ISSN 0017-8748

Headache  doi: 10.1111/head.13658

© 2019 American Headache Society Published by Wiley Periodicals, Inc.

Review Articles
What is Needed for Evidence-Based Dietary Recommendations
for Migraine: A Call to Action for Nutrition and Microbiome
Research
Margaret Slavin, PhD, RD; Huilun (Amber) Li, BS; Cara Frankenfeld, PhD;
Lawrence J. Cheskin, MD, FACP, FTOS

Background.—The gastrointestinal symptoms of migraine attacks have invited numerous dietary hypotheses for migraine
etiology through the centuries. Substantial efforts have been dedicated to identifying dietary interventions for migraine attack
prevention, with limited success. Meanwhile, mounting evidence suggests that the reverse relationship may also exist – that the
biological mechanisms of migraine may influence dietary intake. More likely, the truth involves some combination of both, where
the disease influences food intake, and the foods eaten impact the manifestations of the disease. In addition, the gut’s microbiota
is increasingly suspected to influence the migraine brain via the gut-brain axis, though these hypotheses remain largely
unsubstantiated.
Objective.—This paper presents an overview of the strength of existing evidence for food-based dietary interventions for
migraine, noting that there is frequently evidence to suggest that a dietary risk factor for migraine exists but no evidence for
how to best intervene; in fact, our intuitive assumptions on interventions are being challenged with new evidence. We then look
to the future for promising avenues of research, notably the gut microbiome.
Conclusion.—The evidence supports a call to action for high-quality dietary and microbiome research in migraine, both to
substantiate hypothesized relationships and build the evidence base regarding nutrition’s potential impact on migraine attack
prevention and treatment.

Key words: migraine, diet, food, dietary recommendation, microbiome

Abbreviations: C
 D celiac disease, CGRP calcitonin gene-related peptide, CNS central nervous system, ENS enteric
nervous system, GI gastrointestinal, HA headache, LPS lipopolysaccharide, MNT medical nutrition therapy,
NCGS non-celiac gluten sensitivity, RCTs randomized controlled trials, SCFAs short chain fatty acids

(Headache 2019;59:1566-1581)

INTRODUCTION
Dietary interventions for migraine have not yet
sufficiently satisfied evidence-based nutrition stan-
From the Department of Nutrition and Food Studies, George dards to support their recommendation by any major
Mason University, Fairfax, VA, USA (M. Slavin, H. Li, and nutrition or medical organization. Nonetheless, sug-
L. Cheskin); Department of Global and Community Health, gested dietary interventions for migraine are wide-
George Mason University, Fairfax, VA, USA (C. Frankenfeld).
spread. Potential dietary interventions for migraine
Address all correspondence to M. Slavin, Department of Nutrition can be classified into a few major categories, based
and Food Studies, George Mason University, Fairfax, VA, USA,
email: [email protected]

Accepted for publication June 7, 2019. Conflict of Interest: None

1566
Headache 1567

Fig. 1.—Spectrum of dietary approaches suggested to improve migraine symptoms. Note: Dietary supplements are not a major part
of this review.

on the mode of dietary intervention (Fig. 1). These EVALUATING DIETARY RECOMMENDATIONS
include following a particular eating pattern; mod- FOR MIGRAINE IN LIGHT OF EVIDENCE-
erating intake to lose weight; consuming adequate BASED NUTRITION GUIDELINES
amounts of a beneficial food/ingredient/nutrient; The United States Department of Agriculture’s
or avoiding a noxious, irritating food/ingredient/ Nutrition Evidence Systematic Review (NESR, for-
nutrient. The focus of this review is on food-based merly the Nutrition Evidence Library) and the Academy
dietary interventions. Evidence regarding dietary of Nutrition and Dietetic’s Evidence Analysis Library
supplements has been reviewed substantially else- produce evidence-based nutrition recommendations
where and is included in an ongoing American through systematic reviews.3,4 The results of the NESR
Academy of Neurology and American Headache reviews are incorporated into the Dietary Guidelines
Society evidence-based non-pharmacologic guideline for Americans, which are Congressionally-mandated
development.1 to be updated every 5 years.
As with any treatment, risks and benefits of the Most of the research in diet and migraine falls below
potential dietary intervention must be weighed before the desirable threshold for making evidence-based
its prescription. Among the benefits, dietary interven- ­dietary recommendations, frequently for low quality
tions have the potential to reduce the migraine disease and inconsistent study designs, inconsistency across
burden, by reducing attacks and chronic comorbidity results, and inadequate sample sizes. Martin and Vij
risks. Dietary interventions may be less costly, more suggest that large scale randomized controlled trials
logistically feasible, and carry fewer side effects than (RCTs) of comprehensive diets are necessary “before
pharmacological intervention. However, the risks of widespread use” in widespread clinical practice.5,6
the restrictive dietary treatments have not always been There are also numerous potential sources of bias in
adequately appreciated, not solely from physical risks the available data. The absence of high-quality evi-
associated with nutrient deficiencies, but also due to dence allows for expert opinion and interpretation of
the increased demands on executive function that di- available lesser quality evidence to take hold in nutri-
etary self-regulation incurs2 in individuals already liv- tion practice. In particular, this lack of evidence has
ing with a chronic, debilitating disease. The subsequent generally favored the acceptance of perceived low-risk
sections present the quality of evidence for diet and nu- dietary interventions that are biologically plausible, de-
trition interventions in migraine, with a vantage from spite low to moderate evidence of efficacy and incom-
this risk:benefit balance. plete consideration of the diets’ burdens.
1568 October 2019

Favorable Risk: Benefit Analysis.—Omega-3:Omega-6 protein-containing small meals and snacks frequently
Ratio.—The dietary pattern with the strongest throughout the day, avoid foods high in refined
evidence for mitigating migraine attacks is an sugars, and consume foods which are high in complex
eating pattern with an increased omega-3:omega-6 carbohydrates and fiber. However, the impact of such
ratio, as compared to the typical American diet. recommendations on migraine attack frequency has not
Ramsden and others have undertaken a series of trials been tested, and several lines of inquiry question their
investigating the clinical and nociceptive mechanistic relevance. Blood glucose levels are not directly related to
outcomes relating omega-3:omega-6 content of the precipitation of headache: hypoglycemia is inadequate to
diet to migraine and chronic daily headache.7-11 In the produce fasting headache,23 it is not always present when
initial 12-week feeding study in a population with fasting headache (HA) occurs,24 and HA is not a major
chronic daily headache – the vast majority of whom complaint of symptomatic hypoglycemia patients in
had migraine disease or migraine features – 2 treatment the emergency department.25 The interictal fasting
groups received intensive counseling and provisioned blood glucose levels in a variety of studies do not reveal
foods: either a low omega-6 diet (<2% of calories) or a consistent pattern when comparing individuals with
a low omega-6 plus high omega-3 (1500-2000 mg/day) migraine vs healthy controls. The ketogenic diet’s early
diet. The high omega-3:low omega-6 group experienced successes documented in older literature and more
significantly fewer headache days per month than the recent case studies (see the altered macronutrients
low omega-6 only group (−8.8 vs −4.0), as well as section below) further fuels questions of whether
greater decreases in headache hours per day (−4.6 vs frequent, carbohydrate-containing meals is truly the
−1.2), Headache Impact Test (HIT-6) scores (−7.5 vs best dietary strategy for fasting-induced migraine.
−2.1), and improvements in psychological distress and While direct evidence of dietary interventions
health-related quality of life.7,10 to avoid fasting-induced migraine attacks is low, the
The results are extremely promising and provide current recommendations to eat regularly and favor
insight into mechanisms underlying the involvement complex carbohydrates are low risk, low burden, and
of lipid metabolism in pain nociception. However, the consistent with general dietary guidelines.
extremely low omega-6 intake levels in both treatment Maintain Hydration.—Headache is a common
groups are impractical in the existing modern food symptom of dehydration, which may lead to a migraine
environment. Omega-6 fatty acids are omnipresent in attack in susceptible individuals. Existing trials of
high levels in the primary vegetable oils used in food fluid intake interventions to prevent migraine were
processing (canola, sunflower, corn, and soy) and in not adequately designed to detect differences nor
many restaurants. The results suggest a diet with a very recommend specific fluid levels.26,27 Considering the
high burden for most individuals to learn and adapt. myriad health advantages of proper hydration and its
Work in this group is ongoing to determine if the ex- relatively low burden,28 patients with migraine may be
tremely low omega-6 levels are necessary for efficacy coached toward consistently meeting the existing fluid
of high omega-3 treatments.11 Until further evidence is intake standards.29,30
available, a dietary pattern high in omega-3 fatty acids The adequate intake (AI) levels for water in the
is advisable for migraine patients and consistent with U.S. Dietary Reference Intakes29 are 2.7 L total water
general dietary guidelines. for adult females (including approximately 2.2 L con-
Avoidance of Prolonged Fasts and Meal Skipping.— sumed as fluids, and the remaining volume coming
Natural experiments of religious fasts12-19 and regular from the water content in foods) and 3.7 L total water
overnight fasts20-22 recognize fasting as a trigger for adult males (including approximately 3.0 L of flu-
of both headaches and migraine attacks. Common ids), whereas the more recent water AIs recommended
recommendations for prevention of fasting-induced by the European Food Safety Authority are lower, at
migraine attacks mimic those recommended for 2.0 L total water/day for adult females and 2.5 L total
controlling blood glucose in individuals with diabetes: water/day for adult males.30 The AI values are median
avoid long periods without food, consume 5-6 intake levels of healthy populations, and are intended
Headache 1569

