Migraines plague more than a billion people worldwide and affect women three times more often than men. [ref] That is a lot of people who know the pain, mental fogginess, sensitivity to light, and overwhelming desire to crawl into a dark hole and hide from the world.
Migraine symptoms generally include:
Somehow that list of symptoms doesn’t really do a migraine justice. For many, migraines are more than a headache — and usually, the pain isn’t even the worst part. Instead, it’s the altered ability to think, irritability, nausea, slowed reflexes, and body temperature fluctuations.
There are a couple of different types of migraines:
Some people get premonitory or prodromal symptoms – these symptoms can occur up to a day or two prior to the migraine. Premonitory symptoms can include irritability, fatigue, food cravings, stiff neck, sensitivity to sounds, and yawning. On a PET scan, these symptoms accompany an increased blood flow to the hypothalamus. [ref]
Chronic migraines affect around 2% of the population. The condition is differentiated from regular migraines if a person is plagued by migraines at least 8 days per month and headaches at least 15 days per month. [ref]
In the 1960s, researchers found that people with migraines have higher levels of a serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in their urine. This prompted a lot of research over the past five decades into the relationship between the serotonergic system and migraines. More recently, researchers have also investigated how CGRP, neuroinflammation, and altered ion levels impact migraines. [ref]
Long story short, research provides a lot of competing theories but no simple answers.
Migraines are often described as an excitatory state in the brain – also known as a state of hypersynchrony. Other researchers describe migraines as the brain over-responding to stimulus. [ref]
The research can be broken down into three paths:
Part of what is happening in your brain during a migraine is thought to be vasodilation – or the increase in the size of the blood vessels in your brain. This causes decreased blood pressure. Vasodilation is thought to be a reaction to an initial period of vasoconstriction; however, the blood vessels inside the cranium don’t always act in the same manner as the rest of the body. [ref]
These vascular causes may be due, at least in part, to serotonin signaling.
Serotonin (5-hydroxytryptamine, 5-HTP) is a neurotransmitter that causes the signal to flow from one neuron to the next. It is found in abundance in both the digestive system and the brain.
Brain morphology, the way the neurons in the brain are shaped and formed, is also affected by serotonin. There are different serotonin receptors found throughout the brain and intestinal tract that cause the diverse effects of serotonin. [ref]
Genetic studies show a link between migraine susceptibility and a type of genetic variant known as a variable number tandem repeat in the serotonin gene. [ref]
One big link between migraines and serotonin is that triptans, the most commonly used migraine prescription medication, work by amplifying the serotonin signal. Triptans act on the serotonin receptors (5-HT1B) in the blood vessels of the brain, constricting them and inhibiting the release of neuropeptides. [ref]
Using PET scans on people who had been migraine free for at least 48 hours, researchers have begun studying the 5-HT1B (serotonin) receptor in the brain. These scans showed migraine patients having lower 5-HT1B binding than people without migraines. One caveat the study makes is that the lower serotonin receptors may either be contributing to the cause of migraines or be decreased over time as a result of repeated exposure to migraines. [ref]
Researchers also found lower melatonin levels in people with chronic migraines when compared to a control population. This is notable especially because serotonin is needed for the reaction in the pineal gland that produces melatonin. [ref]
One review that considers the role of serotonin in migraines found that the data supports the idea that serotonin levels are low between migraine attacks, but are shown to increase at the beginning of a migraine. This initial surge of serotonin causes vasoconstriction and is thought to be part of the aura phase. When serotonin is then broken down (which happens pretty quickly), the levels drop causing vasodilation and headache pain. [ref]
Another key player in vasodilation during a migraine is the vasodilator CGRP. CGRP stands for calcitonin gene-related peptide and is released from the trigeminovascular system.
The trigeminovascular system includes both the trigeminal nerve neurons and the cerebral blood vessels. The trigeminal nerve is the largest cranial nerve. It branches to the eyes and the jaw.
Time for a picture:
Notice how the trigeminal nerve goes to the root of the teeth… my teeth often hurt during a migraine.
These sensory nerve fibers of the trigeminal nerve can activate the release of neuropeptides CGRP, substance P, and neurokinin A. CGRP is a potent vasodilator making it important for both migraines and normal blood pressure regulation in the body. It is also thought to influence the pain portion of the migraine.[ref][ref]
The release of CGRP is then thought to activate receptors on a number of different cell types including mast cells. These mast cells degranulate, releasing histamine and pro-inflammatory compounds. This degranulation of mast cells causes a “prolonged state of excitation in meningeal nociceptors”. The meninges line the skull, and nociceptors are pain receptors.[ref][ref]
Here is an image of the meninges, which includes three layers surrounding the brain (dura mater, arachnoid, and pia mater).
