Junk Food, Pt. 1: Exorphins
Do you know every time you drink a glass of milk or eat a slice of bread, you are being exposed to opioids? These opioids are the exorphins, a class of bioactive peptides (BAPs) that bind to and affect our opioid receptors, giving a whole new meaning to the phrase “Junk Food”. The name “exorphin” distinguishes these exogenous opioid peptides from our bodies own “endogenous” opioid peptides, the “endorphins”. In most cases, these exorphins are not present in the food, rather they form during the chemical breakdown of certain dietary proteins; that is our body generates them while digesting proteins. Most of us are exposed to exorphins daily, if not at every meal. Despite our body’s familiarity, most of us know little if anything about them. I must admit, I was ignorant about exorphins until a month ago when I encountered them while watching a documentary on diet and health. Ashamed of my ignorance, I went down the exorphin rabbit hole, the result is this chimera of a blog post and a scientific review article.
If you are unfamiliar with the biochemistry of peptides and proteins, here is a quick introduction. In general, proteins are biomolecules composed of a straight or linear chain of amino acid building blocks linked together, by sharing of electrons, in what are called covalent bonds. In this case, these bonds are called peptide or amide bonds (-(C=O)-N-). Nature uses a surprisingly simple palette of just 20 amino acid building blocks to construct the millions of diverse proteins on earth.[1] Except for a single variable chemical group (the R-group) these amino acids are structurally identical (Figure 1). The R-group is what bestows each amino acid with it's the distinct chemical properties; some love water (hydrophilic), some despise water (hydrophobic), some will be negatively charged, some positively charged, etc. Like all things in biology, there are exceptions; a few rare amino acids exist and amino acids are sometimes modified on proteins post production. But the bulk of proteins in biochemistry are made from just 20 amino acids.
Figure 1. Structure of a generic amino acid and the amino acid tyrosine.
Peptides, like proteins, are straight chains of amino acids but, by definition, are shorter. The typical definition you will find is: greater than or equal to 50 amino acids you have a protein and less than 50 amino acids you have a peptide. An example of a peptide is the exorphin BCM-7 which contains 7 amino acids and is shown below in Figure 2. In this example, each component amino acid is labeled. Although peptides and proteins are a linear chain of amino acids, these chains fold up into various 3-dimensional structures that are important in their biological activities.
Figure 2. Structure of peptide exorphin BCM-7 with the seven amino acid subunits labeled. These amino acids are linked through the –(C=O)-N- peptide bonds, an example of which is contained in the red box.
When we consume proteins in our diet, they are digested or broken down (i.e., the peptide bonds are broken or “cut”) in our gastrointestinal (GI) tract. It is in the stomach and small intestines that this breakdown occurs. This breakdown is a form of catabolic metabolism that is facilitated or more technically “catalyzed” by cannibalistic proteins called proteases. These cannibals act like tiny molecular scissors, snipping the peptide bonds connecting the amino acid building blocks. The snipping is actually achieved by hydrolysis – which involves adding a water molecule across the bond to break it. There are many variants of proteases and each has a preference for cutting specific amino acid sequences within a protein. As a protein is cut up it produces smaller amino acid chains, which themselves may be cut into smaller and smaller fragments. Some of the peptides formed during this process are exorphins
By definition, the exorphins interact with a family of protein receptors known as the opioid receptors through a phenomenon called binding. By binding, exorphins affect the 3-diminensional structure of an opioid receptor. Depending on the exorphin and the resulting structural changes, this can turn the receptor on, off, or simply prevent other molecules from binding and effecting the receptor. Through their effects of opioid receptors, exorphins exert biological effects on our bodies. Exorphins exist that can affect one or more of the three main types of opioid receptors; mu-opioid receptor (MOR), kappa opioid receptor (KOR) and delta opioid receptor (DOR). Technically this should also apply to the fourth opioid receptor, the nociceptin opioid receptor (NOP), though I have yet to see evidence illustrating that exorphins affect NOP. I am sure some do, it's just a matter of looking. Although there are four opioid receptors, it is the MOR that is responsible for the classic opioid-like drug effects such as analgesia, euphoria, respiratory depression, constipation, etc. For this reason, I will focus mostly on the MOR targeting exorphins in this post. The other opioid receptors are equally fascinating and worthy of our affection, but for brevity a line has to be drawn. Importantly, a number of exorphins lack high selectivity for a given opioid receptor, meaning they will affect more than one type.
