Powerful Pathways of B Vitamins for Mental Health
July 01, 2021
It's just a vitamin, right?
Actually, it's a suite of essential vitamins that are tied into every pathway of the body and with our focus, the brain.
There's been a slow creep of information on two critical gene pathways:
- MTHFR - controls folate function
- MTRR - controls vitamin B12 function
This isn't a rare thing.
Roughly 30-40% of the US population has a version of the MTHFR called C677T (relates to the position) where they don't process folate sufficiently.
MTRR has a worldwide prevalence of about 30%.
Some people have both!
You can check your status via 23andme or other genetic test studies and doctors can even run quick tests now to see if you have variants of either.
Interestingly, you can also get simple lab tests for folate and B12 levels. Most doctors don't run it unless you request it.
Such a simple test with such powerful effects.
Outside of Vitamin D deficiency (see here), there's probably not a simpler fix for the full range of mental health issues.
We're going to dive into the research below with these topics:
- A quick intro to your Vitamin B's
- Vitamin B's and mental health
- Vitamin B12 and mental health
- Folate and mental health
- Riboflavin and mental health
- Vitamin B6 and mental health
- Methylated versions of Vitamin B
Let's get started!
A quick intro to your Vitamin B's
Simply put, Vitamin B's operate as gatekeepers for a range of chemical processes that occur in the body and brain.
They are generally needed to facilitate other processes. Nothing runs without B vitamins!
Everything from breaking down carbs, proteins, and sugars to repair and management of DNA.
Our bodies don't synthesize Vitamin B's internally so we need to get it from our food and unfortunately for the vegan crowd, the primary source is animal-based.
Dairy, meat, organs, etc.
Hence the tie with anemia:
Vitamins linked to vitamin deficiency anemia include folate, vitamin B-12, and vitamin C.
Since almost every key pathway requires one or more of the B vitamins to even function, we can quickly get lost in the weeds.
Instead, let's zero into mental health since that's a big part of our focus on CBD (CBD and mental health).
How do the vitamin B's work in the brain?
Vitamin B's and mental health
Okay...this gets so interesting.
Let's start with the very powerful neurotransmitters.
Just two big ones for mood and mental health:
Through their role in one-carbon metabolism, B vitamins act as cofactors in the synthesis and regulation of dopaminergic and serotonergic neurotransmitters.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770181/
Serotonin is your master mood regulator and the governor of ALL human behavior.
We don't use that term lightly...check out our Serotonin review to learn more.
It's intimately linked to anxiety, depression, and personality disorders.
Generally speaking, serotonin manages stress response and brain repair (see BDNF).
If we had to pick one neurotransmitter most integrated into mental health, it would be serotonin since it's a master regulator of other messengers.
Such as dopamine!
Dopamine is our reward circuit player with critical control over motivation, addiction, and "verve".
See our Dopamine review.
Serotonin partially manages dopamine function and both require B vitamins.
Cofactor means that B vitamins are a rate-limiting player.
If B vitamins go down, serotonin and dopamine production and "regulation" are reduced.
Remember, 30% of the population has an internal downregulation of B vitamins due to the MTRR and MTHFR gene variants.
They're starting off with one paddle!
That's just one avenue of dozens if not hundreds.
What about homocysteine?
Homocysteine is an amino acid that gets broken down into other key proteins needed by the body.
B12 is needed to break it down and if we're low in B12, we end up with too much homocysteine...a known marker of B12 deficiency.
There's a long history of this effect on cardiovascular health but what about mental health?
lower plasma tHcy concentrations were associated with reduced depression symptoms in older patients recovering from acute illness.
https://academic.oup.com/ageing/article/40/6/702/46684
Interestingly, we absorb fewer B vitamins through the gut as we get older.
A great deal of mental health revolves around stress response.
You can think of a spectrum of stress thresholds for different individuals.
Higher B-vitamin supplementation's effect:
Supplementation reduced the levels of perceived stress (standard mean difference [SMD]=0.35; 95% confidence interval [CI]=0.47-0.22; p=.001), mild psychiatric symptoms (SMD=0.30; 95% CI=0.43-0.18; p=.001), and anxiety (SMD=0.32; 95% CI=0.48-0.16; p<.001)
https://pubmed.ncbi.nlm.nih.gov/23362497/
So, a reduction in perceived stress, anxiety, and psychiatric symptoms. Confusion also dropped.
