine exposure is known to result in adenosine
receptor up-regulation [55,56] but the clinical impact of
chronic regular caffeine intake on headache is less well under-
stood. Certainly, caffeine intake may exacerbate primary
Table 2 (continued) Triggers Paper Prevalence
(%)
Coffee Yadav 2010 (India, n=182,withoutaura) 0.0
Mollaoğlu 2013 (Turkey, n= 126, with and without aura) 6.3
Peatfield 1984 (UK, n= 500, with and without aura) 7
Fukui 2008 (Brazil, n= 200, not specified) 14.5
Caffeinated drinks/
caffeine
Van den Bergh 1987 (Belgium, n= 217, not specified) 6.4
Andress-Rothrock 2010 (USA, n= 200, not specified) 8
Scharff 1995 (USA, n= 172, without aura) 10.6
Citrus Yadav 2010 (India, n=182,without aura) 0.0
Fukui 2008 (Brazil, n= 200, not specified) 4
Peatfield 1984 (UK, n= 500, with and without aura) 11.1
Aspartame Fukui 2008 (Brazil, n= 200, not specified) 8.5
Scharff 1995 (USA, n= 172, without aura) 9.4
MSG Yadav 2010 (India, n=182,withoutaura) 0.0
Fukui 2008 (Brazil, n= 200, not specified) 2.5
Scharff 1995 (USA, n= 172, without aura) 12.9
a
18.4 % to all alcoholic drinks, 11.8 % to red wine but not to white; 28 % for beer
b
Red wine: 19.5 %
a
; white wine: 10.5 %
c
BBitter chocolate^
101 Page 4 of 11 Curr Neurol Neurosci Rep (2016) 16: 101

headaches by triggering secondary headaches recognized by
the ICHD III-beta criteria as two related disorders: caffeine
withdrawal headaches and medication overuse headaches
[24]. The observed higher frequency of migraines during the
weekends compared to weekdays is felt by some to be related
to caffeine withdrawal [57]. The prevalence of caffeine with-
drawal headaches varies widely in survey studies ranging
from 0.04 [58]to56%[59] and in experimental studies be-
tween 9 and 100 % [59].
The prevalence of coffee as a trigger for migraine in
the reported literature ranges from 6.3 [19]to14.5%[60]
(Table 2). In the Daisen study, the odds ratio associated
with daily coffee or tea intake and the prevalence of mi-
graines was 2.4 (CI 0.6–1.9, P<0.0001) compared to
those with occasional coffee or tea intake but it is difficult
to attribute this to a causal relationship as opposed to
increased use of caffeine for headache alleviation among
migraine sufferers [32]. The Head-Hunt study, which an-
alyzed cross-sectional data from 50,483 Norwegian indi-
viduals over 20 years, also found increased headache
prevalence, including migraines, in those with the highest
amount of daily caffeine intake (>540 mg/day) compared
with those from the lowest group (0–240 mg/day) (odds
ratio (OR) = 1.13, 95 % CI 1.07–1.20) [61]. However, the
bulk of the effects are seen to be driven by non-migraine
headaches (OR = 1.14, 95 % CI 1.07–1.21) rather than
migraine headaches (OR = 1.10, 95 % CI 1.01–1.20).
Interestingly, in Head-Hunt study, chronic headaches
(>14 days/month) were more prevalent among individuals
with low caffeine intake compared to those with moderate or
high intake. This is in contrast to other studies showing pa-
tients with chronic migraines and chronic daily headaches are
more likely to have higher caffeine consumption [62,63], with
one study finding the high caffeine intake predating the devel-
opment of a chronic daily headache [63].
Alcohol
The recreational use of ethanol is ubiquitous across cultures
and likely dates as far back as 10,000 BC [64]. Because of its
popularity, its relationship to migraines has been well docu-
mented (Table 2). However, due to the heterogeneity of alco-
holic beverages available, these results are not easy to inter-
pret. Wine, beer, and whiskey are all known to contain vaso-
active bioactive amines (discussed below) where as other li-
quors like gin and vodka generally do not in appreciable quan-
tities [65]. Furthermore, wine and beer can contain other com-
pound such as sulphites and phenolic flavonoids, which may
further confuse interpretation.