Exorphins are classified based on the precursor or parent protein from which they are derived. These parent proteins are present in an astoundingly diverse range of dietary sources. In this way we have “casomorphins, lactorphins, lactoferroxins, and casoxins (from mammalian milk), gluten exorphins (from wheat), rubiscolins (from spinach), soymorphins (from soybean), and oryzatensin (from rice)” [Ul Haq and Ul Haq. 2020]. Table 1 summarizes the most commonly studied exorphin classes, the parent protein(s) from where they are derived, and major dietary sources. There are certainly many more exorphins that exist; some known and many others unknown. One potential source I am interested in are hemp seeds. To date no one has detected any such “cannorphins”, but I suspect this will change someday as hemp seeds are an excellent source of protein, containing two major types: edestin and albumin. Albumin protein from rice produces the exorphin oryzatensin, therefore it is not a stretch to think cannorphins could exist. And while we are speculating, what about exorphins from protein rich poppy seeds? The Papavorphins…. come on, these names alone justify the search.
Table 1. Exorphin classes, parent proteins, and dietary sources. References: Ul Haq and Ul Haq. 2020 and Woodford. 2021. Note: Cannorphins are speculative and being proposed here.
The first identified and most studied exorphins are those derived from bovine milk proteins. Two principal protein types are present in bovine milk; casein and whey proteins. Caseins comprise ~80% of bovine milk proteins with several subtypes existing based on subtle differences in amino acid sequence [Ul Haq and Ul Haq. 2020]. In 1979, three β-casomorphins (BCMs) were isolated from digested bovine casein and found to exhibit opioid-like activity [Henschen et al. 1979, Ul Haq and Ul Haq. 2020]. Since then, other BCMs have been discovered. Many of the BCMs bind to and activate MOR, much like morphine. Pharmacologists call a molecule that activates a receptor, an agonist. BCM-4, BCM-5, BCM-6 and BCM-7, the number referring to the number of amino acids present in the peptide, act as MOR agonists, with BCM-5 reportedly the most potent [Ul Haq and Ul Haq. 2020]. In addition to bovine milk, casomorphins from the milk of other mammalian species including Homo sapiens exist. Depending on the casein variant and its amino acid sequence, distinct casomorphins are produced and these can have different physiological effects [Meisel and FitzGerald. 2000, Ul Haq and Ul Haq. 2020]. Another consideration is that genetic variation in the protein can alter the amount of exorphins produced. Bovine milk is classified based on the presence of two major β-casein variants into A1 and A2 type milk. These differ based on a single amino acid difference which changes the susceptibility to metabolic breakdown to produce BCMs. As a result of this difference, higher BCM levels are produced after consuming A1 type milk. Most of the milk consumed in the US is A1 type from Holstein cows, but some A2 is available.
For the reader with the impulse to sprint over to whole foods to grab three gallons of milk and a beer bong, please read further as I can spare you the trip. If it were that easy, you’d already know; the federales would be kicking in doors of dairies all over the country, locking up farmers, and incinerating cattle with flamethrowers all to ensure your liberty and freedom. There are several issues with catching a milk buzz, but a big one is, similar to proteins, peptides tend to be quickly broken down by proteases in the GI tract. In essence, they have brief lifespans once formed, making it unlikely they will linger around long enough to exert physiological effects beyond the GI tract. Efforts made to detect BCMs in adult human plasma following consumption of milk have been unsuccessful [Teschemacher et al. 1986] and BCM-7 added into human blood was found to be rapidly degraded [De Pascale et al. 2004]. So, it is best to stick to adrenochrome for your zoopharmacological fix or keep it simple and just get drunk like a respectable citizen.