Remember that B vitamins are key to serotonin production and serotonin is our primary stress responder.
That's the damaging side (stress).
Let's look at the repair side...BDNF!
This is our brain's fertilizer and it's implicated across the range of mental health.
B vitamins??
combined supplementation of both vitamin B12 and omega-3 fatty acids together increases the levels of BDNF in the cortex and hippocampus region of the brain
https://www.brainanddevelopment.com/article/S0387-7604(13)00350-1/fulltext
In our 1 million+ words on CBD, BDNF was the common ground across mental health and addiction.
- Positive effects on the brain from exercise? BDNF
- Mindful meditation and yoga? BDNF
- Psilocybin? BDNF
In fact, the two most common triggers for addiction relapse were:
- Stress levels
- BDNF levels
It's the best-kept secret for mental health and B vitamins directly figure into its function.
BDNF is key to the process of neurogenesis or basically...brain repair, growth, and change.
Check out our review of how SSRIs (antidepressants) really work (hint hint...BDNF).
We could go down multiple avenues but let's zero in on the specific B vitamins and mental health issues.
Vitamin B12 and mental health
B12 is tied to the MTRR gene variant that's so prevalent (check your 23andme or David Lynch's Stratagene).
B12 is one of the main issues with a purely vegan diet.
It's tied to the protective sheaths around nerves, energy production, and general brain function.
Let's walk through some common mental health issues.
B12 and depression
To start off...
B12 and depression:
At three months follow up 100% of the treatment group showed at least a 20% reduction in HAM-D score, while only 69% in the control arm showed at least a 20% reduction in HAM-D score (p<0.001). The findings remained significant after adjusting for baseline HAM-D score (p=0.001).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856388/
HAM-D is the main test for depression levels.
There is now substantial evidence of a common decrease in serum/red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression.
https://pubmed.ncbi.nlm.nih.gov/15671130/
Remember how homocysteine (elevated when b12 is low) blocked serotonin function and serotonin is the main target for SSRIs (see CBD versus SSRIs).
Then there's the whole spectrum of anxiety, panic attack, and OCD.
They all share one key pathway...GABA!
It's our brain's brake pedal (see CBD and GABA).
- When it's exhausted from too much stress (cortisol) or activity (glutamate), anxiety, panic, repetitive thoughts, and insomnia are the results.
- Vitamin B12 enhances GABA content but reduces glutamate content in the rat suprachiasmatic nucleus
https://pubmed.ncbi.nlm.nih.gov/9249572/
Okay...so… a boost to our calming powerhouse and a reduction to our excitability (gas pedal) player...glutamate.
The area they were looking at is very fascinating...the trigger switch for sleep!
When our founder was in the middle of rolling anxiety and panic attacks from brutal perimenopause (estrogen drives serotonin and progesterone manages GABA), a B12 shot felt like a powerful sedative.
Stress can eat up B12 and B vitamins in general.
We can't go through every issue but some other key examples.
B12 and schizophrenia (see CBD and schizophrenia):
A study by Silver (2000) on 644 bedridden psychotics reported that 78.3% of schizophrenic patients had vitamin B12 deficiency
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252772/
Adding in mania from bipolar:
The most common psychiatry symptoms reported in the literature associated with vitamin B12 deficiency was depression, mania, psychotic symptoms, cognitive impairment and delirium.
https://www.sciencedirect.com/science/article/abs/pii/S0924933817315729
Get your B12 checked...it's very popular (finally) and check your MTRR status.
You'll notice that in many of the studies on B12, another B vitamin is generally linked.
Folate!
Folate and mental health
The connection isn't surprising since the two need each other to function correctly.
In fact, they intersect at a very powerful player in mood control...SAMe:
It activates such big-time biochemicals as the neurotransmitters serotonin and dopamine and increases the fluidity of nerve cell membranes to make neurons more responsive.
https://www.psychologytoday.com/us/articles/200203/the-sam-e-story
There's serotonin and dopamine...our mood booster and motivator.
