Gamma linolenic acid

Synonym(s): borage oil, common evening primrose, GLA, evening primerose oil , Oenothera biennis, Omega-6 fatty acids

Nutrient group: fatty acids

Sources and physiological effects

Dietary sources
Gamma-linolenic acid (GLA) is one of the polyunsaturated omega-6 fatty acids. In nutrition, only a few foods contain a significant amount of GLA (excluding in breast milk). Borage oil, evening primrose oil and the oil from the seeds of black currant are particularly rich in omega-6 fatty acids.
Physiological effects
Cell membranes	Important building block for cell membranes and tissue
Nervous system	Protection of nerve cells
Inflammation	Formation of anti-inflammatory eicosanoids
Immune system	Reduction of histamine Cofactor of T-lymphocyte maturation
Skin	Support of skin regeneration and skin formation

Detailed information

Anti-inflammatory effects of gamma-linolenic acid in other diseases
Physiological functions of gamma-linolenic acid
Gamma-linolenic acid (GLA) is a polyunsaturated fatty acid of the omega-6 type, which is required in the human body for the synthesis of prostaglandins and leukotrienes and serves as a component of biological membranes.
Gamma linolenic acid from borage and evening primrose oil
Gamma-linolenic acid (GLA) is found in evening primrose and borage oil in high quantities. The seeds of the borage plant (Borago officinalis) provide an oil characterized by an unusually high content of omega-6 type polyunsaturated fatty acids. While borage blossoms and herbs contain liver toxic pyrrolizidine alkaloids and are unsuited for medical application, the cold-pressed oil is free of these substances. Borage oil is recommended as a herbal remedy for dry skin and diseases associated with a lack of GLA. The cold-pressed oil from the seeds of black cumin (Nigella sativa) is an important, traditionally used natural drugs in various cultures. Studies show that the components thymoquinone and alpha-hederin are particularly promising chemopreventive substances and are probably responsible for the majority of pharmacological effects. These include immunomodulating, anti-inflammatory, antioxidant and cytoprotective properties as well as a cytotoxic and cytostatic effect on tumor cells (6).
The limiting factor: enzyme delta-6-desaturase (D6D)
GLA is synthesized from alimentary linoleic acid using the enzyme delta-6-desaturase (D6D). However, this process is a limiting step in the production of the subsequent substances in the omega-6 line. The activity of D6D decreases with age and appears to be severely limited in diseases such as arthritis, diabetes, hypertension, atopic eczema or psoriasis (1). Especially in cardiovascular diseases associated with metabolic syndrome, the altered composition of fatty acids in the cell membranes seems to be due to impaired activity of D6D (2)(3). Factors such as stress, smoking, alcohol and an increased intake of saturated fatty acids also reduce the activity of this enzyme. A deficit of magnesium, zinc or vitamin B₆ also has a negative influence on the efficiency of the enzyme (4)(5). The lack of synthesis of GLA ultimately leads to an imbalance in prostaglandin/leukotriene synthesis in favor of proinflammatory prostaglandins. An increased oral GLA supply avoids the critical step of converting linoleic acid to GLA and ensures sufficient availability. This restores the balance between pro-inflammatory and anti-inflammatory prostaglandins. This mechanism could explain the therapeutic success of GLA use in inflammatory processes (6).
Gamma-linolenic acid in atopic dermatitis
Patients with atopic dermatitis usually present low GLA and high linoleic acid levels. This supports the assumption that this disease is also caused by a lack of D6D activity (7)(8)(9). A deficiency of omega-6 fatty acids is often observed in atopic dermatitis (10) and a gradual improvement in symptoms (erythema, itching, flaking) has been achieved in several clinical studies by increasing the supply of GLA (7)(11). Overall, there are contradictory results on the effectiveness of GLA substitution in atopic dermatitis, though meta-analysis reports convincing improvement of clinical symptoms. It can be assumed that patients with mild forms of atopic dermatitis will respond positively to borage oil supplementation (12)(13). The dose administered is also relevant. A significant improvement in GLA values in blood serum compared to EASI values (Eczema Area and Severity Index) was achieved by administering 2x 320 mg/d evening primrose oil, which contains a lower proportion of gamma linolenic acid. In fact, there is an indirect relationship of proportion to the concentration of GLA to SCORE (SCORing Atopic Dermatitis), another assessment scale for the severity of atopic dermatitis (7) In children with high family predisposition, early supplementation with GLA could not prevent the development of atopic dermatitis later in life, but a positive influence on the severity of the disease was observed (14).
Gamma-linolenic acid in rheumatoid arthritis
The inflammatory processes typical of rheumatic diseases are also influenced by polyunsaturated fatty acids and their metabolism. In particular, the omega-3 fatty acids (EPA and DHA) are documented in this indication framework (15), but there is also evidence of a favorable influence of omega-6 fatty acid GLA supplementation. For example, an 18-month randomized double-blind, placebo-controlled study did not detect any differences in effects between omega-3 fatty acids and GLA. After only nine months, considerable improvements in the clinical picture and the immunological parameters were observed, which continued for a further 18 months. The study participants who received borage oil were able to significantly reduce the intake of usual DMARD (disease-modifying anti-rheumatic drugs) (16). The beneficial effects on rheumatoid arthritis are usually only effective from a dose of 500 mg GLA per day (6).
Gamma linolenic acid to improve skin metabolism
Evening primrose and borage oil are used for dry skin and disorder of skin metabolisms. The GLA component plays an important role in maintaining epidermal protective functions. Several clinical studies have shown that supplementation with GLA can improve the skin's water-binding capacity and thus increase the suppleness of dry skin (10)(17). A twelve-week application of borage oil in women led to a significant reduction of skin irritations and transepidermal fluid loss (18). In a randomized placebo-controlled nutritional intervention study, a significant decrease in inflamed and non-inflamed acne lesions and a decrease in interleukin-8 could be achieved after ten weeks of GLA administration (19)
Inflammatory processes underlie most chronic and degenerative diseases. The gamma-linolenic acid of borage oil regulates the expression of genes of signal transduction factors and proinflammatory cytokines and inactivates NF-κB and AP-1 by suppressing oxidative stress (20)(21). In healthy subjects, ex vivo leukotriene B(4) production by activated neutrophils was reduced by 31% (22) after two weeks of supplementation. Even in slightly asthmatic patients an increased concentration of circulating, polyunsaturated fatty acids and significantly reduced leukotriene production ex vivo could be observed after three weeks of supplementation with borage oil - and ultimately also a decrease in inflammation (23). In a 30-month Phase II study in patients with relapsing-remitting multiple sclerosis, linoleic acid, gamma-linolenic acid (2: 1) and vitamin E– ingredients also contained in borage oil capsules were successfully combined with omega-3 fatty acids (DHA: EPA = 3:1). The annual relapse rate decreased by 64% and the probability of disability progression was 10 % (vs. placebo: 58 %) (24).
Evening primrose oil and premenstrual syndrome (PMS)
Failure to convert linoleic acid to gamma-linolenic acid is suggested as a cause of premenstrual syndrome symptoms. Studies have shown that women suffering from PMS have a higher proportion of linoleic acid in their blood than women without symptoms. Fewer tissue hormones such as prostaglandin E1 are produced, which in turn seems to be responsible for the typical symptoms of PMS (26). The trigger to produce progesterone in the ovaries is based on prostaglandin E1. With reduced progesterone, both physical and psychological symptomes of PMS occur. By supplementation of the direct precursor of prostaglandin E1, gamma linolenic acid, the process of progesterone formation is improved (27).
Evening primrose oil to improve immune defense and tumor prevention
Even a general improvement of the immune response can be achieved with evening primrose oil. Here the polyunsaturated fatty acids seem to increase the activity of macrophages and neutrophils (17). Cytotoxic effects with respect to tumor cells were also observed. Gamma-linolenic acid can inhibit the growth of tumor cells by peroxidation and prevent damage to the genetic code of healthy cells (18) (25).

