Evolutionary Psychiatry

The hunt for evolutionary solutions to contemporary mental health problems.

Diet and Autism - Newer Studies and Intriguing Links

The real data linking gluten and casein to autism

In my first post on diet and autism, we discussed how gluten-free casein-free (casein is a protein found in cow's milk) diets for treatment of autism had insufficient evidence to recommend them as a standard treatment. However, some new evidence has come out in the last year, with some intriguing biologic findings, which may lead future research in dietary directions.  

So why are researchers (and celebrities) stuck on gluten-free, casein-free diets to treat autism? The whole idea is based on the idea that the exorphins (these are dietary opiate fragments - yes, opiate as in morphine or heroin) found in gluten and casein somehow cause or exacerbate the neurological issues in autism spectrum disorders (ASDs). Also, it is well documented that kids with ASDs seem to have more gut and dietary issues than other kids, so a dietary culprit was an obvious place to look.

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A weakness to these theories is that we have been eating gluten and casein for a long time (the beta casein A1 is found in about 50% of cows of European descent, which are also the cows who make American, Australian, and New Zealand milk at least), and the autism rates have been (possibly) escalating only recently. Or have they?

Back in 2003, the Journal of the American Medical Association released a study and editorial (the link is to the full text, which is worth a read) on the rates of autism. At the time, most studies were showing that rates were somewhere around 1 per 1,000 children. Since previous studies (from the 60s and 70s) usually estimated around 4-5 per 10,000 children, that means a doubling of prevalence from the 1970s to the 1990s and early 2000s. (There are many issues with trying to put a reliable number together - the main issue being that the definition for autism spectrum disorders widened considerably between 1960 and 1990, which could certainly explain an increase in prevalence in studies without an actual increase in prevalence in the population).

Since 2003, a number of very large survey studies were done, including 78,000 parents in the National Children's Health Study (1), and another multi-site study in the Autism and Developmental Disabilities Monitoring (ADDM) Network (2). These were all big news in 2009, as several of these studies came out at the same time, and the rate had jumped to approximately 110 per 10,000 children. Here is a quote from the second study ("ASDs" are autism spectrum diseases):

"Approximate range: 1:80--1:240 children [males: 1:70; females: 1:315]. The average prevalence of ASDs identified among children aged 8 years increased 57% in 10 sites from the 2002 to the 2006 ADDM surveillance year. Although improved ascertainment accounts for some of the prevalence increases documented in the ADDM sites, a true increase in the risk for children to develop ASD symptoms cannot be ruled out. On average, although delays in identification persisted, ASDs were being diagnosed by community professionals at earlier ages in 2006 than in 2002."

The data points to a 57% increase in autism spectrum disorders in a mere four years! That sounds really, really bad. However, much of this increase was felt to be due to increased awareness, and recognition that early intervention and treatment could help kids with ASDs, so kids were being diagnosed earlier, and the diagnosis would be made more readily so kids could be eligible for early intervention services. In fact, the latest studies may be the ones that actually have a more realistic estimate of the number of kids affected, and previous studies grossly underestimated the number of cases.

In my opinion, the best evidence that autism may not be increasing at all is a report from the Adult Psychiatric Morbidity Study from the UK in 2007 (3). They found that approximately 1% of adults living in households have symptoms consistent with ASDs. Since that is pretty close to the 110 per 10,000 number we have for today's children, it suggests that the enormous increase in diagnosis in kids may be due to increased outreach and widening of diagnostic categories. However, it must be said that a more recent increase can't entirely be ruled out.

In any event - that means that we don't necessarily have to look for something brand new or rapidly changing in our society to explain the increase (especially something that might have changed rapidly in the early 21st century). We can take a broader view. So back to gluten and casein and those pesky exorphins.

There are a couple of interesting tidbits to keep in mind. Really, the theorized mechanism of wheat and casein exorphins causing neurotoxic events that are expressed as our brains develop is quite similar to the same theory in schizophrenia. It's probably coincidence, but schizophrenia and autism both affect about 1% of the population and some of the same genetic chromosomal deletion syndromes are implicated in both autism and schizophrenia.

And, frankly, the exorphin question is an easy one to test, at least indirectly. We have naltrexone, after all, a readily available, relatively inexpensive opiate blocker in pill form. Once taken, it will sit on our opiate receptors like a lock on a door, blocking exorphins from casein and gluten just as readily as heroin or morphine, and keep the opiates from activating our opiate receptors. So if dietary exorphins worsen autism in those of us with vulnerable phenotypes, naltrexone should help.

Fortunately, there are several studies of naltrexone and autism (4)(5)(6). And, overall, the studies lean towards naltrexone being a useful treatment for some kids. It seems most effective in decreasing self-injurious behavior (interesting in light of the findings I wrote about in this post on my other blog, linking alterations in the opiate symptoms and self-injurious behavior), such as self-picking, finger-biting, and head-banging. It also seems to help some kids with improved attention and eye contact, hyperactivity, agitation, stereotyped behaviors, social withdrawal, and temper tantrums. (Naltrexone is not FDA approved for use in autistic disorder in kids, but due to the limitations of therapeutic alternatives, it is mentioned often in review papers as a useful medicine that might be worth giving a try).  It would be interesting to see if children who benefited from naltrexone would be part of a likely subset of autistic kids who might benefit from a gluten-free, casein-free diet, but to my knowledge, that study hasn't been done.  

