Life Extension Magazine®

When Homocysteine Levels Won’t Come Down

For most people, supplementing with folic acid, vitamins B12 and B6, and trimethylglycine (TMG) will reduce homocysteine to optimal levels. But what if your homocysteine remains persistently high despite high-dose supplementation with these nutrients? Find out novel approaches aging adults can use to bring stubbornly high homocysteine levels under control.

Scientifically reviewed by Dr. Gary Gonzalez, MD, in May 2022. Written by: William Faloon.

Twenty-five years ago, the Life Extension Foundation warned its members about the dangers of elevated homocysteine. Since then, excess homocysteine has been correlated with common disorders that include Alzheimer’s disease,1-8 osteoporosis,9,10 heart disease,11-18 stroke,3,19,20 depression,21-23 and cognitive impairment.24-38

A simple blood test can measure one’s homocysteine level. If homocysteine blood levels exceed 7-8 µmol/L,39 increasing one’s intake of folic acid,40-49 vitamin B12,50,51 vitamin B6,41-44,49 and/or TMG (trimethylglycine)52-55 usually reduces homocysteine to safe ranges.

Over the past six months, we have received calls from some of our medical advisors and members who report incidences of stubbornly high homocysteine levels, despite aggressive use of homocysteine-lowering nutrients.

While investigating what could be done for these people, I had my own blood tested and was shocked to find my homocysteine had skyrocketed to 15.6 µmol/L, a level that puts me at higher risk for a host of age-related diseases. Serendipitously, I was interacting with our doctors to develop a protocol for members whose homocysteine remains persistently elevated even when high doses of nutrients like folic acid and B6 are ingested.

The encouraging news is that we have been able to identify reversible causes of excess homocysteine occurring in otherwise healthy individuals. Now that these mechanisms are better understood, most members should be able to keep their homocysteine levels in optimal ranges.

Kidney Function, Cardiovascular Risk, and Homocysteine Levels

It has long been known that those with severe kidney disease have startling high homocysteine levels and very high rates of cardiovascular disease. A number of published papers have discussed how excess accumulation of homocysteine in the blood of dialysis patients is one reason for the epidemic of cardiovascular mortality observed in these individuals.56-70 In fact, the risk of cardiovascular disease in chronic kidney disease is up to 30 times that of the general population!71

Recently, scientists have begun to publish papers describing cases of excess homocysteine in people with even mild kidney impairment.72-78 What most doctors don’t know is that the kidneys facilitate the removal of homocysteine from the blood.79,80 The kidneys are also involved in enzymatic reactions that transform homocysteine into safer substances in the body.81 Any impairment in kidney function can result in excess homocysteine accumulation, even when one takes large quantities of classic homocysteine-lowering supplements.

As soon as I saw my homocysteine reading of 15.6 despite my very aggressive homocysteine-lowering strategy (with high-dose B vitamins), I knew I had a kidney problem. At first, even nephrologists (kidney specialists) did not think there was anything wrong with my kidneys. I had to inform these doctors of published scientific studies showing that if one takes high doses of homocysteine-lowering nutrients and homocysteine levels remain elevated, this indicates an underlying kidney problem.82-86

In those with kidney disease, homocysteine levels can remain at dangerously high levels despite supplementation with vitamins B6 and B12, folic acid, and TMG.85,87-91 Some people with end-stage kidney disease may not be able to reduce their homocysteine even with doses of folic acid as high as 60,000 mcg per day!92

I Demanded More Sophisticated Kidney Function Tests

The most widely used screening tool for evaluating kidney function is the creatinine blood test. Most standard CBC/chemistry blood profiles include the creatinine test to evaluate kidney function.

According to standard reference ranges, a creatinine blood level of up to 1.5 mg/dL is considered normal. My creatinine level was 1.3, which made my doctors initially question why I thought my kidneys were impaired. I had to remind them that I was taking massive doses of folic acid and vitamins B12 and B6. That meant my homocysteine reading should have been below 8 µmol/L, whereas in fact it was a startlingly high 15.6. The only reason my homocysteine could be this high, I argued, was a failure of my kidneys to remove and neutralize the excess homocysteine.

