Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Emotion, Cognition, and Attention: A Double-Blind, Placebo-Controlled, Randomized Experimental Trial in Healthy Volunteers

Timo Woelfl, Cathrin Rohleder, Juliane K Mueller, Bettina Lange, Anne Reuter, Anna Maria Schmidt, Dagmar Koethe, Martin Hellmich, F Markus Leweke, Timo Woelfl, Cathrin Rohleder, Juliane K Mueller, Bettina Lange, Anne Reuter, Anna Maria Schmidt, Dagmar Koethe, Martin Hellmich, F Markus Leweke

Abstract

The two main phytocannabinoids-delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)-have been extensively studied, and it has been shown that THC can induce transient psychosis. At the same time, CBD appears to have no psychotomimetic potential. On the contrary, emerging evidence for CBD's antipsychotic properties suggests that it may attenuate effects induced by THC. Thus, we investigated and compared the effects of THC and CBD administration on emotion, cognition, and attention as well as the impact of CBD pre-treatment on THC effects in healthy volunteers. We performed a placebo-controlled, double-blind, experimental trial (GEI-TCP II; ClinicalTrials.gov identifier: NCT02487381) with 60 healthy volunteers randomly allocated to four parallel intervention groups, receiving either placebo, 800 mg CBD, 20 mg THC, or both cannabinoids. Subjects underwent neuropsychological tests assessing working memory (Letter Number Sequencing test), cognitive processing speed (Digit Symbol Coding task), attention (d2 Test of Attention), and emotional state (adjective mood rating scale [EWL]). Administration of CBD alone did not influence the emotional state, cognitive performance, and attention. At the same time, THC affected two of six emotional categories-more precisely, the performance-related activity and extraversion-, reduced the cognitive processing speed and impaired the performance on the d2 Test of Attention. Interestingly, pre-treatment with CBD did not attenuate the effects induced by THC. These findings show that the acute intake of CBD itself has no effect per se in healthy volunteers and that a single dose of CBD prior to THC administration was insufficient to mitigate the detrimental impact of THC in the given setting. This is in support of a complex interaction between CBD and THC whose effects are not counterbalanced by CBD under all circumstances.

Keywords: cannabidiol; cannabinoids; cannabis; healthy subjects; model psychosis; rct; tetrahydrocannabinol.

Copyright © 2020 Woelfl, Rohleder, Mueller, Lange, Reuter, Schmidt, Koethe, Hellmich and Leweke.

Figures

Figure 1
Figure 1
CONSORT Flow Diagram. CBD, cannabidiol; PLA, placebo; THC, delta-9-tetrahydrocannabinol.
Figure 2
Figure 2
Changes of aspects of emotion from baseline to investigational assessment. From six emotional categories covered by the adjective mood rating scale (EWL), four categories were differentially affected by cannabinoid treatment. (A) Subjects who received the 800 mg of cannabidiol orally (CBD) prior to 20 mg of delta-9-tetrahydrocannabinol orally (THC; CBD/THC) showed significantly reduced performance-related activity difference scores (investigational day—baseline) in comparison to placebo (PLA) prior to placebo (PLA/PLA) (p = 0.002), and CBD prior to placebo (CBD/PLA) (p = 0.035) treated participants. Furthermore, the administration of CBD followed by THC (CBD/THC) led to significantly more pronounced self-rating of depressiveness compared to PLA/PLA (p = 0.015) and CBD/PLA (p = 0.026) at the investigational day (B). Rating of extraversion (C) was significantly lower in subjects treated with CBD/THC in comparison to PLA/PLA (p = 0.013) and CBD/PLA (p = 0.017), indicating a more introverted behavior. (D) Regarding emotional excitability, the overall group difference did not reach significance (p = 0.058). However, by trend, participants treated with CBD/PLA showed decreased excitability difference scores, while the administration of THC/CBD resulted in increased values. PLA/PLA, placebo/placebo; CBD/PLA, cannabidiol/placebo; THC/PLA, delta-9-tetrahydrocannabinol/placebo; CBD/THC, cannabidiol/ delta-9-tetrahydrocannabinol.
Figure 3
Figure 3
Changes of cognition from baseline to investigational assessment. (A) While subjects treated with placebo (PLA) prior to placebo (PLA/PLA) and 800 mg cannabidiol orally (CBD) prior to placebo (CBD/PLA) improved their cognitive processing at the interventional day compared to baseline (reflected by positive difference scores in the Digit Symbol Coding task), subjects receiving 20 mg of delta-9-tetrahydrocannabinol orally (THC) proceeded by placebo (PLA/THC) or CBD (CBD/THC) showed a slightly reduced performance. The difference scores of both PLA/THC and CBD/THC) was significantly lower compared to the CBD/PLA group (PLA/THC: p = 0.039; CBD/THC: p = 0.016). (B) After CBD/PLA, the change in working memory performance (from baseline to 205 min post drug intake) assessed by the Letter Number Sequencing task seemed to be most pronounced. Interestingly the difference score observed for CBD/PLA was significantly higher than the score of the CBD/THC group (p = 0.005). (C) At the interventional day, we observed higher mean attentional d2 scores compared to baseline after PLA/PLA, CBD/PLA, and PLA/THC treatment. In subjects who received CBD/THC, an increased attentional performance was not observed, and the difference score was significantly lower compared to the PLA/PLA (p = 0.005) and CBD/THC (p = 0.010) group. PLA/PLA, placebo/placebo; CBD/PLA, cannabidiol/placebo; THC/PLA, delta-9-tetrahydrocannabinol/placebo; CBD/THC, cannabidiol/ delta-9-tetrahydrocannabinol.

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