For those curious to learn more on the ability of exorphins to be absorbed into the blood, research on the stability of exorphins and their absorption into the blood supply was recently reviewed. While absorption seems unlikely in healthy adults, it may be possible under some pathological states where the gut-blood barrier is compromised [Daniloski et al. 2021]. There may also be hope for infants looking for a milk buzz, as there is evidence exorphins reach the systemic circulation in newborn mammals as a result of differences in peptide metabolism and gut leakiness [Umbach et al. 1985, Belyaeva et al. 2009, Ul Haq et al. 2014, and Ul Haq and Ul Haq. 2020]. This difference may be biologically intentional. Which brings up an important question - what are the physiological functions of milk-derived exorphins? From an evolutionary perspective, it seems these “encrypted peptides” evolved to exert specific physiological effects on nursing infants, the intended milk consumer. Many experts thus believe the milk-derived exorphins serve key roles in mammalian development exerting vital local and systemic effects on nursing infants [Dubynin et al. 2008, Ul Haq et al. 2014]. We will discuss these biological effects shortly. As to an intentional physiological function in adults, remember as Homo sapiens we are unique in our relationship with milk. First, we consume the milk of other species and second, many of us continue to consume milk as adults. Most other mammals are quickly weaned from the milk tap as infants and develop an intolerance that would prevent continued consumption. In evolutionary time frames our atypical milk consumption is thought to be a recent phenomena, approximately 8,000-10,000 years old. It is its own fascinating story outside our scope here. All this is to say milk-derived exorphin almost certainly evolved to benefit nursing infants, and it seems unlikely they evolved to affect an adult imbibers, especially one of a separate species!
So, what are the physiological effect of exorphins? To help answer this, let’s look at the MOR. MOR is found in the cell membrane of cells throughout the body but the population most relevant to our discussion are cells of the GI tract. More specifically, neurons in the enteric nervous system, which is also called the “gut-brain” or “second brain”. Yes, your gut has its own brain and it runs on opioids too. The endogenous opioid system found in the enteric nervous system is well-known to help regulate digestion and nutrient absorption by affecting intestinal transit, electrolyte transport, bile secretion, mucus production, and hormone secretion [Hautefeuille et al. 1986, Sternini et al. 2004 Wood and Galligan. 2004]. This population of MOR is why opioids like morphine and fentanyl slow intestinal transit causing constipation. MOR agonists have long been used medically for their anti-diarrheal effects. In the case of diarrhea this is therapeutically valuable, whereas when opioids are used for other indications, constipation is an undesirable side effect. This is an excellent illustration that a desirable effect and a side effect of a drug depend on the intended use. Given the known physiological role of MOR in the GI tract, a very reasonable hypothesis is that exorphins can affect intestinal transit times [Meisel and FitzGerald. 2000, Shah. 2000]. Supporting this, the MOR agonist BCM-7 reduced the frequency of intestinal contractions in rats, slowing intestinal transit times [Daniel et al. 1990]. Similarly, exorphins have been found to influence GI mucus production and secretion through their activation of MOR [Ul Haq et al. 2014, Robinson et al. 2024]. Supporting the physiological relevance of milk derived exorphins, oral β-casein has been found to slow intestinal transit in rodents and humans [Barnett et al. 2014, Brooke-Taylor et al. 2017]. Research has also shown that physiologically relevant levels of exorphins are produced in the human intestine following ingestion of casein proteins [Boutrou et al. 2013]. Such physiological changes in the GI tract will influence digestion and nutrient absorption. By affecting the GI tract environment, exorphins may aid digestion and nutrient uptake in nursing infants. In adults, this may be less beneficial, even problematic, as we will see shortly. As to the question of exorphins having direct central effects on the brains of nursing infants, there is not a lot known. Most studies I found reporting central effects, administered exorphins in pure form by injection. As an example, see: Blass and Blom. 1996. While such studies suggest it is possible for exorphins to get into the brain in these animals, it is unclear if naturally produced exorphins could achieve this.