Fortunately, one of our scientific advisors enlightened me to a new blood test called Cystatin-C that provides a far more accurate measure of kidney function. Cystatin-C readings of up to 0.91 mg/L are considered normal. When I tested my own Cystatin-C level, it turned out to be 0.95 mg/L. I was thus able to document for my kidney specialist that I indeed had early-stage kidney impairment.

What Causes So Many Kidneys to Fail

Most people over the age of 65 suffer from some degree of kidney dysfunction. Symptoms are usually not present, but blood tests show that a lot of otherwise healthy aging individuals have less-than-optimal kidney function. This fact is not widely recognized by mainstream medical doctors.

Kidney disorders are very common in diabetics.93,94 Those suffering from atherosclerosis,95,96 chronic inflammation,97-100 hypertension,101-103 and certain other disorders also often display diminished kidney function.

In my case, I suffered from none of the underlying medical disorders known to cause kidney impairment. I was, however, taking relatively high doses of the anti-inflammatory drug ibuprofen for its cancer-preventive and sleep-inducing effects. Quite a bit of science supports the anti-cancer effects of drugs like ibuprofen.104-108 Regrettably, however, some people’s kidneys cannot handle the side effects of ibuprofen, and I turned out to be one of them. The good news is that within two months of discontinuing the use of ibuprofen, my creatinine level dropped to 1.0 mg/dL (from 1.3) and my Cystatin-C declined to 0.75 mg/L (from 0.95). It appears that ibuprofen was the culprit, though the FDA does not mandate a kidney warning to be included on the label of these drugs. A quick search of the scientific literature, however, reveals potential risk to the kidneys with long-term ibuprofen use.109-112

Based on our review of the published scientific literature, we are now advising members to pay very close attention to their blood indicators of kidney function. In my case, creatinine levels had risen from 0.8 mg/dL in January 2005 to 1.3 in November 2005—a clear indication that my kidneys were heading downhill. Keeping copies of previous blood tests and comparing the magnitude (or velocity) of change in certain biomarkers can help you identify newly emerging problems.

In addition to the standard blood markers of kidney function (creatinine, BUN, BUN/creatinine ratio), excessive homocysteine in someone taking homocysteine-lowering supplements is also an indication of potential kidney impairment.

Life Extension members already take supplements to protect their kidneys, such as coenzyme Q10,136-138 carnitine,139-143 taurine,144-147 curcumin,148-153 and others. We have published an extensive protocol on the prevention and treatment of kidney disease in our Disease Prevention and Treatment reference book.

How to Suppress Stubbornly High Homocysteine

The aging process often inhibits one’s ability to maintain optimal homocysteine levels. For most people, however, the proper use of folic acid, vitamins B6 and B12, and/or TMG will bring homocysteine down to safe ranges.

Several years ago, I learned that I needed exceptionally high doses of homocysteine-lowering nutrients compared to most people. For instance, while 100 mg of vitamin B6 is all most people need, I required around 1000 mg/day of vitamin B6 to suppress my homocysteine adequately.

Based on what we now know, improving kidney function is another way to reduce homocysteine blood concentrations. In my case, as my blood indicators of kidney function improved (in response to halting the use of ibuprofen), my homocysteine levels steadily declined. I was finally able to lower my homocysteine to the optimal range of below 7-8 µmol/L by taking additional TMG and a new prescription drug that I will describe next.

It is important to remember that I have a genetic predisposition to high homocysteine and have historically had to take large amounts of B vitamins to keep my homocysteine level around 8. Most members respond to homocysteine-lowering supplements much better than I do.

Fortunately, there is a form of folic acid for people like me whose bodies do not properly break down homocysteine. I am going to tell you all kinds of positive data about this form of folic acid, but the best news is that most of you do not even need it.

Ibuprofen and Cancer Prevention

Studies show that people who regularly use pain relievers like ibuprofen have sharply reduced risks of esophageal,113,114 brain,115 colon,114,117 prostate,114 and other cancers.114,117 Ibuprofen’s mechanism of action is thought to be its inhibiting effects on the cyclooxygenase-2 (COX-2) enzyme. Cancer cells use COX-2 as biological fuel to propagate, and studies find that suppressing COX-2 may indeed reduce cancer risk.118 Fortunately, safe nutrients like curcumin also suppress COX-2, but do not inflict damage to the liver or kidneys.

