Solving the Mystery of Ehlers-Danlos: Is Folate the Missing Piece?

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Finally, a hallelujah moment. We may have a breakthrough in our understanding of Ehlers-Danlos Syndrome (hEDS), a baffling condition that has stymied medical professionals for years. In this article, we delve into the game-changing research suggesting folate might just be the missing piece of the puzzle. We also provide convenient links so that you can order methyl folate supplements directly from Fullscript, making the first steps towards possible symptom management as simple as a click. Buckle in as we embark on this revolutionary journey towards understanding and managing hEDS.

“This is real, it’s been vetted out well and clinically we’re noticing a difference,”

Jacques Courseault, MD – Tulane University

The What and Why of Ehlers-Danlos

Did you ever meet a kid in the schoolyard that could twist themselves into weird positions? We called it “being double jointed”, but this incredible flexibility can come from a condition you might not have heard of before– Hypermobile Ehlers-Danlos Syndrome, or hEDS for short. This is a complex condition that primarily affects the body’s connective tissue – the “glue” that helps hold our bodies together. From unusually flexible joints to delicate skin, people living with hEDS experience a wide range of symptoms that can impact their day-to-day lives.

Hypermobile Ehlers-Danlos Syndrome (hEDS) presents a range of health challenges that can significantly impact an individual’s daily life. Fatigue is a common issue, with sufferers often feeling perpetually drained, impacting their ability to carry out routine tasks. Pain, especially in the joints, is another major symptom, varying from occasional discomfort to constant agony. hEDS patients may also experience Postural Orthostatic Tachycardia Syndrome (POTS), a condition marked by rapid heartbeat and dizziness upon standing up, making even simple movements a challenge. Joint subluxation, where the joints partially dislocate, adds to the host of difficulties, causing discomfort and reducing mobility.

Diagnosing and managing hEDS is not an easy task. Because symptoms include so many different organ systems and such vague complaints, physicians unfamiliar with hEDS often mistake these patients for attention seekers and send them to psychiatrists. Tests are all normal. Unlike other conditions, hEDS doesn’t come with a handy lab test or genetic marker that doctors can use to confirm a diagnosis. This means that many people with hEDS face years of misdiagnoses before they finally get answers. To say this is a challenge would be an understatement. These patients often give up and stop being open with their physicians because of their long histories of not being believed.

The Breakthrough Discovery: Unusual Folate Levels and the MTHFR Connection

On the frontlines of understanding Ehlers-Danlos, a team of dedicated scientists at Tulane University has just published their exciting discovery. After treating numerous hEDS patients at their clinic, they started noticing a peculiar trend: these patients all had unusually high levels of folate in their blood.

When they looked deeper, they found that these high folate levels were consistently coupled with mutations in a gene known as MTHFR. In a nutshell, MTHFR is a gene that provides instructions for making an enzyme that helps our bodies process folate, a B vitamin, into its active form.

The connection between high folate levels and mutations in the MTHFR gene in Ehlers-Danlos patients was an eye-opening revelation. The team then connected the fact that animal model studies suggest that 5-methylTHF is necessary to deactivate an enzyme called MMP-2. MMP-2 (matrix metalloproteinases 2) breaks down a molecule named decorin — the “glue” that binds the scaffold that secures cells in place. So, the fragmentation of decorin by MMP-2 causes connective tissue to be loosely bound.

The Proposed Solution: Methylated Folate Supplements

The Tulane researchers’ breakthrough findings point towards an intriguing possibility for managing hEDS symptoms: a supplement containing 5-methyltetrahydrofolate, or 5-methylTHF. This is a form of folate that’s ready for the body to use without the need for the MTHFR enzyme to convert it first. [PMC10122021]

It’s an innocuous treatment. It’s not dangerous, and it’s a vitamin that can improve people’s lives. That’s the biggest thing: We know what’s going on here, and we can treat it.

Dr. Bix

You might be wondering, “Why not just eat more foods high in folate?” It’s a reasonable question. The folate that we typically get from our diet needs to be converted by our bodies into 5-Methyltetrahydrofolate 5-MTHF before it can be used. This process is precisely what’s disrupted in hEDS patients due to the MTHFR gene mutation. Therefore, eating more folate-rich food wouldn’t necessarily lead to higher levels of 5-methylTHF. In fact, it could lead to even higher levels of unprocessed folate in the blood, which is exactly the problem. High folic acid levels are what drive an increase in MMP-2.

