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Folate is water-soluble essential nutrient that your body cannot make on its own. This means you must get folate from food or supplements. Regardless of where you get the folate from, your body must convert it into a usable form by using an enzyme that has a super long name → 5,10-methylenetetrahydrofolate reductase. That’s a mouthful, we know. More commonly, this enzyme is simply referred to as MTHFR. (Yes, it also looks like shorthand for a really not-so-nice word, but we promise, we’re not making it up.) We’ll get more into MTHFR and what it means below.
**Why are you calling this vitamin Folate instead of Vitamin B9? Good question! This is because the word “folate” or “folic acid” is more commonly used than “Vitamin B9”. However, there is a difference between the two! Folate is the form of Vitamin B9 that naturally occurs in plant foods we eat, like spinach. Folic acid is manufactured. (See Supplementation below)
In addition to providing energy, folate is important for many cellular processes including the creation of DNA, essential neurotransmitters like dopamine, norepinephrine, and serotonin, and red blood cells. It is an important cofactor for certain enzymatic reactions in the body and is interdependent with other B vitamins, most notably Vitamins B2, B6, and B12. You need sufficient levels of folate for normal function of your nervous system, production of neurotransmitters and hormones, and for healthy immune system function. (Think: sitting at work or in class and having no energy/focus/motivation to get a project done).
| Brain | Body |
|
Depression Confusion Brain fog Irritability Forgetfulness |
Fatigue and lack of energy Muscle weakness Shortness of breath |
Causes of deficiency
There are a variety of factors that can contribute to Folate deficiency or insufficiency. We’re going to use some very medical terms for some of them, but the main thing you need to keep in mind is that folate deficiencies are most commonly caused by problems related to inadequate intake, increased demand from the body, impaired absorption, altered metabolism, and/or increased excretion. There are also genetic factors which we’ll get into further in the discussion. Intake is how much your body “takes in”, demand is how much your body needs, absorption is how well your body “soaks up” the available folate when it is released from its source, metabolism involves how your body accesses and uses folate, and excretion is how your body rids itself of folate.
| Inadequate intake |
• Poor diet → lacking in fresh green vegetables • Chronic alcoholism • Total Parenteral Nutrition (TPN) |
| Increased demand |
• Pregnancy and lactation • Infancy |
| Impaired absorption |
• Celiac disease, ulcerative colitis, Crohn’s disease, and tropical sprue • Anticonvulsant medications • Genetic factors • Smoking |
| Altered metabolism |
• Medications that antagonize or “block” folate (see below) • Genetic enzyme deficiency • Acquired enzyme deficiency • Alcoholism or alcohol abuse |
| Increased excretion |
• Dialysis |
Risk factors
Age. Folate deficiencies notably worsen as people age. This mostly occurs in individuals 60 years or older but can start in the 50s.
Diet. Since 1996, the US Food and Drug Administration required all flour and cereals in the United States be fortified with folic acid, the manufactured or synthetic form of folate. Because of the fortification of food products, most diets contain adequate amounts of folic acid. However, it is important to remember (and we cannot state this enough) that folic acid is synthetic whereas folate naturally occurs in plant products (citrus fruits, green leafy vegetables) and liver and an unhealthy diet increases the risk for a folate deficiency. Additionally, cooking vegetables too long destroys folate.
Alcoholism or excessive consumption of alcohol also reduces the body’s ability to absorb folate from food sources.
Medications.
| Common Over-the-counter (OTC) | Commonly Prescribed |
|
Omeprazole (Prilosec) Lansoprazole (Prevacid) Someprazole (Nexium) Rabeprazole (Aciphex) Cimetidine (Tagamet) Famotidine (Pepcid) Ranitidine (Zantac) Ibuprofen (Advil, Motrin) Naproxen (Aleve) |
Metformin 5-Fluorourcail Methotrexate Phenobarbital Phenytoin (Dilantin, Phenytek) Lamotrigine (Lamictal) Primidone (Mysoline) Carbamazepine (Tegretol) Sulfasalazine (Azulfidine) Triamterene (Dyrenium) Trimethoprim (Primsol, Trimpex) Pyrimethamine (Daraprim) Barbiturates Colestipol (Colestid) Cholestyramine (Questran) Colsevelam (Welchol) |
Common Over-the-Counter (OTC) medications for the treatment of heartburn, ulcers, and acid reflux (GERD) like:
Decreased release and absorption = decreased folate in your body!
