Forget cholesterol—homocysteine is a more accurate test of your risk of dozens of conditions, including vascular disease and cognitive decline. And you can lower it without drugs, says Celeste McGovern
Case No. 19471, published in the New England Journal of Medicine, describes an eight-year-old Irish American boy admitted to Massachusetts General Hospital in 1933. He had begun vomiting four days earlier, but clearly, he had been ill for some time.
There was so little tissue beneath his sallow skin that he appeared emaciated. The lenses of both of his eyes, which seemed extraordinarily bright blue against his yellow complexion, had detached. His mother thought his poor vision accounted for his slow learning—he had attended kindergarten, but his school had refused him entry to upper grades.
His tongue protruded to the left, and tests suggested he may have suffered a stroke. His breathing was shallow and irregular, his blood pressure sky-high at 150/92. Four days later, he died of a stroke.
Looking at images from the autopsy report, doctors reviewing the puzzling case wondered how a boy of eight could have the completely clogged carotid artery of an elderly man.1
More than 30 years later, in 1965, a nine-year-old Irish American girl was seen at Massachusetts General Hospital for slow mental development. Her eye lens was detached, and she had other symptoms of homocystinuria, a rare genetic disease that had recently been discovered in Belfast, Northern Ireland. It was characterized by high levels of the amino acid homocysteine in the urine and blood plasma.
Laboratory tests confirmed soaring levels of homocysteine in her blood. Taking her family history, the doctors learned that her uncle had died in his childhood of a similar condition. He was, in fact, the eight-year-old who had mysteriously died of a stroke three decades earlier.
About this time, Dr Kilmer McCully, a young pathology instructor at Harvard, became intrigued by these rare homocystinuria autopsy reports, including that of a two-month-old baby boy who had died of heart failure and whose arteries looked exactly like those of a very elderly patient with advanced vascular disease.
Drawing on other research in animals showing that homocysteine is a toxic intermediary in metabolism, McCully developed a theory for the pathology of arteriosclerosis: What if homocysteine is the primary driver of arterial damage, and what if that damage, which is so obvious and devastating in these rare young cases, is also occurring more subtly in the population at large, among people with high homocysteine levels in their blood?
McCully didn’t dismiss the importance of cholesterol in vascular disease, but he suspected homocysteine was the underlying cause of arteriosclerosis, triggering cholesterol’s oxidation, buildup and artery-ravaging inflammatory effects. In other words, homocysteine metabolism and biochemistry determine the more downstream effects of cholesterol.
With the importance of B vitamins in homocysteine’s metabolism and its breakdown into harmless building blocks recently elucidated, McCully proposed that deficiencies of vitamins B6 (pyridoxine), B9 (folate) and B12 (cobalamin) allow homocysteine, normally benign, to rise to toxic levels.
At every turn, his research seemed to confirm his theory: When he injected rabbits with homocysteine, they developed arteriosclerotic plaques in their coronary arteries within weeks. The plaques were larger if the animals were also fed a diet deficient in vitamin B6.
But when he gave them these vitamins, the animals’ homocysteine levels plummeted, sometimes within hours. Other researchers reported similar findings in baboons. Then, in 1976, Australian researchers published their discovery that coronary heart disease was linked to elevated blood homocysteine in humans as well.2
McCully’s theory was unwelcome at Harvard and in mainstream medicine, however, which had latched onto the cholesterol-heart hypothesis.
The homocysteine theory also threatened a burgeoning industry around cholesterol-lowering drugs—within a decade these drugs launched as the biggest blockbusters of all time and today still generate more than $30 billion a year.3 There was no commercial interest in cheap, readily available and unpatentable B vitamin therapy for potential heart attack and stroke victims.
Under a new chief at Harvard in the 1970s, McCully’s theory was ridiculed, his funding dried up and he was moved to the basement. Eventually he lost his tenure and was told not to return.
At a new position at the Veterans Affairs Medical Center in Rhode Island, he quietly continued his research while other labs around the world continued looking at homocysteine, confirming its critical role in cardiovascular disease.4
Eventually, almost two decades after McCully’s dismissal, homocysteine made its way back to Harvard. Nearly 15,000 male physicians aged 40–84 years, with no prior heart attack or stroke, gave plasma samples and were followed up for five years.
The Physicians Health Study found that homocysteine was strongly correlated with heart disease. Participants who had levels in the top 5 percent of the normal range were three times more likely to have a heart attack.5
It was a turning point for homocysteine research. The story got bigger, too.
In a cohort study in Norway, nearly 5,000 men and women aged 65–67 were recruited as part of a national cardiovascular screening program that followed them for four years. Those with higher homocysteine didn’t just die of cardiovascular disease more often, they died of all causes more often.
