SIBO stands for small intestinal bacterial overgrowth – a condition in which bacteria overgrow within the small intestine, where they normally don’t exist in large numbers.
When bacteria overpopulate the small intestine, they ferment carbohydrates from the food we eat, causing uncomfortable symptoms.
Because the symptoms of SIBO are so general (abdominal pain, diarrhea and/or constipation, bloating), it can be difficult to correctly diagnose without using tests.
The most common way to test for SIBO is through breath testing, but there are several different types.
This article will explain the science behind testing for SIBO, the pros and cons of each method, and which test is best.
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What is SIBO?
Typically, we think of having a lot of gut bacteria as a good thing, and it usually is!
The right balance of gut bacteria provides a long list of benefits – it aids in digestion, nutrient production, and immunity, to name a few (1).
But sometimes there are TOO MANY bacteria hanging out in places they don’t belong, like the small intestine. This is called small intestinal bacterial overgrowth, or SIBO.
In a healthy gut, bacteria are prevented from entering and thriving in the small intestine through several defense mechanisms (2, 3):
Hydrochloric acid in the stomach kills bacteria that we’ve ingested.
Pancreatic enzymes and bile destroy bacteria that have survived the stomach.
The cells that line the small intestine (and probiotics) release antimicrobial peptides that fight infection.
Intestinal mucus traps bacteria while intestinal contractions (peristalsis) transport them out of the small intestine.
Immune cells attack pathogenic bacteria.
The ileocecal valve (between the small intestine and colon) prevents colonic bacteria from moving backward into the small intestine.
SIBO occurs when one or more of these defense mechanisms fail, and bacteria begin to colonize the small intestine in large numbers.
When bacteria are in the small intestine, they digest carbohydrates from our food, producing large amounts of gas that can cause VERY unpleasant symptoms.
Symptoms can vary, but these are some of the most common (2, 3):
Abdominal pain or cramping
Belching
Bloating (often extreme)
Brain fog
Depression and anxiety
Diarrhea, constipation, or both
Fat malabsorption
Fatigue
Flatulence
Food sensitivities or intolerances
Gastroparesis
Heartburn
Nausea
Nutrient deficiencies
Weight loss
Unfortunately, SIBO can’t be diagnosed by symptoms alone, because the symptoms are too general.
Instead, diagnostic tests should be used to rule in or rule out SIBO.
Who Should Be Tested for SIBO?
Anyone who has persistent unexplained gastrointestinal symptoms like bloating, gas, and diarrhea and has not had success with medical or dietary interventions should consider being tested for SIBO.
The best candidates for testing are those who, in addition to displaying the symptoms listed previously, have one or more of the following conditions linked with SIBO (2, 4).
Of course, SIBO is not present in everyone who has one of these conditions, and we still don’t know whether it is a cause, consequence, or unrelated co-occurring phenomenon.
Since testing can be expensive out of pocket, some practitioners choose to treat suspected SIBO with antibiotics (prescription or herbal), based on symptoms alone.
Ultimately, it’s up to the practitioner to screen patients and determine who might benefit most from SIBO testing.
What Types of SIBO Tests Are Available?
To diagnose SIBO, we have to be able to measure whether there are large amounts of bacteria present in the small intestine.
Currently, this can be done either by performing a small intestine aspirate and culture or breath testing.
1. Small Intestine Aspirate and Culture
A “small intestine aspirate and culture” is considered the gold standard for diagnosing SIBO (2, 4).
A sample of fluid from the small intestine (usually the duodenum or jejunum) is collected using a flexible tube called an endoscope (41).
To get a more reliable result, samples are taken from multiple sites throughout the small intestine, because the bacteria can vary depending on the location (4).
The samples are then taken to a microbiology lab where they can be cultured and the bacteria can be quantified.
For a diagnosis of SIBO, there must be greater than 100,000 CFU (colony-forming units) per milliliter of sample fluid (although some researchers prefer a much lower cut-off of 1,000 CFU per mL) (4, 42).
Unfortunately, experts disagree about the validity of using these cultures to diagnose SIBO because they have several issues that may interfere with the results (43).
For example, samples can be contaminated by bacteria from the mouth or stomach as the endoscope passes through the GI tract (42).
In addition, some species of bacteria found in the small intestine can’t actually be grown outside the gut on a culture medium, so the results may be falsely low or skewed (44).
Despite these issues, small intestine aspiration and culture is still considered the gold standard for SIBO diagnosis.
However, it isn’t commonly used in clinical settings because it is a very expensive and invasive procedure. Instead, most practitioners prefer to use non-invasive breath tests.
2. SIBO Breath Testing
Breath testing is based on the fact that gut bacteria produce gases when they ferment carbohydrates.
The main gas produced is hydrogen (H2), but some gut microbes can convert hydrogen into methane (CH4), an odorless gas, or hydrogen sulfide (H2S), which smells like rotten eggs (45, 46).
About 80% of gases formed in the gut are expelled when we pass gas. The other 20% diffuse into the bloodstream and travel to the lungs, where they are exhaled and can be measured in our breath (2).
Any hydrogen, methane, or hydrogen sulfide gas found in the breath can be assumed to be a product of bacterial or archaeal fermentation because there are no other sources of these gases in the human body (45).
Breath levels of these gases serve as INDIRECT measurements of gut microbes because they only estimate the number of bacteria based on the amount of gas produced. They do not measure bacteria levels directly (47).
Some tests only measure hydrogen, but it’s better to measure BOTH hydrogen and methane since hydrogen can be converted into methane by archaea in the gut (42, 48, 49).
It would be ideal to measure hydrogen sulfide levels as well, but as of early 2019, no tests are commercially available (50).
In general, methane-dominant SIBO is linked to constipation, while hydrogen and hydrogen sulfide-dominant SIBO are linked to diarrhea.
Understanding which type of bacteria (methane, hydrogen, and/or hydrogen-sulfide producing) are colonizing the small intestine can guide treatment recommendations since different antimicrobials are better at eradicating each type.
For diagnosing SIBO, breath tests are recommended because they are non-invasive, inexpensive, and simple to perform (42, 45).
How does SIBO breath testing work?
During a breath test, you will be asked to first provide a breath sample to establish your baseline breath hydrogen levels.
Then, you will consume a liquid carbohydrate substrate (either glucose, lactulose, or both) and continue to provide breath samples every 15-20 minutes for 2-3 hours (42).
The breath samples are later sent to a lab where the gases can be measured and interpreted.
Is breath testing reliable?
Of course, there are some issues that may limit the usefulness of breath testing.
The biggest problem with breath testing is that it’s not standardized, so results may differ based on how the test was performed and interpreted by your provider (47).
New data also suggests that breath testing does not correlate well with the supposed “gold standard” jejunal aspirate testing (51).
Despite these issues, breath testing is still the best clinical tool available for diagnosing SIBO at the moment (42).
Which SIBO Breath Test is Best?
All breath tests measure hydrogen (and sometimes methane), but different carbohydrate substrates can be used in the testing beverage.
The two main carbohydrates used are glucose and lactulose (47).
Other substrates, like fructose, lactose, and sorbitol are available but used to diagnose carbohydrate malabsorption, not SIBO (47).
1. Glucose Breath Test
How does it work?
Glucose is a monosaccharide (the simplest form of carbohydrate) that is primarily absorbed in the proximal (first section) of the small intestine (4).
This means that glucose typically does not reach the colon where bacteria are, and thus, does not lead to the production of hydrogen or methane gas.
However, in someone with SIBO, there are bacteria within the small intestine (where they really shouldn’t be in) that WILL ferment the glucose and produce gas (52).
Thus, if breath hydrogen or methane levels increase significantly after consuming glucose, then SIBO is likely present (47).
Pros of glucose breath testing:
The main benefit of using glucose is that it is less likely to produce false positive results (47, 53, 54).
Since glucose is usually completely absorbed in the small intestine, it is less likely that fermentation from bacteria in the colon will interfere with results (47).
If a large increase in gas production occurs during the testing period, you can be fairly confident that there is SIBO.
Cons of glucose breath testing:
However, there is a potential downside to using glucose.
Since glucose is rapidly absorbed in the small intestine, it may not be able to identify SIBO that occurs in the distal (last section) of the small intestine (47, 54).
People with this type of overgrowth may show false-negative results on a glucose breath test because the sugar never reaches the bacteria for fermentation.
While this is the general consensus amongst most healthcare practitioners, new data suggests that glucose actually can reach the colon in some people.
One study traced the path of glucose through the intestines while simultaneously doing a breath test, and found that it WAS able to reach the colon and be fermented by colonic bacteria in 13% of the study population (55).
These participants had glucose breath tests that looked positive for SIBO, but were actually indicative of normal colonic fermentation.
Because of these findings, some researchers argue that glucose breath tests may be better indicators of glucose malabsorption than actual SIBO (51).
Additionally, there is some evidence from animal studies that diet may impact how well the gut absorbs glucose. Those who consume a lot of glucose are better able to absorb it than those who eat low-carb, which could also impact results (56, 57, 58).
Still, glucose is preferred by many experts (4, 59, 60).
Overall, the diagnostic accuracy of the glucose breath test is estimated to be around 72% (4).
2. Lactulose Breath Test
How does it work?
Lactulose is a disaccharide (consisting of fructose and galactose) that is poorly absorbed by the intestines (47).
When consumed by healthy individuals, lactulose makes its way to the large intestine, where it is metabolized by colonic bacteria and hydrogen and methane gases are produced (4).
In those with SIBO, however, the large number of bacteria in the small intestine begin to metabolize lactulose before it reaches the large intestine, causing an early increase in gas production (47).
Any remaining lactulose then travels to the large intestine, where it is metabolized by colonic bacteria, causing a second increase in gas production (47).
Pros of lactulose breath testing:
The benefit of using lactulose is that it travels through the entire small intestine, so you can get a better idea of what’s happening in the ileum (the final section of the small intestine), where SIBO sometimes occurs (61).
Cons of lactulose breath testing:
The downside to using lactulose is that it’s especially prone to false positive results (47, 54).
If intestinal transit time (the time it takes for food to move through the intestines) is faster than average, lactulose might reach the colon too soon.
When this happens, the gas production that occurs looks very similar to a SIBO positive test result.
Those who experience frequent diarrhea typically have a faster transit time, so lactulose breath tests aren’t as reliable for these patients (47).
Also, lactulose itself has been shown to reduce transit time and has been used as a laxative (62, 63).
Additionally, concerns have been raised about the reproducibility of lactulose test results.
One study found no significant correlation between test results conducted on the same people just two weeks apart (64).
Overall, the diagnostic accuracy of the lactulose breath test is estimated to be around 55% (4).
3. Doing Both Breath Tests
Since both glucose and lactulose breath tests have limitations, some practitioners choose to do both tests in order to aid in making a diagnosis.
Labs that offer both glucose and lactulose testing kits typically offer a discount when purchased together.
Pros of Glucose + Lactulose Breath Testing:
By using both substrates, it may be easier to detect SIBO located at either end of the small intestine, potentially reducing the likelihood of false-negative test results.
Cons of Glucose + Lactulose Breath Testing:
Ordering both tests is more expensive than using a single-substrate test and is not guaranteed to provide more clarity.