The exorphins that bind to MOR are not only MOR agonists, some of them are MOR antagonists - molecules that bind to and block the endorphin binding site on MOR. In this way, antagonists prevent MOR activation by agonists. Examples of exorphin antagonists are the casoxins, such as casoxin A and casoxin 4, also found in milk [Ul Haq and Ul Haq. 2020]. When MORs are blocked by an antagonist they cannot be activated by endorphins or other exorphins. Just as we can compare the MOR agonist exorphins to drugs like morphine and fentanyl, MOR antagonist exorphins can be compared with naloxone and naltrexone. Consistent with this, casoxin 4 blocked the intestinal effects of morphine in mice and guinea pigs [Patten et al. 2011]. The existence of both agonist and antagonist exorphins produced from bovine milk, complicates things, as now the net effect of exorphins on GI function at any given time will depend on the sum of the agonist and antagonist exorphins present. If this is not complicated enough, consider the influence of other BAPs, the various small molecules also present from food consumed, and that from various endogenous molecules like the endorphins and other signaling molecules, including hormones and allosteric modulators. You can see how things get really fucking complicated. But we aren’t done, we also should consider the dynamic nature of physiological systems; the expression levels of the relevant receptors which can change based on previous exposures, receptor post-translational modifications, the presence and levels of different intracellular signal transducers that are activated by the receptors, as well as various other intracellular proteins involved in carrying out the signaling function and thus the ultimate impact on the cell, tissue, organ and organism. If this seems a little overwhelming to you, welcome to the phantasmagoric world of molecular biology!
By activating MORs some exorphins are able to affect the release of hormones including insulin, somatostatin, and growth hormone [Schusdziarra et al. 1983a and 1983b, Qin et al. 2004]. It is important to note that in many studies, the exorphins are administered by injection in pure form and thus any physiological relevance this has to dietary exorphins is unclear. This is a common limitation in this field and while I will not continue to emphasize it for this blog post, please keep it in mind. Related to stimulating hormone release, there is a hypothesis that exorphins could serve a hormonal signaling function in a lactating individual. The idea is that exorphins are produced in the mammary glands and released to enter the systemic circulation, where they activate MORs in the hypothalamus of the brain to stimulate prolactin release [Yen et al. 1985, Teschemacher and Koch, 1990]. Another interesting effect reported with several BCMs are immunomodulatory effects [Elitsur & Luk, 1991, Robinson et al. 2024]. It is thought by some that exorphins are involved in “the development of innate immunity, lymphocyte proliferation and cellular immunity” [Ul Haq et al. 2014]. These immunological effects may be especially important for the development of the GI immune function during development. In case you are wondering how much this matters, it is estimated that 70% of our entire immune system is located in our GI tract.
Given the many possible physiological effects, it is easy to speculate on potential beneficial role of milk derived exorphins on nursing infants. But what about plant protein derived exorphins? What evolutionary function could plant derived exorphins possibly serve? For one, plant derived exorphins have been shown to affect feeding behavior, as orally administered soymorphins 5, 6, and 7 reduced food intake in fasted mice as well as slowed intestinal transit times [Kaneko et al. 2010]. By affecting feeding behavior, the intestinal environment and transit times, dietary exorphins could benefit the parent plant species by limiting over predation, aiding in seed dispersal, or enhancing the biological fitness of the plant in some other way. The effects could be mutually beneficial with exorphins enhancing the biological fitness of the plant as well as the consumer species; after all, plants have a vested interest in the health of their pollinators and seed dispersers. It is certainly no coincidence that most fruits are eye-catching delicious wonders packed full of energy dense nutrients, vitamins, and antioxidants. The situation with seeds, which tend to be high sources of proteins and thus potential exorphin sources, is obviously more complex. Digesting seeds prevents their reproductive function, but some, damaged during ingestion, may be sacrificed for the benefit of their siblings, essentially a form of passive statistical altruism. Many seeds only germinate after passing through a GI tract, presumably extending their dispersal distances. Slowing transit and aiding nutrient uptake, may allow the healthy well-fueled seed disperser to travel greater distances before depositing the seeds.
