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See also Jim Adam’s journal in this site:

·      Overview of Autism Research, Testing, and Treatments

·      Summary of Montreal’s 3rd Annual Medical Conference on Autism

·      Summary of Defeat Autism Now! (DAN!) October 2001 Conference

·      CV of  Prof. James Adams

 

Literature Review of Essential Fatty Acids

By James B. Adams

jim.adams@asu.edu (comments welcome)

 

Published in this site by written permission of the author, Prof. James Adams

 

 

 

Essential fatty acids (EFA’s) are long-chain polyunsaturated fatty acids that are necessary for normal cellular function.  They are an essential dietary nutrient, as are vitamins, minerals, and amino acids (protein).  The EFA’s are omega 3 and omega 6 fatty acids which cannot by synthesized by humans, but instead must be consumed in their diet.  The most concentrated sources of omega-3 EFA’s are fish and fish oils, flax seed, canola oil, soybean oil, walnuts, and wheat germ.  Vegetables, beans, fruits, meat, and poultry contain lesser amounts.  Omega 3 fatty acids are much less stable than omega 6 fatty acids and monounsaturated and saturated fatty acids, so foods containing omega 3 fatty acids have a much shorter shelf life.  During the last 100 years, commercial food processing (hydrogenation, heat, bleaching, and deoderizing) has led to a major reduction of omega-3 EFA’s in processed foods, in an effort to increase shelf life.  Also, changes in the diet of farm-raised animals has significantly reduced their intake of essential fatty acids; for example, farm-raised fish have significantly lower levels of omega-3 fatty acids than wild fish[1], presumably because the farm-raised fish consume less algae (their source of omega-3 fatty acids).  Whereas prehistoric humans consumed a ratio of approximately 1:1 of omega 3 to omega 6, it is estimated that the average American today consumes a ratio of approximately 1:15 of omega 3 to omega 6, primarily due to a decrease in omega-3 consumption [2].  

 

The three major omega 3 fatty acids are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).  Humans can convert ALA to EPA and DHA, which are the useful forms, provided they have the necessary vitamin/mineral cofactors for the enzymes to function properly.  However, recent evidence shows that the capacity to produce EPA and DHA from ALA is limited and unlikely to supply requirements, especially in rapidly growing young children. EPA and DHA play many roles in the human body.  For example, over 20% of the dry weight of the brain is made up of EFA’s, primarily DHA and arachidonic acid.  Those fatty acids form structural components of cell membranes and are concentrated in neuronal membranous phospholipids, including the myelin sheath.  Postnatal DHA status has been found to correlate with visual acuity (retinal function)[3] and neurodevelolpment[4].  Moreover, EFA’s are important in the regulation of many biochemical events including neurotransmitter release and uptake, receptor function in the central nervous system[5], and various enzymatic processes[6].  Specifically, during normal synaptic function, DHA and arachidonic acid are released into the synaptic junction, followed by reuptake of the EFA’s and the neurotransmitters.  EFA’s also form an integral part of the membrane of every cell, and their concentration affects membrane fluidity and ion transport across cell membranes, and hence affect all cell-to-cell communication.  Omega 6 and Omega 3 fatty acids are also important in the production of prostaglandins. 

 

There have been many reports of significantly reduced levels of EFA’s in several psychiatric disorders.  In schizophrenia, there have been several reports of significantly reduced levels of linoleic acid, arachidonic acid, EPA and DHA in red blood cell membranes compared to healthy controls[7] [8] [9].  A recent study of never-medicated first episode people with schizophrenia also found reduced arachidonic acid and DHA levels (p<0.001), so the reduced concentration appears to be linked to the disorder, not to the medications used to treat it.[10] 

 

EFA’s are also very relevant to post-partum depression, which may be due to the large loss of omega-3 EFA’s that a mother experiences due to pregnancy and lactation.  A large epidemiological study by Dr. Hibbeln at NIH found that countries with high fish consumption (Japan, Hong Kong, Sweden, and Chile) had the lowest level of post-partum depression, and nations with the lowest levels of fish consumption (Brazil, South Africa, West Germany, Saudi Arabia) had the highest rates of postpartum depression[11].  A similar analysis found that major unipolar depression also correlated strongly with fish consumption.[12]

 

In a study of 53 boys with ADHD compared to 43 boys without ADHD, the boys with ADHD were found to have significantly lower levels of EPA, DHA, total omega-3 EFA’s, and arachidonic acid in their RBC[13]   Another study of children with ADHD also reported reduced plasma concentrations of EPA, DHA, and archidonic acid.[14]  In a study of boys with behavior, learning, and health problems, it was found that boys with lower omega 3 EFA levels had more behavior problems, more temper tantrums, and more sleep problems.[15]   It should be pointed out that all of those symptoms are commonly observed in autism.

 

A recent study of EFA levels in children with Rett’s syndrome (which has many similarities with autism) found that very long chain fatty acid levels were significantly lower than the reference range for healthy children[16].

