Vitamin B9 (Folate, folic acid, 5-methylenetetrahydrofolate) is water-soluble, and one of 8 B-Vitamins.
As a nootropic, folate is also involved in gene expression, amino acid synthesis, myelin synthesis, and is required for the synthesis of the neurotransmitters dopamine, epinephrine, norepinephrine and serotonin.
Many neurohackers, including doctors and other health professionals confuse folate with folic acid. They are NOT the same.
In this article, we’ll explore the differences between folate and folic acid. And how Vitamin B9 (folate) is critical for the fully optimized brain.
Vitamin B9 (Folate) helps:
- Brain Optimization: Folate is involved in DNA and RNA synthesis, gene expression, amino acid synthesis and metabolism, and myelin synthesis and repair.
- Neurotransmitters: Folate is required for the synthesis of dopamine, epinephrine and serotonin.
- Mood: It is thought within research circles that folate’s involvement in neurotransmitter synthesis is most responsible for mood and cognition. Even increasing the effect of SSRI’s in those being treated for depression.
Table of Contents
Vitamin B9 (Folate, folic acid, 5-methylenetetrahydrofolate) is water-soluble, and one of 8 B-Vitamins.
Folate is a critical component of DNA and RNA synthesis, gene expression, amino acid synthesis, and myelin synthesis and repair. Folate is required as part of the cycle that produces most of your major neurotransmitters including dopamine, epinephrine, norepinephrine and serotonin.
Folate is used in red blood cell production, helps break down and use proteins, and just about every other process in your body.
Folate deficiency is found in at least a third of those suffering from depression. Folate touches nearly everything happening in your brain. And the reason why we’re investigating it here. Folate should be part of your nootropic stack.
When you eat vegetables containing folate, or eat flour-enriched with folic acid, an enzyme called MTHFR (5,10-methylenetetrahydrofolate reductase) converts folic acid and food folate into 5-methylenetetrahydrofolate (methyl-folate or 5-MTHF).
Folate is a general term for a group of various tetrahydrofolate (THF) derivatives naturally found in food. Folic acid refers to an oxidized synthetic compound used in dietary supplements and food fortification.
THF can enter the main and natural folate metabolic cycle which starts out in the mucosa of your small intestine. Synthetic Folic acid on the other hand undergoes initial reduction and methylation in your liver, where conversion to the THF form requires the enzyme dihydrofolate reductase.
One of the problems with choosing the unnatural folic acid version is if there is low activity of the dihydrofolate reductase enzyme, combined with high intake of folic acid, you end up with unnatural levels of unmetabolized folic acid entering your circulation.
Several studies have reported the presence of this unmetabolized folic acid in blood following consumption of folic acid supplements, or folic acid-fortified food.[ii]
We have growing evidence in Western society that we generally test for excess levels of unnatural folic acid. Due mainly to eating processed foods and folic acid-enriched flour. And still suffer from a folate deficiency.
High doses of synthetic folic acid may increase your risk of cancer, immune system damage and other health problems.[iii]
Problems with MTHFR
Another major problem affecting folate deficiency is problems with the MTHFR gene. Remember that this enzyme called MTHFR (5,10-methylenetetrahydrofolate reductase) is needed to convert folic acid and food folate into 5-methylenetetrahydrofolate.
There are two common variants in this gene that affects the functioning of MTHFR. They are called C677T and A1298C. Both variants are genetically inherited. And depending on their presence in your system, can reduce the effectiveness of MTHFR from 30 – 70%. Another cause for folate deficiency.
Estimates of the prevalence of these mutations in our general population are up to 60%. Some doctors report that nearly every patient in their practice have one or both MTHFR mutations.[iv]
And we have clinical evidence of the association between both MTHFR mutations in depression, bipolar disorder, and schizophrenia.[v]
Folate is one busy molecule in your body:
- Donates a methyl group to homocysteine to make SAMe. The methyl donor SAMe is involved in the formation of phospholipids, glutathione, myelin, coenzyme Q10, carnitine and creatine in your brain
- Synthesizes the enzyme cofactor biopterin (BH4) which is critical for the synthesis of major neurotransmitters including dopamine, epinephrine, norepinephrine and serotonin
- Synthesizes DNA and tRNA
- Recycles and reduces the inflammatory amino acid homocysteine
- Builds red and white blood cells and platelets.
How does Vitamin B9 (Folate) work in the Brain?
Vitamin B9 (Folate) boosts brain health and function in several ways. But two in particular stand out.
