Food-derived opioids are a medical frontier

In late 2020, I was invited to write a paper on food derived-opioids for the International Journal of Environmental Research and Public Health, with a focus including effects on microbiota.  Eight months later and the paper has been written, then refereed by three scientists chosen by the journal, then modified in response to the referees’ critiques and now published. The paper draws on and integrates evidence from 125 prior-published papers. It is available online via a link at the end of this post.

The key messages are that food-derived opioids from A1 beta-casein and also from gluten are a medical frontier, with clear evidence that they affect the microbiota in our digestive system, but also linking within a complex system to the brain and multiple internal organs.

Fundamental to this system is the widespread presence of opioid receptors to which the food-derived opioids attach. These opioid receptors are present in the brain, intestines, pancreas, lungs, heart, kidneys, liver, adrenal glands and many other places.

The natural role of opioid receptors is as part of the internal messaging system between the gut, brain, internal organs and peripheral tissues. But when external opioids are consumed, either in the form of drugs or within food, then the internal messaging is disrupted. The body then reacts to this in multiple ways, including inflammation and autoimmune responses.

Writing the paper was a stimulating but demanding exercise. At the outset I was aware of much of the relevant evidence I would need to draw on, but I still  had to search widely to minimise the risk of missing any evidence of fundamental importance.  

My main investigatory tool was PubMed, which is a database containing some 32 million biomedical references, which I searched using key words of relevance. Without key-word searching, it would have been impossible to pull together the various strands of evidence to tell the overarching story.

Many people who know me will be aware that I have long been interested in the opioid peptides released from A1 beta-casein. It was way back in 2007 that I wrote the first edition of ‘Devil in the Milk’ on the science and politics of A1 and A2 milk, with this creating quite some controversy.

 Since then, together with medical and nutrition scientists, I have co-authored a stream of papers in nutrition and medical journals relating to A1 beta-casein. However, my interest in the opioid peptides from gluten came later, linked in part to a surprise discovery that I was myself intolerant to opioid peptides from wheat. Once I discovered that, then a range of unpleasant inflammatory conditions that I suffered from came under control.  Inevitably, that piqued my interest to try and understand more about the mechanisms.

That then led me towards the idea of this latest paper, stepping back a little from the specifics of A1 beta-casein, to explore more generally the concept of food-derived opioids, and using emergent knowledge of opioid receptors to help bring together the stands of evidence.  It is the widespread presence of the opioid receptors that explains why these food-derived opioids can have so many effects depending on where they land.

Most of the evidence about opioid receptors comes from research into the effect of opioid drugs such as heroin, morphine and fentanyl. We have long known that the food-derived opioids attach to these same receptors, but the strands of evidence had simply not been brought together.

Taking Type 1 diabetes as an example, there has long been evidence linking this disease to A1 beta-casein and the derived opioid peptide called betacasomorphin-7 (BCM7). For clarification, Type 1 diabetes is the form of diabetes that can strike at any age, including in early childhood. Sufferers have to take insulin every day. It is an autoimmune disease where the body destroys particular cells in the pancreas. It is a different disease to Type 2 diabetes which is very much a lifestyle disease of older people.

 Back in 2017, together with six medical and nutrition specialists, I co-authored a paper for the journal Nutrition and Diabetes setting out the evidence [https://www.nature.com/articles/nutd201716] linking A1 beta-casein to Type 1 diabetes, and laying out how A1 beta-casein could trigger the disease. But we failed to make mention of the presence of opioid receptors within the islets of Langerhans in the pancreas, despite this being the precise location where insulin is produced. The likely explanation is that none of us were aware of opioid receptors being present there. Quite simply, we had not found that literature within the 32 million published biomedical research papers.

What we did know back then was that there was a close relationship between the level of A1 beta-casein in diets and the incidence of Type 1 diabetes.  We also knew that A1 beta-casein releases the opioid peptide BCM7 and that this has direct effects within the gut system. We also knew that in some people the BCM7 passes through into the circulatory system. And we knew that BCM7 can then go rapidly to the brain.

We also knew that there was an amino-acid sequence within the islets of Langerhans that resembled BCM7 and this gave a rationale as to why an autoimmune reaction could occur. But we failed to identify that the reason BCM7 is attracted to those islets of Langerhans is because of the opioid receptors located there to which it attaches.

Other groups of scientists have been studying microbiota in the gut and have linked specific microbiota to Type 1 diabetes but without explicating the mechanisms for the effects, or drawing a link to BCM7. In the same way that we had not found the literature on opioid receptors, they had not found the literature on A1 beta casein and BCM7.

Despite considerable research interest, it remains unclear whether particular gut microbiota are themselves directly causal in relation to Type 1 diabetes. It may well be that it is simply a case of BCM7 from A1 beta-casein affecting both the microbiota, which we know to be true, and also with BCM7 being a direct trigger for Type 1 diabetes, for which there is considerable evidence. The apparent link between microbiota and Type 1 diabetes may therefore be because each is triggered by A1 beta-casein and BCM7, rather than through a causal link from the gut microbiota directly to Type 1 diabetes.

