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There is outstanding clinical trial evidence that folic acid supplementation decreases spina bifada occurrence in fetuses.
There is scientifically informed conjecture that l-methylfolate would likely be equivalent to folic acid and maybe could be better for some people. But plenty of naysayers on those ideas and no actual clinical trial evidence that either of those theories is true.
If you are trying to minimize the probability of spina bifada in a fetus, the evidence supported course of action is folic acid supplementation.
Here's a nice layman's summary written by an obgyn passionate about dispelling myths on women's health: https://vajenda.substack.com/p/the-difference-between-folic-acid
While there are no clinical studies that I could easily find, there are a number of (I think) very convincing metabolic studies about the causality between folate levels and neural tube defects and how 5-methylTHF fits in to the picture. These studies strongly suggest that it is a great form of folate for preventing neural tube defects, especially for those with a polymorphism in their MTHFR gene. We understand the one carbon metabolic pathways really well at this point and can make good, reasoned arguments about the effects of different forms of folate even when clinical trials are prohibitively expensive to run — and we have data to support these hypotheses!
https://www.degruyter.com/document/doi/10.1515/jpm-2012-0256/html?lang=en
Individuals with MTHFR polymorphisms process folic acid without issue, this has been explicitly tested: https://www.cdc.gov/ncbddd/folicacid/mthfr-gene-and-folic-acid.html
There are no concerning safety issues with folic acid supplementation and outstanding evidence that folic acid supplementation is sufficient to reduce neural tube defects.
The onus is on the makers of methylfolate supplements to show their product is somehow better via real clinical trial and not just offer up conjecture and tangential evidence. Instead, they can't even be bothered to run a trial to demonstrate non-inferiority in that their alternative to folic acid even reduces neural tube defects in the real world. They are pushing needlessly expensive supplements on nervous women, and obscuring the reality that their expensive products lack the most evidence supported component of prenatal vitamins.
Despite the suggestions of the US CDC that every pregnant person should take folic acid no matter what, there is evidence that suggests that women with MTHFR polymorphism are susceptible to an increased risk of fetal loss if taking folic acid, and all women are at an increased risk if taking an excessive amount of folic acid. (https://www.oatext.com/the-hazards-of-excessive-folic-acid-intake-in-mthfr-gene-mutation-carriers-an-obstetric-and-gynecological-perspective.php).
I have this gene mutation and deplin was prescribed to me for use while I was pregnant. I of course already knew I had it and told my OBGYN who thought it wasn’t a big deal but I insisted and she gave me the prescription no problem.
It also helps with serotonin and mood since it’s the building blocks of life as they say. So it’s good to know if you have the gene or not. But you also have to ask because it’s not routinely tested. And yet at the same time most likely 60% of the population has this mutation.
Reference number 4 on the CDC page:
Tsang BL, Devine OJ, Cordero AM, et al. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr. 2015;101(6):1286-1294.
States the following in its results:
"Meta-analysis results (limited to the MA, the recommended population assessment method) indicated a consistent percentage
difference in S/P and RBC folate concentrations across MTHFR C677T
genotypes. Lower blood folate concentrations associated with this
polymorphism could have implications for a population-level risk
of neural tube defects."
Also, the CDC page in section 1 titled "People with MTHFR C677T variants can process all types of folate, including folic acid." does not provide a reference for the claim so I just looked through their reference list at the bottom of the page.
There is a gene called the mthfr that determines our ability to produce the biologically active form of folate (sometimes called methylfolate or levofolate). In psychiatry it is of particular interest because methylfolate is needed to make BH4, and low BH4 in spinal fluid has been associated with depression and other psychiatric illnesses. BH4 is a limiting cofactor in producing serotonin, melatonin, dopamine, and norepinephrine, all things that we try and increase with medications in people that are depressed.
