Opioid excess theory

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The opioid excess theory is a theory which postulates that autism is the result of a metabolic disorder in which opioid peptides produced through metabolism of gluten and casein pass through an abnormally permeable intestinal membrane and then proceed to exert an effect on neurotransmission through binding with opioid receptors. [1] It is believed by advocates of this hypothesis that autistic children are unusually sensitive to gluten, which results in small bowel inflammation in these children, which in turn allows these opioid peptides to enter the brain. [2]

Contents

Early years

This hypothesis was first proposed by Jaak Panksepp in a 1979 paper, in which he speculated that autism might be "an emotional disturbance arising from an upset in the opiate systems in the brain." [3] Kalle Reichelt then emerged as one of the leading advocates of this theory, publishing papers alleging that "the patterns of peptides and associated proteins from urinary samples [from people with autism] differ considerably from each other and from normal controls." In addition, Reichelt's research has concluded that autistic individuals have increased levels of these peptides in their cerebrospinal fluid. [4] Additionally, in a 1991 paper, Reichelt argued that gluten and casein may play a causative role in autism, as the incomplete digestion thereof may produce certain opioid peptides. [5] Thus, those, such as Paul Shattock, who advocate this theory also advocate the use of a gluten-free, casein-free diet as a treatment for autism.[ citation needed ]

Wakefield study

In 1998, a fraudulent paper by Andrew Wakefield was published in The Lancet presenting apparent evidence of a link between the MMR vaccine, gastrointestinal disease and autism. In this paper, which has since been retracted, Wakefield et al. speculated that food-derived peptides "may exert central-opioid effects, directly or through the formation of ligands with peptidase enzymes required for breakdown of endogenous central-nervous-system opioids, leading to disruption of normal neuroregulation and brain development by endogenous encephalins and endorphins." [6]

Later research

Reichelt has published a number of papers concluding that autistic children excrete higher levels of peptides in their urine, [7] as well as that such peptides may cause autistic gaze aversion; specifically, by interfering with corticothalamocortical processing of visual stimuli. [8] As a result of this theory, others, particularly Panksepp, have speculated that opioid antagonists such as naloxone and naltrexone may be useful in the treatment of autism. [9] [10] In addition, Christopher Gillberg of Gothenburg University has published some studies showing that animals treated with opiates exhibit less clinging, in line with the behavior of autistic children, who, his research has also shown, "do not seem concerned when their parents are not near" and "exhibit less crying than infants without autism," [11] and has also linked an excess of endogenous opioids to stereotypic (i.e. repetitive) behavior. [12] However, more recently, two studies were published which failed to find a difference in levels of peptides in the urine of autistic children as opposed to those without autism. [13] [14] A 2009 review found that no evidence exists that urinary peptide levels are correlated with gut permeability. [15]

Possible implications for treatment

Several double blind studies experimented with low dose opioid antagonists, such as naltrexone, for treatment of autism. A recent systematic review, published in 2014 [16] showed statistically significant improvement in symptoms of irritability and hyperactivity in 77% of children treated with naltrexone. Core autism symptoms were unaffected. Side effects were mild and the drug was generally well tolerated. The number of children undergoing such therapy in the 10 analysed studies was only 128.

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Paul Shattock is a British autism researcher and scientific consultant to the charity Education and Services for People with Autism, of which he is also the founder. He was formerly the director of the Autism Research Unit at the University of Sunderland. He is well known for his disputed research into dietary therapy and autism, having claimed that autistic children may have a "leaky gut" which allows certain peptides to enter the bloodstream, and claimed that they excrete unusually high levels thereof. As a result of this speculation, he has promoted the use of a gluten-free, casein-free diet to ameliorate the symptoms of autism, a theory he developed along with Kalle Reichelt. In addition, he has claimed that a protein found in milk may play a role in the etiology of autism. He is also the former president of the World Autism Organization.

