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Atopic Dermatitis / Eczema

evening-primrose-oilSome unfortunate persons are not able to convert essential fatty acids (EFA’s) from their parent forms to their more active metabolites, such as converting linoleic acid, the primary omega-6, to gamma-linolenic acid (GLA). More than twenty years of research points to the inefficiency of this active conversion pathway as causative of inflammatory skin conditions. Wherever and whenever a metabolite cannot be made by the body on its own, administration of that substance may be in order.

At the start of the twenty-first century, research scientist David Horrobin described a positive relationship between evening primrose oil as a source of pre-formed GLA and the improvement in symptoms of atopic dermatitis, namely eczema.  He relates that, “In most but not all studies, administration of GLA has been found to improve the clinically assessed skin condition, the objectively assessed skin roughness, and the elevated blood catecholamine concentrations of patients with atopic eczema.”  Understandably, the condition may be ascribed a hereditary genesis.  (Horrobin. 2000)

When one of the crowd upsets the apple cart he becomes noticed because of the chaos he spawned.  David Horrobin is such a person.  He was responsible for opening the eyes of the research community to the potential of complementary and alternative medicine in the treatment of fatty acid deficiency conditions, including inflammatory skin conditions, schizophrenia, rheumatoid arthritis, and diabetes, to name but a few.  Horrobin—and others after him— discovered that metabolic inefficiency in the conversion of linoleic acid to gamma-linolenic acid (GLA) might be responsible for inflammatory skin responses that present as eczema, despite the presence of adequate linoleic acid in blood and adipose tissue.  (Dobryniewski. 2007. p. 100)

It is such that omega-6 and omega-3 fatty acids compete for the enzymes that transform them into super hero molecules known to control the inflammation activities that promote health. The omega-3 fatty acids prevail at the expense of the omega-6s, leading to a deficit of omega-6 metabolites and their benefits.  Therefore, it makes sense to overcome deficiencies by administering these metabolites directly, as in the oral and/or topical use of evening primrose oil (EPO), an omega-6 fatty acid accepted for its GLA content.  Horrobin’s desire to herald the attributes of GLA spread to the European continent, where scientists from Poland agreed that GLA is one of the most frequently deficient fatty acids, and that supplementation brings hopeful effects in the treatment of eczema and other conditions.  (Horrobin. 1993)  (Dobryniewski. 2007. p. 91)

There are predisposing factors in acute or chronic skin disease, including family history of allergic disorders and sensitivity to contact allergens or to certain foods.  Chronic disease is difficult to treat.  Itching causes scratching, which increases inflammation, which causes itching … The cycle is hard to break.  But evening primrose oil (EPO), with a history of efficacy that predates Dr. Horribin’s interest, has produced “…significant clinical improvement on atopic eczema.” (Ebden. 1989)  In meta analyses conducted in the late 1980’s, the British Journal of Dermatology recounted significant improvement in eczema symptoms using a commercial EPO product called Epogam (the name seemingly gleaned from EPO and GLA), after which use, “ The effects on itch were particularly striking.” (Morse.1989).

BodyBio evening Primrose Oil contains ten percent GLA and a sufficient amount of its precursor, linoleic acid, to help the body make the molecules that inhibit the pro-inflammatory series 2 prostaglandins and series 4 leukotrienes.  There is a distinct correlation between improvements in clinical scoring devices and an elevation of fatty acid levels.  Compared to placebo, children treated with EPO significantly improved the symptoms of atopic eczema.  (Bordoni. 1988)

References

Horrobin DF.
Essential fatty acid metabolism and its modification in atopic eczema.
Am J Clin Nutr. 2000 Jan;71(1 Suppl):367S-72S.

Dobryniewski J, Szajda SD, Waszkiewicz N, Zwierz K.
The gamma-linolenic acid (GLA)–the therapeutic value.  [Article in Polish]
Przegl Lek. 2007;64(2):100-2.

Horrobin DF.
Fatty acid metabolism in health and disease: the role of delta-6-desaturase.
Am J Clin Nutr. 1993 May;57(5 Suppl):732S-736S; discussion 736S-737S.