Most practitioners prefer one test over the other (usually glucose) and only order a single substrate test kit.
Where to Get Tested
Physicians’ orders are required to obtain a lactulose breath test, but glucose breath tests can be ordered directly, without a physician.
Laboratories like QuinTron and Aerodiagnostics offer glucose or lactulose breath testing, while BioHealth offers dual glucose and lactulose kits.
Make sure that whatever testing company you choose reports BOTH hydrogen and methane levels for the most accurate results.
How to Interpret Test Results
Unfortunately, there are no universally accepted standards for interpreting SIBO breath tests (4, 42, 47).
Interpretation can be difficult, so we’ve provided a few examples of what positive and negative test results may look like for both glucose and lactulose breath tests.
It’s important to note that these are just examples and results can vary quite a bit, so it’s best to follow interpretation guidelines and consult with experienced practitioners.
General Guidelines for Interpretation
The first step in interpreting a breath test is to check baseline hydrogen and methane levels.
A baseline hydrogen level greater than 16 ppm is considered high, which may be a sign of hydrogen-dominant SIBO, but could also be a sign of improper test prep (59, 65).
A baseline methane level greater than 10 ppm is suggestive of methane-dominant SIBO (42).
The next step is to look at the pattern of hydrogen and methane levels over the two or three hour breath collection period.
When hydrogen levels rise from baseline by more than 20 ppm within 90 minutes, this is typically considered a positive test result (42).
If methane levels are greater than or equal to 10 ppm at any time, including at baseline, it is considered a positive test result (42).
However, it should be noted that interpretation of methane levels is not very well studied and consensus is lacking (42).
Sometimes, hydrogen and methane levels remain low or nonexistent throughout the duration of the test, but it’s unclear why this happens in some people.
If this occurs in someone who displays SIBO-like symptoms, they may have an overgrowth of bacteria that convert hydrogen to hydrogen sulfide, which is not yet detectable on commercially-available breath tests (66).
Sample SIBO Test Results
1) Glucose Breath Test: Possible Negative for SIBO
If someone without SIBO takes a glucose breath test, it should look like this (59, 67):
As you can see, hydrogen does not increase more than <20 ppm after the glucose is consumed, which usually means there is no bacterial overgrowth in the proximal small intestine (47).
However, if the person has symptoms (especially diarrhea and rotten egg smelling gas), they may have an overgrowth of hydrogen sulfide-producing bacteria that is not detectable on current breath tests.
2) Glucose Breath Test: Positive for SIBO
If someone with proximal SIBO takes a glucose breath test, it might look similar to this (59):
Here, you can see that hydrogen increases to form a single peak after the glucose is ingested, showing that bacteria in the small intestine are likely metabolizing it (4, 47, 67).
Because the rise in hydrogen is greater than 20 ppm within the first 90 minutes, this is considered a positive test result (42).
However, if someone is a methane-producer, a positive result might look like this instead (67):
You see methane levels greater than 10 ppm throughout the test, so this is considered a positive result as well (42).
Note that methane production reduces hydrogen levels in the gut, so low hydrogen levels on a methane-positive test does not exclude the possibility of hydrogen-producing bacteria in the small intestine.
No firm guidelines exist for the interpretation of methane levels, so most practitioners follow the generic recommendation that anything above 10 ppm is positive.
3) Lactulose Breath Test: Negative for SIBO
If someone without SIBO takes a lactulose breath test, it should look like this (68):
Because this person’s gut bacteria are residing where they should (in the colon), you only see an increase in hydrogen once, when the lactulose reaches the colon and is metabolized.
4) Lactulose Breath Test: Positive for SIBO
If someone with SIBO takes a lactulose breath test, it might look a little like this (45, 68):
In this case, you see two peaks: one when the lactulose reaches the small intestine and begins to be metabolized by bacteria there, and another when the remaining lactulose reaches the large intestine and is metabolized by colonic bacteria (4).
The rise in hydrogen is greater than 20 ppm within the first 90 minutes, so this is considered a positive test result (42).
However, often a positive SIBO lactulose breath test won’t have a double-peak and will look like this instead (68):
Here, you can see that lactulose quickly begins to be metabolized by bacteria in the small intestine and hydrogen levels continue to rise throughout the test.
In the past, many experts agreed that two peaks were required for a lactulose breath test to be positive for SIBO (42).
However, this single peak presentation is actually more common, and newer recommendations suggest that two peaks are no longer required for the diagnosis of SIBO (42, 68).
Issues with SIBO Breath Testing
Although breath testing is the current preferred diagnostic tool for SIBO, there are several factors that may alter test results.
Fortunately, many of these can be minimized by following a few simple guidelines to prepare for the test.
1. Antibiotic Interference
Antibiotics can interfere with breath testing by killing bacteria and therefore depressing hydrogen and methane production (69).
Some antibiotics are more effective at killing gut bacteria than others, so the effects on hydrogen or methane production will vary (70).
Because it’s still unclear exactly to what degree antibiotics affect breath test results, it’s best to avoid them entirely before taking the test (42, 71).
Antibiotics are often used to treat SIBO, so sometimes a breath test is performed again immediately after finishing treatment to confirm that it was successful (42, 70, 71).
To improve test reliability: Wait at least 4 weeks after finishing any antimicrobials (including herbal treatments) before testing for SIBO (4).
2. Laxative Interference
When laxatives or bowel cleanses are used, large numbers of gut bacteria are eliminated through diarrhea (72).
Because there are fewer bacteria in the gut available to produce gas, excretion in the breath is reduced (4).
In fact, breath hydrogen tests have been used in research settings to evaluate the effectiveness of different laxatives used for colonoscopy preparation. Low breath hydrogen test results show that the preparation was adequate (73).
Unfortunately, taking any type of laxative before breath testing may cause a false negative result (4).
Before testing, patients should be asked if they’ve taken any laxatives, including supplements that have a laxative effect, like magnesium oxide.
Sometimes patients don’t realize that they have been given laxatives for a procedure, so it is a good idea to ask if they’ve had a colonoscopy or barium enema recently as well (74, 75).
To improve test reliability: Wait at least 1 week (but preferably 4 weeks) after using any laxatives or other colon-cleansing solutions before breath testing (4, 42). However, this may not be practical for patients with severe constipation or gastroparesis.
3. Prebiotic and Probiotic Effects
Prebiotics and probiotics both have the potential to interfere with breath test results.
Prebiotics are carbohydrates that humans cannot digest, but gut bacteria can. They remain in the gut until they reach the colon, where the bacteria that live there can consume them as food.
Consuming prebiotics (via supplements or food) may promote the growth of any bacteria currently living in the small intestine, increasing gas production and making SIBO symptoms worse.
It is generally advised to avoid prebiotic-rich foods or supplements prior to testing for SIBO (4).
Probiotics, on the other hand, are living bacteria that can be consumed via fermented foods or supplements.
They can alter the composition of gut bacteria, which in turn, may change the amount of hydrogen or methane produced (4).
However, actual scientific studies are inconclusive as to whether probiotics actually alter breath test results (76, 77).
Align probiotic has been shown to increase methane gas levels in some (but not all) healthy people undergoing a lactulose breath test, without causing symptoms (78).
This suggests that the probiotics caused a transient increase in bacteria in the small intestine as they moved through the digestive tract, but did cause a true overgrowth.
To improve test reliability: To be on the safe side, it might be worth discontinuing any prebiotic or probiotic supplements for up to 4 weeks before taking the test, but it’s unclear if this is absolutely necessary (4, 42).
4. Effects of fermentable carbohydrates (FODMAPs)
As discussed earlier, breath testing depends on the ability of bacteria in the small intestine to ferment a set dose of carbohydrates.
If any other carbohydrates are available for the bacteria to ferment, excess hydrogen will be produced, and the test results won’t be reliable (42).
Fermentable carbohydrates (also known as FODMAPs) include fermentable oligosaccharides (fructans and GOS), disaccharides (lactose), monosaccharides (fructose), and polyols (sugar alcohols) (79).
They can be found in a variety of whole grains, legumes, nuts, seeds, fruit, vegetables, dairy, and artificial sweeteners (80).
Some practitioners disagree about which foods are acceptable to consume the day before the test, but most recommend following a low-fiber diet with foods such as: (81, 82, 83, 84)
Baked or broiled chicken or fish
Eggs
Plain steamed white rice
Limited fat and oils (no butter or margarine)
Salt and pepper (no other herbs or spices)
Non-flavored black coffee or black tea (no sweeteners of any kind)
Plain water
Certain testing centers also allow white potatoes and white bread, but these may cause greater hydrogen excretion than plain white rice, so it’s probably best to avoid them (85).
For best results, it’s also recommended to complete an overnight fast from ALL food and drink (except for water) before the test (42).
To improve test reliability: Consume a diet low in fermentable carbohydrates the day before the test. Fast from all food and drink (except for water) 8-12 hours before the test (42).
5. Cigarette smoking interference
Several gases, including hydrogen and methane, are produced during the combustion of tobacco (4).
Increased hydrogen or methane from smoking could interfere with the test and potentially cause a false-positive test result.
It’s not clear how long it takes for hydrogen levels to return to normal after smoking, but one study found that it took only 15 minutes for hydrogen levels to normalize in young, healthy volunteers (86).
However, hydrogen levels may remain high for longer periods of time in individuals who have chronic lung disease, because normal lung function is impaired (87).
To improve test reliability: At the very least, smoking should be avoided for 15 minutes prior to taking a breath test, but avoiding it entirely on the day of the test is better (4, 42).
6. Impact of oral hygiene products
Over 700 species of bacteria have been detected in the oral cavity, many of which produce gases, such as hydrogen, when they ferment sugar from the food we eat (88, 89).
During a breath hydrogen test, these bacteria will produce some hydrogen gas from the glucose or lactulose substrate in the mouth (89)
Mouthwash kills these bacteria and may prevent interfering hydrogen excretion, reducing the risk of a false positive result.
However, some labs ask that you don’t use mouthwash before the test, so it is best to follow their guidelines.
To improve test reliability: Follow the lab instructions to know whether or not to use mouthwash before the test (4).
7. Impact of physical activity
Studies have shown that hydrogen excretion can vary depending on your breathing rate (90).
Hyperventilation (rapid breathing), such as occurs during exercise, leads to decreased hydrogen levels in your breath, which could cause a false negative test result during a breath hydrogen test (91).
To improve test reliability: Do not perform any activity that increases your breathing rate, such as exercise, right before or during the test (4, 42).
Future Directions for SIBO Testing
There have been recent advances in SIBO testing methods and exciting developments are on the horizon.
1. Testing for Hydrogen Sulfide SIBO
As mentioned above, a new breath testing device that is capable of measuring hydrogen, methane, and hydrogen sulfide is slated to hit the market within the next year or so.
High tech devices used in research studies suggest that hydrogen sulfide levels above 1.2 ppm likely indicate the presence of SIBO (92).
2. Antibody Testing
In some cases, food poisoning may trigger an autoimmune attack on the migrating motor complex (MMC) that messes up gut motility, increasing the risk of SIBO.
Researchers believe this occurs when pathogenic bacteria secrete a toxin known as CDT-B.
CDT-B is very similar in structure to a protein called vinculin, which is involved in coordinating peristalsis waves in the gut.