as general recommendations and not precise goals for energy intake and/or weight should therefore be viewed
individuals; further, individual fluid needs vary by as containing a potential source of bias.
physical activity, altitude, temperature, certain medi- Established Medical Nutrition Therapy for Co-Morbid
cations, and dietary factors such caffeine, alcohol, so- Conditions and/or GI Symptoms.—Management of
dium, and protein intake. Thus, practical and accurate chronic comorbidities falls among the many
individualized recommendations for water consump- considerations while treating patients with migraine.
tion levels remain enigmatic. Instead, monitoring of There are evidence-based medical nutrition therapy
urine color according to a standardized color scale has (MNT) protocols for many of migraine’s comorbidities
been demonstrated to detect an elevated urine osmolal- including cardiovascular disease, diabetes, irritable
ity in free-living individuals, and has been suggested to bowel syndrome, and celiac disease, in addition to
be a sufficient monitoring of hydration status for the MNT for management of gastrointestinal symptoms of
general population,31 which may be a useful, low bur- varied causes.47 A subset of patients may benefit from
den technique in individuals with migraine. a referral to a Registered Dietitian Nutritionist to
Maintain a Healthy Weight.—Obesity is associated manage these risks and/or symptoms.
with both a higher prevalence of migraine disease and Limit Dietary Caffeine.—Caffeine is widely consumed
a higher risk of progression from episodic to chronic in the standard American diet, with over 85% of American
migraine.32-36 Migraine symptoms improved in most adults consuming at least one caffeinated beverage per
studies after weight loss in overweight and obese day and an average daily consumption of 165 mg/
patients, by bariatric surgery37-41 or lifestyle changes day.48 The general health intake recommendation for
(including diet) in adults39,41 and adolescents.42,43 adults is below 400 mg/day, but this recommendation
Specific mechanisms connecting weight loss with is not directed at migraine outcomes.49 Caffeine’s
migraine improvement have yet to be elucidated. effects on headache are complex and well-reviewed
Results of lifestyle interventions were relatively mod- elsewhere.50,51 For people with migraine disease, chronic
est in comparison to bariatric surgery results, in both consumption of caffeine increases the risk of developing
weight loss and migraine outcomes, and the largest chronic migraine and the risk of analgesic rebound
lifestyle intervention trial to date, which resulted in headache.51
an average 3.8 kg weight loss in the behavioral weight Avoidance of caffeine withdrawal headaches is
loss group vs 0.9 kg weight gain in the education con- also one reason why people habitually consume cof-
trol group, did not detect changes in the number of fee and tea, because individuals recognize the with-
migraine days.44 Current evidence is limited in pre- drawal symptoms if they were to stop.51 Caffeine
dicting the best non-surgical weight loss modality withdrawal has been reviewed and is observed in
for migraine outcomes, but multiple organizations about 50% of regular consumers52 but research de-
recognize behavioral weight loss programs,45 which tailing the methods and results of caffeine discon-
compliments evidence that behavioral therapies al- tinuation specifically in people with migraine are
leviate migraine.46 Weight management presents a limited; Lee and others reported in an abstract that
high burden for many patients. While weight loss abrupt discontinuation of caffeine results in higher
may produce reductions in current symptoms, pre- rates of migraine improvement after 1 month than
vention of future weight gain may also be important those who partially reduced caffeine intake or made
to prevent future migraine exacerbation and chronic no change,53 and further reported that abrupt dis-
comorbidities. continuation of caffeine may improve the efficacy of
Importantly, weight changes are considered a pos- acute migraine treatment by triptans.54
sible mediating factor in many dietary migraine stud- The perceived burden of discontinuing caffeine
ies. Unplanned weight loss in a diet intervention trial varies widely among individuals and may factor into
must be considered as a potential reason for witnessing a decision whether or not to discontinue intake on
decreases in migraine symptoms, and feeding studies the basis of limited evidence of its efficacy in reduc-
testing a particular diet pattern that do not control ing migraine attacks and contribution to increased
1570 October 2019

risk of chronic migraine and rebound headache. For life.65 Very likely, existing food challenge trials did not
those who choose to continue consuming caffeine, use adequate replications to account for the consid-
daily doses of moderate amounts (<400 mg) may be erable variability in mediators noted long after their
necessary to avoid withdrawal headache. For those publication.
choosing to discontinue intake, dietary counseling An alternate explanation for the widespread per-
may be helpful to avoid or manage caffeine with- ception and acceptance of food triggers has arisen.
drawal headaches, including strategies on gradual Recently observed hypothalamic activity during the
weaning from caffeine. preictal phase of a migraine attack suggests a biologi-
Manage Alcohol Consumption.—Alcohol’s ability to cal underpinning for the observed food cravings during
produce headache, and specifically migraine attack, is this phase.66-68 If these cravings prompt individuals to
a well-recognized phenomena.55 Patients with migraine eat foods they might not otherwise choose (ie, choc-
appear to be more susceptible to hangover headache, olate), this connection may explain why individuals
experiencing it more frequently and in response to lower associate particular and infrequently consumed foods
alcohol doses.56-63 Also, it may be difficult to distinguish with migraine attack.
between alcohol hangover headache (a delayed alcohol The risks of avoiding suspected food triggers with-
response) and alcohol acting as a trigger (immediate out evidence include following a needlessly restrictive
alcohol-induced headache).25 diet (with unintended consequences to nutrient intake,
Strictly, there is not published evidence to demon- social consequences to extreme limitations in eating
strate that abstaining from alcohol improves migraine options, and added demands on executive function,
symptoms, nor its impact on quality of life. Many stress, and anxiety to manage the list of “foods to
persons with migraine already avoid alcohol.64 More avoid”), as well as the opportunity cost of not spending
research is needed to provide guidance to those seek- that time doing treatments that have evidence. To our
ing to identify their own response to alcohol con- knowledge, no studies have been done to evaluate the
sumption. In consideration of the potential social prophylactic effectiveness or burden of implementing
considerations of alcohol abstinence, individuals with the “food avoidance lists” that are widely distributed
migraine may instead find it beneficial to drink less to migraine patients. The current state of evidence sug-
frequently, in moderate amounts, and in awareness gests that avoidance of unconfirmed food triggers may
of other triggers, but not necessarily avoid alcoholic not be warranted, and questions whether adherence to
drinks altogether.59 lengthy food avoidance lists may cause harm.
Unfavorable Risk: Benefit Analysis.—Food Triggers, Elimination diets have also been suggested as a
Food Avoidance Lists, and Elimination Diets.—Most means of identifying food triggers, by first severely re-
migraine trigger research has used retrospective, stricting intake to a handful of suspected non-­provoking
self-reported data to identify food triggers, asking foods and gradually reintroducing foods while mon-
patients to report which foods trigger their migraine itoring for migraine attacks.69,70 Alternatively, sev-
attacks. These studies do not meet standards for high- eral tests have been explored for immunologically
quality research that can meaningfully contribute to targeting offensive foods via antibody tests. The use
causal inference. of IgG antibodies to predict a successful elimination
Food challenge trials were previously considered diet are the most promising,71-75 but lack of antibody
to be the gold standard for detecting migraine trig- standardization across manufacturers and inconsis-
ger foods, but the ability to reliably detect food trig- tencies in study design have resulted in considerable
gers in this manner is increasingly doubted. Statistical heterogeneity in study results, precluding widespread
evaluations of the variance of well-accepted factors conclusions.
influencing migraine attack show that it is statisti- Gluten Free Diet (Without Celiac Disease).—
cally implausible that baseline factors would be stable Accumulating evidence suggests the potential existence
enough to decipher whether any additional factors act of a relationship between gluten and migraine disease,
as a trigger under “natural experimentation” in daily as populations with both celiac disease (CD) and
Headache 1571

