Opioid excess theory

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The opioid excess theory 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 In this paper, which has since been retracted, Wakefield et al.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.

Related Research Articles

<span class="mw-page-title-main">Gluten</span> Group of cereal grain proteins

Gluten is a structural protein naturally found in certain cereal grains. The term gluten usually refers to the elastic network of a wheat grain's proteins, gliadin and glutenin primarily, that forms readily with the addition of water and often kneading in the case of bread dough. The types of grains that contain gluten include all species of wheat, and barley, rye, and some cultivars of oat; moreover, cross hybrids of any of these cereal grains also contain gluten, e.g. triticale. Gluten makes up 75–85% of the total protein in bread wheat.

<span class="mw-page-title-main">Asperger syndrome</span> Formerly recognized subtype of autism

Asperger syndrome (AS), also known as Asperger's syndrome or Asperger's, was a diagnosis used to describe a neurodevelopmental disorder characterized by significant difficulties in social interaction and nonverbal communication, along with restricted, repetitive patterns of behavior and interests. Asperger syndrome has been merged with other conditions into autism spectrum disorder (ASD) and is no longer a diagnosis in the WHO's ICD-11 or the APA's DSM-5-TR. It was considered milder than other diagnoses which were merged into ASD due to relatively unimpaired spoken language and intelligence.

<span class="mw-page-title-main">Coeliac disease</span> Autoimmune disorder that results in a reaction to gluten

Coeliac disease or celiac disease is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barley. Classic symptoms include gastrointestinal problems such as chronic diarrhoea, abdominal distention, malabsorption, loss of appetite, and among children failure to grow normally.

<span class="mw-page-title-main">Casein</span> Family of proteins found in milk

Casein is a family of related phosphoproteins that are commonly found in mammalian milk, comprising about 80% of the proteins in cow's milk and between 20% and 60% of the proteins in human milk. Sheep and cow milk have a higher casein content than other types of milk with human milk having a particularly low casein content.

A gluten-free casein-free diet, also known as a gluten-free dairy-free diet, is a diet that does not include gluten, and casein. Despite an absence of scientific evidence, there have been advocates for the use of this diet as a treatment for autism and related conditions.

<span class="mw-page-title-main">Casomorphin</span> Chemical compound

Casomorphin is an opioid peptide derived from the digestion of the milk protein casein.

<span class="mw-page-title-main">Naltrexone</span> Medication

Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol use or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been found effective in the treatment of other addictions and may be used for them off-label. An opioid-dependent person should not receive naltrexone before detoxification. It is taken orally or by injection into a muscle. Effects begin within 30 minutes, though a decreased desire for opioids may take a few weeks to occur.

Gluten exorphins are a group of opioid peptides formed during the digestion of the gluten protein. These peptides work as external regulators for gastrointestinal movement and hormonal release. The breakdown of gliadin, a polymer of wheat proteins, creates amino acids that stop the gluten epitopes from entering the immune system to activate inflammatory reactions. During this process, gluten does not fully break down, thus increasing the presence of gluten exorphins. Because of this, researchers think this is what might lead to various diseases.

<span class="mw-page-title-main">Gliadorphin</span> Chemical compound

Gliadorphin is an opioid peptide that is formed during digestion of the gliadin component of the gluten protein. It is usually broken down into amino acids by digestion enzymes. It has been hypothesized that children with autism have abnormal leakage from the gut of this compound. This is partly the basis for the gluten-free, casein-free diet. Abnormally high levels of gliadorphin have been found in the urine of autistic children via mass spectrometry testing.

<span class="mw-page-title-main">Opioid peptide</span> Class of peptides that bind to opioid receptors

Opioid peptides or opiate peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble those of opiates. Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, control of food intake, and the rewarding effects of alcohol and nicotine.

<span class="mw-page-title-main">Causes of autism</span> Proposed causes of autism

Many causes of autism, including environmental and genetic factors, have been recognized or proposed, but understanding of the theory of causation of autism is incomplete. Attempts have been made to incorporate the known genetic and environmental causes into a comprehensive causative framework. ASD is a neurodevelopmental disorder marked by impairments in communicative ability and social interaction, as well as restricted and repetitive behaviors, interests, or activities not suitable for the individual's developmental stage. The severity of symptoms and functional impairment vary between individuals.

<span class="mw-page-title-main">Autism therapies</span> Therapy aimed at autistic people

Autism therapies include a wide variety of therapies that help people with autism, or their families. Such methods of therapy seek to aid autistic people in dealing with difficulties and increase their functional independence.

<span class="mw-page-title-main">Naltrindole</span> Chemical compound

Naltrindole is a highly potent, highly selective delta opioid receptor antagonist used in biomedical research. In May 2012 a paper was published in Nature with the structure of naltrindole in complex with the mouse δ-opioid G-protein coupled receptor, solved by X-ray crystallography.

<span class="mw-page-title-main">Classic autism</span> Former neurodevelopmental disorder now classified under autism spectrum disorder

Classic autism, also known as childhood autism, autistic disorder, or Kanner's syndrome, is a formerly diagnosed neurodevelopmental disorder first described by Leo Kanner in 1943. It is characterized by atypical and impaired development in social interaction and communication as well as restricted, repetitive behaviors, activities, and interests. These symptoms first appear in early childhood and persist throughout life.

Autism spectrum disorder (ASD), or simply autism, is a neurodevelopmental disorder "characterized by persistent deficits in social communication and social interaction across multiple contexts" and "restricted, repetitive patterns of behavior, interests, or activities". Sensory abnormalities are also included in the diagnostic manuals. Common associated traits such as motor coordination impairment are typical of the condition but not required for diagnosis. A formal diagnosis requires that symptoms cause significant impairment in multiple functional domains; in addition, the symptoms must be atypical or excessive for the person's age and sociocultural context.

<span class="mw-page-title-main">(+)-Naloxone</span> Drug

(+)-Naloxone (dextro-naloxone) is a drug which is the opposite enantiomer of the opioid antagonist drug (−)-naloxone. Unlike (−)-naloxone, (+)-naloxone has no significant affinity for opioid receptors, but instead has been discovered to act as a selective antagonist of Toll-like receptor 4. This receptor is involved in immune system responses, and activation of TLR4 induces glial activation and release of inflammatory mediators such as TNF-α and Interleukin-1.

Exorphins are exogenous opioid peptides, distinguished from endorphins, or endogenous opioid peptides.

Martha Herbert is an American physician and assistant professor of neurology at Harvard Medical School and pediatric neurologist at Massachusetts General Hospital. Herbert is also director of the TRANSCEND program at the Athinoula A. Martinos Center for Biomedical Imaging.

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.

<span class="mw-page-title-main">6β-Naltrexol</span> Chemical compound

6β-Naltrexol, or 6β-hydroxynaltrexone, is a peripherally-selective opioid receptor antagonist related to naltrexone. It is a major active metabolite of naltrexone formed by hepatic dihydrodiol dehydrogenase enzymes. With naltrexone therapy, 6β-naltrexol is present at approximately 10- to 30-fold higher concentrations than naltrexone at steady state due to extensive first-pass metabolism of naltrexone into 6β-naltrexol. In addition to being an active metabolite of naltrexone, 6β-naltrexol was itself studied for the treatment of opioid-induced constipation. It was found to be effective and well-tolerated, and did not precipitate opioid withdrawal symptoms or interfere with opioid pain relief, but development was not further pursued.

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. (Retracted, see doi:10.1016/S0140-6736(10)60175-4, PMID   20137807,  Retraction Watch)
  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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