Subject: Summary (Long): Opioids from Gluten
In this file the stuff in Blue are the replies from various list members. The stuff in black is from me. These are pretty much the eMail I got in reply to my post, followed by my responses to the posters. Thanks to everyone for an interesting discussion. -- Steve Holland, M.D.

Hogan posted that the fog of celiacs is due to opioids from gluten. I
wrote Ron, who sent me the citation. The article can be found at
Opioid peptides derived from food proteins. The exorphins.

Problems I have with concluding that any mental obtundation is due to
gluten derived opiates is related to dose issues and habituation to
narcotics. In the article 7 mg of peptides is derived from 50 grams of
gluten. Assuming equal yield in synthesis in the stomach as was
achieved in vitro, and if 10% of the protein makes it through the gut
then you have a 0.7 mg dose reaching the bloodstream. The article used
several measures of milligram potency. The CNS specific assay showed a
potency on the order of Morphine Sulphate. Even 7 mg of MS given over
the course of a few hours is not that much, and less is likely to have
made it into the bloodstream. Additionally, chronic narcotic use
induces tachyphylaxis through up-regulation of the morphine receptors,
so chronic exposure should be tolerated without CNS effects. Given
these issues is it reasonable to infer that patients are affected by
opiate effects?

Any thoughts from the group?

Stephen Holland, M.D.

Replies to the post were very thoughtful:

On Friday, September 26, 2003, at 06:36 PM, Ron Hoggan wrote:


Can we back up just a little bit? I did not post that the fog of celiac
disease is definitely and exclusively due to opioids in gluten. In fact,
here is exactly what I said: "This is likely a factor in why gluten has
repeatedly been shown to impact on brain function, behavior, and on the
immune system." I simply pointed out one weakness in the physician's
assertion that brain fog is not a symptom of celiac disease. There is quite
a difference. I suspect that brain fog is a function of many converging
elements of celiac disease, not the result of a single, isolated factor.

I agree. However I suspect that opioid effects per se have little to do with the "fog" for the reasons listed as well as the reasons in this further discussion. Here the issue is CNS opioid receptor stimulation. What opioid effects there may be in the gut associated lymphoid tissue or the rest of the immune system is another matter.

Secondly, I'm not sure where your 10% absorption rate comes from, but it
does seem very conservative. What basis did you use to formulate your

Morphine sulphate given orally has a 50% bioavailability. It is a small molecule. Most proteins have trace to 0% bioavailability. Gluten, being proline and glutamine rich is not as well digested as other proteins, but I would imagine at least 80% of wheat protein is metabolized. Imagining such a poor digestion of wheat you end up with 20%. If half of it is absorbed into the bloodstream you would have 10% bioavailability. However, peptides will have a lower bioavailability than MS. Celiac patients often have antibodies against gliadin. Since the antibodies are polyclonal the variety of binding sites would have to bind out a portion of the gluten derived proteins. Lastly, serum proteases are numerous and working in concert with each other would not be as specific as the pepsin used in the paper cited, so additional serum losses would diminish the bioavailability further. I thought 10% was generous.

Third, 50 grams also seems a conservative estimate for gluten consumption.

Bread flour is 10-12% protein with other flour types having less wheat. Wheat protein is 80% gluten, for a gluten content then of 8-10%. 50 grams gluten would have to come from 500 grams of flour. Flour has 3.3 calories per gram, so 500 grams of flour would have 1650 calories. That is a lot of wheat a day, so I disagree. 50 grams of gluten is a generous estimate of gluten consumption.

Fourth, tolerance may not be as predictable in the context of the
variability of intestinal permeability that has long been recognized as a
feature of celiac disease.

The above discussion was based on maximal absorptions. If the absorption is variable then absorption would even be less at times, for even less getting into the system. Patients on intermittent narcotics can easily become tolerant of the narcotics. But then the fog seems more related to Celiac disease state rather than getting foggy after eating wheat. Actually, I wish my patients DID get foggy with wheat. At least then they would make a better connection with eating wheat and getting foggy!

Fifth, my name is spelled with a double g (which denotes a Scottish
influence, although the evidence suggests an earlier common Irish

Whoops. Too much watching of Crocodile Dundee movies. ;-)

Finally, since you posted to the list before giving me a chance to respond,
I would appreciate a post from you correcting your overstatement of my
position. I want to avoid debate on the celiac list. It already carries a
heavy volume.

Actually, I wanted education rather than debate. The paper cited about opiod effects is only suggestive. The paper was an in vitro study, so in-vivo follow up is important. For example, have you ever given naloxone to a patient? Issues of pharmacokinetics and pharmacodynamics need evaluation. The paper came up a while ago, so I was hoping there were follow up articles that would appear in the literature.