A five-point rise in homocysteine level translated into a 49 percent increase in all-cause mortality, a 50 percent increase in cardiovascular mortality, a 26 percent increase in cancer mortality and a 104 percent increase in death by other causes.
“These results should encourage studies of [homocysteine] in a wider perspective than one confined to cardiovascular disease,” the Nordic researchers of the Hordaland Homocysteine Study concluded.6
As links to killer cancer and Alzheimer’s were uncovered, homocysteine research exploded. Meanwhile, a few randomized trials, such as the HOPE and NORVIT trials, tested whether lowering homocysteine with supplementary B vitamins would reduce the risk of vascular disease after an event, and the results were disappointing.7
Harald Bønaa was the lead researcher in the NORVIT trial, which found that B vitamin supplementation did not prevent a second heart attack. At a European Society for Cardiology press conference in 2005, he announced, “The homocysteine hypothesis is dead. Homocysteine is not a causal risk factor. It is an innocent bystander.”
It virtually became mainstream medical dogma that B vitamins “don’t work” for vascular disease—or anything else, for that matter. Many researchers noted that studies of previous heart attack and stroke sufferers were biased, however, and that research should be done on those who hadn’t had a vascular event.
The dissenters said the trials were too short and questioned the doses. They also noted that the folic acid supplementation mandated in some countries in the late 1990s obscured the vitamins’ benefits in the trials.
One critique, titled “Homocysteine: Call Off the Funeral,” said the HOPE trial had found supplementation did not prevent heart attacks but buried any mention of its own data showing it did prevent strokes. There were just too many unanswered questions about homocysteine to call it a dead end, its authors reasoned.8
Fast-forward another two decades, and many of those questions are still unanswered, while the cholesterol theory has gone virtually unchallenged by mainstream medicine and the lipid-lowering drug bonanza has continued.
Many researchers, however, say that if homocysteine is central to even just 10–15 percent of vascular incidents, that’s too many to ignore when there are 4,400 heart attacks and strokes daily in the US alone. Add that to other diseases, and at higher levels perhaps, and the homocysteine carnage looks enormous.
“We have reviewed the literature and have identified more than 100 diseases or conditions that are associated with raised concentrations of plasma total homocysteine,” say David Smith, emeritus professor of pharmacology at the University of Oxford, and Helga Refsum, a professor of nutrition at the University of Oslo in Norway and a lead author on the Hordaland Homocysteine Study.
“The commonest associations are with cardiovascular diseases and diseases of the central nervous system, but a large number of developmental and age-related conditions are also associated. Few other disease biomarkers have so many associations.”
The list of diseases and conditions that high homocysteine has been linked to reads like a pathology text: alcohol abuse, Alzheimer’s, anxiety, autism, cardiovascular disease, cancer, cognitive impairment, congenital defects, depression, diabetes, gum disease, low birth weight, Parkinson’s disease, polycystic ovarian syndrome, schizophrenia and more.9
Homocysteine sits at the center of two key biochemical pathways in the body: oxidation-reduction (redox) and methylation. The body constantly produces “free radicals” as byproducts of normal reactions, and it makes even more when we exercise too much, eat bad oils or burned food, get a sunburn, breathe dirty air or live with an inflammatory disease.
This oxidation process, which is at the heart of aging, is countered by antioxidants. The body’s master anti-aging antioxidant, glutathione, is low when homocysteine is high—something is choking the system that converts homocysteine into glutathione, which is needed for detoxification and oxidation, so homocysteine builds up. Like high homocysteine, low glutathione is linked to death from all causes.
Methylation is another key chemical process that happens billions of times a minute as our body does things like break down nutrients into usable molecules, convert neurotransmitters or hormones, or detox poisons from food or the environment. The donation of a methyl molecule (made of one carbon and three hydrogen atoms), called methylation, happens in all these processes. Methylation is used to repair broken DNA and switch genes on and off, including those in many cancers.
“Homocysteine rises if you’re not doing methylation properly,” says Patrick Holford, author of The Homocysteine Solution with Dr James Braly (Piatkis Books, 2012).
Methionine, which we consume in protein-rich foods like meat and fish, is methylated to become homocysteine. That in turn is either converted into glutathione or remethylated and turned into the body’s most important methyl donor molecule, S-adenosyl-methionine (SAMe) which fuels myriad other major methylation reactions.
This biochemistry all depends on levels of B vitamins as well as nutrients like zinc and magnesium that catalyze the conversions. If those nutrients are in scant supply, homocysteine builds up and begins its wrecking cascade, increasing free radicals, stiffening blood vessels, triggering inflammatory pathways10 and mitochondrial dysfunction,11 and damaging proteins,12 the blood-brain barrier13 and DNA.14
The following are common factors causing homocysteine to rise:
B vitamin deficiencies. High homocysteine almost always occurs in tandem with low levels of vitamins B2 (riboflavin), B6, B9 and B12.1
Magnesium deficiency. Without magnesium, it’s harder for the body to convert homocysteine to glutathione or SAMe.
