pain

headaches & migraines

HTR2C

Serotonin Genetics in Migraine Development (HTR2C)

Written by Aleksa Ristic, MS (Pharmacy) on August 25th, 2020

Serotonin makes us happy, but can it trigger migraines? The HTR2C gene encodes a serotonin receptor with crucial roles in mental health, weight, and pain control — read on to learn about its role in migraine development.

The HTR2C Gene in Serotonin Functions

Serotonin is a crucial signaling molecule found throughout the brain and body. It is commonly known as the “happiness neurotransmitter” or the “happiness hormone” due to its prominent role in regulating mood and behavior [R, R].

The HTR2C gene encodes a serotonin receptor, 5-HT2C, present mostly in the brain. Changes in this receptor’s activity play a role in [R, R, R, R]:

Mental health
Weight and metabolism
Pain management

The serotonin receptor encoded by the HTR2C gene plays crucial roles in mental health, metabolism, and pain control.

Roles in Pain Control & Migraine

Impairments in serotonin signaling are among the culprits behind migraine development. According to most studies, people with migraines have lower serotonin levels during attack-free periods and higher levels during migraine attacks [R, R].

Sudden changes in serotonin levels impact brain circulation, which may trigger attacks [R].

The effects of serotonin also depend on the type of receptors being activated: activation of first-class receptors (5-HT1A and 5-HT1B) generally relieves pain, while activation of the second class (5-HT2A and 5-HT2C) may induce pain [R, R].

Based on the above findings, scientists have developed 5-HT2C inhibitors (such as pizotifen and methysergide) for migraine prevention [R].

Serotonin controls brain blood flow and pain perception. Activation of 5-HT2C receptors may trigger migraine attacks.

The Link Between HTR2C Variants and Migraine

Earlier genetic studies found no link between the SNPs in the HTR2C gene and migraine development [R, R].

However, a 2016 study of 274 Turkish subjects identified a significant effect of one variant: rs3813929. People carrying the “T” allele had 53% higher rates of migraine [R].

Another SNP, rs6318, may change the activity of 5-HT2C receptors and influence pain perception [R]. In a small trial of 34 people with nerve pain, those with the “C” allele had 15x higher odds of a positive response to drug treatment [R].

One Japanese study found a link between this variant and migraine [R], but other papers and one meta-analysis failed to confirm the association [R, R, R].

One HTR2C variant, rs3813929, may correlate with higher rates of migraine.

How It Works

A detailed analysis has revealed that rs3813929-T may increase HTR2C gene expression, leading to a higher density of 5-HT2C receptors [R].

As mentioned, activation of these receptors can contribute to migraine attacks due to brain blood flow changes. Additionally, 5-HT2C activation may inhibit dopamine and norepinephrine — neurotransmitters that also play a role in migraine [R].

The HTR2C gene is on the X chromosome. Men have only one X chromosome, so their genotypes contain only one allele. For this reason, HTR2C variants may affect men and women differently, but that doesn’t seem to be the case for migraine.

The “T” allele at rs3813929 may increase HTR2C gene expression, leading to a higher density of migraine-triggering 5-HT2C receptors.

Your HTR2C Results for Migraine

SNP Table

variant	genotype	frequency	risk allele
rs3813929

SNP Summary

Primary SNP:

HTR2C rs3813929

‘C’ = not associated with migraine
‘T’ = associated with higher rates of migraine

Population Frequency: Around 23% of European descendants carry the migraine-associated “T” allele. It’s slightly less common in the general population (19%).

Recommendations

Lifestyle

Relaxation & Massage

Stress is one of the most common migraine triggers [R, R]. It may be particularly harmful to people with the HTR2C variant, given its potential to activate 5-HT2C serotonin receptors [R, R].

According to a meta-analysis of seven studies, massage may be as effective as conventional drugs for migraine prevention. However, the authors warned that the quality of the studies was low. Massage seems to help by reducing psychological stress [R].

People with rs3813929-T should do their best to avoid psychological stress and practice massage and other relaxation techniques.

Acupuncture

Acupuncture is an alternative treatment approach with promising results in pain management. According to a review of 37 studies, the painkilling properties of acupuncture partly stem from its effects on serotonin receptors, including 5-HT2C [R].

In a study of 401 patients with chronic headache, mostly migraines, acupuncture provided significant pain relief and improved the quality of life [R].

A 2016 meta-analysis proclaimed acupuncture to be effective at reducing migraine frequency. It has shown a slightly higher efficacy and better safety profile compared to drug treatment [R].

