Table 1.

Published systematic reviews on the use of cannabis‐based medicines in people with MS

Author year country	SR (search)	Included studies	Interventions	Primary outcomes	RoB/quality	Meta‐analysis	Conclusion
Amato 2017 Italy	SR: yes (updated September 2016)	RCTs (n 15) Parallel and cross‐over	• Cannabis in any dose, used either as monotherapy or adjunct to conventional drugs • Placebo	• Spasticity ‐ Ashworth scale* ‐ NRS scale • Pain • Quality of sleep	RoB GRADE	Yes	Concerning the efficacy of cannabis (compared with placebo) in patients with MS. Quality or confidence in the estimate was high in favour of cannabis for spasticity (NRS and VAS scales but not the Ashworth scale) and pain but not for sleep (confidence in estimate moderate).
HPRA 2017 Ireland	SR: no Source: Barnes 2016 commissioned by the UK All‐Party Parliamentary Group (APPG) and other reports	−	−	−	Criteria of the American Academy of Neurology	No	The scientific evidence, and the availability of an authorized medicine, support the use of cannabis in the treatment of spasticity associated with MS, where other treatments have failed.
NASEM 2017 USA	SR: yes (January 1999 to August 2016) Source: Koppel 2014; Whiting 2015 Updated search to 2016	• RCTs parallel (Koppel 2014; Whiting 2015) and cross‐over (Koppel 2014) • Non randomised studies	• All types of plant derived and synthetic cannabis • Placebo	• Spasticity ‐ Ashworth scale ‐ NRS scale • Pain	RoB Newcastle‐Ontario scale. Five weight‐of‐evidence categories	No (reported results of Whiting	Conclusion 4‐1. There is substantial evidence that cannabis is an effective treatment for chronic pain in adults. Conclusion 4‐7. There is substantial evidence that oral cannabinoids are an effective treatment for improving patient‐reported MS spasticity symptoms (NRS), but limited evidence for an effect on clinician‐measured spasticity (Ashworth scale).*
Whiting 2015 UK	S: yes (up to April 2015)	RCTs parallel and cross‐over Pain: 1 RCT Spasticity: 11 RCTs (2138 participants)	• Cannabinoids • Usual care, placebo, or no treatment	• Spasticity ‐ Ashworth scale ‐ NRS scale • Pain	RoB GRADE	Yes	• Cannabinoids (nabilone and nabiximols) were associated with a greater average improvement in spasticity assessed using numerical rating scales (MD −0.76 (95% CI −1.38 to −0.14; 3 trials). There was no evidence of a difference in association according to type of cannabinoid for either analysis. • Cannabinoids (nabiximols, dronabinol, and THC/CBD) were associated with a greater average improvement on the Ashworth scale* for spasticity compared with placebo, although this did not reach statistical significance (WMD, −0.12, 95% CI, −0.24 to 0.01; 5 trials). • The average number of patients who reported an improvement on a global impression of change score was also greater with nabiximols than placebo (OR 1.44, 95% CI 1.07 to 1.94; 3 trials). This was supported by a further crossover trial of dronabinol and oral THC/CBD that provided continuous data for this outcome (Killestein 2002). • Sensitivity analyses that included crossover trials showed results consistent with those based on parallel group trials alone. Conclusion: there was moderate quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity.
Australian Government 2017	Based on overview of Nielsen 2018 and qualitative reviews done by 5 working groups	−	−	−	−	−	• Overall, there is low to moderate quality evidence that suggests pharmaceutical‐grade THC (dronabinol or THC extract) is effective for treating symptoms of pain. • THC:CBD (nabiximols, Sativex) may be effective for treating symptoms of pain and spasticity in MS, in certain patient populations. • Findings were mixed as to whether cannabinoids assisted in improving bladder function, sleep, patient quality of life, ataxia or tremor, and disability/disease progression. • No studies included active alternatives (non‐cannabinoid medicines) as comparators, which is an important limitation.
Nielsen 2018 Australia	Yes, overview (1980 up to 30 November 2016)	SR (n = 11) (AMSTAR criteria 3 and 6). Included studies RCTs and non randomised studies	• Plant‐based and pharmaceutical cannabinoids	• Disability and disability progression • Pain • Spasticity • Bladder function • Ataxia and tremor • Sleep • Quality of life • Adverse effects	SIGN (for the reviews) GRADE	No	Recent high‐quality reviews find cannabinoids may have modest effects in MS for pain or spasticity.
Meza 2017 Chile	Epistemonikos database	SRs (n = 25) Spasticity: 4 RCTs (1247 participants) Pain: 3 RCTs (327 participants)	−	• Pain: evaluated according to VAS or NRS • Bladder dysfunction: evaluated according to NRS or irritative symptoms •Spasticity: evaluated according to Ashworth scale* or NRS • Adverse effects: such as sedation, dizziness, headache, euphoria, among others • Quality of life: according to subjective evaluation by participants • Coordination: according to subjective evaluation by participants • Mobility: according to subjective evaluation by participants • Others: sleep quality, tremor, posture and balance, dependence	GRADE	Yes	• Cannabinoids do not reduce spasticity in MS. The certainty of the evidence is high. • Cannabinoids do not reduce pain in MS. The certainty of the evidence is high. • Cannabinoids are associated to adverse effects, which are probably frequent in MS. The certainty of the evidence is moderate.
Mücke 2018 Germany	Cochrane Review	RCTs. Parallel, cross‐over, and enriched enrolment randomized withdrawal design with at least 10 participants per treatment arm. Participants: different types of participants including central neuropathic pain (e.g. MS)	• Cannabis‐based medicines, either herbal cannabis (hashish, marijuana), plant‐based cannabinoids (dronabinol: nabiximols), or pharmacological (synthetic) cannabinoids (e.g. levonantradol, nabilone)	• Pain	RoB GRADE	Yes	The potential benefits of cannabis‐based medicine in chronic neuropathic pain might be outweighed by their potential harms.

Abbreviations: SR systematic review; RCTs randomised controlled trials; RoB risk of bias; NRS Numeric Rating Scale; VAS Visual Analogue Scale; WMD weighted mean difference; CI confidence interval.

* The Ashworth scale (Ashworth 1964) has been criticized as unreliable, insensitive to therapeutic benefit, and reflective only of passive resistance to movement and not of other features of spasticity (Pandyan 1999; Wade 2010).