This similarity can trigger the immune system to accidentally attack vinculin, disrupting the migrating motor complex (the electrical signals that control gut peristalsis between meals) (93, 94).
There are tests available to check if the body is creating antibodies to CDT-B and vinculin. If it is, antimicrobial treatment and a prokinetic are often used to eliminate the infection and restore proper gut motility.
However, food poisoning (and a disordered MMC) is just one possible cause of SIBO, so a negative antibody test does not rule out SIBO caused by other factors.
Additionally, a positive test does not guarantee the presence of SIBO, since it is possible for a disordered MMC to trigger IBS without an overgrowth of bacteria in the small intestine.
This test is most helpful in determining whether disordered MMC may be a root cause of a person’s SIBO so it can be addressed accordingly, not for diagnosing SIBO itself.
3. Capsule Based Testing
One of the most exciting innovations in the SIBO testing space is the development of a smart capsule that can be swallowed and detect hydrogen levels every 5 minutes as it travels throughout the entire GI tract.
What’s even cooler, is that the data is automatically sent to an app on your phone so you can see what’s happening in real time!
This technology is currently being piloted with promising results and is slated to hit the market in the next 2 to 3 years (95).
4. Microbial Sequencing
Ideally, we would be able to assess both the amount and type of bacteria present in the small intestine.
This can be done by taking a sample of the fluid in the small intestines and performing PCR (polymerase chain reaction) analysis to detect microbes in the gut based on their DNA (96).
This methodology allows us to identify microbes that don’t grow well on a typical growth medium and wouldn’t show up in the “gold standard” aspirate and culture method.
PCR analysis of small intestinal aspirates is not routinely done at the present time, but holds a lot of promise for furthering our understanding of the gut microbiome.
Final Thoughts
Breath tests are currently the simplest, most convenient method for diagnosing SIBO.
Tests that use glucose as a substrate have the highest diagnostic accuracy but may be unable to detect SIBO that occurs in the distal small intestine.
Lactulose, on the other hand, can detect SIBO in any part of the small intestine but has a lower diagnostic accuracy and is more prone to false positive results.
Choosing a test that combines both glucose and lactulose is an excellent way to gain a better understanding of the patient’s clinical picture and can make interpretation easier.
To improve the reliability of breath tests, it’s necessary to follow test preparation guidelines, which includes fasting 8-12 hours prior to the test.
Because of the limitations of breath testing, some practitioners may choose to do a “therapeutic trial,” which involves treating for SIBO even without a positive test result, if the patient has a predisposing condition and is presenting with many of the symptoms.
Navigating this can be tricky, and ultimately, only a physician is qualified to make a definitive diagnosis of SIBO.
Amy is a registered dietitian nutritionist and certified LEAP therapist. Her passion is finding ways to communicate nutrition research in an interesting and easy-to-understand way. She has an undying love for food, especially homemade almond butter, steamed asparagus, and fresh summer cherries.
The terms folate and folic acid are often used interchangeably, but don’t be fooled – they’re not the same!
Folate is the natural form of vitamin B9 found in foods, while folic acid is the synthetic form added to supplements and fortified or enriched foods.
The chemical structures of folate and folic acid are similar, but not identical, so there are differences in how they’re processed and used by our bodies.
In this article, we’ll discuss the structural and functional differences between folate and folic acid and which one is a better supplement choice for most people.
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Folate: The Natural Form of Vitamin B9
Sometimes, researchers use the term “folate” to refer to all forms of vitamin B9 (including folic acid).
However, for the purposes of this article, we will use “folate” to describe the form that is found naturally in food.
Natural Folate Metabolism
Natural folate exists in many different forms, but polyglutamates (folate molecules with a tail of several glutamates) are the most common (1).
In order to be absorbed, the glutamate tail must first be removed by enzymes located on the lining of the small intestine (also known as the brush border) (2).
After being absorbed into the cells of the small intestine, these folate molecules are converted to the active form of folate known as L-5-methyltetrahydrofolate (L-5-MTHF) or L-methylfolate:
After this process is complete, activated folate (L-5-MTHF) is released into the bloodstream where it can be distributed throughout the body, taken up by cells, and either metabolized or converted back to the polyglutamate form for storage.
The intestines are very efficient at converting natural food forms of folate into the active form, even at high doses, so there is no tolerable upper limit for natural food folate.
Folate’s Role in Health
The primary role of folate is to participate in one-carbon metabolism (3).
One-carbon metabolism is the transfer of one-carbon units, such as methyl groups (CH3), between molecules (4).
This process is necessary because one-carbon groups are too unstable by themselves and must constantly be attached to something.
One-carbon transfers are required for many metabolic processes, including amino acid metabolism, DNA synthesis, and cell division.
Here’s an overview of how the process works:
There are a few important steps to note:
1. Conversion of homocysteine to methionine.
First, you can see that folate (L-5-MTHF) donates a methyl group to homocysteine (a byproduct of protein metabolism) in order to form methionine (an amino acid that is required for growth and tissue repair) (4, 5).
If folate is not available to provide a methyl group for this conversion (or if there is not enough vitamin B12 as a cofactor), homocysteine can build up in the blood (6).
Elevated levels of homocysteine have been associated with increased risk of several chronic conditions, including heart disease and Alzheimer’s disease (7, 8).
However, interventions focused on lowering homocysteine levels have not consistently reduced the risk of these conditions, so it may be more of a risk marker than a direct cause of disease. More research is needed (9).
2. Formation of SAM and methylation reactions.
Second, methionine goes on to participate in methylation reactions, which are especially important for DNA synthesis and the regulation of gene expression (10).
Once methionine has been formed, it can be converted to S-adenosylmethionine (SAM), which is one of the body’s most important methylators.
SAM transfers a methyl group (CH3) to other molecules, like DNA or proteins, and participates in over 100 methylation reactions (3, 11).
Without enough folate to spur the one-carbon metabolism cycle, methylation reactions may be impaired throughout the body.
3. Recycling L-5-MTHF back to THF & nucleotide synthesis.
Finally, after L-MTHF donates a methyl group to homocysteine, it is converted back to THF.
From there, it can be converted again to 5,10-MTHF, the form of folate used to make nucleotides (the building blocks of DNA and RNA).
Thus, it is clear that folate is involved in many many important processes in the body.
Folate Deficiency
In the United States, folate deficiency is rare (<2%), but still possible (12).
Deficiency is most often caused by low-intake of folate-containing foods, but can sometimes be caused by malabsorption issues or medications as well (2, 13).
The most common sign that you might have a folate deficiency is megaloblastic anemia (although, megaloblastic anemia can also be caused by vitamin B12 deficiency, so it is important to rule that out too) (14).
Megaloblastic anemia is a condition in which red blood cells (RBCs) are too large (macrocytic), immature (megaloblastic), and low in number.
This occurs because a lack of folate impairs DNA synthesis and disrupts cell division within the bone marrow (where blood cells are formed). This leads to RBCs that aren’t formed properly or rapidly enough.
These megaloblastic RBCs result in blood that has a decreased oxygen-carrying capacity, which translates to symptoms like fatigue and shortness of breath (15).
Anemia isn’t the only consequence of folate deficiency – many other conditions have been linked with inadequate folate consumption, including the following:
Thankfully, folate deficiency can generally be avoided by consuming a diet rich in folate or by taking supplements as needed.
Want to learn more about folate and methods for testing for deficiency? Check out our membership site, The Functional Nutrition Library!
Foods High in Folate
Folate is found in many whole foods, especially poultry liver, legumes, and green vegetables.
Here are some of the foods with the highest amounts of folate (33):
Turkey liver: 587 mcg (146% DV) per cooked 3 ounces
Chicken liver: 491 mcg (122% DV) per cooked 3 ounces
Edamame: 482 mcg (121% DV) per cooked cup
Chickpea flour: 392 mcg (98% DV) per cup
Cranberry beans: 366 mcg (92% DV) per cooked cup
Roasted soybeans: 363 mcg (90% DV) per cup
Lentils: 358 mcg (90% DV) per cooked cup
Black-eyed peas: 358 mcg (90% DV) per cooked cup
Wheat germ: 323 mcg (80% DV) per cup
Mung beans: 321 mcg (80% DV) per cooked cup
Sunflower seeds: 319 (79% DV) per cup
Adzuki beans:317 mcg (79% DV) per cooked cup
Pinto beans: 294 mcg (74% DV) per cooked cup
Pink beans: 284 mcg (71% DV) per cooked cup
Chickpeas: 282 mcg (71% DV) per cooked cup
Baby lima beans: 273 mcg (68%) per cooked cup
Spinach: 263 mcg (66% DV) per cooked cup
Black beans: 256 mcg (64% DV) per cooked cup
Navy beans: 255 mcg (64% DV) per cooked cup
Yardlong beans: 250 mcg (62% DV) per cooked cup
White beans: 245 mcg (61% DV) per cooked cup
Asparagus:243 mcg (60% DV) per cooked cup
Mustard spinach:238 mcg (59% DV) per raw cup
Kidney beans: 230 mcg (58% DV) per cooked cup
Conch: 227 mc (56% DV) per cooked cup
Beef liver:221 mcg (55% DV) per cooked 3 ounces
Avocado:205 mcg (51% DV) per cup
Artichokes:200 mcg (50% DV) per cooked cup
Pigeon peas:186 mcg (46% DV) per cooked cup
Peanuts:185 mcg (46% DV) per roasted cup
Okra:184 mcg (46% DV) per cooked cup
Fava beans:177 mcg (44% DV) per cooked cup
Turnip greens: 170 mcg (42% DV) per cooked cup
Broccoli: 168 mcg (42% DV) per cooked cup
Brussels sprouts:157 mcg (39% DV) per cooked cup
Beets: 136 mcg (34% DV) per cooked cup
Hazelnuts: 130 mcg (32% DV) per cup
Collard greens:129 mcg (32% DV) per cooked cup
Split peas:127 mcg (31% DV) per cooked cup
Chayote:123 mcg (30% DV) per raw cup
Escarole:117 mcg (29% DV) per cooked cup
Walnuts:115 mcg (28% DV) per cup
White potato:114 mcg (28% DV) per large baked with skin
Mustard greens:105 mcg (26% DV) per cooked cup
Broccoli: 103 mcg (25% DV) per cooked cup
Corn: 103 mcg (25% DV) per canned cup
Green peas:101 mcg (25% DV) per cooked cup
Cashews:95 mcg (23% DV) per cup
Parsley:91 mcg (22% DV) per cup
Parsnips:90 mcg (22% DV) per cooked cup
Durian:87 mcg (21% DV) per cup
Chinese broccoli:87 mcg (21% DV) per cooked cup
Guava:81 mcg (20% DV) per cup
Red potatoes:81 mcg (20% DV) per large baked with skin
However, the folate levels of various foods can be affected by preparation methods.
For example, boiling folate-rich green vegetables can leech up to 49% of the folate into the cooking water, while steaming retains most of the nutrients (34).
In contrast, sprouting dried legumes can actually triple thefolate availability, making them an excellent folate-rich food (35).
Frozen vegetables are a convenient and cost-effective option, but freezing initially reduces folate by about 25% and can lead to losses as high as 97% after 3 months in the freezer (36).