Deficiency symptoms

Impact on	Symptoms
Immune system	Increase in susceptibility to infection Tendency to atopy
Skin	Disorders of wound healing Tendency to eczema
Liver	Increased probability of developing fatty liver

Indications

Effect	Indication	Dosage
Physiological effects at a low intake	For therapeutic support in Neurodermatitis and Psoriasis	100 - 200 mg/d
	For increase of gamma-linolenic acid status	50 - 100 mg/d
	Complementary therapy for diseases of rheumatic diseases	100 - 200 mg/d
	For support of dry skin, scaling and redness especially in menopause	100 - 200 mg/d



Pharmacological effects at a high intake	For therapy of premenstrual complaints	100 - 200 mg/d

Administration

General mode of administration
When	Gamma linolenic acid should be taken with meals. Notes: It should be taken regularly over a long period of time (several months) to achieve the desired results. To protect the GLA from oxidative processes, it should be combined with antioxidant micronutrients (such as vitamin E).
Side effects
In rare cases gastrointestinal side effects can occur (nausea).
Contraindications
Epilepsy, children < 1 year

Interactions

Drug interactions
NSAIDs (e.g. diclofenac, ASS, ibuprofen)	Gamma-linolenic acid can reduce the therapeutic need and side effects of NSAIDs.
Nutrient interactions
None	No relevant interactions are known to date.

References

1) Gröber, U. Orthomolekulare Medizin. 2008. Ein Leitfaden für Apotheker und Ärzte, Wissenschaftliche Verlagsgesellschaft GmbH Stuttgart.

2) Le, C. H. et al. 2014. Delta-6-desaturase links polyunsaturated fatty acid metabolism with phospholipid remodeling and disease progression in heart failure. Circ Heart Fail. 7(1):172-83.

3) Mayneris-Perxachs, J. 2014. Plasma fatty acid composition, estimated desaturase activities, and their relation with the metabolic syndrome in a population at high risk of cardiovascular disease. Clin Nutr. 33(1):90-7.