Regular users of drugs like ibuprofen have reduced risks of Alzheimer’s disease.119-124 Fortunately, nutrients such as gamma tocopherol,125-127 curcumin,128-130 fish oil,130-132 and resveratrol133-135 may also protect against Alzheimer’s without inducing the toxic side effects associated with ibuprofen.

A Different Kind of Folic Acid

When you consume folic acid, it goes through several metabolic steps before being converted to Metafolin®, which is the active form of folate in the body that actually reduces homocysteine. Some people fail to convert folic acid to L-methylfolate, which results in them accumulating higher-than-desired levels of homocysteine.

A patented form of folic acid called Metafolin® provides enormous benefits for those who do not naturally produce enough L-methylfolate. L-methylfolate is available both as a dietary supplement and as a prescription drug called Cerefolin®. The manufacturer of Cerefolin® claims that L-methylfolate reduces homocysteine almost three times more than folic acid.154

Because Cerefolin® is a prescription drug, it is very expensive. The manufacturer’s claims, however, appear to be somewhat embellished. The study citied by the manufacturer (showing almost three times greater homocysteine reduction) compared one-time dosing of 5200 mcg of L-methylfolate to 5000 mcg of regular folic acid. Since Cerefolin® is absorbed much quicker than folic acid, it would be expected that one-time dosing of Cerefolin® would produce faster results.

What the manufacturer fails to mention is that dietary supplement users seeking to lower homocysteine usually take vitamin B12, vitamin B6, and sometimes TMG with their folic acid. If a group of dietary supplement users were compared to a group that took only L-methylfolate, there might be not be a significant average difference in homocysteine levels over the long term.

The key factor here is individual need. For people who are unable to efficiently convert folic acid to L-methylfolate in their bodies, the more expensive L-methylfolate product will benefit them tremendously. Most people, however, can achieve desired homocysteine reduction merely by taking enough conventional homocysteine-lowering supplements.

All of this points to the critical importance of having your blood tested to assess your homocysteine level. If you are taking high doses of homocysteine-lowering nutrients and your homocysteine level remains persistently high, then you should first make sure that you do not suffer from kidney impairment. Whether or not you suffer from kidney impairment, if your homocysteine remains persistently high, consider taking 800-5600 mcg of L-methylfolate two times a day to achieve at least some improvement.

Where to Obtain L-methylfolate

The drug company Merck holds the patent on L-methylfolate and has set up a number of barriers that prevent it from being more widely available as a dietary supplement. Fortunately, a few supplement companies (such as Source Naturals) were able to overcome these hurdles and make L-methylfolate available without a prescription.

Remember, this form of folic acid is not required if the supplements you take are keeping your homocysteine below 7-8 µmol/L of blood. For those who take proper doses of folic acid, B12, B6, and TMG, but still suffer higher-than-optimal homocysteine, L-methylfolate may be the solution.

Some people need only 800 mcg twice a day of L-methylfolate to optimize homocysteine. Others will need much higher potencies of L-methylfolate and may want to consider asking their doctor to prescribe Cerefolin® at a dose of one to two tablets daily. Each tablet of Cerefolin® provides:

  • L-methylfolate 5635 mcg
  • Vitamin B12 1000 mcg
  • Vitamin B6 50 mg
  • Vitamin B2 5 mg

Cerefolin® can be obtained in pharmacies and some insurance companies may cover it. The downside is that you have to get your doctor to prescribe it.

The Life Extension Buyers club offers Source Naturals’ L-methylfolate supplement to members at a discount off the retail price. The trade name of this supplement is Metafolin® and it comes in bottles containing 120 800-mcg tablets. The retail price is $17.98 per bottle, but members of the Life Extension Foundation can obtain it for only $12.50. Please remember that L-methylfolate is for those who are unable to lower their homocysteine with lower-cost conventional supplements. Most people do not need it.

