Classification of chronic headaches can be challenging. The most common types of headaches are tension headaches, sinus headaches, and migraines.

Tension headaches tend to be bilateral, and the pain originates at the top of the shoulders and neck due to muscle tension, hence the name.

Sinus headaches usually are secondary to allergies and sinus infections, and tend to be worse with movement, sometimes with tenderness behind the forehead, upper cheeks, or teeth.

Migraines tend to be unilateral, and throbbing, often behind one eye, though not always. They can come with aura or not, nausea and vomiting, or not. Cluster headaches tend to be similar, but they are usually sharp pain, unilateral, and occur in “clusters” of time (i.e. repeatedly for a certain period of time, and the not again for weeks or months at a time). But the pathophysiology between migraine and cluster headaches may be similar, and are often treated the same way. So for the time being, I’ll lump those two together.

Here’s what we do know about migraine physiology.

Nitric Oxide and Migraines

There is a clear correlation between migraines and nitric oxide release, as nitric oxide donors (like nitroglycerin) can clearly induce migraines in clinical trials. Blocking nitric oxide formation has been shown to treat migraines, too—though this isn’t considered a great therapeutic option, since nitric oxide is a well known vasodilator—which is a good thing, to a point, like anything else. Too much nitric oxide is associated with all manner of negative physiological states (perhaps because nitric oxide is an emergency vasodilator). The primary gasotransmitter in the body for this purpose is carbon dioxide.)

Besides, even if we know that nitric oxide can trigger migraines, we’re still a long way from determining the root cause. What causes its release, and why do some people develop migraines from nitric oxide but not others?

There’s speculation that the problem could be the vasodilation itself: too much blood flow in too small a space (like the brain) will cause pain just from the pressure, and this is why migraines have a characteristic throbbing pain. Another hypothesis is that because nitric oxide is a rather unstable molecule, it serves as a ready precursor for peroxynitrite, one of the most reactive known free radicals, and perhaps the real problem is the oxidative stress, leading to inflammation and pain.

This animal study also implies that migraines could be secondary to mitochondrial dysfunction from the peroxynitrite oxidative stress, to which females are more susceptible than males (possibly accounting for why women are more prone to migraines than men). Indeed, neutralizing peroxynitrate does seem to neutralize the pain, which lends some credence to this hypothesis.

But still, we’re not at root cause yet.

The Serotonin, Estrogen, and Hypothalamic Migraine Theory

Leaving nitric oxide aside for a moment, another theory of migraines has to do with an overactive hypothalamus—which is typically associated with lower levels of serotonin. This is why, from a pharmacological standpoint, triptans, which stimulate serotonin receptors, are considered the best “rescue” for a migraine. From a naturopathic standpoint, 5HTP, a serotonin precursor, can be effective for symptomatic relief as well.

But why?

Like nearly everything in the body, serotonin operates hormetically: its effects at low levels are exactly opposite its effects at higher levels. At high levels, serotonin triggers vasoconstriction, and this is what triptans do by stimulating serotonin receptors—suggesting (perhaps) that the migraine relief has to do with less pressure from the increased blood flow. (But triptans aren’t a great long-term migraine solution either, since side effects can be severe, most of them vascular in nature. This is because too much serotonin gets absorbed by platelets, triggering the clotting cascade and increased clot formation).

At lower levels, though, serotonin triggers nitric oxide release, leading to vasodilation.

This study suggests that the reason why some migraine sufferers experience migraines from barometric pressure changes is due to a small dilation of blood vessels in the brain. This triggers release of serotonin from platelets, where it’s stored—because your body is trying to create balance, and serotonin causes the blood vessels to constrict. When this compensation is too much, you get an “aura”, and sometimes tingling and numbness—resulting from too little blood flow to the brain. You then break down the excess serotonin to try to compensate again. As serotonin drops, the body (presumably) releases nitric oxide, leading to either the pain from the pressure itself, or from the peroxynitrite formation.

Some also note that sunlight exposure tends to trigger migraines. Well, sunlight also triggers serotonin release. Often people will note that it’s after a long day in the sun that the migraine occurs.

So perhaps the issue is the rapid change in serotonin levels that lead to the compensatory effects, which include nitric oxide release.

