Peptides and Exorphins in the Autism Spectrum


Problem: Some researchers have not found the opioids in urine of autistic children. We have therefore looked at this problem again. Method: Mass spectrometry and fragmentation mass spectrometry (MS/MS) have been carried out on peaks from the HPLC that show co-chromatography with synthetic standards and peaks that are shared by different autistic children. Results: In quickly frozen urine we find the presence of exorphins, and can also demonstrate a rather fast break down at room temperature of these peptides in urine. Conclusion: Exorphins are present in urine in autistic children, but must be protected against break down and aggregation by fast freezing or acetic acid and adjusting declustering potential and collision potential during mass-spectroscopy. Specific antibody increases and the effect of removing precursor proteins from the diet reinforce this view.

Share and Cite:

Tveiten, D. , Finvold, A. , Andersson, M. and Reichelt, K. (2014) Peptides and Exorphins in the Autism Spectrum. Open Journal of Psychiatry, 4, 275-287. doi: 10.4236/ojpsych.2014.43034.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Reichelt, K.L., Knivsberg, A.M., Lind, G. and Nodland, M. (1991) Probable Etiology and Possible Treatment of Childhood Autism. Brain Dysfunction, 4, 308-319.
[2] Shattock, P., Kennedy, A., Rowell, F. and Berney, T. (1990) Role of Neuropeptides in Autism and Their Relationship with Classical Neurotransmitters. Brain Dysfunction, 3, 328-345.
[3] Cade, R.J., Privette, R.M., Fregly, M., Rowland, N., Sun, Z., Zele, V., et al. (2000) Autism and Schizophrenia: Intestinal Disorders. Nutritional Neuroscience, 3, 57-72.
[4] Shanahan, M.R., Venturini, A.J., Daiss, J.L. and Friedman, A.E. (2000) Peptide Diagnostic Markers for Human Disorders. European Patent Application, EP 0 969 015 A2: 1-44.
[5] Hole, K., Bergslien, A.A., Jorgensen, H., Berge, O.G., Reichelt, K.L. and Trygstad, O.E. (1979) A Peptide Containing Fraction from Schizophrenia Which Stimulates Opiate Receptors and Inhibits Dopamine Uptake. Neuroscience, 4, 1139-1147.
[6] Reichelt, K.L., Hole, K., Hamberger, A., Salid, G., Edminson, P.D., Braestrup, C.B., et al. (1981) Biologically Active Peptide-Containing Fractions in Schizophrenia and Childhood Autism. Advances in Biochemical Psychopharmacology, 28, 627-698.
[7] Sun, Z. and Cade, J.R. (1999) A Peptide Found in Schizophrenia and Autism Causes Behavioural Changes in Rats. Autism, 3, 85-95.
[8] Sun, Z., Cade, R.J., Fregly, M.J. and Privette, R.M. (1999) Beta-Casomorphine Induces Fos-Like Immunoreactivity in Discrete Brain Regions Relevant to Schizophrenia and Autism. Autism, 3, 67-83.
[9] Dettmer, K., Hanna, D., Whetstone, P., Hansen, R. and Hammock, B.D. Autism and Uinary Exogenous Neuropeptides; Developing an on Line SpE-HPLC Modem Mass Spectroscopy Method to Test the Opioid Excess Theory. Analytical and Bioanalytical Chemistry, 3007, 1643-1651
[10] Cass, H., Gringras, P., March, E., McKendrick, I., O’Harwe, A.E., Owen, I. and Pollinc, C. (2008) Absence of Urinary Opioid Peptides in Children with Autism. Archives of Disease Childhood, 93, 745-750.
[11] Kost, N.V., Sokolov, O.Y., Kurasova, O.B., Dimitriev, A.D.,Tarakanova, J.N., Gabaeva, M.V., et al. (2009) Beta-Casomorphin-7 in Infants on Different Type of Feeding and Different Levels of Psychomotor Development. Peptides, 30, 854-860.
[12] Reichelt, K.L. and Knivsberg, A.M. (2003) Can the Pathophysiology of Autism be Explained by the Nature of the Discovered Urine Peptides? Nutritional Neuroscience, 6, 19-28.
[13] Sacco, R., Curatolo, P., Manzi, B., Militerni, R., Bravaccio, C., Froll, A., et al. (2010) Principal Pathogenetic Components and Biological Endophenotypes in Autism Spectrum Disorders. Autism Research, 3, 237-252.
[14] Sponheim, E., Myhre, A.M., Reichelt, K.L. and Aasen, O.C. (2006) Peptidmonstre i Urin Hos Barn Med Mildere Former for Autisme. Tidsskr Nor Laegeforen, 126, 1475-1477.
[15] Reichelt, K.L., Ekrem, J. and Scott, H. (1990) Gluten, Milk Proteins and Autism: Dietary Intervention Effects on Behavior and Peptide Secretion. Journal of Applied Nutrition, 42, 1-11.