Does that mean that dietary exorphins are definitely the cause of the problem, or at least piece of the cause? Not so fast. The whole reason scientists studied naltrexone in autism in the first place had nothing to do with wheat or casein. Turns out a paper in 1979 hypothesized a link between internal derangements in the opiate systems of autistic children and the symptoms of autism, and later naltrexone studies showed that some kids with autism seem to produce an excess of beta-endorphin (our own, natural opiates). Theory goes like this - flooding the immature brains of kids with beta-endorphins may delay or hamper maturation in some way, causing the brains of autistic kids to stay in an infantile stage of development, particularly with regards to social interaction and sensory response. Kids who responded best to naltrexone had the biggest decreases in the amount of their own beta-endorphins.

All right, let's bring it all together. A large subset of autistic kids seem to have leaky guts ( it is important to remember there was no robust link between the amount of leakiness in the gut and either positive celiac markers, thus a high risk of having celiac disease, OR gastrointestinal symptoms such as diarrhea, bloating, or abdominal pain - you can't tell if a kid has a leaky gut by using GI symptoms or celiac disease as your criteria - you have to measure the actual leakiness specifically!). Another subset of autistic kids have elevated levels of their own natural beta-endorphins and seem responsive to an opiate blocker, naltrexone. Gluten and casein have exorphins (opiates) which can hypothetically wriggle through that leaky gut and may have an effect on the central nervous system.

There, finally, a plausible link between gluten, casein, and autism! Not as necessarily a cause, but perhaps as an exacerbating factor, with scientific data suggesting that gluten-free, casein-free diets might indeed be helpful for a subset of kids. But, before April 2010, the dietary studies just weren't done very well. They were too small, not randomized, and the diagnostic criteria for entering the study weren't standard. Enter the ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Published in Nutritional Neuroscience in April 2010, this study combined a lot of nice features and was in fact designed to address the serious limitations of the previous studies. It had a decent sample size - 72 Danish kids with ASDs (established by standard diagnostic criteria), and it was long - two years. It had a sort of modified cross-over design. It was honest about being single blind - meaning the researchers (except the nutritionists) didn't know which kids were getting the special diets, but the parents (of course) knew. The kids' urine was tested for any abnormal metabolic byproducts.

Here's what the researchers did - for the first year, they put about half the kids on a gluten-free, casein-free diet and monitored their progress for 8 months. If the improvements in the kids on the diet were significantly better than the kids off the diet, they would extend the trial and put everyone on the GF-CF diet at 12 months, and monitor them for a total of 24 months (this is what happened in the actual trial - there was significant improvement in the study diet kids, and a worsening in the kids on the standard diet, so everyone was put on the study diet for the last 12 months). The researches used a battery of different tests, measuring a bunch of different subsets of autistic behaviors and ADHD symptoms at points along the trial. The results?

"Introducing a gluten-free, casein-free diet had a significant beneficial group effect at 8, 12, and 24 months of intervention on core autistic and related behaviors..." The improvement was less dramatic after the first 8 months, and could represent a plateau effect. Attentional and communication symptoms seemed to improve the most. About half the kids dropped out in the second year, perhaps the kids that didn't benefit. The researchers note that there aren't long-term safety studies of gluten-free casein-free diets in kids, and that a knowledgeable nutritionist should be consulted.

Whew.  Beyond all the theory and speculation, finally, solid evidence that there most likely is a subset of kids with autistic spectrum disorders who will benefit from a gluten-free, casein-free diet.

One last little thing. The leaky gut study I wrote about extensively in my first post on diet and autism had a very interesting component I didn't mention then.  A few of the kids in that study, turns out, were already on a gluten-free, casein-free diet. The leakiness of the gut was measured via the IPT test - two sugars, lactulose and mannitol, are given orally to fasting kids, and their urine is collected for the next five hours. Mannitol is small and absorbed via the cells of the gut, and the amount absorbed reflects the "absorptive capacity of the gut." Lactulose is too large to be absorbed directly by the cells, so it has to squeeze in between the cells.  If a lot of lactulose can squeeze through, the gut is "leaky" and the ratio of lactulose to mannitol in the excreted urine goes way up. A "normal" ratio is less than 0.03, and the higher the number is, the more leaky the gut is. I really like the idea of this test for gut leakiness - it is literally a molecular sieve.  

The control kids in that study had ratio average of 0.023, which means that the average child without autism in that study did not have a leaky gut.  Among the autistic kids, the ratio was an average of 0.041, meaning, on average, kids with autism had a leakier gut than the kids without autism.  However, in the autistic kids who were on the gluten-free, casein free diet, the ratio was less than 0.02 (notice then these kids had gut leakiness less than the average of the control children without autism!).  Even more interestingly, when only data from the autistic kids not on the special diet was used, the average ratio jumped up to approximately 0.055.  To be perfectly fair, there were only a few children on the gluten-free, casein-free diet, and as far as I know, no control children on the gluten-free, casein-free diet, so this data should be viewed with interest, but is not enough by any means to convict gluten and casein in causing gut leakiness.

The take-away point? Once again, I think there is enough scientific evidence to suggest that some kids with autism spectrum disorders will, in fact, benefit from a gluten-free, casein-free diet, and while it is no cure and may not be a part of the original cause (some known teratogens that cause autism seem to work at around 8 weeks gestation (7)), it may be worth a try. It shouldn't be attempted without some professional nutritional advice, especially in a picky kid. And it's clearly no holy grail.

More posts on autism and vitamin D, autism and energy efficiency, and an intriguing trial of ketogenic diets for treatment of autism coming soon!

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Copyright Emily Deans, MD

Emily Deans, M.D., is a psychiatrist with a practice in Massachusetts.

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