Autism and the Gluten-Free, Casein-Free diet

By AnthonyLast updated: Wednesday, June 4, 2008 • Save & Share6 Comments

Recently The Daily Mail has reported on the industry that hawks autism “cures” to vulnerable parents. The suppliers of such cures are often critics of MMR vaccine. Edzard Ernst has also noted that providers of alternative medicine are often skeptical of MMR vaccine. Fitting this general pattern, Dr John Briffa is a doctor who has gravitated towards “nutritional and naturally-oriented medicine”, and he is also skeptical of MMR vaccine’s safety. In the past he has written on nutritional approaches to autism. The following is a guest post from Holford Watch.

Autism and the GFCF diet

Despite the lack of supporting evidence, many nutritionists promote the idea that a gluten-free, casein-free diet may benefit children with ASD.

Evidence suggests that autistic children may lack the ability to properly digest dietary proteins such as gluten (found in wheat, oats, rye and barley) and casein (found in dairy products such as milk, cheese and yoghurt). Once absorbed into the body, these partially digested proteins (known as peptides) have the ability to exert effects on the brain similar to opiate drugs such as morphine. There is mounting evidence that the traits of autism may be the result of brain chemistry disruption due to these so-called ‘opioid-like peptides’.

Importantly, studies and reports published in the scientific literature show that a diet free from gluten and casein can be effective in reducing autistic behaviour and improving social and communication skills.

There may be a reason why that series of assertions does not contain any links or references. It is difficult to address all of the canards in this section so we shall highlight some and overlook some glaring questions such as how many children with ASD manifest symptoms that indicate an impaired ability to digest gluten and/or casein.

The idea that some behaviours result from opioid peptides derived from incompletely digested proteins is built on Panksepp’s speculations[1] concerning his observations of rats and their response to morphine.

We have approached the possible neurochemical causes of autism by assuming that the fundamental problem of the autistic child is emotional. Some of the earliest observed symptoms of autism include a lack of crying during infancy, a failure to cling to parents, and a generally low desire for social companionship, which, we believe, shows that the autistic child is constitutionally unable to feel properly the emotions arising from social relationships. Injections of low doses of morphine can generate such behaviour patterns in animals..

The speculation was combined with several other reports and received undue prominence in the Wakefield et al. 1998 paper.[2]

The “opioid excess” theory of autism, put forward first by Panksepp and colleagues[1] and later by Reichelt and colleagues[3] and Shattock and colleagues[4] proposes that autistic disorders result from the incomplete breakdown and excessive absorption of gut-derived peptides from foods, including barley, rye, oats, and caesin from milk and dairy produce. These peptides may exert central-opioid effects…

The typical explanation for the sequence of events is as follows. An insult injures the gut wall. The gut wall becomes ‘leaky’ and there is a general disruption caused by inflammation that also dysregulates the digestion of dietary proteins. These partly-digested proteins are opioid-like; they escape into the blood-stream and are transported across the blood-brain barrier where they intoxicate the brain, resulting in damage that manifests as a spectrum of symptoms labelled ASD.

Thus, the Gluten-Free, Casein-Free (GFCF) diet for children with ASD was born. It is a markedly inconvenient diet to follow for a family that is accustomed to the western diet and one that precludes care-free socialising. Dr James Laidler provides an account of his family’s experience with the GFCF diet and outlines the restrictions and associated difficulties.

So, it’s difficult, but who cares if the evidence shows that it works and that the ideas behind it are sound? Except, almost 30 years later, there is a scarcity of any such evidence in a well-documented, peer-reviewed form.

What about that leaky gut, those compromised intestinal walls that are allowing free passage to these putative opioid peptides? Back in 1996, D’Eufemia et al.[5] reported altered intestinal permeability in 9 out of 20 autistic subjects with no known intestinal disorders as compared with 0 of 40 controls. It was an interesting report and indicated a need for replication to validate or question the findings: it was lent further weight when Horvath and Perman[6] reported an incidence of increased permeability in 19/26 participants in their 2002 study. However, this year, there have been two papers that report small-scale studies, and neither of them support findings of increased gut permeability. Kemperman et al.[7] looked at 23 children with pervasive developmental disorder (PDD) and reported: “[n]one exhibited elevated intestinal permeability”. Robertson et al.[8] scrutinised 14 children with autism and 15 controls and found: “[our] study did not detect differences in these measures of gastrointestinal function in a group of children with autism”.