The best way to maximize your folate intake is to consume a variety of high-folate foods and to choose fresh, steamed vegetables whenever possible.
Folate Requirements
Only about 50% of natural folate found in food is bioavailable (able to be absorbed) (37, 38).
Folic acid, on the other hand, has higher bioavailability.
About 85% of folic acid is absorbed when consumed with a meal, while 100% is absorbed on an empty stomach (39, 40, 41).
Because folic acid is more easily absorbed, less is needed to meet daily requirements.
The RDA (Recommended Dietary Allowance) for folate takes these differences into account by expressing requirements as “dietary folate equivalents” (DFE) (39):
1 mcg of food folate = 1 mcg DFE
1 mcg of folic acid taken with food = 1.7 mcg DFE
1 mcg of folic acid taken on an empty stomach = 2 mcg DFE
Adults need 400 mcg DFE each day, which might look something like this:
400 mcg of folate from natural food sources
OR 235 mcg of folic acid (from a supplement or fortified food) taken with food
OR 200 mcg of folic acid (from a supplement or fortified food) taken on an empty stomach
OR some combination of the above
During pregnancy and breastfeeding, folate needs are increased to 600 and 500 mcg DFE per day, respectively (40, 41). To meet these higher needs, supplements are often used.
Folic Acid: The Synthetic Form
The synthetic (man-made) form of folate is called folic acid, and it is found mainly in fortified or enriched foods and supplements.
The History of Folic Acid
Folic acid was first synthesized in the 1940s and was initially used to treat megaloblastic anemia caused by folate deficiency (42).
Compared to natural folate, folic acid was less expensive and more chemically stable, making it ideal for supplements (2).
However, it wasn’t until the 1960s that the use of folic acid supplements became widespread.
Around this time, scientists discovered that supplementing with folic acid could reduce the risk of neural tube defects (NTDs) in pregnancy (42, 43).
NTDs are severe birth defects, such as spina bifida and anencephaly, that occur when the neural tube fails to close during the early stages of fetal development (44).
In 1991, a large randomized controlled trial (RCT) found that women who took 4000 mcg of folic acid daily reduced their risk of having a pregnancy affected by an NTD by 70% (45).
Other studies showed that lower amounts of folic acid could also reduce the risk of NTDs, so it was eventually recommended that all women consume 400 mcg of dietary folate equivalents per day from food or supplements (39, 46, 47).
Unfortunately, most women weren’t consuming the recommended amount, so the FDA mandated that enriched grain products be fortified with folic acid in 1998 (48, 49).
After implementing these new rules, folate deficiency decreased to <2%, and the prevalence of NTDs in the United States was reduced by 20-50% (50, 51, 52).
Foods High in Folic Acid
Folic acid does NOT occur naturally in foods, but it is added to some processed foods.
In the United States, the FDA requires food manufacturers to add 140 mcg of folic acid to every 100 grams of “enriched” grain products (48, 53, 54).
“Enriched” products are foods that have had the nutrients lost during processing added back in, so that the final product is roughly nutritionally equivalent to the original (55).
In the US, most white bread, baked goods, cornmeal, white rice, white pasta, and refined breakfast cereals are enriched with folic acid.
It has been estimated that these fortified foods contribute an extra 100-200 mcg of folic acid per day to the average American’s diet (56, 57).
Non-Food Sources of Folic Acid
In addition to food, many people also take multivitamin-mineral supplements that contain folic acid.
While folic acid is not the best option for supplements (we’ll talk about this later), it is cheap and shelf-stable, so it is used by many inexpensive over the counter brands.
Doses in adult daily multivitamins are typically around 400 mcg (680 mcg DFE), which is above the RDA for folate (400 mcg DFE).
It is easy to see how people who take vitamins and eat folic acid enriched foods can easily surpass the recommended daily intake.
Structure & Metabolism of Folic Acid
Folate and folic acid have a few major differences:
Oxidized vs Reduced: Natural folate is in the reduced form, whereas folic acid is in the oxidized form. (This is a fancy way of saying that folic acid has fewer hydrogen atoms than folate.)
Poly vs mono glutamate: Natural folate is in the polyglutamate form and must be converted to the monoglutamate form before it can be absorbed, whereas folic acid is already a monoglutamate and can be absorbed as-is.
Steps to activation: Activation of natural THF folate requires only 2 steps, whereas the activation of folic acid requires 4 steps (see below).
Studies show that at doses above 200 mcg per day, the DHFR enzyme can max out, leaving excess folic acid to be absorbed directly into the bloodstream (2).
Some of this unmetabolized folic acid heads to the liver where it can be converted to L-5-MTHF (58, 59).
However, the activity of the DHFR enzyme in the liver is relatively low, so unmetabolized folic acid can circulate in the bloodstream for a while before it is fully metabolized (60).
The Problem with Folic Acid
In countries that have implemented fortification, unmetabolized folic acid can be detected in up to of 95% of people tested (61, 62, 63).
Folic acid is only beneficial if it can be converted to the active form, L-5-MTHF, so high levels of unmetabolized folic acid may pose a problem.
Potential Health Risks of Too Much Folic Acid
Although more research is needed, some studies suggest that consuming too much folic acid may negatively impact our health.
1. It May Increase Cancer Risk
Around the time that the United States started fortifying foods with folic acid, there was an increase in the incidence of colon cancer (64).
Since then, many studies have shown increases in both prostate cancer and colon cancer in participants who take folic acid supplements (65, 66, 67).
However, this is only a correlation and does not prove causation. Other studies have shown no increase in cancer risk with folic acid supplementation (68, 69, 70).
Some researchers hypothesize that excessive folate may spur the growth of pre-existing cancers or precancerous growths since cancer cells grow rapidly and have a higher need for folate, but more research is needed (71, 72).
2. It May Reduce Immune Function
A few studies have looked at the relationship between immunity and folic acid (73, 74).
These studies found that circulating unmetabolized folic acid is linked to reduced natural killer cell activity – an important part of the innate immune system (75).
Much more research is needed to understand the significance of these findings, but it is certainly interesting.
Folate and Genetic Mutations
Earlier, we briefly mentioned the importance of the MTHFR enzyme in folate metabolism.
MTHFR is responsible for the last step in the activation of folate (converting 5,10-MTHF to L-5-MTHF) (76).
Mutations in the genes that code for MTHFR are fairly common and can impair this conversion (77, 78).
The most common MTHFR mutations are C677T and A1298C (79).
With the C677T mutation, the activity of MTHFR can be impaired by 35% in those who are heterozygous (one copy of the mutation) and up to 70% in those who are homozygous (two copies of the mutation) (80).
When MTHFR activity is impaired, folic acid can’t be activated as quickly, leading to higher levels of unmetabolized folic acid and lower levels of active folate in the blood (81, 82).
MTHFR mutations have been linked to increased risk of the following conditions:
People who have the MTHFR mutation may benefit from avoiding foods that contain folic acid and choosing supplements L-5-MTHF, the already active form of folate (99, 100).
How to Choose the Right Folate Supplement
Supplements that use the active form of folate (L-5-MTHF) are generally preferred over those containing folic acid.
Studies have shown that L-5-MTHF is well absorbed and can raise folate levels as well as or even more effectively than folic acid (101, 102, 103).
To make sure you’re getting a supplement that contains L-5-MTHF, check the label for any of the following (104):
Metafolin
Quatrefolic
Levomefolic acid
L-methylfolate
L-5-MTHF
5-MTHF
These are alternative names for L-5-MTHF, so any supplement that uses one of the above is usually a good choice.
Benefits of L-5-MTHF Over Folic Acid
Supplements that contain methylated folate (L-5-MTHF) are better than folic acid for the following reasons (2):
1. Less likely to mask a vitamin B12 deficiency.
High doses of folic acid supplementation can “mask” a vitamin B12 deficiency by preventing the development of megaloblastic anemia (see graphic below for more details).
This is not good since B12 deficiency can still cause neurological damage, even if someone doesn’t know they have it.
For many people, the presence of megaloblastic anemia is the 1st sign of B12 deficiency.
If someone is B12 deficient, but megaloblastic anemia never develops because of folic acid supplements, the deficiency may go unnoticed until more severe signs, like nerve damage, occur.
This is of particular concern in older adults since vitamin B12 malabsorption is much more common in that age group (105).
Because of this concern, the Institute of Medicine has advised adults to not take more than 1000 mcg (1 mg) of folic acid per day, and some researchers argue this should be lowered to 500 mcg per day (106).
However, the active form of folate (L-5-MTHF) does NOT mask megaloblastic anemia caused by vitamin B12 deficiency.
This is because without vitamin B12, L-5-MTHF cannot be converted back into the form used in DNA synthesis, so megaloblastic anemia will still develop.
Thus, if L-5-MTHF is being taken as a supplement and megaloblastic anemia is present, it is most likely due to a vitamin B12 deficiency.
2. Still works for those taking DHFR inhibiting medications.
A second reason why folate supplements are superior to folic acid is that they still work for people who are taking medications that interfere with the DHFR enzyme.
DHFR is the enzyme that converts folic acid into the intermediate forms DHF and THF.
Methylated folate doesn’t require these enzymes since it is already in the active form. Therefore, even people on DHFR-blocking medications can properly utilize it.
Examples of medications that can interfere with the DHFR enzyme include (2):
Antiparasitics like pyrimethamine.
Diuretics like triamterene.
Folate-inhibiting antibiotics like trimethoprim.
Immunosuppressants and chemotherapeutics like methotrexate and aminopterin.
3. Suitable for people with MTHFR mutations.
As discussed previously, some people have genetic mutations that impair MTHFR activity and the ability to convert folate to its active form.
For these people, supplementing with folic acid (or even an intermediate form like folinic acid) may not be very helpful, since their bodies will struggle to convert it to L-5-MTHF.
This poor conversion may also result in higher amounts of circulating unmetabolized folic acid, which has been associated with negative health outcomes.
However, taking L-5-MTHF directly bypasses the MTHFR enzyme and provides the body with active folate that it can use right away.
For this reason, people with MTHFR mutations often choose supplements that contain L-5-MTHF rather than folic acid.
Our Favorite Folate-Containing Supplements
There are hundreds of folate supplements to choose from, so we’ve compiled a list of our favorite high-quality products.
Please note that as an Amazon Associate I earn from qualifying purchases.
Folate-Containing Multivitamin:
Pure Encapsulations O.N.E. Multivitamin
For a high-quality multivitamin/mineral that contains L-5-MTHF, Pure Encapsulations is a great choice.
In this supplement, you’ll find 400 mcg of L-5-MTHF (667 mcg DFE) per capsule, along with other nutrients.
Smarty Pants has several gummy multivitamins for men, women, and children, all of which contain methylated folate, rather than folic acid.
Six of the adult chewable gummies provide 400 mcg of L-methylfolate calcium salt.
Smarty Pants make a good option for those who cannot swallow pills and can be purchased online here.
It is important to note that these gummies do not contain important minerals like calcium, magnesium, or selenium, so an additional multimineral supplement may be needed.
Folate Lozenges or Drops:
Seeking Health
Another option for those who experience difficulty swallowing pills is drops or lozenges, which are available through Seeking Health.
These products can be purchased online here and here.