Zinc deficiency. Like magnesium, zinc is needed to convert homocysteine to other molecules.
Trimethylglycine (betaine) deficiency. This molecule is also used to remethylate homocysteine, converting it to SAMe.
Vegetarian/vegan diet. A plant-only diet risks methionine and vitamin B12 deficiency.
Carnivore diet. A strict carnivore diet may lead to high methionine intake and low vitamin B9.
Low stomach acid or impaired digestion. If you are unable to digest your food well to extract nutrients like methionine, or if you can’t absorb B vitamins, the effect is like deficiency.
High alcohol consumption. Excessive alcohol use may block absorption and can lead to deficiencies in vitamins B1 (thiamine), B6, B9 and B12 as well as zinc.
In alcoholics, higher homocysteine is related to alcohol cravings, withdrawal seizures and increased dependency in a deadly feedback loop that spikes other health risks as well.2
Smoking. Long-term smokers tend to become deficient in B9 and B12 and have higher homocysteine.3
Obesity. People who are obese have significantly higher homocysteine levels.4
High coffee consumption. Drinking more than 3 cups a day raises homocysteine, an effect that appears only partially related to its caffeine content.5
Kidney impairment. High homocysteine impairs kidney function, accelerates kidney disease and raises the risk of heart attack and stroke in people who have kidney disease.6
MTHFR genetic variation. MTHFR is the gene that codes for methylenetetrahydrofolate reductase (MTHFR), an enzyme important for metabolizing folate. In Europe and North America, 10–15 percent of the population has a variant that significantly interferes with methylation of B vitamins, and about 40 percent carry a variant but aren’t greatly affected by it.
Some prescription drugs. Methotrexate, corticosteroids, arthritis drugs, metformin, L-dopa (for Parkinson’s), fibric acid derivatives and cholestyramine (for high cholesterol and cardiovascular disease), theophylline (for asthma and other lung diseases) and phenytoin (for seizures) may raise homocysteine sharply.7
Nitrous oxide (laughing gas), used to calm anxious patients, can “irreversibly oxidize” vitamin B12 and lead to serious problems, especially for those with MTHFR mutations, as in the case of a child who died after receiving nitrous oxide during dental treatment.8
Of the 100 diseases and conditions linked to high homocysteine, Smith and Refsum identify five that may be prevented by lowering total homocysteine: neural tube defects, impaired childhood cognition, macular degeneration, a first stroke and cognitive impairment in the elderly.1
Neural tube defects
Neural tube defects are birth defects of the brain, spine or spinal cord that begin early in pregnancy and have been linked to poor B9 and/or B12 status.2
When public health agencies in the US and Canada introduced mandatory food fortification with folic acid (synthetic B9) in the late 1990s, the incidence of neural tube defects fell 27 percent in the US between 1995 and 2000, and homocysteine in the women with high levels, above 13 mcmol/L, dropped by 72 percent. Similar findings were reported in Canada, suggesting high homocysteine in mothers due to folate deficits is related to these defects.3
Impaired childhood cognition
Studies have found taking folic acid during pregnancy, 400 mcg per day during weeks 15–40, leads to better cognitive performance in children at age three and better language use at age seven.4 But high supplementation (above 1 mg) before conception has the opposite effect.5
Macular degeneration
Daily supplementation with folic acid (2.5 mg) and vitamins B6 (50 mg) and B12 (1 mg) over 7.3 years has been shown to reduce the risk of any age-related macular degeneration (AMD) by 34 percent. For AMD affecting vision, it fell by 41 percent.6
First stroke
In a Chinese landmark study, more than 20,000 patients with hypertension and high homocysteine levels but no history of stroke or heart attack were randomized equally into groups treated with either the antihypertensive drug enalapril (10 mg) or the drug plus folic acid. After four years, the folic acid group was 29 percent less likely to have a stroke.7
As serum vitamin B12 in the whole Chinese cohort was low, Smith and Refsum believe that “addition of B12 to the treatment arm would have led to a bigger fall in total homocysteine and so to a larger reduction in risk of stroke.”
Cognitive decline in the elderly
Almost half of people over age 65 have high homocysteine,8 making them 10 times more likely to develop dementia.9 But a combination of B vitamins and omega-3 fats lowers homocysteine in the brain, reducing brain shrinkage by as much as 73 percent.10
In medical literature, homocysteine levels are typically defined as follows:1
However, the 1995 Framingham Heart Study found that levels 11.4 or greater and low vitamin B9 and B12 levels increased the risk of heart disease.2 Many experts consider 6–7 mcmol/L optimal and figures beyond 11 mcmol/L risky.