4) Reed, S. et al. 2014. Dietary zinc deficiency affects blood linoleic acid: dihomo-γ-linolenic acid (LA:DGLA) ratio; a sensitive physiological marker of zinc status in vivo (Gallus gallus). Nutrients. 6(3):1164-80.

5) Zhao, M. 2013. Vitamin B-6 restriction impairs fatty acid synthesis in cultured human hepatoma (HepG2) cells. Am J Physiol Endocrinol Metab. 304(4):E342-51.

6) Kapoor, R. et al. 2014. Gamma-linolenic acid levels correlate with clinical efficacy of evening primrose oil in patients with atopic dermatitis. Adv Ther. 31(2):180-8.

7) Simon, D. et al. 2014. Gamma-linolenic acid levels correlate with clinical efficacy of evening primrose oil in patients with atopic dermatitis. Adv Ther. 31(2):180-8.

8) Schaeffer, L. et al. 2006. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Hum Mol Genet. 15(11): 1745-56.

9) Lattka, E. et al. 2009. FADS gene cluster polymorphisms: important modulators of fatty acid levels and their impact on atopic diseases. J Nutrigenet Nutrigenomics. 2(3):119-28.

10) Yen, C. H. 2008. Linoleic acid metabolite levels and transepidermal water loss in children with atopic dermatitis. Ann Allergy Asthma Immunol. 100(1): 66-73.

11) Fiocchi, A. M. et al. 1994. The efficacy and safety of gamma-linolenic acid in the treatment of

infantile atopic dermatitis. J Int Med Res. 22: 24-32.

12) Henz, B. M. et al. 1999 Double-blind, multicentre analysis of the efficacy of borage oil in patients with atopic eczema. Br J Der-matol. 140 (4): 685-8.

13) Foster, R.H. et al. 2010. Borage oil in the treatment of atopic der-matitis. Nutrition. 26(7-8):708-18.

14) Van Gool, C. J. et al. 2003. Gamma-linolenic acid supple-mentation for prophylaxis of atopic dermatitis - a randomized controlled trial in infants at high familial risk. Am J Clin Nutr. 77(4):943-51.

15) Hahn, A. et al. 2005. Ernährung. Physiologische Grundlagen, Prävention und Therapie.

16) Reed, G.W. et al. 2014. Treatment of Rheumatoid Arthritis with Marine and Botanical Oils: An 18-Month, Randomized, and Double-Blind Trial. Evidence-Based Complementary and Alternative Medicine 2014: 1–9.

18) De Spirt, S. et al. 2012. Intervention with flaxseed and borage oil supplements modulates skin condition in women. Br J Nutr. 101(3):440-445.

19) Jung, J. et al. 2014. Effect of Dietary Supplementation with Omega-3 Fatty Acid and Gamma-Linolenic Acid on Acne Vulgaris: A Randomised, Double-Blind, Controlled Trial. Acta Dermato Venereologica 94, no. 5: 521–525.

20) Chang, C. S. et al. 2010. Gamma-linolenic acid inhibits inflammatory responses by regulating NF-kappaB and AP-1 activation in lipopolysaccharide-induced RAW 264.7 macrophages. Inflammation. 33(1):46-57.

21) McCusker, M.M., Grant-Kels, J.M. 2010. Healing fats of the skin: the structural and immunologic roles of the omega-6 and omega-3 fatty acids. Clin Dermatol. 28(4):440-51

22) Weaver, K. L. et al. 2009. Effect of dietary fatty acids on inflammatory gene expression in healthy humans.Biol Chem. 284(23):15400-7

23) Arm, J. P. et al. 2013. Impact of botanical oils on polyunsaturated fatty acid metabolism and leukotriene generation in mild asthmatics. Lipids Health Dis. 12:141.

24) Pantzaris, M. C. et al. 2013. A novel oral nutraceutical formula of omega-3 and omega-6 fatty acids with vitamins (PLP10) in relapsing remitting multiple sclerosis: a randomised, doubleblind, placebo-controlled proof-of-concept clinical trial. BMJ Open. 3(4). pii: e002170.

25) Burgerstein, L. 2002. Handbuch Nährstoffe. Vorbeugen und heilen durch ausgewogenen Ernährung.

26) Brush, M. G. et al. 1984. Abnormal essential fatty acid levels in plasma of women with premenstrual syndrome. Am J Obstet Gynecol. 150(4):363-6

27) Pavlovic A: PMS- Prämenstruelle Spannungen. Institut für angewandete Biologie. Artikel in www.orthomedis. ch/pms/htm

References Interactions:
Stargrove, M. B. et al. Herb, Nutrient and Drug Interactions: Clinical Implications and Therapeutic Strategies, 1. Auflage. St. Louis, Missouri: Elsevier Health Sciences, 2008.

Gröber, U. Mikronährstoffe: Metabolic Tuning –Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.

Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.