21587 Health Library | Health and Wellness | Wellmont Health System
  • Gamma-Linolenic Acid (GLA)

    Supplement Forms/Alternate Names

    • Omega-6 Oil(s)
    • Omega-6 Fatty Acids
    • Sources of GLA Include: Black Currant Seed Oil, Borage Oil, Evening Primrose Oil
    GLA (gamma-linolenic acid) is one of the two main types of essential fatty acids . These are "good" fats that are as necessary for your health as vitamins. Specifically, GLA is an omega-6 fatty acid. (For more information on the other major category of essential fatty acids, omega-3, see the article on fish oil .)
    The body uses essential fatty acids to make various prostaglandins and leukotrienes. These substances influence inflammation and pain; some of them increase symptoms, while others decrease them. Taking GLA may swing the balance over to the more favorable prostaglandins and leukotrienes, making it helpful for diseases that involve inflammation.
    There is some evidence that GLA may be helpful for diabetic neuropathy . The supplement is widely used in the UK and other parts of Europe to treat eczema and cyclic mastalgia (a condition marked by breast pain associated with the menstrual cycle). Current evidence, however, suggests that it may not help. There are many other proposed uses of GLA based on fairly weak evidence.

    Requirements/Sources

    The body ordinarily makes all the GLA it needs from linoleic acid, an omega-6 essential fatty acid found in many foods. In certain circumstances, however, the body may not be able to convert linoleic acid to GLA efficiently. These include advanced age, diabetes, high alcohol intake, eczema, cyclic mastitis, viral infections, excessive saturated fat intake, elevated cholesterol levels, and deficiencies of vitamin B 6 , zinc, magnesium, biotin, or calcium. 1-5 In such cases, taking GLA supplements may make up for a genuine deficiency.
    Very little GLA is found in the diet. Borage oil is the richest supplemental source (17% to 25% GLA), followed by black currant oil (15% to 20%) and evening primrose oil (7% to 10%). Borage and evening primrose are the most common sources used in studies.
    It is commonly stated that people require a certain optimum ratio of omega-3 to omega-6 fatty acids in the diet; however, there is no real evidence that this is true, and some evidence that it is false. 91

    Therapeutic Dosages

    The typical dosage of GLA when it is used in hopes of alleviating cyclic mastalgia or eczema is about 200 to 400 mg daily (about 2 to 4 g of evening primrose oil or 1 to 2 g borage oil). Diabetic neuropathy is typically treated with about 400 to 600 mg daily (about 4 to 6 g of evening primrose or 2 to 3 g of borage oil), and in rheumatoid arthritis doses as high as 2,000 to 3,000 mg have been tried. (Doses this high can only be obtained from purified GLA, as one would need impractically high doses of evening primrose oil or borage oil to get enough).
    GLA should be taken with food. Full benefits (if there are any) may take more than 6 months to develop.

