Some breeds of dog are susceptible to developing a mutation in the MDR 1 gene (for Multi Drug Resistance).

This anomaly is responsible for increased sensitivity to certain common medications such as antiparasitics or antidiarrheals.

The mutation of the MDR1 gene in dogs causes neurological toxicity phenomena (which can lead to the death of the animal) following the ingestion of these molecules, even at normal doses.

The Australian Shepherd and the Shetland are among the breeds at risk.

The list of drugs involved is long and varied.

What about CBD and MDR1? Is cannabidiol potentially dangerous for our Aussies?

On this subject, scientists are rather reassuring, pointing out a cerebral action of CBD independent of the MDR1 mutation in dogs.

 

What is the MDR1 gene in dogs?

This gene codes for a protein essential in the elimination of certain toxins.

Dog MDR1 gene: definition

The MDR1 gene codes for a protein, P-glycoprotein , which is found in the blood-brain barrier, i.e. the membrane that surrounds the brain.

This barrier is filled with blood vessels which will bring nutrients to the brain but also allow the passage of certain medications.

P-glycoprotein serves as a transporter across the membrane . It pumps various drugs and toxins that have entered the brain and releases them into the bloodstream.

The mutation of the MDR1 gene in dogs was recently discovered (2001) by a team of American researchers (1).

They highlighted a deletion mutation of the MDR1 gene associated with sensitivity to ivermectin in the Collie.

The deletion of the gene results in the formation of several stop codons that prematurely terminate the synthesis of P-glycoprotein: When the gene is mutated, P-glycoprotein does not function properly. It no longer performs its role as a “purifier” and drugs accumulate in the brain, causing overdose symptoms.

The mutation of the MDR1 gene in dogs can be complete or partial: Some animals will have a mutation on their 2 chromosomes (canine chromosomes like those of humans come in pairs), they are said to be homozygous mutated . All their P-glycoproteins are truncated and they are at high risk of drug poisoning.

Dogs that are homozygous normal (no mutations) are at no risk.

Finally, some animals received from their parent a mutated MDR1 gene and a valid MDR1 gene.

They are said to be heterozygous ; the activity of P-glycoprotein is about 50% compared to a normal homozygous dog. These dogs therefore present a risk, but more moderate.

What dog breeds are at risk for MDR1 mutation?

The breeds concerned in France are essentially:

• The Collie and the Shetland
• The Australian Shepherd and the American Shepherd (or Miniature Australian)
• The Swiss White Shepherd

And, to a lesser extent, the Bobtail, the Border Collie and the German Shepherd .

Be careful, crossbred dogs from these at-risk breeds are also likely to have the MDR1 mutation.

Why the Collie or the Australian Shepherd? The mutation is said to have appeared spontaneously in the 18th century on a sheepdog, the ancestor of the Collie breed.

The genetic mutation then spread through generations in the Collie, but also in related breeds.

What are the symptoms associated with MDR1 mutation in dogs?

As we have seen, when the MDR1 gene is mutated, the P-glycoprotein is non-functional and certain drugs accumulate in the dog’s brain, causing different clinical signs:

• Uncoordinated gait, paralysis
• Prostration or, on the contrary, excitement
• Hypersalivation, vomiting
• Dilated pupils, blindness
• Tremors , convulsions
• Coma and death

There is no antidote as such for this poisoning.

Usually, the veterinarian hospitalizes the animal to administer symptomatic and eliminatory treatment.

Please note: Apart from this drug sensitivity, the mutation of the MDR1 gene has no impact on the health and vitality of affected animals.

What medications should be avoided in the event of an MDR1 mutation?

Historically, it was the sensitivity of Collies to ivermectin that was first highlighted.

This antiparasitic is currently little used in dogs for which it does not have a Marketing Authorization (MA), except in cases of stubborn demodicosis (a parasitic skin disease).

The drugs at risk are those transported by P-glycoprotein . Among them:

• Antiparasitics: ivermectin, moxidectin and doramectin
• Emodepside (Profender ®), a dewormer
• Loperamide (Loperal ®, Imodium ®), a very common antidiarrheal

But also anticancer drugs, tranquilizers ( acepromazine ) or painkillers (butorphanol).

