Vitamin B-12 and depression: Are they related?

Vitamin B-12 and other B vitamins play a role in producing brain chemicals that affect mood and other brain functions. Low levels of B-12 and other B vitamins such as vitamin B-6 and folate may be linked to depression.

Low levels of a vitamin can result from eating a poor diet or not being able to absorb the vitamins you consume. Older adults, vegetarians and people with digestive disorders such as celiac disease or Crohn's disease may have trouble getting enough B-12.

How Can B12 Impact Brain Health?

Vitamin B12 has the largest and most complex chemical structure of all the vitamins. It is present in several unique forms, each of which actually has the mineral cobalt hidden within. For this reason, you will also see all of the variations of vitamin B12 called the “cobalamins.” The impressive chemical constitution of cobalamins makes a lot of sense when we think of the wide range of functions these nutrients are expected to play in the body.

Looking at the nervous system alone, vitamin B12 works in a diverse number of areas.

Here are just some of the ways in which vitamin B12 supports the brain and central nervous system:
·         assists in normal nerve growth and development
·         improves communication between nerve cells
·         promotes stable adrenal function
·         provides emotional and mental energy
·         helps with the ability to concentrate
·         bolsters memory function
·         has calming effects to balance moods

B12 supports myelin (which allows nerve impulses to conduct) and when this vitamin is deficient, has been suspected to drive symptoms such as dementia, multiple sclerosis, impaired gait, and sensation. Clinically, B12 may be best-known for its role in red blood cell production. Deficiency states may result in pernicious anemia. But what about B12’s role in psychiatric symptoms such as depression, anxiety, fatigue, and even psychosis?

The one-carbon cycle refers to the body’s use of B vitamins as “methylators” in DNA synthesis and the management of gene expression. There are three concepts that relate to B12’s role in chronic, long-latency neuropsychiatric syndromes:

1.       Methylation
This process of marking genes for expression, like little “read me!” signs, is also critical for detox and elimination of chemicals and hormones (estrogen), building and metabolizing neurotransmitters, and producing energy and cell membranes.

2.       Homocysteine recycling B12 is a primary player in the one-carbon cycle and a co-factor for the methylation, by activated folate, of homocysteine, to recycle it back to methionine. From there, SAMe is produced, the body’s busiest methyl donor.

3.       Genetic override
Sufficient supply of an activated/bioavailable form of a vitamin (i.e. methylfolate vs folic acid) is even more necessary in the setting of gene variants such as transcobalamin II, MTHFR, and MTRR which may function less optimally in certain individuals and result in pathology under stress. An example of this is a report of death in a B12-deficient patient with genetic variants who underwent anesthesia with nitrous (which causes stress to the system). Notably the B12 blood level was normal, so this fatal case was attributed to functional deficiency, suggesting that access to B vitamins may not always guarantee proper utilization. For this reason, supplementing with activated forms of B vitamins enhances their likelihood of effectively supporting cellular processes.

How Do We Test for B12 Deficiency?

There are few empirical treatments, meaning treatments that apply to everyone, in functional medicine, but I believe B12 to be one of them, particularly in light of the fact that some 2/5ths of the population present with severe deficiency. Testing is available, and most data on deficiency has relied on blood levels, with deficiency defined as being below 150-200 pg/ml. It turns out that testing for deficiency by blood level is not always a reliable indicator of what is going on in the brain, or functionally, in the body.

An important study in women identified markers of B12 deficiency in 27% of depressed patients by using methylmalonic acid instead of B12 levels. Relatedly, an excellent review of clinical improvement with B12 treatment speaks to ten studies which demonstrated “normal” B12 levels, often finding mean levels in the 3-400pg/ml range (but never above 600) in patients with fatigue, sleep disorders, depression, and dementia.

Correlation with cerebrospinal fluid levels is also inconsistent, including in cases of postpartum depression where women improved with empirical application of B12. High copper levels – potentially caused by zinc deficiency – postpartum have been associated with depression and may effectively impair B12 transport. Utilization of a given vitamin is more clinically relevant than its sufficiency, and for this reason, two tests have been proposed as reliable surrogate markers:
* Homocysteine May be elevated in the setting of either B12 or folate insufficiency or dysfunction (often related to genetic variants).
* Methylmalonic Acid (urine or serum) This value is more specific for B12 deficiency, but potentially insufficiently sensitive.

