Neurology: Amyotrophic Lateral Sclerosis
The Potential Benefits of Cannabis for a Disease With Many Physiological Processes
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive and fatal disease of the nervous system. There’s no cure for ALS, and treatments focus on symptom relief and slowing the progressive degeneration of motor neurons, which causes an increasing loss of motor control. ALS is one of the most common neurodegenerative diseases, with incident rates roughly equal to those of multiple sclerosis. It’s estimated to cause as many as 5 in 100,000 deaths in people aged 20 or older.1
Ongoing research has improved the prognosis for people living with ALS; according to Johns Hopkins Medicine, 50% of affected patients live at least three years after diagnosis, 20% live five years or more, and up to 10% survive more than 10 years.1 Recently, researchers have begun investigating the potential of cannabis as a therapeutic to improve quality (and perhaps quantity) of life for patients with ALS.
The overlap of many abnormal physiological processes, which occur simultaneously in patients with ALS, makes treatment complex and often requires a multidrug regimen. Given these challenges, Gregory T. Carter, MD, MS, and colleagues became interested in the potential of the broad-spectrum properties of cannabis to potentially delay disease progression and manage the multitude of symptoms.3
The symptoms of ALS commonly develop between age 40 and 70 and may include the following2:
- fasciculations in the arms, legs, shoulders, or tongue;
- muscle cramps;
- tight and stiff muscles (spasticity);
- muscle weakness that affects the arms, legs, neck, or diaphragm;
- slurred and nasal speech; and
- difficulty chewing or swallowing.
For some, the first symptoms of ALS occur in the arms or hands and may present as difficulties buttoning a shirt or writing. Other patients may first experience symptoms in one leg and trip or stumble more often. These initial symptoms are considered limb onset. Another group of patients will first experience difficulty with speech or swallowing (bulbar onset).
According to Carter, “cannabis can help with pain, spasticity, drooling, loss of appetite, sleep, and depression, among other symptoms in ALS.”
Carter and colleagues also believe cannabis has potential for disease modification by addressing the mechanisms involved in the disease, such as the following:
- glutamate excitotoxicity;
- increased oxidative stress from free radical toxicity;
- degeneration of astroglia and microglia;
- mitochondrial dysfunction; and
- growth factor deficiency.
The Potential of Cannabis
The potential of cannabis as an effective therapeutic is seen predominantly in animal models, specifically in the G93 A-SOD1 ALS mutant mouse, genetically engineered to replicate familial ALS. One such study found that the sensitivity of CB1 receptors controlling for both glutamate and gamma aminobutyric acid transmission was greatly potentiated in the ALS mice model.4 From this study, the researchers believe that the endocannabinoid system may be involved in the pathology of ALS and may play a role in reducing cell excitability.
In another study aimed at understanding the role of the endocannabinoid system in ALS, researchers genetically ablated fatty acid amide hydrolase, resulting in increased levels of the endogenous cannabinoid anandamide, which acts on both CB1 (predominantly found in the central nervous system) and CB2 (predominantly found in peripheral and immune tissues) receptors. While the results showed delayed disease progression in the 90-day-old mouse, there was no effect on lifespan. Ablation of C1 receptors had no effect on disease progression but did significantly prolong the lifespan.5
Another possibility is that cannabis modulates glutamatergic excitotoxicity indirectly. In vitro and in vivo, the addition of tumor necrosis factor alpha (TNF alpha) to neurons has been shown to potentiate glutamatergic excitotoxicity. CB1 activation has been shown to decrease this glutamatergic excitotoxicity by reducing TNF alpha–induced surface expression of AMPA-type glutamate receptors.6
This neuroinflammation is a major precipitating factor in ALS as well as in other neurodegenerative diseases. The activation of CB1 receptors may delay disease progression and help relieve symptoms by decreasing inflammatory markers, specifically TNF alpha.6
Antioxidants are another potential approach to delaying disease progression and extending the lifespan for patients with ALS. The antioxidant properties of cannabis have been documented and have likewise been achieved with CBD alone.7
Concerning the degeneration of astroglia and microglia, a study analyzing activated microglia from spinal cord in human ALS patients demonstrated an increase in CB2 receptors, suggesting an important role of the endocannabinoid system in disease management and progression.8
And while cannabis may act on specific aspects of ALS, the diverse pathologies of the disease diminish the success of any single targeted treatment. Carter believes this is the largest potential of cannabis and a basis for more robust clinical trials. “The main issue with using cannabis to treat ALS is the lack of human data. In terms of symptom treatment, the lack of specificity is a good thing. Cannabinoids do have the potential for disease modification in ALS. There is no human data, although there is some compelling data in a mouse model of ALS,” he says.