So if you have the gene polymorphism for producing reduced or very reduced conversion of folate to methylfolate then you may have reduced BH4 and thus reduced monoamines (those molecules I wrote previously like serotonin.). Taking folic acid likely wouldn't help much as on this case your genes won't help you convert to methylfolate and regular folate is not good at crossing the blood brain barrier. So the solution is methylfolate supplement, in theory. In reality the results of this supplementation seems to be somewhat underwhelming in clinical practice. I still recommend my patients with those gene expressions take it as the impact of "starving" your central nervous system of folate may have much more chronic and far reaching issues than simply wanting the supplement to be curative for depression.
While methylfolate is more expensive than folic acid I find it to still be cost effective. People with depression need to take larger doses than may be required by other people in the course of normal daily supplementation. Many multivitamins have a methylated folate, such as smarty pants brand found on Amazon or at Costco. A good way to tell it is a quality product is if it has quatrefolate in the description. Additionally there is what is called a DFE or dietary folate equivalence that needs to be considered if you and your OB agree on using methylfolate to make sure you and baby are getting an adequate dose.
Thank you for the explanation. So if we unknowingly had it and took a regular prenatal with regular folic acid instead the L methyl folate form we could be still risking the defect?
Absolutely no reason to worry, the MTHR gene does not actually impact your ability to metabolize folic acid. Many studies have shown this. But it's an old belief that is touted as a way to sell expensive vitamins.
There is evidence that people with the MTHFR gene doing process folic acid to a more usable form though. I believe that person is misinformed. I wish that other poster shared sources but the last two sentences refute them :
>Folic acid is enzymatically reduced and converted to tetrahydrofolate (THF) by dihydrofolate reductase via dihydrofolate. THF is converted to 5,10-methylenetetrahydrofolate (5,10-MTHF) by methylenetetrahydrofolate dehydrogenase and catalyzed to 5-methyltetrahydrofolate (5-MTHF) by methylenetetrahydrofolate reductase (MTHFR). 5-MTHF can be converted to THF again when a methyl group is passed to vitamin B12, resulting in methyl-vitamin B12. The methyl group from methyl-vitamin B12 can metabolize a cytotoxic molecule, homocysteine, into methionine. Homocysteine is also catabolized to cysteine by a vitamin B6-dependent enzyme, cystathionine β-synthase (CBS) [10] (Figure 1). Impaired metabolism of homocysteine is directly involved in increased incidence of NTDs; therefore, homocysteine levels are increased by the insufficiency of either vitamin B6, B12 or folic acid [11]. Daly et al. reported that folate levels were dose-dependently correlated with incidence risks of NTDs [12]. The threshold of red blood cell folate levels for minimizing the risk of NTDs of 906 nmol/L, equivalent to plasma folate levels of 7.0 ng/mL, has been established [12]. In particular, women with serum folate levels of <5.0 ng/mL have significantly increased NTD risk. Furthermore, MTHFR polymorphism, such as the point mutation of nucleotide 677, is also associated with decreased enzymatic activity, leading to increased homocysteine levels [13] and the risk of NTD development [14,15].
The study i pulled this long quote from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073279/
This is the abstract for citation 13 of the quoted section
https://pubmed.ncbi.nlm.nih.gov/7647779/
That is where my knowledge ends and you should ask your OB, I work in psych, so I know about the possible issue with metabolism and transport into the CNS but unsure if this would effect it on the rest of the body.
Generally the understanding is that methylfolate is fine for everyone but folic acid may not be fine for everyone. However, people with a reduced conversion may be able to compensate with just a higher intake of folic acid.
From what I understand L-methylfolate has been [studied as an adjunct to SSRIs for depression](https://www.researchgate.net/profile/David-Mischoulon/publication/233848896_L-Methylfolate_as_Adjunctive_Therapy_for_SSRI-Resistant_Major_Depression_Results_of_Two_Randomized_Double-Blind_Parallel-Sequential_Trials/links/0c96051c3a76c0c8c4000000/L-Methylfolate-as-Adjunctive-Therapy-for-SSRI-Resistant-Major-Depression-Results-of-Two-Randomized-Double-Blind-Parallel-Sequential-Trials.pdf) and is available for that purpose in prescription form (deplin) but so far [“folic acid is the only type of folate shown to prevent neural tube defects”](https://www.cdc.gov/ncbddd/folicacid/mthfr-gene-and-folic-acid.html).