Caution is required for all P-glycoprotein substrates.

However, in 2016, the CNITV (Veterinary Poison Control Center) had not highlighted any problems with molecules such as milbemycin (Milbemax®) at the doses recommended by the manufacturer.

What should I do if my dog ​​is a breed at risk for MDR1?

Always seek advice from your veterinarian before administering any medication to your dog!

And read the leaflets, the potential serious adverse effects in MDR1 mutant dogs are often indicated there.

You can also have your dog tested to find out how at risk it is.

Not all at-risk breed dogs have the MDR1 mutation; some are also heterozygous with a lower (but not zero) risk.

It is estimated that approximately 10% of Australian Shepherds and Shetlands are at high risk and 40% are at moderate risk .

In the Collie, it is approximately 45% of individuals at low risk and 40% at high risk !

The test to determine the dog’s MDR1 status is a DNA test .

A painless oral swab is taken by rubbing the oral mucosa or a blood sample is taken.

Some breeders provide testing of the parents, allowing a posteriori assessment of the puppy’s risk: for example, a normal homozygous male and female will give birth to unaffected offspring.

In the case of heterozygous or mutated parents, the puppy will need to be tested.

 

CBD and MDR1 in dogs: friends or foes?

Given the seriousness of the poisonings linked to this genetic anomaly, any owner of a dog at risk is in a position to wonder whether they can safely administer CBD to their companion.

Here are some answers.

How does CBD work?

CBD or cannabidiol is an extract from hemp.

It has been used for many years in humans and animals for its relaxing , analgesic and even anti-convulsant properties.

Unlike THC (delta9-tetrahydrocannabinoid), another component of hemp found in cannabis, CBD is not a narcotic; it does not cause addiction or psychotropic effects.

CBD works in the body by activating the endocannabinoid system (ECS).

This natural system regulates many functions such as mood, sleep, appetite… CBD modifies certain receptors (the cannabinoid receptors CB1 and CB2) to activate the ECS. However, the CB1 are found in the brain, where cannabidiol will penetrate .

So what about our MDR1 mutated dogs, since we know that due to the P-glycoprotein deficiency, certain substances can accumulate in their brain tissue and cause serious poisoning?

CBD and MDR1 in dogs: is there a risk?

Can cannabidiol cause serious side effects in MDR1 mutant dogs, such as some Australian Shepherds, when at the same dose it is safe for a healthy animal?

Scientists provide the beginnings of an answer in a 2016 study on… mice (2).

The aim of the experiment was to determine whether or not CBD was a substrate for the famous P-glycoprotein.

The researchers administered cannabidiol to two groups of mice. One carried the double mutation on the MDR1 gene; its P-glycoprotein was not functional.

The other group of mice was healthy. CBD levels were measured before and after administration of the product in the rodents’ brains and blood.

These levels were equivalent in healthy mice and mutant mice; the researchers conclude that CBD is not a substrate for P-glycoprotein.

In short, CBD is eliminated from the brain of mice by a process other than P-glycoprotein since mutant mice do not have higher brain levels of cannabidiol; MDR1 mutated mice are no more at risk of overdose than non-mutated mice, and it is very likely that this good news is transposable to dogs.

How to administer CBD to an MDR1+ dog?

Given this reassuring experience, it seems natural to give our Collies and Australian Shepherds the benefits of CBD . However, as with any dog, some precautions are necessary:

• Before administering CBD to your companion, make sure to choose a quality product, without THC and certified by an independent laboratory.
• Use CBD for dogs (not for humans!). Do not give cannabis to your pet.
• Always follow the prescribed doses . Ideally, start with the smallest possible dose and gradually increase to the recommended dosage for your pet.
• Store your CBD in a place inaccessible, even to stuntmen!

CBD is an ally of choice to combat stress, anxiety or joint pain in our dear companions… In addition, since cannabidiol is not a substrate of P-glycoprotein, its use in dogs suffering from a mutation on the MDR1 gene is possible by respecting the indicated dosage. MDR1 mutation in dogs and CBD are therefore not incompatible!