Regarding the diverse pathologies, some scientists are looking to the kynurenine pathway as a potential target for ALS treatment. By acting as a route of metabolism for tryptophan, this pathway generates metabolites that may play a role in communication between nervous and immune systems that modulate cell proliferation and tissue function.9 The pathway is involved in neuropathological features present in ALS, such as neuroinflammation, excitotoxicity, oxidative stress, immune system activation, and dysregulation of energy metabolism.10 The ability of cannabis to reduce inflammation, decrease excitotoxicity, relieve oxidative stress, and help regulate the immune response makes it a potentially multifactorial treatment that warrants further study.
Practical Applications of Cannabis for Patients With ALS
Despite recent progress, there are few therapeutic options for patients with ALS. There are four FDA-approved therapies. The first two are forms of the glutamate-antagonist drug, riluzole; Rilutek was the first branded form of riluzole, and Tiglutek is the thickened liquid form of riluzole. Edaravone (brand name Radicava) is an antioxidant and free radical scavenger that has been shown to reduce excess oxidative stress and cell death. Finally, Nuedexta is approved for patients with ALS to treat pseudobulbar affect—frequent, involuntary, and often sudden episodes of crying and/or laughing that are exaggerated and/or don’t match a person’s actual feelings.11 None of these treatments is dramatically effective in decreasing symptoms or prolonging life.
Treatment for patients with ALS can focus on improving both the quantity and quality of years. While there’s a lack of robust, clinically controlled studies on cannabis, the side effect profile is considered reasonable low. Specifically, nabiximols (Sativex), which contains both THC and CBD, is approved in the United Kingdom, Canada, and several European countries for treating spasticity and neuropathic pain, often associated with multiple sclerosis.12
Medicinal cannabis may help improve quality of life in ALS. One large survey of ALS patients who used cannabis products found that cannabis was preferred to currently available prescriptions for ALS. Survey participants reported that using cannabis helped to alleviate pain and muscle spasms. Cannabis was also found to decrease feelings of depression, improve appetite, and manage sialorrhea (excessive saliva).13 Cannabis can also alleviate pain, which is a common symptom of ALS and is often poorly addressed. A systematic review and meta-analysis of double-blind randomized controlled trials found that cannabis had efficacy as an analgesic to manage pain.14
Although scientists are still working to understand the many physiological implications in ALS, Carter believes that, in addition to managing symptoms, cannabis can potentially slow disease progression and extend quality life years. He also stresses that the research doesn’t exist to say this for certain, nor are there enough data to recommend dosing with certainty. “There is very compelling evidence of this in mice, but human research of cannabis to treat ALS is almost entirely lacking.”
When recommending medicinal cannabis, dosing, THC to CBD ratio, and route of administration are generally the most important considerations. For the purposes of ALS treatment, research points to the benefits of both CBD and THC, as both compounds affect the mechanisms thought to be involved in ALS. Dosing depends on each patient and on the route of administration. It should be noted that cannabis may take days to build up in a person’s system, so any dosage should be trialed for days or weeks before increasing the amount administered. Because ALS decreases motor function and ultimately effects the respiratory system, smoking cannabis is not advised. “ALS patients should not smoke anything, including cannabis. Tinctures or edibles would be the preferred route and can also be given through a PEG [percutaneous endoscopic gastrostomy] tube,” Carter says.
Finally, the long-term effects of cannabis aren’t fully understood, nor are the various ways it interacts with a person’s physiology. At the same time, the causes and mechanisms of ALS require greater research and understanding. Given a devastating disease with few therapeutic options, cannabis may offer a new approach and new hope.
— Jennifer Lutz is a freelance journalist who covers health, politics, and travel. She’s written for both consumer and professional medical magazines as well as popular newspapers. Her writing can be found in Practical Pain Management, Endocrine Web, Psycom Pro, The Guardian, New York Daily News, Thrive Global, BuzzFeed, and The Local Spain. In addition to journalism, Lutz works as a strategies and communication consultant for nonprofits focused on improving community health.
1. ALS - amyotrophic lateral sclerosis. Johns Hopkins Medicine website. http://hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/als/conditions/als_amyotrophic_lateral_sclerosis.html. Accessed June 1, 2021.
2. Amyotrophic lateral sclerosis (ALS) fact sheet. National Institute of Neurological Disorders and Stroke website. https://www.ninds.nih.gov/disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet. Updated May 26, 2021. Accessed May 27, 2021.
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11. FDA-approved drugs. ALS Association website. https://www.als.org/navigating-als/living-with-als/fda-approved-drugs. Accessed June 1, 2021.
12. Marijuana research report: is marijuana safe and effective as medicine? National Institute on Drug Abuse website. https://www.drugabuse.gov/publications/research-reports/marijuana/marijuana-safe-effective-medicine. Updated July 2020. Accessed June 1, 2021.
13. Amtmann D, Weydt P, Johnson KL, Jensen MP, Carter GT. Survey of cannabis use in patients with amyotrophic lateral sclerosis. Am J Hosp Palliat Care. 2004;21(2):95-104.
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