B Vitamins, Mood, and Methylation - It’s Complicated

by J.D. Moyer

There’s a great deal of misinformation on the internet regarding B-vitamins and health.  I know this because I’ve read most of it.  During the 5 years or so when I was researching how to cure my own asthma, I devoured every text I could find regarding the physiological effects of specific vitamins and minerals - especially the B-vitamins.  Large doses of B-complex or individual B-vitamins are recommended to improve mood, reduce PMS, reduce asthma symptoms, reduce the risk of various cancers, reduce the risk of heart disease, fight yeast infections, ward off mosquitoes, and prevent or cure numerous other ailments.

Which of these claims are based on reputable clinical research, and which are bullshit?

A quick overview — B-vitamins are water-soluble nutrients found in whole foods, and less so in refined/processed foods (unless they are added back in, as is the case with most white flour and breakfast cereals).  They are needed for various metabolic processes, are generally non-toxic, and deficiencies can result in serious illness and death.  The B-vitamins [wikipedia] include:

• B1 (thiamine) — deficiency results in beriberi
• B2 (riboflavin) — deficiency results in ariboflavinosis
• B3 (niacin or niacinamide) — deficiency results in pellagra
• B5 (pantothenic acid) — deficiency can contribute to acne
• B6 (pyridoxine and other forms) — deficiency can lead to microcytic anemia or depression
• B7 (biotin) — deficiency may cause growth problems in children
• B9 (folic acid) — deficiency results in macrocytic anemia and can cause birth defects
• B12 (cyanocobalamin and other forms) — deficiency results in macrocytic anemia, memory loss and other cognitive problems

Unless your diet is terrible or you’re a raging alcoholic, you’re unlikely to develop beriberi or pellegra.  However, many people can benefit from careful, controlled supplementation of one or more of B-vitamins. Clinical research supports supplemental doses of various B vitamins being effective in the following ways:

• reducing severe anxiety (niacinamide)
• reducing Type-2 diabetes symptoms (niacinamide)
• preventing/improving Alzhemier’s (niacinamide)
• reduce the risk of colon cancer (B6)
• improve reaction times (B1)
• boost HDLs and reduce arterial plaque (niacin)
• improve acne and reduce sebum production (B5)
• reduce intensity of migraine (riboflavin/B2)

Mosquitoes — B1 won’t protect you.

In no way is the above list meant to be comprehensive — there are hundreds of clinical studies demonstrating positive effects from supplemental and dietary B-vitamin intake.  Other claims, such as the idea that B-6 can cure carpal tunnel, or that B-1 can repel mosquitoes, haven’t held up under clinical scrutiny.

Less frequently noted are the side effects of taking very large doses of various B-vitamins, which can include:

• rapid and/or irregular heartbeat (B1)
• poor circulation/cold hands (B6)
• irritability, hostility (B6)
• numb hands/feet, neuropathy (B6)
• inability to fall asleep, interrupted sleep (almost all)
• increased histamine levels, worsened asthma symptoms (B3, B12)
• neon yellow pee (B2)
• loose stools/diarrhea/nausea (niacin)
• facial/skin flushing (niacin)
• liver damage (high doses of niacin, niacinamide)
• worsen acne (biotin)

I’ll share what I’ve learned and experienced - but consult your doctor before taking or stopping any supplements or medications.  I don’t have any medical training - I’m just an interested blogger.

Methylation, Health, and B-Vitamins

The same B-vitamins can affect different people in different (and even opposite) ways.  These differences may have to do with a genetic predisposition to being a “fast methylator” or a “slow methylator.” Methylation is a process by which a molecule donates or accepts a methyl group (CH3).  In biological systems DNA can be methylated, as well as proteins (lysine and arginine).  One type of protein methylation - the transfer of methyl groups from SAMe to histones - affects epigenetic expression (the degree to which certain genes are turned on or off).

