The 3 Main Biological Causes of Migraines (Vascular)

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The Main Cause of Migraines and Headaches: Inflammation


It’s still controversial in the scientific arena whether a migraine is primarily a vascular (blood vessels) or a neurological dysfunction (dysfunction of neurons), but it’s likely that both have a significant role to play.

Whether vascular or neurological, the source is likely brought on by inflammation.  Inflammation directly affects the vascular system and can damage neurons by causing ROS.

This post will focus on the role of “vascular instability” and how it’s affected in various ways.  I talk about various imbalances, but the source of these imbalances is usually a deranged immune system.  I don’t speak about the causes of inflammation in this post.

The neurological dysfunction aspect will have mitochondrial dysfunction as an additional underlying source.

I don’t discuss “spreading depression“, which is a significant mechanism in aura migraines (R).

Migraines vs Headaches

A chronic migraine is a disease which has headaches as the main symptom.

Isolated headaches are usually not caused by the same processes as migraines.  Chronic migraines are usually caused by too much vasodilation.

Headaches can be caused by either too much vasodilation or vasoconstriction.

If someone has a tendency for either state, certain triggers can be tipping points which lead to a headache.

Migraines are more consistent and chronic, while vasoconstriction headaches are more sporadic and much more likely to be induced by environmental triggers such as stress or tyramines (both of which cause vasoconstriction).

Migraines, cluster headaches, and exercise headaches are generally caused by vasodilation. Tension headaches  are caused by vasoconstriction.

The 3 Main Causes of Vascular Instability

These three causes are highly connected to one another and one cause can contribute to another.There are many interactions taking place.

Inflammation influences our endocrine and neurotransmitter levels and these can, in turn, modulate inflammation. Any hormone could lead to an increase or decrease of another hormone.

1) Inflammation.


Inflammation is a natural and healthy response to injury, but chronically high levels are problematic.

Specifically, a cytokine called IL-1b increases COX-2, which causes  the trigeminal nerve, which mediates pain, to release CGRP (R).

CGRP release is perhaps the most significant cause of migraines.  During some migraine attacks, increased concentrations of CGRP can be found in both saliva and plasma drawn from the external jugular vein. (R)

Furthermore, intravenous administration of alpha-CGRP is able to induce a headache in individuals susceptible to a migraine (R).

TNF, another cytokine, can also increase the expression of the CGRP gene (R).  iNOS, which is induced by TNF and NF-kb ( a transcription factor), also increases the expression of the CGRP gene (R).  MAPK also has a significant role in the inflammatory process that releases CGRP (R).  MAPK is caused by AGEs, which is caused by sugar, especially fructose.

iNOS produces nitric oxide, which causes vasodilation.  People with migraines with aura have an increased sensitivity to endothelial nitric oxide.  The result is more vessel dilation than is warranted when there is increased blood flow. (R)

Further supporting the role of inflammation, studies have found people with migraines are more likely to have a variation of the gene that makes TNF-alpha.  These people have the “TNF-α -308G/A polymorphism”, which is associated with migraine risk (R).  This variation makes these people have a larger spike of TNF in response to an injury, infection or inflammatory agent (R).

This released CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, mast cell degranulation and ‘leaky’ blood vessels (extravasation) (R).

Acute bouts of inflammation from injuries can, therefore, exacerbate these migraines.

In general, acute inflammation is characterized by marked vascular changes, including vasodilation, increased permeability and increased blood flow, which is induced by the actions of various inflammatory mediators. (R)

Inflammation can also damage our mitochondria.  Mitochondrial dysfunction can amplify inflammation through ROS production and NF-κB activation (R).

Inflammation  causes glutamate excitotoxicity and the cytokine IL-1b plays an important role in this, too (R).

Excitotoxicity causes a cascade of events such as an increase in free radicals and phospholipases, which break down the neuronal membrane, allowing harmful chemicals and ions to enter and ultimately degrading the cell’s mitochondria.

Inflammation also contributes to migraines because it causes changes in the trigeminal nerve, one of the main facial nerves that also houses a major pain pathway (R).

Migraine sufferers  also are more likely than other people to have an incomplete network of arteries that supply blood to the brain.  This structural difference may cause frequent headaches or occur as a result of the headaches.