There are 5 well-studied causes of folate deficiency a person could be born with. We won’t get into the details of each here but will instead focus more on a specific genetic mutation that has to do with that very long word above, 5,10-methylenetetrahydrofoate reductase, better known as MTHFR.
It is important to understand that MTHFR stands for two things:
Depending upon what genes (the factory) your parents gave you, your body could have a problem (think: not enough workers) with turning folate or folic acid → into an important “bioactive” (think: easily used in the body) vitamin “Methyltetrahydrofolate or MTHF that is important for many, many things, including creating and repairing DNA, and recycling homocysteine.
| Sidebar on homocysteine → homocysteine is a natural substance in your body that you need for certain things, but it’s kinda like Goldilocks. You don’t want too little and you don’t want too much. You want it to be “just right.” Too little homocysteine and your body can’t make other things it really, really needs to have, like glutathione which is like the Superman of antioxidants. Too much homocysteine and things get “gunked up” like your brain and cardiovascular system. |
Back to the factory. The MTHFR gene can have many polymorphisms which is a fancy way of saying “a variation in a specific DNA sequence” (thank you Miriam-Webster Dictionary!). There are two “main”polymorphisms we feel are important to point out, the C677T and the A1298C. Every person has both of these but whether or not you have a mutation depends on what your parents gave you (don’t blame them if you don’t like what you got, it’s not like they had a choice!).
Let’s look at the first one because it’s a biggie, C677T. With this MTHFR gene, a person can either have CC, CT, or TT and what they have impacts their body’s ability to turn folate or folic acid → into that “bioactive” vitamin, MTHF. Having a CC is considered “normal” (yay!), having a CT is associated with a reduced ability to turn folate or folic acid into MTHF by about 50% (ehh, could be better), and having a TT is associated with a significantly reduced ability to turn folate or folic acid into MTHF by about 60% to 70% (not good).
So, what does that mean and why does it matter? If your body struggles to turn folate or folic acid → into MTHF, you can have some significant health consequences including elevated homocysteine. This also affects your body’s ability to make important neurotransmitters like dopamine, serotonin, and norepinephrine which you kinda need to have for things like focus and concentration, sleep, mood, and energy. Don’t freak out if you have a T or TT.
Both of us each have one T, so we can promise you it’s not the end of the world. It is important though to make sure you’re taking the right kind of Vitamin B9 (see below under Supplementation).
Now let’s look at the A1298C. With this MTHFR gene, a person can have either AA, AC, or CC. As with the C677T, the A1298C also affects how the body turns folate or folic acid → into the "bioactive" vitamin MTHF, just not to the same degree as the C677T. Still, it’s pretty important, particularly if you have a T on your C677T PLUS (+) a C on your A1298C. (We told you it would get more complicated!)
Having AA is considered “normal”, having an AC is associated with a reduced ability to turn folate or folic acid → into MTHF by about 10% to 20% (ehh, could be better), and having a CC is associated with a reduced ability to turn folate or folic acid → into MTHF by about 30% to 40%. We are sure by now your head is probably spinning with all the As, Cs, Ts, and percentages, but we have to throw in a little bit of math, too, because it is just so darn important.
If you have a T on your C677T + a C on your A1298C, this means your body’s ability to turn folate or folic acid → into the bioactive MTHF is probably somewhere around 60%. Again, this is not the end of the world. One of us has exactly this combination. What is important to remember, and we cannot stress this enough, is to make sure you’re getting the right kind of Vitamin B9 (see below under Supplementation).
The main takeaway from this section is to just be aware that mutations on the MTHFR gene can cause folate deficiencies .