It is presently difficult to understand why these research groups report such different findings for gut permeability. Confirmation requires a large-scale, multi-centre investigation. So, this might be an open question for now as to whether enhanced gut permeability might be a mechanism for unleashing putative opioid peptides into the bloodsteam where they are transported around to wreak havoc.

Whatever the remaining questions about gut permeability, if researchers assert that these opioid-peptides exist, and they are not akin to sightings of Our Lady of Fatima where only a select, few believers can perceive them, then it should be possible to test for them. Cass et al.[9] performed this testing on the urine of 65 boys with autism and 158 boys without autism. The team used HPLC (high-pressure liquid chromatography) and MALDI-TOF MS (matrix-assisted laser desorbtion ionisation-time of flight mass spectroscopy) that are accepted techniques and should identify opioid peptides, if they are present. They report:

There were no significant differences between the HPLC urinary profiles of the children affected by autism and the typically developing controls. In those cases where HPLC showed peaks in the locations at which opioid peptides might be expected to be found, MALDI-TOF established that these peaks did not, in fact, represent opioid peptides at all…
Given the lack of evidence for any opioid peptiduria in children with autism it can neither serve as a biomedical marker for autism, nor be employed to predict or monitor response to a casein and gluten exclusion diet.

Cass et al. confirmed the earlier, small-scale findings of Hunter et al.[10] who had failed to find urinary opioid peptides in a sample of children with ASD and their siblings. There have been refinements of analysis techniques since the early 1980s and these latest results suggest that Karl Reichelt and his colleagues may not have identified opioid peptides in the urine of children diagnosed with autism.

Opioid peptides do not exist in the urine of the children tested in these recent studies. Ignoring the issue that this is one of the primary justifications for the GFCF diet, and overlooking the claim for “mounting evidence”, shouldn’t it be possible to argue that tests and numbers pale into insignificance when weighed against clinical findings that the GFCF diet works to alleviate particular symptoms and behaviours for people with ASD?

Unfortunately, the clinical evidence is not there. Several groups of researchers have assessed the GFCF diet: some because they are looking to reduce the production of opioid peptides from incompletely digested gluten and/or casein; others because they believe that some children and adults with autism are especially sensitive to gluten and casein.

Millward et al. recently updated the Cochrane Report: Gluten- and casein-free diets for autistic spectrum disorder (Review).[11] Although the reviewers identified more than 30 papers in the scientific literature, only 2 studies met the criteria for inclusion in the review (pg. 11 details why the other papers were excluded). The two studies reported on different outcomes so it wasn’t practical to perform a meta-analysis on the results (and n=35).

Reichelt was an investigator for the Knivsberg et al.[12], [13] studies and the presence of an abnormal pattern of urinary peptides was a pre-requisite for inclusion in the trial. Knivsberg et al. assessed a number of outcomes and reported a positive benefit for the GFCF diet for several of them, e.g., ‘reducing autistic traits’. Elder et al 2006[14] report the results of a cross-over small-scale pilot trial but did not find any significant difference in the outcomes for the intervention and control groups. Overall, in the plain language summary[11] (pg. 2), the Cochrane reviewers conclude:

there is a lack of evidence to support the use of gluten and/or casein free diet as an effective intervention for persons with autism and also a lack of research on potential harms and disbenefits of such diets. Despite the problems of maintaining the integrity of such diets in the community it is possible to carry out randomised control trials to address these questions and more and adequately powered trials are needed in this area.

Investigators such as Hanson et al.[15] have surveyed parents of children with ASD and they report high levels of use for complementary and alternative therapies that include dietary supplements and restrictive diets. Wong and Smith[16] also reported a high rate of gluten or casein free diets in their study of families with a child with ASD.

