Opioids in the diet, absorption and effect in autism

Introduction

The work of Reichelt suggested that there was an absorption of opioid compounds from the gut in autism. The indication was that these would then cause damage to the activity of the brain, and potentially to its long term structure. He showed them to be derived from gliadin and casein and he could demonstrate them to be present in the urine. He also put forward that the same effect may be concerned with schitzophrenia. This was at a time when no demonstration had been made of non-specific uptake of compounds and no ‘leaky gut’ had been suggested and demonstrated by D’Euphemia et al.

Problems have appeared with many factors but it still remains a major potential explanation of certain aspects of the pathology of the condition. What is not realised is that many other compounds with endorphin activity that may also have neurological activity may also be being absorbed.

Opioids in diet and being absorbed from the gut
Opioid toxicity
Diet modification as treatment
Anti-opioids as treatment
Endorphins in autism

Discussion: are opioids in diet significant?

So far it seems that the opioid peptides that we can show in the diet, do not appear in the urine or in the blood in adequate amounts to be measured. However, changes in the diet seem to show an advantage (although more research would be useful) in some cases, and naltrexone does seem to be an advantage. It is as if Reichelt may have been right to some degree but pathology mechanisms have not been demonstrated.

Sites at which morphine interacts with brain tissue. Red>yellow>green>blue. Positron emission tomography scanning

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Opioid peptides (exorphins) being absorbed from the gut

Originally Reichelt’s work showing the opioid peptides (beta-caseomophine and beta-endorphins) involved the demonstration of the beta-encephalins in urine. In the end it appears that specific peptides that were being sought simply were not present (Hunter et al). However, there did seem to be an excess of peptides, many of which were not understood or identified. So currently this is complex. One factor that is difficult is that some opioids can be in exceptionally small quantities and yet have activity.

Dettmer K, Hanna D, Whetstone P, Hansen R, Hammock BD. Autism and urinary exogenous neuropeptides: development of an on-line SPE-HPLC-tandem mass spectrometry method to test the opioid excess theory. Anal Bioanal Chem. 2007 Aug;388(8):1643-51. They did not find one.

Cass H, Gringras P, March J, McKendrick I, O'Hare AE, Owen L, Pollin C. Absence of urinary opioid peptides in children with Autism. Arch Dis Child. 2008 Mar 12. (they found none…but they were looking for very specific pepetides and hence it is difficult to know that there were none that were simply none the ones they were looking for or were modified!)

Reichelt et al., Biologically active peptide-containing fractions in schizophrenia and childhood autism. Adv Biochem Psychopharmacol. 1981;28:627-43. Review. (yes)

Reichelt KL, Knivsberg AM. Can the pathophysiology of autism be explained by the nature of the discovered urine peptides? Nutr Neurosci. 2003 Feb;6(1):19-28. Review

Hunter LC, O’Hare A, Herron WJ, Fisher LA, Jones GE. Opioid peptides and dipeptidyl peptidase in autism. Dev Med Child Neurol. 2003 Feb;45(2):121-8. (Not found in either the urine or the plasma of either the ASMs or their siblings)

Sponheim E, Myhre AM, Reichelt KL, Aalen OO. [Urine peptide patterns in children with milder types of autism] Tidsskr Nor Laegeforen. 2006 May 25;126(11):1475-7. (no difference found in peptides between autistics and controls)

Le Couteur A, Trygstad O, Evered C, Gillberg C, Rutter M. Infantile autism and urinary excretion of peptides and protein-associated peptide complexes. J Autism Dev Disord. 1988 Jun;18(2):181-90. Sixty-nine early morning urine samples obtained from three groups of young adult males (autistic, mentally handicapped, and a group of men of normal intelligence) were analyzed using the methods described by Trygstad et al. (1980). No consistent patterns of urinary chromatographic profiles were identified. A number of possible contributing factors are discussed in relation to this failure to replicate the results of previous studies.

Hunter LC, O’Hare A, Herron WJ, Fisher LA, Jones G. Opioid peptides and dipeptidyl peptidase in autism. Dev Med and Child Neurol. 2003;45:121-8 (Could not find any excess opioid in plasma of autistic children but the CD26/dipeptidyl peptidase antigen was low indicating that T cells were low. They use MS to look for very specific compounds that they consider to be the opioids)

Zioudrou C, Streaty RA, Klee WA. Opioid peptides derived from food proteins. The exorphins. J Biol Chem. 1979 Apr 10;254(7):2446-9. (also see other work by Zioudrou about food derived opioids).