 

In a recent study of EFA levels in the plasma of children with autism[17], it was found that they had normal levels of omega-6 EFA’s, but 20% lower levels of EPA and DHA (p= 0.03).  It should be noted that the control group was a group of children with mental retardation, but their levels were generally consistent with other reported values for typical children.  Their work is consistent with preliminary results by Dr. Gordon Bell at the University of Stirling, who reported that, in seven children with autism, the red blood cells contained less EPA and DHA, and sometimes more arachidonic acid, than control subjects. [18]

 

Due to the research data which shows low levels of omega-3 EFA’s in several psychiatric disorders, there have been studies of the use of EFA supplements for treating those disorders.  This includes three studies of schizophrenia [19] [20] [21] and one study of ADHD [22], where the symptoms of those conditions were reduced after EFA supplementation.

 

A study of 30 subjects with bipolar disorder found that a four-month, double-blind, placebo-controlled treatment with fish oil (6.2 g EPA, 3.4 g DHA) resulted in a statistically-significant improvement in short-term symptoms, and longer periods of remission in most outcome measures[23].  Mild GI side-effects were reported in the supplement group.

 

Similarly, two double-blind, placebo-controlled studies of EPA supplementation found that it was effective in reducing the symptoms of unipolar depression[24] [25].  However, a similar study of DHA found that it was not effective in treating unipolar depression[26], so it appears that it plays a different role than EPA.

 

Fish oil may also be useful in reducing the gastrointestinal problems commonly observed in children with autism.  One epidemiological study found that increasing incidence of Crohn’s disease correlated strongly (r=0.792) with ratio of omega 6 to omega 3, such that low levels of omega-3 corresponded to a higher incidence of Crohn’s disease.[27]  A one-year, double-blind, placebo-controlled trial of fish oil (1.8 g of EPA, 0.9 g of DHA) in people with Crohn’s disease found that subjects taking the fish oil had a significantly reduced relapse rate, with no significant adverse effects[28].   Similar gastrointestinal problems seem to be common in autism.  For example, our previous study of 50 children with autism and 50 controls found that parents reported children with autism had significantly more GI problems (p<0.0001)[29].  Similarly, endoscopies of children with autism have found mild inflammation typically throughout most of the GI tract, which has been termed “autistic enterocolitis”.[30]  [31]  So, the fish oil supplements which were shown to be useful for Crohn’s disease may also be useful in reducing the GI problems found in children with autism. It has been hypothesized that those GI problems may result in an exacerbation of some of the behavioral and sleep problems in autism.

 

In summary, changes in food production in the US have significantly reduced the dietary consumption of omega 3 fatty acids, so that many people in the US may be consuming suboptimal amounts of them.  Many studies have found omega-3 EFA levels to be significantly reduced in people suffering from a variety of psychiatric disorders, including two recent studies of children with autism.  Several double-blind, placebo-controlled studies have found that supplementation with omega-3 essential fatty acids, in the form of fish oil, have significantly reduced some of the symptoms of schizophrenia and other disorders.  Thus, fish oil may help reduce some of the behavioral problems in autism.  Also, fish oil has been reported to reduce the symptoms of Crohn’s disease, so there may also be a benefit of fish oil in reducing the GI problems that often occur in children with autism.

 

Therefore, we believe it makes sense to consider a controlled trial of omega-3 fatty acid supplements in children with autism.  We believe that such a trial is likely to provide some reduction of symptoms in some of this population, for whom there are few other options.  Also, such a trial should be very safe, with small risk of side-effects, as will be discussed later.  Finally, if this treatment is found to be effective, it would be possible to implement it widely due to its low cost and safety.

 

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[1]             Van Vliet, T. and Katan, M.B. 1990. Lower ratio of n-3 to n-6 fatty acids in cultured than in wild fish. Am. J. Clin. Nutr. 51: 1-2.

[2]             A.P. Simopoulos, The importance of the ratio of omega-6/omega-3 essential fatty acids, Biomed Pharmacother 2002 56:365-379.

[3]             E.E. Birch, D.G. Birch, D.R. Hoffman, R. Uauy, Dietary essential fatty acid supply and visual acuity development, Invest Ophthalmol Vis Sci 1992 33:3242-3253.

[4]             C. Agostoni, E. Riva, S. Trojan, R. Bellu, M. Giovanni, Docosahexanoic acid status and development quotient of healthy term infants.  Lancet 1995 346: 638.

[5]             M.G. Murphy Dietary fatty acids and membrane protein function, J. Nutr. Biochem 1990 1:68-78

[6]             J.M. Bourre, M. Francois, A. Youyou, M. Dumond, M. Piciotti, G. Pascal, et al. The effects of dietary alpha-linolenic acid on the composition of nerve membranes, enzymatic activity, amplitude of electrophysiological parameters, resistance to poisons and performance of learning tasksin rats.  J. Nutr 1989 119:1880-1892.

[7]             A. I. M Glen, E.M.T. Glen, D. Horrobin, K.S. Vaddadi, M. Spellman, N. Morse-Fisher, et al A red cell membrane abnormality in a subgroup of schizophrenic patients:  evidence for two diseases.  Schizophr Res. 1994  12:53-61.