2) Endocrine Dysregulation


This is a dysfunction in the endocrine/hormonal system, sometimes of the HPA axis leading to unbalanced levels of:

This hormonal list is not comprehensive, but these are large players.

Since every one of these hormones plays a role in modulating the vascular system, it seems apparent to me that dysregulation of the endocrine system will result in either vasodilation or vasoconstriction.

When hormonal signaling is out of whack and too little or too much of one or more hormones is excreted at the wrong time you get excess vasodilation or vasoconstriction.

There also may be a role played by substance P and pain perception. Substance P is released along with glutamate, so if too much glutamate is released then there may be an increase in pain perception.  Substance P also causes neurogenic inflammation.

3) Neurotransmitter Dysregulation.

Glutamate (and aspartate), serotonin, acetylcholine, and GABA play the following role in vasodilation and vasoconstriction:

  • Glutamate causes vasodilation.
  • GABA causes vasodilator.
  • Serotonin is a vasoconstrictor – Serotonin deficiency causes vasodilation.
  • Acetylcholine is a vasoconstrictor. Acetylcholine deficiency  causes vasodilation.

It was found that glutamate, a major neurotransmitter, is vasoactive in the cerebral circulation. Glutamate  vasodilation is mediated by nitric oxide through NMDA receptors (R).

The levels of serotonin, a vasoconstrictor, seem to decrease during a migraine whereas an i.v. infusion of serotonin can abort a migraine. In fact, serotonin as well as ergotamine, dihydroergotamine and other antimigraine agents invariably produce vasoconstriction in the external carotid circulation (R).

Acetylcholine is a vasoconstrictor (R).

According to one study, administration of GABA (1-100 micrograms) directly into the cerebral circulation produced dose-dependent increases in cerebral blood flow. (R)

Substance P is released along with glutamate, so if too much glutamate is released then there may be an increase in pain perception.

Which Category Are You In?

Vasodilatory headaches


Your headaches may be caused by vasodilation if it occurs as result of:

  • Heat,
  • Sex and masturbation (both vasodilators)
  • Exercise (during or post),
  • An infection or sickness,
  • An injury
  • Ingestion any food or chemical that they are sensitive to (gluten, casein, etc..).
  • Hypoglycemia
  • MSG
  • Hot flushes by perimenopausal women (increases vasodilation from estrogen).  Estrogen also fluctuates in pregnancy and  menarche
  • After menstruation –  estrogen levels peak ~11-13 days after

Exercise, infection, injury and food intolerances cause inflammation, which leads to vasodilation.

People will usually, but not always, have lower than average blood pressure because of vasodilation lowers blood pressure.

MSG or excess glutamine/glutamic acid consumption can worsen vasodilatory migraines because glutamate excess causes vasodilation.  The degree of harm caused by MSG is probably minimal.

Instead, glutamate excess is more likely caused by a host of other factors not related to dietary consumption of glutamates such as hypoglycemia caused by eating high glycemic index foods, hyperinsulinemia, fasting/skipping meals or really low carb dieting.

Also, low oxygen can cause glutamate excitotoxicity, such as when we are so stressed we forget to breathe, but more likely as a result of sleep apnea (if you get a headache in the morning check for sleep apnea).

Vasodilatory headaches are least responsive to NSAIDs like aspirin because while aspirin will block the pain to a certain extent and bring down inflammation, it is a vasodilator itself.  So in one way it makes it better (by decreasing inflammation) and in another it exacerbates the problem (by increasing vasodilation).  If your headaches don’t improve with aspirin, that’s another indicator that it’s caused by vasodilation.

NSAIDs have been shown not to work for vasodilatory headaches like cluster or exercise headaches because NSAIDs vasodilatory actions will only help for vasoconstrictive headaches.

Allergies and allergic reactions cause an inflammatory response which will trigger or make this headache worse.

Vasoconstriction headaches

People with vasoconstriction headaches  will usually have higher blood pressure and experience episodes during times of stress. Tension headaches are a good example of this.

Stress and tyramines, for example, can trigger vasoconstriction.  Stress triggers vasoconstriction through cortisol, epinephrine, and norepinephrine.

Any stimulus that causes the body to release stress hormones such as  fasting or skipping meals, emotional stress, cold, bright lights and loud noise can aggravate these headaches.