Along those lines, women with estrogen dominance tend to experience more migraines, particularly around their cycles when estrogen is dropping (but perhaps not as quickly as progesterone). Higher estrogen means higher serotonin, which decreases migraines the rest of the month. But, perhaps, as estrogen declines and therefore so does serotonin, the nitric oxide release gets triggered, leading to both vasodilation and, potentially, peroxynitrite formation.

The Methylation Migraine Theory

Another piece to the puzzle is the methylation cycle, which is necessary to make serotonin. The cycle requires folate, B12, and vitamin B6, as well as a few other ancillary nutrients. When it’s not working properly, among other things, homocysteine tends to build up. Elevated levels of homocysteine are linked to migraines, though it’s unclear whether this is correlation or causation. (Homocysteine is directly inflammatory to the vasculature itself, after all.)

Undermethylation can occur for a number of reasons—it can be genetic, due to toxicity (think of it like a bottleneck—in addition to making neurotransmitters, this is also one of your liver’s main pathways for detoxification, or due to low levels of the nutritional cofactors needed.

Vitamin B12 has specifically been studied with respect to migraines. Low levels are decidedly associated with migraine risk–in fact, once levels rise substantially, migraine risk drops by around 80%. But is that because of B12 itself—does that imply that low B12 is the cause of migraines 80% of the time—or is that because (if it’s low), B12 causes the methylation cycle to be more efficient, which in turn raises serotonin production, which lowers nitric oxide?

Even if it’s the latter, there’s evidence that B12 might be more primary than that, because it actually acts like a nitric oxide scavenger—in other words, if there’s an excess of nitric oxide, B12 will bind to it and render it harmless. This study suggests that hydroxycobalamin does this more effectively than other forms of B12.

Excessive amounts of nitric oxide (such as with nitrous oxide administration, or ‘laughing gas’), can induce B12 deficiency, too, probably just because B12 is being consumed with so much to neutralize.

So B12, and methylation support in general, seem to be indicated for migraines at least in situations where homocysteine is high and/or B12 is low… but even if B12 isn’t low, if the nitric oxide is the final migraine trigger, adding it in should help with symptom management in the short-term.

Allergies and Histamine Migraine Theory

Other than a hormonal cause, the most common causes of migraines I’ve seen in practice are mycotoxin exposure and toxicity, and allergens.

Mycotoxins, according to the above theories, could cause migraines due to the fact that, among other detoxification routes, they require methylation for elimination.

It’s also possible there could be an overlap between mold and allergies—some people have an allergic response to certain toxic molds too. The allergic mechanism is this: when you’re exposed to a substance to which your body has a toxic response, the mast cells will release histamine. Mast cells also carry serotonin, though… and release of serotonin along with histamine can trigger the above vasoconstriction and rebound vasodilation mentioned above.

Also, once histamine is released, it has to get methylated for elimination—further compounding the methylation issue if it’s already present, too.

The Tyramine Diet and the Histamine Connection

Many migraine sufferers who have kept headache diaries have noticed that foods high in tyramines, especially red wine and aged cheese, are common triggers.

I suspect that, unless there is a piece of the mechanism we haven’t yet found, the problem isn’t really the tyramines at all, but the histamines, as there is almost a complete overlap in the two food lists. As mentioned above, histamines require methylation for elimination. If someone’s histamine levels are already high, these foods might trigger a tipping point—raising homocysteine, and perhaps dropping B12 as the body is trying to break histamines down… which might mean the nitric oxide it might have been able to scavenge is able to accumulate instead.

This alone probably won’t trigger a migraine, except in someone already susceptible—say, due to high levels of nitric oxide perhaps secondary to low(er) levels of serotonin, and (maybe) inability to cope with oxidative stress due to poor antioxidant status.

The Upshot

In this article, I’ve mostly strung together a lot of current theories and speculated on connections between them. What we know is that migraines are related to nitric oxide release, low serotonin, high homocysteine, low B12, and either histamine or tyramines.

My theory is that rapid changes in serotonin levels, whatever the cause (weather, allergens, hormone fluctuations), leads to nitric oxide release—but as long as the methylation cycle isn’t overwhelmed and B12 levels are adequate, there might be no problem. If the methylation cycle is overwhelmed (due to low cofactors, toxicity, high histamines, etc), now you’ve got a recipe for a migraine.

The Mechanism of Migraines