Alcohol-related headaches have been documented since
antiquity [66], and the ICHD III-beta lists two secondary
headaches directly associated with alcohol: immediate and
delayed alcohol-induced headaches [24]. Immediate alcohol-
induced headaches develop within 3 h of alcohol ingestion
and resolve within 72 h post alcohol cessation, and the head-
ache is either pulsatile, bilateral, or worsen with physical ac-
tivity [24]. Delayed alcohol-induced headaches, one of the
most common types of secondary headaches, have similar
features to immediate alcohol-induced headache except the
headache develops within 5–12 h.
With regards to its effect on migraine, within the Head-
Hunt study, migraine prevalence was found to be lower
among both consumers of wine (0.8 %; 95 % CI 0.7–0.8)
and liquor (0.8 %; 95 % CI 0.7–0.9) compared with those
who abstain, and prevalence was found to decrease with in-
creased units of alcohol consumption [67]. A causal relation-
ship should not be inferred as migraine patient may self-
restrict alcohol use as alcohol is known to be a dietary trigger
for many migraine patients with 1.4 to 51.6 % of patient af-
fected (Table 2). Those with cluster headache also tend to
consume less alcohol than the general population [68].
Whether this effect is driven purely by bioactive amine
contained within alcoholic beverages is uncertain. One study
demonstrated that headache was provoked by 300 ml of red
wine but not a vodka and lime mixture of equal ethanol con-
tent [69]. There is still little certainty on what the culprit mech-
anism leading to alcohol-triggered migraines is though it is
likely multifactorial involving histamine, tyramine, sulphites,
flavonoids, and 5-HT release [70].
Dairy
As with alcohol, studies looking at the relationship of dairy
and migraines are difficult to interpret due to the heterogeneity
of dairy products being studied. In particular, aged cheeses
contain more vasoactive compounds such as tyramine when
compared to milk or fresh cheeses like cottage cream and
cream cheese. When the dietary intake of common foods
was reviewed within the Women’s Health Study, a cohort of
American women with and without headaches, a reduction in
reported total dairy product, aged cheese, sour cream, and
milk consumption was seen in those with migraines compared
to those without headaches [71••]. The authorsinterpreted this
as a possible indication of self-restriction of a self-identified
migraine trigger.
In general, processed dairy products seem to be report-
ed more often than milk as a trigger among migraine
patients (Table 2). One study tracking dietary migraine
triggers among patients in Brazil found that while 8.5 %
identified cheese as a trigger, only 2.5 % identified milk
[60]. A Belgium study reported that 4.6 % thought ice
cream a migraine trigger while only 2.3 % identified milk
as a trigger [27].
Curr Neurol Neurosci Rep (2016) 16: 101 Page 5 of 11 101

Tyramine
Tyramine is a naturally occurring biogenic monoamine de-
rived from the amino acid tyrosine. It has been proposed that
migraine patients with certain food sensitivity may have a
genetic deficiency in the enzyme responsible for the sulfate
conjugation of tyramine [72]. Tyramine may underlie the as-
sociate of chocolate, alcohol, and dairy to migraines. One
study was able to demonstrate precipitation of migraines in
food-triggered migraineurs after 100 mg of tyramine but not
with a 100 mg placebo of lactose while patients with no his-
tory of dietary triggers and controls were not affected by the
tyramine [73]. A study by Peatfield looking at food triggers
discovered an association between sensitivity to cheese/choc-
olate, red wine, and beer (P< 0.001) within migraine patients
further supporting a shared factor in these food sensitivities
[74].
However, a review conducted in 2003 on dietary intoler-
ance of biogenic amines reviewed 12 available studies looking
at tyramine and migraines where subjects were given an oral
challenge of tyramine including Peatfield’s study [75]. Six of
these 12 studies were from E. Hanington and had considerable
overlap in data. The 12 studies reviewed had mixed results
with all of the Hanington studies and one other study finding a
relationship between tyramine ingestion and headaches while
the other five studies found no such relationship. The review
identifiedmethodological flaws with all but two of the studies,
both of which concluded there was no elevated incidence of
headaches after tyramine ingestion among patients with
migraine.