Screening for signs of anemia (megaloblastic) is no longer reliable because of wrong-headed recommendations that toxic foods like flour be “fortified” with synthetic folic acid. For those unable to metabolize this synthetic compound, levels may build up with unknown consequences, but at least one study suggests deleterious effects including immune impairment. Additionally, folic acid may “mask” B12 deficiency by correcting for blood changes without actually allowing for the one-carbon cycle to proceed as it would like to.

B12 Deficiency: A Trigger for Depression and Anxiety?

Once it is established that a patient has overt serologic evidence of deficiency (in blood) and/or they respond to treatment, we must ask how they became deficient in the first place. Here are some considerations:

1. Achlorhydria
This is the fancy term for low stomach acid, something which sometimes occurs in the setting of low thyroid function, chronic stress, aging, and most salient to a recent (December 2013) paper – acid blocking medications.

A Common Scenario

A patient is eating foods that they are unable to properly digest and that promote local inflammation, further perpetuating poor digestion and transit. These may include processed dairy, foods fried in vegetable oils, and cereal grains. The patient experiences the reflux of this poorly mobile, poorly digested sludge, or chyme, as a sign that they have high stomach acid.

They are put on a medication (or buy one over the counter) that has never been studied for long-term use, and that population-based observational studies link to pathogenic overgrowth of bacteria, fracture, and nutrient deficiency. Why? Because stomach acid is critical for triggering digestive enzymes along with an escort called “intrinsic factor” for B12 absorption and managing local microbial populations.

If this patient’s B12 deficiency and digestive imbalance goes unattended, they will likely develop symptoms that will earn them a prescription for an antidepressant, and the medications start to pile up.

2. Dietary Restriction
Animal foods are primary sources of B12, although algae and fermented foods may represent promising options for some diligent individuals. Stores deplete over time, and deficiency-related symptoms may present long after dietary restriction. Carefully sourced animal foods are also a unique source of pre-formed fat-soluble vitamins, creatine, choline, and carnitine.

3. Autoimmune
One of the possible mechanisms of deficient B12 absorption is pernicious anemia, an autoimmune response to parietal cells, associated with atrophic body gastritis in the stomach. H. pylori infection and associated molecular mimicry are thought to represent a plausible trigger.

 4. GMO/Gluten
The powerful synergy of gluten-containing and genetically modified processed foods may have an impact on everyone’s guts, not just those people with biopsy-confirmed Celiac disease. In fact, the biopsy is fast losing position as the gold standard diagnosis because of extra intestinal manifestations of gluten immune response that don’t cause observable changes to the small intestinal villi (joint pain, or rash, or gait-instability without obvious gut symptoms). In these individuals, the innate immune system responds to gluten in these grains, and food fragments may pass into the blood stream through zonulin-gated tight junctions. Direct damage to the cells in the small intestine may result from whole grain foods with high amounts of inflammatory lectin.

Genetically modified corn may be playing a part in small intestinal villious changes as demonstrated in this study, in mice consuming corn oil. There is also reason to believe that Bt-toxin from Monsanto’s GMO corn plays a role in intestinal permeability as it was found in the blood of 93% of pregnant women and 80% of their fetuses. The herbicide itself also changes the existing flora, preferentially killing beneficial bacteria, and potentially allowing for growth of pathogenic microbes in the small intestine.

5. Medications
Notably, Metformin, the blood sugar regulating medication, has been demonstrated to be a risk factor for deficiency, a fact that few patients are informed of before complying with their prescribed treatment.

Recognizing a B12 deficiency

Vitamin B12 deficiency can be slow to develop, causing symptoms to appear gradually and intensify over time. It can also come on relatively quickly. Given the array of symptoms it can cause, the condition can be overlooked or confused with something else. Vitamin B12 deficiency symptoms may include:
·         strange sensations, numbness, or tingling in the hands, legs, or feet
·         difficulty walking (staggering, balance problems)
·         anemia
·         a swollen, inflamed tongue
·         yellowed skin (jaundice)
·         difficulty thinking and reasoning (cognitive difficulties), or memory loss
·         paranoia or hallucinations
·         weakness
·         fatigue

While an experienced physician may notice the symptoms and be able to detect a vitamin B12 deficiency with a good interview and physical exam, a blood test is needed to confirm the condition.

