Decreased Cannabinoid CB1 Receptors in Male Tobacco Smokers Examined With Positron Emission Tomography

Abstract

Background: Previous studies showed reduction of brain cannabinoid CB1 receptors in adults with cannabis and alcohol use disorders. Preclinical data suggest that these receptors also contribute to nicotine reward and dependence. Tobacco smoking may confound clinical studies of psychiatric disorders because many patients with such disorders smoke tobacco. Whether human subjects who smoke tobacco but are otherwise healthy have altered CB1 receptor binding in brain is unknown.

Methods: We measured CB1 receptors in brains of 18 healthy men who smoke tobacco (frequent chronic cigarette smokers), and 28 healthy men who do not smoke tobacco, using positron emission tomography and [18F]FMPEP-d2, a radioligand for CB1 receptors. We collected arterial blood samples during scanning to calculate the distribution volume (VT), which is nearly proportional to CB1 receptor density. Repeated-measures analysis of variance compared VT between groups in various brain regions.

Results: Brain CB1 receptor VT was about 20% lower in subjects who smoke tobacco than in subjects who do not. Decreased VT was found in all brain regions, but reduction did not correlate with years of smoking, number of cigarettes smoked per day, or measures of nicotine dependence.

Conclusions: Tobacco-smoking healthy men have a widespread reduction of CB1 receptor density in brain. Reduction of CB1 receptors appears to be a common feature of substance use disorders. Future clinical studies on the CB1 receptor should control for tobacco smoking.

Trial registration: ClinicalTrials.gov NCT00816439.

Keywords: Addiction; Brain imaging; Cannabinoid CB(1) receptor; Positron emission tomography; Smoking; Tobacco.

Conflict of interest statement

DISCLOSURES

The authors report no biomedical financial interests or potential conflicts of interest.

Copyright © 2018 Society of Biological Psychiatry. All rights reserved.

Figures

Figure 1.

Distribution volume (VT) of [18F]FMPEP-d2 (a measure of cannabinoid CB1 receptor density) is lower in male tobacco smokers (black bars, n = 18) than in nonsmokers (gray bars, n = 28) in both cortical and subcortical regions. Values are estimated marginal means from the repeated-measures analysis of variance and are adjusted to an average body mass index of 26.8 kg/m2. Error bars are standard error of the mean. *p < .05; **p < .005; post hoc contrasts of marginal means from analysis of variance. ACC, anterior cingulate cortex; AMY, amygdala; CAU, caudate nucleus; CER, cerebellum; HIPP, hippocampus; INS, insula; MIDBR, midbrain; OCC, occipital cortex; PAR, parietal cortex; PCC, posterior cingulate cortex; PFC, prefrontal cortex; PHIPP, parahippocampal gyrus; PUT, putamen; TEMP, lateral temporal cortex; THA, thalamus; VST, ventral striatum; WM, white matter.

Figure 2.

Individual body mass index–adjusted [18F]FMPEP-d2 distribution volume (VT) values in average cortical, subcortical, and white matter regions in nonsmokers (open circles) and smokers (closed circles).

Figure 3.

Whole-brain statistical parametric mapping analysis shows lower cannabinoid CB1 receptor density (distribution volume [VT]) in male tobacco smokers (n = 18) than in nonsmokers (n = 28) as a large single cluster. This cluster comprised 132,291 voxels with a maximum t value of 6.0 at [22, 10, 46] and a cluster-level familywise error corrected p value of <.001. Color bar represents t value in each voxel within the significant cluster. (A) Transaxial section. (B) Coronal section. (C) Sagittal section.