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References

  1. ↑ Millward, C.; Ferriter, M.; Calver, S. J.; Connell-Jones, G. G. (2008). Ferriter, Michael (ed.). "Gluten- and casein-free diets for autistic spectrum disorder". The Cochrane Database of Systematic Reviews (2): CD003498. doi:10.1002/14651858.CD003498.pub3. PMC   4164915 . PMID   18425890.
  2. ↑ Special diets and autism
  3. ↑ Panksepp, J. (1979). "A neurochemical theory of autism". Trends in Neurosciences. 2: 174–177. doi:10.1016/0166-2236(79)90071-7. S2CID   54373822.
  4. ↑ Reichelt, K. L.; Hole, K.; Hamberger, A.; et al. (1981). "Biologically active peptide-containing fractions in schizophrenia and childhood autism". Advances in Biochemical Psychopharmacology. 28: 627–643. PMID   7010949.
  5. ↑ Probable etiology and possible treatment of childhood autism
  6. ↑ Wakefield, A. J.; Murch, S. H.; Anthony, A.; Linnell, J.; Casson, D. M.; Malik, M.; Berelowitz, M.; Dhillon, A. P.; Thomson, M. A.; Harvey, P.; Valentine, A.; Davies, S. E.; Walker-Smith, J. A. (1998). "RETRACTED: Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children". The Lancet. 351 (9103): 637–641. doi:10.1016/S0140-6736(97)11096-0. PMID   9500320. S2CID   439791.
  7. ↑ Knivsberg, A. M.; Reichelt, K. L.; n⊘Dland, M.; h⊘Ien, T. (1995). "Autistic Syndromes and Diet: A follow-up study". Scandinavian Journal of Educational Research. 39 (3): 223–236. doi:10.1080/0031383950390304.
  8. ↑ Lensing, P.; Schimke, H.; Klimesch, W.; Pap, V.; Szemes, G.; Klingler, D.; Panksepp, J. (1995). "Clinical case report: Opiate antagonist and event-related desynchronization in 2 autistic boys". Neuropsychobiology. 31 (1): 16–23. doi:10.1159/000119167. PMID   7708177.
  9. ↑ Sahley, T. L.; Panksepp, J. (1987). "Brain opioids and autism: An updated analysis of possible linkages". Journal of Autism and Developmental Disorders. 17 (2): 201–216. doi:10.1007/BF01495056. PMID   3038836. S2CID   46566945.
  10. ↑ Bouvard, M. P.; Leboyer, M.; Launay, J. M.; Recasens, C.; Plumet, M. H.; Waller-Perotte, D.; Tabuteau, F.; Bondoux, D.; Dugas, M.; Lensing, P.; Panksepp, J. (1995). "Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: A double-blind, placebo-controlled study". Psychiatry Research. 58 (3): 191–201. doi:10.1016/0165-1781(95)02601-R. PMID   8570775. S2CID   26253683.
  11. ↑ "Social Dysfunction in Autism and Connection with Endogenous Opiads". www.macalester.edu. Archived from the original on 2003-09-24.
  12. ↑ Gillberg, C. (1995). "Endogenous opioids and opiate antagonists in autism: Brief review of empirical findings and implications for clinicians". Developmental Medicine & Child Neurology. 37 (3): 239–245. doi:10.1111/j.1469-8749.1995.tb11998.x. PMID   7890130. S2CID   28604551.
  13. ↑ Hunter, L. C.; O'Hare, A.; Herron, W. J.; Fisher, L. A.; Jones, G. E. (2007). "Opioid peptides and dipeptidyl peptidase in autism". Developmental Medicine & Child Neurology. 45 (2): 121–8. doi:10.1111/j.1469-8749.2003.tb00915.x. PMID   12578238. S2CID   38949901.
  14. ↑ Cass, H.; Gringras, P.; March, J.; McKendrick, I.; O'Hare, A. E.; Owen, L.; Pollin, C. (2008). "Absence of urinary opioid peptides in children with autism". Archives of Disease in Childhood. 93 (9): 745–750. doi: 10.1136/adc.2006.114389 . PMID   18337276.
  15. ↑ Mulloy, Austin; Lang, Russell; O’Reilly, Mark; Sigafoos, Jeff; Lancioni, Giulio; Rispoli, Mandy (July 2010). "Gluten-free and casein-free diets in the treatment of autism spectrum disorders: A systematic review". Research in Autism Spectrum Disorders. 4 (3): 328–339. doi:10.1016/j.rasd.2009.10.008.
  16. ↑ Roy, A; Roy, M; Deb, S; Unwin, G; Roy, A (2014). "Are opioid antagonists effective in attenuating the core symptoms of autism spectrum conditions in children: A systematic review". Journal of Intellectual Disability Research. 59 (4): 293–306. doi:10.1111/jir.12122. PMID   24589346. S2CID   11896817.
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