Dobryniewski J, Szajda SD, Waszkiewicz N, Zwierz K.
Biology of essential fatty acids (EFA). [Article in Polish]
Przegl Lek. 2007;64(2):91-9.

Ebden P, Bevan C, Banks J, Fennerty A, Walters EH.
A study of evening primrose seed oil in atopic asthma.
Prostaglandins Leukot Essent Fatty Acids. 1989 Feb;35(2):69-72.

P.F. MORSE, D.F. HORROBIN,, M.S. MANKU, J.C.M. STEWART, R. ALLEN, 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
British Journal of Dermatology. Volume 121, Issue 1, pages 75–90, July 1989

Bordoni A, Biagi PL, Masi M, Ricci G, Fanelli C, Patrizi A, Ceccolini E.
Evening primrose oil (Efamol) in the treatment of children with atopic eczema.
Drugs Exp Clin Res. 1988;14(4):291-7.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

Beta-Glucans, The Healer

oatmeal-and-white-backgroundThere are quite a few products on the market that promise to heal wounds quickly. The one made from a combination of bacitracin, neomycin and polymyxin is so popular that it’s been copied as a generic. But it isn’t all-natural. For those interested in a natural alternative, there’s a new kid on the block, called beta-glucans, found in baker’s yeast and a few other common sources, and destined to be on the shelves as a gel in 2012. Heralded as a “super medicine,” beta-glucans are currently used in veterinary medicine, dietary supplements, and cosmetics. And Norwegian scientists say it has even more potential.

The Research Council of Norway announced the results of a study headed by Rolf Einar Engstad, of Biotec Pharmacon, that proclaimed, “Since the mid-1980’s we have known that these substances (beta-glucans) fight infection and have a bearing on the body’s ability to kill cancerous cells, but never knew why.”  At the start of the project, the researchers were uncertain of the efficacy of the delivery method, but in infected laboratory animals, “…determined that animals receiving beta-glucans orally acquired protection that was at least as good as rats that received an injection into their bloodstream.”  Effectiveness of topical application in the healing of wounds was welcome news.  Incisions, bed sores, diabetic ulcers, and other skin insults can be treated with topical beta-glucans.  A matter that has since been addressed is short shelf life, something that can happen to any organic material, such as organic produce.  To add to beta-glucans’ acclaim is its capacity to enhance the innate immune system, that immunity with which we are born and which is first mobilized if the body is invaded by a pathogen.  (The Research Council of Norway.  2011)

As a supplement, beta-glucans has been around for a while.  These sugars are found in the cell walls of bacteria, fungi, yeasts, algae, lichens, and plants, such as oats and barley.  Orally, they have been used for treating cholesterol, diabetes, cancer and HIV/AIDS, and for bolstering the immune systems of those suffering from chronic fatigue syndrome and emotional or physical stress.  It may be given IV post-surgery to prevent infections.  Topically, it’s been used for dermatitis, eczema, wrinkles, bedsores, radiation burns, and other skin conditions.  The enhancement of macrophage function aids in healing wounds, although the exact mechanism of this improved healing is uncertain. (Portera. 1997)  Besides that, increases in collagen manufacture have been noticed, resulting in improved tensile strength of the new wound covering.  (Browder. 1988)  The activity in this arena includes the stimulation of growth factors and the release of cytokines, regulatory proteins that mediate the immune response.  (Wei. 2002)  This results in stimulation of fibroblast (giving rise to connective tissue) collagen biosynthesis.

Yeast-based beta-glucans is being taken more and more seriously as an immune health ingredient.  Because it can stand a wide range of body pH, yeast-based product could supplant—or at least enhance—probiotics as a first line of defense against invasion by bacteria and viruses.  (Watson, 2011)

Beyond healing wounds, beta-glucans may prevent the absorption of cholesterol from the stomach and intestine when it is taken orally.  The beta-glucan found in oats led oatmeal makers to petition the FDA to allow such a claim on their labels.  The FDA agreed, as long as the amount is 10% of the product.  (Federal Register. 2002)

By injection, beta-glucans stimulate the immune system by increasing chemicals that prevent infections.  Used in immunotherapy, as in treating certain invasive diseases, beta-glucans incites cytotoxicity (cell toxicity) in neoplastic (abnormal new growth) tissue while leaving healthy tissue alone.  (Vetvicka. 1996)

As with any promising developments in alternative approaches to wellness, funding for additional studies becomes a roadblock.  The promise of beta-glucans, which, because it appears in food cannot be patented as a drug (yet), paints a rosy picture for treating cuts and scrapes, and perhaps for the prevention of contagious diseases and chronic illnesses.

