In addition to modifying the diet, the intake of polyunsaturated fatty acids may be increased by taking supplements. Some of these supplements actually have been studied in clinical trials of people with MS.
Omega-Six Polyunsaturated Fatty Acids
Studies of Linoleic Acid. Supplementation with linoleic acid, the first chemical in the omega-six fatty-acid pathway (see Figure 18.1), has been extensively studied. In EAE, an animal model of MS, supplements of linole-ic acid are beneficial, whereas deficiencies of linoleic acid are harmful. Three studies have been undertaken of linoleic acid supplements in people with relapsing MS. Linoleic acid was given as some form of sunflower seed oil in these studies. All three studies meet the formal clinical research criteria of being randomized, blinded, and placebo-controlled.
The first study was reported in 1973 (4). Seventy-five people were studied over 2 years, and the daily dose of linoleic acid was 17.2 grams. Treatment produced decreased duration and severity of attacks. No effect was noted on the frequency of attacks or the progression of the disease.
The second study was published in 1978 (5). Over a 2-year period, 116 people were studied. As in the first study, the severity and duration of attacks were significantly improved, but there was no change in the frequency of attacks or the progression of disability.
The third study also was reported in 1978 (6). Seventy-six people with MS were monitored over 2.5 years. In contrast to the two other studies, no benefit was found in this investigation.
In summary, two studies produced limited positive results and one study found no benefit. To attempt to clarify the mixed results of these studies, a combined analysis was published in 1984 (7). The information on a total of 172 people from all three studies was pooled. It was noted that, in the third study, which did not report any benefit, the people had more severe MS and had MS for a longer time than did people in the other two studies. Using the combined analysis, linoleic acid treatment slowed the progression of disability in people with little or no disability at the start of the treatment. Regardless of the duration or severity of the disease, linoleic acid treatment was associated with reduced length and severity of attacks. The statistical methods used in this combined analysis have been questioned. Overall, the effects of linoleic acid supplements on MS are suggestive but not definitive.
Sources of Linoleic Acid. Good sources of linoleic acid are the oils of seeds and nuts, such as safflower oil, sunflower oil, and sesame seed oil. Flaxseed (or linseed) oil contains linoleic acid as well as omega-three fatty acids (see section on omega-three fatty acids). Seeds and nuts themselves also contain linoleic acid.
A simple measure to increase linoleic acid intake is to increase the consumption of linoleic acid-containing foods, including oils. A more aggressive approach is to take oil supplements. The optimal dosage of linoleic acid is not known. In addition, the amount of omega-six fatty acids relative to the amount of omega-three fatty acids (the omega-six:omega-three ratio) is probably important, but the most desirable ratio of these fatty acids has not been established.
It is sometimes recommended that approximately 4 teaspoons of linoleic acid-containing oils be taken daily. The oil may be used in salad dressings or mixed in with vegetables, yogurt, or soft cheese. It should not be heated and should be stored under cool and dark conditions.
Risks of Linoleic Acid. The most significant concern that has been raised about this type of supplementation is that it may increase the risk of cancer. This concern is based primarily on studies in animals. A 1998 review of all animal and human studies in this area of research concluded that it was unlikely that linoleic acid supplementation increased the risk of several types of cancer in humans. This issue has not yet been fully resolved.
Other issues are important to consider with linoleic acid supplementation. The oily taste may be unpleasant, and diarrhea may occur in some people. Omega-6 fatty-acid supplements may increase triglyceride levels in those with elevated triglyceride levels. Polyunsaturated fatty acids in general may produce vitamin E deficiency; low doses of vitamin E supplements may be indicated (see the next section). The possible adverse effects of long-term supplementation have not been studied formally and consequently are not known.
Gamma-Linolenic Acid (GLA)
Studies of GLA. Evening primrose oil is a popular supplement sometimes recommended for MS because it contains GLA, which is one step beyond linoleic acid in the omega-six biochemical pathway (see Figure 18.1).
There are some theoretical reasons why GLA may be better than linoleic acid, but scant clinical information exists in this area. A preparation of evening primrose oil (Naudicelle) was used in one of the linoleic acid trials in 1978. Eight capsules daily were not effective. In the same trial, linoleic acid alone was somewhat beneficial for relapsing MS. It should be noted that low doses of GLA (340 milligrams daily) were used in this trial, and it is possible that higher doses could have produced a benefit. However, this would have meant consuming up to 40 evening primrose oil capsules daily!
