Cannabidiol attenuates deficits of visuospatial associative memory induced by Δ(9) tetrahydrocannabinol

Abstract

Background and purpose: Recent human studies suggest that recreational cannabis strains that are relatively high in cannabidiol (CBD) content produce less cognitive impairment than do strains with negligible CBD and similar Δ(9) tetrahydrocannabinol (THC) content. Self-selection in such studies means it is impossible to rule out additional variables which may determine both cannabis strain selection and basal cognitive performance level. Controlled laboratory studies can better determine a direct relationship.

Experimental approach: In this study, adult male rhesus monkeys were assessed on visuospatial Paired Associates Learning and Self-Ordered Spatial Search memory tasks, as well as additional tests of motivation and manual dexterity. Subjects were challenged with THC (0.2, 0.5 mg·kg(-1) , i.m.) in randomized order and evaluated in the presence or absence of 0.5 mg·kg(-1) CBD.

Key results: CBD attenuated the effects of THC on paired associates learning and a bimanual motor task without affecting the detrimental effects of THC on a Self-Ordered Spatial Search task of working memory. CBD did not significantly reverse THC-induced impairment of a progressive ratio or a rotating turntable task.

Conclusions and implications: This study provides direct evidence that CBD can oppose the cognitive-impairing effects of THC and that it does so in a task-selective manner when administered simultaneously in a 1:1 ratio with THC. The addition of CBD to THC-containing therapeutic products may therefore help to ameliorate unwanted cognitive side-effects.

Linked article: This article is commented on by Mechoulam and Parker, pp 1363-1364 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12400.

Keywords: Macaca mulatta; cannabis; marijuana; working memory.

Figure 1

Bimanual Motor Skill Task: The mean (n = 9; ± SEM) latency to retrieve 15 raisins in the Bimanual Motor Skill task is depicted. A significant difference from the baseline and the respective timepoint after vehicle treatment is depicted with the &, from the baseline with @ and between THC and THC/CBD conditions by #. CBD, cannabidiol; THC, Δ⁹tetrahydrocannabinol. 0.5 = intramuscular dose in mg·kg⁻¹ bodyweight.

Figure 2

Visuospatial Paired Associates Learning Task: The mean (n = 8; ± SEM) overall task completion accuracy and percent task completed is presented for the four trial difficulty conditions of the visuospatial Paired Associates Learning task. This figure illustrates that the effect of THC administered alone is most pronounced on the most-difficult trial types. A significant difference from the vehicle condition is depicted with *. CBD, cannabidiol; THC, Δ⁹tetrahydrocannabinol. 0.2, 0.5 = intramuscular dose in mg·kg⁻¹ bodyweight.

Figure 3

Cannabidiol reverses the THC effect on the vsPAL task: The effect of CBD on the THC-induced impairment of mean (n = 8; ± SEM) overall task completion accuracy and percent task completed is presented for the four-stimulus trials of the visuospatial Paired Associates Learning task. A significant difference from the vehicle condition is depicted with * and differences associated with the presence/absence of CBD with #. CBD, cannabidiol; THC, Δ⁹tetrahydrocannabinol. 0.2, 0.5 = intramuscular dose in mg·kg⁻¹ bodyweight; vsPAL, visuospatial paired associated learning.

Figure 4

Self-Ordered Spatial Search Task: The mean (n = 6; ± SEM) trial completion accuracy is presented for the three trial types within the Self-Ordered Spatial Search task. A significant difference from the vehicle condition within trial type is depicted with *. CBD, cannabidiol; THC, Δ⁹tetrahydrocannabinol. 0.2, 0.5 = intramuscular dose in mg·kg⁻¹ bodyweight.

Figure 5

Progressive Ratio and Rotating Turntable Tasks: The mean reinforcers acquired and time of last response in the Progressive Ratio (n = 9; ± SEM) task (upper panel) and the mean retrieval threshold for the Rotating Turntable (n = 10; ± SEM) task (lower panel) are presented. A significant difference from the vehicle condition is depicted with *. CBD, cannabidiol; THC, Δ⁹tetrahydrocannabinol. 0.2, 0.5 = intramuscular dose in mg·kg⁻¹ bodyweight.