    Therapeutic Uses

    GLA has shown some promise for the treatment of diabetic neuropathy , 12,13 a complication of diabetes . This condition consists of pain and/or numbness due to progressive nerve damage. However, supporting evidence that GLA is effective for this use is quite limited.
    Perhaps the most common use of GLA has been as a treatment for eczema . It was once widely dispensed for this purpose by the British healthcare system, but the balance of the evidence indicates that for eczema, GLA is just a placebo treatment. 14-18, 87
    GLA is also a popular treatment for cyclic mastalgia (breast pain that cycles with the menstrual period), but the evidence regarding its effectiveness is more negative than positive. 46-49, 83-85,96 GLA is additionally said to be useful for general premenstrual syndrome (PMS) symptoms, but the supporting evidence for this use is very weak. 11
    Despite many positive anecdotes, 42 GLA has failed to prove effective for attention deficit and hyperactivity disorder (ADHD) . 79, 90 One study that used GLA plus fish oil did find weak evidence of benefits. 88 Extremely weak evidence hints that evening primrose oil might be more effective for ADHD if combined with zinc, but this is more of an untested hypothesis than a conclusion. 89
    GLA has been studied for numerous other conditions, such as rheumatoid arthritis , 21-24,97Raynaud's phenomenon (a condition in which the fingers and toes react to cold in an exaggerated way), 25,26weight loss , 27,28ulcerative colitis , 30,82kidney stones , 19,20,31,32multiple sclerosis , 33,36 and increasing the effectiveness of the drug tamoxifen in the treatment of breast cancer . 29Note : Individuals undergoing treatment for cancer should not take GLA (or any other supplement) except under physician supervision.
    Other studies have investigated the potential benefits of combination treatment using GLA and fish oil. Conditions studied include osteoporosis , 40,41chronic fatigue syndrome , 37,38periodontitis (gum disease), 90 and Huntington’s disease. In these trials, some promising (but far from definitive) results have been seen. However, this combination therapy has failed to prove effective for cyclic mastalgia . 85
    GLA is sometimes suggested as a treatment for tardive dyskinesia , but two double-blind studies have failed to find it helpful for this disorder. 39 GLA has also failed to prove effective for the itching caused by kidney dialysis. 64
    There is some evidence that GLA may benefit patients with eye problems. One randomized trial indicated that orally administered evening primrose oil was more effective than olive oil (placebo) at reducing dry eye symptoms and improving comfort in users of soft contact lens. 93 In addition, Sjogren's syndrome , an autoimmune condition in which the immune system destroys moisture-producing glands, often causes dry eyes due to lack of tears. One small double-blind study found that a combination of GLA and the omega-6 fatty acid linoleic acid (found in many vegetable oils) may improve dry eye symptoms in Sjogren's. 94 Finally, patients who undergo laser surgery for vision correction (photorefractive keratectomy) are sometimes left with a hazy appearance to their cornea. Another small randomized trial found some potential benefit of a supplement containing omega-6 fatty acids in preventing this complication. 95
    Thus far, we have mentioned only a fraction of the conditions for which GLA has been proposed as a treatment. Others include: asthma , allergies , bursitis , endometriosis , heart disease , irritable bowel syndrome , prostate cancer , benign prostatic hyperplasia (BPH) , and Sjogren's disease . However, none of these potential uses has as yet been scientifically evaluated to any significant extent.

    What Is the Scientific Evidence for Gamma-Linolenic Acid?

    Diabetic Neuropathy

    Diabetic neuropathy is a gradual degeneration of nerves caused by diabetes. There is some evidence that GLA can be helpful, if you give it long enough to work. In one double-blind, placebo-controlled study, 111 people with mild diabetic neuropathy received either 480 mg daily of GLA or placebo. 51 After 12 months, the group taking GLA was doing significantly better than the placebo group. Good results were seen in a smaller study as well. 52 However, these promising findings lack further research validation.
    There is some preliminary evidence that GLA may be more effective for diabetic neuropathy when it is combined with lipoic acid . 55,56

    Eczema

    Despite the fact that GLA (usually as evening primrose oil) is widely used in Europe to treat eczema , it appears most likely that the treatment is not truly effective. The anecdotes of cure that abound are, most likely, simply testimonials to the placebo effect (as well as a strong marketing campaign by one evening primrose oil supplier).
    A 1989 review of the literature found significant benefit in the 9 double-blind controlled studies performed to that date, all involving evening primrose oil. 57 This study led to widespread sales of one evening primrose oil product. However, this review has been sharply criticized for including poorly designed studies and possibly misinterpreting study results. 58
    Improvements in symptoms were also seen in a later double-blind study of 48 children with eczema. 59
    However, more recent and better conducted research has failed to find any benefit. For example, a 16-week, double-blind study involving 58 children with eczema found no difference between the effects of evening primrose oil and placebo (substantial improvements were seen, but to the same extent for placebo and evening primrose oil). 60 Lack of specific benefit was also seen with evening primrose oil or evening primrose oil plus fish oil in a 16-week, double-blind, placebo-controlled study of 102 individuals with eczema. 62 Finally, a double-blind trial followed 39 people with hand dermatitis for 24 weeks, and again found no greater benefits than those produced by placebo. 63
    GLA taken orally from borage oil has also failed to prove effective. In a 24-week, double-blind study of 160 adults with eczema, the treatment provided no greater benefits than placebo. 61 The same was seen in a 12-week, double-blind, placebo-controlled study of 151 adults and children with eczema. 87
    Finally, in a double-blind, placebo-controlled study of 118 infants at high risk for developing eczema in the future, a GLA supplement made from borage oil failed to provided a significant protective effect. 86
    However, an interesting double-blind study tested the use of undershirts coated with borage oil for treatment of eczema . 92 In this 2-week study of 32 children aged 1-10 years old, use of these coated undershirts appeared to reduce eczema symptoms. However, additional higher quality research studies need to be undertaken to establish whether or not this method of delivery really works.

