Effects of inhaled cannabis high in Δ9-THC or CBD on the aging brain: A translational MRI and behavioral study

Abstract

With the recent legalization of inhaled cannabis for medicinal and recreational use, the elderly represents one of the newest, rapidly growing cohorts of cannabis users. To understand the neurobiological effects of cannabis on the aging brain, 19–20 months old mice were divided into three groups exposed to vaporized cannabis containing ~10% Δ9-THC, ~10% CBD, or placebo for 30 min each day. Voxel based morphometry, diffusion weighted imaging, and resting state functional connectivity data were gathered after 28 days of exposure and following a two-week washout period. Tail-flick, open field, and novel object preference tests were conducted to explore analgesic, anxiolytic, and cognitive effects of cannabis, respectively. Vaporized cannabis high in Δ9-THC and CBD achieved blood levels reported in human users. Mice showed antinociceptive effects to chronic Δ9-THC without tolerance while the anxiolytic and cognitive effects of Δ9-THC waned with treatment. CBD had no effect on any of the behavioral measures. Voxel based morphometry showed a decrease in midbrain dopaminergic volume to chronic Δ9-THC followed but an increase after a two-week washout. Fractional anisotropy values were reduced in the same area by chronic Δ9-THC, suggesting a reduction in gray matter volume. Cannabis high in CBD but not THC increased network strength and efficiency, an effect that persisted after washout. These data would indicate chronic use of inhaled cannabis high in Δ9-THC can be an effective analgesic but not for treatment of anxiety or cognitive decline. The dopaminergic midbrain system was sensitive to chronic Δ9-THC but not CBD showing robust plasticity in volume and water diffusivity prior to and following drug cessation an effect possibly related to the abuse liability of Δ9-THC. Chronic inhaled CBD resulted in enhanced global network connectivity that persisted after drug cessation. The behavioral consequences of this sustained change in brain connectivity remain to be determined.

Chronic exposure to inhaled vaporized cannabis high in Δ9-THC alters brain structure in adult female mice

“…Whether the changes we found in adult females would persist following an extended period of abstinence is unknown. Our laboratory extended these studies on chronic cannabis exposure and age-related changes in brain neurobiology to include very old female mice ( Sadaka et al, 2023 ). Again using the same cannabis sample, vaporization procedure and exposure duration, we found no volumetric changes in the brain with the exception of the DA system as discuss below.…”

“…The present study on adult female mice also found ADC changes in numerous forebrain areas and the olfactory system but only a few changes in the hindbrain. However, in very old female mice there were no significant changes in ADC values with chronic cannabis exposure ( Sadaka et al, 2023 ). Higher or lower values of ADC usually reflect an increase or decrease, respectively, in extracellular water and have been used to follow subtle changes in gray matter microarchitecture with head injury ( Kulkarni et al, 2015 ).…”

“…Would males have shown the same changes in measures of VBM and DWI? The recent study by Sadaka et al (2023) on old mice was composed of 19 females and 4 males. There were no obvious differences between the two sexes, so while the sample was very small there is no reason to assume a sex difference in Δ9-THC induced neuroplasticity in adult animals exposed to vaporized cannabis.…”

“…Interestingly, the Coleman study on periadolescent mice exposed to vaporized cannabis found no change in the DA system with VBM and a modest change in ADC values, and only then to the accumbens core (Coleman et al, 2022). The Sadaka et al (2023) study on old female mice found a significant reduction in volume in the DA system but no change in ADC values in response to chronic cannabis exposure.…”

“…While there have been many studies on adults ranging from 18 to 40 years of age, the participants have a long history of cannabis use, so it is not possible to discern the effects of chronic cannabis exposure on the drug naïve, adult brain. In a recent study Sadaka et al (2023) exposed old female mice, 19–20 months of age, to vaporized cannabis high in THC (10.3%) for 28 days and reported structural changes in the dopaminergic (DA) system. This finding is evidence that the drug-naïve, aged brain can make neuroadaptive changes to repeated exposure to inhaled cannabis and raises the possibility of abuse liability in the elderly population.…”