## 3 Human Studies  
### Cannabinoids Are Only Moderately Effective in Reducing MS Related Spasticity  
Hyperactive spinal reflexes cause velocity-dependent tonic stretch reflexes with significant tendon jerks, (more commonly known as spasticity) is a significant cause of disability in pwMS [35; 36]. The literature shows that cannabinoids can reduce spasticity in EAE models of multiple sclerosis in rats, but the literature only partly supports the use of cannabinoids in reducing symptoms of spasticity in humans. In support of the findings of animal studies, [PERSON], [PERSON], [PERSON] et al. examined the effects of a \(\Delta^{9}\)-THC:CBD spray in pwMS at baseline and after a 4-week treatment phase. After the 4-week treatment phase, a significant reduction in electromyography data was reported in 20 out of 36 patients (56%). No significant difference was reported in 22% and a significant increase was reported in the other 22% of patients. The authors reported a significant reduction in the muscle stretch reflex and a significant reduction in the Modified Ashworth scale (MAS) during treatment in \(\Delta^{9}\)-THC:CBD responders. With regard to this study, it should be noted that patients were still actively receiving treatment with first-line spasticity medications (mainly baclofen), which may have influenced subjective and objective spasticity results. Further supporting the findings of animal studies, [PERSON] and colleagues studied the effects of Sativex as an add-on therapy in pwMS in a two-phase study design [68]. Participants were permitted to up-titrate their dose to a maximum of 12 sprays a day until optimal symptom relief was observed. Patients who reported \(\geq\)20% improvement in spasticity numerical rating scale (NRS) were classed as responders in phase A (70.5% of the sample) and were randomised into either placebo or treatment groups in phase B. When compared to baseline measures, these responders had significantly improved mean spasticity NRS, mean pain NRS and MAS scores when compared to patients receiving placebo. The authors concluded that in patients with moderate to severe resistant MS spasticity who initially responded to \(\Delta^{9}\)-THC:CBD spray during the 4 week trial period, adding \(\Delta^{9}\)-THC:CBD spray to already optimised antispasticity treatment is a better alternative to simply readjusting first-line medications only. Similar to the design of the study described above, [PERSON] et al. also implemented a two-phase design; a four-week titration phase followed by a treatment phase. Again, pwMS who had \(\geq\)20% reduction in spasticity NRS in the four-week phase A were classed as responders and were continued to phase B. The authors reported that 90.6% of patients classified as responders to Sativex in phase A, continued to show clinical benefit and good tolerability to the drug treatment even beyond the 14 weeks follow up period. These benefits were still evident at a one year follow up on spasticity NRS scores and MAS scores, but not on tests of walking ability, most likely due to its low sensitivity. These results suggest that Nabiximols are as effective as first-line treatments for spasticity. [PERSON] et al. [69] studied the effects of the Sativex (i.e., \(\Delta^{9}\)-THC:CBD) spray as either an add-on therapy in 95 patients or as a monotherapy in 25 patients who had experienced weakness or instability on first-line anti-spasticity medications such as tizanidine or baclofen. The authors reported a mean reduction of 57% in the NRS (mean scores of 7.0 to 3.0) within 10 days of the therapy commencing. It was shown that patients receiving \(\Delta^{9}\)-THC:CBD as a monotherapy did not develop an increase in muscle weakness and showed NRS score reductions similar to those receiving the drug as an add-on therapy. It should be noted that 23 patients (13.9%) withdrew from the study due to adverse reactions such as dizziness, vertigo, fatigue, and incontinence.