- Folate influences neuroplasticity and neurotransmitters. Folate is required for the synthesis of the neurotransmitters dopamine, epinephrine, and serotonin.
The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF, L-methylfolate), participates in re-methylation of the amino acid homocysteine, creating methionine. S-adenosylmethionine (SAMe), the downstream metabolite of methionine, is involved in numerous biochemical methyl donation reactions, including reactions forming the above-mentioned neurotransmitters.
Without the participation of 5-MTHF in this process, SAMe and neurotransmitter levels decrease in the cerebrospinal fluid, contributing to the disease process of depression.
Studies have shown that those being treated for depression with SSRI antidepressants, and not responding to these drugs, can get a much better response by taking folate with their antidepressants.[vi]
- Folate helps reduce depression. Folate is involved in one-carbon metabolism in the brain. This folate cycle is responsible for the synthesis of methyl groups, which are utilized by SAMe in several methylation reactions involving nucleoproteins, proteins, phospholipids, neurotransmitters and monoamines.
Deficiency of both folate and Vitamin B12 will impair methylation processes. Causing the accumulation of homocysteine. Low concentrations of folate in your blood, red blood cells and cerebrospinal fluid are associated with depression and dementia.
Research shows that cognitive function is related to methylation processes in your brain.[vii] This depression hypothesis is supported by the similar effect of SAMe on monoamine neurotransmitter metabolism, which is also implicated in depression.[viii]
The lowest concentrations of folate and SAMe in cerebrospinal fluid are found in dementia, including Alzheimer’s Disease.[ix]
How things go bad
The metabolic process called methylation occurs when one molecule provides a methyl group, which is a carbon atom linked to three hydrogen atoms, to another molecule. And makes things like creatine, carnitine, CoQ10, phosphatidylcholine (PC), melatonin and a bunch of other crucial neurotransmitters and substances in your body.
Methylation is involved in cognition, repairing DNA, turning genes on and off, fighting infections and inflammation, getting rid of toxins and much, much more.
Problems with methylation (which can be caused by not enough folate) can contribute to addictions, Alzheimer’s, anxiety, ADD and ADHD, bipolar and manic depression, chronic fatigue syndrome, dementia, diabetes, fibromyalgia, schizophrenia, and hypothyroidism.
Methylation is not only involved in the synthesis of neurotransmitters, but breaking them down as well. This critical step, when broken, causes a buildup of neurotransmitters that can lead to seizures, insomnia, panic attacks, fits of rage, and more. Much more.
A deficiency of methyl-folate (5-MTHF) in your body caused by problems with this methylation pathway leads to a deficiency of glutathione, your major antioxidant. This can take shape as fibromyalgia, chronic fatigue, increased immune activation, chemical sensitivities and even diseases like ALS, MS, and Parkinson’s.
Not enough folate and you can experience:
↓ Depression, mood and social function decline
↓ Cognitive function declines
↑ Risk of Alzheimer’s and dementia increase
↑ Risk of anemia increases
↑ Irritability, forgetfulness, and mental sluggishness increase
Vitamin B9 supplementation can help increase the density of serotonin and dopamine neurotransmitters in your brain. And improve neurotransmitter signaling. Helping you to cope with stress, lessen depression and improve memory.
Vitamin B9 (Folate) to the rescue
Depression affects about a quarter of the US population who will have at least one depressive episode in their lifetime. (My apologies to our readers from other countries. I only have statistics for the USA).
But world-wide, folate deficiency is found in at least a third of those suffering from depression. And research shows that folate levels even in the “normal range” might be inadequate for methyl donation and neurotransmitter synthesis.
By adding folate, or methyl-folate to your nootropic stack, you’re adding a necessary ingredient for the synthesis of the neurotransmitters dopamine, epinephrine, norepinephrine and serotonin.
The active metabolite of folate (5-MTHF, L-methyl-folate) participates in the re-methylation of the amino acid homocysteine creating methionine. SAMe, the downstream metabolite of methionine, is involved in several methyl donor reactions, including forming most of your major neurotransmitters.
Methyl-folate also seems to save the day by stepping in, and substituting for tetrahydrobiopterin (BH4), an essential cofactor in neurotransmitter synthesis (when BH4 is low).
The bottom-line: folate helps boost alertness, attention, cognition, memory, and mood. And helps alleviate brain fog, anxiety and depression.
How does Vitamin B9 (Folate) feel?