non-celiac gluten sensitivity (NCGS) exhibit higher FUTURE DIRECTIONS OF DIETARY

rates of migraine disease than the general population. MIGRAINE RESEARCH
It is frequently suggested to screen migraine patients for Microbiome and the Gut-Brain Axis.—The
CD, in the case that migraines are indicative of the gut establishment of the Human Microbiome Project
disease.76,77 Migraine patients with CD often experience in 2008 by the National Institute of Health
a significant improvement in migraine symptoms upon initiated the proliferation of novel studies aiming
commencement of the gluten-free diet.78-80 Nonetheless, to investigate the microbiome and human health.96
the imprecision of the NCGS diagnosis remains The human microbiota is defined as a collection of
problematic in conducting repeatable research, and commensal, symbiotic, and pathogenic microorganisms
gluten-free dietary intervention trials have not that live in association with the human body, and the
consistently shown benefits to migraine outcomes in combined genomes of these microorganisms is known
NCGS patients.81 as the microbiome.97 The microbiota located in the
Other Macronutrient Patterns.—The macronutrients gastrointestinal (GI) tract of humans is known by
are those which contribute energy (carbohydrates, several names, including the intestinal microbiota,
fats, and proteins), and many therapeutic and fad gut microbiota, gut microflora, or gut bacteria.
diets modify the ratio of the various macronutrients to Though direct evidence of a connection between gut
achieve desired effects. Invariably, to maintain energy microbiota and migraine is still limited, a putative
homeostasis, modifications to consumption of 1 relationship can be hypothesized based on the
macronutrient require changes to the amounts of other connection between the microbiota and its effects on the
macronutrients in the diet. (For example, when initiating enteric nervous system (ENS) and central nervous
a low-carbohydrate diet, the decrease in carbohydrate system (CNS).
consumption necessitates an increase in fat and/or protein The gut microbiota resides primarily in the lumen
intake to prevent a significant energy deficit.) Various and the outer mucus layer, atop the chemical barrier
macronutrient patterns have been studied for their of mucus and antimicrobial proteins secreted by and
impact on migraine symptoms, but this interdependency resting on the epithelial cells of the intestinal wall98
among the macronutrient levels poses unique and (see Fig. 2). Below are the physical and immunological
difficult challenges to adequately control confounding barriers of the epithelial cells and lamina propria, the
factors. Nonetheless, a wide variety of macronutrient muscularis mucosa and the submucosa. The submuco-
patterns have shown promise in early trials to decrease sal plexus, ganglia belonging to the ENS, are located
migraine attack frequency, including low-carbohydrate/ in the submucosa layer, which provide opportunity for
moderate protein; low-carbohydrate/ketogenic; and the microbiota’s influence on migraine, by influencing
low-fat dietary patterns.82-95 With the exception of the
omega-3:omega-6 modified diet discussed above, the
study designs did not adequately control to isolate
the effect of the macronutrient modifications within
the diet. Thus, macronutrient-modified dietary patterns
are included with an unfavorable rating here because
of the combined lack of evidence and significant
burden in adopting any such diet. Until such evidence
is generated, we encourage the consumption of a
dietary pattern consistent with general nutritional
recommendations, including fruits, vegetables, whole
grains, and lean proteins (with emphasis on fish and
plant-based proteins), while limiting consumption of
salt, added sugars, solid fats, and the ultra-processed Fig. 2.—Layers of the intestinal barrier. [Color figure can be
foods that typically contribute these ingredients. viewed at wileyonlinelibrary.com]
1572 October 2019

the bidirectional communications between the ENS enteroendocrine cells, impacting their hormonal
and CNS via the gut-brain axis. release.109
The set of known functions of the gut microbi- Dysbiosis.—Whereas a definitive measure for a
ota is growing rapidly in number and complexity, and “healthy” microbiota has been elusive, it has been useful
cannot be discussed comprehensively here. In short, to identify cases of dysbiosis, where a compositional
the gut microbiota facilitates nutrient absorption by change in the microbiota and/or an abnormal interaction
metabolizing indigestible dietary compounds, defends between the host and the commensal microbiota
against pathogen colonization of the gut, guides mat- has occurred.109 Consequences of this imbalanced
uration and functionality of host immunity, and mod- gut microbiota include disturbance of the multiple
ulates neuronal functions. To impact migraine, these roles of the gut microbiome, such as disruption of tight
actions of the gut microbiota may impact the CNS junction integrity and increased permeability of the
by neural, immunological, endocrine, and metabolic intestinal epithelium.110,111 The more permeable intestine
pathways.99-101 allows bacterial translocation from the lumen into
Gut Microbiota Influence on Diet.—Perhaps the extraintestinal sites, along with their lipopolysaccharide
most classically recognized function, gut bacteria (LPS) endotoxins,112,113 triggering a cascade of immune
metabolize dietary compounds otherwise indigestible responses at both local and distant sites, including
to humans, thereby producing microbial metabolites systemic elevation of proinflammatory cytokines.112,114,115
which serve as messengers throughout the GI tract and Additionally, LPS can activate dendritic cells, which
distant organs. Short chain fatty acids (SCFAs) are influences the secretion and storage of serotonin.115
chief among these metabolites and are produced Dysbiosis and its cascade reactions have been
through microbial fermentation of certain dietary associated with a variety of chronic disease states,
fibers. SCFAs provide the primary source of energy including several neurological disorders or conditions
for colonocytes, promote integrity of the intestinal comorbid to migraine disease, including nociceptive
barrier, and have broad implications for immune and pain, depression, and anxiety.110
inflammatory regulation through their inhibition of Dietary Influence on Gut Microbiota.—A human’s
histone deacetylases and activation of G protein- intestinal microbiota is influenced by multiple
coupled receptors.102,103 The impact of SCFAs factors, including environment, diseases, genetics,
on broader health and metabolism is increasingly diet, and drug use. The majority of research has
appreciated, including reduced risk for cardiovascular been conducted in animal models or in small-scale
disease and regulation of appetite.103,104 Notably, human trials of single nutrients, limiting the ability to
a fraction of the microbially produced SCFA are understand the influence of an overall diet on the gut
absorbed into the bloodstream and are capable of microbiome. This research is beginning to highlight
crossing the blood-brain barrier to exert these effects. some specific dietary influences on the gut microbial
The gut microbiota are also differentially capable of composition and functions.
biotransforming numerous bioactive compounds found The most studied individual nutrient for influ-
in diet, including various polyphenols,105 and parent ence on the host microbiome is dietary fiber, which is
compounds and metabolites may have differing a diverse group of polysaccharides that are undigest-
potential to impact host metabolism and physiology. ible by human enzymes and therefore enter the colon
There is limited study of whether these compounds intact. The commensal intestinal microbiota have the
may also influence neurological conditions. However, ability to metabolize certain fibers (those deemed to
there is evidence that several of these compounds act be “fermentable”), and as a result, they can outcom-
in the inflammation pathways.106,107 Furthermore, the pete pathogenic bacteria that are unable to hydrolyze
secretion of GI hormones from the enteroendocrine polysaccharides like Salmonella and Shigella species.98
cells allows crosstalk between the ENS and CNS,108 Other contents of the colon which can be metabolized
and the microbes that reside closely to these are protein residues and bile acid, which were found
enterocytes are proposed to communicate with these to be metabolized to inflammatory and carcinogenic
Headache 1573