References

Siw Ellen Jakobsen and Else Lie
Baker’s yeast aids healing
The Research Council of Norway. Published: 07.09.2011

Portera CA, Love EJ, Memore L, Zhang L, Müller A, Browder W, Williams DL.
Effect of macrophage stimulation on collagen biosynthesis in the healing wound.
Am Surg. 1997 Feb;63(2):125-31.

Browder W, Williams D, Lucore P, Pretus H, Jones E, McNamee R
Effect of enhanced macrophage function on early wound healing.
Surgery. 1988 Aug;104(2):224-30.

Wei D, Zhang L, Williams DL, Browder IW.
Glucan stimulates human dermal fibroblast collagen biosynthesis through a nuclear factor-1 dependent mechanism.
Wound Repair Regen. 2002 May-Jun;10(3):161-8.

Elaine Watson
Biothera on a roll as yeast beta-glucan moves into the mainstream
Nutra-Ingredients-USA.com.  12 September, 2011

Food and Drug Administration, HHS
Food labeling: health claims; soluble dietary fiber from certain foods and coronary heart disease. Interim final rule.
Fed Regist. 2002 Oct 2;67(191):61773-83.

Vetvicka V, Thornton BP, Ross GD.
Soluble beta-glucan polysaccharide binding to the lectin site of neutrophil or natural killer cell complement receptor type 3 (CD11b/CD18) generates a primed state of the receptor capable of mediating cytotoxicity of iC3b-opsonized target cells.
J Clin Invest. 1996 Jul 1;98(1):50-61.

Charlotte Sissener Engstad, Rolf Einar Engstad, Jan-Ole Olsen and Bjarne Osterud
The effect of soluble beta-1,3-glucan and lipopolysaccharide on cytokine production and coagulation activation in whole blood.
Int Immunopharmacol 2(11):1585-97 (2002) t

Suzuki I, Hashimoto K, Ohno N, Tanaka H, Yadomae T.
Immunomodulation by orally administered beta-glucan in mice.
Int J Immunopharmacol. 1989;11(7):761-9.

Delatte SJ, Evans J, Hebra A, Adamson W, Othersen HB, Tagge EP.
Effectiveness of beta-glucan collagen for treatment of partial-thickness burns in children.
J Pediatr Surg. 2001 Jan;36(1):113-8.

Borchers AT, Stern JS, Hackman RM, Keen CL, Gershwin ME.
Mushrooms, tumors, and immunity.
Proc Soc Exp Biol Med. 1999 Sep;221(4):281-93.

Akramiene D, Kondrotas A, Didziapetriene J, Kevelaitis E.
Effects of beta-glucans on the immune system.
Medicina (Kaunas). 2007;43(8):597-606.

Ross GD, Vetvicka V, Yan J, Xia Y, Vetvicková J.
Therapeutic intervention with complement and beta-glucan in cancer.
Immunopharmacology. 1999 May;42(1-3):61-74.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

Essential Fats Explained

fattyacid-sourceThe essential fatty acids (EFA’s) are just that—essential, meaning they have to come from the diet because the body can’t manufacture them. They might be used as fuel, but they are absolute components of the biological processes that make us work. Only two fatty acid families are vital to humans, omega-6’s and omega-3’s. It’s been shown that their ratio is more important than their volume. The parent fatty acid (FA) in the omega-6 (n-6) line is linoleic acid, abundant in many vegetable oils and ultimately responsible for the biosynthesis of arachidonic acid and related prostaglandins, which are compounds that regulate physiological activities. Alpha-linolenic acid (ALA) is the mother omega-3 (n-3) fatty acid, commonly extracted from seed oils such as flaxseed and hemp, but also found in walnuts. Nearly every aspect of human physiology is affected by essential fats, receptors for which are located in practically every cell.