Folate-Containing Prenatal:
Seeking Health Optimal Prenatal
Seeking Health also makes a wonderful prenatal that contains L-methylfolate (in the form of Quatrefolic), along with other important nutrients like choline.
However, it is important to note that it does not contain some minerals, iron, or DHA, so additional supplementation may be needed.
It is important to remember that nutrients do not exist in a vacuum, and many other vitamins and nutrients are needed for proper methylation and one-carbon metabolism.
While some people who discover they have an MTHFR mutation may jump straight into high dose supplementation with methylated folate, this is not always a good idea.
Overloading yourself with folate without knowing whether you are deficient in other important methylation nutrients or without having functional labs to guide you could be a recipe for trouble.
Working with a dietitian or other qualified healthcare practitioner is always recommended before beginning a new supplement or dramatically changing your diet.
Your practitioner will analyze your health history and current diet, lifestyle, and medications to provide custom recommendations just for you.
Final Thoughts
Vitamin B9 is an important nutrient for one-carbon metabolism, DNA synthesis, and amino acid metabolism.
Deficiency can lead to megaloblastic anemia and is associated with an increased risk of cancer and other diseases.
There are two main forms of vitamin B9: folate (the natural form) and folic acid (the synthetic form).
Both must be converted to the active form, L-5-MTHF, in order to be used by the body, but folic acid requires more conversions and therefore can be more difficult for the body to use.
If too much is consumed, excess folic acid can build up in the blood and may have negative effects on health.
Additionally, some people also have genetic mutations that impair the MTHFR enzyme, making it even more difficult to activate folic acid.
For these reasons, it’s generally best to consume folate from food or through supplements containing L-5-MTHF, rather than folic acid.
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Amy is a registered dietitian nutritionist and certified LEAP therapist. Her passion is finding ways to communicate nutrition research in an interesting and easy-to-understand way. She has an undying love for food, especially homemade almond butter, steamed asparagus, and fresh summer cherries.
We use the term “functional nutrition” a lot around here, so you might be wondering what it’s all about.
Maybe you’ve heard it used by dietitians, but you have absolutely no idea what it means.
Or maybe you ARE a dietitian, and you’ve heard about functional nutrition, but you don’t fully understand how to implement it.
If so, then keep reading!
We’ll define functional nutrition, explain the philosophies behind it, and provide examples of how a dietitian might use it in practice.
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Overview of Functional Nutrition
The term “functional nutrition” is actually a component of a concept known as “functional medicine.”
Functional medicine is a model or framework that some doctors use to address the root cause of disease.
Before we can truly understand functional nutrition, we’ll have to take a closer look at functional medicine.
What Is Functional Medicine?
The concept of functional medicine was created by a biochemist named Jeffrey Bland in 1990 (1).
Bland was familiar with integrative medicine, a kind of healthcare that focuses on the patient as a whole person (mind, spirit, body) and uses both conventional and alternative treatments (2).
But being a biochemist, he saw the value of molecular medicine, which seeks to understand and treat disease based on the causes and mechanisms at a molecular level (3, 4).
So, he decided to combine integrative medicine with molecular medicine to form a framework called “functional medicine” (5).
In 1991, the Institute for Functional Medicine (IFM) was founded as a way to promote functional medicine and provide education to healthcare practitioners.
In a nutshell, functional medicine is a model that allows patients and practitioners to work together to address the underlying causes of disease by evaluating biological systems (6).
Functional medicine may look a little different depending on who’s using it, but in general, it can be summed up by these characteristics:
Characteristics of Functional Medicine
1. It is patient-centered rather than disease-centered, with the goal of promoting health that extends beyond the absence of disease (7).
2. The practitioner evaluates clinical imbalances within biological systems and identifies points of connection that reveal the underlying cause of disease or dysfunction (5, 8).
3. The aim is to treat the root cause of disease to promote healing, instead of treating symptoms to provide temporary relief (6).
4. Lifestyle changes are heavily emphasized in the prevention and treatment of chronic diseases(7).
5. Through a therapeutic partnership, the practitioner and the patient work together to achieve goals (6).
How Functional Medicine Differs from Conventional Medicine
In practice, the functional medicine approach looks very different from conventional medicine.
For example, let’s say a patient presents with eczema, an inflammatory condition characterized by itchy, scaly skin.
If this patient sees a doctor who practices conventional medicine, they’ll most likely be prescribed several drugs and ointments that suppress the immune system and lower inflammation in order to relieve symptoms (9, 10).
But a functional medicine doctor will ask the question, “WHY is the immune system reacting this way?”
Maybe they have food allergies, sensitivities, imbalanced gut bacteria, or high stress levels that are triggering their eczema (11, 12, 13).
So their treatment will include further investigation into possible root causes, plus diet and lifestyle interventions to address them.
The real difference is that the functional approach aims to provide true healing from the bottom up, while the conventional approach to many chronic illnesses is often like a band-aid.
In acute care (emergency situations), conventional medicine works beautifully, using drugs and surgery to save lives.
But when it comes to chronic diseases, which are often diet and lifestyle-related, many drugs only MASK symptoms, leaving the root causes unresolved.
Doctors who practice functional medicine believe it is a better model for addressing chronic disease, because of its focus on prevention through lifestyle changes such as diet, exercise, and stress management.
Because nutrition plays such an important role in functional medicine, doctors often refer patients to dietitians and nutritionists who practice functional nutrition.
What Is Functional Nutrition?
The IFM defines functional nutrition as an approach that “emphasizes the importance of high-quality foods and phytonutrient diversity to address clinical imbalances and move people to the highest expression of health” (14).
My dietitian friends may be thinking, “Well, that doesn’t sound any different than what I learned in school!”
In some ways, you’re absolutely right.
Just like traditional dietetics, functional nutrition also uses the nutrition care process and personalized dietary interventions to improve health (7).
The main difference is that functional nutrition requires dietitians to take a closer look at the patient as a whole person (mind, body, spirit) and base nutrition and lifestyle recommendations on the underlying causes of disease or dysfunction.
For example, let’s say you’re evaluating a patient who has been diagnosed with diarrhea-prominent irritable bowel syndrome (IBS-D).
The non-functional approach might include advising the patient on the low-FODMAP diet, how to identify and avoid trigger foods, and nutrition education to prevent diarrhea-related dehydration.
A functional approach, on the other hand, would involve functional testing for underlying causes, like SIBO, gut dysbiosis, parasites, food sensitivities, allergies, or intolerances and a thorough evaluation of lifestyle and health history (15, 16). The root causes would then guide the interventions.
Because this approach requires in-depth knowledge and critical thinking skills, many dietitians who want to practice functional nutrition find it helpful to obtain additional certifications or training.
Using Functional Nutrition in Practice
The concept of functional nutrition isn’t too difficult to understand, but if you’re a dietitian you may be wondering how to actually APPLY it to your practice.
Thankfully, there are tools to help guide you as you begin to implement the functional nutrition framework.
Two of the most widely used are the functional medicine matrix and the 5-R protocol. Let’s explore these below!
1. The Functional Medicine Matrix
Functional medicine practitioners use tools to organize information, analyze that information, and guide treatment decisions while still allowing for flexibility and personalized care.
They prefer using systems and models that allow them to focus on a patient’s unique clinical picture, rather than “cookie cutter” formulas or templates.
Basically, the matrix is a reminder to put on your detective hat and consider ALL of the patient’s potential causes of dysfunction so that you can prescribe nutrition interventions that address these root causes.
It was designed to be used by doctors, but it works for dietitians and nutritionists as well.
The actual functional medicine matrix is copyrighted by IFM, so we are not including the image in this article, but will summarize the main points below. You can find a digital copy of the matrix here.
Section 1: The 7 Core Imbalances
The functional medicine matrix contains a box in the center that prompts the practitioner to organize the patient’s clinical presentation based on what the IFM considers to be the “seven potential core imbalances” that may underlie any disease state (17).
These include:
Assimilation includes digestion, absorption, respiration, and the gut microbiome.
Defense & repair refers to immunity, inflammation, and infection.
Energy deals with energy regulation and mitochondrial function.
Biotransformation & elimination involves toxicity and detoxification.
Transport describes the cardiovascular and lymphatic systems.
Communication is comprised of neurotransmitters, endocrine, and immune messengers.
Structural integrity encompasses everything from subcellular membranes to musculoskeletal structure.
Section 2: The Patient’s Story
The column on the left side of the matrix (“retelling the patient’s story”) is a way to organize the patient’s disease pathogenesis into “antecedents, triggers, and mediators” (18).
Antecedentsare any factors that predispose the patient to illness. These could be genetic or environmental (nutrition, physical fitness, etc.).
Triggers are any factors that provoke the signs and symptoms of illness. Some examples are infection, trauma, environmental toxins, or foods that the patient is allergic or sensitive to.
Mediators are any factors that contribute to pathological changes and dysfunctional responses. These mediators can include biochemical factors like cytokines and hormones, or they might be psychosocial factors, like the patient’s thoughts and beliefs.
Section 3: Lifestyle Factors
Finally, the bottom row organizes the patient’s modifiable lifestyle factors into five categories: sleep & relaxation, exercise & movement, nutrition, stress, and relationships.
Functional nutrition practitioners are equipped to address all of these lifestyle factors to some degree, but their area of special expertise and focus is nutrition.
2. The 5-R Protocol
Many functional dietitians and nutritionists also use a modified version of the IFM’s “5-R protocol” to address gastrointestinal issues in patients with chronic conditions:
The 5-R protocol is as follows:
1. Remove: Remove any foods from the diet that you are allergic, sensitive, or intolerant to, as well as any pathogens in the digestive tract.
2. Replace: Replace anything you are deficient in, such as vitamins, minerals, fatty acids, digestive enzymes, bile, etc.
3. Repopulate: Repopulate your gut with the right balance of gut bacteria, as needed, using probiotics & fermented foods.
4. Repair: Repair damage to the gut as needed, with supplements to support the process.
5. Rebalance: Examine your current lifestyle & look for places in which it is unbalanced. Things to examine include sleep quality, stress levels, work-life balance, social support, and stress-relieving activities.
The 5-R protocol is a helpful tool because it provides a framework for addressing complex issues that require multiple nutrition interventions.
The steps can be done in order or as a simultaneous multi-pronged approach.
Additional Resources
If you’re reading this and thinking, “Wow, all of this sounds great! Where can I learn more?”, then these resources are for you:
1. The Functional Nutrition Library
Interested in learning more about functional nutrition on your own time and at an affordable price point?
It’s our membership site for dietitians and other wellness professionals to use as an educational/reference tool in their practices.
It includes functional nutrition recommendations for a variety of conditions, plus information on special diets and supplements, tips for lab interpretation, and more!
The notes are updated weekly in order to make the content more comprehensive and helpful for you. It’s really the perfect online reference for functional dietitians!
It is an online training and credentialing program offered by dietitians Kathie Swift and Sheila Dean.
Enroll in your choice of online training courses to complete at your own pace. Do them all, and you’re eligible for the IFNCP credential, which is recognized by CDR!
PS – IFNA also offers a FREE listserv that is open to ALL dietitians (even if you are not an IFNA student) 🙂 Just email info@ifnacademy.com to request an invite.
