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New Approaches To Joint Health And Arthritis

Cetyl myristoleate is the latest ingredient to address the burgeoning arthritis market. Marcia Zimmerman, C.N., looks at some of the research conducted on the compound that promises to ease joint pain and stiffness for millions.

In the United States, 1 million patients develop arthritis each year. It is estimated 60 million people will have arthritis by the year 2020, according to the National Arthritis Action Plan: A Public Health Strategy, jointly proposed by the Arthritis Foundation, the US Centers for Disease Control and Prevention, and the Association of State and Territorial Officials. Nearly 50 per cent of people older than 65 feel arthritic pain; younger people have less risk of arthritis but still comprise half of those affected. Arthritis also affects about 250,000 children in the US.

The quest for new drugs or nutritional supplements to prescribe for symptom relief for patients with chronic and disabling rheumatic conditions is constant and ongoing. The research drive has led to the discovery of cetyl myristoleate (CM), a supplement that may help people with osteoarthritis, rheumatoid arthritis and several other painful joint disorders.

Cetyl myristoleate is the cetyl alcohol ester of myristoleic acid. Technically, myristoleic acid is known as 9-cis-tetradecenoic acid or by its molecular name, C14 H26 02, a 14-carbon mono-unsaturated omega-5 fatty acid. Myristoleic acid has undetermined biological significance in humans. It's a natural component of the fat of whales, beavers and bovines, and its acetylated form, cetyl myristoleate, is found in a particular species of lab mouse. It's therefore surprising that CM became a potential palliative for arthritis and other rheumatic conditions. Current use of this remarkable material stems from a serendipitous event that occurred in the early 1960s at the US National Institutes of Health (NIH).

The Discovery OF CM
The late Harry Diehl, a research chemist at NIH, discovered cetyl myristoleate in 1964 after spending two years trying to isolate the substance that protected Swiss albino mice from getting arthritis. He tested the compound on laboratory rats that normally developed arthritis after exposure to Freund's adjuvant. Some of the rats were injected with CM doses totalling 350­375mg per kg of body weight before being administered the adjuvant. Others were injected with a lower dose of CM before being exposed to the toxin, and a third group of rats served as controls, getting only the adjuvant. The rats in the first group were 100 per cent 'immunised' against arthritis. The other groups of rats developed arthritis symptoms. Accordingly, Diehl was awarded three patents between 1976 and 1996 for the use of cetyl myristoleate in preventing and treating various forms of arthritis.1

Unable to garner interest in his discovery, Diehl cloaked his knowledge for 30 years until, on the advice of his physician, he published his findings in the Journal of Pharmaceutical Sciences.2 By then Diehl himself was suffering from arthritis, and he alleviated his pain in just 10 days by using a topical CM preparation.

For his treatment, Diehl isolated myristoleic acid from butter, esterified it with cetyl alcohol, and applied it topically in a 10 per cent CM solution of dimethyl sulfoxide (DMSO). He was pain-free for five years.

Some physicians took note of the published article and began treating arthritis patients with CM. Many patients experienced relief in 30 to 60 days—relief that often lasted for months or even years.

It should be noted that CM is always a complex of acetylated fatty acids. Other fatty acids that naturally occur with it are lauric, myristic, pamitic, palmitoleic, stearic and oleic acids. In preparing the raw material, the relative amounts of these other fatty acids can be controlled by distillation and crystallisation to yield the desired fatty acid profile. This is what distinguishes the various CM products. According to Charles Cochran, DC, who has worked with CM for many years, the best results come from products that contain between 20 and 30 per cent CM. The ratios of the other fatty acids appear to be less important. However, Cochran suggests that cetyl myristate and cetyl myristoleate may also have biological value, while cetyl palmitate and cetyl oleate may interfere with CM activity.3

Clinical Findings
Humberto Siemandi, M.D., Ph.D, conducted a multicentre, double-blind, placebo-controlled clinical trial in 1997 involving 382 patients with osteoarthritis, rheumatoid arthritis and psoriatic arthritis. The patient group was selected to assess the effectiveness of CM against several rheumatic conditions. One group of patients used 90g/day CM complex containing 12 per cent CM. A second group took the same amount of CM complex plus glucosamine hydrochloride (GH), sea cucumber (SC) and hydrolysed cartilage (HC). The third group took a placebo. Outcome was measured by patient response, physician assessment, joint pain, swelling scores and several measures of range of motion. Patients in the treated groups showed significant improvement in symptoms, especially after 60 days. Patient and physician reports were similar: 63 per cent for the CM group; 87 per cent for the CM plus GH-SC-HC group; and 14 per cent for the placebo group.4 Many clinicians include glucosamine and chondroitin, which have been shown to improve arthritic symptoms, as part of a CM treatment protocol.5

