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The 3 Main Biological Causes of Migraines (Vascular)

If you just want to see natural treatments, read this article.

The Main Cause of Migraines and Headaches: Inflammation

It’s still controversial in the scientific arena whether 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

Migraines 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 states, certain triggers can be tipping points which leads 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 headache in individuals susceptible to 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 are 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:

  • Cortisol– causes vasoconstriction
  • AngiotensinII – causes vasoconstriction
  • Vasopressin – causes vasoconstriction
  • Neuropeptide Y – causes vasoconstriction
  • Epinpehrine and norepinephrine – causes vasoconstriction
  • Testosterone – causes vasoconstriction
  • Melatonin – causes vasoconstriction
  • Substance P – causes vasodilation
  • Estrogen – causes vasodilation

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

Since every one of these hormones play 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 vasocontrictor. 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 migraine whereas an i.v. infusion of serotonin can abort 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 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 vasodilation lowes 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 glutamate such as hypoglycemia caused by eating high glycemic index foods, hyperinsulinema, 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 breath, but more likely as a result of sleep apnea (if you get 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 norepineprhine.

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 vasocontricting headaches are more likely to have:

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

8 Responses to The 3 Main Biological Causes of Migraines (Vascular)

  1. Sarah January 25, 2016 at 9:30 am #

    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.

  2. Ta December 4, 2014 at 12:00 am #

    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.

  3. Laura May 17, 2014 at 11:04 am #

    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?

  4. Duchess February 5, 2014 at 7:42 pm #

    Excellent and much more comprehensive than the average article on migraines

  5. sameul541 December 6, 2013 at 4:28 am #

    This is a good post, indeed a great job. You must have done good
    research for the work

    • Selfhacked December 7, 2013 at 10:37 pm #

      Thank you

      • Jes January 22, 2016 at 2:00 pm #

        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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