Already an IFNA student or alumnus? Email us at erica@functionalnutritionlibrary.com for an exclusive 50% discount to The Functional Nutrition Library.
3. Dietitians in Integrative and Functional Medicine
This is an excellent resource for any dietitian who is part of AND and interested in practicing functional nutrition.
Final Thoughts
At its core, functional nutrition is a philosophy that promotes the use of food as medicine to prevent and alleviate diet and lifestyle-related disease.
By addressing the root cause of disease or dysfunction, functional nutrition practitioners are able to promote healing instead of simply masking symptoms.
If you are a patient looking for a dietitian who practices functional nutrition, you can search for one here or here.
If you are a dietitian who wants to learn more about functional nutrition training and resources, consider joining our Functional Nutrition Library!
Want to save this article? Click here to get a PDF copy delivered to your inbox.
Amy is a registered dietitian nutritionist and certified LEAP therapist. Her passion is finding ways to communicate nutrition research in an interesting and easy-to-understand way. She has an undying love for food, especially homemade almond butter, steamed asparagus, and fresh summer cherries.
Did you know that roughly 1 out of every 6 Americans suffers from migraines (1)?
Migraines are severe headaches that are often accompanied by symptoms such as nausea, vomiting, sensitivity to light or sound, and vision disturbances.
Unfortunately, there is no definitive cure for migraines (though many have had success with food sensitivity testing), so treatment is usually focused on reducing the number of attacks and managing symptoms.
Medications, such as over-the-counter painkillers and prescription drugs, are often used to treat and prevent migraines, but natural remedies are becoming more popular.
One promising option for those seeking natural migraine relief is to try magnesium supplements.
In this article, we’ll explain the link between magnesium and migraines and tell you which magnesium supplement is best for preventing migraines.
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What Is Magnesium?
Magnesium is an essential mineral, meaning that it can’t be made by the body, so instead, we have to get it from food.
This often overlooked mineral is involved in over 300 biochemical reactions in the body (2).
It plays important roles in energy production, muscle contraction, DNA synthesis, neurological function, and bone structure.
The Recommended Dietary Allowance (RDA) for magnesium is 400 mg per day for males and 310 mg per day for females. After age 30, this increases to 420 mg and 320 mg, respectively (2).
The Standard American Diet, which consists mostly of meat, processed carbohydrates, and vegetable oils, usually does NOT provide enough magnesium. In fact, nearly half of Americans fail to meet their magnesium needs, typically falling short of the RDA by 100-200 mg (3, 4).
Even people taking multivitamins may fall short since magnesium is a large mineral that is hard to fit into a daily multivitamin-mineral supplement. It is often included only in small quantities (<100 mg) or excluded entirely.
Magnesium Deficiency
Symptomatic magnesium deficiency is rare, especially in people who don’t have any diseases (5).
This is because magnesium is an important electrolyte, and the consequences of not having enough in the bloodstream can be very severe.
To avoid these complications, the body tightly regulates levels of magnesium in the blood and will pull from body stores to avoid low levels.
However, it’s still possible to have inadequate magnesium even if you don’t have an obvious deficiency.
This is called a “subclinical deficiency,” which means that you might not have obvious symptoms, but your body is not functioning optimally and may suffer long-term negative consequences.
It is thought that subclinical magnesium deficiency is VERY common, affecting 10-30% of people (5). It may even be one of the leading causes of heart disease worldwide (6).
Some signs and symptoms of overt magnesium deficiency include (7):
Loss of appetite
Nausea and vomiting
Fatigue
Muscle weakness
Numbness and tingling
Leg and foot cramps
Tremors
Seizures
Personality changes
Depression
Irregular heart rhythms
Of course, if you have a subclinical deficiency, you might not experience any of these symptoms, so it can be helpful to test your magnesium levels.
Testing Magnesium Levels
The most common and inexpensive way to check magnesium levels is to test serum (blood) magnesium.
Unfortunately, this isn’t a very accurate picture of magnesium status because only 2% of the magnesium in the body is found in the blood. The majority (67%) is found in bone, and 31% is found inside cells (8).
This means that your serum will be the LAST place to show a deficiency since levels won’t become low until you’ve exhausted your body’s available stores.
There are more accurate ways to test for low magnesium or subclinical deficiency, such as looking at the amount of magnesium in your red blood cells, white blood cells, or tissues, but these tests are usually more time-consuming and expensive to do (6, 9, 10).
Magnesium deficiency may increase your risk for certain diseases. A long list of conditions has been linked with low magnesium levels, including high blood pressure, heart disease, arrhythmias, osteoporosis, diabetes, and premenstrual syndrome (2, 11).
Because of magnesium’s role in brain function, it is also thought that the deficiency of this nutrient may be one of the causes of migraines (12).
What Is the Link Between Magnesium and Migraines?
Studies have found that up to 50% of migraine sufferers have low magnesium levels (13, 14, 15, 16).
They have also shown that daily magnesium supplements can reduce the frequency and severity of migraines (17, 18, 19, 20)
One study even found that magnesium supplementation was more effective and fast-acting than a common drug used for the treatment of acute migraines (21).
Still, other research has found no benefit from magnesium supplementation, but this may be because the dose was not high enough (22).
Also, because magnesium status is so difficult to test, it’s possible that some studies’ results are thrown off by including both magnesium-deficient and non-magnesium-deficient patients.
How Does It Work?
Researchers aren’t sure exactly how magnesium works to prevent migraines, but they do have some theories.
First, let’s review the mechanisms that cause migraines. Scientists believe it goes something like this (12):
A trigger causes brain cells to release neurotransmitters (chemical messengers), such as calcitonin gene-related peptide (CGRP) and substance P.
These chemical messengers cause increased blood flow, swelling, and inflammation in the brain.
Nerve cells transmit messages to other parts of the brain, where pain is perceived.
Human and animal studies have shown that treatment with magnesium can decrease CGRP levels and block pain receptors, which may explain its therapeutic effects (23, 24).
However, these are likely just a couple of the ways that magnesium affects migraines, and there are probably other mechanisms we are not yet aware of.
What’s the Official Recommendation?
According to the American Academy of Neurology and the American Headache Society guidelines, magnesium supplementation is probably effective for migraine prevention, but no recommended dosage or form has been established (25).
Even though there is no formally recommended dosage for migraine prevention, most studies have used between 400 and 600 mg of magnesium per day (12, 26).
Magnesium supplements can be taken with food to reduce stomach upset and increase absorption. However, they should be taken away from calcium supplements and high-phytate foods, since these can interfere with absorption (27, 99, 100).
What Types of Magnesium Are Available?
Because magnesium is unstable by itself, it likes to be combined with other minerals to form what is called a “salt.”
Magnesium can also be combined with organic acids to form magnesium acid complexes or with amino acids (the building blocks of protein) to form magnesium chelates.
Depending on what chemical is combined with magnesium, the “bioavailability” might change.
Bioavailability basically means the amount of a substance that is absorbed by the body. So, if a supplement has HIGH bioavailability, then most of it is absorbed.
There are MANY types of magnesium available to choose from, so we’ve broken down some of the most common forms below.
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1. Magnesium Ascorbate (Poor Choice)
Magnesium ascorbate is the salt of magnesium and ascorbic acid, the synthetic form of vitamin C.
Since it contains more vitamin C than magnesium, it is typically used as a source of vitamin C, not magnesium.
For this reason, it is probably not the best choice for migraine prevention.
2. Magnesium Aspartate (Poor Choice)
Magnesium aspartate is formed by bonding (chelating) magnesium with the amino acid aspartate.
Chelated forms of magnesium, like magnesium aspartate, are more bioavailable than magnesium salts since they are absorbed as proteins, rather than via passive diffusion (28).
According to one study using rat intestines, magnesium chelates were nearly twice as bioavailable as magnesium citrate (28).
While magnesium aspartate is well absorbed, it may not be the best choice for people with migraines. This is because the amino acid aspartate is an excitatory neurotransmitter that may worsen migraines (29, 30).
3. Magnesium Carbonate (Poor Choice)
Magnesium carbonate is a form of magnesium usually used as an antacid to treat heartburn and upset stomach (31).
This is because the carbonate in the supplement acts as a base and neutralizes excess stomach acid.
Magnesium carbonate is an inorganic salt and is not very soluble in the gut. Because of its low bioavailability, magnesium carbonate is not the best choice for migraine prevention (32).
Ironically, diarrhea and upset stomach are common side effects of this supplement due to its poor absorption.
4. Magnesium Citrate (Good Choice)
Magnesium citrate is one of the most commonly used magnesium supplements. It considered an organic salt and is made by combining magnesium with citrate.
It is relatively cheap and has a higher bioavailability than inorganic magnesium salts, like magnesium oxide (33, 34).
This form of magnesium has been widely studied and is recommended for migraine prevention by several organizations, including the American Headache Society (25, 35).
However, citrate is typically produced via corn dextrose fermentation, so it may need to be avoided by people with corn sensitivities. (If you are not sure whether the citrate in your supplement is made from corn, you can always call the manufacturer and ask.)
Our favorite brands of magnesium citrate can be found here in capsule form and here in powdered form.
5. Magnesium Gluconate (Poor Choice)
Magnesium gluconate is made by combining magnesium with gluconic acid, a tart-tasting organic acid that naturally occurs in fruit, honey, wine and other foods (36).
Compared to nine other magnesium supplements, magnesium gluconate was found to have the highest bioavailability (67%) in one study performed on rats (32).
Because it is well-absorbed, it also tends to cause less diarrhea than other magnesium supplements (37).
However, magnesium gluconate pills tend to contain a smaller amount of magnesium per serving, so may not be a practical way to get the dosage needed for migraine prevention.
6. Magnesium Glutamate (Poor Choice)
Magnesium glutamate is formed by bonding (chelating) magnesium with the amino acid glutamate.
Like other chelated forms of magnesium, magnesium glutamate has good bioavailability.
However, glutamate is an excitatory neurotransmitter and may worsen, rather than improve, migraines (38, 39, 40).
For this reason, magnesium glutamate is probably not a good choice for people with migraines.
7. Magnesium Glycinate (Good Choice)
Magnesium glycinate (also called magnesium bisgylcinate) is a chelate of magnesium and the amino acid glycine.
The bioavailability of magnesium glycinate is relatively high (23.5%), and it tends to be well-tolerated (41).
It has been studied most in the treatment of depression, but no studies on migraines have been conducted (42). The glycine in magnesium glycinate can also have other benefits, including improved sleep (43).
Many practitioners recommend this form of magnesium, especially for people with GI upset, since it is less likely to cause diarrhea than other less-absorbed forms of magnesium.
Our favorite brands can be found here in tablet form and here in powdered form.
A similar product, magnesium glycinate/lysinate is also available. It contains 1 molecule of magnesium bonded to 1 glycine and 1 lysine (rather than 2 glycines in magnesium glycinate).
8. Magnesium Hydroxide (Poor Choice)
Also known as “Milk of Magnesia,” magnesium hydroxide is an antacid that is commonly used as a laxative. It has a lower bioavailability (15%) than other forms of magnesium (44).
Because of its laxative effect, this is definitely NOT the type of magnesium you want to use to prevent migraines.
9. Magnesium Lactate (Good Choice)
Magnesium lactate is an organic salt of magnesium and lactic acid.