[8]             M. Peet, J.D. E. Laugharne, N. Rangarajan, D. Horrobin, G. Reynolds  Depleted red cell membrane essential fatty acids in drug-treated schizophrenic patients  J. Psychiatry Res 1995   29:227—232.

[9]             J.K. Yao, D.P. Van Kammen, J.A. Welker Red blood cell membrane dynamics in schizophrenia II Fatty acid composition.  Schizophr Res. 1994  13:216-226.

[10]           M.M. Khan, D.R. Evans, V. Gunna, R.E. Scheffer, V.V. Parikh, S. P. Mahadik, Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics.

[11]           J.R. Hibbeln, Long-chain polyunsaturated fatty acids in depression and related conditions, Phospholipid Spectrum Disorder, M. Peet, I. Glen, and D. Horrobin, eds.  Lancshire, England:  Marius Press, 1999, 195-210.

[12]           J.R. Hibbeln, “Fish consumption and major depression, Lancet 1998 351:1213.

[13]           L. J. Stevens, S.S. Zentall, J.L. Deck et al., Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder.  Am. J. Clin. Nutr. 1995 62:00-00.

[14]           J.R. Burgess, L. Steens, W. Zhang, L. Peck Long-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorder.  Am. J. Clin. Nutr 2000  71: 327-330.

[15]           L.J. Stevens, S.S. Zentall, M.L. Abate, T. Kuczek, and J.R. Burgess, Omega-3 Fatty Acids in Boys with Behavior, Learning, and Health Problems, Physiology and Behavior 1996, 59:915-920.

[16]           T.J. Stradomska, A. Tylki-Szymanska, Z. Bentkowski Very long-chain fatty acids in Rett syndrome.  Eur J. Pediatr 1999  158:226-229.

[17]           S. Vancassel, G. Durand, C. Barthelemy, B. Lejeune, J. Marineau, D. Guilloteau, C. Andres, S. Chalon, Plasma fatty acid levels in autistic children, Prostaglandins Leukot Essent Fatty Acids 2001 65:1-7.

[18]           Bell, J.G., Dick, J.R., MacKinlay, E.E., Glen, A.C.A., MacDonald, D.J., Boyle, R.M. and Riordan, D.V. (2002) Abnormal fatty acid metabolism in autism and Asperger’s syndrome. In: Phospholipid Spectrum Disorder in Psychiatry and Neurology (2nd edition) “in press”.

[19]           W.S. Fenton, J. Hibbeln, M. Knable Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of Schizophrenia.  Bio. Psychiatry 2000  47:8-21.

[20]           M. Peet, J.D. E. Laugharne, J. Mellor, C.N. Ramchand, Essential fatty acid deficiency in erythrocyte membranes from chronic schizophrenic patients, and the clinical efects of dietary supplementation.  Prostaglandins Leukot Essent Fatty Acids 1996 55:71-75.

[21]           J.E. Mellor, J.D. E. Laugharne, M. Peet Omega-3 fatty acid supplementation in schizophrenic patients.  Human psychopharmacol 1996  11:39-46

[22]           M.G. Aman, E. A. Mitchell, S.H. Turbott The effects of essential fatty acid supplementation by Efamol in hyperactive children J. Abnorm Child Psychol 1987; 15: 75-90.

[23]           A.L. Stoll, W.E. Severus, M.P. Freeman, et al. Omega 3 fatty acids in bipolar disorder, Arch Gen Psychiatry 1999 56:407-412.

[24]           Peet et al, EPA for unipolar major depression, presented at Biological Psychiatry 2001.

[25]           Nemets et al. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder, Am. J. Psychiatry 2002 159:477-479.

[26]           Marangell et al.  DHA in unipolar major depression, presented at ISSFAL, Tsukuba, Japan 2000.

[27]           R. Shoda, K. Matsueda, S. Yamato, N. Umeda  Epidemiologic analysis of Crhon disease in Japan:  Japan Aam. J. Clin. Nutr. 1996 63:741-745.

[28]           A. Belluzi, C. Brignola, M. Campieri, et al. Effect of an enteric-coated fish-oil preparation on relapses in Crohn’s disease, N. Engl J. Med. 1996 334:1557-1560.

[29]           C. Holloway, J.B. Adams, M. Margolis, X. Liu,  “Evaluation of Autistic Symptoms and Risk Factors,” in preparation.

[30]           Wakefield AJ, Anthony A, Murch SH, Thomson M, Montgomery SM, Davies S, O'Leary JJ, Berelowitz M, Walker-Smith JA  Enterocolitis in children with developmental disorders.  Am J Gastroenterol 2000 Sep;95(9):2285-95

[31]           Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT Gastrointestinal abnormalities in children with autistic disorder. J Pediatr 1999 Nov; 135(5):559-63

 

 

See also Jim Adam’s journal in this site:

·      Overview of Autism Research, Testing, and Treatments

·      Summary of Montreal’s 3rd Annual Medical Conference on Autism

·      Summary of Defeat Autism Now! (DAN!) October 2001 Conference

·      CV of  Prof. James Adams

 

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