Up to 60% of us do not produce enough of the enzyme needed to break down the synthetic folic acid found in supplements and fortified foods like breakfast cereal and bread. And the simple presence of this impostor in our diet is likely contributing to many of our modern diseases.
Neurohackers report that dosing with methyl-folate:
- Boosts alertness and energy levels
- Relief from chronic pain
- Tolerance for heat increases
- Sociability increases
- Relief from depression, fatigue and paranoia
- Fewer headaches
- Mental clarity increases
- Much happier, calmer, more energetic
- Gingivitis and gum inflammation decreases
Folate as an Antidepressant
Many who use antidepressants experience little to no relief in depressive symptoms. And researchers set out to find out why antidepressant meds were not working.
Dr. Jerome Sarris of the University of Melbourne decided to do a meta-analysis of clinical trials using ‘nutrients’ along with antidepressants in PubMed, CINAHL, Cochrane Library, and Web of Science up to 2015.
The research team found that Omega-3’s combined with antidepressants boosted the success of using these meds for depression. The team also found strong evidence for methyl folate, Vitamin D, and SAMe.
The research showed that using folic acid or inositol provided no benefit. The team concluded there was strong evidence for using methyl folate, Omega-3, Vitamin D and SAMe with antidepressants to reduce depression.[xi]
Another study in Milan compared using methyl-folate with the antidepressant Trazadone. 96 patients with dementia received either 50 mg of methyl-folate per day, or 100 mg of Trazadone.
After 4 weeks of treatment, depression scores for the methyl-folate patients decreased more than for the Trazadone patients.[xii]
Folate Reduces Risk for Dementia
Folate deficiency is associated with a tripling in the risk of developing dementia among elderly people. Researchers tracked 518 people over the age of 65 for 2 years for dementia development. The study found that the onset of dementia was much more likely in those whose folate levels fell over 2 years.[xiii]
Another study published in the British Medical Journal looked at the neurological status of 24 folate-deficient patients compared with a control group of 21 normal folate-level patients.
The study showed a significant increase in organic brain syndrome in the folate-deficient group.[xiv] Organic brain syndrome is a general term used to describe decreased mental function caused by something other than psychiatric illness.
Vitamin B9 (Folic Acid) Improves Memory
A study published in the Journal of the American Medical Association evaluated nutritional status and cognitive function in 260 men and women older than 60 years. The study showed there was a significant relation between impaired abstract thinking ability and memory, and lower folate levels and intake.[xv]
In another open study of 38 folate deficient subjects with depression, lethargy, and memory impairment, 50 mg of folinic acid per week for 120 days significantly improved visuomotor performance, visuospatial memory, logical reasoning, associative memory, and activities for daily living.[xvi]
Recommended dosage for Vitamin B9 (Folate) is 500 mcg.
If you decide to add folate to your nootropic stack, start with B12 in the form of methylcobalamin. And then introduce your dose of methyl-folate and cofactors such as Vitamin B2, Vitamin B3, Vitamin B6, trimethyl glycine, and Vitamin C
If you have an adverse reaction to methyl-folate (agitation, increased anxiety, headache), you can take Vitamin B3 (nicotinic acid or niacinamide) in 50 mg dosages every 30 minutes until you experience relief.
Note that Vitamin B3 (niacin) requires SAMe for its metabolism. And can contribute to a drop in methylation if you’re low in SAMe. It is also a cofactor for the enzyme COMT that breaks down norepinephrine, epinephrine, and estrogen, which are all potentially elevated if you are experiencing anxiety.
Vitamin B9 (Folate) is non-toxic. So is considered well-tolerated and safe.
But note that higher doses of Vitamin B9 like those used in clinical trials nearly always use synthetic folic acid. If you are deficient in Vitamin B12, and many people are, can manifest as anemia. And is undisguisable from folate deficiency.
Large doses of folate could correct anemia. Without correcting the underlying B12 deficiency. And leave you at risk for irreversible brain damage.
This is why the US Institute of Medicine advises that all adults limit their intake of folic acid supplements to 1 mg daily.
Note that it is unlikely that you’ll encounter this problem by using folate or methyl-folate instead of folic acid. But we don’t have the science yet to back this claim up.
High concentrations of unmetabolized folic acid in your blood, especially if you’re low in Vitamin B12, could result in a compromised immune system. And problems with cognition.
Other side effects of using folic acid, particularly in high doses include stomach problems, insomnia, skin reactions, confusion, loss of appetite, nausea and seizures.