metabolites by intestinal microbiota.116 Also, adequate difficile-­associated diarrhea and respiratory tract infec-
vitamin D consumption (above 600 IU per day for tions were considered evidence-based in recommenda-
most adults) has also been deemed essential for main- tions for probiotics.125
taining intestinal homeostasis and microbiota diver- Notably, bacteria activities are highly genus,
sity,117,118 though prior studies provide little support species, and even strain-specific. Therefore, the ad-
for Vitamin D3 supplementation as an effective pro- ministration of probiotics with intention of treating
phylactic for migraine attack frequency.6 Both dietary different disorders requires examination of the mecha-
vitamin D deficiency and vitamin D receptor defects nism and cascade response of each individual bacteria
can disrupt the gut microbiota community and intesti- strain or cocktail. It is possible that more general pro-
nal homeostasis.117 Thus, the level of consumption of biotic species may help migraine by promoting wide-
fermentable fibers and other select nutrients influence spread microbiota functionality of SCFA production,
the composition of gut bacteria. competitive exclusion of pathogens, and maintenance
Research has also investigated the impact of di- of proper gut permeability, whereas strain-specific ef-
etary patterns on the gut microbiota. Changes in fects may exist that have neurological or immunologi-
dietary pattern were found to influence the propor- cal effects specific to the pathophysiology of migraine
tions of gut flora species as well as the diversity and disease.126
richness of gut microbial species, which appear to Existing Microbiome Evidence for Migraine.—
impact host metabolism and the long-term health out- Studies exploring the direct relationship between the
comes.119-123 In human studies, a 6-month high-fat diet microbiome and migraine are limited. One study of oral
was associated with increased Alistipes, Bacteroides microbiomes showed that the populations of oral cavity
and decreased Faecalibacterium; while a low-fat diet bacteria in participants with migraine contained higher
was associated with increased abundance of Blautia, levels of nitrate, nitrite and nitric oxide reductase
Faecalibacterium, and Prevotella.122,123 The cascade genes.127
interactions of a high-fat diet are also observed, in- We are aware of 2 open-label trials and 2 RCTs
cluding decreased SCFA production, increased LPS which have investigated the impact of probiotics on
biosynthesis, and increased inflammatory mediator adult migraine. Sensenig and colleagues128 investi-
concentrations.122 gated the administration of a blended probiotic sup-
Though dietary interventions are capable of pro- plement containing multiple species (Lactobacillus
ducing detectable changes to the microbiome compo- adiophilus, L. bulgaricus, Enterococcus faecium, and
sition within 24 hours of a dietary change, enterotype Bifidobacterium bifidum), bioactive peptides and
clustering only correlates with long-term diet,123 sug- amino acids, and a multivitamin for 90 days in adults
gesting that long-term dietary habits would be needed who reported at least 2 migraine attacks per month
to produce a stable change in intestinal microbiome for 1 year. Results showed approximately 60% of
composition. the participants experienced almost total relief from
Probiotics are living microorganisms that, by defi- migraine symptoms, and 20% experienced significant
nition, confer a health benefit on the host when admin- improvement in quality of life. More recently, de
istered in adequate amounts.124 Such direct benefits Roos and others129 reported that a 12-week adminis-
could include increasing the secretion of antimicrobial tration of another multispecies supplement contain-
peptides and anti-inflammatory mediators. The most ing 5.0 × 109 cfu per day of 8 different Lactobacillus
commonly administered probiotics are bacteria from and Lactococcus strains resulted in a significant
the genera Lactobacillus and Bifidobacterium, and the reduction of migraine attack frequency and inten-
yeast Saccharomyces boulardii. The significant varia- sity. Number of migraine days dropped from 6.7 to
tion in probiotic clinical trial protocols (species, doses, 5.2 days/month. However, the results were not con-
and measured outcomes) has made systematic reviews firmed when their group proceeded to test the same
and meta-analyses difficult to conduct effectively. probiotic mixture, dose, and duration in a parallel
In a 2017 review, only antibiotic- and Clostridium arm, placebo-controlled RCT.130 Migraine disability
1574 October 2019

assessment test scores decreased significantly in both only the ways in which diet might influence
groups, and the number of headache days, medica- migraine attacks. More recently, several lines of
tion use, and indicators of intestinal permeability evidence are converging to imply that the physiological
and inflammation were not significantly different mechanisms of migraine may influence diet. The limited
across groups. Finally, Martami and others tested a epidemiological data documenting dietary intake in
14-strain probiotic mixture vs placebo for 10 weeks free-living people with migraine differs from their peers
in a double-blind RCT and documented decreases across several nutritional metrics, including nutritional
in migraine attack frequency and severity in both quality,133 macronutrient composition of the diet,134
chronic and episodic migraine patients, as com- regularity of eating schedule,135 and consumption
pared to placebo, but no differences in inflammatory levels of a variety of individual foods.136-138 Second,
markers.131 activation of the hypothalamus, the brain’s hunger
Interpretation and Future Research.—Research and feeding center, is observed during the premonitory
connecting the microbiome and migraine is in its phase of migraine and coincides with the timing of food
infancy, and it is too early to recommend dietary cravings.66-68 Levels of hypothalamic neurotransmitters,
interventions intended to change the microbiome hormones, and adipocytokines have been found to
for the purpose of influencing migraine. Another differ in migraine patients as compared to controls
emerging avenue of research is not whether to in such a way that may impact hunger/feeding or
change the microbiome, but whether to exploit metabolic control: orexin A was higher during the pain
interindividual differences toward personalized phase of chronic migraine,139 serotonin levels were
nutrition recommendations. Given the mechanistic decreased interictally,140,141 insulin resistance is
parallels, it is easy to be optimistic for their potential. detected in higher levels in migraine disease,142
It is possible that existing dietary trials with a positive as well as increased adipocytokines like leptin.143
influence on migraine may have exerted influence Anecdotally, the overall symptoms of migraine
through impact on the microbiome. Moving forward, (pain and other feelings of unwell) are likely to influence
research is needed to identify any enterotypes or food choices, such that individuals will likely choose
patterns of dysbiosis occurring in persons with migraine convenience and ease, which do not favor a nutritious
disease and across categories of migraine, as one avenue profile in much of the modern world. Combined, these
to establish a therapeutic target for future trials. Early observations may help to explain the well-documented
probiotic trials have provided mixed results, and suggest correlation between obesity and migraine disease, and
that standard inflammatory markers may not predict improved understanding in this area in the future
efficacy for migraine. Research investigating probiotic may inform better interventions for prevention and
effects on migraine would be wise to follow the treatment of obesity in migraine.
lessons learned from trailblazing probiotic research: Diet’s Impact on Calcitonin Gene-Related Peptide.—
selection and specificity of probiotic strains is essential, The ability of foods and food components to impact
attention should be paid to processes necessary calcitonin gene-related peptide (CGRP) expression and
to ensure and demonstrate probiotic viability in secretion levels has been observed in limited laboratory
supplements used in research, and detailed information studies. Primarily, Cady and Durham observed
including background diet should be collected for significant decreases in expression of CGRP in
participants.132 Research is also needed to identify rat trigeminal ganglia cells after eating cocoa-
whether interindividual differences in response to enriched diets for 14 days, as compared to control.144
dietary interventions are due to identifiable microbes or Further, grape seed and ginger extracts, and the pure
microbial profiles. chemical petasin – the suspected active component
Impact of Migraine on Diet and Metabolic in the botanical butterbur dietary supplement –
Control.—For centuries, the working hypothesis for a have been shown to decrease CGRP secretion in
relationship between diet and migraine was essentially cell models.145,146 Given the recent pharmaceutical
unidirectional, and research similarly investigated successes in targeting CGRP, the impact of human’s
Headache 1575

