Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers

Abstract

Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB(1) (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB(1) receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ∼4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB(1) receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB(1) receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.

Figure 1

V_T of [¹⁸F]FMPEP-d₂ in cortical regions is lower at baseline in chronic daily cannabis smokers (black bars, n = 30) than in control subjects (gray bars, n = 28). Values are estimated marginal means from the repeated measures analysis variance that controls for BMI. Values are adjusted to an average BMI of 24.8 kg m⁻². Error bars are s.e.m. Abbreviations: 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; *P < 0.05; **P < 0.005, two-tailed t-test.

Figure 2

BMI-adjusted V_T of [¹⁸F]FMPEP-d₂ at baseline was unchanged in cerebellum (−2%, P = 0.703, two-tailed t-test; a), but decreased in anterior cingulate cortex (−21%, P = 0.0005, two-tailed t-test; b) in chronic daily cannabis smokers (n = 30) compared with control subjects (n = 28). Ratio of V_T in anterior cingulate cortex to that in cerebellum decreased variance in both groups and showed a more significant reduction in cannabis smokers (−20%, P = 0.0000001, two-tailed t-test; c).

Figure 3

Statistical parametric mapping (SPM) analysis shows lower V_T in chronic daily cannabis smokers (n = 30) than in control subjects (n = 28) at baseline as a large single cluster that includes only cortical regions. This cluster comprised 67 513 voxels, had a maximum t-value of 2.8 at [−34, −78, 16] and had a cluster-level corrected P-value of 0.043. Color bar represents t-value in each voxel within the significant cluster.

Figure 4

V_T of [¹⁸F]FMPEP-d₂ increased after abstinence in the 14 cannabis smokers who completed two PET scans before and after abstinence. Significant increases were mostly seen in regions with reduced V_T at baseline. Error bars are s.d. of percent change. Abbreviations of brain regions are the same as those in Figure 1. *P < 0.05, two-tailed paired samples t-test.