Dietary Intervention for Migraine Relief

The purpose of this clinical trial is to evaluate whether a low-glutamate diet is an effective treatment for migraine and to explore how this dietary approach may influence biological processes related to migraine. The low-glutamate diet reduces intake of free glutamate commonly found in ultra-processed foods and food additives, while emphasizing whole foods rich in nutrients that support brain health and reduce oxidative stress.

The study is based on prior research showing that this diet led to substantial improvements in migraine symptoms among individuals with chronic pain, with migraine remission often observed after one month. These improvements were also associated with measurable changes in brain structure, suggesting a potential link between dietary glutamate exposure and migraine-related brain changes.

The primary goals of this study are to:

Determine whether one month on a low-glutamate diet reduces migraine frequency, severity, and duration and improves quality of life

Examine changes in blood markers related to migraine pain signaling

Assess whether dietary changes are associated with changes in brain structure or chemistry in a subset of participants

Participants will first complete a 4-week run-in period during which they will continue their usual diet and record headaches and migraines using a daily electronic diary. Eligible participants will then be randomly assigned to either begin the low-glutamate diet immediately or continue their usual diet for one additional month (wait-list control). All participants will complete questionnaires, provide blood and urine samples, and undergo in-person assessments at the end of each study phase. A subset of participants will also undergo Magnetic Resonance Imaging (MRI) scans.

Participants assigned to the diet will receive structured dietary training, educational materials, and weekly follow-up support to promote adherence. After the initial dietary phase, participants will complete a double-blind, placebo-controlled crossover challenge, during which they will receive short courses of monosodium glutamate (MSG) and placebo while remaining on the low-glutamate diet. This phase is designed to determine whether migraine symptoms return specifically in response to glutamate exposure.

Throughout the study, participants will continue to track migraine symptoms using daily diaries. The results of this study may help determine whether a low-glutamate diet is a safe, non-pharmacologic treatment option for migraine and may provide insight into dietary factors that contribute to migraine development and persistence.

Inclusion criteria

• Men and women of all races and ethnicities
• Age 18-75 years
• Documented diagnosis of chronic or episodic migraine for at least 6 months, based on International Classification of Headache Disorders, 3rd edition (ICHD-III) criteria, defined as:

• 8 headache days per month, and
• 4 migraine days per month
• Migraine onset before age 50
• On a stable medication regimen for at least 1 month prior to enrollment
• Willing to maintain stable medications throughout the study
• Willing to discontinue supplements during the study period
• Women of childbearing potential must be willing to use birth control during the study timeframe

Exclusion criteria

• Current pregnancy, plans to become pregnant during the study timeframe, or current breastfeeding
• Current use of medications affecting glutamatergic or gamma-Aminobutyric Acid (GABA) neurotransmission (unless discontinued under physician guidance)
• Current use of quarterly injectable migraine preventive medications
• Unwillingness to modify dietary intake or to stop alcohol and marijuana use during the study
• Substance use disorder within the past year
• Diagnosed seizure disorder
• Severe asthma requiring past hospitalization