In a recent review for the journal Neural Regeneration Research, Italian researchers Dr. Emanuela Mazzon and Sabrina Giacoppo discuss the therapeutic potential of cannabinoids for amyotrophic lateral sclerosis (ALS).
ALS, also known as Lou Gehrig's Disease, is a rare fatal degenerative disease that affects motor neurons. As the authors describe "the condition is characterized by a relentless progression of muscle wasting and weakness until death ensues typically due to respiratory muscle failure". Symptoms include pain, spasticity, dementia, cachexia, and drooling, among many others.
According to ALS Canada there are 200,000 people currently living with ALS, of which around 3,000 are Canadians. Every day 2 to 3 Canadians succumb to the disease.
Some progress has been made in identifying genetic causes for ALS. We know that mutations in specific genes responsible for producing antioxidant enzymes, regulating DNA transcription and neuronal functioning are involved. However, these can only explain those 10% of the cases that are of genetic origin, leaving the remaining 90% that arise sporadically unexplained.
Some hypotheses for the emergence of sporadic ALS include dysfunctions in the 'cells' batteries', abnormal clustering of proteins, oxidative stress, inflammation, and excessive excitatory neuronal signalling (excitotoxicity). The latter cause is the one targeted by the only drug approved for ALS—riluzole.
Unfortunately, the efficacy of riluzole is very limited and alternatives are direly needed. In this realm, cannabinoids have started to receive some attention, as evidence from preclinical studies suggests that they can exert protective effects against oxidation, inflammation, and excitotoxicity.
The authors go back to a 2004 animal study where THC was shown to improve motor condition and survivability (5%) in a rat model of ALS. In the same study it was shown that THC protected against excitotoxicity via CB1 receptor activity and against oxidation via an unknown mechanism.
In the following year, a different group showed that Cannabinol (CBN) could delay the onset of ALS in mice, but not change their survival rate. The mechanism was not identified.
In 2006, another step was made when researchers showed that a synthetic cannabinoid mimetic and the ablation of the FAAH enzyme (which degrades the endocannabinoid anandamide) could also delay disease onset without altering the survival rate. The genetic removal of CB1 receptors did not change disease onset, suggesting that the effects were not CB1-dependent.
Another piece of the puzzle was added the following year when researchers showed that CB2 receptors were specifically up-regulated in the spinal cords of mice with ALS in a way that matched the progression of the disease. In the same study it was shown that a synthetic CB2 activator was able to delay motor impairments after ALS onset and increase survival by an astonishing 56%.
CB2 has not been the assumed target because, unlike CB1, it is rarely expressed in neurons, being mostly found in immune cells. However, this and other data showing that CB2 regulates immune inflammatory responses suggest that it could be the key to cannabinoid modulation of ALS.
The next study mentioned by the reviewers came out in 2014. Sativex (containing a 1:1 ratio of THC and CBD) was proven effective in delaying ALS progression in mice at the early stages, with only modest results in more advanced stages. Changes in CB2 expression were observed once again.
The authors note that evidence in humans is more flimsy. Analysis of human spinal cords shows an increase in CB2 activity, as seen in the animal models. One survey of patients who happened to also use cannabis (10%) suggested a moderate relief of symptoms such as appetite loss, pain and drooling, as well as subjective spasticity. More controlled trials have indicated that cannabis is safe for this population but have failed to find any significant clinical outcomes.
According to the authors, there are no human studies probing the potential of cannabis to alter disease progression. Their hope is that these "studies could be an alert to encourage the scientific community to further studies to confirm the therapeutic use of cannabinoids in this devastating disease".