The n-6 fatty acids have been denigrated in recent years because their excess has been linked to several metabolic upsets. Unbalanced diets are harmful to health, and the n-6’s that overpopulate processed foods and rancid supermarket oils have contributed to myriad health woes. What possibly started out as a 1 to 1 or 2 to 1 ratio of n-6 fatty acids to n-3 fatty acids in the human diet eons ago has become a physiological disaster of imbalance, where the ratio exceeds 10 to 1 in the typical Western diet, and may even approach 20 to 1, or worse, in personal food intake. All fatty acids go through a process of desaturation and elongation to become eminently bioactive compounds. The ultimate products of the process are beneficial to human health, especially if they are made step-by-step by the body and not forced upon it through manufactured meals, unnaturally finished meat products, stale/oxidized vegetable oils, and fossilized eggs, not to mention horrific snack foods. In a healthy body, linoleic acid is converted to gamma-linolenic acid (GLA), which becomes arachidonic acid, from which come the chemicals that control inflammation. After adulthood, the body’s ability to make those conversions is uncertain, so starting with GLA gives us a head start. However, mother linoleic acid is anti-inflammatory in its own right and even a marginal conversion to GLA has been held effective in the management of conditions as diverse as rheumatoid arthritis, eczema and ADD/ADHD.

The n-3 parent, ALA, also must come from diet because humans lack the enzymes necessary to convert it from other fats. But it’s the downstream omega-3’s that get the publicity:  EPA and DHA. Like the n-6’s, the conversion of ALA to EPA and later to DHA is an uncertain proposition in adulthood, which is why most adults use fish oil, a source of pre-made fatty acids. Even in the absence of the requisite conversion co-factors (vitamin B6, Mg, biotin, vitamin B3, vitamin C and Zn), ALA is anti-inflammatory and cardiac friendly (Pan, 2012) (Vedtofte, 2012), with recent scrutiny heralding its potential to inhibit progression of atherosclerosis (Bassett, 2011). The most readily available source of ALA is flaxseed, although chia, the newest kid on the block, is entering the marketplace.

Signs of fatty acid deficiency include a dry scaly rash, impoverished growth in youngsters, increased susceptibility to infections and poor wound healing, but are uncommon. The enzymes that convert the parent fatty acids act preferentially toward the n-3’s. By the time these enzymes deal with the omega-3 fats, some of the omega-6’s have been used for energy, hence the need to get more 6’s than 3’s, in a ratio of about 4 to 1, as evidenced by intensive research done in the 1990’s and early-mid 2000’s (Yahuda, 1993, 1996) (Simopoulos, 2002, 2008). But this ratio is based on the body’s own manufacture of the downstream fatty acids, GLA and arachidonic acid (ARA) along the n-6 line (the latter now included in products designed for infants to insure proper brain development) and EPA/DHA down the n-3 line. Deficiency of essential fatty acids sometimes strikes those suffering from cystic fibrosis or fat malabsorption issues. If patients receive total parenteral nutrition without the inclusion of EFA’s, deficit will appear in about a week or two.

The dry weight of the brain is about 80% lipids, the highest of any organ. The long-chain polyunsaturated fats, especially the n-6 and n-3, are crucial in modulating neural function. They occupy as much as 30% of the brain’s dry weight, making their influence on neural membrane dynamics profound. The shift away from EFA’s in the Western—typically American—diet parallels a rise in mental disorders. The need to address EFA supplementation is real and current, with the inclusion of omega-6 fats a necessity, since GLA, the downstream scion of linoleic acid, has held its own in mental health studies (Vaddadi, 2006). Together, the n-6’s and n-3’s cooperate in a number of cellular functions that affect membrane fluidity, allowing the passage of food and energy into the cell and wastes out. Arachidonic acid is a precursor to signaling molecules in the brain and is a key inflammatory intermediate, while EPA and DHA work to support the cardiovascular system, and the brain and retina.