EMail being what it is I took your comment to be that opiate effect of wheat was one of several established reasons why celiacs get foggy. I don't doubt some celiacs get foggy, but I do doubt it is an opiate effect for the reasons discussed. This is not a small issue, however. If it is an opiate effect then there is an opioid of some type that causes obtundation without tolerance or euphoria. This would be a major find.

On Friday, September 26, 2003, at 10:12 PM, John Maines wrote:

Doctor- In my opinion the dose of opioid absorbed from
a normal breakfast of cereal, milk and toast via a
leaky gut is about the same as clinical dose of oral
opium in a non celiac- about 5mg as I recall-stupor in
about 20 minutes. I learned this from watching my wife
fade away at the breakfast table about seven years ago
before we were aware, at age 73, that most of her
symptoms which we both had attributed to aging were
due to celiac sprue. The swiftness of the response
clinched it for me. Entirely different from the
autoimmune intestinal and (in some people) autoimmune
systemic responses following gluten ingestion from
other sources. A Norwegian MD, Karoly Reichelt has
written extensively and did the original research, or
so I thought until I read Ron Hoggan's response to the
brain fog post last week cited someone else.

I am glad to see you participating as you do in the
daily give and take of this list. I am retired and it
is easy for me. And I enjoy it. Also we both
participate in a local support group. The group
dynamic and the magic of the internet information
explosion adds a whole new slant to the old
doctor-patient relationship. For those who can stand
the gaff. Jack Maines (North Creek NY).

Interesting response. I don't doubt there is a fog. However, I suspect the dosing issue is wrong. Anyone ever give her a dose of naloxone before a meal to see what happens?

Steve Holland

On Friday, September 26, 2003, at 10:36 PM, David Nelsen wrote:

I would hardly jump to causality at this point; Zioudrou, the author of
this very old work seems to have moved to more fertile research grounds
if you look at her publications after the cited one.

I found more recent work from a Japanese shop:


Unique Identifier

Medline Identifier

Yoshikawa M. Takahashi M. Yang S.

Division of Food Science and Biotechnology, Graduate School of
Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan.

Delta opioid peptides derived from plant proteins. [Review] [32 refs]

Current Pharmaceutical Design. 9(16):1325-30, 2003.

Local Messages
Not locally available; ask about Interlibrary Loan

Opioid peptides showing selectivity for delta receptor have been
isolated from enzymatic digests of plant proteins. Five peptides were
derived from wheat gluten, and named gluten exorphins A5, A4, B5, B4 and
C. Two opioid peptides were also released from spinach
ribulose-bisphosphate-carboxylase/oxygenase (Rubisco), and named
rubiscolins-5 and -6. Among them, gluten exorphin 5A
(Gly-Tyr-Tyr-Pro-Thr) and rubiscolin 6 (Tyr-Pro-Leu-Asp-Leu-Phe)
improved learning performance in step-through type passive avoidance
test after post-training oral administration in mice at doses of 300
mg/kg and 100 mg/kg, respectively, which are smaller than those required
for antinociceptive activity. [References: 32]

All the reported AA sequences I saw are different from the sequences
reported to cause the autoimmunity of celiac disease so there'd have to
be independent actions of these peptides, one stimulating the
autoimmunity of CD and one mimicking morphine in the nervous system.

For the so called exorphins to have CNS effects you'd expect that they
would have to--

1--be ingested in the first place (e.g. contaminant or gross gluten

2--escape degradation in the gut (possible, perhaps likely from the
cited work)

3--cross the normally "tight" junctions between the enterocytes
(possible with celiac or other causes of "leaky gut")

4--cross the blood-brain barrier (less likely if this is intact although
other works have demonstrated the affinity for CNS vasculature for
transglutaminase & resultant inflammation which might be present in
celiac patients).

We're only starting to understand the role of neuroregulatory peptides
so it's hard to say what a particular one or group might do from a
clinical perspective.

Although it's certainly possible that the "brain fog" of celiac disease
could be related to this action, it's clear clinically that the "fog"
often persists despite gluten withdrawal from the diet and "healing" of
the gut lesion. Perhaps there are chronic effects of receptor
up-regulation, etc but no science here at all.

Also consider the (many more) patients without demonstrable celiac who
complain of "brain fog", chronic fatigue, etc, etc. Also the presumed
prevalence of "leaky gut" (whatever that is). As an affliction, if it
is one, I'd consider it to be more likely these folks since they
continue to ingest large volumes of the proposed offending protein.

Similarly, you might expect that something like naloxone might alleviate
or at least modulate these symptoms in affected individuals. Lots of
areas ripe for research.