Nutrients That Keep Homocysteine Levels Low

Most members are already supplementing with nutrients that adequately suppress homocysteine levels. The minimum doses we recommend to control homocysteine are:

  • Folic acid — 800 mcg
  • Vitamin B12 — 300 mcg
  • Vitamin B6 — 100 mg
  • TMG (trimethylglycine) — 500 mg

Those with a homocysteine level over 7-8 µmol/L of blood should consider daily supplementation with:

  • Folic acid — 1600-3200 mcg
  • Vitamin B12 — 1000-2000 mcg
  • Vitamin B6 — 250-1000 mg
  • TMG — 4000-8000 mg

(Watch out for symptoms of peripheral neuropathy when B6 daily doses exceed 200 mg for an extended period. This is a rare occurrence, but it has been reported in mainstream medical journals.)

If homocysteine levels remain persistently elevated despite high-dose supplementation with these nutrients, carefully monitor kidney function and take 1600-11,000 mcg a day of L-methylfolate.

Blood Testing Probably Saved My Life

Had I not had regular blood tests performed, I would have assumed that the nutrients I took every day were adequately suppressing my homocysteine levels. I was fortunate to learn a long time ago that I needed a lot of vitamin B6 to reduce my homocysteine to safe ranges.

The blood tests I took in November 2005 alerted me to an underlying kidney disorder that I was able to reverse simply by discontinuing a drug (ibuprofen). Many other drugs can adversely affect the liver, kidneys, and bone marrow. A CBC/chemistry blood test reveals drug-induced pathologies before they cause irreversible damage. If I had not taken this blood test, I may have continued taking ibuprofen for its sleep-inducing and cancer-preventive effects. Since early-stage renal failure does not usually present symptoms, I could have suffered irreversible kidney damage, along with the life-threatening complications—such as sharply increased risk for heart attack and stroke—caused by that kidney disease.

Kidney disease is a leading cause of death in the United States, yet most cases of renal dysfunction are preventable if annual blood tests are taken to rule out factors such as diabetes, drug-induced toxicities, early-stage atherosclerosis, and chronic inflammation.

Recommended Blood Tests for Men and Women


  • CBC/Chemistry
  • Total Testosterone
  • DHEA
  • Free Testosterone
  • PSA (prostate-specific antigen)
  • Estradiol
  • Homocysteine
  • C-Reactive Protein


  • CBC/Chemistry
  • Total Testosterone
  • DHEA
  • Free Testosterone
  • Estradiol (an estrogen)
  • Progesterone
  • Homocysteine
  • C-Reactive Protein

To order these blood tests for yourself, call 1-800-208-3444 (24 hours a day). The member price for the Male or Female Panel is $299.

By making this one phone call, you will be sent a requisition form and list of blood drawing stations in your area. Most of the time, no appointment is necessary. This means that you can pick a time convenient to you to have your blood drawn.

The test results are usually mailed to you in 7-10 days. If you have any questions, Life Extension’s health advisors are available by calling 1-800-226-2370.

Discount Blood Testing Available to Foundation Members

Since the early 1980s, Life Extension has advised its members to have annual blood tests to identify disease risk factors that can be reversed before serious illness develops.

Some members are able to obtain blood tests from their doctors. A problem that I frequently encounter is that even when doctors order all the blood tests requested, the phlebotomist often fails to check off the appropriate codes on the laboratory requisition form or does not properly draw the blood. When the results come back incomplete, another blood draw becomes necessary, thus inconveniencing the patient.

Even today, many doctors still refuse to prescribe blood tests for important cardiovascular risk factors such as homocysteine and C-reactive protein. Life Extension resolved this problem 10 years ago by offering blood tests directly to its members.

Members can obtain blood tests for a fraction of the price charged by commercial laboratories. For example, the comprehensive Male or Female Panels cost around $1,100 at a commercial laboratory, yet Foundation members can obtain these identical tests for only $299.

Based on what I have discovered as a result of having my own blood tested regularly, I am convinced that I have corrected a number of genetic risk factors that would have predisposed me to a premature death. Whether using your own doctor, a commercial laboratory, or our blood-testing service, I encourage every member to have his or her blood tested at least once a year.

For longer life,
William Faloon


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