One of the most remarkable papers I have read in the psychiatric literature was about a 57 year old woman who was treated with months of both antipsychotic and antidepressant medications and given two rounds of electroconvulsive treatment before anyone bothered to check her vitamin B12 level.
Her symptoms were years in the making including tearfulness, anxiety, movement abnormalities, constipation, lethargy, and eventually perceptual disturbances (hearing her name called) and the ultimate in severe psychiatric pathology: catatonia. Despite her inpatient treatment, she remained suicidal, depressed, and lethargic.
Within two months of identifying her deficiency, and subsequent B12 treatment, she reverted to her baseline of 14 years previous, and remained stable with no additional treatment.
If this is not a wake up call to the average psychiatric prescriber, I’m not sure what is. Much of what we attribute to serotonin and dopamine “deficiencies” melts away under the investigative eye of a more personalized style of medicine that seeks to identify hormonal, nutritional, and immune imbalances that can “look” psychiatric in nature.
How can B12 impact brain health?
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:
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.
- 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.
- Genetic override
Sufficient supply of an activated/bioavailable form of a vitamin (ie 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?
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:
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.
What causes deficiency?
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:
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.
The aforementioned paper, Proton Pump Inhibitor and Histamine Receptor 2 Antagonist Use and Vitamin B12 Deficiency, was a case control evaluation of 25,956 patients on acid-blocking mediation, which found that 12% of those taking these medications were deficient in B12 at a two year evaluation, and that the higher their daily dose, the stronger the association. We’ve already reviewed the false negative rate of this blood test for B12 sufficiency, so we can only assume that many more of those pill-popping patients were suffering from the effects of deficiency that was not detected.
2. Dietary Restricition
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.
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.
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 extraintestinal 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.
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.
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 (nice!), 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.
This perspective on the role of B12 in mental health was recently featured on Mercola.com in an article entitled Long-Term Use of Proton Pump Inhibitors and Other Antacids Can Cause Vitamin B12 Deficiency.
February 8, 2014 at 12:18 pm
Is it ever possible to react negatively to methyl b12 ie with anxiety for some reason? If so what might cause this. In someone who started with b12 of 73…
February 8, 2014 at 1:11 pm
Kelly Brogan MD says
Yes – this is definitely possible. Alternative forms (hydroxy), coadministration with methylfolate, and/or niacin may be used as an “antidote”. MTHFR.net discusses this in more depth.
February 8, 2014 at 5:49 pm
Jessica Cox says
What type of B12 is usually injected? Is it safe?
February 9, 2014 at 5:28 am
I’m aware of blood profiling for cholesterol / lipoproteins as a common practice in the states, here in the UK I know of testing for allergies and things like anemia. But is there a similar practice to look at the overall vitamin/mineral levels, or indeed hormonal profiling of someone’s blood? If not would this be a feasible or indeed viable as an alternative medical service?
One of the challenges to this here in UK is that you are not allowed to do blood tests as an alternative medical practitioner unless its an ‘official’ service because its an invasive procedure.
February 9, 2014 at 2:29 pm
Kelly Brogan MD says
As I mention in the post, I believe B12 supplementation to be a safe and potentially high yield empirical intervention (meaning try it regardless of testing)…
February 10, 2014 at 7:20 pm
Debbie Simons says
I am a nurse practitioner in an out patient psychiatric practice. Thank you for the B12 information. I try to look at the whole person before prescribing medication. This is a level I will add to my initial new client lab work.
February 12, 2014 at 3:28 am
Karen Thompson says
I thank Kelly Brogan for bringing the initial case study relating to the mis-diagnosis to our attention. To differentiate between the emotional and pragmatic issues this example highlights is very difficult. The patient in question, in my opinion, underwent procedures and drug administration, that in light of her real illness, were no less than toturous – this kind of practice belongs in mediavel society, not contemporary. I find it hard to get past what this woman was subjected to. Yet the problems still occur – patients whether they are suffering from physical symptoms or psychiatric have their concerns dismissed or misattributed. The attention given to functional disorders, which essentially has become the ‘pit’ into which all symptoms and patients are tossed when medics cannot find substantive ‘evidence’ of injury, should be covered over. This avenue of diagnostics should be closed to the medical profession. B12 deficiency and the neurological problems it causes is typical of the problems that result relating to functional disorders. It is difficult to initially diagnose with current tests. It is difficult to substantiate physical injury with current tests (especially in cases where the patient has undergone treatment) and the medical profession, although surrounded on a daily basis by examples of it, are woefully ignorant of the condition outside that of haematological indicators. It is time for the individual observation to return to science. Functional disorders give science an answer, a reason, an excuse and are in essence ensuring that science is regressing rather than advancing. And, as if any further evidence is necessary, the one case highlighted proves that. What we need to ask ourselves is, how many more like that are there? How many more are not getting this illness picked up because they are either not tested or not treated correctly (doctors treat haematological symptoms not physical) and are condemed to institutions or certain death?