GFCF diets can be both expensive and restrictive. For families who are accustomed to a western diet, the GFCF diet is difficult to enforce and requires careful monitoring if it is adopted for extended periods of time if adequate calorie intake is to be maintained as well as essential micro-nutrients such as calcium.

Some nutritionists might wish to persuade parents of children with ASD that there is strong scientific support for their dietary and other recommendations; however, there is no unequivocal support or even a preponderance of persuasive evidence of acceptable quality. Despite the claims for “mounting evidence”, there are substantial reasons to question both the leaky gut and opioid peptide hypotheses that underpin the GFCF diet for ASD. Similarly, despite assertions to the contrary, there is no substantial clinical support for the value of a GFCF diet in “reducing autistic behaviour and improving social and communication skills”.


[1] Panksepp J. A neurochemical theory of autism. Trends Neurosci 1979; 2: 174-77.
[2] Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998 Feb 28;351(9103):637-41.
[3] Reichelt KL, Hole K, Hamberger A, Saelid G, Edminson PD, Braestrup CB, Lingjaerde O, Ledaal P, Orbeck H. Biologically active peptide-containing fractions in schizophrenia and childhood autism. Adv Biochem Psychopharmacol. 1981;28:627-43.
[4] Shattock P, Kennedy A, Rowell F, Berney TP. Role of neuropeptides in autism and their relationships with classical neurotransmitters. Brain Dysfunction 1991; 3: 328-45. [as cited in [2]]
[5] D’Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagnini M, Cardi E, Giardini O. Abnormal intestinal permeability in children with autism.
Acta Paediatr. 1996 Sep;85(9):1076-9.
[6] Horvath K, Perman JA. Autism and gastrointestinal symptoms. Curr Gastroenterol Rep. 2002 Jun;4(3):251-8.
[7] Kemperman RF, Muskiet FD, Boutier AI, Kema IP, Muskiet FA. Brief report: normal intestinal permeability at elevated platelet serotonin levels in a subgroup of children with pervasive developmental disorders in Curaçao (The Netherlands antilles). J Autism Dev Disord. 2008 Feb;38(2):401-6
[8] Robertson MA, Sigalet DL, Holst JJ, Meddings JB, Wood J, Sharkey KA. Intestinal Permeability and Glucagon-like peptide-2 in Children with Autism: A Controlled Pilot Study. J Autism Dev Disord. 2008 Feb 29.
[9] 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.
[10] 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.
[11] Millward C, Ferriter M, Calver S, Connell-Jones G. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD003498. DOI: 10.1002/14651858.CD003498.pub3. pdf or PubMed abstract.
[12] Knivsberg A-M, Reichelt KL, Høien T, Nødland M. A randomised, controlled study of dietary intervention in autistic syndromes. Nutritional Neuroscience 2002;5(4):251–61.
[13] Knivsberg A-M, Reichelt KL, Høien T, Nødland M. Effect of dietary intervention on autistic behavior. Focus on Autism and Other Developmental Disablities 2003;18(4):247–56. [from [ref 11]]
[14] Elder JH, Shankar M, Shuster J, Theriaque D, Burns S, Sherrill L. The gluten-free, casein-free diet in autism: results of a preliminary double blind clinical trial. J Autism Dev Disord. 2006 Apr;36(3):413-20.
[15] Hanson E, Kalish LA, Bunce E, Curtis C, McDaniel S, Ware J, Petry J. Use of complementary and alternative medicine among children diagnosed with autism spectrum disorder. J Autism Dev Disord. 2007 Apr;37(4):628-36.
[16] Wong HH, Smith RG. Patterns of complementary and alternative medical therapy use in children diagnosed with autism spectrum disorders. J Autism Dev Disord. 2006 Oct;36(7):901-9.

Filed in Autism, MMR, Science

6 Responses to “Autism and the Gluten-Free, Casein-Free diet”

Comment from mike stanton
Time 4/6/2008 at 8:30 pm

An excellent summary. The diet does attract a lot of interest from families. In an NAS survey even parents whose child did not display any symptoms of gut disorders had tried it. And it topped their list for further research. So a large scale definitive study would be useful.