The brain itself doesn’t have pain receptors, but there are pain receptors and blood vessels throughout the meninges.
Let’s return to what mast cells are and how they can cause problems in migraines…
Mast cells are part of the body’s immune system and are found in all of our body tissues. They stand ready to release a payload of histamine, serotonin, and inflammatory cytokines when activated by a pathogen, allergic reaction, or other signaling molecules such as CGRP. [ref]
Some researchers theorize that mast cells and neuroinflammation are at the root of migraine pathology. Histamine, which is released when mast cells degranulate, is found in elevated amounts during migraine attacks.[ref] Tryptase is also released in degranulation and is thought to sensitize pain receptors.[ref]
Other researchers theorize that central sensitization is at the root of migraines. Central sensitization involves enhanced signaling through pain pathways and is caused by overexcited pain receptors and decreased inhibition. This term is applied to various pain-related conditions such as peripheral neuropathy, IBS, and migraines.[ref]
Another observation of researchers is that ion levels are often altered in migraineurs. Sodium, potassium, calcium, and chloride are integral parts of how neurons fire. Neurons send signals to other neurons by transmitting electrical impulses that are carried by positive and negative ions.
A recent study found that sodium (Na) levels are higher in the cerebral spinal fluid (CSF) of people with migraines compared with a control group. This backs up previous work that also showed an increase in CSF sodium levels during the course of a migraine. The other ion levels – calcium, potassium, and magnesium – did not change, nor did the sodium levels in the plasma. [ref][ref]
There have been large studies trying to determine if sodium intake affects migraine risk. One study found that for women with low BMI and men at any BMI, a low intake of sodium slightly increased the risk of headaches and migraines. [ref]
Another study found that people who have migraines have, on average, lower magnesium levels than a healthy control group. [ref]
A migraine aura is the altered sensory perception that migraine sufferers experience. These include visual alterations like sparkles and waviness of images. The Mayo Clinic explains that “A visual aura is like an electrical or chemical wave that moves across the visual cortex of your brain. The visual cortex is the part of your brain that processes visual signals. As the wave spreads, you might have visual hallucinations.” Sensory auras may also cause tingling and problems with speaking.
The aura is thought to be a result of cortical spreading depression (CSD). CSD is a massive depolarization of neurons that occurs in the brain. A wave of hyperexcitability of the neurons is followed by a wave of inhibition. This depolarization causes the release of potassium, hydrogen, nitric oxide, and glutamate ions as well as arachidonic acid. [ref]
Here is a visual:
This cortical spreading depression causes the pain receptors in the meninges to start firing after a bit of a delay. This firing of the pain receptors continues for a long while. Animal studies show that inducing CSD by various different means caused the pain receptors to start firing about 14 minutes later. [ref]
We have the involvement of the serotonin system that can cause changes in blood vessel dilation. The trigeminal neurovascular system releases CGRP, which is a vasodilator that also acts on mast cells. This causes sterile neuroinflammation. Mast cells release histamine, tryptase, and other inflammatory cytokines. This is acting on the meninges, the lining of the cranium, causing pain. If the migraine is preceded by an aura, the cortical spreading depression may be what is triggering the nociceptors (pain receptors) in the meninges to fire.
People often identify various triggers for their migraines. Traveling, foods, stress, hormones, odors, sleep deprivation, and flashing/bright lights often top the list.
One problem with identifying migraine triggers is that the premonitory or prodromal symptoms (up to a day or two ahead of the migraine) may overlap with what people identify as triggers. Food cravings are one prodromal symptom, and various food triggers are often blamed. Altered sleep patterns are another thing identified as a trigger but could be a prodromal symptom. Bright light sensitivity could also fall into this conundrum.
That said, a lot of people have identified specific foods as being likely to cause migraines for them. Some of these include gluten, wine, cheese, and chocolate. (Read more about tyramines increasing blood pressure and genes related to histamine intolerance.) Other top triggers for migraines include MSG and beer. [ref][ref]
Studies show, though, that overall dietary patterns don’t relate to migraine risk. One study did show that women with migraines eat a slightly higher amount of fat and a very slightly lower amount of protein on average. [ref][ref]
Some people are sensitive to odors and find that certain smells (floral, perfumes, strong cleaning chemicals, paint, gasoline, plastics) can trigger migraines. [ref]
This isn’t just all in your head (pun intended). A small study looked at cerebral blood flow in people with migraines vs a control group. The migraineurs had altered blood flow in certain areas of the brain when stimulated with odors. [ref]
One really common migraine trigger for many women is the change in estrogen levels around the time of their period or during ovulation. Migraines often go away for these women during pregnancy and after menopause.