Lottspeich F, Henschen A, Brantl V, Teschemacher H. Novel opioid peptides derived from casein (beta-casomorphins). III. Synthetic peptides corresponding to components from bovine casein peptone. Hoppe Seylers Z Physiol Chem. 1980 Dec;361(12):1835-9

Brantl V, Teschemacher H, Bläsig J, Henschen A, Lottspeich F. Opioid activities of beta-casomorphins. Life Sci. 1981 Apr 27;28(17):1903-9. (however they could not find any opioid from milk in the blood of normal humans after digesting a large amount of milk)

Nyberg F, Sanderson K, Glamsta E-L. The haemophins: a new clas of opioid peptides derived from the blood protein hemoglobin. Biopoly 1997;43:147-156. Just to show that there are opioid peptides from many sources!

Ashkenazi A, Levin S, Krasilowsky D. Gluten and autism. Lancet. 1980 Jan 19;1(8160):157. (I cannot get hold of a copy currently but this is well before others suggesting it)

The researchers were hoping to find that the body tried to produce antibodies against opioids…but this was more complex than they expected, with some serum being less active than expected. They suggested that the antibodies were ‘used up’ i.e. the reason that the levels were low was because they were interacting with the absorbed dietary peptides and hence their test would not work. The toxicity in the brain was put forward to be due to interaction of the endorphins with encephalin stimulating sites. It should be realised that opioid peptides have many activities outside the brain e.g. see Zagon below.

Leboyer M, Bouvard MP, Recasens C, Philippe A, Guilloud-Bataille M, Bondoux D, Tabuteau F, Dugas M, Panksepp J, Launay JM, et al. Difference between plasma N- and C-terminally directed beta-endorphin immunoreactivity in infantile autism. Am J Psychiatry. 1994 Dec;151(12):1797-801. Median N-terminally directed beta-endorphin immunoreactivity appeared to be slightly lower in subjects with autism (7 pg/ml) and clearly higher in the girls with Rett’s syndrome (40 pg/ml) than in the comparison subjects (9 pg/ml). Median C-terminally directed beta-endorphin immunoreactivity was higher in the girls with Rett’s syndrome (35 pg/ml) and much higher in patients with autism (70 pg/ml) than in comparison subjects (8 pg/ml).

Shattock P, Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83. (explanation of how changing of the diet and the absorption would be expected to change the autistic symptoms. As such it was not that surprising that secretin may have an effect

Tordjman S, Anderson GM, McBride PA, Hertzig ME, Snow ME, Hall LM, Thompson SM, Ferrari P, Cohen DJ. Plasma beta-endorphin, adrenocorticotropin hormone, and cortisol in autism. J Child Psychol Psychiatry. 1997 Sep;38(6):705-15. Higher serum endorphin and ACTH taken by authors to be due to stress responses. Comparison of log transformed data from the three groups revealed that levels of BE and ACTH were significantly higher (p < .05) in the autistic individuals than in normal controls.

McCarthy DM, Coleman M. Response of intestinal mucosa to gluten challenge in autistic subjects. Lancet. 1979 Oct 27;2(8148):877-8. (no gut problems were seen as gut habit, or weight loss in children fed gluten)

Peterson PK, Molitor TW, Chao CC. The opioid-cytokine connection. J Neuroimmunol. 1998 Mar 15;83(1-2):63-9. (as part of an attempt to describe how opioids might affect the immune system in autism; Because the CNS is populated predominantly by astroglia and microglia which have properties of immune cells, it is possible that certain of the CNS effects of opioids involve cytokine-like interactions with glial cells. Although there is mounting evidence supporting the concept that opioids are members of the cytokine family, the relative contribution of the opioids to immunoregulation remains unclear.)

Zagon IS, Rahn KA, McLaughlin PJ. Opioids and migration, chemotaxis, invasion, and adhesion of human cancer cells. Neuropeptides. 2007 Dec;41(6):441-52. (opioid peptides and receptor interacting with many cell forms. This article also contains a small review)

Zagon IS, McLaughlin PJ. Identification of opioid peptides regulating proliferation of neurons and glia in the developing nervous system. Brain Res. 1991 Mar 1;542(2):318-23

Gluten/Casein free diets

The gluten-free, casein-free (GFCF) diet in autism: results of a preliminary double blind clinical trial were good and useful. The work from Knivsberg et al showed that as the diet (in which all wheat and milk associated food was stopped) continued there was a clinical improvement in the autistic children, but when they stopped the diet, they returned to the position that they were before it started. The Cochrane group could not show that there was not enough data to indicate that the diet procedure worked or did not.

