by Kelly Brogan
Anxiety - All In Your Head?
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,
...and the ultimate in
severe psychiatric pathology:
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?
myelin (which allows nerve
impulses to conduct) and when this vitamin is deficient, has been
suspected to drive symptoms such as,
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,
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
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.
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.
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
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
Related, an excellent
review of clinical improvement with B12 treatment speaks to ten
studies which demonstrated "normal" B12 levels, often finding mean
levels in the 300-400pg/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
be elevated in the setting of either B12 or folate
insufficiency or dysfunction (often related to genetic
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
- 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
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.
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.
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.
Animal foods are primary sources of B12, although algae and
fermented foods may represent promising options for some
Stores deplete over
time, and deficiency-related symptoms may present long after
animal foods are also a unique source of,
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
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
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
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.
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.
Is B12 the
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 2-3×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