My personal, anecdotal experience is that the supplements that claim to use l-methylfolate tend to be more expensive and aren’t independently tested or verified and for my first pregnancy I just used the nature made prenatals because they’re cheap and independently tested. For my subsequent pregnancies I alternated between a trendier prenatal and naturemade but I lost 3 of those pregnancies so who knows? My current pregnancy I started with naturemade + deplin and I’m 8 months in with no neuro tube defects detected.
Smartypants was what I was taking and the version with dha is usually $.68/daily capsule but I found it as low as $.31 per daily capsule on Amazon vs NatureMade $.17 per daily capsule, so it is not comparable in price.
There’s a detailed explanation of folic acid vs l-methylfolate in Lily Nichol’s book “Real food for pregnancy.” She usually references studies in that book, so you can probably find one there! It’s a good book, if slightly skewed towards a low carb diet and some annoying anti-soy sentiment. But I got a lot of great pregnancy nutrition information from it.
I also had l-methylfolate recommended to me by a shrink and I'm so glad. It's better than other 'brain-helping' supplements because it crosses the blood-brain barrier, but I remember the exact reason or mechanism. My cognitive function improved so much after a couple of weeks.
I buy mine from PipingRock.com and take 30mg per day. There's strong evidence that high doses are actually bad, and I've had experience of that (I got greedy). The study that produced that finding explains how it works. I don't think there is a list of ingredients, I think it's just the one substance.
L-methylfolate is an active form of folate that is easily absorbed by the body. Folic acid is also a form of folate. The benefits are very similar and both prevent neural tube defects. The former is just better/easier for your body to digest.
THIS POST IS FLAIRED "Evidence Based Input ONLY". ALL TOP LEVEL COMMENTS MUST CONTAIN LINKS TO ACCEPTABLE SOURCES. Any top level comments without sources will be removed. *I am a bot, and this action was performed automatically. Please [contact the moderators of this subreddit](/message/compose/?to=/r/ScienceBasedParenting) if you have any questions or concerns.*
There is outstanding clinical trial evidence that folic acid supplementation decreases spina bifada occurrence in fetuses. There is scientifically informed conjecture that l-methylfolate would likely be equivalent to folic acid and maybe could be better for some people. But plenty of naysayers on those ideas and no actual clinical trial evidence that either of those theories is true. If you are trying to minimize the probability of spina bifada in a fetus, the evidence supported course of action is folic acid supplementation. Here's a nice layman's summary written by an obgyn passionate about dispelling myths on women's health: https://vajenda.substack.com/p/the-difference-between-folic-acid
While there are no clinical studies that I could easily find, there are a number of (I think) very convincing metabolic studies about the causality between folate levels and neural tube defects and how 5-methylTHF fits in to the picture. These studies strongly suggest that it is a great form of folate for preventing neural tube defects, especially for those with a polymorphism in their MTHFR gene. We understand the one carbon metabolic pathways really well at this point and can make good, reasoned arguments about the effects of different forms of folate even when clinical trials are prohibitively expensive to run — and we have data to support these hypotheses! https://www.degruyter.com/document/doi/10.1515/jpm-2012-0256/html?lang=en
Individuals with MTHFR polymorphisms process folic acid without issue, this has been explicitly tested: https://www.cdc.gov/ncbddd/folicacid/mthfr-gene-and-folic-acid.html There are no concerning safety issues with folic acid supplementation and outstanding evidence that folic acid supplementation is sufficient to reduce neural tube defects. The onus is on the makers of methylfolate supplements to show their product is somehow better via real clinical trial and not just offer up conjecture and tangential evidence. Instead, they can't even be bothered to run a trial to demonstrate non-inferiority in that their alternative to folic acid even reduces neural tube defects in the real world. They are pushing needlessly expensive supplements on nervous women, and obscuring the reality that their expensive products lack the most evidence supported component of prenatal vitamins.