It is arachidonic acid that supports membrane fluidity in the hippocampus, the part of the brain that directs memory, spatial relations and inhibition (Fukaya, 2007). It is arachidonic acid that protects the brain against oxidative stress and activates proteins in charge of the growth and repair of neurons (Darios, 2006). There is conjecture that ARA supplementation during the early stages of Alzheimer’s disease may slow its progress and stave off symptoms (Schaeffer, 2009). That’s a pretty good promise for something that’s been spurned…for lack of knowledge. Of the n-3’s, EPA may be effective in addressing depressive conditions and behavioral anomalies, besides being able to reduce inflammation (Brind, 2001) (Song, 2007). There had been some concern that EPA adversely affects clotting factors and fibrinogen concentrations, increasing the likelihood of bleeding. That is not so (Finnegan, 2003). It does, however, improve blood viscosity and red blood cell deformity, which allows red cells to adjust their shape to squeeze through narrow blood vessels, like capillaries. Downstream from EPA is DHA, a major fatty acid in sperm, brain phospholipids and the retina of the eye, and found to lower triglycerides. But its claim to fame is its rapid accrual in the developing brain during the third trimester of pregnancy and early postnatal period (Auestad, 2003) (Wainwright, 2000).

You can safely bet the farm that endogenous (made by the body itself) substances are more tightly regulated than exogenous. For example, the arachidonic acid your body makes from linoleic acid is more respectable than that from a haphazardly slaughtered steer, which may or may not be completely lifeless before the abattoir starts to dress it. In fear and pain, the animal releases a torrent of adrenal hormones throughout its flesh, confounding the integrity of its innate fatty acids. Endogenous fatty acids are, therefore, more wholesome.

How do we acquire the parent fatty acids?  You could buy oils that boast omega-6 and omega-3 fatty acid content from the supermarket, but it’s almost guaranteed that the balance will be too far out of whack to deliver a benefit, and the purity of the oils is possibly iffy. In fact, they might upset the apple cart. An overabundance of n-3’s can shut the immune system down for lack of guidance by the n-6 inflammation directors. On the other hand, BodyBio Balance Oil is a blend of organic, cold-pressed sunflower and flaxseed oils that are purposely geared to supply a 4 to 1 ratio of fatty acids that the body needs to initiate the cascade to longer chain fats that present vibrant physiological activity. Just the anti-inflammatory properties of the mother fatty acids, linoleic from sunflower and alpha-linolenic from flax, are enough to warrant using the oils to bolster the body’s well-being and to work out some metabolic kinks. Used to make salad dressings or to dress vegetables in place of butter, Balance Oil has the potential to set straight that which is awry, and the essential fatty acid metabolites can help to clear the brain fog on a hazy day. Cerebral lipids, especially the long-chain fatty acids, have significant direct and indirect activity on cerebral function. Not only do they affect the membranes, but also many are converted to neurally active substances. There is good evidence that mental challenges are related to EFA depletion, the supplementation of which can ameliorate the most defiant state of affairs.

References

Auestad N, Scott DT, Janowsky JS, Jacobsen C, Carroll RE, Montalto MB, Halter R, Qiu W, et al
Visual, cognitive, and language assessments at 39 months: a follow-up study of children fed formulas containing long-chain polyunsaturated fatty acids to 1 year of age.
Pediatrics. 2003 Sep;112(3 Pt 1):e177-83.

Bassett CM, McCullough RS, Edel AL, Patenaude A, LaVallee RK, Pierce GN.
The α-linolenic acid content of flaxseed can prevent the atherogenic effects of dietary trans fat.
Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2220-6. doi: 10.1152/ajpheart.00958.2010. Epub 2011 Sep 30.

Caramia G.
The essential fatty acids omega-6 and omega-3: from their discovery to their use in therapy.
Minerva Pediatr. 2008 Apr;60(2):219-33.

Chang CS, Sun HL, Lii CK, Chen HW, Chen PY, Liu KL.
Gamma-Linolenic Acid Inhibits Inflammatory Responses by Regulating NF-kappaB and AP-1 Activation in Lipopolysaccharide-Induced RAW 264.7 Macrophages.
Inflammation. 2009 Oct 20.

Darios F, Davletov B.
Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3.
Nature. 2006 Apr 6;440(7085):813-7.

da Rocha CM, Kac G.
High dietary ratio of omega-6 to omega-3 polyunsaturated acids during pregnancy and prevalence of post-partum depression.
Matern Child Nutr. 2012 Jan;8(1):36-48. doi: 10.1111/j.1740-8709.2010.00256.x. Epub 2010 Jun 21.