Comment from Jennifer
Time 5/6/2008 at 3:35 am

An excellent summary. One additional point is important, I think. Parents often test for opioid peptides (even though, as you point out, those tests are now known to be meaningless). However, there are lots of other reasons children might benefit from a “GF/CF” diet. They might have lactose intolerance, they might have a conventional allergy to either milk or wheat. All are very common in children, but parents are not encouraged to do those tests. Such a child would feel physically better once milk and or wheat was removed from their diet. And it is much simpler to simply remove lactose from a child’s diet than to go fully GF/CF.

My belief is that parents are not encouraged to do this conventional medical testing because it would be clear that the special diet was not a direct treatment for autism. And the DAN! doctors recommending this testing are supposed to treat autism, not lactose intolerance.

Comment from dvnutrix
Time 5/6/2008 at 11:05 am

Mike, I’m constantly surprised at the number of people who claim to eliminate wheat and dairy or gluten and casein, “just in case and it has to be better for everyone to lower the number of allergens in their life”. It’s good to have UK figures for the number of parents who have tried some form of the GFCF diet, even in the absence of GI indications.

Jennifer, I agree that it would be more straightforward for parents to request testing for lactose intolerance via the hydrogen breath test etc.: it is very unhelpful if they are dissuaded from these in favour of hunting for opioid peptides in the urine.

I have no idea what techniques are used by the ‘diagnostic labs’ that DAN! doctors recommend. However, it would be disappointing if they are relying solely upon UV chromatography. Both Cass et al. and Hunter et al. papers are persuasive on the point that this is wholly inadequate as a stand alone technique for identifying the presence of specific opioid peptides. It is not even entirely clear what reference samples of synthetic opioid peptides earlier researchers used to calibrate their machine by spiking control samples so that they would know that they could identify what they thought they were identifying.

Do you have any idea how DAN! doctors are still persuading parents that urinary opioid peptides:
i) exist as advertised
ii) can be detected by their labs
iii) have any relevance as a biomarker for ASD?

Comment from Jennifer
Time 5/6/2008 at 12:52 pm

dvnutrix said: “Do you have any idea how DAN! doctors are still persuading parents that urinary opioid peptides:
i) exist as advertised
ii) can be detected by their labs
iii) have any relevance as a biomarker for ASD?”

The doctors simply ignore the more recent science, and continue to espouse the theory that opioid peptides leak from the gut to make the child appear “stoned”. It’s a plausible theory for parents, and it offers hope of treating a core symptom of autism, not just a simple health issue.

If you look at these papers, there are hundreds of chromatographic peaks detected. It’s easy to attribute one or more to opioid peptides even if you don’t really know this.

Comment from jdc
Time 5/6/2008 at 3:57 pm

The section in the Cochrane review on the Knivsberg and Elder results [pp 7-9 of the PDF] is interesting – of all the results, only Knivsberg shows results that favour the intervention group and then only for autistic trait and social isolation scores (and overall ability to communicate and interact). The other results (including those for Communication and linguistic ability, Cognitive functioning and Motor problems) are variously described as ‘no significant difference’, ‘results not statistically significant’ or ‘mean difference not reported as data skewed’. The comment on the individual patient scores from Knivberg was also of interest: “[the authors wanted to] subtract the baseline score from the end of trial score for each individual patient and calculate the mean and standard deviation for each arm of the trial from this. However, in all cases the data could not be used because it was skewed.” Helpfully, the authors even define ‘skewdness’ for us [when the mean is less than twice the standard deviation]. I like the completeness of Cochrane reviews.

Comment from dvnutrix
Time 6/6/2008 at 11:21 am

I like the completeness of Cochrane reviews.

They are so helpful like that, aren’t they. Which is why it is more than irritating when people like Visiting Professor Patrick Holford claim that reviewers arbitrarily leave out studies ‘they don’t like’ and only include ones ‘they like’.

Knivsberg is very interesting in several ways. The Cochrane was updated before the Cass et al. was published, which raises the interesting question of how the Knivsberg will be handled in the next update, given that the presence of an abnormal pattern of urinary peptides was a pre-requisite for inclusion in the trial.