The last decade has seen a sudden interest in homocysteine, a type of amino acid involved in the breakdown of certain compounds in the body. This interest is largely due to the discovery that elevated levels of homocysteine are a major risk factor for serious vascular diseases such as stroke.
In fact, a study published in the British Medical Journal has revealed that high levels of homocysteine in blood plasma can significantly increase the risk of death from cardiovascular disease in older people - more so than high cholesterol, blood pressure, or smoking.
And that’s not all. Elevated homocysteine is also now linked to migraines, dementia, poor memory function, reduced concentration and judgment, and low mood. Women with high homocysteine levels may struggle to conceive and are at risk of recurrent miscarriage.
Clearly, homocysteine is a serious risk factor for ill health, and something we all need to be aware of.
But what is homocysteine?
Homocysteine is a naturally-occurring amino acid that’s created when your body breaks down the essential amino acid methionine. Methionine is broken down into homocysteine, and then homocysteine is ‘recycled’ back to become methionine again. Methionine is a sulfur-containing amino acid involved in building proteins and producing certain substances in the body, including the antioxidant glutathione and the molecule SAMe.
A host of important nutrients are created throughout the methionine-homocysteine pathway; all of which play a part in various other biochemical reactions such as detoxification, healthy immune function, the formation of connective tissues, as well as brain and cardiovascular function.
The specific enzymes required for this pathway require many important nutrients, especially B
vitamins. A lack of any particular nutrient can lead to an undesirable elevation in homocysteine levels. It’s for this reason that the level of homocysteine in your blood plasma becomes an important indicator of overall health.
The metabolism of homocysteine
Normally, homocysteine is broken down by your body’s stores of vitamin B12, vitamin B6, and folate and changed into substances that your body actually needs.
There are two pathways through which the methylation cycle can convert homocysteine to methionine.
- The cobalamin (vitamin B12) and folate-dependent re-methylation pathway that regenerates methionine. This is ‘“long way” around the cycle via the MTR and MTRR enzymes that requires B12 and the forward reaction of the MTHFR (where the C677T impairs the activity) for function.
- The second is a “shortcut” through the middle of the cycle that bypasses MTR, MTRR and MTHFR via the BHMT enzyme. If you think of this portion of the cycle as a clock, the BHMT enzyme can use phosphatidylserine, phosphatidylcholine and TMG as substrates to go directly from homocysteine at 6:00 to methionine at 12:00 skipping 7:00 through 11:00. The use of phosphatidylcholine, phosphatidylserine and TMG therefore help to bypass these mutations. This pathway generates more norepinephrine relative to dopamine.
When this happens properly, there should be very little homocysteine left in your bloodstream.
Research has shown that high levels of homocysteine in your blood may indicate deficiency in B vitamins. In other cases, it may indicate heart disease or a genetic condition.
Why is high homocysteine so bad?
Homocysteine accumulates in the body if the biochemical transformation process is not working properly. This is usually due to a lack of folate, B6, and vitamin b12. If untreated, hyperhomocysteinemia can lead to vascular damage, cognitive impairment, neurological complications, congenital defects, and pregnancy complications.
Raised homocysteine affects the way cells use oxygen, resulting in a build-up of damaging free radicals. Oxidation has already been linked to the onset of numerous diseases of the heart, brain, and immune system. Reactive chemical forms such as free radicals can oxidize low-density lipoproteins, which result in the buildup of oxidized fats and proteins within developing arterial plaques. This oxidation injury - along with methylation defects and impaired DNA repair due to poor folate metabolism - is also implicated in carcinogenesis.
Homocysteine is also shown to stimulate the growth of smooth muscle cells, causing the deposition of extracellular matrix and collagen. Artery walls can become tough and thickened, increasing the risk of cardiovascular disease.
As if that weren’t enough, homocysteine has also been linked to neurodegenerative disorders, particularly in the case of vitamin B12 deficiency.
What is considered high homocysteine?
A normal level of homocysteine in the blood is less than 15 micromoles per liter (mcmol/L) of blood. Higher levels of homocysteine are split into three main categories:
- Ideal: 5-9 mcmol/L
- Moderate: 15-30 mcmol/L
- Intermediate: 30-100 mcmol/L
- Severe: greater than 100 mcmol/L
The tricky thing about hyperhomocysteinemia is that it typically doesn’t produce any noticeable symptoms. Most people will only have their homocysteine levels tested if they appear to have symptoms of a vitamin deficiency.
This is why it’s important to be aware of the signs of deficiency in B12, folate, or both.