Histamine
Histamine isalso a naturally occurring biogenic amine derived
from the amino acid histidine. Some authors have proposed
that defects in diamine oxidase leading to inadequate hista-
mine degradation may be found in a portion of individuals
with food- and wine-triggered headaches [76]. Individuals
who suffer from this disorder can also experience sneezing,
diarrhea, pruritis, and shortness of breath. Wine intolerance is
a manifestation because alcohol competitively inhibits the di-
amine oxidase enzyme. This theory of wine-triggered mi-
graines was challenged by a study showing no difference be-
tween histamine antagonists vs. placebo for alleviation of
wine-induced headaches among migraine patients [77].
Phenylethylamine
Phenylethylamine is another biogenic monoamine, which is
synthesized from the amino acid phenylalanine. It is found in a
variety of foods, including animal products, wine, and
chocolate. Because phenylethylamine (PEA) is metabolized
by monoamine oxidase, it is thought that reduced monoamine
oxidase activity may be the underlying mechanism behind
PEA-triggered migraines [78].
There is not a great deal of evidence supporting this theory.
One non-randomized PEA oral challenge study in those with
self-reported chocolate sensitivity found PEA capsule trig-
gered more migraines when compared with lactose capsules
[78]. Another study involving 66 women with a history of
chronic headaches randomized to either 60 g of chocolate
(with 1.9 μg/g of phenylethylamine) or 60 g of carob (with
0.4 μg/g of phenylethylamine) after a restrictive 2-week diet
found no difference in headache frequency between the
groups [79].
Aspartame
Aspartame is a dipeptide, which consists of the methyl ester of
phenylalanine and aspartic acid. It iseventually converted into
methanol and oxidized to formaldehyde and formic acid.
Since its approval as a sweetener by the FDA in 1980s, nu-
merous complaints have been made to the FDA regarding
adverse side effects including headache (45 %), dizziness
(39 %), confusion/memory loss (29 %), and insomnia
(14 %) [80].
Evidence from five randomized double-blind studies ex-
ploring aspartame-triggered headaches yield mixed results
with three studies involving 40, 48, and 108 patients, respec-
tively, revealing no difference in headache frequency between
those exposed to placebo vs. those exposed to aspartame
[81–83] and two other studies, which demonstrated higher
frequency of headaches among certain subjects’exposure to
aspartame compared to placebo [84,85].
Case reports exist of migraines triggered after ingesting
aspartame-containing rizatriptan [86] and chewing gum [87],
and aspartame has been identified by 9 % migraine patients as
a trigger in two studies [60,88].
Nitrites
In 1972, Henderson and Raskin published a case of nitrite-
sensitive headache, which later became known as the Bhot-
dog headache^[89]asnitratesareoftenusedaspreservatives
for meats. While previously thought to be an inert degradation
productive of nitric oxide, it is now known that dietary nitrites
and nitratesserve tohelp regulate nitric oxide hemostasis [90].
The reduction of nitrite to nitric acid can lead to vasodilation
via activation of soluble guanylyl cyclase in smooth muscle
[91]. Nitric oxide is also produced and released during cortical
spreading depression and may be directly involved in pain
modulation within the central trigeminal pathway [92].
101 Page 6 of 11 Curr Neurol Neurosci Rep (2016) 16: 101

Plasma nitrite levels of migraine patients have been shown
to increase during attacks compared to when in periods of
remission [93]. However, a recent review of four RCTs and
an open-labeled clinical trial concluded that non-selective
NOS inhibitors likely are ineffective in migraine treatment
and carry significant cardiovascular side effects [94]. Work
on neuronal nitric oxide synthesis inhibition in headache treat-
ment remains an area of ongoing research.