Two other limited studies have been undertaken of evening primrose oil in relapsing MS. One of these studies also used a drug known as colchicine. Both studies produced some positive results. However, they involved a small number of people and did not include a placebo-treated group. Consequently, it is difficult to be confident about the results. A 1977 study of people with progressive MS found no benefit for evening primrose oil (8).
Scientific studies indicate that GLA suppresses immune system activity. In rats, evening primrose oil decreases the activity of T cells, a type of immune cell. GLA supplementation decreases the severity of disease in mice and rats with EAE, an animal model of MS.
Evening primrose oil has been claimed to be effective for many other conditions. Conflicting results have been obtained in studies of other immune diseases, such as rheumatoid arthritis. Evening primrose oil may decrease breast pain (mastalgia), increase bone density in those with osteoporosis, and be helpful for two skin conditions — eczema and atopic dermatitis.
In summary, the limited clinical information about GLA supplementation in MS does not strongly support its use. However, only low doses have been studied clinically, and scientific studies and clinical studies in other diseases suggest that it may be effective. In theory, GLA could provide the same benefits as linoleic acid, but high doses may be necessary, and such high doses may not be practical on a regular basis because of its cost.
Sources of GLA. Very few sources of GLA exist. Evening primrose oil is one of the most commonly recommended sources. It contains 8 to 10 percent GLA and approximately 70 percent linoleic acid. A single evening primrose oil capsule generally contains about 40 milligrams of GLA. Some capsules of evening primrose oil also contain vitamin E in low levels, such as 10 international units (IU) per capsule.
An Australian study evaluated the consistency of evening primrose oil preparations (9). Fourteen of 16 different preparations contained reasonable amounts (7 to 10 percent) of GLA. Because of the presence of other fatty acids in some of the capsules, it was proposed that borage seed oil, another source of GLA, may have been added to these preparations.
If evening primrose oil is taken, approximately six capsules daily are often recommended. It should be kept in mind that GLA is present in low levels; six capsules daily result in a daily dose of only approximately 240 milligrams. As a result, other omega-six fatty acids (see the earlier sections) may need to be taken as well if one is attempting to significantly increase the total intake of omega-six fatty acids.
GLA is found in several other sources. Borage seed oil, which is sometimes recommended, is a rich source of GLA. It contains 20 to 26 percent GLA, more than twice the amount in evening primrose oil. However, borage seed oil may contain chemicals (pyrrolizidine alkaloids) that are toxic to the liver. As a result, it is safest to avoid borage seed oil. Some borage seed oil preparations claim to be free of pyrrolizidine alkaloids.
Like borage seed oil, black currant seed oil contains a higher concentration of GLA (14 to 19 percent) than does evening primrose oil. However, this oil has not been well studied with regard to possible toxic chemicals or adverse effects. Spirulina, or blue-green algae, may contain high concentrations of GLA, but the amount of GLA in a given spirulina product usually is not specified and may be negligible (see "Herbs"). Finally, one of the more obscure sources of GLA is human breast milk.
In conclusion, evening primrose oil generally is preferred over other products for supplementation with GLA. Borage seed oil, black currant seed oil, and spirulina are of uncertain safety or contain variable and uncertain amounts of GLA.
Risks of GLA. In general, evening primrose oil is well tolerated. Long-term human studies indicate that a daily dose up to 2,800 milligrams of GLA is not generally associated with any serious side effects.
Some concerns arise with the use of evening primrose oil and other sources of GLA. Because sources of GLA usually contain linoleic acid, the adverse effects and risks of linoleic acid are present. These include an unpleasant taste and soft stools or diarrhea. Additional concerns with evening primrose oil include the expense, as well as nausea and headache. Evening primrose oil and borage seed oil may provoke seizures in people taking antipsychotic medications. Evening primrose oil may affect blood clotting. Therefore, it probably should be avoided by people who take blood-thinning medications or high doses of aspirin, people who have blood-clotting disorders, and people who are undergoing surgery. The safety of black currant seed oil and Spirulina are not known, and borage seed oil may contain liver toxins.
All supplements containing polyunsaturated fatty acids may produce vitamin E deficiency. Consequently, low doses of vitamin E supplements should be taken if vitamin E is not already present in the fatty-acid supplement.