Another intriguing area of study is the interaction between exorphins and the gut microbiome. It is estimated that there are >100-trillion microorganisms making up the microbiome of an adult human; these include bacteria, fungi, and viruses [Robinson et al. 2024]. The effects of dietary β-casein milk proteins (source of BCMs) on the gut microbiome are being actively studied [Robinson et al. 2024]. Many BAPs including exorphins, like the lactoferrins, have antimicrobial actions which could influence the microbiome composition [Ul Haq and Ul Haq. 2020]. While it is interesting to consider how exorphins impact the microbiome, it is also conceivable that the microbiome is active in the production and clearance of exorphins given that many of these microorganisms produce their own metabolic enzymes. This adds an additional layer of complex interspecies interactions. Microorganisms can produce exorphins outside the gut as well. BCMs are produced by bacteria used in cheese and yogurt production [Hamel et al. 1985, Ul Haq and Ul Haq. 2020]. BCM-7 has been detected in Cheddar, Gouda, Gorgonzola, and Brie cheeses, albeit in a low concentration range of 0.01-0.11 µg/g [Ul Haq and Ul Haq. 2020].
Constantly exposing ourselves to milk exorphins as adults may have adverse health effects. Exorphins, especially milk-derived, are suggested to be responsible for numerous health issues in adults including gut dysfunction, autoimmune disorders (e.g., type 1 diabetes, celiac disease, food allergies), heart disease, sudden infant death syndrome, and even schizophrenia and autism [Ul Haq et al. 2014, Ul Haq and Ul Haq 2020b, Bolat et al. 2024, Robinson et al. 2024]. The potential adverse health effects have led to catchy phrases in the medical literature that demonize exorphins like “Devil in the Milk” [Woodford. 1990]. This is quite the spectrum of purported health harms and many of the claims are based on very scant evidence. But we can’t throw the baby out with the bathwater, as in a few cases the evidence is fairly persuasive. For example, a study by Ho et al. (2014) associated the consumption of A1 type milk with abdominal pain and changes in stool consistency in humans. Remember A1 type milk is associated with higher levels of BCM-7 production. Similar findings have been reported by others and this has been reviewed in Robinson et al. 2024. BCM-7 has also been implicated in other milk sensitivities and allergies, which typically involve GI distress [Bolat et al. 2024]. The association of MOR agonist exorphins with GI dysfunction seems reasonable. As a nearly lifelong chronic pain patient, I am quite familiar with the GI dysfunction associated with MOR agonists. Like other opioid users, I experience a number of GI issues, but one strange one is that over the years I have become increasingly sensitive to fatty foods – to the point I now become nauseous, violently vomit, and endure severe intestinal cramps following even mild indulgence. While researching exorphins, I learned that MOR agonists can affect the sphincter of Oddi, reducing bile secretion and that chronic use of opioid agonists can cause bile-related GI dysfunctions [Sherman and Lehman. 1994]. This seems a reasonable hypothesis as bile salts play an essential role in the absorption of fats. This issue first started with a fried seafood basket about a year or so after starting daily use[2]. So, it would not shock me at all if like other opioids [Brock et al. 2012], exorphins can cause GI complications.