Monosodium Glutamate
Monosodium glutamate is the sodium salt of glutamic acid, a
naturally occurring nonessential amino acid, which enhances
the savory (Bumami^) taste of many foods. It was first identi-
fied by the Japanese chemist Kikunae Ikeda in 1908 [95]and
is now a common food additive and flavor enhancer. With its
increasing prevalence, especially among packaged fast food
and Chinese food, there have been many subjective reports of
adverse reactions. Headaches due toingestion of monosodium
glutamate (MSG) are typically pressing/tightening or burning
in quality; however, in patients with migraines (Table 2), it
may be pulsatile. Flushing of the face; pressure in the face and
chest; burning sensations in the neck, shoulders, and/or chest,
dizziness; and abdominal discomfort may accompany the
headache in response to MSG [24]. According to ICHD III-
beta criteria, MSG-induced headache must have developed
within 1 h of MSG ingestion and resolve within 72 h after
ingestion.
The authors of a recent review concluded that the available
evidence suggests that due to its distinctive taste, beverages
containing 1.3 % MSG (2 g/150 ml) or more should be dis-
tinguishable by taste from placebo, which affects blinding
within RCTs [96]. The review identified five papers describ-
ing six RCTs studying the effects of MSG in food. There was
no difference in headache found between placebo and admin-
istrations of 1.5 and 3.0 g of MSG in capsule form prior to
food, 3.15 g of MSG in 300 ml of beverage, 3.0 g of MSG in
boiled rice with pork, and 3.0 g of MSG in 150 ml beef broth.
The only significant difference was within female subjects
administered 3.0 g MSG in 150 ml (2.0 %) of beef bouillon
but not in male subjects. No MSG effect of headache was
found within the three studies that were felt to be adequately
blinded by the authors of the review [97–99].
Elimination Diets Based on Serum Food Antibody
Test ing
Recent efforts for more objective identification of food hyper-
sensitivities among migraine patients have led to research in-
volving serological testing of antibodies against various food
antigens.
An early study found no difference in serum titers of total
IgE or IgG antibodies directed against cheese, milk, and choc-
olate in migraine patients with food triggers compared to those
without headaches [100]. However, since then, there has been
an association found between atopic conditions such as aller-
gic rhinitis, eczema, and asthma to migraine and elevated total
serum IgE antibody titers in migraine patients compared to
controls [101]. Additionally, higher IgE titers were found in
patients with more severe migraines [102] and during mi-
graine periods than in remission [103]. However, a prospec-
tive study looking at IgE skin prick testing for food trigger
identification in migraine patients failed to trigger any attacks
after oral challenges with foods positive on IgE skin testing
[104].
There has also been revitalized interest in IgG antibodies
after promising research for IgG-guided elimination diets
among patients with irritable bowel syndrome (IBS) [105].
A study involving 56 migraine patients from Mexico found
that the patients had elevated IgG titers to many more food
triggers compared to controls and that 43 out of 65 patients
showed a complete remission of their migraine after 1 month
of an IgG-guided elimination diet [106]. Since then, there
have been two small blinded cross-over studies within mi-
graine patients showing a reduction in headache days and
number of attacks on IgG-guided food elimination diets
[107,108]. A larger-scale RCT involving 167 subjects with
self-endorsed migraines showed a small decrease in the num-
ber of migraine-like headaches over 12 weeks between those
randomized to an IgG-guided elimination diet compared to a
sham elimination diet, though the result did not reach statisti-
cal significance [109].
However, there are some who believe that elevated titers of
food-directed IgG in many migraine patients represent an epi-
phenomenon of increased baseline inflammation rather than
true allergic reaction [110]. As in IBS, the use of IgG-guided
elimination diets for migraine control remains an area of con-
tention and is not yet standard of care until more evidence is
available regarding its efficacy.
The Impact of Dieting
An association between migraine headaches and an elevated
body mass index (BMI) has been found in numerous large
population studies, particularly among those of reproductive
age (<50 years old) or younger [111]. One of these studies
reported an 1.5-fold (OR 1.48, 95 % CI 1.12–1.96) increase
in odds of migraines for those with class I obesity (BMI 30–
34.9), a 2-fold (OR 2.07, 95 % CI 1.27–3.39) increase in those
with class II obesity (BMI 35–39.9), and an almost 3-fold (OR
2.75, 95 % CI 1.60–4.70) increase in those with class III
obesity (BMI >40) [112].
