Discussion
CUD, anxiety
BLIND
We used a comprehensive cognitive task battery to assess performance before and after 4-week treatment with daily oral 400 mg CBD, 800 mg CBD or placebo in a double-blind, randomised and placebo-controlled clinical trial. Contrary to our hypotheses, there was no effect of CBD on delayed prose recall compared to the placebo. There was a lack of effects of CBD on other cognitive outcomes, apart from a significant dose-by-time interaction indicating that 800 mg CBD improved performance from baseline to week 4 for backwards digit span, a measure of working memory. On the delayed prose recall task (the pre-registered primary outcome), performance increased in all groups from baseline to week 4. Taken together, these results suggest that CBD may not produce broad cognitive effects in people with CUD but could benefit working memory manipulation.Previous evidence has indicated that verbal memory is the key cognitive domain impacted by CBD treatment; however, this was not supported by the current findings. An open-label trial of 200 mg daily CBD over 10 weeks found better verbal learning and memory performance at end of treatment compared to baseline (Solowij et al. We found that 800 mg CBD improved the manipulation of information in working memory indexed via backwards digit span and did not affect maintenance indexed by forward digit span. Previous studies have indicated null effects of CBD on digit span tasks. One experimental study administering a single dose of 600 mg oral CBD did not find a significant effect on forwards or backwards digit span compared to a placebo (Bloomfield et al. Of note, performance improved across some cognitive outcomes from baseline to end of treatment, including both measurements of the prose recall task, psychomotor speed, and category fluency. There are several potential explanations for this. Firstly, cognition may have improved due to lower exposure to THC or general improvement in wellbeing caused by the reduction in CUD over the trial. However, exploratory analyses indicated that the effect of time remained significant after adjustment for urinary THC:COOH levels (except for psychomotor speed), indicating that this was not responsible for the increase in performance. Across the trial, all groups including the placebo group reduced their cannabis use considerably, which might potentially explain why the addition of a urinary marker of recent cannabis use did not alter the pattern of results. Moreover, there was no evidence for the effect of CBD on cognition being greater than placebo in the adjusted models. Secondly, the cognitive tasks used might be sensitive to practice effects, with participants scoring higher at the end of treatment as they are more familiar with the task and its instructions. It is also possible that there was an exposure effect to the testing environment over time which may reduce participants’ anxiety.This analysis benefits from robust RCT methodology including randomisation, double-blinding and placebo control. The trial used an intention-to-treat analysis, with 97% of participants providing data at baseline and end of treatment. The 4-week exposure period and two doses of CBD investigated allow for a thorough investigation of daily CBD treatment on cognition, using pre-registered hypotheses. One limitation is that the trial may have had limited power to detect potentially true effects of CBD with small effect sizes. As this was an analysis of a fixed sample from an existing dataset, an a priori power analysis could not be conducted. Given the 1.5 times larger increase for delayed prose recall and 2 times larger increase for immediate prose recall in the 800 mg group compared to placebo, there may be potential for pro-cognitive effects of daily CBD treatment on verbal memory, but larger sample sizes would be needed to detect small effect sizes. Another consideration to note is that all groups (including placebo) received motivational interviewing. This technique has demonstrated efficacy in reducing cannabis use in previous trials (Lees et al. In conclusion, this randomised, double blind and placebo-controlled trial found that 400 mg and 800 mg of CBD treatment did not significantly improve verbal learning and memory performance over 4 weeks, compared to placebo. There was evidence of a small beneficial effect of CBD on working memory as assessed by the backwards digit span.
