Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis? This is an open access article distributed under the terms of the Creative Commons In recent years, cannabis, or marijuana, has been assessed in amyotrophic lateral sclerosis (ALS) and has shown some beneficial effects for patients.
Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis?
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. Over the last years, a growing interest was aimed to discovery new innovative and safer therapeutic approaches in the ALS treatment. In this context, the bioactive compounds of Cannabis sativa have shown antioxidant, anti-inflammatory and neuroprotective effects in preclinical models of central nervous system disease. However, most of the studies proving the ability of cannabinoids in delay disease progression and prolong survival in ALS were performed in animal model, whereas the few clinical trials that investigated cannabinoids-based medicines were focused only on the alleviation of ALS-related symptoms, not on the control of disease progression. The aim of this report was to provide a short but important overview of evidences that are useful to better characterize the efficacy as well as the molecular pathways modulated by cannabinoids.
Keywords: amyotrophic lateral sclerosis, cannabinoids, symptomatic ALS treatment, experimental ALS model, clinical trials, mechanisms of neuroprotection
Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. The incidence is about 1–3 cases per 100,000 population per year. In Italy it is estimated that at least 3,500 patients and 1,000 new cases per year (http://www.osservatoriomalattierare.it/sla). ALS is characterized by relentless progression of muscle wasting and weakness until death ensues typically due to respiratory muscle failure. Generally, ALS patients present a number of clinical symptoms, including weakness, spasticity, cachexia, dysarthria and drooling, and pain secondary to immobility, among others (Zarei et al., 2015).
The most abundant forms of ALS are sporadic (90%), but the disease may be also familiar (10%), associated with mutations in the superoxide dismutase-1 gene (SOD-1), that encodes for a key antioxidant enzyme, and also in TAR-DNA binding protein-43 (TDP-43) and FUS (fused in sarcoma) which encode proteins involved in pre-mRNA splicing, transport and stability (Hardiman et al., 2011). Recently, mutation in non-coding hexanucleotide repeat sequence (GGGGCC) in the C9orf72 gene was considered as the most common genetic cause of ALS (Matamala et al., 2016). The exact function of this protein remains undefined; however, it seems to play a major role in cellular trafficking, mainly in neurons (Williams et al., 2013). The C9orf72 mutation was found also in frontotemporal dementia (FTD) patients (Farg et al., 2014). Since 20% of ALS patients develops dementia with a frontotemporal phenotype, this mutation may explain the link between familial FTD and ALS (Farg et al., 2014).
Although the pathogenic mechanisms that underlie ALS are yet unknown, it is believed that ALS could have a multifactorial etiology, where environmental factors can greatly contribute to pathology triggering. Moreover, several mechanisms including mitochondrial dysfunction, protein aggregation, oxidative stress, excessive glutamate activity, inflammation and apoptosis are involved in ALS pathogenesis leading to motor neuron cell death in the brain and spinal cord (Zarei et al., 2015).
To date, the only therapy available for ALS is the glutamate-antagonist riluzole that was able to inhibit the presynaptic release of glutamate, most likely by blockade of voltage-gated sodium channels. However, riluzole has limited therapeutic efficacy and also it is able to moderately prolong patient survival (Miller et al., 2007). Therefore, new innovative and safer therapeutic approaches are urgently needed, at least aimed at delaying the neurodegenerative processes of the ongoing disease.
Over the last years, a growing interest has been focused to cannabinoids, the bioactive compounds of Cannabis sativa, for their antioxidant, anti-inflammatory and anti-excitotoxic effects exhibited in preclinical models of central nervous system disease (Croxford, 2003). Here, we provided an overview of the potential usefulness of cannabinoid agents in the management of ALS.
Overview on Cannabinoids
The Cannabis plant, also known as marijuana, contains over 500 natural compounds and about 70 of these are classified as cannabinoids (Fischedick et al., 2009). The discovery of Δ9 -tetrahydrocannabinol (THC) as the major psychoactive principle in Cannabis, as well as the identification of numerous non-psychoactive cannabinoids such as cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), Δ9 -tetrahydrocannabivarin ( Δ9 -THCV) and cannabidivarin (CBDV), has led to a significant growth in research aimed at understanding the therapeutic effects of these compounds.