Curr Neurol Neurosci Rep (2016) 16: 101 Page 7 of 11 101

So far, no difference has been found in the number of
migraine days in obese migraine patients and those with nor-
mal BMI [113]. However, obese individuals with episodic
headache have a greater risk of transformation to chronic
headaches than those with episodic headache who are not
obese [111]. Additionally, two case series involving bariatric
surgery in overweight migraineurs have demonstrated signif-
icant improvements in frequency and duration of the attacks
(P= 0.02) as well as lower medication use for migraine at-
tacks after surgery [114,115]. All this would suggest that there
may be significant benefits to healthy diets promoting weight
loss among migraine patients.
Care should be taken during this process as hunger or
skipped meals are among one of the most consistently identi-
fied dietary triggers (Table 1). Furthermore, headache attrib-
uted to fasting is also a well-described secondary headache
with its own specific diagnostic criteria in the ICHD III-beta
[24]. A study looking at patients during Yom Kippur found
that 39 % (82 patients) developed headache as compared to
7 % (9 patients) in the non-fasting control group [116]. Studies
looking at patients fasting for Ramadan found similar results
[117,118] with perhaps a tripling of migraine days during
Ramadan compared to a control month.
It is difficult to tease out the contribution of caffeine with-
drawal and hydration in fasting headaches. Recent case re-
ports have noted that water deprivation can trigger migraines
[119], and a very small study looking at 18 migraineurs
showed an increase of one liter per day of water intake was
associated with an average reduction of headaches by 21 h in
2 weeks as well as a reduction in subjective headacheintensity
as rated by a visual analog scale [120].
In terms of a diet that may be beneficial, the Dietary
Approaches to Stop Hypertension (DASH)-sodium RCT found
that reduced sodium intake was associated with a significantly
reduced risk of headaches [121]. This may be secondary to
blood pressure benefits associated with the DASH diet.
The effect of dietary fat on migraine is more nuanced. One
population study identified a higher lipid intake among mi-
graine patients compared to the rest of the population [25],
and certain patients find fatty food to be a migraine trigger
[27]. Several studies have reported that lower dietary fat signif-
icantly decreases the number andintensityofacutemigraine
attacks [122,123]. However, the ketogenic diet, which shifts
the majority of caloric intake from carbohydrates to lipid
sources, has also been extensively studied as a method of im-
proving migraines since as early as 1928 [124,125]. Most
recently, one study involving 96 overweight female migraine
patient randomized to either 1 month of low-calorie ketogenic
diet followed by a standard low-calorie diet for 5 or 6 months of
the standard low-calorie diet found that while headache fre-
quency and total headache days decreased in both the groups,
the decrease occurred much morerapidlyinthoserandomized
to a period of ketogenic diet first [126].
Conclusion
The impact of diet on headache is clearly variable between
patients. Studies attempting to quantify the frequency of trig-
gers among migraine patients yield widely discrepant infor-
mation (Tables 1and 2). One potential source of variation may
be from patient selection as some of these studies recruited
from headache clinics whereas others were cross-sectional
population studies. Most studies in Tables 1and 2were retro-
spective studies using self-reporting, which is vulnerable to
small variations within the data collection method. For exam-
ple, one study showed that while only 75.9 % of patients
initially endorsed having migraine triggers when asked, this
number rose to 94.6 % when the patients were questioned
regarding specific triggers [127]. Intuitively, prospective stud-
ies either using either oral challenges or food diaries would
likely yield information that is less sensitive to bias but these
study designs are less feasible for studying larger populations.
There is clearly still much to discover in the relationship
between diet and headache. However, given the prevalence of
dietary triggers, clinicians should encourage the use of a food
diary for headache patients to identify these triggers. A trial of
eliminating the identified triggers from the diet is a relatively
benign intervention that may significantly lessen morbidity.
Other strategies like ensuring regular meals to avoid hunger
and dehydration, a sodium-restricted diet, and calorie-
restricted diets for overweight migraine patients are other prom-
ising adjunctive strategies to traditional headache management.
Compliance with Ethical Standards
Conflict of Interest Zoya Zaeem, Lily Zhou, and Esma Dilli declare
that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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