Studies. One large study has been undertaken of omega-three fatty-acid supplement use in MS (10). This 2-year study, reported in 1989, involved 312 people and daily treatment with 10 grams of fish oil. The daily doses of specific fatty acids were 1.7 grams of EPA and 1.1 grams of DHA (see Figure 18.2). People in this study also were instructed to increase omega-six fatty-acid intake and to decrease animal fat intake. In the untreated group, 52 percent worsened, whereas in the treated group, 43 percent worsened. A trend was noted toward a beneficial effect, but formal analysis showed that this effect was not quite statistically significant.
A small 1986 study evaluated the effect of cod-liver oil supplements, which contain omega-three fatty acids, on the MS attack rate in 10 people with MS (11). A beneficial effect of treatment was noted, but this study is limited by several factors, including the absence of a placebo-treated group and treatment that involved vitamin D, calcium, and magnesium in addition to cod-liver oil.
Another study of 16 people with MS evaluated the effects of omega-3 fatty-acid supplements, other dietary supplements (vitamins A, B, C, D, and E), and dietary advice (including decreased saturated fat and increased fish intake) over 2 years (12). Compared with clinical status before the study, treatment was associated with a significant decrease in the attack rate and improvement in the level of disability. No placebo group was used in this small study.
A study of 31 people with MS assessed the effects of omega-3 fatty-acid supplements in combination with glatiramer acetate (Copaxone) or interferons (Avonex, Betaseron, Rebif) (13). People were treated with the conventional MS medications along with either fish oil and a very low-fat diet or with olive oil and a low-fat diet. A trend for improved emotional and physical functioning was found in those taking fish oil—these results were not statistically significant. Both dietary approaches were associated with a decrease in attack rate.
Other scientific and clinical aspects of omega-three fatty acids are under active investigation. Studies of immunologic function indicate that, in laboratory animals and in humans, omega-three fatty-acid supplementation decreases the activity of several components of the immune system. In limited studies of EAE, omega-three fatty acids have produced variable effects. Some studies actually indicate that omega-three fatty acids worsen the disease, but others indicate beneficial effects.
Studies of immune diseases other than MS have indicated a possible therapeutic effect with the use of omega-three fatty acids. Omega-three fatty-acid supplements appear to decrease joint stiffness and joint swelling in rheumatoid arthritis. These supplements may be helpful for another immune condition known as antiphospholipid antibody syndrome.
Omega-three fatty acids may have other important health benefits. They have the potential to prevent and treat heart disease. They appear to decrease blood levels of triglycerides and mildly decrease blood pressure.
Sources of Omega-Three Fatty Acids. Fish is a common food source of omega-three fatty acids. Thus, a simple approach to increase omega-three fatty-acid intake is to increase the consumption of fish, especially fatty fish such as salmon, Atlantic herring, Atlantic mackerel, bluefin tuna, sardine, and cod liver. Two to three servings of fish weekly are sometimes recommended. A very high intake of fish raises concerns about mercury toxicity, especially among women who are pregnant or may become pregnant. Fish with relatively high mercury levels include shark, swordfish, and king mackerel.
Omega-three fatty acids also may be consumed as supplements. The optimal dose of omega-three fatty acids is not known. Also, the amount of omega-three fatty acids relative to that of omega-six fatty acids (omega-six:omega-three ratio) may be important, but currently not enough information is known to make specific recommendations.
Fish oil and cod liver oil supplements are available as liquid oil or as capsules. Concentrated EPA and DHA also are available. Multiple fish oil products have been analyzed and have not been found to contain any detectable mercury. Total daily doses of 3 grams or less are believed to be safe. One tablespoon of fish oil contains approximately 140 calories and 14 grams of fat.
A unique source of omega-three fatty acids is flaxseed (or linseed) oil, which contains both omega-three and omega-six fatty acids. The omega-three fatty acids are in the form of alpha-linolenic acid (see Figure 18.2), as opposed to EPA and DHA, which are present in fish oil and cod-liver oil. Of note, alpha-linolenic acid may not produce as potent effects as do EPA and DHA. (Interestingly, walnuts are also a source of alpha-linolenic acid.) Linoleic acid is the omega-six fatty acids in flaxseed oil. Consuming flaxseed oil is a way to obtain both omega-three and omega-six fatty acids from a single source. One tablespoon of flaxseed oil daily sometimes is recommended.