February 12, 2014 at 12:36 pm
Marilyn Gill says
Finally! a doctor of psychiatry who is looking for the underlying causes of illness/mental disorders and taking action and talking about it. Yeah! I have eschewed psychiatry for many years now seeing the neurological damage done to our son. I have known for years that his condition is due to allergies, toxicity and deficiencies. I remember a psychiatrist telling me that the drug was out of his blood after 2 weeks and therefore what we saw was truly mental illness. I retorted with, “Man is not made of blood alone”. Unfortunately, I didn’t have anyone in this environment who saw it as I did and unfortunately, I was not well enough educated in what some of the tests (if they existed then) or the solutions might be. I would be more than willing to work with a psychiatrist who was looking for these underlying causes of deviating-from-the-norm behaviors.
From my perspective, a psychiatrist who is willing even to look at these issues and work with a nutritionist and any other doctor the client wants is one whom I would endorse and employ in a heartbeat. I once suggested to Dr. Grace Jackson before she wrote her books that she ought to think of titling herself as an ‘environmental psychiatrist’. She seemed to like the idea. I think that this is definitely the time for psychiatry to restructure itself. Unfortunately, psychiatric labels stick with a person for years and with the kind of Big Brother society we have – these labels may affect some folks lives in ways they never dreamed of. Perhaps, the whole medical lot needs revamping.
WELL DONE, Dr. Kelly Brogan! How about getting your male counterparts in on your more holistic approach and getting Big Pharma less in the picture when it comes to psych drugs? Thank you.
February 12, 2014 at 5:21 pm
Dr. Mike Greenberg says
Thank you for this insightful article. I can utilize the information immediately.
March 7, 2014 at 3:44 am
I had a biomeridian body scan done. My intestinal cilia is in good shape, but my intrinic factor is low and I’m not absorbing B vitamins as I should. Does this require the GAPS Diet as opposed to just eating a Weston Price type diet but adding in more broth?
If so, for how long? I”ve read that this problem is autoimmune.
March 18, 2014 at 1:19 pm
In point #4 about GMOs, I was very interested in reading the study about fetal contamination of the Bt toxin. However, upon reading the abstract, I noticed there was a comment from PubMed essentially saying the study was weak and used incorrect methods. Do you know of any studies worth referencing? I mean according to the comment, they didn’t even use a test validated for mammalian tissue. That seems pretty flimsy to me. I don’t doubt the presence of unwanted toxins in our blood, and of course, the fetus within, but I don’t like crappy science either.
March 22, 2014 at 10:46 am
Kelly Brogan MD says
Hello and thank you for your insightful point. Yes, the kit uses an enzyme linked immunoassay to assess for Bt protein. There is the possibility for cross-reactivity with the human proteome; however, this would only substantiate further risks of molecular mimicry. Given these possibilities, this study raises a substantial signal of harm that should activate the precautionary principal until proven otherwise.
April 24, 2014 at 9:29 am
B12 Deficiency and Neuro-Psychiatric Disorders by Jeffrey Dach MD - Jeffrey Dach MD says
[…] with related interest: See this excellent article, Vitamin B12 Deficiency and Brain Health by Kelly Brogan […]
June 10, 2014 at 2:43 pm
What is best to take for b12? Like what brand?
June 11, 2014 at 12:44 pm
I would also love to know recommended brands for vitamin supplements. What is superior? And, am I wasting my money and time taking other brands?
June 11, 2014 at 12:51 pm
Kelly Brogan MD says
The important factor is that it is not a cyanocobalamin and that there aren’t a bunch of additives. You can peruse some of my selections here, but I don’t endorse any specific companies…https://www.healthwavehq.com/welcome/kbrogan
June 16, 2014 at 1:01 pm
Thank u for the wonderful article..my mom is into depression on and off since the last 20 yrs…last week a pyschiatrist recommended a vitamin b12 test …we found it to b 176..can vitamin b12 supplement help her
July 20, 2014 at 10:02 pm
I liked this article. I have been sick for about 7 year and been to many doctors it wasn’t till I got into the uc neurology system that I found out I’ve been b12 deficient for along time. I’ve gone though years of nausea abdominal pain changes in balance vision and personality. Nerve pain tingling pins and needles through out my body and really think I’m going to diagnosed with dementia. I’m 31 and just started shots. Which I find I’m walking little better. Looks like I had issues with mtfr genes antacids and gut absorption.
August 4, 2014 at 1:56 am
I had anxiety for 15 years that was just a b12 deficiency. a lot of doctors. none of them figured it out or even checked it until I lost feeling in 3/4ths of my body. then the MRI report suggested I had it, and a blood test confirmed. Now I feel so great, with my 1x a month shot. but the shots…the doctors are so hesitant to give shots and its really bad b/c the pills and sublingual do NOT work as well. thank you for bringing awareness to this issue!
