Wheat and Schizophrenia

Schizophrenia is an unfortunate disease of the brain. A progressive disorder, it often presents with social withdrawal, paranoia, hearing voices, that sort of thing. After quite a while (sometimes decades) you get a kind of "burnout" effect where the voices and whatnot lessen, but the afflicted is left with all the negative symptoms of social withdrawal, thought blocking, and an inexpressiveness known as "flat affect." MRI of the brain will show "large ventricles" at this point, meaning cell death (brain damage) has caused the active, lively part of the brain to shrink. You'll see schizophrenia in any large public park in any major city. If you ask the guy on the bench that everyone is avoiding if he wants something to eat, and he answers with paranoid meaningless word salad, that's schizophrenia, most likely. He had parents, brothers, sisters, maybe even a college degree. Even if he wanted to stay in a treatment facility or group home, in most places there aren't enough spots for all the mentally ill, so many end up homeless or in jail. A tough road for someone with an organic brain disease.

Most of the research on schizophrenia is focused on the neurotransmitters dopamine, acetylcholine, and histamine and genetic polymorphisms of transporters and receptors. The usual questions are asked about ineffective brain chemistry. The usual treatment is neuroleptic medication (hopefully decreases excess dopamine in the right place and leaves it well enough alone in other corners of the brain). And I've seen medicine do a decent job of clearing up the psychosis symptoms many times. Medicine tends to have pretty serious side effects, though, so a big push in research these days is to identify those folks at high risk for schizophrenia before it happens, hopefully to prevent the illness in the first place through various means. Often those means include more medications - but with Big Pharma funding many studies, those are the solutions that are found.



One intrepid researcher, F. Curtis Dohan, spent a lot of his career chasing an unlikely suspect in the pathogenesis of schizophrenia, wheat. His fascinating paper, Genetic Hypothesis of Idiopathic Schizophrenia: It's Exorphin Connection, can be found in free full text via the link.

Anyway, there's a funny thing about schizophrenia, turns out that quite a few of the adult schizophrenics on an inpatient psychiatric unit in 1967 happened to have a major history of celiac disease (gluten/wheat intolerance) as children. As in 50-100 times the amount of celiac disease that one would expect by chance. Celiac doctors also noticed their patients were schizophrenic about 10X as often as the general population. That's a lot! In addition, epidemiological studies of Pacific Islanders and other populations showed a strong, dose-dependent relationship between grain intake and schizophrenia. The gluten-free populations had extremely rare occurrence of schizophrenia - just 2 in 65,000 versus about 1 in 100 as we have in the grain-eating West. When populations Westernized their diets (flour, sugar, and beer), schizophrenia became common. In some clinical trials, gluten made new-onset acutely ill schizophrenics much worse, but only occasional long-term patients responded to gluten restriction. The long-term sufferer has already had a lot of damage - if wheat somehow toxic to the brain, then it would be vital to stop the insult early on in the course of the disease to see improvement.

National Institutes of Health investigators looked for poisonous protein fragments derived from gluten, gliadin (wheat proteins), and casein (a milk protein). They found them - potent opiate (yes, opiate as in morphine. Or heroin) analogs they called "exorphins." Many of these studies were done in rats, and the results are very creepy if you are fond of bread and milk (or rats). Turns out, you take wheat gluten, add stomach enzymes, and you end up with fragments of proteins that are potent opiates (1). The cute thing is these fragments aren't digested by the small intestine and definitely end up in the body and brain of rats that are fed gluten orally. Inject these same proteins directly into the brains of poor unfortunate rats, and you get rat seizures. Interestingly, people with schizophrenia seem to have a lot of these opioid-like small gluten-derived peptides in their urine. Way more than people without schizophrenia.

Let me review what is perhaps the most important part of the Dohan paper - a gluten-free diet definitely improved some of the new-onset schizophrenics on the inpatient unit. Not all of them. But 2 out of 17 or so. Putting back the wheat made the affected a lot worse. In another study, 115 patients on a locked ward were all given a gluten free milk free diet. They were released into the community on average twice as fast as the similar patients on another, diet as usual ward (p=.009). It is of note that repeat studies didn't show the same thing, but instead of 17 or 115 patients, these studies had 4 or 8 patients, and these were studies of people who had schizophrenia for many years, where much damage was already done.

Historically, prior to WWII, when grain consumption was super-high and neuroleptics (those medications, as you recall, which affect brain dopamine levels and are used to treat schizophrenia) did not yet exist, there are reports of schizophrenics having marked and unexplained fluctuations in weight and gut symptoms, poor iron absorption just like celiac sufferers, and "post-mortem abnormalities like those subsequently discovered in celiac patients." Why aren't these found now? Well, Dohan contended that a side effect of these neuroleptic medications is that they decrease the permeability of the gut. Meaning gluten may not be able to weasel through quite so easily.

Which begs the question, is that the side effect? Or perhaps the principle effect? Who knows? Dohan's paper was published in 1988 and ended with some ideas about how to study the question further (such as by feeding identical twins of schizophrenics a high gluten diet to see what happens - somehow I don't think that experimental design would pass an institutional review board nowadays.) Well, nothing much happened research-wise until around 2005, but what has been discovered is interesting. There is no "smoking gun," but there certainly is a lot of smoke.

In Markers of Gluten Sensitivity and Celiac Disease in Recent-Onset Psychosis and Multi-Episode Schizophrenia it was found that individuals with recent-onset psychosis and with multi-episode schizophrenia who have increased antibodies to gliadin may share some immunologic features of celiac disease, but their immune response to gliadin differs from that of celiac disease.

In this very clever work done by Samaroo and Dickerson et al, published as Novel immune response to gluten in individuals with schizophrenia, immune responses and celiac disease biomarkers were tested in schizophrenics. It turns out that schizophrenics tended to have a lot of anti-wheat antibodies floating around in their systems, but these antibodies were nearly entirely different from the ones that people with celiac disease have. That means that the usual test for gluten issues, the tests for celiac, wouldn't come up positive in schizophrenics, even though they have unusual immune reactions to wheat.

In A Case Report of the Resolution of Schizophrenic Symptoms on a Ketogenic Diet, a high fat, low carb, low protein diet (thus very low in wheat) results in the remission of psychotic symptoms in a single case report.