Risks of Omega-Three Fatty Acids. In 1997, the U.S. Food and Drug Administration (FDA) determined that fish oil supplements were generally safe when the total daily intake of EPA and DHA was less than 3 grams. In one long-term study of 295 people, no serious adverse effects were observed with 7 years of fish oil use.
Cod-liver oil has a fishy taste, and flaxseed oil has a bitter taste; these unpleasant tastes may be lessened by cooling the oils. Daily doses greater than 45 grams of flaxseed oil may have a laxative effect, and daily doses greater than 60 grams may theoretically increase blood levels of cyanide-containing compounds. Vitamin E deficiency may potentially develop when taking omega-three fatty acids; supplemental vitamin E should be taken.
Most commercial fish oil products do not contain vitamin A. However, halibut, shark, and cod-liver oils contain relatively high levels of vitamin A. Excessive doses of these oils should be avoided, because high levels of vitamin A may be toxic, especially during pregnancy (see "Vitamins, Minerals, and Other Nonherbal Supplements").
Omega-three fatty-acid supplements impair lung function in those with aspirin sensitivity. These supplements also may increase blood sugar levels in diabetic patients and produce excessive mental and physical activity, a condition known as hypomania, in people with depression or manic-depressive illness, It is not known if omega-three fatty-acid supplements are safe in women who are pregnant or breast-feeding.
Finally, fish oils, specifically EPA, may inhibit blood clotting. These oils should be used with caution by people who are undergoing surgery, people who have blood-clotting disorders, and people who take blood-thinning medication or high doses of aspirin.
Polyunsaturated fatty acids may decrease vitamin E levels. As a result, if high levels of polyunsaturated fatty acids are consumed in the diet or through the use of supplements, vitamin E intake must be increased. However, high doses of vitamin E do not appear to be necessary. According to many recommendations, the ratio of vitamin E (in international units, or 1U) to polyunsaturated fatty acids (in grams) should be 0.6 to 0.9. This means that, on a daily basis, 0.6 to 0.9 1U of vitamin E are needed for each gram of polyunsaturated fatty acids. Consequently, given an intake of 25 grams of polyunsaturated fatty acids, only 15 to 22 1U of vitamin E would be required. 1t is sometimes stated that hundreds of 1U of supplemental vitamin E are needed if polyunsaturated fatty-acid supplements are taken. This does not appear to be true. In fact, because it may be best to avoid high doses of vitamin E and other antioxidants in MS, as discussed elsewhere in the section on vitamins, lower doses of vitamin E, such as 100 1U may be adequate and may actually be more appropriate. Some omega-three fatty-acid supplements, such as evening primrose oil capsules, contain vitamin E, in which case additional vitamin E may not be necessary.
Other Supplements Sometimes Recommended with Polyunsaturated Fatty Acids
In addition to vitamin E, several other supplements sometimes are recommended with the use of polyunsaturated fatty acids. Vitamin B6 (pyridox-ine) and zinc are recommended by some because the fatty-acid chemical pathway uses vitamin Bg and zinc. In fact, the intake of these micronutri-ents from the diet is probably adequate and, in the case of zinc, supplements pose a theoretic risk because they may stimulate the immune system (see "Vitamins, Minerals, and Other Nonherbal Supplements"). If these supplements are taken, the daily dose of vitamin Bg should not exceed 50 milligrams, and low doses of zinc should be taken (see "Vitamins, Minerals, and Other Nonherbal Supplements").
For antioxidant supplementation, vitamin C and beta-carotene sometimes are recommended in addition to vitamin E. As noted, only low doses of additional vitamin E appear to be needed, and there is no strong evidence that additional antioxidant vitamins are required. Because the benefits and risks of antioxidant vitamins in MS are not known, as discussed in the section on vitamins, it is not clear that vitamin C and beta-carotene supplements are beneficial. In fact, it is possible that, in higher doses, they may be immune-stimulating and therefore may negatively affect the course of MS. If vitamin C and beta-carotene supplements are used, they probably should be taken in moderation (see "Vitamins, Minerals, and Other Nonherbal Supplements").
In summary, low doses of supplemental vitamin E may be required when high levels of polyunsaturated fatty acids are consumed. It is not clear that a need exists for any other supplements, including vitamin Bg, zinc, vitamin C, and beta-carotene.
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