Cade R, Privette M et al. “Autism and Schizophrenia: Intestinal Disorders” Nutr. Neurosci 3 (2000) 57-72. Published by Overseas Publishers Association, (OPA) N.V. Cade found that long-term use of digestive enzymes was beneficial, but that the GFCF diet was even more helpful. Cade’s large study of 150 children with autism found that 87% had IgG antibodies (allergy) to gluten, vs. 1% of the age and gender-matched controls, and 90% had IgG antibodies to casein, vs. 7% of the controls. He also studied 70 autistic children who followed a GFCF diet for 1-8 years, and found that 81% improved significantly by the third month, with improvements continuing over the next 12 months. Large improvements were observed in social isolation, eye contact, mutism, learning skills, hyperactivity, stereotypic activity, and panic attacks. Among the 19% who did not improve, about 1/3 of them were not following the GFCF diet, and had lots of gluten and casein peptides still in their blood.

Single-blind study of 10 children with autism found that 8 benefited from a GFCF diet. Knivsberg AM, Reichelt KL, Hoien T, Nodland M. A randomised, controlled study of dietary intervention in autistic syndromes. Nutr Neurosci. 2002 Sep;5(4):251-61.

Elder et al J Autism Dev Disord. 2006 413-420A 12-week, double-blind, cross-over study…. Of a GFCF diet in 15 children with autism did not find significant benefits, but parents reported benefits that were not identified by the testing.,

Millward C, Ferriter M, Calver S, Connell-Jones G. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev. 2004;(2):CD003498. Review. They admit that there is not enough data at present and ask for good studies. This are article has been repeated in 2008: Millward C, Ferriter M, Calver S, Connell-Jones G. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003498. Again it says that the method is used widely but the data is currently inadequate and asks for good studies.

Lucarelli S, Frediani T, Zingoni AM, Ferruzzi F, Giardini O, Quintieri F, Barbato M, D’Eufemia P, Cardi E. Food allergy and infantile autism. Panminerva Med. 1995 Sep;37(3):137-41. We noticed a marked improvement in the behavioural symptoms of patients after a period of 8 weeks on an elimination diet and we found high levels of IgA antigen specific antibodies for casein, lactalbumin and beta-lactoglobulin and IgG and IgM for casein.

Huebner FR, Lieberman KW, Rubino RP, Wall JS. Demonstration of high opioid-like activity in isolated peptides from wheat gluten hydrolysates. Peptides. 1984 Nov-Dec;5(6):1139-47. (this is one of the first but there have been plenty more individual peptides with a similar effect in blood, milk and bread).

Cazzullo AG, Musetti MC, Musetti L, Bajo S, Sacerdote P, Panerai A. Beta-endorphin levels in peripheral blood mononuclear cells and long-term naltrexone treatment in autistic children. Eur Neuropsychopharmacol. 1999 Jun;9(4):361-6. Decreased the level of beta endorphin, and notably to the author the naltrexone had a remarkable effect. The autistic patients had higher beta endorphin levels than controls.

Potential treatments using specific opioid inhibitors

There are in fact 14 separate trials of naltrexone in autism. This acts as a direct inhibitor of opioids in the brain. They found that there was a reasonable activity and that this was reliable, with the effect disappearing when the drug is stopped.

Ann Pharmacother. 2006 Jun;40(6):1086-95. Epub 2006 May 30. Review. It reported “Naltrexone has been used most commonly at doses ranging from 0.5 to 2 mg/kg/day and found to be predominantly effective in decreasing self-injurious behaviour. Naltrexone may also attenuate hyperactivity, agitation, irritability, temper tantrums, social withdrawal, and stereotyped behaviours. Patients may also exhibit improved attention and eye contact. Transient sedation was the most commonly reported adverse event.” (There have been 14 clinical trials of naltrexone for children with autism but mostly it was a case of modifying personality and with low toxicity)

Scifo R, Cioni M, Nicolosi A, Batticane N, Tirolo C, Testa N, Quattropani MC, Morale MC, Gallo F, Marchetti B. Opioid-immune interactions in autism: behavioural and immunological assessment during a double-blind treatment with naltrexone. Ann Ist Super Sanita. 1996;32(3):351-9 The behavioural improvement (naltrexone) was accompanied by alterations in the distribution of the major lymphocyte subsets, with a significant increase of the T-helper-inducers (CD4+CD8-) and a significant reduction of the T-cytotoxic-suppressor (CD4-CD8+) resulting in a normalization of the CD4/CD8 ratio. Changes in natural killer cells and activity were inversely related to plasma beta-endorphin levels.

Endorphins in Autism

Encephalins are the compounds that interact with the opioid receptors within the brain of the normal brain. The question must be whether or not these compounds are in fact modified in autism. Currently there is little data.