It has relatively good bioavailability in humans, much better than inorganic salts like magnesium oxide (45).
It has been shown to effectively raise red blood cell magnesium levels in humans, so could be a good choice for correcting magnesium deficiency, but has not been studied for migraines specifically (46).
Magnesium lactate is not as popular as other types of magnesium salts but is available from a few reputable companies, including this one.
10. Magnesium L-Threonate (Good Choice)
In recent years, a new form of magnesium, called magnesium L-threonate, has become available.
Studies have found that this form of magnesium can cross the blood-brain barrier and enter the brain better than other forms, which may be especially beneficial for learning and memory (47).
In fact, magnesium threonate has been shown to improve memory and enhance learning in both rodents and humans, although more research is needed (48, 49, 50).
These effects may be due to the synergism between magnesium and threonate, improving neuroplasticity (the ability of the brain to form new connections) and increasing the availability of magnesium within the brain (51).
No research has investigated whether magnesium threonate is effective for migraines, but the fact that it easily enters the brain is promising.
Our favorite brand of magnesium l-threonate can be found here.
11. Magnesium Malate (Good Choice)
Magnesium malate is the salt of magnesium and malic acid – a naturally occurring organic acid that is responsible for the tart flavor of many fruits (52, 53).
Magnesium malate has been studied as a possible treatment for fibromyalgia, but other than that, there isn’t much research about this supplement (54, 55).
One recent study on rats found that this form of magnesium was more bioavailable than magnesium citrate, so it might be a good choice (56).
Our favorite brand of magnesium malate is this one.
12. Magnesium Orotate (Poor Choice)
Magnesium orotate is magnesium combined with orotic acid, which is a chemical that helps create energy in the muscle of the heart (57).
This combination has been studied for its potential beneficial effects in heart failure and cardiovascular disease, but no research has been done on migraines (58, 59, 60).
It also doesn’t seem to cause as much diarrhea as other forms of magnesium, which could be a benefit for people with already loose stools (61).
However, magnesium orotate contains far less magnesium per serving than other types of magnesium, so it is probably not the best option for people with migraines.
13. Magnesium Oxide (Poor Choice)
Of all the forms of magnesium that have been studied, magnesium oxide consistently shows the lowest bioavailability at 4-5% (34, 45).
It is typically used to treat constipation because it has a strong laxative effect (62). For this reason, it’s not a great choice to increase magnesium levels.
Magnesium oxide is one of the most frequently used forms to prevent migraines, but that doesn’t mean it’s the best.
14. Magnesium Taurate (Good Choice)
Magnesium taurate is another chelated form of magnesium, made by bonding magnesium with the amino acid taurine.
This form of magnesium is believed to be especially helpful for the prevention and treatment of migraines.
This is because it provides magnesium AND taurine, which can help dampen neuronal hyperactivity in the brain and reduce the likelihood of developing a migraine (63).
More research is needed, but magnesium taurate appears to be a good option for migraine headaches.
Our favorite brand of magnesium taurate is this one.
15. Sucrosomial Magnesium (?)
One of the newest forms of supplemental magnesium is called sucrosomial magnesium, and is available from companies like Pure Encapsulations.
In this form, the magnesium ions are encapsulated inside a membrane with sugars. This combination increases the permeability of the gut, allowing more magnesium to cross into the bloodstream (64).
However, it is debatable whether increasing gut permeability to boost magnesium absorption is actually a good thing since increased gut permeability has been linked to lots of negative health outcomes (65).
One small human study found that sucrosomial magnesium is more effective at raising magnesium levels than magnesium citrate, oxide, or bisglycinate (64). However, more human research is needed.
16. Liquid Magnesium (Good Option)
Magnesium can also be taken in a liquid form, which is typically made by dissolving magnesium chloride or magnesium citrate in water.
Magnesium chloride has been shown to have good bioavailability, but it has not been studied specifically for migraines (45).
Liquid magnesium is very concentrated and can be taken in very small quantities (no more than a few teaspoons). It is a good option for people who do not tolerate pills.
One of the most popular liquid magnesium supplements is this one.
17. Intravenous (IV) Magnesium (Not for Home Use)
People whose migraines are accompanied by auras (visual disturbances) and women who experience menstrual migraines may be more likely to benefit from intravenous magnesium sulfate (12).
This form of magnesium is given through an IV in large doses (1 gram) and is usually administered only in hospitals.
18. Topical Magnesium (?)
Magnesium oil and bath salts (Epsom salts) are gaining popularity as magnesium sources and can be used in several different ways:
Magnesium oil is actually not an oil – it’s made from magnesium chloride flakes and water. It can be applied directly to the skin and can be used during massages or added to baths.
Magnesium oil spray can be sprayed on the skin after showering. Most people use just enough spray to lightly coat the skin, then rub it in.
Magnesium lotion is made from magnesium oil and works great for dry skin.
Epsom salts are made from magnesium sulfate and can be used for foot soaks or baths.
The idea is that magnesium can be absorbed through the skin and enter the bloodstream without the unwanted side effects that can come with oral magnesium supplements.
No high-quality research has been conducted on this topic, but the studies that do exist report mixed results (66, 67, 68).
It appears that magnesium is absorbed through the skin, but it is unclear in what amounts. Therefore the optimal dosage of magnesium cream/oil/salts for boosting magnesium levels is not known.
There haven’t been any studies to test whether topical forms of magnesium are able to prevent migraines, but some people anecdotally report that it helps.
Which Form of Magnesium Is Best?
The majority of studies have used magnesium oxide or magnesium citrate to prevent migraines (17, 26).
The American Headache Society officially recommends magnesium citrate since it is well studied, affordable, readily available, and has a relatively high bioavailability.
But, just because some forms of magnesium haven’t been studied specifically for the treatment of migraines doesn’t mean they aren’t effective.
Many practitioners recommend other forms, like magnesium glycinate, lactate, or malate since they are also well absorbed can have other health benefits.
Some formulations, like magnesium taurate or threonate are especially promising for migraines due to their beneficial effects on the brain, but more research is needed.
The forms that should probably be avoided for migraines are magnesium ascorbate, aspartate, carbonate, gluconate, glutamate, hydroxide, orotate, and oxide.
If you find that you can’t tolerate any of the oral magnesium supplements, it might be worth trying magnesium lotion, spray, or Epsom salt baths.
At the end of the day, the best supplement is the one you will actually use! If you can’t tolerate one brand or variety, you can always try another.
Safety and Side Effects
The most common side effect from magnesium supplementation is mild diarrhea which tends to get worse with higher doses (2).
This is because unabsorbed magnesium functions as an osmotic laxative, pulling extra water into your digestive tract and softening your stool (69).
To avoid diarrhea, the tolerable upper intake level (UL) (the largest amount that can be taken each day without causing negative side effects) for magnesium is 350 mg per day for adults (2).
However, diarrhea seems to be the only potential adverse effect from taking more than this amount.
No evidence has shown any negative effects from magnesium supplementation during pregnancy and breastfeeding, so the UL is the same for pregnant women (2).
There is a higher risk of toxicity for those with impaired kidney function, so it is important to consult your doctor before deciding to take supplements (2).
Overall, taking magnesium supplements carries a very low risk for most people.
Magnesium in Food
Typically, the best and most natural way to consume nutrients is through food.
If you find that you can’t tolerate magnesium supplements, or you would like to avoid having another pill to take, consuming food sources high in magnesium is an option.
In fact, some researchers even recommend getting your magnesium from food as a BETTER alternative to supplements (70).
Here are some foods with the highest amounts of magnesium:
About 50% of dietary magnesium is absorbed, which is MUCH better bioavailability than most of the supplements mentioned above (2).
If you don’t mind making some lifestyle changes, dietary magnesium is a great alternative to supplementation.
Final Thoughts
For people who suffer from migraines, magnesium supplements may be a safe and affordable alternative to medications.
Magnesium oxide is the most commonly used magnesium for migraine prevention, but it isn’t well-absorbed and causes diarrhea in many people.
A better option is to take 400-600 mg of magnesium citrate, glycinate, taurate, or threonate each day.
Undesirable side effects like diarrhea can be avoided by taking several, smaller doses (200-300 mg each) throughout the day.
But supplements aren’t the only answer. If you’re willing to make changes to your diet, getting your magnesium through food can also be effective.
It’s important to remember that magnesium is just one possible treatment for migraines. Typically, migraines have more than just one cause, so it’s unlikely that one single treatment will completely eliminate your symptoms.
Amy is a registered dietitian nutritionist and certified LEAP therapist. Her passion is finding ways to communicate nutrition research in an interesting and easy-to-understand way. She has an undying love for food, especially homemade almond butter, steamed asparagus, and fresh summer cherries.
Have you been instructed to follow a low-histamine diet, but are feeling a little confused about what that means?
We get it! There are so many things to think about.
Which foods contain histamine? What foods might provoke histamine release? What supplements might worsen your symptoms?
This comprehensive article will explain the science behind histamine intolerance and help you understand the best diet and supplements for managing your symptoms.
Want to save this article? Click here to get a PDF copy delivered to your inbox.
What Is Histamine?
Histamine is a chemical that is naturally found in some foods and also produced by the body.
Histamine In Food
Histamine forms when certain bacteria or yeasts transform the amino acid histidine into histamine (1).
This means that any food containing protein can form histamine under the right conditions.
Generally speaking, aged and fermented foods or beverages contain the highest levels of histamine, while fresh foods contain almost none.
Histamine In the Body
Our bodies also naturally produce histamine.
It is released by our immune cells during allergic and inflammatory reactions that occur when our immune system detects a threat.
When released, it causes stomach cramps and diarrhea, low blood pressure, mucus secretion in the nasal passages and GI tract, and many other physiologic effects that are intended to fight off invaders (2).
Once the perceived threat is over, histamine levels are reduced back to normal, and symptoms subside.
Histamine Breakdown
The body has two enzymes that are capable of degrading histamine: N-methyltransferase (HNMT) and diamine oxidase (DAO) (2).
HNMT exists only in the cytoplasm, so it is responsible for breaking down any histamine found inside of cells.
The highest concentrations of HNMT have been found in the kidney and liver but it also exists in many other tissues.
DAO, on the other hand, is produced and stored by epithelial cells (cells that line our organs and blood vessels).
When stimulated, it is secreted into the bloodstream and gut where it picks up and degrades any histamine that might be floating around.
DAO is produced in large amounts within the intestines, but also by the placenta during pregnancy.
However, in some people histamine degradation doesn’t work the way it should, causing a condition known as histamine intolerance.
What Is Histamine Intolerance?
Histamine intolerance occurs when more histamine accumulates in the body than we are able to break down effectively.
This build-up eventually causes symptoms that are very similar to an allergic reaction.
It is estimated that 1% of the population has histamine intolerance, and most of those are middle-aged women (2, 3).
It’s unclear why women are more often affected than men, but one theory is that an imbalance of female sex hormones may cause the body to produce more histamine than it normally should.
Studies have shown that estrogen activates histamine release from mast cells (cells that exist in the lining of our tissues), while progesterone inhibits it (4, 5, 6).
So, if the amount of estrogen being produced is higher than the amount of progesterone, more histamine is released.