I'm not ready to buy a causal relationship but there are certainly some
interesting coincidences...


I am jumping away from causality on this, but for the reasons in my post
as well as some dosing issues that will come up when I respond to Hoggan's
response in the next digest. My reason for putting up the post was to see
if anyone could trace a research thread. I didn't find anything in a medline search
to suggest follow up work was fruitful. Thanks for checking what Zioudrou did
in followup.

I did read your post, but reread it again for more detail. Interesting points. I missed where you suggested use of naloxone. You clearly know some pharmacology. Hepatic encephalopathy is due to proteinaceous materials that act through the GABA receptor. Besides naloxone which would be relevant if it were an opiate effect, there could be benefit from lactulose or neomycin administration if there is some peptide that is not well cleared by the liver. A bit of a stretch, but more plausible in my mind than opiate effects.


On Saturday, September 27, 2003, at 12:22 AM, Heidi Schuppenhauer wrote:

. Given
these issues is it reasonable to infer that patients are affected by
opiate effects?

Any thoughts from the group?

Stephen Holland, M.D.

I know first hand that gluten kills my brain.
I come from a very Aspergerish family,
and have had problems with it myself, and most of the brain fog
I associated with that disease is gone now IF I keep GF/CF.
I don't know, obviously, if it is REALLY opioid related or not.

There have been a lot of studies about
this related to autistic kids, where they measured the urine output,
so presumably someone has measured the absolute dose? The argument
I heard against the opioid theory in autism was that the
skeptics didn't think it was the last word, because the opioids shouldn't
be getting into the blood or the brain that easily.

So in regards to the brain, I was interested to read a bit about a study
by Dr. Fasano on zonulin. He found (if I read it right) that:

1. Zonulin causes the gut membrane to become more permeable.
2. Zonulin causes the blood/brain barrier to become more permeable.
3. Eating gluten (at least for some people) causes the body to
produce zonulin.

Now if you make the blood/brain barrier more permeable, wouldn't
you get higher doses of all kinds of stuff in your brain? If you give
people a small dose of morphine, does it reach the brain faster if
you give them zonulin too? What chemicals are in the blood that
affect the brain if the person gets zonulin, besides opioids?
What other foods cause the body to produce zonulin, besides gluten?
Why in the world would the body produce a chemical like zonulin

I'd love to hear more about that ...

-- Heidi

I hope the discussion goes that way. Clearly there are people getting foggy on wheat. I doubt it is opioid effects. As you say, there's lots of stuff in the gut that could be important.

Steve Holland
On Saturday, September 27, 2003, at 12:16 PM, Heidi Schuppenhauer wrote:

I hope the discussion goes that way. Clearly there are people getting foggy on wheat. I doubt it is opioid effects. As you say, there's lots of stuff in the gut that could be important.

Steve Holland

Well, I tend to agree for one reason ... I have taken morphine on occasion (medically) and it didn't
feel like "brain fog" (though it felt quite good, actually ...). Also you get used to morphine -- you
(good clinical observation, the stupor having a different character ... [SH])
may have said that. So if you always get x amount of morphine you would get used to it. I never got used to "brain fog". Though it made me a much better computer programmer. Since "healing"
my brain it is much harder to do those all-night intense programming sessions. Someone should take an MRI of someone on a wheat overdose and then a week later, with no wheat.

Personally I think the rise of modern technology has to do with a bunch of Asperger folks who were in a semi-trance with wheat and milk, inventing all kinds of strange things (DaVinci comes to mind, probably living off pasta ...). Note how technology started in the "cradle of civilization" -- the first place wheat was grown. The Mayans grew corn, and never even bothered with wheels.

-- Heidi

LOL, and his goofy helicopters! Obviously a gluten stupor!

Oh, this makes my day!


Hi Steve,

If the celiac list was a forum for scientific discussion, such as the
Paleodiet listserv, I would gladly leap in and argue the issue with you.
However, the celiac list is primarily aimed at mutual support and
information sharing. The owners have adjusted the rules considerably since I
first joined, deliberately structuring it to minimize such debate. I'd be
happy to debate the issue with you elsewhere, but not on the celiac list. I
value it highly for what it does offer and I am not prepared to oppose the
list owners because they do not want to host debates.

I suspect that they fear that celiac list members will become more confused
and less empowered by such debates.... and, although I disagree, I think
there is some legitimacy to their perspective.

Again, I would ask that you post an amendment to the list indicating that
you overstated my position on opioid peptides.