Cannabinoids exert many of their activities by binding cannabinoid (CB) receptors. To date, two types of receptors have been identified to have different tissue distribution and mechanisms of signaling. CB1 receptors are expressed mainly on neurons and glial cells in various parts of the brain, CB2 receptors are found predominantly in the cells of immune system. Both CB1 and CB2 receptors belong to the family of G-protein coupled receptors (GPCRs) that, after cannabinoid agonist binding and signaling, exert an inhibitory effect on adenylate cyclaseactivity, activation of mitogen-activated protein kinase, regulation of calcium and potassium channels, and other signal transduction pathways (Munro et al., 1993). Moreover, there is increasing evidence supporting the existence of additional cannabinoid receptors (no-CB1 and no-CB2) in both central and peripheral system, identified in CB1 and CB2-knockout mice, involving intracellular pathways that play a key role in neuronal physiology. This kind of receptors includes transient receptor potential vanilloid type 1 (TRPV1), G protein-coupled receptor 55 (GPR55), G protein-coupled receptor 18 (GPR18), G protein-coupled receptor 119 (GPR119) and 5-hydroxytryptamine receptor subtype 1A (5-HT1A) (Pertwee et al., 2010). Δ9 -THC, of which is well-known psychotropic effects, is believed to perform the majority of itsactions in the CNS binding CB1 and CB2 receptors. Non-psychotrophic phytocannabinoids exert multiple pharmacological effects via CB1/CB2 receptors as well as no-CB1 and no-CB2 receptors (Pertwee et al., 2010).
Overall, recent studies showed that cannabinoids inhibit the release of pro-inflammatory cytokines and chemokine in neurological preclinical models suppressing in this way the inflammatory response (Velayudhan et al., 2014). They show also a potent action in inhibiting oxidative and nitrosative stress, modulating the expression of inducibile nitric oxide synthase and reducing the production of reactive oxygen species (ROS) (Velayudhan et al., 2014). Moreover, cannabinoids were found to exert anti-glutamatergic action by inhibiting glutamate release and enhancing the effect of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) (Croxford, 2003). Just about all these properties exhibited by these compounds, have prompted researchers to investigate their potential therapeutic effects in ALS, providing interesting results.
Neuroprotective Effects of Cannabinoids in Experimental Model of ALS
Recent in vivo studies support that cannabinoids may be beneficial as neuroprotective agents in ALS. The most commonly used murine model for human ALS is the hSOD (G93A) transgenic mouse, which is genetically engineered to develop clinical symptoms similar to those observed in humans with ALS.
Treatment with Δ9-THC in ALS hSOD(G93A) mice, either before or after signs onset, improves motor impairment and increases survival by 5% probably via its anti-glutamatergic and anti-oxidant activity (Raman et al., 2004). Moreover, it was demonstrated that Δ9 -THC attenuates oxidative stress in ALS hSOD(G93A) mouse spinal cord primary cultures, that were exposed to the oxidant tert-butyl hydroperoxide (TBH) in the presence of Δ9 -THC and SR141716A, the CB1 receptor antagonist, as assessed by lactate dehydrogenase (LDH) and SOD-1 release. Specifically, the antioxidant effect of Δ9 -THC was not CB1-receptor mediated; since the CB1 receptor antagonist SR141716A did not diminish the antioxidant effect (Raman et al., 2004). Δ9 -THC was found also to protect against excitotoxicity produced by kainic acid in primary neuronal cultures, obtained from ALS hSOD(G93A) mouse spinal cord, by activation of CB1 receptor. In this case, the neuroprotective effect was blocked with the CB1 receptor antagonist, SR141716A, indicating a receptor-mediated effect (Raman et al., 2004). Therefore, treatment with cannabinoids may reduce elevated glutamate levels observed during ALS by modulating excitotoxicity events.
Moreover, treatment with cannabinol (CBN), a non-psychotropic cannabinoid, through its residual affinity to CB1 receptors, is able to delay significantly disease onset in ALS hSOD(G93A) mice subcutaneously implanted with osmotic mini-pumps. However, the molecular mechanisms remain undefined. On the contrary, survival was not affected (Weydt et al., 2005).
Likewise, a significant delay in disease progression was found when CB1/CB2 receptor agonist WIN 55,212-2 was intraperitoneally administered to ALS hSOD(G93A) mice beginning after onset of motor impairment and tremor (at 90 days old), however, survival was not extended (Bilsland et al., 2006). Genetic ablation of the fatty acid amide hydrolase (FAAH) enzyme, which results in raised levels of the endocannabinoid anandamide, prevented the appearance of disease signs in 90-day-old to ALS hSOD(G93A) mice. However, elevation of cannabinoid levels with either WIN55, 212-2 or FAAH ablation had no effect on life span. On the contrary, CB1 deletion had no effects on disease onset in ALS hSOD(G93A) mice, but extend lifespan by 15 days, a 13% increase in survival. Therefore, the beneficial effects exhibited by cannabinoids may be mediated by non-CB1 receptors, but presumably by CB2 ones. Moreover, the neuroprotective effects of cannabinoids were ascribed to a decrease of microglial activation, presynaptic glutamate release and formation of ROS (Bilsland et al., 2006).