Dupasquier CM, Dibrov E, Kneesh AL, Cheung PK, Lee KG, Alexander HK, Yeganeh BK, Moghadasian MH, Pierce GN.
Dietary flaxseed inhibits atherosclerosis in the LDL receptor-deficient mouse in part through antiproliferative and anti-inflammatory actions.
Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2394-402. Epub 2007 Jul 6.

Fernandes FS, de Souza AS, do Carmo Md, Boaventura GT.
Maternal intake of flaxseed-based diet (Linum usitatissimum) on hippocampus fatty acid profile: implications for growth, locomotor activity and spatial memory.
Nutrition. 2011 Oct;27(10):1040-7.

Finnegan YE, Howarth D, Minihane AM, Kew S, Miller GJ, Calder PC, Williams CM.
Plant and marine derived (n-3) polyunsaturated fatty acids do not affect blood coagulation and fibrinolytic factors in moderately hyperlipidemic humans.
J Nutr. 2003 Jul;133(7):2210-3.

Fukaya T, Gondaira T, Kashiyae Y, Kotani S, Ishikura Y, Fujikawa S, Kiso Y, Sakakibara M.
Arachidonic acid preserves hippocampal neuron membrane fluidity in senescent rats.
Neurobiol Aging. 2007 Aug;28(8):1179-86. Epub 2006 Jun 21.

C. Gómez Candela, L. M.ª Bermejo López and V. Loria Kohen
Importance of a balanced omega 6/omega 3 ratio for the maintenance of health.Nutritional recommendations
Nutr Hosp. 2011;26(2):323-329.

Ángeles Guinda, M. Carmen Dobarganes, M. Victoria Ruiz-Mendez, Manuel Mancha
Chemical and physical properties of a sunflower oil with high levels of oleic and palmitic acids
European Journal of Lipid Science and Technology. 105(3-4); Apr 2003: 130-137

BRIAN HALLAHAN, MRCPsych and MALCOLM R. GARLAND, MRCPsych
Essential fatty acids and mental health
The British Journal of Psychiatry (2005); 186: 275-277

William S. Harris, PhD, FAHA, Chair;  Dariush Mozaffarian, MD, DrPH, FAHA;  et al
Omega-6 Fatty Acids and Risk for Cardiovascular Disease
A Science Advisory From the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention
Circulation. 2009; 119: 902-907

Kakutani S, Ishikura Y, Tateishi N, Horikawa C, Tokuda H, Kontani M, Kawashima H, Sakakibara Y, Kiso Y, Shibata H, Morita I.
Supplementation of arachidonic acid-enriched oil increases arachidonic acid contents in plasma phospholipids, but does not increase their metabolites and clinical parameters in Japanese healthy elderly individuals: a randomized controlled study.
Lipids Health Dis. 2011 Dec 22;10:241.

Lands B.
Consequences of essential Fatty acids.
Nutrients. 2012 Sep;4(9):1338-57.

Eric L. LIEN, Kurt STEINER and John C. WALLINGFORD
The Proper Balance of Essential Fatty Acids for Life
Journal of Oleo Science. Vol. 50 (2001) , No. 5 399-405

Maekawa M, Takashima N, Matsumata M, Ikegami S, Kontani M, Hara Y, Kawashima H, Owada Y, Kiso Y, Yoshikawa T, Inokuchi K, Osumi N.
Arachidonic acid drives postnatal neurogenesis and elicits a beneficial effect on prepulse inhibition, a biological trait of psychiatric illnesses.
PLoS One. 2009;4(4):e5085. doi: 10.1371/journal.pone.0005085. Epub 2009 Apr 8.

Osumi N.
Fatty acid signal, neurogenesis, and psychiatric disorders
Nihon Shinkei Seishin Yakurigaku Zasshi. 2010 Jun;30(3):141-8.

Pan A, Chen M, Chowdhury R, Wu JH, Sun Q, Campos H, Mozaffarian D, Hu FB.
α-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis.
Am J Clin Nutr. 2012 Dec;96(6):1262-73. doi: 10.3945/ajcn.112.044040. Epub 2012 Oct 17.