In 2000, researchers from the Genesis Center for Integrative Medicine in Washington state completed a six-week, open trial with CM complex. Thirteen pre-menopausal women diagnosed with rheumatoid arthritis were treated with a 2,200mg/day oral dose of CM (15 per cent CM) for four weeks (total CM was 9.2g), followed by a two-week washout period. Researchers measured patient symptoms before supplementation, then at four weeks and again at six weeks (after a two-week washout period).

Arthritis symptoms were evaluated using the Arthritis Impact Measurement Scale, which measures the patient's physical and psychological disability. Researchers also assessed hand-grip strength and associated inflammation. The trial participants experienced a 20 per cent reduction in pain, a 20 per cent increase in grip strength, and more than a 350 per cent improvement in their ability to complete household tasks. No change in inflammation rate was seen. Symptoms continued to improve even after the two-week washout period.6 Although this study was not published, the results are similar to those reported in 2001.

Raj Barathur, M.D., and colleagues conducted a large, double-blind, placebo-controlled study at the Medical Centre of Manipal, India. Results of this study were presented at the March—April 2001 meeting of the Federation of American Societies for Experimental Biology (FASEB). Sixty-four patients with chronic osteoarthritis (OA) of the knee were divided into two groups and evaluated three times during 68 days. Half of the patients were given three capsules twice daily containing 350mg of CM complex including 74mg of CM. The total amount of CM administered during the 68-day trial was 30 g. The other group of patients was given a vegetable oil placebo. Among the patients, a total of 37 joints were affected with OA. The McMaster Toronto Arthritis Patient Preference Questionnaire (MACTAR) was used to measure multi-joint function. Another test, Lequesne's Disease Severity Index (LDSI), identified knee pain, stiffness and loss of function related to OA of the knee. Physicians use a standard goniometer to measure loss or improvement of knee joint flexion. None of the patients was taking corticosteroids, had inflammatory or autoimmune arthritis or had had his or her gall bladder removed.

After 30 days, the CM group experienced a significant improvement in the MACTAR score (pre-15.6 and post-10.4) compared to the placebo group (pre-15.3 and post-13.1) and a reduction in the LDSI (pre-15.6 and post-10.6) compared with placebo (pre-15.8 and post-13.9). Greater ease of movement while performing activities such as walking and climbing stairs was also reported. Knee flexion motion range improved by 10.1 degrees compared to 1.1 degrees in the placebo group. These benefits continued after 60 days.7

Absorption And Safety Of CM
Cetyl myristoleate appears to be a safe supplement and well tolerated by most patients, although there is no published information available on its absorption and metabolism. The digestibility of CM has been questioned, since some patients fail to respond and a few have reported digestive disturbances. Consequently, physicians may have advised taking high-lipase digestive enzymes to improve utilisation. On the flipside is concern that hydrolysis of CM into cetyl alcohol and fatty acids in the gut might reduce its effectiveness.

Imagenetix, a marketer of CM products, sponsored an animal study at the University of Minnesota to help answer the question of digestion and absorption. Rats that had been on a purified diet for several days were divided into groups—one that continued on the diet and another that was fed chow containing two per cent CM. After two hours, the stomach and intestinal contents of the rats were collected and the intestinal mucosa scraped. Lipids were extracted, separated by thin-layer chromatography (TLC), and hydrolysis was evaluated by the presence of cetyl alcohol. No cetyl alcohol was found in any sample from the rats that ate the CM-free chow. In those eating the CM diet, no cetyl alcohol was found in the stomach, intestinal contents or mucosa, indicating hydrolysis had not taken place. However, intact CM was found inside mucosal cells, demonstrating absorption.

While CM is capable of absorption in rats as an intact molecule, dietary and environmental factors may impair its absorption in humans. Presumably, that's why some people who don't respond well to oral CM may get better results with topical.