Why would a change in estrogen levels trigger a migraine? Mast cells have estrogen and progesterone receptors, and the fluctuation of estrogen can cause mast cell degeneration and subsequent migraine pain.
Migraine drug classifications include triptans, ergotamines, CGRP monoclonal antibodies, and botox. One thing to note about these trials on preventative medications is that most are investigating an endpoint that represents a 50% reduction in migraine frequency. If you normally have 6 days of migraines per month, a medication is considered effective if it reduces migraines to 3 days/month. So, the goal of these medications seems to be a reduction in frequency rather than actually eliminating migraines.
Ergotamines were originally derived from ergot, a fungus that infects rye and other grains. Ergot is famous for outbreaks in the Middle Ages causing what was known as St. Anthony’s fire. Ingesting grains infected with the fungus caused extreme vasoconstriction, causing a severe burning sensation in the limbs. Ergots also affect neurotransmission and cause hallucinations.
Ergotamines are available in prescription form for migraine attacks. They bind to the serotonin receptors, causing vasoconstriction as well as other effects. [ref] Migergot is one brand name that combines ergot with caffeine. There are possible serious side effects (black box warning).
Triptans are often the first line of prescription medication offered to people with migraines. They target specific serotonin receptors in the brain (5HT1B, 5HT1D). These receptors are located in the trigeminal nerve endings, so it is thought that activating them prevents the release of CGPG and substance P. Triptans are used as prophylactics to prevent migraine attacks.[ref]
How well do triptans work? They seem to work better for some people than others…
A meta-analysis of 133 randomized controlled trials looked at the efficacy of triptan medications for migraines. The conclusion was “most triptans are associated with equal or better outcomes compared with NSAIDs, ASA, and acetaminophen”. Looking at the data, triptans relieved pain in two hours for between 42 and 76% of patients. NSAIDs, aspirin (ASA), and acetaminophen (Tylenol) relieved pain in two hours for 46 – 52% of patients. [ref]
What the meta-analysis showing that triptans and aspirin/NSAIDs are about equivalent doesn’t tell us is whether those ~50% of people that triptans work for are the same people that aspirin/NSAIDs work for… In other words, if aspirin/NSAIDs don’t work for you, would triptans be a better option? Or are 50% of the people just kind of screwed when it comes to effective medications?
Another study comparing naproxen sodium (Aleve, OTC headache medicine) with a combo naproxen sodium along with a triptan (Treximet, prescription med) found that only naproxen sodium (Aleve) was statistically significant in the reduction of migraines and Treximet was not. The current cost of Treximet is well over $200 for 9 tablets [source]. 43% of subjects who just took Aleve for migraine had a 50% reduction in migraine frequency (compared to 17% with the expensive prescription med). [ref]
CGRP receptor inhibitors:
Several small-molecule GCRP inhibitors have been tested and are in current clinical trials for migraine usage. They are generally termed ‘gepants’.
A new monoclonal antibody targeting CGRP, fremanezumab, was tested in a group of over 700 study participants. The injection of fremanezumab once a month reduced migraine frequency from 9 per month to 5 per month. This was compared with placebo which reduced migraine frequency from 9 per month to 6.5 per month. [ref]
OnabotulinumtoxinA, often called Botox, is a neurotoxin injected into the face and approved for the prevention of chronic migraines.
The PREEMPT study on the initial phase III clinical trial showed a statistical decrease in migraine-free days, going from 8.4 migraine days to 6.6 days per month on average. [ref]
One study compared botox injections to amitriptyline, a tricyclic antidepressant used for migraines. The results showed that both were about equally effective, with around 70% of trial participants having a reduction in the number of days of migraines each month. [ref]
There are several ways to approach a medical problem:
In studies, quite a few different gene variants show an association with either an increased or decreased risk of migraines. You will find below a few of those variants commonly included in 23 and Me or AncestryDNA testing. This isn’t the whole picture, but it does cover quite a few of the variants involved in migraine risk.
How do you use this info? Identifying the genetic variants you carry that influence migraine susceptibility may help you figure out how you get migraines and, hopefully, which migraine ‘lifehacks’ will be most effective for you.
