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

Abstract

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/. https://doi.org/10.1111/jnc.14651.

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

“…A systematic review of CBs in ALS-murine models29 demonstrated the efficacy of CBs in prolonging survival of SOD1-G93A mice. A high-CBD-low-THC formulation was chosen because this most closely resembles the preparation used in an animal model study30 which demonstrated prolonged survival.…”

Protection from the Pathogenesis of Neurodegenerative Disorders, including Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Huntington’s Disease, and Parkinson’s Diseases, through the Mitigation of Reactive Oxygen Species

“…In addition, zinc is also known to perform key functions in various pathological mechanisms traditionally correlated with ALS [220]. Cannabinoids have also been postulated as therapeutic options for ALS owing to their anti-in lammatory, antioxidant, and anti-excitotoxicity properties [221,222]. Cannabinoid sources include lax seeds, hemp oil, seeds, eggs, and anchovies [223].…”

Directions of searching for new drugs for ALS

“…Istnieją także nieobjęte jeszcze badaniami klinicznymi interesujące kierunki poszukiwań skutecznej terapii opisywanej choroby, takie jak wpływ kanabinoidów na stan pacjentów z SLA -ich skuteczność została dobrze opisana na modelu zwierzęcym [7], ale brak jest dowodów na skuteczność ich stosowania u ludzi.…”

“…Jednak zwracając uwagę na charakter choroby, statystykę jej występowania (jest to choroba rzadka) i konieczność unifikacji grupy pod względem parametrów klinicznych oraz dotychczas przeprowadzone doświadczenia, nie są one dyskredytujące. Należy zauważyć, że badanie rejestracyjne leku zawierającego edaravon zostało przeprowadzona na grupie 184 pacjentów, z których 68 przyjmowało badany lek [7]. Zwraca więc uwagę niejednolite podejście badaczy do określenia efektywności leczenia.…”