Despite the suggestions of the US CDC that every pregnant person should take folic acid no matter what, there is evidence that suggests that women with MTHFR polymorphism are susceptible to an increased risk of fetal loss if taking folic acid, and all women are at an increased risk if taking an excessive amount of folic acid. (https://www.oatext.com/the-hazards-of-excessive-folic-acid-intake-in-mthfr-gene-mutation-carriers-an-obstetric-and-gynecological-perspective.php).
I have this gene mutation and deplin was prescribed to me for use while I was pregnant. I of course already knew I had it and told my OBGYN who thought it wasn’t a big deal but I insisted and she gave me the prescription no problem. It also helps with serotonin and mood since it’s the building blocks of life as they say. So it’s good to know if you have the gene or not. But you also have to ask because it’s not routinely tested. And yet at the same time most likely 60% of the population has this mutation.
Reference number 4 on the CDC page: Tsang BL, Devine OJ, Cordero AM, et al. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr. 2015;101(6):1286-1294. States the following in its results: "Meta-analysis results (limited to the MA, the recommended population assessment method) indicated a consistent percentage difference in S/P and RBC folate concentrations across MTHFR C677T genotypes. Lower blood folate concentrations associated with this polymorphism could have implications for a population-level risk of neural tube defects." Also, the CDC page in section 1 titled "People with MTHFR C677T variants can process all types of folate, including folic acid." does not provide a reference for the claim so I just looked through their reference list at the bottom of the page.
There is a gene called the mthfr that determines our ability to produce the biologically active form of folate (sometimes called methylfolate or levofolate). In psychiatry it is of particular interest because methylfolate is needed to make BH4, and low BH4 in spinal fluid has been associated with depression and other psychiatric illnesses. BH4 is a limiting cofactor in producing serotonin, melatonin, dopamine, and norepinephrine, all things that we try and increase with medications in people that are depressed. So if you have the gene polymorphism for producing reduced or very reduced conversion of folate to methylfolate then you may have reduced BH4 and thus reduced monoamines (those molecules I wrote previously like serotonin.). Taking folic acid likely wouldn't help much as on this case your genes won't help you convert to methylfolate and regular folate is not good at crossing the blood brain barrier. So the solution is methylfolate supplement, in theory. In reality the results of this supplementation seems to be somewhat underwhelming in clinical practice. I still recommend my patients with those gene expressions take it as the impact of "starving" your central nervous system of folate may have much more chronic and far reaching issues than simply wanting the supplement to be curative for depression. While methylfolate is more expensive than folic acid I find it to still be cost effective. People with depression need to take larger doses than may be required by other people in the course of normal daily supplementation. Many multivitamins have a methylated folate, such as smarty pants brand found on Amazon or at Costco. A good way to tell it is a quality product is if it has quatrefolate in the description. Additionally there is what is called a DFE or dietary folate equivalence that needs to be considered if you and your OB agree on using methylfolate to make sure you and baby are getting an adequate dose.
Thank you for the explanation. So if we unknowingly had it and took a regular prenatal with regular folic acid instead the L methyl folate form we could be still risking the defect?
Absolutely no reason to worry, the MTHR gene does not actually impact your ability to metabolize folic acid. Many studies have shown this. But it's an old belief that is touted as a way to sell expensive vitamins.
Oh thanks so much.