diet on CGRP represents an interesting but unexplored STATEMENT OF AUTHORSHIP

area of research.
Category 1
CONCLUSIONS (a) Conception and Design
Existing evidence suggests that the presence, type, Margaret Slavin
frequency, and severity of migraine may be associ- (b) Acquisition of Data
ated with various aspects of the diet of persons liv- Margaret Slavin, Huilun (Amber) Li
ing with the pain and disability of migraine disease. (c) Analysis and Interpretation of Data
Nonetheless, data should be interpreted cautiously, Margaret Slavin, Huilun (Amber) Li, Cara
given significant potential for bias in the existing data. Frankenfeld, Lawrence Cheskin
Further, when studying a dietary pattern, it is often
impossible to distinguish which individual factor(s) Category 2
is/are impacting migraine. There remains significant (a) Drafting the Manuscript
opportunity to systematically study the dietary habits Margaret Slavin, Huilun (Amber) Li
of diverse individuals with migraine disease. (b) Revising It for Intellectual Content
Without significant supporting evidence, current di- Margaret Slavin, Huilun (Amber) Li, Cara
etary recommendations for migraine are primarily based Frankenfeld, Lawrence Cheskin
on minimizing risks of the intervention, and should also
consider the burden of following any diet recommenda- Category 3
tions. Most recommendations for migraine now fall in (a) Final Approval of the Completed Manuscript
line with general modern nutrition evidence suggesting a Margaret Slavin, Huilun (Amber) Li, Cara
healthy diet, focusing on a dietary pattern that promotes Frankenfeld, Lawrence Cheskin
consumption of fruits, vegetables, whole grains, and
lean proteins (with emphasis on fish and plant-based
proteins) – with a variety of foods consumed within REFERENCES
each food group – while limiting consumption of salt, 1. American Academy of Neurology. Guidelines Under
added sugars, solid fats, and the ultra-processed foods Development. Available at https​ ://www.aan.com/
that typically contribute these ingredients. policy-and-guide​lines/​guide​lines/​guide​lines-under-
The well-designed, mechanism-driven dietary re- devel​opmen​t/. Accessed March 14, 2019.
search that is needed to truly provide evidence-based 2. Dohle S, Diel K, Hofmann W. Executive functions
dietary recommendations specific to migraine is ex- and the self-regulation of eating behavior: A review.
pensive and time-consuming, with limited available Appetite. 2018;124:4-9.
funding to drive it forward. Yet, this evidence will be 3. Handu D, Moloney L, Wolfram T, Ziegler P,
necessary to strengthen the evidence for causal infer- Acosta A, Steiber A. Academy of nutrition and
ence, and justify insurance reimbursement for nutrition dietetics methodology for conducting systematic
reviews for the evidence analysis library. J Acad Nutr
counseling as an important component of treatment
Diet. 2016;116:311-318.
for migraines. Looking to the future, dietary recom-
4. U.S. Department of Agriculture. Home | Nutrition
mendations for migraine will hopefully aid in immedi-
Evidence Systematic Review. Available at https​://nesr.
ate control of the disease, slow progression, and prevent usda.gov/. Accessed April 1, 2019.
complications due to diet-related comorbidities includ- 5. Martin VT, Vij B. Diet and headache: Part 1.
ing obesity, diabetes, and cardiovascular disease. Headache. 2016;56:1543-1552.
6. Martin VT, Vij B. Diet and headache: Part 2.
Acknowledgments: The authors thank the Southern Headache. 2016;56:1553-1562.
Headache Society for the opportunity to present this 7. Ramsden CE, Faurot KR, Zamora D, et al. Targeted
manuscript. alteration of dietary n-3 and n-6 fatty acids for the
1576 October 2019

treatment of chronic headaches: A randomized trial. 18. Mosek A, Korczyn AD. Yom Kippur headache.
Pain. 2013;154:2441-2451. Neurology. 1995;45:1953-1955. Available at http://
8. Ramsden CE, Mann JD, Faurot KR, et al. Low www.neuro​ l ogy.org/conte​ n t/45/11/1953.short ​ .
omega-6 vs low omega-6 plus high omega-3 dietary Accessed February 18, 2015.
intervention for Chronic Daily Headache: Protocol 19. Mosek A, Korczyn AD. Fasting headache, weight
for a randomized clinical trial. Headache. 2010. loss, and dehydration. Headache. 1999;39:225-227.
Available at http://www.biome​dcent​ral.com/conte​nt/ 20. Fox AW, Davis RL. Migraine chronobiology.
pdf/1745-6215-12-97.pdf. Accessed March 2, 2015. Headache. 1998;38:436-441.
9. MacIntosh BA, Ramsden CE, Faurot KR, et al. 21. Hsu LKG, Crisp AH, Kalucy RS, et al. Early morn-
Low-n-6 and low-n-6 plus high-n-3 diets for use in ing migraine. Nocturnal plasma levels of catechol-
clinical research. Br J Nutr. 2013;110:559-568. amines, tryptophan, glucose, and free fatty acids and
10. Ramsden CE, Faurot KR, Zamora D, et al. Targeted sleep encephalographs. Lancet. 1977;309:447-451.
alterations in dietary n-3 and n-6 fatty acids im- 22. Solomon GD. Circadian rhythms and migraine.
prove life functioning and reduce psychological dis- Cleve Clin J Med. 1992;59:326-329. Available at  
tress among chronic headache patients: Secondary http://www.ccjm.org/conte​nt/59/3/326.short​. Accessed
analysis of a randomized trial. Pain. 2015;156: April 20, 2015.
587-596. 23. Pearce J. Insulin induced hypoglycaemia in migraine.
11. Mann JD, Faurot KR, MacIntosh B, et al. A sixteen- J Neurol Neurosurg Psychiatry. 1971;34:154-156.
week three-armed, randomized, controlled trial in- Available at http://jnnp.bmj.com/conte​ nt/34/2/154.
vestigating clinical and biochemical effects of tar- short​. Accessed April 20, 2015.
geted alterations in dietary linoleic acid and n-3 24. Dalton K. Food intake prior to a migraine attack-
EPA+DHA in adults with episodic migraine: Study study of 2313 spontaneous attacks. Headache. 1975;
protocol. Prostaglandins Leukot Essent Fatty Acids. 15:188-193.
2018;128:41-52. 25. Headache Classification Committee of the
12. Abu-Salameh I, Plakht Y, Ifergane G. Migraine International Headache Society (IHS). The
exacerbation during Ramadan fasting. J Headache International Classification of Headache Disorders,
Pain. 2010;11:513-517. 3rd edition. Cephalalgia. 2018;38:1-211.
13. Awada A, Jumah MA. The first-of-Ramadan head- 26. Spigt MG, Kuijper EC, Schayck CP, et al. Increasing
ache. Headache. 1999;39:490-493. the daily water intake for the prophylactic treat-
14. Drescher MJ, Alpert EA, Zalut T, Torgovicky R, ment of headache: A pilot trial. Eur J Neurol.
Wimpfheimer Z. Prophylactic etoricoxib is effective 2005;12:715-718.
in preventing Yom Kippur headache: A placebo- 27. Spigt M, Weerkamp N, Troost J, van Schayck CP,
controlled double-blind and randomized trial of Knottnerus JA. A randomized trial on the effects of
prophylaxis for ritual fasting headache. Headache. regular water intake in patients with recurrent head-
2010;50:1328-1334. aches. Fam Pract. 2012;29:370-375.
15. Drescher MJ, Wimpfheimer Z, Abu Khalef S, 28. Popkin BM, D’Anci KE, Rosenberg IH. Water, hy-
Gammaitoni A, Shehadeh N, Torgovicky R. dration, and health. Nutr Rev. 2010;68:439-458.
Prophylactic etoricoxib is effective in preventing 29. Institute of Medicine (U.S.). Dietary Reference
“first of ramadan” headache: A placebo-controlled Intakes for Water, Potassium, Sodium, Chloride,
double-blind and randomized trial of prophylactic and Sulfate / Panel on Dietary Reference Intakes
etoricoxib for ritual fasting headache. Headache. for Electrolytes and Water, Standing Committee
2012;52:573-581. on the Scientific Evaluation of Dietary Reference
16. Drescher MJ, Elstein Y. Prophylactic COX 2 inhib- Intakes, Food and Nutrition Board. Washington, DC:
itor: An end to the Yom Kippur headache: CME. National Academies Press; 2004.
Headache. 2006;46:1487-1491. 30. European Food Safety Authority. Scientific opinion
17. Latsko M, Silberstein S, Rosen N. Frovatriptan as on dietary reference values for water. EFSA panel on
preemptive treatment for fasting-induced migraine. dietetic products, nutrition, and allergies. EFSA J.
Headache. 2011;51:369-374. 2010;8:1459.
Headache 1577