[16] Kawashti, M.I., Amin, O.H. and Rowely, N.G. (2008) Possible Immunological Disorders in Autism. Concomittant Autoimmunity and Immunetolerance. Egyptian Journal of Immunology, 13, 99-104.
[17] Trajkovski, V., Petlichkovski, A., Efinska-Mladenovska, O., Trajkov, D., Arsov, T., Strzova, A., et al. (2008) Higher Plasma Concentrations of Food Specific Antibodies in Persons with Autistic Disorder in Comparison to Their Siblings. Focus on Autism and Other Developmental Disabilities, 23, 176-186.
[18] Vojdani, A., O’Bryan, T., Green, J.A., McCandless, J., Woeller, K.N., Vojdani, A.A., et al. (2004) Immune Response to Dietary Proteins, Gliadin and Cerebellar Peptides in Children with Autism. Nutritional Neuroscience, 7, 151-161.
[19] Lau, F.M., Green, R.H.P., Taylor, A.K., Helberg, D., Ajamian, M., Tan, C.Z., et al. (2013) Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS One, 8, Article ID: e66158.
[20] Panksepp, J., Normansell, L., Sivily, S., Rossi, J. and Zolovick, A.J. (1978) Casomorphins Reduce Separation Distress in Chickens. Peptides, 5, 829-831.
[21] Svedberg, J., De Haas, J., Leimanstoll, G., Paul, F. and Teschemacher, H. (1985) Demonstration of Beta-Casomorphin Immunoreactive Materials in Vitro Digests of Bovine Milk and in Small Intestinal Contents after Bovine Milk Ingestion in Adult Humans. Peptides, 6, 825-831.
[22] Chabance, B., Marteau, P., Rambaud, J.C., Migliore-Samour, D., Boynard, M., Perrotin, P., et al. (1998) Casein Peptides Release and Passage to the Blood in Humans during Digestion of Milk and Yogurt. Biochimie, 80, 155-165.
[23] Gardner, M.L.G. (1994) Absorption of Intact Proteins and Peptides. In: Johnson, L.R., Ed., Physiology of the Gastrointestinal Tract, Raven Press, New York, 1795-1820.
[24] Mahe, S., Tome, D., Demontier, A.M. and Desjeux, J.F. (1989) Absorption of Intact Morphiceptin by Diisopropylflurophosphate-Treated Rabbit Ileum. Peptides, 10, 45-52.
[25] Bouras, M., Huneau, J.F. and Tome, D. (1996) The inhibition of Intestinal Dipeptidylaminopeptidase-IV Promotes the Absorption of Enterostatin and Des-Arginine-Enterostatin across Rat Jejunum in vitro. Life Sciences, 59, 2147-355.
[26] Kastin, A.J., Nissen, C., Schally. A.V. and Coy, D.H. (1979) Additional Evidence That Small Amounts of a Peptide Can Cross the Blood Brain Barrier. Pharmacology Biochemistry and Behavior, 14, 717-719.
[27] Ermisch, A., Brust, P., Kretzchmar, R. and Buhle, H.J. (1983) On the Blood-Brain Barrier to Peptides (3H) Beta-Casomorphin-5 Uptake Byeighteen Brain Regions in Vivo. Journal of Neurochemistry, 41, 1229-1233.
[28] Husby, S., Jensenius, J.C. and Cant, A.J. (1984) Passage of Undegraded Dietary Antigen into the Blood of Healthy Adults. Scandinavian Journal of Immunology, 22, 83-92.
[29] Seifert, J., Ganser, R. and Brebdel, W. (1979) Die resorption eines proteolytischesproteins pflanzlichen ursprunge aus dem magen-darmtraktin das blut und in die lymphe von erwachsenen ratten. Z Gastroenterol., 17, 1-8.
[30] Axelsson, I., Jacobsson, I., Lindberg, T. and Benediktsson, B. (1986) Bovine Lactoglobulin in Human Milk. Acta Paediatrica. Scand., 75, 702-707.
[31] Troncone, F., Scarcello, A., Donatiello, A., Cannataro, P., Tabusco, A. and Auricchio, S. (1987) Passage of Gliadin into Human Breast Milk. Acta paediatrica Scandinavica, 76, 453-456.
[32] Langer, S.Z. (1997) 25 Years since the Discovery of Presynaptic Receptors: Present Knowledge and Future Perspectives. Trends in Pharmacological Sciences, 18, 95-99.
[33] Hadjivassiliou, M., Boscolo, S., Davies-Jones, G.A.B., Grünewald, R.A., Not, T., Sanders, D.S., et al. (2002) The Humoral Response in the Pathogenesis of Gluten Ataxia. Neurology, 58, 1221-1226.
[34] Horvath, K., Papadimitriou, J.C., Rabaztyn, A., Drachenberg, C. and Tildon, I.T. (1999) Gastrointestinal Abnormalities in Children with Autistic Disorder. Journal of Pediatrics, 135, 559-563.
[35] Torrente, F., Ashwood, P., Day, R., Marchado, N., Furlano, R.I., Anthony, A., et al. (2002) Small Intestinal Enteropathy with Epithelial IgG and Complement Deposition in Children with Regressive Autism. Molecular Psychiatry, 7, 375-382.
