What is ALS?
ALS (amyotrophic lateral sclerosis) is a neurodegenerative disease characterized by the death of voluntary motor neurons, and the subsequent atrophy (weakening) of the muscles they control due to inactivity. Also known as Lou Gehrig’s disease, ALS affects a relatively small portion of the population (0.002%), but has achieved notoriety due to its severity, and also for the pseudo-miraculous story of Professor Stephen Hawking, who was diagnosed over 40 years ago but is still alive today (nearly 1000% the average lifespan of an individual diagnosed with ALS).
ALS occurs when motor neurons in the brain and spinal cord die. These are the neurons which control our muscles, so the symptoms progress from a lack of coordination to complete paralysis within 2-4 years. Symptoms present after fully ⅓ of the motor neurons have died, so catching the disease early can be very difficult. The exact cause of the nerve death is not known, but there are many processes involved, including excitotoxicity, inflammation, genetic mutations, and oxidative stress.
A notable correlation exists between dysfunctional SOD1 genes and ALS. SOD1 is a gene that codes for superoxide dismutase, an important antioxidant enzyme that breaks down the highly-reactive waste products of glutamate neurotransmission and mitochondrial activity. Without this enzyme, these antioxidants remain in the cell and damage vital components including membranes and DNA. 20% of individuals with ALS have completely nonfunctional SOD1 genes, and an unknown percentage have dysfunctional SOD coding mechanisms; this all leads to an accelerating state of oxidative stress inside motor neurons.
Glutamate is the primary excitatory neurotransmitter in humans and most mammals. Its role is to “excite” the neurons it binds to and increase their activity, and it is also the main signal used by our motor neurons to generate muscle contractions. Glutamate transmission excites neurons by increasing the calcium ion concentration inside the neuron. Motor neurons cannot remove calcium as easily as other neurons, so when there is too much glutamate released, the build up causes the eventual death of the cell; this is called excitotoxicity.
There are several signs of disease in the glutamatergic systems of individuals with ALS. Not only are motor neurons intrinsically more sensitive to glutamate neurotransmission, but motor neurons with ALS are unable to clear the same amount as healthy cells.
How can CBD help individuals with ALS?
A trend among the conditions and disorders known to be positively affected by therapeutic administration of CBD is a lack of understanding surrounding their causalities. ALS stands out, as it has several known mechanisms of pathology (how the disease produces symptoms), and we haven’t even completely decoded one of them yet. Nonetheless, there has been some progress in slowing down disease progression and extending lifespan by several months or years.
Riluzole is the only current prescribed treatment for ALS; it’s a glutamate receptor inhibitor, which means it decreases the rate at which neurons can bind with glutamate, and therefore the effect that glutamate has in the cell. This has helped some patients by preventing excitotoxicity, but it is not a cure by any means. CBD has shown some promise in attenuating several of the causes of ALS progression including excitotoxicity, neuroinflammation, and oxidative stress. It also represents a palliative treatment for the acute symptoms of ALS including depression and lack of appetite.
CB1 receptor-mediated effects
The overwhelming majority of CB1 receptors are expressed on neurons in the central nervous system. While there are hundreds of thousands of differently-specialized neuron types, they all have nearly homogenous expression of CB1 receptors. These receptors facilitate retroactive signalling, which is fancy terminology for when the postsynaptic neuron tells the presynaptic neuron to send more or less of a signal. Scientists knew there had to be some sort of two-way communication between neurons, but did not know of its specific mechanism until the cannabinoid receptors were isolated in the 1990s.
These receptors are able to do this because when they’re activated by endocannabinoids, like anandamide, or THC, they reduce the cellular level of adenylate cyclase activity, which is the enzyme that derives energy from ATP to power the cell. Not only does this reduce the overall level of cellular activity, but it also reduces the concentrations of the primary cellular neurotransmitters, which vary by cell type. In excitatory (glutamatergic) neurons, this means activation of cannabinoid receptors would lower the amount of glutamate produced by the neuron, reducing the possibility of excitotoxicity. CBD has little affinity for CB1 receptors, but it increases the effect of other compounds which do bind with the receptor, so full spectrum CBD oil is much more effective than pure CBD in reducing the excitotoxicity of glutamatergic overload.
CB2 receptor-mediated effects
While CB1 receptors are found mainly on neurons, CB2 receptors are located in the immune system, including microglial cells in the brain. Glia are cells that provide structure to neurons and maintain their health. Microglia are a type of glial cell which function as the immune system in the brain, since typical immune-related cells cannot cross the blood-brain barrier. Microglia become activated in the presence of chemokines released as distress signals by damaged or infected neurons or glia. Once activated, microglia initiate a chain reaction release of neurotoxic mediators like reactive oxygen species (ROS) and free radicals which break down the membranes and DNA of cells near where they were released. This leads both to neuron death and to an increase in the release of these inflammatory signals which leads to more neuron death. In many neurodegenerative diseases and traumatic brain injuries, overactive microglia cause the death of healthy neurons and therefore many of the symptoms of these conditions.
Although CBD doesn’t specifically bind to CB1 receptors, it does agonize CB2 receptors. These receptors have the same essential function as CB1, with the main difference being the type of cell which expresses them. When these receptors are activated on microglia, they raise the threshold at which the cell will become “activated” and start the release of neurotoxic mediators. By delaying the activity of these cells, CBD is able to reduce the death of healthy neurons. Unlike many single compound traditional pharmaceuticals, because CBD doesn’t fully block receptor activity, a neuron that is actually in distress will still release enough of the distress chemokines that it will activate the microglia. In this way, CBD reduces neuroinflammatory cell death without compromising immunity like other-such immunosuppressants.
Non-receptor-mediated activity of CBD
While many of the effects of phytocannabinoids like CBD are mediated via the cannabinoid 1 & 2 receptors, a large portion of its therapeutic value comes from activity that doesn’t involve cannabinoid receptors at all. In addition to acting as an agonist (activator) at serotonin 5-HT1a receptors, it also has the ability to downregulate NMDA and vanilloid receptors which are involved in several different mechanisms of excitatory cell death, which is highly implicated in the pathology of ALS along with most other neurodegenerative diseases.
Furthermore, CBD shares potent antioxidant characteristics with the majority of phytocannabinoids. This gives it the ability to neutralize dangerous ROS and free radicals which are produced by several cellular processes; excitotoxicity causes a rapid increase in the production of these compounds, so CBD’s effect at reducing excitation indirectly reduces the production of these compounds in addition to its ability to break them down when they are synthesized.