Thursday, September 9, 2010

Diet and Autism 2

One of the questions that came up in the comments on my first post of the series was 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 (dietary opiate proteins) 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.

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, JAMA released a study and editorial 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- I recommend you read the editorial I linked as it seems to be a very fair presentation of the data - 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).   Then a number of very large survey studies were done in 2006-2009, 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 last year, as several of these studies came out at the same time, and the rate had jumped to approximately 110 per 10,000 children.  I'll let the second study speak for itself at this point:

"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."

A 57% increase in 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 1 in 110 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, 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 spanking new or rapidly changing in our society to explain the increase.  We can take a broader view.  So back to gluten and casein and those pesky exorphins. 

Couple of interesting tidbits.  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.  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, linking alterations in the opiate symptoms and self-injurious behavior), like 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).

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 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 (remember - no robust link between the amount of leakiness in the gut and either positive celiac markers OR gastrointestinal symptoms such as diarrhea, bloating, or abdominal pain - you can't tell if a kid has a leaky gut using these kinds of criteria or tests!).  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, and certainly not a cure, but perhaps as an exacerbating factor.  But, before April 2010, the dietary studies were crap.  And too small.  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.  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.


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.  Some 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, and if a lot 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.  Control kids in that study had ratio average of 0.023.  In the autistic kids overall, the ratio was an average of 0.041.  But in the autistic kids who were on the gluten-free, casein free diet, the ratio was less than 0.02, and when only data from the autistic kids not on the special diet was used, the average ratio jumped up to approximately 0.055.   And, once again, the leakiness measured in these kids had no relation to GI symptoms or positive celiac marker testing.

The take-away point?  Once again, I think there is enough scientific evidence to suggest that some kids with ASDs 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.

Another point - gluten is (once again) creepy.  Gliadin and zonulin do not a good combination make.  No one wants a leaky gut.  Just something to think about.


  1. Emily,

    You probably know the works of Dr. Jaquelyn McCandless, who treats autisc children with gluten-free, casein-free diet and LDN (low dose naltrexone). Don't you?

  2. Thank you - highly informative, and nicely written!

  3. Mario - As an adult outpatient psychiatrist, I am not on the forefront of autism research, nor does it arrive in my mailbox too often, so I'd never heard of Dr. McCandless. However, her work sounds very interesting! Thanks for the link. I've always used low dose naltrexone in adults - 50mg daily is typical. Side effects seem to be minimal. You're supposed to check liver function tests (which I do), but I've never seen them elevated on naltrexone.

    Leon - thanks! I've dabbled in actual writing now and again, but the lack of college English courses (I clepped out of them...) I fear might show up with these blog posts. First drafts, often composed with a 3 year old pulling on one arm while the 16 month old is causing some destruction in the next room. Can be distracting. I'm amazed I get a cogent thought out sometimes. Such is blogging!

  4. Emily,

    Sorry, but low dose naltrexone does not mean the minimal dose (50mg) used in psychiatry. LDN means a small dose from 1.5mg to 4.5mg (adults), and is used to help with autoimmune diseases, AIDS, cancer, autism, among others diseases.

    A small excerpt from of how it works:

    "The brief blockade of opioid receptors between 2 a.m. and 4 a.m. that is caused by taking LDN at bedtime each night is believed to produce a prolonged up-regulation of vital elements of the immune system by causing an increase in endorphin and enkephalin production. Normal volunteers who have taken LDN in this fashion have been found to have much higher levels of beta-endorphins circulating in their blood in the following days. Animal research by I. Zagon, PhD, and his colleagues has shown a marked increase in metenkephalin levels as well."

  5. Mario - one of the studies I read was "Low-dose natlrexone effects on plasma chemistries and clinical symptoms in autism; a double-blind placebo-controlled study" and the dose was 0.5mg per kg per day in kids, and on the site you linked I saw the first discussion talked about the studies with 5mg to 50mg naltrexone in children daily or every other day. I see now, looking farther down the 4.5mg transdermal doses. Interesting.


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