Also, it was demonstrated that mRNA, receptor binding and function of CB2, but not CB1, receptors are dramatically and selectively up-regulated in the spinal cords of ALS hSOD(G93A) mice in a temporal pattern paralleling disease progression (Shoemaker et al., 2007). It was found that daily intraperitoneal administration of the selective CB2 agonist, AM-1241, initiated after disease onset in ALS hSOD(G93A) mice, delayed motor impairment and increased survival by 56%. The beneficial effects of cannabinoids could potentially be mediated via CB2 receptor-mediated suppression of microglial/macrophage activation in the spinal cords of symptomatic G93A mice and that CB2 receptors are selectively up-regulated in spinal cords as a compensatory, protective measure (Shoemaker et al., 2007).
Few years ago, the neuroprotective effects of a mixture of two extracts in approximately a 1:1 ratio (2.7 mg of Δ9 -THC and 2.5 mg of CBD) commercially known as Sativex® were investigated by using ALS hSOD(G93A) transgenic mice (Moreno-Martet et al., 2014). Sativex® was found to be effective in delaying ALS progression in the early stages of disease and in animal survival, although the efficacy was decreased during progression of disease. Also, it has been demonstrated that changes occur in endocannabinoid signaling, particularly a marked up-regulation of CB2 receptors in SOD(G93A) transgenic mice together with an increase of N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) enzyme, which is responsible for the generation of anandamide (N-arachidonoylethanolamine), the ligand of cannabinoid and vanilloid receptors (Moreno-Martet et al., 2014). Therefore, the efficacy of cannabinoids in slowing ALS progression, in extending life expectancy and in reducing the overall gravity of the disease is mainly due to activation of CB2 receptors. More specifically, it was widely demonstrated that drugs activating CB2 receptors, expressed predominantly in immune cells and non-neuronal tissues, successfully improve the symptoms of several inflammatory diseases (Walter and Stella, 2004). However, further studies are necessary to assess the neuroprotective effects of cannabinoids that target CB2 receptors. Molecular mechanisms underlying cannabinoids-driven neuroprotective effects in ALS hSOD(G93A) mice model are illustrated in Figure 1 .
Schematic illustration of the neuroprotective mechanisms of action of cannabinoids into ALS hSOD(G93A) mice.
Amyotrophic lateral sclerosis (ALS) is a disease characterized by extensive damage over time to motor neurons in the brain and spinal cord. Motor neurons are nerve cells that are responsible for the communication, the signals, taking place between the brain and the muscles.
Due to this damage, the brain is increasingly unable to control muscle movement, and patients progressively loses the ability to easily do activities that most people take for granted, like walk, swallow, or speak. There is currently no cure for ALS, but treatments can help manage its symptoms.
One potential treatment is cannabis sativa, otherwise known as marijuana. Cannabis, as medical marijuana, is being assessed in its various forms for its potential in easing ALS symptoms.
How cannabis works
The active ingredients in cannabis — tetrahydrocannabinol (THC) and cannabidiol (CBD) — are called cannabinoids. They are believed to work as antioxidants and as anti-inflammatory and neuroprotective agents, and for these reason might slow or prevent further damage to nerve cells in ALS.
Both CBD and THC mainly function by binding to the cannabinoid receptor proteins CB1 and CB2 of the endocannabinoid system. The endocannabinoid system is responsible for regulating brain function, hormone secretion, and the immune system. CB1 receptors are present on the surface of nerve cells in the brain and spinal cord, and regulate neurodevelopmental activities; CB2 receptors are predominantly present in immune cells, and modulate inflammation and immune cell function.
Binding of THC to the CB1 receptor activates the receptor’s anti-glutamatergic action, meaning it inhibits the release of excess glutamate by nerve cells. Glutamate is a neurotransmitter, and in excess can cause nerve cell damage or excitotoxicity. In ALS, excitotoxicity is thought to compound nerve cell damage and increase neurodegeneration.
Since THC prevents excitotoxicity via the CB1 receptors, treatment with THC may be neuroprotective for ALS patients. A study showed that neuronal cells obtained from the spinal cord of ALS mouse models and treated with THC were protected from induced excitotoxicity.
