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β-casein is a major protein expressed in human and cow's milk and is present in many food products derived from milk. In cow's milk, two primary variants of β-casein, termed A1 and A2, and several rarer sub-variants have been identified. A1 and A2 β-casein differ in their protein structure by a substitution of the amino acid at position 67. A1 β-casein contains a histidine residue at this position, which allows cleavage of the preceding seven amino acid residues to yield the peptide β-casomorphin-7 (BCM-7) (Figure 1).

figure 1

Figure 1. Formation of β-casomorphin-7 (BCM-7)

A2 β-casein contains a proline residue, which prevents cleavage of this peptide.

The other major peptides formed by the cleavage of β-casein are indicated in Figure 1B. The digestion of β-casein is rapid, and is thought to be completed within about 60 min under gastro-analogous conditions.3 BCM-7 has the potential to cross the gastrointestinal wall to enter the systemic circulation, where it may influence systemic and cellular activities by acting on opioid receptors. BCM-7 may also be able to cross the blood–brain barrier to influence central nervous system activities. β-casein proteins derived from human breast milk,4 goat's milk,5 and sheep's milk6 are homologous to bovine A2 β-casein,7 based on the published protein sequences.

A2 β-casein is the original beta-casein type

A1 β-casein is thought to have arisen from natural genetic mutation in European cattle breeds (Bos Taurus) ~5000 years ago. Prior to this time and in some existing breeds of cattle outside of Europe (Bos Indicus) A2 β-casein was the original type.

Due to the high milk yield from European cattle breeds (e.g. Holstein Fresian), it is thought that much of the world drinks a mixture of A1 and A2 β-casein.

BCM-7 is an exorphin that influences opioid signalling throughout the body

BCM-7 and other derivatives of β-casein are potent exogenous agonists of opioid receptors (exorphins), with greatest affinity for μ opioid receptors. The role of opioid receptors in mediating the effects of BCM-7 is supported by the finding that naloxone, a μ opioid receptor-specific competitive antagonist, prevents many of the effects of BCM-7, including effects on gastrointestinal motility and mucus secretion, lymphocyte proliferation, and histamine release from peripheral leukocytes. The affinity of bovine BCM-7 to opioid receptors is approximately 10 times greater than that of human BCM-7, as it requires a 10- fold greater naloxone concentration to prevent receptor binding.

Opioid receptors are expressed by many cell types in most organs. Levels of μ opioid receptors are highest in the hypothalamus, cerebral cortex, and spleen, moderate in the cerebellum, intestine, kidney, adrenal, and reproductive organs, and lowest in the lung and liver. μ opioid receptors are not expressed in the stomach, heart, or endothelium. Opioid receptors are also expressed on inflammatory cells, including lymphocytes and leukocytes.

Experimental studies have shown that BCM peptides and analogues may be able to cross the blood–brain barrier. This is particularly evident in regions with ‘leaky' capillaries, such as the pineal gland, the neurohypophysis, and the choroid plexus. Therefore, BCM peptides may influence central signalling pathways after crossing the blood–brain barrier.

BCM-7 is metabolised by dipeptidyl peptidase 4 (DPP4)

BCM-7, and other related peptides with an amino acid sequence of Tyr-Pro-Phe-Pro-Gly- Pro-Ile, including their C-terminally shortened fragments, are primarily degraded by DPP4.

DPP4 is a protease that selectively removes the N-terminal dipeptide from peptides bearing a Pro or Ala residue at position 2.

It is principally expressed on T lymphocytes and a soluble form exists in plasma. A recent study of infants revealed that infants with apparent life- threatening apnoea had markedly elevated BCM-7 levels but much lower serum DPP4 activity compared with healthy infants of the same age. Those results suggested that individuals with lower DPP4 activity may be more prone to the potential adverse effects of BCM-7; however, the results need to be confirmed in further studies.

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Neurological effects of BCM-7

BCM-7 has the potential to cross the gastrointestinal wall and the blood–brain barrier, so it may influence peripheral and central systems.

In fact, BCM-7 has been linked with several neurological disorders, including autism, schizophrenia, respiratory depression/apnoea and psychomotor development.

Associations of β-casein with autism and schizophrenia

Several studies have reported a link between casein and autism spectrum disorders, including elevated urinary peptide secretion and the presence of antibodies to casein in individuals with autism and schizophrenia. However, some studies have reported no such association. This has given rise to the popularity of gluten-free casein free diets amongst patient groups centred on the management of behavioural symptoms.
However, the effects of casein augmenting the symptoms of autism and schizophrenia are hypothesised to be attributed to exorphin activity in the brain.

Evidence from Animals Models:

Indeed, it was reported that BCM-7, a product of A1 β-casein digestion, significantly reduced normal behaviours, such as rearing, walking and grooming in rats, and enhanced abnormal activities, such as explosive motor behaviour, circling and decreased social interaction.

These behavioural effects of BCM-7 were caused by its interaction with opioid receptors, as the effects were abolished by the specific opiate- receptor antagonist naloxone.
BCM-7 also induced fos-like immunoreactivity in brain regions relevant to schizophrenia, particularly the prefrontal cortex, the nucleus accumbens, the bed nucleus of the stria terminalis, and the caudate–putamen.

BCM-7 inhibits cysteine re-uptake

BCM-7 may also augment the symptoms of schizophrenia and autism by inducing oxidative stress in the brain. In vitro, BCM-7 was reported to lower cellular levels of glutathione, an antioxidant, by inhibiting cysteine uptake.


Source. Trivedi et al. (2014)

β-casein can also promote low-density lipoprotein (LDL) oxidation, which is normally associated with atherosclerosis. However, abnormal lipid oxidation may also occur in the central nervous system, and may exacerbate the oxidative environment in neurological disorders like schizophrenia. This oxidative environment can result in impaired methylation of DNA and phospholipids, for example, and neurological deficits that ultimately manifest as symptoms of schizophrenia and autism.

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