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July 1997

The Word is Out on Homocysteine

By Paul Frankel, Ph.D. and Terri Mitchell

The importance of homocysteine in relation to heart disease is becoming well-known outside of research institutes. In addition to NBC Nightly News with Tom Brokaw, articles have been published in Newsweek (2/17/97), The Wall Street Journal (8/19/92 and 2/2/95), The Los Angeles Times (7/4/96), Prevention magazine (7/94), and more. Spots have been aired on the radio by Cedars-Sinai Medical Center, and McCully is coming out with a new book. The relationship between homocysteine and heart disease is so firm that some insurance companies are paying for homocysteine testing in some circumstances. From JAMA to Prevention magazine, homocysteine has become the word in heart disease.

An International Symposium is Held

In 1995, the Journal of Nutrition (the official publication of the American Institute of Nutrition) asked researchers from around the world to present data on the relationship between homocysteine and heart disease.Dr. Peter Harpel of Mt. Sinai School of Medicine reported that lipoprotein(a) and fibrinogen damage the cardiovascular system much more actively in the presence of homocysteine. In the Hordaland Homocysteine Study of over 10,000 people in Norway, it was found that being female and taking vitamins were associated with low homocysteine levels. After reviewing the data, Dr. Lars Brattström of Kalmer County Hospital in Sweden reported that levels of homocysteine directly correlate with cardiovascular disease. A major theme of the seminar was that while some people may not respond to a particular homocysteine-lowering supplement, the combination of TMG, vitamin B6, folic acid, and vitamin B12 decreased homocysteine in nearly every patient. That's why the standard treatment for lowering homocysteine, from Prince Henry Hospital in Australia, to University Hospital Nijmegen in the Netherlands-to Harvard Medical School-is a supernutrient combination of TMG, B6, B12 and folic acid.

Lowering Homocysteine

Supernutrient dietary supplements, taken in the right amounts, can lower levels to normal in 95% of cases. Lowering homocysteine through supplements is the single most important and well-documented use of vitamins and quasi-vitamins to date. According to Dr. Stampfer of Harvard (and seven other researchers from well-known U.S. research institutions), Betaine (TMG or trimethylglycine), folic acid (folate), vitamin B12, vitamin B6, and choline are effective in lowering homocysteine.Unfortunately, neither researchers nor clinicians agree on what constitutes a safe level of homocysteine. One study has suggested that every 4µmol/L (4µmol/mL) increase in homocysteine equals a 40% increase in risk. Other studies confirm that there is a very fine line between what is a safe level and what is not. In the Physicians' Health Study, the men who had heart attacks or died of cardiovascular disease were separated in their homocysteine levels from the ones who didn't by only a few micromoles difference in homocysteine. It is far from clear at this point that any of the large-scale studies have been conducted long enough, and with sufficient scrutiny, to determine what is a safe level of homocysteine. There is no magic "cut-off" or "safe" level of homocysteine at the present time.Part of the problem may lie in the methods used to measure homocysteine. According to McCully's work, there are different forms of homocysteine - some of them more reactive than others. Presently, all homocysteine is measured together, without separating out the more damaging form. The situation is analogous to the problem with cholesterol: while it is oxidized cholesterol that is problematic, standard tests measure all cholesterol, and don't distinguish between oxidized and non-oxidized. The failure of both cholesterol and homocysteine tests to quantify the more dangerous forms of both substances causes problems when trying to determine what is safe and what is not safe. However, it does not negate the fact that both are associated with heart disease. People who are wondering whether they should have their homocysteine levels tested should be aware that certain risk factors are associated with elevated homocysteine. According to the Hordaland Homocysteine Study, being male, smoking cigarettes, and being over 65 raises the risk both for high homocysteine and heart attack. Elevated heart rate and blood pressure also are associated with elevated homocysteine. It also appears that lack of exercise and high cholesterol levels are particularly risky for men and women in their 40s. People who have one or more of these risk factors should be tested for their homocysteine levels. Laboratory reference ranges are not definitive, but they can give an indication of risk on the high end. There was a 3.4 increased risk of heart attack in the Physicians' Health Study when homocysteine levels were greater than 15.8 µmol/mL. Normally, homocysteine is a short-lived product in the body. There is no known danger in having too little of it.

SAMe Level

SAMe Levels
A high-dose version of the Methyl Formula causes dramatic increases in SAMe levels (results on a patient with homocystinuria, T. Kishi, et at 1994).

Interestingly, most of the same supplements that lower homocysteine, elevate S-adenosylmethionine (SAM). SAM is a bioactive form of methionine that is made naturally in the body. It is what is known as a "methyl donor" because it contributes a methyl group (CH3) to other molecules to change their activity. SAM, as discussed in previous articles in Life Extension magazine, is critical for human health. The synthesized version has proven to be valuable therapy for several conditions, including liver cirrhosis, depression, osteoarthritis and fibromyalgia.

What is Betaine? There is confusion about the terms TMG, betaine, and betaine HCL. TMG stands for "Trimethylglycine", which is the chemical term for betaine. TMG is sometimes sold under the name "anhydrous betaine" (TMG without water), "betaine monohydrate" (TMG with one water molecule), "glycine betaine", or "oxyneurine". Betaine has a pH between 5 and 8, which is neutral. It is more than twice as soluble in water as Betaine HCL, has a lower molecular weight, and is manufactured differently. Good quality betaine comes from sugar beets through a complex extraction method, that does not introduce any harmful solvents.


Betaine HCL (betaine hydrochloride) is betaine with hydrochloric acid. It is sold as a digestive aid due to its strong acidity. Betaine HCL is usually synthesized, whereas TMG is made from sugar beets. There are no published studies on whether betaine HCL can function as a methyl donor to lower homocysteine and elevate SAMe. Although this is theoretically possible, its extreme acidity (a pH of 1) makes it an unlikely candidate for chronic use. Some clinicians have tried to use betaine HCL to lower homocysteine, but found that compliance was low, with most patients refusing to continue taking it. Several companies have been marketing betaine HCL as TMG (betaine HCL is cheaper), so one should be careful. Fortunately, the acidity of betaine HCL makes it easy to recognize. Simply open the capsule, or chew the tablet, and see if it burns your tongue. If it does, it is probably betaine HCL. Real TMG is somewhat sweet, not acidic. If the TMG is part of a multivitamin formula, look at the dose. If it is 50 mg or less, it is probably betaine HCL. Remember that 500 mg is the suggested dose of TMG, while 50 mg is the suggested dose of betaine HCL. There are companies mislabelling TMG, so always use the taste test. If you want to lower homocysteine, raise SAMe, and increase methylation, make sure you are purchasing pure-grade TMG. And remember, TMG should always be taken with its vitamin co-factors for the best effect - preferably in the morning.