    Cyclic Mastalgia

    Cyclic mastalgia , also known as fibrocystic breast disease, cyclic mastitis, and mastodynia, is a condition in which a woman's breasts become painful during the week or two before her menstrual period. The discomfort is accompanied by swelling, inflammation, and sometimes actual cysts that form in the breasts. It is often associated with other symptoms of premenstrual syndrome (PMS) .
    We do not know the cause of cyclic mastalgia, but some researchers believe that it is associated with an imbalance of fatty acids in the body. 43 On this basis, evening primrose oil became a popular treatment for cyclic mastalgia. However, there are considerable doubts regarding whether it is actually effective.
    The main supporting evidence comes from three controlled studies that appeared to find benefit. 46,83,84 Unfortunately, all of these suffered from significant limitations in study design and reporting, and cannot be taken as reliable. A much better quality study found that evening primrose oil, by itself or with fish oil , is not more effective than placebo for cyclic breast pain. 85 And a randomized trial involving 85 women also did not support the effectiveness of =evening primose (alone or with vitamin E ) for treating breast pain. 96
    Other studies have found evening primrose oil ineffective for established breast cysts. 47-49

    Other Premenstrual Symptoms

    Although several small studies suggest that GLA as evening primrose oil is helpful in reducing overall PMS symptoms, all of these studies suffer from serious flaws that make the results difficult to trust. 50

    Rheumatoid Arthritis

    According to many studies, fish oil, a source of omega-3 essential fatty acids, improves symptoms of rheumatoid arthritis . A few studies suggest that GLA may also help. One double-blind study followed 56 people with rheumatoid arthritis for 6 months. 66 Participants received either 2.8 g daily of purified GLA or placebo. The group taking GLA experienced significantly fewer symptoms than the placebo group, and the improvements grew over time.
    Other studies have found similar results. 67,68,97 The overall conclusion appears to be that purified GLA might offer some benefit for rheumatoid arthritis, especially when used along with standard treatment for rheumatoid arthritis, 69 but the evidence is weak.

    Raynaud's Phenomenon

    High dosages of evening primrose oil may be useful for Raynaud's phenomenon , a condition in which a person's hands and feet show abnormal sensitivity to cold temperature. A small double-blind study found that GLA produced significantly better results than placebo. 70,71 Similar results have been obtained with the omega-3 fatty acids found in fish oil. However, larger studies would be necessary to actually establish effectiveness.

    Osteoporosis

    There is some evidence that essential fatty acids may enhance the effectiveness of calcium for the treatment or prevention of osteoporosis . In one study, 65 postmenopausal women were given calcium along with either placebo or a combination of omega-6 fatty acids (from evening primrose oil) and omega-3 fatty acids (from fish oil ) for a period of 18 months. At the end of the study period, the group receiving essential fatty acids had higher bone density and fewer fractures than the placebo group. 72
    However, a 12-month, double-blind trial of 42 postmenopausal women found no benefit. 73
    The explanation for the discrepancy may lie in the differences between the women studied. The first study involved women living in nursing homes, while the second studied healthier women living on their own. The latter group of women may have been better nourished and already received enough essential fatty acids in their diet.