[36] Wakefield, A.J., Anthony, A., Murch, S.H., Thomson, M., Montgomery, S.M., Davies, S., et al. (2000) Enterocolitis in Children with Developmental Disorders. The American Journal of Gastroenterology, 95, 2285-2295.
[37] Jyonouchi, H., Sun, S. and Itokazu, N. (2002) Innate Immunity Associated with Inflammatory Responses and Cytokine Production against Common Dietary Proteins in Patients with Autism Spectrum Disorder. Neuropsychobiology, 46, 76-84.
[38] Heyman, M. and Desjeux, J.F. (2000) Cytokine-Induced Alteration of Epithelial Barrier to Food Antigens in Disease. Annals of the New York Academy of Sciences, 915, 304-311.
[39] D’Eufemia, P., Celli, M., Finnochiaro, R., Pacifico, L., Viozzi, I., Zaccagnini, M., et al. (1996) Abnormal Intestinal Permeability in Children with Autism. Acta Paediatrica, 85, 1076-1079.
[40] de Magistris, L., Familian, V., Pascotto, A., Sapone, A., From, A., Iardino, P., et al. (2010) Alterations of the Intestinal Barrier in Patients with Autism Spectrum Disorders and Their First-Degree Relatives. Journal of Pediatric Gastroenterology and Nutrition, 51, 418-424.
[41] Knivsberg, A.-M., Wiig, K., Lind, G., Nodland, M. and Reichelt, K.L. (1990) Dietary Intervention in Autistic Syndromes. Brain Dysfunction, 3, 315-327.
[42] Lucarelli, S., Frediani, T., Zingoni, A.M., Ferruzzi, F., Giardini, O., Quintieri, F., et al. (1995) Food Allergy and Infantile Autism. Panminerva Medica, 37, 137-141.
[43] Whiteley, P., Rodgers, J., Savery, D. and Shattock, P. (1999) A Gluten-Free Diet as an Intervention for Autism and Associated Spectrum Disorders: Preliminary Findings. Autism, 3, 45-65.
[44] Klaveness, J. and Bigam, J. (2002) The GFCF Kids Diet Survey. The Autism Research Unit, University of Sunderland, 77-84.
[45] Rimland, B. (2003) Parent Rating of Behavioral Effects of Biomedical Interventions. ARI Publ. 34.
[46] Kniker, W.T., Andrews, A., Hundley, A. and Garver, C. (2001) The Possible Role of Intolerance to Milk/Dairy and Wheat/Gluten Foods in Older Children and Adults with Autism Spectrum Disorder. The Autism Research Unit, University of Sunderland, 183-191.
[47] Brudnak, M.A., Rimland, B., Kerry, R.E., Dailey, M., Taylor, R., Stayton, B., et al. (2002) Enzyme-Based Therapy for Autism Spectrum Disorders—Is It Worth another Look? Medical Hypotheses, 58, 422-428.
[48] Whiteley, P., Haracopos, D., Knivsberg, A.-M., Reichelt, K., Parlar, S., Jacobsen, J., et al. (2010) The Scan Brit Randomised, Controlled, Single-Blind Study of a Gluten- and Casein-Free Dietary Intervention for Children with Autism Spectrum Disorders. Nutritional Neuroscience, 13, 87-100.
[49] Pennesi, C.M. and Klein, L.C. (2012) Effectiveness of the Gluten Free, Casein Free Diet for Children Diagnosed with Autism Spectrum Disorder. Based on Parental Report. Nutritional Neuroscience, 15, 85-91.
[50] Knivsberg, A.-M., Reichelt, K.L., Hoien, T. and Nodland, M. (2002) A Randomized, Controlled Study of Dietary Intervention in Autistic Syndromes. Nutritional Neuroscience 5, 251-261.
[51] Knivsberg, A.-M., Reichelt, K.L., Nodland, M. and Hoien, T. (1995) Autistic Syndromes and Diet: A Follow-Up Study. Scandinavian Journal of Educational Research, 39, 223-236.
[52] Garrecht, M. and Austin, D.W. (2011) The Plausibility of a Role for Mercury in the Etiology of Autism: A Cellular Perspective. Toxicological & Environmental Chemistry, 93, 1251-1273.
[53] Nataf, R., Skorupka, C., Amet, L., Lam, A., Springbett, A. and Lathe, R. (2006) Porphyrinuria in Childhood Autistic Disorder: Implications for Environmental Toxicity. Toxicology and Applied Pharmacology, 214, 99-108.
[54] Yong, L.J., Pitkow, L.J. and Ferguson, I.N. (2001) The Neuropathogenesis of Mercury Toxicity. Molecular Psychiatry, 7, 540-541.
[55] Reichelt, K.L., Tveiten, D., Knivasberg, A.-M. and Bronstad, G. (2012) Peptides Role in Autism with Emphasis on Exorphins. Microbial Ecology in Health and Disease, 23, 18958.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.