September 19, 2014 at 1:18 pm
My son is B12 deficient, according to labs, and has ADHD-inattentive type. We are doing everything holistically, including supplementing iron (per lab test results), magnesium, zinc, and fish oil. Whenever we give him B12, whether is be methyl, hydroxyl, or several others, it affects his moods in extreme ways! I really think the B12 could be the “missing piece” that he needs to be able to focus better, but he just can’t tolerate it. We can’t afford genetic testing right now, so I am looking for something to try. I’ve read about lithium supplements to take with the B12. What do you think about this? Do you have any other suggestions? Thank you!!!!
September 19, 2014 at 6:36 pm
Kelly Brogan MD says
Hi Heather – as the saying goes, “start low and go slow” and use the other cofactors like methylfolate, B1, B2, B3 in conservative doses.
September 24, 2014 at 11:32 pm
“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.”
Why are patients being fed this crap in the first place?
“Let thy food be thy medicine.” -Hippocrates
September 26, 2014 at 6:14 pm
Amy Rossitto says
I am 48 y/o female in good health taking Prilosec every day (1-2 times/day) for a year when I developed tremors, balance issues, speech issues, foggy brain, anxiety, heart palpitations, etc. Went to the ER 3 times and family Dr and they were all mystified. All labs and MRI scans perfectly normal. I read your article and realized that I’m vitamin B12 deficient as a result of the antacid meds. I stopped antacids. I’m taking Vitamin B12 at a dosage of 5000 mcg once a day. What is the normal course of therapy in this situation?
September 26, 2014 at 6:45 pm
Kelly Brogan MD says
orally, it varies, but two months is reasonable.
September 26, 2014 at 11:55 pm
Amy Rossitto says
Do tums also interfere with absorption of vitamin B12? I’m trying to find a less damaging means of dealing with my acid reflux.
October 3, 2014 at 12:24 pm
It is important to keep the brain functioning properly otherwise, the whole body will be disrupted!
October 15, 2014 at 2:54 am
I am so happy I found this article. My teenage daughter has been suffering worsening depression, anxiety and panic attacks over the past year, and after trying to treat it with exercise and diet, the GP has finally put her on medication. But he also suggested a blood test for B12, and the result came back severely deficient. We can’t identify what has caused the deficiency however (it’s not diet, and nothing else seems to fit either ) – can it be the result of illness? Just before the symptoms started showing, she was diagnosed with hand, foot and mouth disease. Also, the chemist has given her a B12 mouth spray, which he says is more efficient than tablets – what are your thoughts?
October 15, 2014 at 8:02 am
Kelly Brogan MD says
I recommend seeing a Functional Medicine doctor, using injections, and exploring the possibility of an autoimmune process (parietal cell) as an underlying cause. Best of luck…
October 25, 2014 at 8:03 am
hey i have experienced severe anxietyand accompanied depersonalization(i think it is),my doctor told me it was just anxiety and prescribed me medicines(anti depressants).i didnt take them though except fora mild doze of opiprol.i have been experiencing anxiety since past 5 months and depersonalization too.i researched a lot on the topic and hence got to know the imp of b12.i got my b12 levels checked and they wer 256pg/ml.
ever since the past week m taking 1500 mcg mecobalamine .
can it be that my anxiety and even depersonalization developed coz of b12?
and they will be fine as soon as b12 levels get back to normal.i have had no traumatic events to cause anxiety otherwise.
October 26, 2014 at 10:11 am
and in any case is 256pg/ml is low enough to cause such conditions?
November 6, 2014 at 12:09 pm
nov 5 2014 says
I’m a 52 yr old male. Approx. 6 months ago anxiety, paranoia, and agoraphobia swept over me. I am a very healthy and active. I have never been on any medication in my life and only had a couple anxiety episodes, many years ago. What came over me was absolutely terrible, I really felt psychotic- that I was “losing it”. I tried to live with it for a few months and see if it would exit as it came. I went to Doctor and got blood tests done. All turned out normal except my B12 was 330. The test sheet said below my B12 reading- “Although the reference range for vitamin B12 is 200-1100 pg/ml, it has been reported that between 5 & 10% of patients with values between 200-400 pg/ml may experience neuropsychiatric and hematologic abnormalities due to occult B12 deficiency. ..”. Wow, yet . My Dr. never mentioned it. After much research and reading the book “Could it be B12″ I started taking methyl B12 5000 mcgs daily. I’ve been doing this now for about 1 month and have seen an absolutely dramatic change for the better. I still have slight symptoms, some days worse than others and sometimes no symptoms at all. I hope full recovery is close. The scary thing is, the doctor offered me antidepressants; I said no. If I had taken them I would be attributing my recovery to them and not B12 if I were taking both.
November 7, 2014 at 12:56 pm
What an irresponsible doctor to want to put you on antidepressants. They are extremely difficult to get off of and they hardly benefit anyone on the long run. The mechanism you might want to look into is methylation. It has a lot to do with B12. If you study the pathway, you can understand that things can happen at more then one of the steps. You can adjust your supplements accordingly.