    Attention Deficit and Hyperactivity Syndrome

    Based on evidence that essential fatty acids are necessary for the proper development of brain function in growing children, essential fatty acids have been tried for the treatment of ADHD and related conditions. A preliminary double-blind, placebo-controlled trial found some evidence that a supplement containing fish oil and evening primrose oil might improve ADHD symptoms. 74 However, a high rate of dropouts makes the results of this study less than reliable. A repeat study found this combination no better than placebo. 88
    Evening primrose oil by itself was found no better than placebo in a double-blind, placebo-controlled trial. 79 In another small placebo-controlled, comparative trial, evening primrose oil proved less effective than standard medical treatment. 80

    Weight Loss

    A 12-week, double-blind study that enrolled 100 significantly overweight women compared the effectiveness of evening primrose oil to placebo. 75 No difference was seen between the groups. However, there was a high dropout rate in this trial (over 25%), which somewhat decreases the meaningfulness of the results. In addition, many participants were known to have "refractory obesity," meaning that they had already failed to respond to other forms of treatment.
    Another double-blind trial, involving 47 people, tested the unusual hypothesis that evening primrose might only work in individuals with a family history of obesity. 76 The results showed that use of evening primrose oil produced a small but significant loss of weight. Interestingly, participants whose parents were both obese showed even better response.
    Considering the contradictory nature of this evidence, more research is necessary to determine whether evening primrose oil is really useful for weight loss.

    Safety Issues

    Most of the safety information we have regarding GLA comes from experience with evening primrose oil.
    Animal studies suggest that evening primrose oil is completely nontoxic and noncarcinogenic. 77 More than 4,000 people have taken GLA or evening primrose oil in scientific studies, and no significant adverse effects have ever been noted.
    Early reports suggested the possibility that GLA might worsen temporal lobe epilepsy, but there has been no later confirmation. 78
    The maximum safe dosage of GLA for young children, pregnant or nursing women, or those with severe liver or kidney disease has not been established.

    References

    1 Horrobin DF. Nutritional and medical importance of gamma-linolenic acid. Prog Lipid Res. 1992;31:163-194.

    2 Horrobin DF. The use of gamma-linolenic acid in diabetic neuropathy. Agents Actions Suppl. 1992;37:120-144.

    3 Horrobin DF, Stewart C. Evening primrose oil in atopic eczema. Lancet. 1990;335:864-865.

    4 Horrobin DF, Manku MS, Brush M, et al. Abnormalities in plasma essential fatty acid levels in women with premenstrual syndrome and with nonmalignant breast disease. J Nutr Med. 1991;2:259-264.

    5 Manku MS, Horrobin DF, Morse NL, et al. Essential fatty acids in the plasma phospholipids of patients with atopic eczema. Br J Dermatol. 1984;110:643-648.

    6 Pye JK, Mansel RE, Hughes LE. Clinical experience of drug treatments for mastalgia. Lancet. 1985;2:373-377.

    7 Pashby NL, Mansel RE, Hughes LE, et al. A clinical trial of evening primrose oil in mastalgia [abstract]. Br J Surg. 1981;68:801.

    8 Mansel RE, Gateley CA, Harrison BJ, et al. Effects and tolerability of n-6 essential fatty acid supplementation in patients with recurrent breast cysts—a randomized double-blind placebo-controlled trial. J Nutr Med. 1990;1:195-200.

    9 Mansel RE, Harrison BJ, Melhuish J, et al. A randomized trial of dietary intervention with essential fatty acids in patients with categorized cysts. Ann N Y Acad Sci. 1990;586:288-294.

    10Drug Evaluations Annual. Vol 2. Milwaukee, WI: American Medical Association; 1991.

    11 Budeiri D, Li Wan Po A, Dornan JC. Is evening primrose oil of value in the treatment of premenstrual syndrome? Control Clin Trials. 1996;17:60-68.

    12 Keen H, Payan J, Allawi J, et al. Treatment of diabetic neuropathy with gamma-linolenic acid. The gamma-Linolenic Acid Multicenter Trial Group. Diabetes Care. 1993;16:8-15.