SAM-e may be the linchpin for how B12 and folate work for mental health when deficient.
Here's the key takeaway:
SAMe and folate are important cofactors in neurotransmitter generation pathways
https://www.psychcongress.com/blog/same-and-folate
SAM-e needs folate and B12 to work.
One note...folic acid is not the same as folate for people with MTHFR gene variants.
In fact, folic acid actually reduces the pathways!
People with MTHFR mutations might have more difficulty converting folic acid into its usable form, and this may cause symptoms to worsen. Check if your current supplements contain folic acid and if they do, stop taking them or switch to another brand.
https://www.parsleyhealth.com/blog/mthfr-mutation/
Folic acid is a synthetic version of folate and if we've learned anything from hydrogenated oil, synthetic hormones (see estrogen safety), and fake sugars, the synthetic never works as well as the natural version.
In fact, there's a synthetic version of CBD with night-and-day difference in side effect profile from real CBD.
To save pennies. We never learn.
There's a great review of folic acid versus folate here:
https://www.drfuhrman.com/blog/16/why-you-need-folate-and-not-folic-acid
Technically, people with MTRR or MTHFR gene variants should look for methylated versions of B12 or folate.
After all, folate's role (same as SAM-e) is to donate a methyl group to turn various pathways on or off including neurotransmitters that govern mental health.
So...let's dive into folate.
Folate and depression
A study looked at supplementing folate for people who were unresponsive to SSRIs:
Depressed individuals with low serum folate also tend to not respond well to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Correcting the insufficiency by dosing folate along with the SSRI results in a significantly better antidepressant response.
Research here.
We know that SSRIs boost serotonin (till they build tolerance) so this is likely the SAM-e connection.
Thus…
Low folate status was found to be most characteristic of recently recovered subjects, and a large proportion of such subjects were folate deficient.
https://www.karger.com/Article/Abstract/68692
There's a significant tie-in between the methionine pathway and developmental disorders like schizophrenia.
Some of this may be tied to deficiency in core B vitamins:
Folate and vitamin B12 reduce disabling schizophrenia symptoms in some patients
https://www.eurekalert.org/pub_releases/2013-03/mgh-fav030413.php
Again, a great deal of this could be due to MTHFR gene variants. Get yours checked.
Such as with bipolar:
Functional deficiency, due to a common genetic variant of the methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR) gene, could also affect the presentation of bipolar disorder.
https://pubmed.ncbi.nlm.nih.gov/23969624/
We could go on and on but the key takeaway:
- Folic acid is NOT folate (folate is better)
- MTHFR gene variant really matters (methyl version of folate then)
Let's turn to some less-known B players.
Riboflavin (B2) and mental health
Riboflavin is a key catalyst for the other B vitamins to work well.
Is it important for brain function?
In fact, it has been found that riboflavin ameliorates oxidative stress, mitochondrial dysfunction, neuroinflammation, and glutamate excitotoxicity; all of which take part in the pathogenesis of PD, migraine headache, and other neurological disorders.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517396/
Goodness. This is a laundry list of things that can derail brain function.
Check out CBD and oxidative stress, CBD and mitochondria, CBD and neuroinflammation, or CBD and glutamate to learn why.
Every mental health issue reflects aspects of each of these pathways.
Every one!
Let's zero in on the Glutamate piece. Glutamate is our brain's "gas pedal".
We need it to run everything in the brain but too much is actually toxic.
- Long-term excess glutamate literally eats up the brain (depression).
- Short-term excess overwhelms GABA and leads to anxiety, panic attacks, OCD, and migraines. Even seizures.
So...riboflavin has management responsibility for very important pathways for mental health:
- Boost B6 - a key neuroprotector and supporter of neurotransmitters like serotonin
- Manages kynurenine and tryptophan (the serotonin pathway)
- Manages homocysteine metabolism (which we don't want too high)
Deficiency is less common in the developed world (due to supplementation) but close to 50% of the developing world is affected.
The glutamate piece is really fascinating...especially for the anxiety spectrum of issues.
Also, the produced kynurenines influence glutamate receptors and their consequent excitotoxicity.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517396/
This is the whole basis behind magnesium glycinate, NAC, and other powerful tools for mental health.