Symptoms of B12 deficiency
Symptoms may vary from person to person, but can include:
- Pale skin
- Weak muscles
- Lack of energy and/or fatigue
- Numbness or tingling sensations (similar to pins and needles) in the hands, arms, legs, or feet
- Light-headedness or dizziness
- Mouth sores
- Noticeable mood changes
- Trouble walking
- Lack of appetite
- Weight loss
- Smooth and tender tongue
- Increased heart rate
Symptoms of folate deficiency
Additional symptoms caused by folate deficiency can include:
- Mouth sores
- Swelling of the tongue
- Problems with growth
Other causes of high homocysteine levels
Heavy metals such as mercury and lead can also interfere with the conversion of methionine to homocysteine, and vice versa. Some sources suggest that mercury fillings may lead to chronic mercury inhalation, which is known to bind to the amino acids cysteine and methionine: both of which are involved in proper metabolism of homocysteine. The absence of these useful amino acids further affects other nutrients in the pathway, which makes nutritional support all the more crucial.
Besides deficiency in folate or B12, other risk factors for hyperhomocysteinemia include:
- Low thyroid hormone levels
- Kidney disease
- Certain medications
A number of factors can deplete your levels of B vitamins; most notably poor diet, poor nutrient absorption, stress, and many medications. However, the lack of symptoms means that many people have no idea how badly their body is being affected by the circulation of excess homocysteine in their body.
How to treat high homocysteine
If you are diagnosed with high homocysteine, it’s crucial that you take steps to lower your levels immediately.
The key to maintaining an optimally functioning homocysteine pathway begins with providing nutrients for necessary biochemical reactions in the body.
Your first step should be to address the food you’re putting into your body. A vitamin deficiency can often come about as a result of poor nutrition and/or weak digestive function. Eating a range of folate-rich foods such as leafy greens and animal products may help, but it’s also important to address whether your body is able to break down and absorb these foods properly. If your digestive health is poor (which is often the case), it is highly advisable to seek a consultation with a naturopath or health practitioner.
Elevated homocysteine levels can often be normalized by supplementing with methylfolate, B6, and an active form of vitamin B12. That’s why the next step is to take the right supplements to restore your body’s required levels of the nutrients required for optimal homocysteine metabolism.
Vitamin B6 (P5P)
The active form of vitamin B6 is known as pyridoxal-5-phosphate (P5P). This nutrient serves as a cofactor for more than 150 enzymes in the body, including those involved in the synthesis of dopamine, serotonin, gamma-aminobutyric acid (GABA), and histamine. Most importantly, vitamin B6 is required for the metabolism of homocysteine and tryptophan.
Research indicates that around 70-80% of vitamin B6 in your plasma is in the form of P5P. The higher your levels of P5P, the lower your inflammatory markers - and vice versa. Inflammation increases the uptake of P5P into the tissues, which reduces the amount available in your plasma and liver.
P5P is necessary for the function of two enzymes, cystathione ß-synthase (CBS) and cystathione γ-lyase (CSE) in the breakdown of homocysteine to cysteine. This is involved in reducing homocysteine levels and also in overall detoxification, as up to 50% of the cysteine produced through this pathway is used to create glutathione.
This means those with increased homocysteine levels almost certainly require additional P5P.
Note, one unique thing about P-5-P for some people is that it can build up and become toxic in some folks due to an inability to clear it. You’ll know if you have this problem if you get tight band headaches that stop when you stop your P-5-P supplementation. So be aware of the fact that you may only tolerate small doses of P-5-P instead of some of the more mega doses that some supplements carry.
Mutations of the MTHFR gene (methylenetetrahydrofolate reductase) are another major contributor to high levels of homocysteine in the blood, along with low levels of folate.
The MTHFR gene is responsible for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays many important roles in your body, including the processing of amino acids. More importantly, it’s required for the conversion of a form of folate called 5,10-methylenetetrahydrofolate to a form called 5-methyltetrahydrofolate. This is the primary active form of folate in your body required for the conversion of homocysteine into methionine.
A mutation on the MTHFR gene can seriously affect the enzyme’s ability to function normally, which has severe implications for the homocysteine cycle.
Trimethylglycine (TMG) is a molecule known as a 'betaine' molecule but referred to as ‘trimethylglycine’ and ‘betaine’ interchangeably.
Betaine is a methyl donor that has two main mechanisms. The first is to either directly donate a methyl group to reduce homocysteine into L-methionine, and the second is to increase the body’s levels of S-Adenosyl Methionine (SAMe) or active folate molecules. This allows SAMe and folate to go on and donate methyl groups to other parts of the body.
