Effects of cannabinoids in Amyotrophic Lateral Sclerosis (ALS) murine models: a systematic review and meta-analysis.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that results from motor neuron damage. Cannabinoids have been proposed as treatments for ALS because of their anti-excitotoxicity, anti-oxidant and anti-inflammatory effects. Preclinical studies in mice models of ALS have been published using a range of cannabinoid formulations and doses. To date, there has been no rigorous evaluation of these trials to assess a potential cannabinoid treatment effect. This review and meta-analysis was undertaken to provide evidence for or against a treatment effect of cannabinoids in murine ALS models. Evidence of a treatment effect in mice may provide motivation for trials in human ALS. We identified a total of 10 studies; nine studies using cannabinoid treatment in transgenic SOD1-G93A ALS-model mice and one study in TDP-43 transgenic mice. Eight of the nine studies that used SOD1-G93A mice expressed similarly high copy numbers of the transgene while one study used a low-copy number line. Outcomes evaluated were survival time and disease progression. The latter was measured by motor function and bodyweight decline. Meta-analysis of the mean difference in survival time across the seven studies showed an increase in survival of 3.84 days (95% CI: 0.35-7.32 days; p = 0.031) for cannabinoid treated compared to control SOD1-G93A mice. It was not possible to conduct meta-analyses for motor function decline or weight loss. However, eight of nine studies reported significant improvements in measures of motor function decline and one reported non-significant improvements. Weight loss was significantly attenuated in four of five studies reporting this measure while the other study reported a non-significant attenuation. This review provides some evidence for the efficacy of cannabinoids in prolonging survival time in an ALS mouse model. A delay in disease progression is also suggested following cannabinoid treatment though it was not possible to consolidate the results from reviewed studies. However, studies have moderate to high risk of bias and are highly heterogeneous. Although this review provides some evidence to support the conduct of a cannabinoid trial in human ALS, more standardized studies on specific cannabinoids are necessary before supporting therapeutic potential of cannabinoids in treating patients with ALS. OPEN SCIENCE BADGES: This article has received a badge for *Preregistration* because the study was pre-registered at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=89274. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Read the Editorial Highlight for this article on page 168.

Effects of cannabinoids in Parkinson's disease animal models: a systematic review and meta-analysis.

Objectives: Cannabis has been proposed as a potential treatment for Parkinson's disease (PD) due to its neuroprotective benefits. However, there has been no rigorous review of preclinical studies to evaluate any potential treatment effect. This systematic review was undertaken to provide evidence in support or against a treatment effect of cannabinoids in animal models of PD. Methods: Databases were searched for any controlled comparative studies that assessed the effects of any cannabinoid, cannabinoid-based treatment or endocannabinoid transport blocker on behavioural symptoms in PD animal models. Results: A total of 41 studies were identified to have met the criteria for this review. 14 of these studies were included in meta-analyses of rotarod, pole and open field tests. Meta-analysis of rotarod tests showed a weighted mean difference of 31.63 s for cannabinoid-treated group compared with control. Meta-analysis of pole tests also showed a positive treatment effect, evidenced by a weighted mean difference of -1.51 s for cannabinoid treat group compared with control. However, meta-analysis of open field test demonstrated a standardised mean difference of only 0.36 indicating no benefit. Conclusion: This review demonstrates cannabinoid treatment effects in alleviating motor symptoms of PD animal models and supports the conduct of clinical trials of cannabis in PD population. However, there is no guarantee of successful clinical translation of this outcome because of the many variables that might have affected the results, such as the prevalent unclear and high risk of bias, the different study methods, PD animal models and cannabinoids used.

Effects of Cannabis in Parkinson's Disease: A Systematic Review and Meta-Analysis.

The legalization of cannabis in many countries has allowed many Parkinson's disease (PD) patients to turn to cannabis as a treatment. As such there is a growing interest from the PD community to be properly guided by evidence regarding potential treatment benefits of cannabis. This systematic review and meta-analysis aims to compile the best available evidence to help guide patients and their family, clinicians and researchers make informed decisions. A systematic search of the literature was conducted in June 2021. Five randomized controlled studies and eighteen non-randomized studies investigated cannabis treatment in PD patients. No compelling evidence was found to recommend the use of cannabis in PD patients. However, a potential benefit was identified with respect to alleviation of PD related tremor, anxiety, pain, improvement of sleep quality and quality of life. Given the relative paucity of well-designed randomized studies, there is an identified need for further investigation, particularly in these areas.

Study protocol for a randomised, double-blind, placebo-controlled study evaluating the Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease: the EMERALD trial.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no known cure and with an average life expectancy of 3-5 years post diagnosis. The use of complementary medicine such as medicinal cannabis in search for a potential treatment or cure is common in ALS. Preclinical studies have demonstrated the efficacy of cannabinoids in extending the survival and slowing of disease progression in animal models with ALS. There are anecdotal reports of cannabis slowing disease progression in persons with ALS (pALS) and that cannabis alleviated the symptoms of spasticity and pain. However, a clinical trial in pALS with these objectives has not been conducted. METHODS AND ANALYSIS: The Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease trial is a randomised, double-blind, placebo-controlled cannabis trial in pALS conducted at the Gold Coast University Hospital, Australia. The investigational product will be a cannabis-based medicine extract (CBME) supplied by CannTrust Inc., Canada, with a high-cannabidiol-low-tetrahydrocannabinol concentration. A total of 30 pALS with probable or definite ALS diagnosis based on the El Escorial criteria, with a symptom duration of <2 years, age between 25 and 75years and with at least 70% forced vital capacity (FVC) will be treated for 6 months. The primary objective of the study is to evaluate the efficacy of CBME compared with placebo in slowing the disease progression measured by differences in mean ALS Functional Rating Scale-Revised and FVC score between the groups at the end of treatment. The secondary objectives are to evaluate the safety and tolerability of CBME by summarising adverse events, the effects of CBME on spasticity, pain, weight loss and quality of life assessed by the differences in mean Numeric Rating Scale for spasticity and Numeric Rating Scale for pain, percentage of total weight loss and ALS specific quality of life-Revised questionnaire. ETHICS AND DISSEMINATION: The study has been approved by the local Institutional Review Board. The results of this study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT03690791.