Check out the glutamate review. In fact, our theory is that people who routinely use THC are doing to suppress too much glutamate (see THC to calm glutamate).
Excess glutamate is one of the biggest and most exciting aspects of mental health research.
It ties into the whole inflamed brain vein of study which affects autism, schizophrenia, Parkinson's, and the range of anxiety/depression issues.
Let's turn to B6, which riboflavin manages.
Vitamin B6 and mental health
Just like B12, B6 is needed to make neurotransmitters that govern mood and brain health.
There are interesting studies with B6 and magnesium for stress response and mental health:
Outcomes included changes from baseline in DASS-42 depression and anxiety scores, and QoL (Short Form-36 Health Survey). DASS-42 anxiety and depression scores significantly improved from baseline to week 8 with both treatments, particularly during the first 4 weeks.
https://pubmed.ncbi.nlm.nih.gov/33864354/
Remember that stress is key to eating up serotonin, GABA, anandamide (see anandamide - our "bliss" molecule).
That's mood, calm, and well-being right there.
Basically, magnesium and B6 together significantly improved stress response.
Magnesium acts as a buffer for stress and excess glutamate so that makes sense. See our review on magnesium glycinate for mood, sleep, and migraines.
In fact, stress response or "resiliency" may be the key driver to full B vitamin family effect:
Of the eight studies in ‘at-risk’ cohorts, five found a significant benefit to mood. Regarding individual facets of mood, B vitamin supplementation benefited stress
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770181/
One more stop.
Vitamin B4 (choline) and mental health
Choline is so fascinating that we did a full review on acetylcholine, the net result neurotransmitter.
It's literally the stuff of thinking. It also governs the rest and digest part of the autonomic nervous system.
This offsets the fight or flight push so the impact on calm is very relevant.
Interestingly, people drawn to nicotine may be trying to self-medicate for low acetylcholine since it plugs directly into the acetylcholine receptors.
It's this curious combination of mentally calm and yet engaged that makes acetylcholine so important.
Think of ADHD, brain fog, and the biggest connection...dementia.
Of course, estrogen boosts acetylcholine and it goes away in our late 40's. See estrogen and mental health which is how we found CBD to begin with (that story is here).
Here's the quick summary of acetylcholine's effect:
It plays a role in motivation, arousal, attention, learning, and memory, and is also involved in promoting REM sleep.
https://www.verywellmind.com/what-is-acetylcholine-2794810
Like we said...the stuff of thinking!
Choline (B4) is the main precursor to acetylcholine which gets made in the Vagus nerve.
This nerve hub connects our two brains...the one in our head and the largest grouping of neurons outside the head...our gut!
There's lots of interesting research about stimulating the vagus nerve (diaphragm breathing, singing, "ooommmmmms", and tapping) to create a sense of calm.
That's acetylcholine release!!
There's interesting research on acetylcholine and developmental issues such as schizophrenia and autism (see schizophrenia review or autism review).
Choline supplementation is associated with positive effects on cognition and behavior, including early behaviors associated with the development of autism and schizophrenia.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331361/
Eggs are a great source of choline but you can supplement directly as well.
One note...many common medications block or "rip" acetylcholine.
Basically, many of the "anti's".
- Antihistamines
- Antidepressants
- Hypertension drugs
- Antiacids
- Statins
That's likely the tie between Benadryl and Tylenol PM and dementia risk.
Check out the full review of acetylcholine to learn more.
Methylated versions of Vitamin B
What type of B vitamins then?
First, work with your naturopath to establish your current status and need.
There are lab tests that show levels of B12 and folate but the homocysteine lab is great to establish if there is an imbalance in this very co-mingled (b vitamins affect each other).
For example, folate can mask B12 deficiencies.
If you have MTRR and/or MTHFR, methylated versions of the B vitamins are really important as your body has trouble processing the standard versions.
Folic acid is NOT folate. It's synthetic and it actually blocks folate from the receptors and floats in the bloodstream with potential issues as the liver can't break it down quickly enough.
Again, work with your naturopath.
See our full review of mental health and CBD here for info and links to detailed reviews across many topics.
Be well. Take care of each other. Take care of yourself.
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.