The cannabinoids exert an anti-inflammatory effect through the CB2 receptors, which regulate immune cells and the production of inflammatory proteins. In this way, they might slow further tissue damage.
Cannabinoids also function as an antioxidant, but in a CB receptor-independent manner. Other receptors, such as the transient receptor potential vanilloid receptor 1, have been found to be involved, but how they work in ALS is still unclear.
Medical marijuana in clinical trials
Cannabis-derived products are being, or were, evaluated for their potential in treating ALS in various clinical trials.
Sativex (nabiximols), being developed by GW Pharmaceuticals, is an oral spray containing the two active components of cannabis. A Phase 2 trial (NCT01776970) in Italy, called CANALS, evaluated the safety, efficacy, and tolerability of Sativex in ALS patients affected by spasticity, or muscle stiffness. A total of 59 patients, ages 18 to 80, were included in the study. Patients were randomly assigned to receive either Sativex (29 patients) or placebo (30 patients). The study’s findings showed that Sativex was well-tolerated with no serious side effects. Spasticity was significantly reduced in treated patients compared to those given the placebo, whose symptoms continued to worsen.
An earlier single-site study (NCT00812851) tested the efficacy of oral THC in alleviating cramps in ALS patients. This was a crossover study, meaning that all 27 patients enrolled, (mean age 57; with moderate to severe cramps) were given THC at some point during the trial. They were randomly divided into two groups, one receiving 5 mg THC twice daily for two weeks, followed by a placebo; and the other receiving placebo first followed by THC for two weeks. A two-week treatment-free, or washout, period preceded changes in treatment status, and patients were evaluated two weeks after their treatment period.
This trial’s primary goal was changes in cramp intensity. The number of cramps per day, the intensity of muscle twitches, change in appetite, depression, and patient’s quality of life and sleep were measured as secondary goals. Study findings failed to show effectiveness in these measures; THC at 5 mg did did not alleviate cramps in ALS patients, and no significant changes were observed in the secondary outcomes, its researchers reported.
An ongoing Phase 3 study (NCT03690791) is testing the effects of CBD oil capsules by CannTrust on slowing disease progression in ALS patients. The study aims to enroll 30 patients, ages 25 to 75, who will be randomly grouped to receive either the CBD oil capsules or a placebo. In this six-month study, changes in a patient’s motor abilities, lung function, pain and spasticity levels, and quality of life will be assessed to evaluate the efficacy of CBD capsules. Enrollment at this trial’s single site, the Gold Coast Hospital and Health Service in Australia, may still be underway; contact information is available here.
In an observational study (NCT03886753), researchers at Children’s Hospital of Philadelphia are evaluating the effects of four formulations of cannabis-based products — the medical marijuana products Dream, Soothe, Shine, and Ease — by Ilera Healthcare used as standard therapy by people with multiple diseases, including ALS. How this therapeutic moves within the body (its pharmacokinetics) and its chemical interaction in the body (pharmacodynamics) will be monitored, and reports of relief of symptoms collected. The study is enrolling patients, ages 2 and older.
Another large and observational study (NCT03944447) in people with multiple diseases, including ALS, aim to assess the safety and efficacy of cannabis use by up to 10,000 people in the more than 38 states that have legalized medical marijuana. As an observational study, medical cannabis as part of person’s standard therapy — regular use — is being evaluated through patient reporting of perceived relief and findings of side effects.
Called OMNI-Can, the study and its investigators will use an anonymous online questionnaire to assess the potential benefits and side effects of medical cannabis on participants, most of whom are expected to be current users. A separate cannabis-naive group, defined as no use in the past year, will also be enrolled. Participants will first be given the survey at a visit with a physician to establish their baseline (start of the study) characteristics. Subsequent surveys will be given follow-up visits every three months for up to five years.
The study’s primary goal is the perceived benefits of cannabis in treating chronic pain, and the safety of its use via reporting of adverse events. Its impact on patients’ quality of life will be also be recorded, as will preferences such as favored type for use (route of administration, like vaping or eating as a candy) and its formulation (THC/CBD ratio). Contact information is available here.
Cannabis use should be in consultation with a treating physician, who can monitor patients for behaviors that may indicate dependence.
CBD, one of the more than 100 pharmacologically active compounds (cannabinoids) that can be retrieved from the cannabis plant, is thought to hold the greatest therapeutic potential. This is largely because it does not have the psychoactive properties common to other cannabis-related compounds. psychoactive properties
In addition to dependence, side effects attributed to medical marijuana use include lung irritation (smoking or vaping), low or elevated blood pressure, anxiety, dry mouth, changes in appetite, and nausea.
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