In an independent study, Hungarian researchers performed an initial dose range-finding toxicity study with rats. Four groups of 10 rats each (five male, five female) were given varying amounts of CM orally for seven days. One group served as controls and the other three groups received 500mg/kg body weight, 1,000mg/kg or 2,000mg/kg daily. None of the animals suffered any ill effects.9

A full 90-day subacute oral toxicity study followed in October 2000. Researchers gave 20 male and 20 female rats 600mg CM/kg body weight—a dose 10 times higher than what is recommended for humans. Test animals did not differ from controls in development, growth, weight gain or blood parameters. No toxicity symptoms were observed; even the highest doses were not lethal.9

CM appears to be safe both on the basis of animal studies and the absence of adverse reactions reported by patients.

Researchers have yet to prove cetyl myristoleate is the answer for arthritis, but it does appear to provide relief to some. CM is a promising ingredient considering the prevalence of arthritis, but more research and consistent raw materials are needed before this product sees success.

Marcia Zimmerman, CN, is author of Eat Your Colors: Maximize Your Health by Eating the Right Foods for Your Body Type (Henry Holt & Co., 2001).


1. Patents (4,049,824) Cetyl Myristoleate, May 3, 1976; (4,113,881) Method of Treating Rheumatoid Arthritis, September 12, 1978; (5,569,676) Method for the Treatment of Osteoarthritis, October, 29, 1996.

2. Diehl HW, May EL. Cetyl myristoleate isolated from Swiss albino mice: an apparent protective agent against adjuvant arthritis in rats. J Pharma Sci 1994 Mar;83:296-9. 3. Personal communication with Charles Cochran, D.C. January, 2002.

4. Siemandi H. The effect of cis-9-cetyl myristoleate (CMO) and adjunctive therapy on the course of arthritic episodes in patients with various autoimmune diseases characterised by the common terminology "arthritis" and "psoriasis." Townsend Letter for Doctors and Patients 1997 Aug/Sep.

5. McAlindon T. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000 Mar15;283(11):1469-75.

6. Barrager E. An open trial investigating the efficacy of cetyl-myristoleate complex (CMS) in the reduction of symptoms associated with rheumatoid arthritis. Genesis Centre for Integrative Medicine, Graham, Wash. 2000 Jul. (unpublished).

7. Barathur R, et al. A fatty acid ester complex (CMC) improves quality of life outcomes in osteoarthritis (OA) patients. FASEB J 2001;15:A265.

8. Gallaher DD, et al. Digestion and metabolism of cetylated fatty acids in rats. University of Minnesota, St. Paul, Minn, 2001 (unpublished).

9. Somfai-Relle S, et al. Seven-day oral dose-range finding toxicity study of cetyl-myristoleate complex powder (CMC) in rats. Pharmaceutical Control and Development Laboratory Co., Ltd. Budapest, Hungary. 2000 Jul. (unpublished).

Three More For Arthritis Relief

Ginger root is a lesser-known source of relief for people with joint pain. In a recent randomised, double-blind, placebo-controlled study conducted at the University of Miami, Florida, researchers gave 261 patients with knee osteoarthritis (OA) and moderate-to-severe pain a standardised extract of two ginger species (Zingiber officinale and Alpinia galanga) for six weeks. Those who took ginger reported greater pain reduction compared with the control group (63 per cent vs. 50 per cent; p = .048).1

Glucosamine and chondroitin are the best-documented approaches for reducing pain, rebuilding cartilage and slowing OA progression. They often are used in tandem because of similar sugar molecules that exist naturally in joints' synovial fluid—the liquid sacks between bones. Although the chondroitin molecule is larger than glucosamine (some scientists believe it is too big to be effectively absorbed into the blood and joints when taken as a supplement), some studies show it may work even better than glucosamine. However, chondroitin is four times more expensive than glucosamine.

In a 14-study meta-analysis published in the Journal of the American Medical Association, researchers at the Arthritis Center at Boston University Medical Center concluded that current evidence supports safety and modest efficacy for both compounds in OA treatment. However, they noted that additional independent studies are needed to confirm these findings, and that physicians may not be as involved in prescribing them to patients because of confusion about wide variability in formulations and purity of preparations.2

There may be a good reason for this. When New York-based independent analytic lab tested 25 major brands of glucosamine and/or chondroitin supplements recently, it found that nearly one-third did not contain the full amount of labelled ingredients. While all 10 of the glucosamine-only products passed the test, almost half of the glucosamine/chondroitin combination products did not pass because of low chondroitin levels.