Tyramines, found in aged cheeses and other foods, displace norepinephrine from neuronal storage vesicles, which leads to vasoconstriction.  These headaches can come often but they aren’t as consistent as vasodilatory headaches.

These headaches are most responsive to NSAIDs like aspirin because aspirin is both a pain killer and vasodilator.  And indeed, the research demonstrates its effectiveness for tension headaches.

People with vasoconstricting headaches are more likely to have:

  • Stress
  • High blood pressure, which is caused by angiotensinII
  • High choline dosage
  • Serotonergic like SSRI’s and tryptophan or foods which contain high levels of tryptophan may increase serotonin levels and possibly exacerbate vasoconstriction headaches


  1. The migraine causes you mention are often associated with increased production of endogenous hydrogen sulfide, which we make in the brain. We break down hydrogen sulfide to sulfite (which is toxic) then to sulfate; that last step is performed by the enzyme sulfite oxidase. Sulfite oxidase needs dietary support with sufficient molybdenum, heme, and chloride (that last is easy to get from NaCl, etc.) and can be overwhelmed by sulfites and nitrites (so try to avoid those). A friend recently tried molybdenum (500 mcg dose for a smallish woman) for her medication-resistant chronic migraines, and it worked on an as-needed basis to make the migraines go away. Molybdenum is an essential trace mineral in many foods; it only seems weird and unusual because almost no one can pronounce it.

  2. Johanna

    Very interesting! I’m woman 43 years old, and the 5 years I’ve had more and more migrains, I assume it has to do with lower estrogen levels. Stopped eating all grain and sugar 2 years ago has helped some, and starting on amitryptilin has also helped. If the migrain is about to start a cup of coffee immediately triggers, and a glas of white wine, but not red can prevent it before it starts. I now understand all this from your vasodilator/constrictor explanation, which wasn’t this clear to me before, and I’m a medical doctor, a general practitioner. So I thank you so much!!

    • A subcatagory of oils-in-isolate, refined oils, which effect people differently, will enter the blood stream and within 20-30 seconds initiate dramatic blood flow restriction and, when it passes, incite a dramatic blood flow increase, precipitating headaches, which are caused either by vasorestriction (blood vessel restriction) or vasodialation (blood vessel expansion).
      Oils-in-isolate: saturated fats: animal fat or refined oil: olive, coconut, canola, peanut, sesame, flax, chia, hemp, corn, soybean, hydrogenated etc. Suggest a product for arterial strength, Invisivein, from Quantum Nutrition Labs. Listen to the proprietor of the website, Dr. Bob Marshall, at QNLABS.COM, a C.C.N. for 40 years, and is considered one of the leading nutritionist in the country. He is on the radio six days a week, and there is a one month radio podcast archive of his program. Also for spot use on headaches, consume up to 500mg. of magnesium. Product suggestions are Pure Encapsulations Magnesium Glycinate or Dr. Marshall’s magnesium malate. His product is available at his website, and you can call his number (1-800-370-3447) and his phone reps will assist you. Also go to his website and draw down his Biofield diet, which he highly recommends for nearly everyone for to be used for life.The diet is a more refined iteration of the diets recommended by the leading experts in the country for diet, Dr. Caldwell Esselsten, Dr. John McDougal and Dr. Michael Gregor

      • Dr. Caldwell Esselstyn – “Prevent & Reverse Heart Disease” (1.) For Dr. Caldwell Esselstyn health information (1.) For Dr. Caldwell Esselstyn health information, recommended by Dr. Marshall, due to this M.D.’s stance against excessive oil-in-isolate ingestion. (1.) Making Heart Attacks History: Caldwell Esselstyn at TEDxCambridge 2011 (1.) Cure Heart Disease Without Drugs | Dr. Caldwell B Esselstyn (1.)
      • Dr. Michael Greger – 2013 – “Uprooting the Leading Causes of Death” (1.) (2.) Essential tremors, shaking hands that especially occur in the elderly, and are NOT Parkinson’s related.
      • Dr. John McDougall – “The Ultimate Diet Therapy” (1.)
      • Dr. John McDougall suggests that starch-based diets are the foods humans were born to eat. He has been studying, writing, and speaking out about the effects of nutrition on disease for over 40 years and is a bestselling author of several titles, including The Starch Solution. (1.)

