Behavioral and Molecular Effects of THC and CBD in Adolescent Nonhuman Primates

Abstract

The marijuana plant produces over 100 different cannabinoids, including Δ9− tetrahydrocannabinol (THC) and cannabidiol (CBD). THC concentrations in retail marijuana have risen dramatically, while CBD levels have declined. High concentrations of THC and high ratios of THC:CBD in marijuana are thought to be associated with more robust psychoactive effects, while CBD has been reported to attenuate THC‐induced effects. The current study sought to compare the behavioral and molecular effects of THC alone and THC combined with CBD in adolescent nonhuman primates in order to investigate, across a wide range of parameters, whether CBD modulates the effects of THC.Twelve male adolescent squirrel monkeys (2.3 – 2.5 years) were divided into three treatment groups: vehicle control, THC, or THC+CBD (n=4/group). Initially they were treated with low doses of THC or THC+CBD weekly for four weeks. Thereafter, at the onset of the testing regimen, animals received THC (1 mg/kg) or THC+CBD (1 mg/kg+3mg/kg) daily for 4 months. The following parameters were measured: 1. Cognitive ability: Animals were trained to engage in touchscreen‐based cognitive tasks according to previously established methods from our laboratory. 2. Observed behavior: behavior was video‐taped weekly in a Plexiglass observation chamber and rated by an observer blinded to the drug regimen. 3. Blood THC, CBD, and THC metabolites were measured four times over the course of the experiment. THC levels in two brain regions were measured following euthanasia. 4. mRNA levels in selected brain regions were assessed by bulk RNAseq and confirmed by RT‐qPCR.THC and THC+CBD compromised initial learning of a repeated acquisition task. On the first day of daily treatment, THC alone induced emesis, but emesis was attenuated by the co‐administration of CBD. THC or THC+CBD suppressed locomotion and foraging; tolerance developed to the behaviorally suppressant effects during continuous daily exposure. Blood levels of THC and CBD remained relatively stable over 100 days of treatment. On the first day of treatment, levels of 11‐OH‐THC, an active THC metabolite, were lower in subjects that received THC+CBD than those that received THC alone; however this effect was not present at any other time point. Brain levels of THC were approximately 2 times higher than blood levels, and levels of THC were not affected significantly when CBD was co‐administered. Furthermore, daily THC or THC+CBD administered to adolescent monkeys for four months was associated with an altered mRNA transcriptome across multiple brain regions.CBD attenuates some but not all THC‐induced effects in nonhuman primates. Attenuation is unlikely to be related to disrupted THC metabolism or brain entry. Our findings warrant further research into the pharmacological and potential pathological consequences of THC and CBD after long term use, and a comparison of adolescent and adult responses to such cannabinoid exposure.Support or Funding InformationThis work was supported by NIDA grant DA042178.