TRPM8 gene: codes for the cold and menthol receptor. When skin temperatures decrease by 15 degrees C, it hurts due to the activation of this pain receptor. [ref]
Check your genetic data for rs10166942 (23andMe v4, v5; AncestryDNA):
CGRP and brain-derived neurotrophic factor (BDNF) coexpress on the trigeminal nerve terminals.[ref]
BDNF Gene: codes for brain-derived neurotrophic factor
Check your genetic data for rs6265 (23andMe v4, v5; AncestryDNA):
MMP16 gene: Several genome-wide association studies looking at large population groups found that a genetic variant in chromosome 8 near the MMP16 gene is consistently associated with a reduced risk of migraines (without aura). The MMP16 gene codes for an enzyme involved in the breakdown of the extracellular matrix and tissue remodeling.
Check your genetic data for rs10504861 (23andMe v4, v5; AncestryDNA):
NNMT gene: The nicotinamide-N-methyltransferase (NNMT) gene codes for an enzyme that transfers a methyl group from SAMe to nicotinamide. There are links between the variants of this gene and increases in homocysteine levels.
Check your genetic data for rs694539 (23andMe v4, v5; AncestryDNA):
MTHFR gene: Several studies have linked the MTHFR C677T variant to an increased risk of migraines, but not all of the studies agree. This one may be a mild increase in risk or perhaps for just certain population groups.[ref]
Check your genetic data for rs1801133 (23andMe v4, v5; AncestryDNA):
C7orf10 gene: codes for an enzyme involved in the production of glutarate from tryptophan (precursor for serotonin) and lysine.
Check your genetic data for rs4379368 (23andMe v4, v5; AncestryDNA):
SLC6A4 gene: codes for a serotonin transporter.
Check your genetic data for rs2066713 (23andMe v4,v5; AncestryDNA):
Note that there are a lot of other genetic variants in the serotonin transport and receptor genes that have been studied and found not to be involved in migraine risk.
AOC1 gene: codes for diamine oxidase, which breaks down histamine in the gut.
Check your genetic data for rs1049793 (23andme v4; AncestryDNA):
Check your genetic data for rs10156191 (23andMe v4; AncestryDNA):
TNF gene: tumor necrosis factor-alpha is one of the body’s main proinflammatory cytokines.
Check your genetic data for rs3093664 (23andMe v5; AncestryDNA):
Check your genetic data for rs1800750 (23andMe v4, v5; AncestryDNA):
Check your genetic data for rs1800629 (23andMe v4, v5; AncestryDNA):
IL1A gene: codes for interleukin-1 a which is part of the body’s inflammatory response
Check your genetic data for rs17561 (23andMe v4; AncestryDNA):
LRP1 gene: codes for an LDL cholesterol receptor. Migraine intensity and frequency are linked (in a small study) to cholesterol levels.[ref]
Check your genetic data for rs11172113 (23andMe v4, v5; AncestryDNA):
Below are some research-based options for either reducing the frequency or taking away the pain of migraines.
Tryptophan to increase serotonin, melatonin:
Serotonin is derived from the amino acid tryptophan. A study using a tryptophan-depletion diet showed that it worsened headaches and nausea in migraine sufferers. [ref]
Tryptophan is generally abundant in diets that contain enough protein. However, if you don’t eat a lot of protein, you may want to track the amount of tryptophan you eat and increase your intake of tryptophan-containing foods such as salmon, eggs, poultry, cheese, and spinach. [ref]
Alternatively, tryptophan is available as a powdered supplement. For it to cross the blood-brain barrier, tryptophan must be eaten with carbs and without other branch chain amino acids.
A couple of clinical trials have evaluated the efficacy of melatonin for preventing migraines. One study compared 3 mg melatonin to placebo and to amitriptyline (25 mg). Melatonin showed to be significantly better than placebo, but about the same as amitriptyline. Another clinical trial compared melatonin to placebo and to sodium valproate (prescription migraine med). Melatonin again was found to be superior to placebo and similar to sodium valproate in reducing migraines. It was also found to have fewer side effects than sodium valproate. [ref][ref]
Tryptophan also is the precursor amino acid for melatonin, so supplementing with tryptophan (with carbs, without other branch chain amino acids) has shown in studies to increase melatonin levels.
Blocking blue light (from TV, laptop, phone, bright overhead lights) at night also naturally increases your melatonin levels.