Homocysteine can also become too low—it’s a central player in methionine metabolism, potentially causing problems such as peripheral neuropathy.3
Low homocysteine can result from a low methionine (vegetarian) or low sulfur diet, or from overdoing methylated supplements like methylcobalamin (B12) and methylfolate (B9). It’s important to recheck homocysteine levels after introducing vitamin therapy—changes usually occur in under two months.
Private labs will do testing, and in the UK, you can order a mail-in spot test from Patrick Holford’s Food for the Brain Foundation (foodforthebrain.org). Genetic testing kits like those offered by SelfDecode (selfdecode.com), Ancestry and 23andMe reveal some of the most common mutations that affect homocysteine metabolism. You can upload a StrateGene report to help interpret your raw data and determine your needs from these genetic tests at Seeking Health (seekinghealth.com).
According to Patrick Holford, a good starting point to lowering homocysteine is to supplement with the Big Four B vitamins, methyl movers vitamin B2 (riboflavin), B6 (pyridoxine), B9 (folate) and B12 (cobalamin), plus zinc, magnesium and trimethylgycine (betaine).
Vitamin B2 (riboflavin)
Riboflavin-rich foods include liver and eggs, beef kidney and mussels.
Suggested daily dosage: 25 mg riboflavin-5’-phosphate sodium
Vitamin B6 (pyridoxine)
The higher homocysteine levels climb, the lower B6 and other vitamin levels fall.1
Suggested daily dosage: 15 mg as pyridoxal-5’-phosphate, or 25 mg in other forms
Vitamin B9 (folate)
Methylation expert Dr Ben Lynch, author of Dirty Genes (HarperOne, 2020), recommends starting with 400 mcg of folate as methylfolate or folinic acid for people with or without MTHFR variation. While most clinical trials substitute folic acid for folate, Lynch calls it a “garbage” synthetic version that’s difficult for the body to use.
“Folic acid interferes with the body’s natural folate,” says Lynch, who cites two case reports in which women given high-dose folic acid (5 mg) saw their homocysteine rise to dangerous levels and then fall dramatically within days of switching to 500 mcg of l-methylfolate.
For some people with MTHFR mutations, folinic acid can be a better-tolerated version of the vitamin, he’s found, and folinic acid or folate lozenges are a good way to control dosing—you can spit them out if unwanted symptoms start to occur.
Suggested daily dosage: Start at 400 mcg, increase as high as 800 mcg if needed
Vitamin B12 (cobalamin)
Vitamin B12 is necessary to metabolize homocysteine into master oxidizer glutathione and master methylator SAMe, but deficiency is frequently missed in mainstream medicine.
Lynch advises working up to vitamin B12, however—if people feel worse on B12, he says, they “aren’t ready for it” and first need to balance their electrolytes with electrolyte solutions and optimize their oxidation. For lowering homocysteine, methylcobalamin is optimal, but for those who can’t tolerate it, hydroxocobalamin is a methyl-free version.
Supplementing with glutathione or its precursor N-acetyl cysteine (600 mg/day) helps.
Suggested daily dosage: 10 mcg/day
Trimethylglycine
Also known as betaine, trimethylglycine is a derivative of choline and a major methyl donor. This means it’s necessary for liver function and detoxification, and it supports homocysteine’s conversion back into methionine.
Research has shown it rapidly decreases high homocysteine levels. One 2013 review of five randomized controlled trials in healthy adults concluded that “supplementation with at least 4 g/day of betaine for a minimum of six weeks can lower plasma homocysteine.”2
Suggested daily dosage: 4–6 g
Magnesium
One major study showed that magnesium and homocysteine are significantly inversely correlated: The higher the homocysteine, the lower the magnesium. Deficiency is common, and individuals with low magnesium and high homocysteine exhibit much higher frequency of damaged DNA markers than those with the reverse.3
Magnesium-rich foods include dark leafy greens, brown rice and pumpkin seeds.
Suggested daily dosage: 150 mg or more in a chelated form like magnesium glycinate
Zinc
Zinc is a critical enzyme to activate vitamin B6 in methionine metabolism. It’s also the most common mineral deficiency.
Vegetarians need more zinc because it’s harder to absorb from plant sources, as do diabetics and people with celiac disease and chronic kidney disease. Alcoholics are often deficient since alcohol blocks zinc absorption and increases zinc loss in urine.
Suggested daily dosage: If your homocysteine is lower (6–9 mcmol/L), take 10 mg of zinc daily; if moderate (10–15 mcmol/L), take 15 mg; if high (over 15 mcmol/L), take 20 mg
For details about how to choose a good vitamin B supplement, see Healthy Shopping: Better B Vitamins.
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