The degree of protein and DNA methylation in an organism profoundly affects numerous aspects of physiology, including prenatal development, growth, metabolic levels, ATP (energy) production, neurotransmitter levels, metabolism of heavy metals, and susceptibility to cancer.  Problems with the methylation cycle may also be related to autism, mental illness, food allergies, asthma, and the development of heart disease.

So what influences rates of methylation?  Four factors, as far as I can tell:

1. Genetic factors, especially variants in the MTHFR and COMT genes
2. Psychological/emotional/physical stress
3. Smoking and other environmental toxins
4. Diet and nutrition (including supplements), especially B-vitamin and methionine intake

The effects of vitamins, even plain-old-regular multivitamins, are not trivial.  This study found that regular multivitamin intake reduced lung-cancer risk in former and current smokers by 43%, and that that risk reduction was associated with the methylated state of eight different genes (p16, MGMT, DAPK, RASSF1A, GATA4, GATA5, PAX5α, and PAX5β) involved in tumor suppression (adequate folate prevents these genes from becoming hypermethylated/turned off).  Eating green leafy vegetables and/or other highly pigmented fruits and vegetables also provided a more modest protective effect.   

This study also found associations between folate and methionine levels and hypermethylation of the RASSF1A and MTHFR genes (also related to cancer suppression).  This study (PDF) found that hypermethylation of the MGMT gene was implicated in prostate cancer and was strongly associated with meat-eating and smoking, and less so with alcohol consumption.

Regarding the MGMT study, why would meat-eating be associated with gene hypermethylation?  One possibility is the higher availability of the essential amino acid methionine (a methyl donor) in meat diets (although vegetarian diets can still be high in methionine if they include eggs, soy, brazil nuts, and/or sesame).  There is some evidence that methionine restricted diets are associated with longevity, with effects similar to caloric restriction.  Another possibility is the (presumed) increased availability of folate (from green leafy vegetables and other vegetable sources) in the diets of the vegetarians in the study.  A third possibility is that the study didn’t control for other lifestyle factors associated with meat-eating that could have influenced MGMT methylation levels.

Edit: This study found that higher B6 and methionine levels protected against lung cancer.  Increased dietary methionine may in fact be protective against many forms of cancer.

One reason to take up smoking — multivitamins will have more of a protective health effect. Wait …

The Biochemistry of Mental Illness

So, can we say that folic acid and folate are good, and methionine is bad, and leave it at that?  Not so fast.  Carl Pfeiffer was a pharmacologist who studied schizophrenia, manic-depression, and other forms of mental illness.  Along with Abram Hoffer, he co-founded the field of orthomolecular psychiatry.  He hypothesized that most people suffering from mental illness could be categorized into one of the following three groups:

“Histapenic” (low-histamine) individuals exhibited the following:

• low blood histamine
• high (toxic) copper levels
• low levels of zinc and manganese
• low levels of folate and/or B12
• high levels of homocysteine
• slower metabolic rates (higher body fat)

These patients tended to suffer from paranoid schizophrenia, bipolar disorder, psychosis, anxiety/panic attacks, hallucinations, hyperactivity, and depression (the latter especially in older patients).  Pfeiffer found that these people often benefited from large doses of folic acid, B12, B3, B6, zinc, and manganese.
“Histadelic” (high histamine) individuals exhibited the following:

• high blood histamine and basophil counts
• normal or low copper levels
• low levels of homocysteine
• higher metabolic rates (lower body fat)

These patients tended to suffer from depression, compulsions (like OCD), addictions (gambling/shopping/sex/alcohol, etc.), eating disorders (anorexia/bulimia), and phobias.  They reacted badly to folate — even dietary folate in fresh vegetables could worsen their depression (dubbed “salad bowl depression” by Pfeiffer).  They responded well to methionine and calcium supplements.

“Pyroluric” (pyroluria) individuals exhibited the following:

• excrete large quantities of kryptopyrrole in urine
• low levels of zinc and B6
• “sweet/fruity” body odor/breath
• pale skin, inability to tan

This condition, which could overlap with either of the other two or exist on its own, was associated with anxiety, depression, food sensitivities/celiac disease, social withdrawal, learning disabilities/ADHD, and autism.  More severe cases resulted in mental retardation and delayed growth and puberty.  In some cases psychological symptoms could be alleviated within just a few days with supplemental B6 and zinc.

