Drug Transporters and Genetic Risk of Dependence

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Scientists have discovered that cannabis dependence is associated with the genetics of a “drug transporter” that controls the entry of THC into your brain.

About 1 in 11 cannabis users will show signs of dependence. The risk of cannabis dependence is dependent on your genetics – in fact, a study of twins found that about 50% of the risk of dependence is hereditary.

There are some genes which confer risk to substance abuse in general, but there are few that are specifically linked to cannabis dependence. One of the genes associated with cannabis dependence is for a drug transporter called P-glycoprotein.

What are drug transporters?

These aren’t the drug transporters that haul narcotics across national borders. These are proteins that control how much of a drug (such as THC) crosses a membrane. Drug transporters do this by acting as a pump – i.e. they move drugs across the membrane, even in the opposite direction of the concentration gradient.

Two important functions of drug transporters are:

  • Limiting how much of a drug gets absorbed from the GI tract
  • Limiting how much of a drug crosses the blood-brain barrier

The neurons in your brain are especially sensitive to the toxic effects of many drugs and also they are not easily replaceable like other cell types. Your neurons are protected by the blood-brain barrier, which limits access of drugs to your brain.thc-drug-transporters-blood-brain-barrier

Drug transporters are an important part of the blood-brain barrier. They are present on the endothelial cells of the blood vessels in the brain, where they pump drugs and toxins back into blood.

The next section will explain the science behind drug transporters and THC.

Drug transporters and THC brain penetration

Here are two of the most well-studied and important drug transporters:

  • P-gp (P-glycoprotein, a.k.a. ABCB1)
  • BCRP (breast cancer resistance protein, a.k.a. ABCG2).

A study in transgenic mice shows that both of these limit how much THC reaches your brain. The transgenic mice were genetically modified to either not express the P-gp protein or not express the BCRP protein.

drug-transporter-transgenic-knockout-thc-brain-penetration

The brain THC concentrations of wild-type mice (which have both transporters) are fairly similar to the P-gp null and BCRP null mice up to about 1 hour after the dose. After this time, brain THC concentrations in wild-type mice start to decline. However, in the mice missing either transporter, brain THC concentrations are stable or even continue to climb.

These scientists also measured the hypothermic (body temperature lowering) effect of THC. They saw that in wild-type mice, body temperature was back to normal by two hours, but the mice missing either transporter were still hypothermic at 3 hours. Thus, we can see that drug transporters control the duration of effect of THC in the brain.

[Want to know which version of the P-gp gene you have? You can use 23andMe to find out.] 

 

Drug transporter genetics determine risk of cannabis dependence

We have seen that completely removing a drug transporter changes THC brain penetration in mice, but what relevance does this have for humans? Well there are genetic variants in the genes for the P-gp and BCRP transporters that can change their expression (i.e. how much of the protein there is) and also their activity (how well they work).

I previously covered the pharmacogenetics of drug metabolizing enzymes on THC metabolism here and here. The first article has much more background on pharmacogenetics if you want to read up.

There is a polymorphism in the gene for P-gp that reduces its expression (called the C3435T polymorphism). In theory, the brain THC penetration of people with this allele will look like the P-gp null mice. After consuming cannabis, they should have an effect that lasts much longer.

One genetic study compared the rate of the C3435T polymorphism in people who showed signs of dependence to cannabis and matched controls who tried cannabis but did not develop dependence.

The C3435T polymorphism was a significant risk factor for cannabis dependence, even after controlling for other risk factors (for example, socio-professional status and prior addictive disorders were also significant).

 However, contrary to what you might think, it was people with the CC genotype (who express more P-gp, and thus have lower THC brain concentrations) who had the highest risk for cannabis dependence.

drug-transporter-p-gp-pharmacogenetics-cannabis-dependenceAmong people with cannabis dependence, half had the CC genotype. Among the controls without cannabis dependence, only 20% had the CC genotype.

[Want to know which version of the P-gp gene you have? You can use 23andMe to find out.] 

 

Why does less brain penetration lead to more cannabis dependence?

There is some evidence that short-acting drugs are more addictive. For example, nicotine and cocaine (two of the most addictive drugs known) both have a short duration of effect. It is this short effect that may induce people to take them more often and thus develop an addiction.

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[Flickr/ volver-avanzar!!!]

It is possible that people with the CC genotype (who have more P-gp, and thus shorter effect of THC) tend to develop cannabis dependence due to the effects wearing off quickly. However, this is all a bit speculative.

Similarly, there are also BCRP polymorphisms in humans that cause decreased activity. Although these haven’t yet been studied in the context of cannabis, it is possible that people with reduced activity in both P-gp and BCRP may be the ones most at risk for cannabis dependence.

[Want to know which version of the P-gp gene you have? You can use 23andMe to find out.] 

[Featured image: Wikipedia]

Last modified: September 11, 2017

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