    13 Jamal GA, Carmichael H. The effect of gamma-linolenic acid on human diabetic peripheral neuropathy: a double-blind placebo-controlled trial. Diabet Med. 1990;7:319-323.

    14 Morse PF, Horrobin DF, Manku MS, et al. Meta-analysis of placebo-controlled studies of the efficacy of Epogam in the treatment of atopic eczema. Relationship between plasma essential fatty acid changes and clinical response. Br J Dermatol. 1989;121:75-90.

    15 Berth-Jones J, Graham-Brown RA. Placebo-controlled trial of essential fatty acid supplementation in atopic dermatitis. Lancet. 1993;341:1557-1560.

    16 Hederos CA, Berg A. Epogam evening primrose oil treatment in atopic dermatitis and asthma. Arch Dis Child. 1996;75:494-497.

    17 Henz BM, Jablonska S, van de Kerkhof PC, et al. Double-blind, multicentre analysis of the efficacy of borage oil in patients with atopic eczema. Br J Dermatol. 1999;140:685-688.

    18 Whitaker DK, Cilliers J, de Beer C. Evening primrose oil (Epogam) in the treatment of chronic hand dermatitis: disappointing therapeutic results. Dermatology. 1996;193:115-120.

    19 Tamimi NA, Mikhail AI, and Stevens PE. Role of gamma-linolenic acid in uraemic pruritus [letter]. Nephron. 1999;83:170-171.

    20 Yoshimoto-Furuie K, Yoshimoto K, Tanaka T, et al. Effects of oral supplementation with evening primrose oil for six weeks on plasma essential fatty acids and uremic skin symptoms in hemodialysis patients. Nephron. 1999;81:151-159.

    21 Zurier RB, Rossetti RG, Jacobson EW, et al. gamma-Linolenic acid treatment of rheumatoid arthritis. A randomized, placebo-controlled trial. Arthritis Rheum. 1996;39:1808-1817.

    22 Leventhal LJ, Boyce EG, Zurier RB. Treatment of rheumatoid arthritis with blackcurrant seed oil. Br J Rheumatol. 1994;33:847-852.

    23 Leventhal LJ, Boyce EG, Zurier RB. Treatment of rheumatoid arthritis with gammalinolenic acid. Ann Intern Med. 1993;119:867-873.

    24 Rothman D, DeLuca P, Zurier RB. Botanical lipids: effects on inflammation, immune responses, and rheumatoid arthritis. Semin Arthritis Rheum. 1995;25:87-96.

    25 Belch JJ, Shaw B, O'Dowd A, et al. Evening primrose oil (Efamol) as a treatment for cold-induced vasospasm (Raynaud's phenomenon). Prog Lipid Res. 1986;25:335-340.

    26 Belch JJ, Shaw B, O'Dowd A, et al. Evening primrose oil (Efamol) in the treatment of Raynaud's phenomenon: a double-blind study. Thromb Haemost. 1985;54:490-494.

    27 Haslett C, Douglas JG, Chalmers SR, et al. A double-blind evaluation of evening primrose oil as an antiobesity agent. Int J Obes. 1983;7:549-553.

    28 Garcia CM, Carter J, Chou A. Gamma linolenic acid causes weight loss and lower blood pressure in overweight patients with family history of obesity. Swed J Biol Med. 1986;4:8-11.

    29 Kenny FS, Pinder SE, Ellis IO, et al. Gamma linolenic acid with tamoxifen as primary therapy in breast cancer. Int J Cancer. 2000;85:643-648.

    30 Greenfield SM, Green AT, Teare JP, et al. A randomized controlled study of evening primrose oil and fish oil in ulcerative colitis. Aliment Pharmacol Ther. 1993;7:159-166.

    31 Buck AC, Jenkins A, Lingam K, et al. The treatment of idiopathic recurrent urolithiasis with fish oil (EPA) and evening primrose oil (GLA)—a double blind study. J Urol. 1993;149:253A.

    32 Tulloch I, Smellie WS, Buck AC. Evening primrose oil reduces urinary calcium excretion in both normal and hypercalciuric rats. Urol Res. 1994;22:227-230.