31. Perrier ET. Shifting focus: From hydration for per- 43. Verrotti A, Carotenuto M, Altieri L, et al. Migraine
formance to hydration for health. Ann Nutr Metab. and obesity: Metabolic parameters and response
2017;70:4-12. to a weight loss programme: Migraine outcome
32. Bigal ME, Liberman JN, Lipton RB. Obesity after weight loss strategy. Pediatr Obes. 2015;10:
and migraine A population study. Neurology. 220-225.
2006;66:545-550. Available at http://www.neuro​ 44. Bond DS, Thomas JG, Lipton RB, et al. Behavioral
logy.org/conte​nt/66/4/545.short​. Accessed April 20, weight loss intervention for migraine: A randomized
2015. controlled trial. Obesity. 2018;26:81-87.
33. Ornello R, Ripa P, Pistoia F, et al. Migraine and 45. American College of Cardiology/American Heart
body mass index categories: A systematic review and Association Task Force on Practice Guidelines,
meta-analysis of observational studies. J Headache Obesity Expert Panel, 2013. Expert panel report:
Pain. 2015;16:27. doi:10.1186/s10194-015-0510-z. Guidelines (2013) for the management of over-
34. Bigal ME, Lipton RB. Obesity is a risk factor for weight and obesity in adults. Obesity. 2014;22(Suppl.
transformed migraine but not chronic tension-type 2):S41-S410. doi:10.1002/oby.20660​.
headache. Neurology. 2006;67:252-257. 46. Cervoni C, Bond DS, Seng EK. Behavioral weight
35. Bigal ME. Body mass index and episodic head- loss treatments for individuals with migraine and
aches: A population-based study. Arch Intern Med. obesity. Curr Pain Headache Rep. 2016;20:13.
2007;167:1964-1970. doi:10.1007/s11916-016-0540-5.
36. Gelaye B, Sacco S, Brown WJ, Nitchie HL, Ornello 47. Academy of Nutrition and Dietetics. Nutrition Care
R, Peterlin BL. Body composition status and the Manual. Available at https​://www.nutri​tionc​arema​
risk of migraine: A meta-analysis. Neurology. nual.org/. Accessed March 14, 2019.
2017;88:1795-1804. 48. Mitchell DC, Knight CA, Hockenberry J, Teplansky
37. Bond DS, Vithiananthan S, Nash JM, Thomas R, Hartman TJ. Beverage caffeine intakes in the U.S.
JG, Wing RR. Improvement of migraine head- Food Chem Toxicol. 2014;63:136-142.
aches in severely obese patients after bariatric sur- 49. Nawrot P, Jordan S, Eastwood J, Rotstein J,
gery. Neurology. 2011;76:1135-1138. Available at Hugenholtz A, Feeley M. Effects of caffeine
http://www.neuro​logy.org/conte​nt/76/13/1135.short​. on human health. Food Addit Contam. 2003;20:
Accessed April 20, 2015. 1-30.
38. Novack V, Fuchs L, Lantsberg L, et al. Changes in 50. Sawynok J. Caffeine and pain. Pain. 2011;152:726-729.
headache frequency in premenopausal obese women 51. Shapiro RE. Caffeine and headaches. Neurol Sci.
with migraine after bariatric surgery: A case series. 2007;28:S179-S183.
Cephalalgia. 2011;31:1336-1342. 52. Juliano LM, Griffiths RR. A critical review of caf-
39. Jahromi SR, Abolhasani M, Togha M, Meysamie feine withdrawal: Empirical validation of symptoms
A, Talebpour M, Sadre-Jahani S. A cross-sectional and signs, incidence, severity, and associated features.
study of migraine improvement after diet/exercise-in- Psychopharmacology (Berl). 2004;176:1-29.
duced weight loss or bariatric surgery [abstract]. Eur 53. Lee CB, Chung CS. Role of caffeine cessation in
J Neurol. 2014;21(Suppl. 1):163. migraine management. Cephalalgia. 2013;33(Suppl.
40. Gunay Y, Jamal M, Capper A, Eid A, Heitshusen 8):248-249.
D, Samuel I. Roux-en-Y gastric bypass achieves sub- 54. Lee MJ, Choi HA, Choi H, Chung C-S. Caffeine
stantial resolution of migraine headache in the se- discontinuation improves acute migraine treatment:
verely obese: 9-year experience in 81 patients. Surg A prospective clinic-based study. J Headache Pain.
Obes Relat Dis. 2013;9:55-62. 2016;17:71.
41. Jahromi SR, Abolhasani M, Ghorbani Z, et al. 55. Panconesi A. Alcohol and migraine: Trigger factor,
Bariatric surgery promising in migraine control: a consumption, mechanisms. A review. J Headache
Controlled trial on weight loss and its effect on mi- Pain. 2008;9:19-27.
graine headache. Obes Surg N Y. 2018;28:87-96. 56. Costanigro M, Appleby C, Menke SD. The wine
42. Verrotti A, Agostinelli S, D’Egidio C, et al. Impact headache: Consumer perceptions of sulfites and
of a weight loss program on migraine in obese ado- willingness to pay for non-sulfited wines. Food Qual
lescents. Eur J Neurol. 2013;20:394-397. Prefer. 2014;31:81-89.
1578 October 2019