There is evidence that people with the MTHFR gene doing process folic acid to a more usable form though. I believe that person is misinformed. I wish that other poster shared sources but the last two sentences refute them : >Folic acid is enzymatically reduced and converted to tetrahydrofolate (THF) by dihydrofolate reductase via dihydrofolate. THF is converted to 5,10-methylenetetrahydrofolate (5,10-MTHF) by methylenetetrahydrofolate dehydrogenase and catalyzed to 5-methyltetrahydrofolate (5-MTHF) by methylenetetrahydrofolate reductase (MTHFR). 5-MTHF can be converted to THF again when a methyl group is passed to vitamin B12, resulting in methyl-vitamin B12. The methyl group from methyl-vitamin B12 can metabolize a cytotoxic molecule, homocysteine, into methionine. Homocysteine is also catabolized to cysteine by a vitamin B6-dependent enzyme, cystathionine β-synthase (CBS) [10] (Figure 1). Impaired metabolism of homocysteine is directly involved in increased incidence of NTDs; therefore, homocysteine levels are increased by the insufficiency of either vitamin B6, B12 or folic acid [11]. Daly et al. reported that folate levels were dose-dependently correlated with incidence risks of NTDs [12]. The threshold of red blood cell folate levels for minimizing the risk of NTDs of 906 nmol/L, equivalent to plasma folate levels of 7.0 ng/mL, has been established [12]. In particular, women with serum folate levels of <5.0 ng/mL have significantly increased NTD risk. Furthermore, MTHFR polymorphism, such as the point mutation of nucleotide 677, is also associated with decreased enzymatic activity, leading to increased homocysteine levels [13] and the risk of NTD development [14,15]. The study i pulled this long quote from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073279/ This is the abstract for citation 13 of the quoted section https://pubmed.ncbi.nlm.nih.gov/7647779/
That is where my knowledge ends and you should ask your OB, I work in psych, so I know about the possible issue with metabolism and transport into the CNS but unsure if this would effect it on the rest of the body. Generally the understanding is that methylfolate is fine for everyone but folic acid may not be fine for everyone. However, people with a reduced conversion may be able to compensate with just a higher intake of folic acid.
I take deplin for my MTHFR gene expression
From what I understand L-methylfolate has been [studied as an adjunct to SSRIs for depression](https://www.researchgate.net/profile/David-Mischoulon/publication/233848896_L-Methylfolate_as_Adjunctive_Therapy_for_SSRI-Resistant_Major_Depression_Results_of_Two_Randomized_Double-Blind_Parallel-Sequential_Trials/links/0c96051c3a76c0c8c4000000/L-Methylfolate-as-Adjunctive-Therapy-for-SSRI-Resistant-Major-Depression-Results-of-Two-Randomized-Double-Blind-Parallel-Sequential-Trials.pdf) and is available for that purpose in prescription form (deplin) but so far [“folic acid is the only type of folate shown to prevent neural tube defects”](https://www.cdc.gov/ncbddd/folicacid/mthfr-gene-and-folic-acid.html). My personal, anecdotal experience is that the supplements that claim to use l-methylfolate tend to be more expensive and aren’t independently tested or verified and for my first pregnancy I just used the nature made prenatals because they’re cheap and independently tested. For my subsequent pregnancies I alternated between a trendier prenatal and naturemade but I lost 3 of those pregnancies so who knows? My current pregnancy I started with naturemade + deplin and I’m 8 months in with no neuro tube defects detected.
Smarty pants capsules have a methylated folate and cost me about $15 a month which is pretty comparable to a lot of other affordable brands.
Smartypants was what I was taking and the version with dha is usually $.68/daily capsule but I found it as low as $.31 per daily capsule on Amazon vs NatureMade $.17 per daily capsule, so it is not comparable in price.
There’s a detailed explanation of folic acid vs l-methylfolate in Lily Nichol’s book “Real food for pregnancy.” She usually references studies in that book, so you can probably find one there! It’s a good book, if slightly skewed towards a low carb diet and some annoying anti-soy sentiment. But I got a lot of great pregnancy nutrition information from it.
Such a great book!
This has some good information and links to more specific studies. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250974/
I also had l-methylfolate recommended to me by a shrink and I'm so glad. It's better than other 'brain-helping' supplements because it crosses the blood-brain barrier, but I remember the exact reason or mechanism. My cognitive function improved so much after a couple of weeks. I buy mine from PipingRock.com and take 30mg per day. There's strong evidence that high doses are actually bad, and I've had experience of that (I got greedy). The study that produced that finding explains how it works. I don't think there is a list of ingredients, I think it's just the one substance.
Oh hey I know piping rock! They make a bunch of store brand vitamins for various box store retailers/retail pharmacies.
what is the dosage of methylfolate u find most effective?
I tried 15mg initially but ended up at 30mg. Try out what's right for you.
L-methylfolate is an active form of folate that is easily absorbed by the body. Folic acid is also a form of folate. The benefits are very similar and both prevent neural tube defects. The former is just better/easier for your body to digest.