There is also evidence suggesting a causative role of BCMs in cases of type I diabetes. This is based in part on epidemiological studies showing correlation between consumption of A1-type milk and an elevated risk of type 1 diabetes [Elliott et al. 1999, Schranz and Lernmark. 1998, Ul Haq and Ul Haq. 2020c]. However, correlation is not causation and many other uncontrolled factors confound a clear interpretation. Some of the evidence that supports a causative link includes the detection of β-casein antibodies in patients with type I diabetes and the induction of “diabetogenic effects” in rodents by chronic β-casein administration [Bolat et al. 2024]. One way this is thought to develop, is that BCM-7 can exerts pro-inflammatory effects while also suppressing white blood cell proliferation. This generates an immune vulnerability to enteroviruses and other pathogens, sensitizing the individual to risk factors for developing an autoimmune disorder like type I diabetes [Graves et al. 1997, Ul Haq and Ul Haq. 2020c, Bolat et al. 2024]. The microbiome may also be important here. Chronic morphine has been reported to alter the microbiome in pathogenic ways in mice [Wang et al. 2018]. These effects include “preferential expansion of Gram-positive pathogenic and reduction in bile-deconjugating bacterial strains” [Banjerjee et al. 2016].
The challenges of implicating exorphins in disease are many and were recently reviewed by de Vasconcelos et al. 2023. Areas that I feel definitely deserve attention are quantifying the levels of specific exorphins reached during digestion and more work assessing MOR receptor mediated effects in vivo under physiologically relevant conditions. It is also important to acknowledge that physiological effects will be highly individualized, dependent on genetics, the microbiome, diet, eating habits, etc. So, all of this needs to be considered. Again, to say biology is complex is an understatement.
Where is the research with exorphins going? I think much will come from this research including better understanding the health impacts of our diet, understanding our physiology, and new ideas for drugs. I can think of many applications for this knowledge, and I’m sure even more exist that I can’t think of. As one example, I envision a future where we design the proteins in our food to contain specific BAPs. Engineering our food at the molecular level is an obvious approach to improving our health. This form of beneficial food engineering contrasts sharply with the current status quo of engineering our food to maximize profitability and reinforce its hedonic impact and addictiveness. This strategy comes with extensive costs to our health and economic wellbeing. Furthermore, a society must possess an extraordinary form of delusion to be able to advocate for a “drug free America” to “protect the children” while seeing no issue in aggressively developing, marketing, and feeding caffeinated corn syrup, silicon-grease soaked fries, and artery clogging grease burgers sandwiched between sugar bread to these very children. Oh, and let’s feed them amphetamine so they sit still while we preach to them about the dangers of drugs. The only conceivable upside is that this kind of extraordinary self-deceit tends to find its way into the history books, to serve as a monument to the rawest form of uncut senselessness, which a society would be wise to avoid going forward.
Anyway, it's about time for my radium bath, so time to wrap this up. The exorphins represent a fascinatingly rich scientific terrain for exploration and discoveries. By exploring these molecules deeper, we better understand our biology and learn much that will help construct a happier and healthier future. So, the next time you drink a glass of milk, enjoy some Gouda, or edamame beans, take a moment to appreciate the various peptide exorphins being formed in your intestines and envision them wiggling around on their journey to a fateful collision with that magnificent receptor, MOR.
Footnotes:
[1] Our DNA codes for the amino acid subunits making up each protein. In essence a gene is a code for making a given protein. Like proteins, DNA is a linear chain, in this case composed of nucleotide building blocks. There are 4 differen nucleotide building blocks. Every 3 nucleotides in the chain codes for one amino acid, start, or stop and is called a “codon”. Specialized proteins can read the codons and “translate” them into proteins in the cell. In reality it is a bit more complicated, there are several types of RNA involved, but that’s the gist.
[2] Eluxadoline is a non-selective MOR and KOR agonist and DOR antagonist opioid receptor ligand that is approved for treatment of diarrhea and diarrhea-predominant irritable bowel syndrome. In 2017, the Food and Drug Administration (FDA) issued an “alert” to raise awareness about an increased risk of developing pancreatitis in patients taking eluxadoline who lack a gallbladder. It is believed that spasms of the sphincter of Oddi can lead to severe pancreatitis in these patients.
Acknowledgements: Michael Dybek, Chris Orme, and Philip White provided valuable feedback and corrections. Any remaining oversights are thus entirely their fault! Chris created the cover image using DALL·E. Sam Greaves provided editorial feedback and formatted.
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