    33 Horrobin DF. Multiple sclerosis: the rational basis for treatment with colchicine and evening primrose oil. Med Hypotheses. 1979;5:365-378.

    34 Field EJ, Joyce G. Effect of prolonged ingestion of gamma-linolenate by MS patients. Eur Neurol. 1978;17:67-76.

    35 Bates D. Dietary lipids and multiple sclerosis. Ups J Med Sci Suppl. 1990;48:173-187.

    36 Horrobin DF. Multiple sclerosis: the rational basis for treatment with colchicine and evening primrose oil. Med Hypotheses. 1979;5:365-378.

    37 Behan PO, Behan WM, Horrobin D. Effect of high doses of essential fatty acids on the postviral fatigue syndrome. Acta Neurol Scand. 1990;82:209-216.

    38 Warren G, McKendrick M, Peet M. The role of essential fatty acids in chronic fatigue syndrome. A case-controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA. Acta Neurol Scand. 1999;99:112-116.

    39 Vaddadi K. Dyskinesias and their treatment with essential fatty acids: a review. Prostaglandins Leukot Essent Fatty Acids. 1996;55:89-94.

    40 Kruger MC, Coetzer H, de Winter R, et al. Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis. Aging (Milano). 1998;10:385-394.

    41 Bassey EJ, Littlewood JJ, Rothwell MC, et al. Lack of effect of supplementation with essential fatty acids on bone mineral density in healthy pre- and postmenopausal women: two randomized controlled trials of EfacalŴ v. calcium alone. Br J Nutr. 2000;83:629-635.

    42Richardson AJ, McDaid AM, Calvin CM, et al. Reduced behavioural and learning problems in children with specific learning difficulties after supplementation with highly unsaturated fatty acids: a randomized double-blind placebo-controlled trial. Presented at: 2nd Forum of European Neuroscience Societies; July 24-28, 2000; Brighton, United Kingdom.

    43 Horrobin DF, Manku MS, Brush M, et al. Abnormalities in plasma essential fatty acid levels in women with premenstrual syndrome and with nonmalignant breast disease. J Nutr Med. 1991;2:259-264.

    44 Horrobin DF, Manku MS, Brush M, et al. Abnormalities in plasma essential fatty acid levels in women with premenstrual syndrome and with nonmalignant breast disease. J Nutr Med. 1991;2:259-264.

    45 Pye JK, Mansel RE, Hughes LE. Clinical experience of drug treatments for mastalgia. Lancet. 1985;2:373-377.

    46 Pashby NL, Mansel RE, Hughes LE, et al. A clinical trial of evening primrose oil in mastalgia [abstract]. Br J Surg. 1981;68:801.

    47 Mansel RE, Gateley CA, Harrison BJ, et al. Effects and tolerability of n-6 essential fatty acid supplementation in patients with recurrent breast cysts—a randomized double-blind placebo-controlled trial. J Nutr Med. 1990;1:195-200.

    48 Mansel RE, Harrison BJ, Melhuish J, et al. A randomized trial of dietary intervention with essential fatty acids in patients with categorized cysts. Ann N Y Acad Sci. 1990;586:288-294.

    49 Kollias J, Macmillan RD, Sibbering DM, et al. Effect of evening primrose oil on clinically diagnosed fibroadenomas. Breast. 2000;9:35-36.

    50 Budeiri D, Li Wan Po A, Dornan JC. Is evening primrose oil of value in the treatment of premenstrual syndrome? Control Clin Trials. 1996;17:60-68.

    51 Keen H, Payan J, Allawi J, et al. Treatment of diabetic neuropathy with gamma-linolenic acid. The gamma-Linolenic Acid Multicenter Trial Group. Diabetes Care. 1993;16:8-15.

    52 Jamal GA, Carmichael H. The effect of gamma-linolenic acid on human diabetic peripheral neuropathy: a double-blind placebo-controlled trial. Diabet Med. 1990;7:319-323.