This is why supplementation of betaine can indirectly support whole-body methylation, as well as directly support a reduction in homocysteine. This has already been shown in moderate to high dose supplementation.
Although TMG (trimethylglycine) and DMG (dimethylglycine) are closely related, they each serve different purposes and use different pathways. Both TMG and DMG are integral parts of the one-carbon cycle, and they both play critical roles in methylation pathways.
TMG transfers its methyl group directly to homocysteine, while DMG uses the folate (methylfolate) pathway. When this works properly, both TMG and DMG send methyl groups into the methyl pool to produce SAM-e (S-Adenosyl methionine) from homocysteine.
If your body can use two pathways, methylation is much more efficient.
The fact that each pathway uses different systems to donate to the methyl pool also means that TMG might work better for some and DMG for others.
Research published in the American Journal of Clinical Nutrition has shown that N-acetyl-cysteine can significantly decrease plasma homocysteine levels as well as blood pressure.
In a placebo-controlled trial involving unmedicated middle-aged men, four weeks of N-acetyl-cysteine supplementation compared to placebo led to a significant decrease in plasma homocysteine levels. In addition, there was a significant reduction in systolic blood pressure in all the subjects given the NAC.
The researchers suggested that oral intake of NAC could be an effective treatment for the primary or secondary prevention of vascular events, particularly in terms of hyperhomocysteinemia and hypertension.
Recommended supplements for lowering homocysteine
Homocysteine Supreme™ contains key nutrients that help maintain a healthy homocysteine pathway by supporting the normal production of necessary end products. This formula includes vitamins B6, B12, and folate, essential nutrients for proper homocysteine metabolism. In addition, it contains trimethylglycine (TMG) and N-acetyl-L-cysteine (NAC) which are required for important biochemical reactions and biological functions, including detoxification and the synthesis of glutathione.
These nutrients work together to optimize the metabolism of homocysteine and thus prevent it from accumulating in the body. This allows the body to create necessary methyl groups and sulfur groups for a range of biochemical reactions, including those involved in detoxification, joint and cartilage repair, and brain health.
Potential Homocysteine Supreme™ side effects
Vitamin B6 is considered safe in doses up to 100 mg per day. In some people, higher doses may cause nausea, vomiting, diarrhea, stomach pain, loss of appetite, headache, tingling, sleepiness, and other side effects.
It’s important to note that those who are B6 deficient may have a genetic disorder or problems with the absorption and conversion of pyridoxamine and pyridoxine into the active form pyridoxal 5’ phosphate in the liver.
- Methylfolate may produce side effects in some people, including irritability, difficult sleeping, sore muscles, aching joints, acne, skin rashes, anxiety, palpitations, nausea, headaches, migraines, burning or stinging in the nerves, runny nose.
- Betaine may cause a fishy smell in the breath and bodily secretions in some people, or when taken at high therapeutic doses. However, taking riboflavin (Vitamin B2) at 100mg twice daily appears to eliminate this odor.
- NAC can produce a variety of adverse reactions, but most of these are due to incorrect dosing. High doses may cause nausea, vomiting, diarrhea and constipation. It can slow blood clotting, so it should not be taken by people with bleeding disorders or taking blood-thinning medications.
Recommended methylfolate and homocysteine-reducing supplements
Some of the best-selling methylfolate supplements for reducing homocysteine are in the Methyl-Life™ product range, including
Each product is designed to support the body’s requirements for energy production, detoxification, balanced homocysteine levels (therefore cardiovascular, nerve and pregnancy health) as well as neurotransmitter synthesis, while also restoring healthy levels of folate.
Methyl-Life’s™ Methylfolate 15 best-selling product contains a high dose (15 mg) of internationally-patented Magnafolate® PRO [(6S)-5-methyltetrahydrofolic acid, Calcium salt, Type C Crystalline molecule (L-Methylfolate)]. This best-selling product is formulated especially for people with a heightened need for bioavailable folate due to genetic (MTHFR) defects, dietary deficiencies or drug-induced need (i.e. taking warfarin, coumadin, metformin, etc.). This product is particularly targeted at raising serotonin levels which can aid in depression and mood-related challenges.
This unique and internationally-patented L-5-Methylfolate ingredient is crystalline calcium salt-based for superior stability and absorption. A recent study has revealed that this proprietary form of methylfolate is three times purer than any other L-Methylfolate competing in the market today. Methylfolate is often known or labeled as L-MTHF, L-5-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.
As with taking any supplement, it is strongly advised that you consult with a qualified healthcare practitioner before beginning any treatment.