Smoking Tobacco is Associated with Reduced CB1R Density in the Brain

Post by Shireen Parimoo

What’s the science?

The cannabinoid type 1 receptor (CB1R) is a presynaptic receptor that’s present throughout the brain. It’s highly concentrated in areas involved in reward and addiction, like the basal ganglia, and it modulates GABA and glutamate (neurotransmitter) release in response to substances such as cannabinoids, alcohol, and nicotine. CB1R density is reduced in the brains of people with alcohol dependence and in chronic cannabis users. As CB1Rs are activated by nicotine, would CB1R density also be lower in smokers? In previous studies, participants who smoked tobacco also had alcohol and cannabis use disorder, making it difficult to find a direct link between nicotine use and CB1R density. This week in Biological Psychiatry, Hirvonen and colleagues systematically examined CB1R density in the brains of participants with nicotine dependence (and no other substance use disorder).

How did they do it?

Forty-six healthy men participated in the study; 18 had mild-to-moderate tobacco use disorder (smokers) and 28 were non-smokers (healthy controls). None of the participants had alcohol or cannabis use disorder. All participants underwent a two hour positron emission tomography (PET) scan, before which they were injected with [18F]FMPEP-d2, a radioligand that binds to CB1 receptors in the brain. This technique allows us to infer the density of CB1Rs by estimating the ratio of the concentration of ligand in the brain to plasma (VT). The authors also obtained genotype data from 43 participants, as carriers of the C allele of a single nucleotide polymorphism (SNP), rs2023239, in the gene CNR1 (encoding the CB1R receptor) tend to have higher levels of [18F]FMPEP-d2 binding. Participants’ smoking habits, like the age at which they started smoking and their frequency of smoking, were collected. Finally, the authors combined data from previous studies that used PET imaging in participants with alcohol and cannabis use disorder in order to examine the effect of smoking, substance use disorder, genotype, and body-mass index (BMI) on CB1R density in the brain.

What did they find?

Smokers had reduced CB1R density across several brain regions versus non-smokers. CB1R density was not reduced uniformly across the brain; it ranged from a 17% decrease in the prefrontal cortex to a 28% decrease in the midbrain. Even after ruling out the effect of BMI and genotype, the difference in CB1R density in the brains of smokers and non-smokers remained significant. Interestingly, CB1R density was not related to the age at which participants started smoking, how often they smoked, or to their level of nicotine dependence. After combining data across multiple studies, the authors also found an effect of smoking, other substance use disorders, and BMI on CB1R density. However, these effects diminished when the authors accounted for the effect of genotype. Finally, participants with a substance use disorder who also smoked did not exhibit additional CB1R down-regulation compared to those who only smoked (although CB1R density in both groups was still lower than in healthy controls).

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What’s the impact?

This is the first study to report reduced CB1R density across various brain regions of male smokers compared to healthy controls, without the confounding effect of other substance use disorders. Importantly, the authors also demonstrated that consumption of multiple substances – such as alcohol and tobacco – does not have an additive effect on CB1R density above and beyond dependence on one substance. These results provide further insight into the effects of nicotine dependence, though more research is needed to determine whether these findings will generalize to females and to other substance use disorders.

Hirvonen et al., Decreased Cannabinoid CB1 Receptors in Male Tobacco Smokers Examined with Positron Emission Tomography. Biological Psychiatry (2018). Access the original scientific publication here.