57. Diaz-Insa S, Rodrigo A, Pamblanco Y, Lacruz L, 72. Aydinlar EI, Dikmen PY, Tiftikci A, et al. IgG-based
Soler A, Guillen C. Headache and wine. Are all wines elimination diet in migraine plus irritable bowel syn-
the same? J Headache Pain. 2013;14(Suppl. 1):P32. drome. Headache. 2013;53:514-525.
58. Evans RW, Sun C, Lay C. Alcohol hangover head- 73. Hernández CMA, Pinto ME, Montiel HLH, Others.
ache. Headache. 2007;47:277-279. Food allergy mediated by IgG antibodies associ-
59. Panconesi A, Bartolozzi ML, Guidi L. Alcohol and ated with migraine in adults. Rev Alerg México.
migraine: What should we tell patients? Curr Pain 2007;54:162-168. Available at http://www.medig​ ra-
Headache Rep. 2011;15:177-184. phic.com/pdfs/reval​emex/ram-2007/ram07​5d.pdf.
60. Sjaastad O, Bakketeig LS. Hangover headache: Accessed July 23, 2015.
Accompanying symptoms. Vågå study of headache 74. Lewis JE, Lopez J, Ganuza A, et al. A pilot study
epidemiology. J Headache Pain. 2004;5:224-229. eliminating immunologically-reactive foods from the
61. Wiese JG, Shlipak MG, Browner WS. The alcohol diet and its effect on symptomatology and quality of
hangover. Ann Intern Med. 2000;132:897-902. life in persons with chronic migraines and headaches.
62. Winter AC, Hoffmann W, Meisinger C, et al. Open J Intern Med. 2013;3:8-14.
Association between lifestyle factors and headache. 75. Mitchell N, Hewitt CE, Jayakody S, et al. Randomised
J Headache Pain. 2011;12:147-155. controlled trial of food elimination diet based on
63. Yokoyama M, Yokoyama T, Funazu K, et al. Associ- IgG antibodies for the prevention of migraine like
ations between headache and stress, alcohol drinking, headaches. Nutr J. 2011;10:85.
exercise, sleep, and comorbid health conditions in a Jap- 76. Cady RK, Farmer K, Dexter JK, Hall J. The bowel
anese population. J Headache Pain. 2009;10:177-185. and migraine: Update on celiac disease and irri-
64. Onderwater GLJ, van Oosterhout WPJ, Schoonman table bowel syndrome. Curr Pain Headache Rep.
GG, Ferrari MD, Terwindt GM. Alcoholic bever- 2012;16:278-286.
ages as trigger factor and the effect on alcohol con- 77. Mormile R. Celiac disease and migraine: Is
sumption behavior in patients with migraine. Eur J there a common backstage? Int J Colorectal Dis.
Neurol. 2019;26:588-595. 2014;29:1571-1571.
65. Houle TT, Turner DP. Natural experimentation is 78. Gabrielli M. Association between migraine and
a challenging method for identifying headache trig- celiac disease: Results from a preliminary case-
gers. Headache. 2013;53:636-643. control and therapeutic study. Am J Gastroenterol.
66. Denuelle M, Fabre N, Payoux P, Chollet F, Geraud 2003;98:625-629.
G. Hypothalamic activation in spontaneous mi- 79. Hadjivassiliou M, Grunewalk RA, Lawden M,
graine attacks. Headache. 2007;47:1418-1426. Davies-Jones GAB, Powell T, Smith CML. Headache
67. Maniyar FH, Sprenger T, Monteith T, Schankin C, and CNS white matter abnormalities associated with
Goadsby PJ. Brain activations in the premonitory gluten sensitivity. Neurology. 2001;56:385-388.
phase of nitroglycerin-triggered migraine attacks. 80. Serratrice J, Disdier P, de Roux C, Christides C,
Brain. 2014;137:232-241. Weiller PJ. Migraine and coeliac disease. Headache.
68. Schulte LH, May A. The migraine generator re- 1998;38:627-628.
visited: Continuous scanning of the migraine cycle 81. Molina-Infante J, Santolaria S, Sanders DS,
over 30 days and three spontaneous attacks. Brain. Fernández-Bañares F. Systematic review: Noncoeliac
2016;139:1987-1993. gluten sensitivity. Aliment Pharmacol Ther.
69. Perkin J. Diet and migraine – A review of the litera- 2015;41:807-820.
ture. J Am Diet Assoc. 1983;83:459-463. 82. Barborka CJ. Migraine: Results of treatment by keto-
70. Egger J, Carter CM, Wilson J, Turner MW, Soothill genic diet in fifty cases. JAMA. 1930;95:1825-1828.
JF. Is migraine food allergy? A double-blind con- Available at http://jama.jaman​etwork.com/artic​le.
trolled trial of oligoantigenic diet treatment. Lancet. aspx?artic​ lexml​
:id=245128. Accessed March 14,
1983;2:865-869. 2015.
71. Alpay K, Ertas M, Orhan EK, Ustay DK, Lieners C, 83. Bic Z, Blix GG, Hopp HP, Leslie FM, Schell MJ.
Baykan B. Diet restriction in migraine, based on IgG The influence of a low-fat diet on incidence and se-
against foods: A clinical double-blind, randomised, verity of migraine headaches. J Womens Health Gend
cross-over trial. Cephalalgia. 2010;30:829-837. Based Med. 1999;8:623-630.
Headache 1579

84. Byer JA, Dexter JD. Hypoglycemic migraine. Mo 98. Hooper LV. Do symbiotic bacteria subvert host im-
Med. 1975;72:194-197. munity? Nat Rev Microbiol. 2009;7:367-374.
85. Dexter JD, Roberts J, Byer JA. The five hour glucose 99. Ma Q, Xing C, Long W, Wang HY, Liu Q, Wang
tolerance test and effect of low sucrose diet in mi- R-F. Impact of microbiota on central nervous sys-
graine. Headache. 1978;18:91-94. tem and neurological diseases: The gut-brain axis.
86. Di Lorenzo C, Coppola G, Sirianni G, et al. J Neuroinflammation. 2019;16:53-53.
Migraine improvement during short lasting keto- 100. Haase S, Haghikia A, Wilck N, Müller DN, Linker
genesis: A proof-of-concept study. Eur J Neurol. RA. Impacts of microbiome metabolites on im-
2015;22:170-177. mune regulation and autoimmunity. Immunology.
87. Di Lorenzo C, Currà A, Sirianni G, et al. Diet tran- 2018;154:230-238.
siently improves migraine in two twin sisters: Possible 101. Martin CR, Osadchiy V, Kalani A, Mayer EA. The
role of ketogenesis? Funct Neurol. 2013;28:305. brain-gut-microbiome axis. Cell Mol Gastroenterol
Available at http://www.ncbi.nlm.nih.gov/pmc/artic​ Hepatol. 2018;6:133-148.
les/PMC39​51260/​. Accessed April 16, 2015. 102. Kim MH, Kang SG, Park JH, Yanagisawa M, Kim
88. Farkas M, Mak E, Richter E, Farkas V. EHMTI-0336. CH. Short-chain fatty acids activate GPR41 and
Metabolic diet therapy in the prophylactic treatment GPR43 on intestinal epithelial cells to promote in-
of migraine headache in adolescents by using keto- flammatory responses in mice. Gastroenterology.
genic diet. J Headache Pain. 2014;15(Suppl. 1):G9. 2013;145:396-406.e10.
89. Ferrara LA, Pacioni D, Di Fronzo V, et al. Low-lipid 103. Tan J, McKenzie C, Potamitis M, Thorburn AN,
diet reduces frequency and severity of acute migraine Mackay CR, Macia L. The role of short-chain
attacks. Nutr Metab Cardiovasc Dis. 2015;25:370-375. fatty acids in health and disease. Adv Immunol.
90. Földes E. Migränebehandlung mit Kohlehydratarmer 2014;121:91-119.
Diät. J Mol Med. 1939;18:390-391. Available at 104. Chambers ES, Preston T, Frost G, Morrison DJ.
http://www.sprin​ g erli​ n k.com/index/​ F 2176​ 6 1737​ Role of gut microbiota-generated short-chain fatty
X15T11.pdf. Accessed April 16, 2015. acids in metabolic and cardiovascular health. Curr
91. Gainsborough H. The therapeutic use of the keto- Nutr Rep. 2018;7:198-206.
genic diet. Practitioner. 1934;132:45-53. 105. Bayram B, González-Sarrías A, Istas G, et al.
92. Kossoff EH, Huffman J, Turner Z, Gladstein J. Use Breakthroughs in the health effects of plant food
of the modified Atkins diet for adolescents with bioactives: A perspective on microbiomics, nutri(epi)
chronic daily headache. Cephalalgia. 2010;30:1014- genomics, and metabolomics. J Agric Food Chem.
1016. Available at http://cep.sagep​ ub.com/conte​ nt/ 2018;66:10686-10692.
30/8/1014.short​. Accessed April 16, 2015. 106. De Bruyne T, Steenput B, Roth L, et al. Dietary
93. Schnabel TG. An experience with a ketogenic di- polyphenols targeting arterial stiffness: Interplay
etary in migraine. Ann Intern Med. 1928;2:341-347. of contributing mechanisms and gut microbiome-
Available at http://annals.org/artic​le.aspx?artic​lexml​: related metabolism. Nutrients. 2019;11:578.
id=669057. Accessed March 14, 2015. 107. Fraga CG, Croft KD, Kennedy DO, Tomás-Barberán
94. Strahlman RS. Can ketosis help migraine sufferers? FA. The effects of polyphenols and other bioactives
A case report. Headache. 2006;46:179-182. on human health. Food Funct. 2019;10:514-528.
95. Wilkinson CF. Recurrent migrainoid headaches as- 108. Kibble JD, Halsey CR. Gastrointestinal physi-
sociated with spontaneous hypoglycemia. Am J Med ology. In: Medical Physiology: The Big Picture.
Sci. 1949;218:209-212. New York, NY: McGraw-Hill Education; 2015.
96. Peterson J, Garges S, Giovanni M, et al. The https​://acces​smedi​cine.mhmed​ical.com/conte​nt.as-
NIH human microbiome project. Genome Res. px?axml:id=11066​ 03180​ . Accessed February 22,
2009;19:2317-2323. 2019.
97. Carroll KC, Hobden JA, Miller S, et al. Chaptor 10: 109. Collins SM, Surette M, Bercik P. The interplay be-
Normal human microbiota. In: Jawetz, Melnick, & tween the intestinal microbiota and the brain. Nat
Adelberg’s Medical Microbiology, 27th edn. New Rev Microbiol. 2012;10:735-742.
York, NY: McGraw-Hill Education; 2015. Available at 110. Wang Y, Kasper LH. The role of microbiome in cen-
https​://acces​smedi​cine.mhmed​ical.com/conte​nt.aspx? tral nervous system disorders. Brain Behav Immun.
axml:id=11147​33298​. Accessed February 20, 2019. 2014;38:1-12.
1580 October 2019