Carl Pfeiffer

This paper from Pfeiffer goes into more detail, especially in regards to zinc and manganese supplementation and reactions to folic acid supplements.

Continued research in this field, carried out primarily by researchers at the Pfeiffer Treatment Center, has revealed that the first two types have methylation problems.  This paper from William Walsh goes into the details, but can be summarized as follows:

1. “Histapenic” (low histamine) types are “over-methylators.”  They tend to have higher methyl to folate ratios, which can result in the overproduction of dopamine, norepinephrine, and serotonin (via the BH4 rate-controlling process in catecholamine synthesis).  These types can benefit greatly from increased dietary and supplemental folate, B12, and other nutrients.  Here’s Dr. Walsh describing over-methylators on youtube.
2. “Histadelic” (high histamine) types are “under-methylators.” They have low methyl to folate ratios, which can result in lower levels of dopamine, norepinephrine, and serotonin.  These types can benefit from supplemental methionine, SAMe, and inositol (methyl donors).  Here’s Dr. Walsh describing under-methylators.
3. The third type, “Pyroluria”, is a genetic disorder which increases B6 and zinc urinary excretion, resulting in deficiencies of both nutrients and increased oxidative stress.  Here’s Dr. Walsh describing pyroluria.

While mainstream psychiatry has generally rejected the field of orthomolecular psychiatry in its entirety, some reputable papers (such as this one, published in The Lancet, and this one) allow that there may be relationships between folate levels, methylation processes, and mental illness.  While serious cases of schizophrenia are usually not treatable with vitamins alone (as is suggested by this study), that doesn’t mean that medical professionals should entirely discount the affects of vitamins on methylation processes when designing treatment protocols.  Schizophrenics may benefit from low methionine diets and the addition of B12, folic acid, niacin, zinc, manganese, and B6, but should avoid excess copper.  Patients with obsessive-compulsive disorders or intense phobias should probably avoid folic acid and manganese supplements, but may benefits from SAMe, methionine, inositol, and other methyl donors, as well as calcium and magnesium.  Depressed or anxious patients who don’t respond to SSRI’s might be pyroluric, and could benefit from B6 and zinc supplementation, as well as evening primrose oil (a source of GLA).  Numerous clinical case studies, like these, make me think there is probably some relationship between methylation processes and mental health.

So, if both cancer and schizophrenia are related to abnormalities in various methylation processes, is there any link between the two diseases?  There is; schizophrenics are less likely to get cancer.  Variations in the genes NRG1, AKT1, PIK3, COMT, PRODH and ErbB4 are implicated in cancer (when these genes trigger rapid, out-of-control cell replication) and schizophrenia (when the same genes slow down various cellular processes).  However, this study found that death rates from cancer were higher in schizophrenics than in the general population.  It may be significant that the latter study took place in France, where rates of either MTHFR polymorphism are extremely low (around 2%).

All Vitamins Are Not Created Equal

There is a difference between folate (absorbed from food) and folic acid (the synthesized form).  The former is methylated, the latter requires a methylation process to become biologically active (metafolin).  In terms of vitamin B12, the cheaper and more common cobalamin is non-methylated, while the more expensive hydroxycobalamin or methylcobalamin are methylated.

Could non-methylated folic acid, B12, and niacin supplements be helpful to  “over-methylators” because they “use up” methyl groups when they are metabolized in excess, thus normalizing the methyl to folate ratio?

Or is the truth more complex?  People with one of two common (about 50% in North America) polymorphisms in the MTHFR gene can’t effectively convert to (and/or use) active folate.  These types have low folate and high homocysteine, but can react badly to folic acid supplements (which can actually reduce blood levels active metafolin in people with the MTHFR gene variants), and do better getting folate from green leafy vegetables and other food sources (and/or supplementing with a methylated form, like l-methylfolate).