Many medications interfere with folic acid absorption including antibiotics, Dilantin, Daraprim, chemo meds, antacids, proton pump inhibitors, anti-seizure medications, NSAIDS (ibuprofen and naproxen), Azulfidine, and Methotrexate.
Vitamin B9 (Folate) is available in capsules, softgels, and in powder form.
Studies have shown that the active form of folate, methyl-folate, which is more easily absorbed, and easily crosses the blood-brain barrier, may be effective in the prevention and treatment of depression and dementia.[xvii]
Look for a folate supplement that says “L-methylfolate”, “5-methyltetrahydrofolate” or “5-MTHF” on the label. Even better, with the word Quatrefolic® or Metafolin® which are branded forms of folate ensuring their purity and effectiveness.
One great option to ensure you are getting all the vitamins and cofactors you need for the methylation cycle is to use a multivitamin.
And all multivitamins include some form of Vitamin B9 (folate) in their formula. But many of these multis don’t contain enough for optimum health. And the majority use the folic acid version of this nutrient.
The Performance Lab® Whole-Food Multi offers a nature-identical form of Vitamin B9 (folate) and is now my favorite daily multivitamin/mineral supplement.
I prefer the Performance Lab® multi because it’s more potent, it’s biologically active and I’ve found to be a far more effective multi compared to every other multivitamin supplement I’ve ever used.
Performance Lab® uses their own priority BioGenesis® vitamins and minerals which are grown on probiotic, plant and yeast cultures in a state-of-the-art lab.
Avoid any product, including multivitamins, which list “folic acid” on the label.
Nootropics Expert Recommendation
Vitamin B9 (Folate) up to 500 mcg
We recommend using Vitamin B9 (Folate) as a nootropic supplement.
Your body does not make Vitamin B9 on its own. So you must get folate from food or a supplement.
Vitamin B9 (Folate) is especially helpful for those suffering from anxiety, depression, panic attacks, or OCD. Folate can help improve energy levels, reduce insomnia, and help increase energy levels.
Experience shows Vitamin B9 helps stop and reverse the symptoms associated with high homocysteine levels.
Vitamin B9 is also particularly helpful to quell anxiety caused by social situations.
Vitamin B9 can help you get a good night’s sleep. You may find it as effective as sleep meds and other nootropics used for sleep. You’ll awaken feeling refreshed and calm. Ready to start your day.
The recommended dosage of Vitamin B9 (Folate) is up to 1,000 mcg per day. Start low at 500 mcg and see how your body reacts.
Please refer to Dosage Notes in this article for adding the other B-Vitamins to your stack for an optimal methylation cycle. Your neurotransmitters are counting on it.
At the very minimum every neurohacker should be using a multivitamin every day that includes Vitamin B9 (folate but NOT folic acid!). The best multi I’ve found and use every day is the Performance Lab® Whole-Food Multi for men or women.
[iii] Troen A.M. et. Al. “Unmetabolized Folic Acid in Plasma Is Associated with Reduced Natural Killer Cell Cytotoxicity among Postmenopausal Women” The Journal of Nutrition January 2006 vol. 136 no. 1 189-194 (source)
[v] Gilbody S., Lewis S., Lightfoot T. “Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review.” American Journal of Epidemiology. 2007 Jan 1;165(1):1-13 (source)
[viii] Bottiglieri T., Crellin R., Reynolds E.H. ‘Folate and neuropsychiatry’. In: Bailey LB, editor. Folate in health and disease. New York: Marcel Dekker; 1995. pp. 435–462
[ix] Bottiglieri T., Godfrey P., Flynn T., Carney M.W., Toone B.K., Reynolds E.H. “Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine.” Journal of Neurology and Neurosurgery Psychiatry. 1990 Dec;53(12):1096-8. (source)
[xi] Sarris J., Murphy J., Mischoulon D. Papakostas G.I., Fava M., Berk M. Ng C.H. “Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses” The American Journal of Psychiatry Volume 173, Issue 6, June 01, 2016, pp. 575-587 (source)
[xii] Passeri M., Cucinotta D., Abate G., Senin U., Ventura A., Stramba Badiale M., Diana R., La Greca P., Le Grazie C. “Oral 5'-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study.” Aging (Milano). 1993 Feb;5(1):63-71. (source)
[xvi] Rapin J.R., Le Poncin M., Grebyl J. “Blood folate deficiencies and cognitive functions in aging.” Trends in Biomedical and Gerontology. 1988;1:221–223.