Acupuncture may help reduce pain by balancing serotonin levels. According to current evidence, it may be a safer alternative to drugs for migraine prevention.

Supplements

Magnesium

Magnesium deficiency can impair serotonin signaling and blood flow in the brain, potentially contributing to migraines [R, R].

People with migraines and other pain disorders are often deficient in magnesium and may thus benefit from supplementation [R, R].

According to a review of clinical trials, magnesium supplementation is possibly effective for migraine prevention. The review authors suggested high-dose magnesium citrate (600 mg) to be the most effective [R].

Magnesium deficiency may worsen the impact of HTR2C variants and trigger migraines. High-dose magnesium supplementation is possibly effective for migraine prevention.

Feverfew

Sometimes called medieval aspirin, feverfew has been traditionally used for fever, rheumatism, arthritis, toothache, psoriasis, headaches, nausea, migraine, and more [R].

An active compound in feverfew reduces serotonin release and blocks serotonin receptors, which may be beneficial during a migraine attack — especially for people with rs3813929-T [R, R].

In three clinical trials of almost 400 people, feverfew extract reduced the number and severity of migraine attacks [R, R, R]. In other studies, it has shown promising results in combination with:

Acupuncture [R]
Ginger [R, R]
Willow extract [R]

However, feverfew extract did not improve migraine symptoms or prevent attacks in two trials of 50 subjects each [R, R].

Feverfew extract may balance serotonin levels and help reduce the number and severity of migraine attacks. Some studies failed to confirm its effectiveness.

Curcumin + Fish Oil

According to limited animal research, curcumin and omega-3 fatty acids from fish oil may reduce the activity of 5-HT2C receptors [R, R].

Interestingly, a combination of these two significantly reduced the frequency and severity of migraine attacks in a trial of 74 patients [R]. A combination of curcumin with coenzyme Q10 helped prevent migraines in 100 young adults [R].

Despite the promising results, stronger clinical evidence is needed to support the effectiveness of curcumin and fish oil for migraine prevention.

A combination of curcumin and fish oil may reduce the activity of 5-HT2C receptors and help prevent migraine, but the evidence is scarce.

Aleksa Ristic

MS (Pharmacy)

Aleksa received his MS in Pharmacy from the University of Belgrade, his master thesis focusing on protein sources in plant-based diets.

Aleksa is passionate about herbal pharmacy, nutrition, and functional medicine. He found a way to merge his two biggest passions—writing and health—and use them for noble purposes. His mission is to bridge the gap between science and everyday life, helping readers improve their health and feel better.

Disclaimer

The information on this website has not been evaluated by the Food & Drug Administration or any other official medical body. This information is presented for educational purposes only, and may not be used to diagnose or treat any illness or disease.

Also keep in mind that the “Risk Score” presented in this post is based only on a select number of SNPs, and therefore only represents a small portion of your total risk as an individual. Furthermore, these analyses are based primarily on associational studies, which do not necessarily imply causation. Finally, many other (non-genetic) factors can also play a significant role in the development of a disease or health condition — therefore, carrying any of the risk-associated genotypes discussed in this post does not necessarily mean you are at increased risk of developing a major health condition.

Always consult your doctor before acting on any information or recommendations discussed in this post — especially if you are pregnant, nursing, taking medication, or have been officially diagnosed with a medical condition.

More pain blogs

Can This Gene Worsen GERD Pain? (GNB3) Can This Gene Make You Prone to Chronic Pain (COMT)? The Heat Receptor’s Role in Pain Perception (TRPV1) Can This Gene Influence Your Sensitivity To Pain (COMT)? A Neurological Connection Between Stress and Migraines? (MEF2D) Can This Gene Influence Your Susceptibility To Headaches And Migraines? (BDNF) Is Excess Histamine Causing Your Migraines? (DAO) Can Too Much Nitric Oxide Trigger Migraines? (NOS2, NOS3)

More headaches & migraines blogs

Are You Genetically Vulnerable to High Brain Histamine, Migraines, or ADHD? (HNMT) A Neurological Connection Between Stress and Migraines? (MEF2D) Is Excess Histamine Causing Your Migraines? (DAO) Can This Folate-Metabolizing Gene Increase Your Risk Of Headaches And Migraines? (MTHFR)

Content

The HTR2C Gene in Serotonin Functions The Link Between HTR2C Variants and Migraine Your HTR2C Results for Migraine

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