We’ll get into the prevalence rate (meaning how commonly it occurs in the population) in a different blog post.
| Brain | Body | Potential Immune/Covid-19 vulnerabilities |
|
Dementia Alzheimer’s Brain shrinkage Depression Insomnia Psychosis Strokes Fetal complications
|
Cardiovascular disorders Reduced immune function Folate anemia Macrocytic anemia Megaloblastic anemia Colon cancers Diabetes Leukemia Glossitis Angular stomatitis Oral ulcers Pregnancy complications Poor growth |
Elevated homocysteine (see our article on homocysteine) Increased reactive oxygen species (ROS) Impaired endothelial functioning Increased pro-inflammatory cytokines (IL-1b, IL6, TNF-a) Insulin resistance Metabolic syndrome |
| Spinach | Dark leafy greens | Asparagus | Turnips | Beets | Mustard greens |
| Brussels sprouts | Lima beans | Soybeans | Beef liver | Brewer’s yeast | Root vegetables |
| Whole grains | Wheat germ | Bulgur wheat | Kidney beans | Lima beans | Mung beans |
| Salmon | Orange juice | Avocado | Milk |
Supplementation with a folic acid, l-methylfolate (AKA methylfolate or 5-MTHF), or folinic acid can be the “work around” if you don’t get enough folate in your diet due to any of the medical diseases, conditions, or risk factors that are listed above.
The 3 forms of folate:
Synthetic (not natural) → Folic acid – found in “enriched” and “fortified” foods (think cereals, breads, all-purpose flour, crackers, cookies, and so on) and in many B complex vitamin supplements. There are some concerns that unmetabolized folic acid can cause adverse health effects .
Natural → 5-methyltetrahydrofolate (5- MTHF) – (AKA) l-methylfolate is a “reduced folate” which is basically a super fancy way of saying “we jumped ahead of the whole MTHFR thing and created 5- MTHF”. This form of Vitamin B9 “bioactive” and well-absorbed even when the pH of stomach acid is altered and is not affected by metabolic defects! Super awesome!!! Now, how much 5-MTHF or l-methylfolate your body could benefit from depends on a couple of factors including any known MTHFR “defects”, your folate level, and your homocysteine level (see below).
Natural → Folinic acid – known as leucovorin, is a prescribed medication that is used to counter folate-depleting and toxic effects of medications like methotrexate and chemotherapy. It is “bioactive” and a “reduced folate” like 5-MTHF (above).
You can learn what your folate level is by asking your medical provider to order labs to assess your folate level. This means a blood draw. As psychiatric providers, we routinely order serum folate levels on our patients. As a rule, we want our patients to have a folate level >20.0 ng/mL. This is the “goal range.” Although someone with a folate level of 14.3 ng/mL might appear “normal” per their lab results, it is important to remember that this is actually a suboptimal level that will not get “flagged” as being “low”. As psychiatric providers, we believe in getting our patients to “optimal” levels.
We also check a homocysteine level on our patients (see our article on homocysteine).
It would also be important to get a Vitamin B12 level checked because there is a form of anemia that occurs due to inadequate B12. If this level is not also checked, a B12 anemia can be missed and this can result in irreversible damage to the nervous system.
Folate is an important B vitamin involved in many important processes in the body including the creation of DNA, essential neurotransmitters like dopamine, norepinephrine, and serotonin, and red blood cells. There are several factors that increase the risk for folate deficiency like excessive use of alcohol, unhealthy diets, advancing age, certain medications, certain medical conditions, and genetic factors like MTHFR mutations. Symptoms that may indicate a folate deficiency include fatigue, lower energy, brain fog, memory problems, sad moods, irritability, shortness of breath, and muscle weakness. At HealthyBrain, we believe folate is critical to many important processes in the body. Whether you get your folate from food and/or supplements, make sure you’re getting enough and make sure you’re also “balancing” this with sufficient B12 and other important B vitamins (like B2 and B6). Focusing on taking only one specific B vitamin can contribute to an imbalance in your body. That’s why we created our Immune Boost and Immune + Mood Boost which have a good balance of important B vitamins. (For more information on individual B vitamins, check out our other blog posts!)
References