111. Saltzman ET, Palacios T, Thomsen M, Vitetta L. 124. Food and Agriculture Organization of the United
Intestinal microbiome shifts, dysbiosis, inflamma- Nations, World Health Organization, eds. Probiotics
tion, and non-alcoholic fatty liver disease. Front in Food: Health and Nutritional Properties and
Microbiol. 2018;9:61. Guidelines for Evaluation. Rome: Food and
112. Jiang W, Wu N, Wang X, et al. Dysbiosis gut mi- Agriculture Organization of the United Nations:
crobiota associated with inflammation and impaired World Health Organization; 2006.
mucosal immune function in intestine of humans 125. Rondanelli M, Faliva MA, Perna S, Giacosa A,
with non-alcoholic fatty liver disease. Sci Rep. Peroni G, Castellazzi AM. Using probiotics in clini-
2015;5:8096. cal practice: Where are we now? A review of existing
113. Boulangé CL, Neves AL, Chilloux J, Nicholson JK, meta-analyses. Gut Microbes. 2017;8:521-543.
Dumas M-E. Impact of the gut microbiota on in- 126. Hill C, Guarner F, Reid G, et al. The International
flammation, obesity, and metabolic disease. Genome Scientific Association for Probiotics and Prebiotics
Med. 2016;8:42. consensus statement on the scope and appropriate use
114. Belkaid Y, Hand T. Role of the microbiota in immu- of the term probiotic: Expert consensus document.
nity and inflammation. Cell. 2014;157:121-141. Nat Rev Gastroenterol Hepatol. 2014;11:506-514.
115. Ahern GP. 5-HT and the immune system. Curr Opin 127. Gonzalez A, Hyde E, Sangwan N, Gilbert JA, Viirre
Pharmacol. 2011;11:29-33. E, Knight R. Migraines are correlated with higher
116. Konstantinov SR. Diet, microbiome, and col- levels of nitrate-, nitrite-, and nitric oxide-reducing
orectal cancer. Best Pract Res Clin Gastroenterol. oral microbes in the American gut project cohort.
2017;31:675-681. mSystems. 2016;1:e00105-e00116.
117. Celiberto LS, Graef FA, Healey GR, et al. 128. Sensenig J, Johnson M, Staverosky T. Treatment
Inflammatory bowel disease and immunonutrition: of migraine with targeted nutrition focused on im-
Novel therapeutic approaches through modula- proved assimilation and elimination. Altern Med Rev
tion of diet and the gut microbiome. Immunology. J Clin Ther. 2001;6:488-494.
2018;155:36-52. 129. de Roos NM, Giezenaar CGT, Rovers JMP,
118. United States Department of Agriculture. Appendix Witteman BJM, Smits MG, van Hemert S. The ef-
7. Nutritional Goals for Age-Sex Groups Based on fects of the multispecies probiotic mixture Ecologic®
Dietary Reference Intakes and Dietary Guidelines Barrier on migraine: Results of an open-label pilot
Recommendations – 2015-2020 Dietary Guidelines – study. Benef Microbes. 2015;6:641-646.
health.gov. Dietary Guidelines 2015-2020. Available at 130. De Roos NM, Van Hemert S, Rovers JMP, Smits
https​://health.gov/dieta​rygui​delin​es/2015/guide​lines/​ MG, Witteman BJM. The effects of a multispe-
appen​dix-7/. Accessed February 24, 2019. cies probiotic on migraine and markers of in-
119. Cotillard A, Kennedy SP, Kong LC, et al. Dietary testinal permeability – Results of a randomized
intervention impact on gut microbial gene richness. placebo-controlled study. Eur J Clin Nutr Lond.
Nature. 2013;500:585-588. 2017;71:1455-1462.
120. Ley RE, Hamady M, Lozupone C, et al. Evolution 131. Martami F, Togha M, Seifishahpar M, et al. The
of mammals and their gut microbes. Science. effects of a multispecies probiotic supplement on
2008;320:1647-1651. inflammatory markers and episodic and chronic mi-
121. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. graine characteristics: A randomized double-blind
Microbial ecology: Human gut microbes associated controlled trial. Cephalalgia. 2019;39:841-853.
with obesity. Nature. 2006;444:1022-1023. 132. Parker EA, Roy T, D’Adamo CR, Wieland LS.
122. Wan Y, Wang F, Yuan J, et al. Effects of dietary fat Probiotics and gastrointestinal conditions: An over-
on gut microbiota and faecal metabolites, and their view of evidence from the Cochrane Collaboration.
relationship with cardiometabolic risk factors: A Nutrition. 2018;45:125-134.e11.
6-month randomised controlled-feeding trial. Gut. 133. Evans EW, Lipton RB, Peterlin BL, et al. Dietary
2019;68:1417-1429. intake patterns and diet quality in a nationally
123. Wu GD, Chen J, Hoffmann C, et al. Linking long- representative sample of women with and with-
term dietary patterns with gut microbial enterotypes. out severe headache or migraine. Headache.
Science. 2011;334:105-108. 2015;55:550-561.
Headache 1581

134. Andreeva V, Szabo de Edelenyi F, Druesne-Pecollo 141. Rossi C, Pini LA, Cupini ML, Calabresi P, Sarchielli
N, et al. Macronutrient intake in relation to mi- P. Endocannabinoids in platelets of chronic migraine
graine and non-migraine headaches. Nutrients. patients and medication-overuse headache patients:
2018;10:1309. Relation with serotonin levels. Eur J Clin Pharmacol.
135. Nazari F, Safavi M, Mahmudi M. Migraine and its 2008;64:1-8.
relation with lifestyle in women: Migraine and life- 142. Rainero I, Govone F, Gai A, Vacca A, Rubino E.
style. Pain Pract. 2010;10:228-234. Is migraine primarily a metaboloendocrine disorder?
136. Nazari F, Eghbali M. Migraine and its relationship Curr Pain Headache Rep. 2018;22:36. doi:10.1007/
with dietary habits in women. Iran J Nurs Midwifery s11916-018-0691-7.
Res. 2012;17(2 Suppl. 1):S65-S71. 143. Domínguez C, Vieites-Prado A, Pérez-Mato M, et al.
137. Rist PM, Buring JE, Kurth T. Dietary patterns Role of adipocytokines in the pathophysiology of
according to headache and migraine status: A migraine: A cross-sectional study. Cephalalgia. 2018;
cross-sectional study. Cephalalgia. 2015;35:767-775. 38:904-911.
138. Takeshima T, Ishizaki K, Fukuhara Y, et al. 144. Cady RJ, Durham PL. Cocoa-enriched diets enhance
Population-based door-to-door survey of migraine expression of phosphatases and decrease expression
in Japan – The Daisen study. Headache. 2004;44: of inflammatory molecules in trigeminal ganglion
8-19. neurons. Brain Res. 2010;1323:18-32.
139. Sarchielli P, Rainero I, Coppola F, et al. Involvement 145. Slavin M, Bourguignon J, Jackson K, Orciga M-A.
of corticotrophin-releasing factor and orexin-A in Impact of food components on in vitro calcitonin
chronic migraine and medication-overuse headache: gene-related peptide secretion – A potential mech-
Findings from cerebrospinal fluid. Cephalalgia. anism for dietary influence on migraine. Nutrients.
2008;28:714-722. 2016;8:406.
140. Ren C, Liu J, Zhou J, et al. Low levels of serum se- 146. Cady RJ, Hirst JJ, Durham PL. Dietary grape seed
rotonin and amino acids identified in migraine pa- polyphenols repress neuron and glia activation in
tients. Biochem Biophys Res Commun. 2018;496: trigeminal ganglion and trigeminal nucleus caudalis.
267-273. Mol Pain. 2010;6:1.