    • lisa

      I have stopped eating grains and sugars also. .just a month ago. It has been a low carb diet consequently.I am Definately experiencing more migraines now which is abit puzzling to me but in your article you state that low carb diet can generate glutamate.I have included millet and buckwheat for protien. I am 53 and am in menopause. After reading the information it would seem to conclude that mine are vasodilation as they have never responded to NSAIDS but do to triptans.So not sure what to think about how to adjust my diet?

  3. Ashlee

    Perhaps your HA’s are related to trigger points in the muscles due to poor posture? if you have not had these treated they can cause constant HA symptoms. Have you seen a myotherapist to get treatment on your muscles and the trigger points in them?

  4. This is the first information that seems relevant to my exercised-indusced headaches/migraines. I’ve even gotten brain MRIs, and other tests. I am really liking this information but it there any follow up info on how we can avoid getting them? Mine definitely seem like vasodilatation headaches and I’m going to start today to not skip meals, and stay with low-glycemic foods.

  5. Have you ever heard of New Daily Persistent Headache? I’ve had it for almost a year. It’s a headache that comes on suddenly and never goes away. It’s there 24/7. There isn’t much research on it and it’s very difficult to treat. It has pretty much ruined my life.

    I can’t tell where it fits in your categories. Stress definitely makes it worse (vasoconstriction type), but so does heat (vasodilation type). My blood pressure tends to be slightly low and NSAIDS definitely do not help. So it sounds like vasodilation?

    Just curious if you’ve heard of the condition and had any thoughts about it. Thanks for the article.

    • Maddy

      Have you tried an epsom salt bath? Magnesium is important and somehow so is sulfate, and epsom is magnesium sulfate. There is some new research on melatonin also in reducing migraine, and what is interesting is that while we sleep our brains transport melatonin into the ventricles and the spinal fluid that resides in there, but it must be bound to sulfate for that transport to happen apparently. sometimes in an ER they will use IV mag sulfate to abort a migraine. It can take a long time for mag levels to build in tissues. So keep taking oral mag too. any head injuries, even if they were months or even a year or two before onset?

    • Maddy

      There is also something tied up with electrolyte balance. Neurons have sodium-potassium “pumps” on them which facilitate the charge necessary for the neuron to “fire” for lack of a better term. If the intracellular/extracellular balance is off the pumps get stuck. We get a lot of potassium from our food, and many have restricted salt. Salt your food. Especially those high in potassium for balance.

  6. Ta

    Interesting, thanks. I’m also trying to figure out how to improve or eliminate my migraines, so I keep looking for relevant angles. Triptans are the only drug that seems to be able to effectively abort a migraine for me. I think they may increase serotonin, but descriptions of the mechanisms of action are not consistent. I have also read that chronically high serotonin can contribute to migraine susceptibility.
    A couple of points.
    My understanding is that low oxygen supply to cells is more commonly a result of unaware hyperventilation, rather than breathing too little. Stress tends to promote hyperventilation. Sometimes people protectively hold their breath after a period of hyperventilation, but except in extreme circumstances (eg drowning or emphysema) its usually blowing out too much CO2 that deprives tissues of O2. CO2 is required to allow hemoglobin to release O2 where it is needed. If blood CO2 level is low, and/or mitochondrial CO2 production is low, you can have high O2 in blood, but it can’t get out to other cells in sufficient quantities.
    Night-time hyperventilation is common, especially when mitrochondrial respiration is not efficient for whatever reason.
    Check out the Bohr effect, and if you are interested in more, Buteyko.
    I also thought that AGEs were promoted by unsaturated fats rather than by sugar.

  7. Laura

    Wow!! Thank you so much for putting so much extensive time into this and explaining why. So helpful. I reluctantly use Ergotamine when I have a migraine to vasoconstrict and wish I could naturally regulate with my food intake. Do yo know of any other foods besides coffee?

      • Jes

        I have suffered from, and dug through countless researches to understand my migraines since i was in my early teens. I’m now 40, and this is the first time i can say i feel enlightened on the matter. Amazing, and what a relief to know which triggers should be treated in which ways. Thank you so much for your efforts.

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