## 3 Human Studies
### Cognitive Effects of Cannabinoid Treatment  
Cognitive dysfunction can affect up to 80% of pwMS and can have severe knock-on effects such as difficulty maintaining employment, sustaining a meaningful relationship, as well as significantly affecting the individual's quality of life [81], does cannabis exacerbate this dysfunction? Not only have [PERSON] et al. used cannabinoids to examine spasticity in pwMS [71], they have also used them to examine the possible cognitive implications of cannabinoid treatments in this clinical population. They reported that treatment with cannabinoids did not cause a statistically significant decline of postural stability, cognitive functioning, mood or psychomimetic effects. Despite this, they did find a slightly clinically relevant deterioration in attention and cognitive functioning had occurred during treatment with ECP002A. These findings are similar to those reported by [PERSON] et al. [76] who reported that their sample of 17 pwMS receiving Sativex (8.2 mean sprays a day) did not score significantly differently on measures of cognitive performance [Paced Auditory Serial Addition Test (PASAT); Multiple Sclerosis Functional Test (MSFT)] or quality of life measures [Visual Analogue Scale (VAS); fatigue severity scale, multiple sclerosis impact scale] in either the placebo or treatment phases. Despite not finding statistical significance in objective measures, a clinically relevant impairment was observed where 11 patients receiving Sativex reported subjective drowsiness and a sense of slower thinking. These non-significant results conflict with the findings of [PERSON] et al. [82] who reported that cannabis users scored significantly lower on PASAT, judgement of line orientation, symbol digit modalities test and the Delis-Kaplan Executive Function System (D-KEFS) when compared to placebo, and on tests of premorbid functioning in a sample of 50 pwMS (25 smoked cannabis users, 25 receiving placebo). Patients were asked to abstain from cannabis use before testing. Patients abstained from use for between 12 h to several days. Considering the half-life of \(\Delta^{9}\)-THC is between 5 and 13 days for regular cannabis users [83] and metabolites being present in urine samples for up to 46 days [57], this begs the question; is this abstinence period long enough to not affect the results? The authors reported that cannabis users were twice as likely to meet the criteria for global impairment, which the authors defined as failure on two of the eleven tests used, as well as being twice as likely to be unemployed. Similar results were reported in a 2017 study by [PERSON] and [PERSON] who examined the cognitive functioning in 140 pwMS who smoke cannabis monthly or more frequently who found that cannabis users had significantly worse on the symbol digit modalities test and on the total learning and long-delayed free recall indices of the California learning test-II [84]. [PERSON] et al. used the Brief Repeatable Neuropsychological Battery (BRNB) for MS along with fMRI data to assess for cognitive dysfunction in 40 patients who began using cannabis after they received their diagnosis, all of whom report using cannabis on average, four times a week for NP,spasticity, incontinence, insomnia and recreational use. Participants were only included in this study if they were deemed by the authors to be globally cognitively impaired, which was classified as failure on two or more domains of the BRNB. Patients were assigned to either cannabis abstinence or cannabis continuation groups and underwent neuropsychological assessment and brain imaging at baseline and after 28 days. The authors reported that by the end of the study period, patients in the abstinence group showed significantly better scores on every cognitive index of the BRNB. Furthermore, the cannabis abstinence group reported more withdrawal symptoms and fewer depressive symptoms, but these changes did not reach statistical significance.