Cognitive outcomes associated with long-term, recreational cannabis use

Cannabis is the most widely used recreational drug in the world. While cannabis harms cognitive functioning during intoxication, less is known about whether cannabis continues to adversely affect cognition once intoxication has passed in individuals who have used cannabis regularly for many years. While researchers are devoting more work to understanding cognitive outcomes associated with cannabis use, evidence is inconsistent to date. The lack of clarity on cannabis-related cognitive outcomes is primarily due to a paucity in the number of well-controlled studies conducted in the field, with many studies not accounting for possible confounding factors (e.g., sex, tobacco, and intelligence). There is also little research into how emerging interventions might impact cognition in cannabis consumers. This is important to understand as researchers have suggested that cognitive deficits may impede psychotherapy, treatment-related outcomes (e.g., relapse), and everyday functioning (e.g., driving). The aim of this thesis was to address some of these limitations across four studies. An original study was undertaken to examine cognitive outcomes associated with regular, long-term cannabis use in abstinent adults while accounting for confounding factors, such as tobacco use. There were mixed findings, with poorer memory recall, information processing speed, and sustained attention for cannabis consumers (n = 19) compared to tobacco-only control participants (n = 16); however, inhibitory control and executive function were similar. Subsequently, a metaanalysis was conducted to clarify what cognitive domains are consistently found in the literature to be impaired by cannabis use. Between cannabis consumers and controls we found large deficits in decision making; modest deficits in learning and memory and executive function; and similar performance for attention, information processing, and working memory domains. Given that some cognitive domains were impaired in the first two studies and considering that cognition plays an important role in everyday functioning and treatment outcomes, we conducted an additional two studies to determine if interventions for cannabis consumers affect cognitive functioning. We conducted a randomised, double-blind, and placebo-controlled study assessing the effects of long-term use of a cannabinoid medication, nabiximols (containing Δ⁹- tetrahydrocannabinol and cannabidiol), on cognition in cannabis-dependent participants. Participants were treated with either nabiximols (n = 44) or placebo (n = 49) for 12 weeks and were assessed on cognitive functioning prior to a scheduled dose and approximately 40 minutes after the dose on day 28. We found no evidence of acute effects, either harmful or beneficial, of nabiximols on inhibitory control, attention, information processing, or working memory. Given limited effects of nabiximols on cognition, we aimed to clarify in a final pilot study if a non-invasive brain stimulation method, transcranial direct current stimulation (tDCS), could be used to enhance cognition in cannabis consumers. This was a randomised, doubleblind, and placebo-controlled pilot study that compared the cognitive outcomes of active tDCS to sham tDCS in control participants (n = 15) and cannabis consumers (n = 5) who had been abstinent for more than 24 hours. We measured urinary metabolites and cortical excitation and inhibition to better understand the physiological effects of tDCS. Recruitment was terminated early due to the novel coronavirus disease-2019 (COVID-2019). A small reduction in commission errors in cannabis consumers indicted that tDCS may have improved inhibitory control. However, there was greater memory interference following active tDCS among cannabis consumers. There were no significant changes in urinary metabolites or cortical excitation or inhibition from active tDCS. Yet, there was a reduction in the abundance of stress-related metabolites from pre- to post-tDCS that suggested the novel procedure induced stressed initially, but this reduced once participants became familiar with tDCS. However, the results of this pilot study should be interpreted with caution due to the limitation of a small sample size of cannabis consumers. Overall, it appears that long-term and regular, recreational cannabis use in adults is associated with small to moderate harms in some cognitive domains (e.g., inhibitory control and learning and memory) after intoxication has passed. In addition, cannabinoid and brain stimulation interventions may have limited benefits for improving performance in these domains. Clarifying the contribution of cannabis use parameters, such as cannabis use frequency, type of cannabis used, and abstinence length, in future work will strengthen knowledge about the extent that cannabis use is associated with cognitive harms and if these parameters impact the effectiveness of interventions