Early detection and treatment is important. “If left untreated, the deficiency can cause severe neurologic problems and blood diseases,” says Dr. Bruce Bistrian, chief of clinical nutrition at Harvard-affiliated Beth Israel Deaconess Medical Center.

B proactive

It’s a good idea to ask your doctor about having your B12 level checked if you:
·         are over 50 years old
·         take a proton-pump inhibitor (such as Nexium or Prevacid) or H2 blocker (such as Pepcid or Zantac)
·         take metformin (a diabetes drug)
·         are a strict vegetarian
·         have had weight-loss surgery or have a condition that interferes with the absorption of food

A serious vitamin B12 deficiency can be corrected two ways: weekly shots of vitamin B12 or daily high-dose B12 pills. A mild B12 deficiency can be corrected with a standard multivitamin.

In many people, a vitamin B12 deficiency can be prevented. If you are a strict vegetarian or vegan, it’s important to eat breads, cereals, or other grains that have been fortified with vitamin B12, or take a daily supplement. A standard multivitamin delivers 6 micrograms, more than enough to cover the average body’s daily need.

If you are over age 50, the Institute of Medicine recommends that you get extra B12 from a supplement, since you may not be able to absorb enough of the vitamin through foods. A standard multivitamin should do the trick.

Is B12 the Cure?

When treating B12 deficiency, while the underlying cause is being investigated, use of an activated form of the vitamin is recommended, and preferentially effective at improving levels. Cyanocobalamin is a synthetic form of B12 that has been bound to a cyanide molecule, while hydroxy, adeno, and methyl are all forms of B12 that are active, natively, in the body.

There is a debate over the comparative efficacy of injectable vs oral dosing, and it has been my clinical experience that injectable dosing yields a more robust and reliable clinical effect. Dosing is typically 1000mcg-5000mcg 2-3x times/week for one to two months depending on patient characteristics and response. Consider the power of this vitamin. Respect its necessity and protect your body’s access. It may very well be the last antidepressant you’ll ever need.

Sources of Vitamin B12

We know that having ample amounts of B12 in the body is an essential piece for maintaining a healthy brain and stable mood. But what does this mean for you?

One of the first steps is to make sure you are getting adequate amounts of B12 in your diet. The Recommended Dietary Allowances (RDA) for vitamin B12 is just 2.4 mcg/day. Many people following a standard, varied diet will reach this amount, however those who avoid or limit proteins for any reason may experience difficulty in getting their RDA. The primary food sources of B12 are animal based and include fish, meat, poultry, eggs, milk and other dairy products.

Specifically, the top 5 foods most concentrated in B12 are:

1. Shellfish (clams, mussels, crab)
2. Organ Meats (like beef liver)
3. Wild-caught Fish (such as salmon, trout, mackerel)
4. Grass-fed Beef
5. Pastured Eggs

If B12 has been depleted for some time, supplementing may be necessary. Generally, vitamin B12 is best assimilated when taken as part of a full spectrum B-Complex that contains all of the other vitamins in the B group (such as B1, thiamine, niacin, riboflavin, folate etc.).

Food-based supplements like grass fed Desiccated Liver (this is the first ever USA sourced grass fed liver) will naturally provide this synergistic combination, as will fermented options like Premier Max-B-ND Live Source Vitamins.

It is also important to note that there are factors aside from diet that influence our B12 levels, and this is where many problems with deficiency arise. For example, certain medications prevent the full absorption of B12 from the gastrointestinal tract. Antacids in particular are known to diminish B12, because hydrochloric acid is necessary for cleaving B12 from foods so that it can be absorbed by the intestines. Health conditions associated with gastric inflammation also create problems with B12 assimilation. Many autoimmune conditions such as thyroiditis fall into this group.

If you are concerned that you may have a B12 deficiency that is impacting your moods and well-being, it is always best to have a conversation with your healthcare provider. Assessing for and treating B12 deficiency can be a very important piece of the recovery process in affected individuals, and a treatment that can be done relatively simply at that.

Sources and Additional Information:


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