The Gluten-Morphine Connection: What you Need to Know about Gluteomorphins

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The Gluten-Morphine Connection: What you Need to Know about Gluteomorphins

By Dr. Miles Nichols and Aaron Mello, CNTP, MNT

Have you wondered why bread and other wheat products can be so addictive? Have you ever felt that you might benefit from reducing or removing gluten-containing foods, only to find yourself still eating them more than you would like?

It’s not just you! There are compounds in gluten called gluteomorphins that are similar in structure to morphine and affect the body in much the same way as this powerful and addictive drug. Read on to find out more about these compounds and how some people have negative immune reactions against these and other compounds in the gluten protein.

What are gluteomorphins?

Also known as gliadorphins, these peptides are opioid-like compounds that behave much like morphine in the brain. They are intermediate byproducts of gluten metabolism that can create feelings of euphoria. Gluteomorhpins can be addictive and even trigger strong withdrawal reactions in some people when gluten is removed from the diet.

Until fairly recently it was believed that gluten was the primary protein responsible for triggering an immune response in the body but we now know that gliadin is actually the primary culprit. But because most people are familiar with gluten many people continue to use that terminology. The terms gluteomorphin and gliadorphin are used interchangeably in this article.

In addition, we now know that it is not one single protein in wheat that causes reactions in people. In fact, over 100 proteins have been identified that can cause an immune response.(1)

How gluteomorphins are formed

Gluteomorphins result from incomplete digestion of the gluten protein. This impaired ability to fully digest gluten is caused by inadequate levels of the enzyme that cleaves gluteomorphin peptides into smaller peptides. This enzyme is called dipeptyl peptidase IV, or DPP IV. DPP IV catalyzes peptides that have the amino acid proline in the second position.

Structure of gliadorphin

Gliadorphin is a peptide that is seven amino acids long in the sequence tyr – pro – gln – pro – gln – pro – phe. DPP IV is used in two different steps of gliadorphin metabolism as it cleaves peptides which have proline in the second position. In the first step, DPP IV cleaves the tyr – pho segment off the beginning of the gluteomorphin peptide. This leaves a peptide with the sequence gln – pro – gln – pro – phe and DPP IV acts a second time to cleave the gln – pro, leaving gln – pro – phe.

Interestingly, the remaining gln – pro – phe tripeptide is an inhibitor of DPP IV. Instead of being acted on a third time by this enzyme, this tripeptide actually inhibits the action of DPP IV. This results in the inactivation of DPP IV and an impaired ability to break down further gluteomorphins. As a result, gluteomorphins may build up to high levels because of the inhibitory effect of the gln – pro – phe tripeptide on DPP IV. (2)


Another peptide similar in both structure and effect to gliadorphin is caseomorphin, also a morphine-like compound that results from incomplete breakdown of casein, a milk protein found in many dairy products. DPP IV also acts on caseomorphin, which is also a seven amino acid peptide with proline in the same positions.

Caseomorphin metabolized by DPP IV meets the same fate as gliadorphin. After being cleaved twice, a tripeptide with proline in the center position remains, which inhibits DPP IV just like the tripeptide that results from gluteomorphin metabolism. Caseomorphin is also picked up on opioid receptors in the brain and produces similar mind-altering effects and withdrawal symptoms. (3)

Because casein can cause the same production of morphine-like compounds, a dairy free diet is often also recommended for children with autism and can greatly reduce symptoms in children for whom caseomorphin is playing a role.

Roles of DPP IV

The DPP IV enzyme does not just catalyze gluteomorphins. It is also a regulator of many other peptides processes in the body and a deficiency of DPP IV can interfere with the action of these peptides. Some relate to digestion directly, including Peptide YY, Pancreatic polypeptide and Substance P. Other peptides that rely on DPP IV regulate immune function and inflammatory response, including Neuropeptide Y and Interleukens 1b, 2, 3, 5, 8, 10, 11 and 13. Depressed levels of DPP IV may lead to problems with these peptides being activated and deactivated.

In addition to autism, other mental illnesses are associated with altered levels of DPP IV, in some cases elevated and in others depressed. For example, low levels of DPP IV are found in people suffering from major depression (4) and also in alcoholics, including recovered alcoholics who have been abstinent from alcohol for some time. (5) Low levels are also commonly found in celiac disease, (6) rheumatoid arthritis, (7) and anorexia. (8) Conversely, high levels of DPP IV are found in patients with schizophrenia. (5)

Hydrolyzed gelatin and autism

Gelatin, especially hydrolyzed gelatin, has been shown to trigger autistic symptom in susceptible children. The MMR vaccine has been shown to be a potent inhibitor of DPP IV due to its hydrolyzed gelatin content. Hydrolysis results in tripeptides with proline in the second position, similar to the tripeptides that result from gluteomorphin metabolism that inhibit DPP IV.

Opiate-blocking drugs like naltrexone can decrease the severity of autistic symptoms. Because naltrexone blocks the effects of opioids on the brain and gluteomorphins behave like opioids to exacerbate autistic symptoms, naltrexone appears to alleviate symptoms of autism by blocking opioids from acting on the brain. (9)

Other factors contributing to gluteomorphin production

Genetic issues

Genetic deficiencies in DPP IV may contribute to the formation of gluteomorphins. Autistic children are thought to be deficient in DPP IV, which leads to high levels of gluteomorphins in children who consume gluten. Gluteomorphins have also been found in the urine of autistic children.

Because gluteomorphins are made from dietary gluten and inhibit DPP IV, which may already be low in autistic children, a gluten free diet is often recommended for autistic children and can reduce autistic symptoms considerably.


Candida albicans is a pathogenic yeast normally present in small quantities in the intestines. In healthy individuals, candida levels are kept at bay by beneficial bacteria. But when those friendly bacteria are low or wiped out by antibiotic use, candida can proliferate out of control.