Edit: This study found that supplementing with methylfolate improved recovery for patients diagnosed with major depression or schizophrenia.

Nutritional Supplements and Medical DIY

Trying to understand methylation processes and how they relate to vitamin supplements and nutrition can tie your brain in a knot.  Most medical professionals are no help at all - they’ll get that “you’re one of those” look if you suggest that vitamin supplements have significant psychological effects.  Probably more than anyone else, parents of bipolar, schizophrenic, and autistic children have pushed the field of orthomolecular psychiatry forward - they are desperate to help their kids thrive and will go to great lengths to understand and experiment with whatever works, including nutritional supplements.

Karen DeFelice’s site is one example.  The It’s Not Mental site and DetoxPuzzle.com are two more.  There are dozens of others.  Many of these parents have effectively cured their children with aggressive nutritional interventions.  Common themes seem to be avoidance of gluten and casein, adding supplements to either slow down or speed up methylation processes (depending on the condition), balancing copper/zinc levels, and troubleshooting bottlenecks in various detoxification processes (phenols, sulfur metabolism, etc.).

My Own Self Diagnosis Process

I began this investigation of B-vitamins and methylation process in an attempt to cure my asthma.  Ultimately I discovered that a more-or-less paleo diet resolved most of my asthma symptoms, with some supplements being helpful as well (notably vitamin D, magnesium, fish oil, evening primrose oil, and vitamin C).  None of the B-vitamins proved to be helpful for asthma, and multivitamins often aggravated my symptoms.

I suspect I have one or both polymorphisms of the MTHFR gene, but if I do, that’s probably not related to asthma.

I do exhibit most of the less severe signs of being an “under-methylator,” including seasonal allergies, hypomania/overconfidence alternating with melancholy/demoralization, calm demeanor but high internal stress/anxiety, stong-willed/stubborn, low tolerance for stress, high libido, high motivation/ambition, perfectionism, a high desire for order/organization, addictive/compulsive tendencies, etc.

I experience a significant energy boost from B6 + zinc, which can quickly escalate into hostility/irritability/agitated depression.  I’m guessing somehow that nutrient combination spikes norepinephrine and lowers serotonin (I have no idea how), but it could be something else (maybe some kind of “detox” reaction, or homocysteine converting too quickly to cysteine).

I experience a calming, mood-boosting effect from taking niacinamide (higher serotonin?).  But too much niacinamide interrupts my sleep cycle and aggravates my breathing.

Taking B12 can improve my sleep, but only if I take it early in the day.

I seem to do well on a high protein, high methionine diet, but if I cut carbs too low I feel agitated and irritable (probably from low serotonin).

I’ve only tried taking SAMe (a methyl donor) a few times and I can’t remember the effects.  People I’m close to have found it to be extremely effective for carpal tunnel and fighting “the blues.”

Designing Your Own Supplement Program

Short of genetic testing (which is now a realistic and affordable option), looking at your family history from a health perspective is probably a good place to start when considering your own supplement program.  For example:

If Alzhemier’s runs in your family, consider supplementing with niacinamide.  Niacinamide may also be effective in reducing anxiety, including severe social anxiety.

If there are cases of cancer in your family, consider increasing folate levels from food sources and vitamins.  B6 may provide additional protection against colon cancer.

If you fall somewhere along the autism spectrum, considering supplementing with zinc + manganese, and restricting copper.

If you have asthma, you might try experimenting with a paleo or gluten-free diet, and supplementing with fish oil, evening primrose oil, magnesium, and C.  Some people have experienced relief from asthma symptoms by increasing vitamins B5 and B6.

If you think you might be experiencing negative side effects from a multivitamin, go cold turkey and see how you feel.  For people with either or both polymorphisms of the MTHFR gene, supplemental folic acid may actually be harmful.  Take methyfolate instead, or just eat more leafy greens and nutritious food and don’t take a multi.

Source: www.jdmoyer.com