A placebo-controlled study investigated riboflavin for migraine prevention. The trial used 400 mg of riboflavin daily for 3 months. About 60% of the participants had reduced migraine frequency using riboflavin (compared to 15% placebo effect).[ref]
Riboflavin is also effective for lowering homocysteine and is important in the methylation cycle. So this may be a good ‘hack’ to try if you have either of the methylation cycle pathway variants listed above.
A study that looked back over medical records for a decade found that people taking aspirin regularly as a way to prevent migraines had fewer migraines.[ref] A meta-analysis of 8 different migraine prevention studies showed that aspirin statistically reduced migraine frequency at a dose of 325mg/day (a single regular strength aspirin).[ref] Of course, you would need to weigh the slight risk of increased bleeding with daily aspirin and talk with your doctor if you have questions on this.
Magnesium to prevent migraines:
The studies showing that people with migraines have lower magnesium levels combines well with a trial of magnesium for the prevention of migraines. So if you think you are low in magnesium, it may be a good supplement to try. [ref] [ref]
Foods high in magnesium include legumes, nuts, chocolate, and avocados. When it comes to supplemental magnesium, most of the migraine studies used magnesium oxide. You may find that other forms of magnesium, such as magnesium glycinate are better absorbed.
The ketogenic diet for migraines?
A ketogenic diet works for certain types of epilepsy, so it makes sense that it may help with migraines as well. And it might help, a little, maybe, for some people… or perhaps just cleaning up your diet, in general, would help.
A study of 96 overweight women with frequent migraines investigated whether a keto diet would help. Half of the women went on a keto diet for 6 months, and the other half went on a standard lower calorie diet. Both groups met with a nutritionist to plan out their diets. The women on the keto diet went from a baseline migraine frequency of 2.9 migraines per month to 2.2 migraines per month at month 6. The women on the standard diet went from 3.2 migraines/month to 2.4 migraines per month. [ref] You should go read the title and abstract of the study – there is a definite bias towards keto, and the results are made to sound like the keto diet worked great. But when you read through the results in the behind-a-paywall study, the standard diet group had just as much improvement over the course of the six months as the keto diet group. Perhaps a better conclusion is that meeting with a dietician helps to decrease migraine frequency a little bit.
If your genetic risk factors for migraines include the TNF-alpha variants, you may want to try decreasing TNF-alpha through some natural supplements.
Black seed oil – Nigella sativa – has shown to reduce TNF-alpha. It has also been shown in an animal study to reduce mast cell degranulation in the meninges. [ref][ref] You can get black seed oil at your local health food store or through Amazon.
Curcumin has shown to reduce inflammatory cytokines in the brain, including TNF-alpha. A clinical trial found that the combo of curcumin and CoQ10 was effective for reducing the number of migraines.[ref][ref] You can get curcumin in your diet by using the spice turmeric. Or it is available as a supplement on Amazon or at your local store- best absorbed with piperine included.
Circadian Rhythm and Migraines:
A study of over 2000 people with migraines found that early morning onset was quite frequent (40%). The study also found that people with chronic migraines were more tired after circadian disruption (staying up late) and less able to cope with being active during times when they weren’t normally active. [ref]
Blocking blue light at night, which causes an increase in melatonin, and sticking to a routine sleep schedule may help with migraine pain.
Exercise and Migraines:
While exercise is a known trigger for some people for migraines, it also raises BDNF levels. A study of exercise and migraines suggests that regular activity may help decrease the frequency of migraines in the long run. [ref]
A clinical trial of yoga found that it did reduce the frequency and intensity of migraines. [ref]
Meditation for Migraines:
A study of mindfulness meditation did not find that it statistically reduced migraines, although there was a trend towards fewer migraines/ month. [ref]
Heat, Cold, and Peppermint:
The TRPM8 cold/menthol receptor is active in the meningeal inflammation of a migraine. Studies show that cooling the head (ice pack) or peppermint oil (menthol) on the forehead is effective for migraine relief for some people. [ref]
Trigger Point Therapy:
Myofascial trigger points are associated with the pain of migraines. These trigger points are often found in the areas around the trigeminal nerve. Here is a good resource on the topic: Temporalis Trigger Points. Or if you like books: Trigger Point Therapy for Headaches and Migraines.
Serotonin is a neurotransmitter that is important in depression, sleep, and many other aspects of health. Learn how your genetic variants in the serotonin receptor genes impact their function.
High histamine levels can cause a variety of symptoms including migraines, hives, sinus drainage, and stomach problems.