However, what we also now know is that A1 beta-casein, through release of BCM7, causes not just a change of microbiota in the gut, but also inflammation therein. This inflammation facilitates the BCM7 being able to get through the gut wall into the circulatory system, and then finding some of the myriad of opioid receptors spread throughout the body.

Here I have focused specifically on Type 1 diabetes as an example, but there are similar lines of evidence linking A1 beta-casein and BCM7 to a wide range of other health conditions. A key explanatory factor is that we now know that once BCM7 from a1 beta-casein manages to get through to the circulatory system, it will find and attach to opioid receptors, with these being present in all major organs.

In the scientific paper, and as I said earlier, I wanted to focus on gluten as well as A1 beta casein. In particular, I wanted to focus on a specific peptide from gluten called gliadorphin-7 which has a similar amino-acid structure to BCM7 as shown in the diagram.

Readers who know something about biochemistry will recognise that both BCM7 and gliadorphin-7 contain the amino acids tyrosine and proline at what we call the N terminus, with this being fundamental to creating the opioid characteristic. The peptides also both contain three proline amino acids in close succession with this creating strong resistance to peptide breakdown. Although both peptides are opioid and resistant to breakdown, the differences in the peptides are still sufficient to ensure that the specific effects will also differ.

We know that gliadorphin-7 is a key peptide linked to coeliac disease, but it is not the only opioid peptide in gluten that seems to be linked to coeliac disease. However, it is the resistance to breakdown that makes gliadorphin-7 particularly important. 

Given the debilitating effects of coeliac disease, it has tended to take attention away from all of the other gluten-intolerance conditions. However, there is now a developing medical literature linking gliadorphin-7 much more generally to health conditions spanning the gut, brain and a range of internal organs. In my own case it includes arthritic joint inflammation. This is all part of the medical frontier with more to be learned.

Both A1 beta-casein and gluten are features of modern but not ancient diets. A1 beta-casein is a consequence of a mutation several thousand years ago, originally affecting cattle in Northern Europe, but with Northern European cattle breeds now dominant across the globe. Sheep, goat and human milk remain exclusively of the A2 type.

Gluten has become important because of the role played by wheat in modern diets. Rice, corn and all of the ancient grains contain no gluten. Most people susceptible to gluten can also consume oat products but not barley.  Modern breads often have additional gluten added to enhance the light fluffy consistency and preferred texture. Pasta wheats contain some but generally less gluten than bread wheats.

It is now becoming much easier, at least in New Zealand where I live, to avoid both A1 beta-casein and gluten products. In my local supermarket there are four brands of A2 milk, three brands of A2 infant formula, and one brand of A2 ice cream. Similarly, the choice of gluten-free products is much greater than even five years ago.

A1 beta-casein and gluten are not the only sources of food-derived opioids. For example, opioids can be released from both soy and spinach. However, soy and spinach do not dominate our diets in the same way as do dairy and wheat. Also, it would seem that the opioids in soy and spinach are broken down much more easily. So, it is A1 beta-casein and gluten where the big focus has to lie.

Proving the health effects of these food-derived opioids is much harder than proving the effects of opioid drugs. This is because opioid drugs can be administered in medical situations at levels that produce quick measurable side-effects as well as the desired pain relief. Also, it is easy to create ‘with-and-without’ comparisons of these drugs. In contrast, with A1 beta casein from milk and gliadorphin-7 from wheat being dominant features of normal diets, together with the effects in autoimmune diseases typically being related to long-term exposure, it is much more challenging to conduct the human trials.

Nevertheless, the body of evidence keeps accumulating. And so, I find it exciting to be able to play a part, along with many other people at the medical frontier, as we pull back the curtain on these food-derived opioids.

Of course, not everybody is happy to see that curtain being pulled back and so there is considerable opposition from entrenched elements of the food industry. I learned this very clearly when I first started writing about A1 beta-casein some 15 years ago. Accordingly, there is much more to be done before the global dairy industry is free of A1 beta-casein. This is despite many of the big global dairy companies now having their own A2 conversion projects as a business-risk-reduction strategy. The first preference of many of these companies is that the issue would simply go away.

Similarly, there are big and powerful forces that don’t like to hear any criticism of gluten content within wheat and also in barley. They would much prefer that this type of research was not undertaken. These industry groups can be influential in multiple ways.

For those who wish to delve into the science, here is the link to the scientific paper.  There is no paywall, with the journal editor on behalf of the publisher also waiving any publication charge.  But remember that it is written for scientists and not for a general audience.

And here is a link [ https://keithwoodford.wordpress.com/category/a1-and-a2-milk/ ] to the A1 and A2 category at my own website, with those articles written for a non-scientist audience.