Best Wishes,

Ron, I am disappointed we don't have a chance to reply in the celiac list. There are so many people of different backgrounds that can appreciate these discussions on several levels, who often reply with interesting insights. I think your post about opioid peptides may have misled some list readers to assume that a study like that was sufficient evidence to conclude opiate effects are important, when in reality the study is not clinically applicable for a number or reasons. It seems to me a digest version doesn't really do justice to the type of dialog needed to show the complexities involved in the study of pharmacologic effects.


On Saturday, September 27, 2003, at 05:38 AM, user1 wrote:

Like I told Ron, I am skeptical that the brain fog is because of an opiate
effect, because my reactions to other foods on food challenge have been
similar. Groggy stupor, can't read, irritability later, tension,
paranoia. You might think of all these as side effects of an opiate-like
drug. But I react that way to apples, corn, oranges ...

It doesn't rule out the brain fog being due to opioids in gluten and milk.
i was eating 6 cups of milk/day before going on my elimination diet. i
didn't have so much brain fog, as it felt like i'd wandered into a marsh
of the mind and my mental feet were stuck, only being picked up with a
loud pop as the mud suction broke. My mind had just stopped and i was
going to bed all wiped out at 8 p.m..

That was before i stopped eating the foods I'm intolerant too. I can't
say if stopping gluten and milk specifically ended the brain marsh.

Just because they found opioid peptides in gluten and milk doesn't mean
that mental difficulties are caused by them.

I agree. There is a condition called hepatic encephalopathy where people with liver dysfunction get very foggy. The problem is due to protein breakdown products that interact with the GABA receptor in the brain. Not opiates, but definitely affect mentation. With celiac proteins interacting with the immune system there are issues of immune complex disease to add to the list of possibilities. Celiac sprue is also associated with peripheral neuropathy, so there are neurologic effects at several levels. Your second post gets to that. I appreciate your sharing this with me. It helps me better understand my patients.

Steve Holland

On Saturday, September 27, 2003, at 09:43 AM, Shughart wrote:

I think you raise some interesting points - perhaps you might find some intelligent response from the likes of Dr. William Shaw of, author of Biological Treatments for Autism and PDD.
I look forward to your summary.
p.s. I don't know what caliber of work this is, but there's info here, too (with citations): . There certainly are a lot of gluten free/casein free families that have results from the diet, but whether it is actually opioid driven or not is another question.

Hey, thanks for pointing to the site. I asked them if they have a reference supporting the contention.

Steve Holland

On Friday, September 26, 2003, at 03:09 PM, Patricia Clark wrote:

I suspect that you are saying that it can't happen. "Something" happens. I notice, however, that I have some of the same side effects from cadeine or morphine that I get from gluten -- such as extremely vivid and frightening dreams. For that reason I always turn down treatment with narcotics if I am given a choice.


Oh, it happens. Look at all the patients who note it. But it may not be as simple as an opiate.

Steve Holland

On Friday, September 26, 2003, at 02:27 PM, wrote:

I know of many people in our support group who say they get brain fog when
they ingest gluten.

That's all I know. Could it be from some cause other than opiates in gluten?

Richmond, VA

I suspect that is the case. Opiates by themselves seem not likely. HOWEVER, if there is such a thing as an opiate that does not cause tolerance that would be a MAJOR ADVANCE IN MEDICINE. Opiate tolerance is a big problem. Also, if there is an opiate receptor that causes the head to go foggy but not be pain relieving then there may be opiates that relieve pain but not cause sedation. So this issue is potentially a VERY BIG THING.

Stephen Holland

On Saturday, September 27, 2003, at 12:41 PM, user1 wrote:

i have wondered whether there might be a syndrome with different symptoms
at different ages: people going crazy when very young, get inhalant
allergies later as I did, when old, get arthritis and osteoporosis
(i haven't gotten there yet) that might all have its root in gluten
intolerance. going crazy was very helpful for me, and i don't think going
crazy is *just* the result of food intolerance, more like
abuse + gluten + stress = crazy.

I knew someone who was a recovering schizophrenic. He was also a wheat
addict I thought, seemed mentally stiffened sometimes, which i related to
as a symptom of food intolerance -- he wasn't on antipsychotics. He was
also mentally loose at other times. I tried to persuade him for a long
time to find out if he had food intolerances. finally he
got the celiac blood tests and they came back positive. But last i heard
he thought a gluten-free diet was too hard to follow. It is really sad, I
think some people get mentally disabled from food intolerance, so much
that they don't have the mental strength to avoid the foods they're
intolerant to. People seem to be addicted to foods they're intolerant to,
although they don't see it that way, so they find other reasons not to
stop eating those foods.

i think it might not be known what causes those stupors on food challenge.
We have a blood-brain barrier to protect our brains from this sort of
thing, maybe cytokines from the immune system can cross it, though.

user1 name withheld by request