Pawels EK, Volterrani D.
Fatty acid facts, Part I. Essential fatty acids as treatment for depression, or food for mood?
Drug News Perspect. 2008 Oct;21(8):446-51. doi: 10.1358/dnp.2008.21.8.1272136.

Peet M, Brind J, Ramchand CN, Shah S, Vankar GK.
Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia.
Schizophr Res. 2001 Apr 30;49(3):243-51.

Sakayori N, Maekawa M, Numayama-Tsuruta K, Katura T, Moriya T, Osumi N.
Distinctive effects of arachidonic acid and docosahexaenoic acid on neural stem /progenitor cells.
Genes Cells. 2011 Jul;16(7):778-90. doi: 10.1111/j.1365-2443.2011.01527.x. Epub 2011 Jun 13.

Sanders TA, Rana SK.
Comparison of the metabolism of linoleic and linolenic acids in the fetal rat.
Ann Nutr Metab. 1987;31(6):349-53.

Schaeffer EL, Forlenza OV, Gattaz WF.
Phospholipase A2 activation as a therapeutic approach for cognitive enhancement in early-stage Alzheimer disease.
Psychopharmacology (Berl). 2009 Jan;202(1-3):37-51.

Simopoulos AP.
The importance of the ratio of omega-6/omega-3 essential fatty acids.
Biomed Pharmacother. 2002 Oct;56(8):365-79.

Artemis P. Simopoulos
The Importance of the Omega-6/Omega-3 Fatty Acid Ratio in Cardiovascular Disease and Other Chronic Diseases
Experimental Biology and Medicine  233:674-688 (2008)

Meharban Singh
Essential fatty acids, DHA and human brain
Indian Journal of Pediatrics. Volume 72, Number 3 / March, 2005: 239-242

Song C, Zhao S.
Omega-3 fatty acid eicosapentaenoic acid. A new treatment for psychiatric and neurodegenerative diseases: a review of clinical investigations.
Expert Opin Investig Drugs. 2007 Oct;16(10):1627-38.

Uauy R, Hoffman DR, Peirano P, Birch DG, Birch EE.
Essential fatty acids in visual and brain development.
Lipids. 2001 Sep;36(9):885-95.

Vaddadi K.
Essential fatty acids and mental illness.
Int Rev Psychiatry. 2006 Apr;18(2):81-4.

Vedtofte MS, Jakobsen MU, Lauritzen L, Heitmann BL
The role of essential fatty acids in the control of coronary heart disease.
Curr Opin Clin Nutr Metab Care. 2012 Nov;15(6):592-6.

Wainwright P.
Nutrition and behaviour: the role of n-3 fatty acids in cognitive function.
Br J Nutr. 2000 Apr;83(4):337-9.

Yehuda S, Carasso RL.
Modulation of learning, pain thresholds, and thermoregulation in the rat by preparations of free purified alpha-linolenic and linoleic acids: determination of the optimal omega 3-to-omega 6 ratio.
Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10345-9.

Yehuda S, Brandys Y, Blumenfeld A, Mostofsky DI.
Essential fatty acid preparation reduces cholesterol and fatty acids in rat cortex.
Int J Neurosci. 1996 Sep;86(3-4):249-56.

Yehuda S, Rabinovtz S, Carasso RL, Mostofsky DI.
Essential fatty acids preparation (SR-3) improves Alzheimer’s patients quality of life.
Int J Neurosci. 1996 Nov;87(3-4):141-9.

Yehuda S, Rabinovitz S, Mostofsky DI.
Essential fatty acids are mediators of brain biochemistry and cognitive functions
J Neurosci Res. 1999 Jun 15;56(6):565-70.

Yehuda S, Rabinovitz S, Carasso RL, Mostofsky DI.
The role of polyunsaturated fatty acids in restoring the aging neuronal membrane.
Neurobiol Aging. 2002 Sep-Oct;23(5):843-53.

Young G, Conquer J.
Omega-3 fatty acids and neuropsychiatric disorders.
Reprod Nutr Dev. 2005 Jan-Feb;45(1):1-28.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.