1. Altman RD, et al. Effects of ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum 2001 Nov;44(11):2531-8.

2. McAlindon T. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000 Mar15;283(11):1469-75.

How Does Cetyl Myristoleate Work?

It is unknown exactly how CM works, but it is worth exploring the many possibilities that have been proposed based on clinical observations of symptom improvement, scientific reviews of the chemistry of CM and published data on one of the fatty acids in the complex.

A review of the recent literature on fatty acids shows standard polyunsaturated fatty acids (PUFAs) are effective agents for inflammation relief.1-4 Fish oils rich in n-3 fatty acids have demonstrated anti-inflammatory effects against arthritis in numerous studies.5-7 Most studies attributed modulation of immune and inflammatory response to eicosanoids and cytokine-mediated effects.8 Cytokines and certain eicosanoids are implicated in inflammatory conditions. It is thought that CM may work through a similar but as yet unknown mechanism, although there is some evidence that n-5 and n-9 fatty acids form oxygenated metabolites through transcellular processing and that these exert anti-inflammatory effects distinct from eicosanoids.9

A striking difference between the effect of CM and PUFAs is the longer-lasting effects CM appears to have. It is thought this may be due to some type of "reprogramming" of T cells. This brings us to another proposed mechanism of action, N-myristoylation.

Cytokine activity is linked to N-myristoylation, a process in which myristic acid is bound to the glycine residues in specific membrane proteins and is responsible for their activation. There is some evidence that human myristoylation may occur with other 14-carbon fatty acids, and perhaps include myristoleic acid.10 And, in fact, a recent study identified myristoleic acid as the cytotoxic component in saw palmetto (Serenoa repens) that induces apoptosis in human prostate cancer cells.11 These receptors bind cytokines with high affinity, which in turn initiates intracellular signals that alter the behaviour of the effector cell.12

Cellular behaviours that can be affected include various secretions, gene transcription, chemotaxis, and proliferation and differentiation of hematopoietic stem cells, including T cells. These behaviours directly affect immune function and inflammatory activities and some affect pain response.13 Research on N-myristolylation and inflammatory cytokines provides some scientific support for a mechanism of action for CM.


1. Kremer JM. Effects of modulation of inflammatory and immune parameters in patients with rheumatic and inflammatory disease receiving dietary supplementation of n-3 and n-6 fatty acids. Lipids 1996 Mar;31 Suppl:S243-7.

2. James MJ, et al. Dietary polyunsaturated fatty acids and inflammatory mediator preduction. Am J Clin Nutr 2000 Jan;71(1 suppl):343S-8s.

3. Rothman D, et al. Botanical lipids: effects on inflammation, immune responses, and rheumatoid arthritis. Semin Arthritis Rheum 1995 Oct;25(2):87-96.

4. Sperling RI. Eicosanoids in rheumatoid arthritis. Rheum Dis Clin North Am 1995 Aug;21(3):741-58.

5. Kremer JM, et al. Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal anti-inflammatory drugs. Clinical and immune correlates. Arthritis Rheum 1995 Aug;38(8):1107-14.

6. James MJ, Cleland LG. Dietary n-3 fatty acids and therapy for rheumatoid arthritis. Semin Arthritis Rheum 1997 Oct;27(2):85-97.

7. Ariza-Ariza R et al. Omega-3 fatty acids in rheumatoid arthritis: an overview. Semin Arthritis Rheum 1998 Jun;27(6):366-70.

8. Calder PC. Dietary fatty acids and the immune system. Nutr Rev 1998 Jan;56(1):S70-S83.

9. Serhan CN, et al. Novel functional sets of lipid-derived mediators with anti-inflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal anti-inflammatory drugs and transcellular processing. J Exp Med 2000 Oct;192(8):1197-204.

10. Kishore NS, et al. Comparison of the acyl chain specificities of human myristoyl-CoA synthetase and human myristoyl-CoA:protein N-myristoyltransferase. J Biol Chem 1993;268(7):4889-902.

11. Iguchi K, et al. Myristoleic acid, a cytotoxic component in the extract from Serenoa repens, induces apoptosis and necrosis in human prostatic LNCaP cells. Prostate 2001;47:59-65.

12. Raju R, et al. Mammalian myristoyl Co:A protein N-myristoyltransferase. MolCell Biochem 1995;149/150:191-202.

13. Plotnikoff NP, ed. Cytokines stress and immunity. Boca Raton, FL. CRC Press, 1999 pp. 101, 115-121, 188-190, 263.

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