Signs and Symptoms of Histamine Intolerance
Symptoms of histamine intolerance can vary depending on the person and the amount of histamine that has accumulated.
The following are some of the most common signs and symptoms of histamine intolerance (2, 7):
Itching, redness, hives and/or swelling of the lips, tongue, or skin
Sneezing and nasal congestion
Asthma
Low blood pressure
Heart arrhythmia
Diarrhea
Headache
Dizziness
Sleep disturbances
Menstrual irregularity
Chronic fatigue
Anxiety
Depression
These symptoms are very general, so experiencing them is not enough to confirm a diagnosis of histamine intolerance. Further investigation is usually needed.
What Causes Histamine Intolerance?
Histamine intolerance may occur for several reasons:
1. The body has produced too much histamine (due to immune reactions or a condition like mastocytosis, in which the body has too many mast cells that release histamine).
2. Too much histamine is ingested (through food or alcohol).
3. The degradation of histamine is impaired (due to genetics, medications, or other medical conditions).
It is thought that the main cause is the impaired breakdown of histamine due to alterations in DAO activity.
Many studies have shown lower serum DAO activity in those with symptoms of histamine intolerance compared to healthy controls (8, 9, 10, 11).
Genetic Causes
While the exact causes of DAO deficiency are unknown, there may be a genetic component that explains why some people experience insufficient DAO activity.
If the DAO gene (known as ABP1) contains certain single-nucleotide polymorphisms (SNPs), this may increase the risk of developing histamine intolerance (12, 13, 14).
In this case, the most relevant SNPs are rs10156191 Thr16Met, rs1049742 Ser332Phe, and rs1049793 His645Asp (15).
With genetic testing, it is possible to determine if you have some of these SNPs, but simply having a SNP does not necessarily mean that you will experience histamine intolerance.
Gastrointestinal Causes
Poor gut health caused by stress or infection may also be a trigger for histamine intolerance (2, 16).
Gastrointestinal diseases, such as Crohn’s disease, have been associated with impaired DAO activity. This is caused by a decrease in DAO production when intestinal cells become inflamed (17, 18).
In many cases, it may be possible to reverse histamine intolerance by healing the gut or removing whatever is inhibiting DAO activity (2).
When Is a Low-Histamine Diet Helpful?
A low-histamine diet can be helpful in both the diagnosis and treatment of histamine intolerance.
Histamine intolerance should be considered in people who have the signs and symptoms but test negative for allergies and other disorders.
The gold standard for diagnosis is a double-blind placebo-controlled oral challenge after a histamine-free diet. This requires following a very strict low-histamine diet for 4 weeks and then reintroducing a few high histamine foods to see if symptoms develop (2).
Other than the oral challenge, there are no reliable tests to diagnose histamine intolerance.
One study found that a histamine skin prick test that measures the rate of reaction resolution showed 79% sensitivity and 81% specificity in diagnosing histamine intolerance, but this test is still considered experimental and is not commonly used (19).
Another test sometimes used for diagnosis is serum DAO activity. In those with histamine intolerance, serum DAO activity is lower than that of healthy controls (8, 9).
Fish and seafood, especially if leftover, smoked, salted, or canned
Ketchup
Pineapple
Soy sauce, tamari, coconut aminos, liquid aminos
Spinach
Spoiled food/old leftovers
Tea (black/green/white)
Tomatoes
Vinegars
Yeast products
*Note that measured histamine levels can vary widely from study to study, even for the same foods. This can make it very difficult to pinpoint which foods might be problematic.
Following a structured elimination diet under the care of a registered dietitian or other nutrition professional who is knowledgeable about adverse food reactions can help immensely.
Histamine Releasers
Some foods are also thought to be “histamine releasers.”
These foods are actually low in histamine but may cause mast cells to release histamine (2, 7).
This is a hypothesis based on old in vitro and animal studies, but there are no randomized controlled trials confirming their findings (21, 22, 23, 24, 25).
Currently, there is not enough scientific support for histamine-releasing foods, so more research is needed before limiting these foods can be recommended routinely (26).
Foods that may be histamine releasers include:
Additives
Alcohol
Bananas
Chocolate/cocoa
Citrus fruits (lemon, lime, grapefruit)
Egg whites
Fish
Legumes
Licorice
Nuts
Papaya
Peanuts
Pineapple
Pork
Shellfish
Some spices
Spinach
Strawberries
Tomatoes
DAO Blockers
There are other foods that are called “DAO blockers” because they inhibit the activity of DAO.
Since alcohol is both high in histamine AND slows its breakdown, it should definitely be avoided by people with histamine intolerance.
Foods to Enjoy on a Low-Histamine Diet
Low-Histamine Foods
Generally, fresh foods have the lowest amounts of histamine.
Some low-histamine foods to try include:
Fruits: apples, apricots, blackberries, blueberries, cherries, coconut, melons, peaches, plums, pomegranate, and raspberries, among others.
Vegetables: arugula, asparagus, bell peppers, beets, bok choy, broccoli, brussels sprouts, cabbage, carrots, cauliflower, garlic, greens, leeks, lettuce, onions, rhubarb, rutabaga, shallot, summer squash, sweet potato, turnip, watercress, winter squash, and zucchini, among others.
Grains: gluten-free options like amaranth, corn, millet, quinoa, rice, teff are less likely to exacerbate an irritated gut than gluten-containing grains.
Fresh herbs
Olive oil
Fresh animal proteins: chicken, beef, lamb, goat
Please note that just because a food is low in histamine does not mean that it will be tolerated well by your body.
Other types of adverse food reactions like allergies, sensitivities, and intolerances are always possible. Listen to your body first!
Food Purchasing and Preparation Tips
Since histamine forms as food ages and ferments, there are some tips for keeping food fresh and reducing the amount of histamine produced.
1. Purchasing Proteins
When purchasing animal-based proteins, the fresher the better. Check the “packaged on” date when shopping for meat, and choose the freshest.
Also look for meat that has been butchered and frozen quickly. Check with local meat suppliers for the best options.
Additionally, whole cuts may be better than ground meats, since the grinding process spreads bacteria throughout the meat, increasing their ability to create histamine.
If buying fish, look for the “frozen-at-sea” (FAS) label.
When shopping, select your animal proteins at the end of your grocery shopping trip and keep in a cooler on your way home.
2. Freezing
Freezing food prevents or slows down the development of histamine (27).
Buying fresh meat or other foods and freezing in individual portions allows for quick thawing and minimal histamine accumulation.
Of course, this doesn’t work for ALL foods, because some are not freezer-friendly.
3. Cooking Method
There’s also some evidence that the histamine level in a food can change based on how it is cooked.
Frying and grilling tend to increase histamine levels, while boiling can maintain or decrease levels, but the difference is relatively small (28).
Other strategies include cooking with a pressure cooker, using quick thaw methods for frozen foods, freezing individual meals, and avoiding slow-cooked foods.
Supplements to Try
While limiting histamine-containing foods is the most effective way to find relief from symptoms of histamine intolerance, low-histamine diets are definitely not easy to follow, and total avoidance of histamine is impossible.
To help reduce symptoms even further, certain medications and supplements can help support the degradation of histamine:
1. Antihistamines
Antihistamines are sometimes used by those with histamine intolerance to block the action of histamine and quell symptoms.
However, antihistamines just mask symptoms and do not address the root cause.
They may provide temporary symptom relief, but it is expensive to routinely take antihistamines and they can cause side effects like excessive drowsiness.
Additionally, antihistamines do nothing to boost DAO activity, which is typically at the root of histamine intolerance.
2. Supplemental DAO
Another option is to take supplemental DAO enzymes orally.
These enzymes will enter the gut and help degrade histamine in food, much like the DAO naturally produced in your gut would.
However, it is important to note that DAO taken orally is NOT absorbed into the bloodstream, and will do nothing to reduce systemic histamine levels.
DAO supplements can be helpful for breaking down histamine from food, reducing the amount of histamine that gets absorbed, but that’s about it.
There has not been a lot of research on the effectiveness of these supplements, but they do have a good amount of anecdotal support.
A couple of small studies testing the effect of DAO supplements on symptoms of histamine intolerance are conflicted about its efficacy (29, 30).
3. Vitamins to Support Histamine Breakdown
There is also some evidence that vitamin B6, vitamin C, and copper increase the activity of DAO and aid in the breakdown of histamine; however, no randomized controlled studies have been conducted to confirm this (31, 32, 33, 34, 35).
Several studies have shown that vitamin B6 deficiency is linked with lowered serum DAO activity, suggesting that status of this nutrient may influence serum DAO activity (31, 36).
Another study found that vitamin C administered by IV significantly decreased serum histamine concentrations in patients with allergies (32). The theory behind this is that vitamin C is actually able to degrade histamine (37).
The effect of copper on histamine has only been studied in vitro (in test tubes); researchers found that a copper solution inhibited the release of histamine from mast cells in a dose-dependent relationship (35).
It’s best to consume foods rich in vitamin B6, vitamin C, and copper rather than rely on supplements, unless you have been diagnosed with a deficiency in one of these nutrients.
{Want to learn more about our favorite brands? Join The Functional Nutrition Library to learn about our favorite supplement options.}
4. Mast Cell Stabilizers
Those suffering from gastrointestinal symptoms may benefit from supplementing with mast cell stabilizers (2).
Mast cell stabilizers inhibit the release of mediators (including histamine) from mast cells in order to reduce their inflammatory effects (36).
The most popular mast cell stabilizer is disodium cromoglycate (DSCG), also known as cromolyn sodium.
It is available by prescription-only as an oral solution under the brand name Gastrocrom and over-the counter as a nasal spray (NasalCrom) or eye drop (Opticrom).
5. Histamine Degrading Probiotics
Optimizing gut bacteria is vital for overall health and disease prevention (37, 38). Unfortunately, that’s not easy to do for those with histamine intolerance because probiotic foods (yogurt, kefir, kombucha, etc.) are high in histamine and should be avoided.
Another option is to use probiotic supplements, but it’s important to choose probiotic supplements containing bacteria that do not produce histamine.
The following strains may be helpful because they have been found to break down or reduce the formation of histamine:
These lists are not comprehensive, because this is still a new area of research, but they can be used to guide decisions about which probiotic supplements to purchase.
{Looking for the best probiotic for histamine intolerance? Join The Functional Nutrition Library to learn about our favorite one.}
Final Thoughts
Most people with histamine intolerance find relief after just a few days of following a low-histamine diet (7).
A generalized low-histamine diet should not be followed long-term, because it may be over-restrictive, increase the risk of malnutrition, and take some of the pleasure out of eating.
Instead, it is better to use the diet as a tool to determine an individual’s histamine tolerance, and craft a customized diet from there (50).
Start by following a low-histamine diet for 2 weeks, and then slowly reintroduce higher histamine foods while documenting symptoms. A tolerance threshold can be determined, which will help guide long-term dietary changes.
Supplements can also be considered to help manage symptoms but should be taken under the guidance of a physician or other healthcare professional familiar with your unique health history.
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Amy is a registered dietitian nutritionist and certified LEAP therapist. Her passion is finding ways to communicate nutrition research in an interesting and easy-to-understand way. She has an undying love for food, especially homemade almond butter, steamed asparagus, and fresh summer cherries.