On the other hand, taking a supplement that contains 5-methylTHF (also known as methylfolate) bypasses the need for this conversion. It’s like giving your body the exact fuel it needs, ready to go. This could potentially help keep the MMP-2 enzyme in check, alleviating the symptoms of hEDS.

Check Your Methylation Status

Since the advent of methylated B vitamins, clinicians have been finding that undermethylation due to a faulty MTHFR gene variant is not the only possibility. It is also possible for a person taking higher doses of methylated B vitamins over a period of time to become “overmethylated”. While the concept of overmethylation is not universally accepted in mainstream medicine, some clinicians and researchers in the field of functional medicine have observed this. Overmethylation can cause various symptoms, including anxiety, insomnia, and irritability.

When discussing lab tests related to methylation, there are both tests for your genetics and tests for your current methylation status. To find out if you have the MTHFR gene variant that affects methylation, genetic tests are available including the Nebula Genomics test which sequences 100% of your DNA, or through our lab affiliate, you could have your MTHFR genetic marker tested. You may also have your methylation status tested to help inform you on whether your intake of methylated B vitamins is right for you.

Choosing the Right Folate Supplement

When considering supplementing with methylfolate, it’s worth exploring the advantages of including it as part of a B-complex supplement or a multivitamin, each offering distinct benefits that cater to varying individual needs and health goals. Where you obtain vitamins also makes a difference.

Why Professionals Choose the Fullscript Formulary

Your health is on the line. Health professionals know that many other online and retail options set a very low bar for quality–sometimes amazingly low. The Fullscript formulary is the most secure online source for the highest quality brands securely sourced to assure freshness and purity. Here’s what makes Fullscript the best:

  • Meticulous vetting of brand quality. Health professionals trust Fullscript to continuously monitor the quality of each item on the platform. Other retailers operate with profit as their highest or only motive when choosing brands. Fullscript cares only about quality and reliability. Unlike discount stores, large online marketplaces, and other retailers you won’t find ingredients sourced from China or other questionable locations or companies.
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  • How It Works:
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    • Search For What You Want: Once inside Fullscript, you can search for the exact brands and products you want from their wide selection of quality brands.

B-Complex with Methyl Folate

Taking methyl folate as part of a B-complex supplement ensures you receive an optimal balance of all eight essential B vitamins, which often work synergistically and can promote a more efficient metabolism of methylfolate within the body. The following product would be a good choice:

B-Complex with Quatrefolic by Patient One MediNutritionals

Suggested Use: Take 1 vegetarian capsule as a dietary supplement, preferably with a meal, or as directed by a qualified health care professional.

Serving Size: 1 capsule

Amount Per Serving
Vitamin B-1
 … 87.5 mg 
(Thiamine HCl)
Riboflavin … 25 mg
(Vitamin B-2) (as Riboflavin-5-Phosphate)
Niacin … 75 mg
(Vitamin B-3) (as Niacinamide)
Pyridoxine … 25 mg
(Vitamin B-6) (as Pyridoxal-5-Phosphate)
Folate … 666 mcg DFE
(as Quatrefolic® [6S]-5-Methyltetrahydrofolic acid equivalent to 800 mcg of [6S]-5-Methyltetrahydrofolic acid, glucosamine salt)
Vitamin B-12 … 400 mcg
(as Methylcobalamin)
Biotin … 300 mcg
Pantothenic acid … 100 mg
(Vitamin B-5) (as D-calcium pantothenate)
Choline … 20 mg
(from Choline bitartrate)
PABA … 25 mg
(para-aminobenzoic acid)
Benfotiamine … 18 mg

Multivitamin With Methyl Folate

Including methylfolate in a multivitamin supplement provides a broad spectrum of essential nutrients beyond just the B vitamins, will overall wellness and filling nutritional gaps in one’s diet, while still delivering the critical benefit of the bioactive form of folate – “methyl-folate”. The following is a high-quality multivitamin including methyl-folate:

O.N.E. Multivitamin — Pure Encapsulations

Serving Size: 1 capsule / Dose: 1 per day

Amount Per Serving
Vitamin A … 1,125mcg (as vitamin A acetate and 73% beta carotene)
Vitamin C … 180mg (as ascorbic acid)
Vitamin D … 50mcg (as cholecalciferol) (D3) (2,000 IU)
Vitamin E … 20mg (as d-alpha tocopherol succinate)
Thiamin … 3mg (as thiamin HCl) (B1)
Riboflavin … 3mg (as vitamin B2 and 43% riboflavin 5′ phosphate (activated B2))
Niacin … 20mg (as niacinamide)
Vitamin B6 … 4mg (as pyridoxine HCl and 38% pyridoxal 5′ phosphate (activated B6))
Folate … 667mcg DFE (as Metafolin®, L-5-MTHF) (L-5-MTHF 400 mcg)
Vitamin B12 … 500mcg (as methylcobalamin)
Biotin … 300mcg
Pantothenic acid … 10mg (as calcium pantothenate) (B5)
Iodine … 150mcg (as potassium iodide)
Zinc … 25mg (as zinc citrate)
Selenium … 70mcg (as selenomethionine)
Manganese … 2mg (as manganese citrate)
Chromium … 200mcg (as chromium polynicotinate)
Molybdenum … 75mcg (as TRAACS™ molybdenum glycinate chelate)
Boron … 1mg (as boron glycinate)
Choline … 10mg (as choline bitartrate)
Inositol … 25mg
Coenzyme Q10 sustained-release … 50mg (as CoQ10 and as 18% from MicroActive® CoQ10-cyclodextrin complex)
Alpha lipoic acid … 50mg
FloraGLO® lutein … 3mg
Zeaxanthin … 500mcg
Lycopene … 500mcg

A Potential Game-Changer: Could it Really Be Simple Vitamin Supplement?

In summary, when there’s a mutation in the MTHFR gene, as is the case with hEDS patients, there is a buildup of unprocessed folate and less of the active folate. Active folate helps control the MMP-2 enzyme. So, people with the mutation in the MTHFR gene have less active folate and high levels of inactive forms, which in turn lets MMP-2 run rampant. When MMP-2 gets out of hand, it starts breaking down a substance called decorin – the “glue” that keeps our tissues tightly held together. This cutting of decorin makes connective tissues looser and activates signals that lead to scarring. This ultimately results in the symptoms we associate with hEDS, like hypermobile joints and fragile skin.

Armed with this new understanding, researchers are now proposing that we may be able to manage hEDS symptoms by raising levels of active 5-methylTHF. Essentially, this just involves taking a supplement of the 5-methylTHF molecule, also known as methyl folate.

“You’ve got millions of people that likely have this, and until now, there’s been no known cause we’ve known to treat. It’s a big deal,”

Gregory Bix, MD, PhD – Tulane University

This isn’t just a game-changer; it’s a potential life-changer for the millions of people living with Ehlers-Danlos. And while more research is needed to fully validate this approach, the future of Ehlers-Danlos treatment is looking brighter than ever.

If you are new to Ehlers-Danlos, CNN published an interesting article on it in 2022.

This Article is Not a Substitute for Medical Advice

Dietary supplements are not designed to diagnose, treat, cure, or prevent any disease. The Supplement Sciences website seeks to provide comprehensive access to the most relevant supplement information along with convenient online ordering. We do not provide medical advice and cannot guarantee that every product suggested is completely without risk. Since each person is unique in their health history and medication use, it is important to discuss supplements with your personal physician. Specifically, pregnant women and individuals being treated for cancer or liver or kidney problems must consult their physician about every nutritional supplement they plan to take. People taking medications for the treatment of HIV or with a history of organ transplant must not take supplements without consulting with their physician.

About the Author

Stephanie Figon, MS, RDN, LD

Creator of Supplement Sciences and NutriScape.NET. As a dietitian since 1992, Steph has had experiences in consulting, 15 years in clinical, and has operated a private practice nutrition counseling office for since 2011. Log in to comment and save this article on your board or send your comments to

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