    53 Stevens EJ, Lockett MJ, Carrington AL, et al. Essential fatty acid treatment prevents nerve ischaemia and associated conduction anomalies in rats with experimental diabetes mellitus. Diabetologia. 1993;36:397-401.

    54 Reichert R. Evening primrose oil and diabetic neuropathy. Q Rev Natr Med. 1995;129-133.

    55 Hounsom L, Horrobin DF, Tritschler H, et al. A lipoic acid-gamma linolenic acid conjugate is effective against multiple indices of experimental diabetic neuropathy. Diabetologia. 1998;41:839-843.

    56 Cameron NE, Cotter MA, Horrobin DH, et al. Effects of alpha-lipoic acid on neurovascular function in diabetic rats: Interaction with essential fatty acids. Diabetologia. 1998;41:390-399.

    57 Morse PF, Horrobin DF, Manku MS, et al. Meta-analysis of placebo-controlled studies of the efficacy of Epogam in the treatment of atopic eczema. Relationship between plasma essential fatty acid changes and clinical response. Br J Dermatol. 1989;121:75-90.

    58 Berth-Jones J, Graham-Brown RA. Placebo-controlled trial of essential fatty acid supplementation in atopic dermatitis. Lancet. 1993;341:1557-1560.

    59 Biagi PL, Bordoni A, Hrelia S, et al. The effect of gamma-linolenic acid on clinical status, red cell fatty acid composition and membrane microviscosity in infants with atopic dermatitis. Drugs Exp Clin Res. 1994;20:77-84.

    60 Hederos CA, Berg A. Epogam evening primrose oil treatment in atopic dermatitis and asthma. Arch Dis Child. 1996;75:494-497.

    61 Henz BM, Jablonska S, van de Kerkhof PC, et al. Double-blind, multicentre analysis of the efficacy of borage oil in patients with atopic eczema. Br J Dermatol. 1999;140:685-688.

    62 Berth-Jones J, Graham-Brown RA. Placebo-controlled trial of essential fatty acid supplementation in atopic dermatitis. Lancet. 1993;341:1557-1560.

    63 Whitaker DK, Cilliers J, de Beer C. Evening primrose oil (Epogam) in the treatment of chronic hand dermatitis: disappointing therapeutic results. Dermatology. 1996;193:115-120.

    64 Tamimi NA, Mikhail AI, Stevens PE. Role of gamma-linolenic acid in uraemic pruritus [letter]. Nephron. 1999;83:170-171.

    65 Yoshimoto-Furuie K, Yoshimoto K, Tanaka T, et al. Effects of oral supplementation with evening primrose oil for six weeks on plasma essential fatty acids and uremic skin symptoms in hemodialysis patients. Nephron. 1999;81:151-159.

    66 Zurier RB, Rossetti RG, Jacobson EW, et al. gamma-Linolenic acid treatment of rheumatoid arthritis. A randomized, placebo-controlled trial. Arthritis Rheum. 1996;39:1808-1817.

    67 Leventhal LJ, Boyce EG, Zurier RB. Treatment of rheumatoid arthritis with blackcurrant seed oil. Br J Rheumatol. 1994;33:847-852.

    68 Leventhal LJ, Boyce EG, Zurier RB. Treatment of rheumatoid arthritis with gammalinolenic acid. Ann Intern Med. 1993;119:867-873.

    69 Rothman D, DeLuca P, Zurier RB. Botanical lipids: Effects on inflammation, immune responses, and rheumatoid arthritis. Semin Arthritis Rheum. 1995;25:87-96.

    70 Belch JJ, Shaw B, O'Dowd A, et al. Evening primrose oil (Efamol) as a treatment for cold-induced vasospasm (Raynaud's phenomenon). Prog Lipid Res. 1986;25:335-340.

    71 Belch JJ, Shaw B, O'Dowd A, et al. Evening primrose oil (Efamol) in the treatment of Raynaud's phenomenon: a double-blind study. Thromb Haemost. 1985;54:490-494.

    72 Kruger MC, Coetzer H, de Winter R, et al. Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis. Aging (Milano). 1998;10:385-394.