One common result of a candida overgrowth is a reduction in hydrochloric acid production in the stomach, called hypochlorhydria. Adequate levels of hydrochloric “stomach acid” are necessary for the beginning stages of protein digestion. Without adequate stomach acid, proteins like gluten and casein may not be digested properly.

Strong stomach acid initiates a series of digestive cascades that turn on many other digestive processes. Pepsin, which is also required to digest proteins like gluten, relies on adequate stomach acid for activation. If stomach acid is inadequate, pepsin is not activated and gluten metabolism suffers.

Another component of digestion that relies on adequate stomach acid is the secretion of pancreatic enzymes like secretin that help digest food. When stomach acid is low, these enzymes are not released into the small intestine to help with digestion and the ability to digest proteins like gluten is impaired.


A third cause of impaired protein digestion is dysbiosis, an unhealthy condition in the intestines. Dysbiosis can lead to overgrowths like candida and also plays a direct role in the final stages of gluten breakdown which takes place lower in the intestines. Imbalances in gut flora inhibit the body’s ability to cleave short gluteomorphin peptides into their individual amino acids.

Testing for gluten / gliadin sensitivity

Older gluten sensitivity tests only looked at alpha gliadin antibodies, but we now know that many proteins are implicated in non celiac gluten sensitivity. Newer tests look at many different antibodies, including several gliadin markers including gamma and omega, glutenin, prodynorphin, and several transglutaminase enzyme antibodies.

In conclusion

Many people are surprised to learn that by eating gluten they may be unwittingly dosing themselves with morphine-like compounds that can be addictive and intoxicating. If you want to evaluate whether gluten is playing a role in your life, here are some action steps you can take:

  • Identify whether you have a gluten sensitivity: Order a Wheat Zoomer (by Vibrant Wellness) or Cyrex Array 3 lab test. Alternatively, you can strictly eliminate gluten for 30-90 days. If you feel much better, keep it eliminated. If you’re not sure, re-introduce it and pay attention to symptoms for three days after re-introduction to see if you are reacting.
  • Investigate genetic issues (HLA-DQ), candida, low stomach acid, and dysbiosis. Find a good functional medicine doctor and test for these issues.
  • Rule out gluten cross-reactivity. Some other foods can cause immune reactions in the body that mimic the effects of gluten. Consider eliminating dairy, coffee, and other grains for a 30-90 day trial period and then re-introduce only one food per  three day period. You can also use Cyrex Array 4 for cross-reactive foods lab testing.
  • Be kind with yourself when removing gluten. Know that it contains opioid-like compounds and there may be a withdrawal period. Get through that time with resolve and then notice how you feel once you’re on the other end after a few weeks.


  1. Punder, Karin De, and Leo Pruimboom. “The Dietary Intake of Wheat and Other Cereal Grains and Their Role in Inflammation.” Nutrients 5.3 (2013): 771-87. Web.
  2. Augustyns, K., G. Bal, G. Thonus, A. Belyaev, X. M. Zhang, W. Bollaert, A. M. Lambeir, C. Durinx, F. Goossens, and A. Haemers. “ChemInform Abstract: The Unique Properties of Dipeptidyl-Peptidase IV (DPP IV / CD26) and the Therapeutic Potential of DPP IV Inhibitors.” ChemInform 30.29 (2010): n. pag. Web.
  3. Sokolov, Oleg, Natalya Kost, Olga Andreeva, Ekaterina Korneeva, Viktor Meshavkin, Yulia Tarakanova, Aleksander Dadayan, Yurii Zolotarev, Sergei Grachev, Inna Mikheeva, Oleg Varlamov, and Andrey Zozulya. “Autistic Children Display Elevated Urine Levels of Bovine Casomorphin-7 Immunoreactivity.” Peptides 56 (2014): 68-71. Web.
  4. Elgun S, Keskinege A, Kumbasar H. “Dipeptidyl peptidase IV and adenosine deaminase activity. Decrease in depression.” Psychoneuroendocrinology 1999 Nov; 24(8): 823-32
  5. Maes M, Lin A, Bonaccorso S, Vandoolaeghe E, Song C, Goossens F, De Meester I, Degroote J, Neels H, Scharpe S, Janca A. “Lower activity of serum peptidases in abstinent alcohol-dependent patients.” Alcohol 1999 Jan; 17 (1): 1-6.
  6. Smith MW, Phillips AD. “Abnormal expression of dipeptidyl peptidase IV activity in enterocyte brush-border membranes of children suffering from coeliac disease.” Exp Physiol 1990 Jul; 75 (4): 613-6
  7. Kamori, Masatoshi, Masako Hagihara, Toshiharu Nagatsu, Hisashi Iwata, and Takayuki Miura. “Activities of Dipeptidyl Peptidase II, Dipeptidyl Peptidase IV, Prolyl Endopeptidase, and Collagenase-like Peptidase in Synovial Membrane from Patients with Rheumatoid Arthritis and Osteoarthritis.” Biochemical Medicine and Metabolic Biology 45.2 (1991): 154-60. Web.
  8. Van West D, Monteleone P, Di Lieto A, De Meester I, Durinx C, Scharpe S, Lin A, Maj M, Maes M. “Lowered serum dipeptidyl peptidase IV activity in patients with anorexia and bulimia nervosa.” Eur Arch Psychiatry Clin Neurosci 250(2): 86-92, 2000.
  9. Eichaar, Gladys M., Nicole M. Maisch, Laura M Gianni Augusto, and Heidi J. Wehring. “Pediatrics Efficacy and Safety of Naltrexone Use in Pediatric Patients with Autistic Disorder.” Annals of Pharmacotherapy 40.6 (2006): 1086-095. Web.

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