    73 Bassey EJ, Littlewood JJ, Rothwell MC, et al. Lack of effect of supplementation with essential fatty acids on bone mineral density in healthy pre- and postmenopausal women: two randomized controlled trials of EfacalŴ v. calcium alone. Br J Nutr. 2000;83:629-635.

    74Richardson AJ, McDaid AM, Calvin CM, et al. Reduced behavioural and learning problems in children with specific learning difficulties after supplementation with highly unsaturated fatty acids: a randomized double-blind placebo-controlled trial. Presented at: 2nd Forum of European Neuroscience Societies; July 24-28, 2000; Brighton, United Kingdom.

    75 Haslett C, Douglas JG, Chalmers SR, et al. A double-blind evaluation of evening primrose oil as an antiobesity agent. Int J Obes. 1983;7:549-553.

    76 Garcia CM, Carter J, Chou A. Gamma linolenic acid causes weight loss and lower blood pressure in overweight patients with family history of obesity. Swed J Biol Med. 1986;4:8-11.

    77 Horrobin DF. Nutritional and medical importance of gamma-linolenic acid. Prog Lipid Res. 1992;31:163-194.

    78 Vaddadi KS. The use of gamma-linolenic acid and linoleic acid to differentiate between temporal lobe epilepsy and schizophrenia. Prostaglandins Med. 1981;6:375-379.

    79 Aman MG, Mitchell EA, Turbott SH. The effects of essential fatty acid supplementation by Efamol in hyperactive children. J Abnorm Child Psychol. 1987;15:75-90.

    80 Arnold LE, Kleykamp D, Votolato NA, et al. Gamma-linolenic acid for attention-deficit hyperactivity disorder: placebo-controlled comparison to D-amphetamine. Biol Psychiatry. 1989;25:222-228.

    81 Vaddadi KS, Soosai E, Chiu E, et al. A randomised, placebo-controlled, double blind study of treatment of Huntington's disease with unsaturated fatty acids. Neuroreport. 2002;13:29-33.

    82 Middleton SJ, Naylor S, Woolner J, et al. A double-blind, randomized, placebo-controlled trial of essential fatty acid supplementation in the maintenance of remission of ulcerative colitis. Aliment Pharmacol Ther. 2002;16:1131-1135.

    83Mansel RE, Pye KJ, Hughes LE. A controlled trial of evening primrose oil (Efamol) in cyclic premenstrual matalgia. Abstract 47. Proceedings of the 2nd International Symposium on Premenstrual, Postpartum, and Meonopausal Mood Disorders; 1987; Kiawah Island, SC.

    84Preece PE, Hanslip JI, Gilbert L. Evening primrose oil (Efamol) for mastalgia. In: Horrobin DF, ed. Clinical uses of essential fatty acids. Montreal, Quebec: Eden;1982: 147-154.

    85 Blommers J, De Lange-De Klerk ES, Kuik DJ, et al. Evening primrose oil and fish oil for severe chronic mastalgia: A randomized, double-blind, controlled trial. Am J Obstet Gynecol. 2002;187:1389-1394.

    86 Van Gool CJ, Thijs C, Henquet CJ, et al. Gamma-Linolenic acid supplementation for prophylaxis of atopic dermatitis—a randomized controlled trial in infants at high familial risk. Am J Clin Nutr. 2003;77:943-951.

    87 Takwale A, Tan E, Agarwal S, et al. Efficacy and tolerability of borage oil in adults and children with atopic eczema: randomised, double blind, placebo controlled, parallel group trial. BMJ. 2003;327:1385.

    88 Stevens L, Zhang W, Peck L et al. EFA supplementation in children with inattention, hyperactivity, and other disruptive behaviors. Lipids. 2003;38:1007-21.

    89 Arnold LE, Pinkham SM, Votolato N. Does zinc moderate essential fatty acid and amphetamine treatment of attention-deficit/hyperactivifty disorder? J Child Adolesc Psychopharmacol. 2000;10:111-117.

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