ALS

Research Abstract:

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig‘s disease, is a disease of neurodegeneration characterized by the loss of motor neurons and the control of voluntary muscles. The symptoms progress from weakness and muscle wasting onto increased difficulty with movement, eating, and speaking until the ability to breathe is lost. The time from diagnosis to death is an average of of two to five years, though the well-known cannabis activist Cathy Jordan has been alive for over three decades since her diagnosis. Patients often experience pain and some develop difficulties with thinking and cognition.

In the majority of cases, the cause of the disease is unknown – but one theory posits that in the genetic familial versions of the disease, a malfunction in the production of a powerful antioxidant called superoxide dismutase 1 (SOD1) means that ALS is a disease of free radicals destroying the nerves. One of the most noted properties of cannabinoids is their antioxidant power, especially in combination. 

Another theory is that too much glutamate (the brain’s most common excitatory neurotransmitter and one heavily regulated by the endocannabinoid system) causes excitotoxicity (overstimulation that leads to cell death).

In an early survey, ALS patients who used cannabis reported it helpful for appetite loss, depression, pain, spasticity, and drooling – but that it did not help for reducing difficulties with speech, swallowing, or sexual dysfunction. A real-world study of 32 patients found them strongly endorsing the use of a THC/CBD spray for controlling moderate to severe spasticity. In addition, in ALS patients, their levels of endocannabinoids were predictive of their disease state. Media reports and case studies confirm the need for more clinical trials on ALS and the cannabinoids.

In a mouse model of ALS:

• Treatment with THC at the onset of tremors delayed motor impairment and prolonged survival. In spinal cell cultures, THC “was extremely effective at reducing oxidative damage” and reducing excitotoxicity
• CBN delayed disease onset
• Activating the CB1 receptor delayed motor impairment loss & the CB1 receptor was very sensitive for controlling the levels of glutamate & GABA (the primary inhibitory neurotransmitter of the brain)
• Sativex (a 1:1 THC:CBD spray) helped via an upregulation of the CB2 receptor, whereas inactivating the CB2 receptor worsened disease progression

In cells of the human spinal cord with ALS, the levels of CB2 are higher, suggesting the CB2 receptor as a therapeutic target.

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Best Review Articles:

2021: For amyotrophic lateral sclerosis (ALS – or Lou Gehrig’s disease), this review suggests targeting the CB2 receptor to delay the disease progression
Targeting the CB2 receptor and other endocannabinoid elements to delay disease progression in amyotrophic lateral sclerosis
https://pubmed.ncbi.nlm.nih.gov/33486755/

2019: A meta-analysis of the ten preclinical studies of cannabinoids & ALS
Effects of cannabinoids in Amyotrophic Lateral Sclerosis (ALS) murine models: a systematic review and meta-analysis
https://pubmed.ncbi.nlm.nih.gov/30520038/

2016: A review of ALS, the cannabinoids & the pathways they use
Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis?
https://www.ncbi.nlm.nih.gov/pubmed/28197175

2008: A review of the ECS in ALS
The endocannabinoid system in amyotrophic lateral sclerosis
https://pubmed.ncbi.nlm.nih.gov/18781981/

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Timeline of Research:

2021: In a mouse model of ALS, inactivating the CB2 receptor worsened the disease progression
Inactivation of the CB 2 receptor accelerated the neuropathological deterioration in TDP-43 transgenic mice, a model of amyotrophic lateral sclerosis
https://pubmed.ncbi.nlm.nih.gov/33983653/

2020: In humans with ALS, their blood levels of AEA, 2-AG & 2-OG were predictive of their disease state (66 patients)
Endocannabinoids and related lipids in serum from patients with amyotrophic lateral sclerosis
https://pubmed.ncbi.nlm.nih.gov/33094490/

2019: In humans with ALS, a combination of THC & CBD found helpful (32 patients in a retrospective mono-centric cohort study)
Real world experience of patients with amyotrophic lateral sclerosis (ALS) in the treatment of spasticity using tetrahydrocannabinol:cannabidiol (THC:CBD)
https://www.ncbi.nlm.nih.gov/pubmed/31493784

2017: In a tissue model of ALS, CBD changed genes related to ALS pathology, oxidative stress, mitochondrial dysfunction, and excitotoxicity
Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis
https://www.ncbi.nlm.nih.gov/pubmed/27714895

2017: A case study of using CBD for ALS
[Self-medication with cannabidiol oil in a patient with primary lateral sclerosis]
https://www.ncbi.nlm.nih.gov/pubmed/28397674

2014: in mouse model of ALS, help seen for ALS with Sativex (a 1:1 THC:CBD formulation) via upregulation of CB2
Changes in endocannabinoid receptors and enzymes in the spinal cord of SOD1(G93A) transgenic mice and evaluation of a Sativex(®) -like combination of phytocannabinoids: interest for future therapies in amyotrophic lateral sclerosis
https://www.ncbi.nlm.nih.gov/pubmed/24703394

2010: In a mouse model of ALS, CB1 receptors very sensitive for controlling glutamate and GABA levels
Abnormal sensitivity of cannabinoid CB1 receptors in the striatum of mice with experimental amyotrophic lateral sclerosis
https://www.ncbi.nlm.nih.gov/pubmed/19452308

2008: In a mouse model of ALS, evidence for changes in level of CB1 & AMPA receptors
Altered presymptomatic AMPA and cannabinoid receptor trafficking in motor neurons of ALS model mice: implications for excitotoxicity
https://www.ncbi.nlm.nih.gov/pubmed/18279310

2007: In a mouse model of ALS, CB2 agonist slowed degeneration and preserved motor function
The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset
https://www.ncbi.nlm.nih.gov/pubmed/17241118

2006: In human spinal cords, the glial cells activated in MS & ALS show more COX2, P2X7 & CB2 – agonists suggested as therapeutic
COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord
https://www.ncbi.nlm.nih.gov/pubmed/16512913

2006: In a mouse model of ALS, synthetic and genetic methods to increase endocannabinoid levels show help for ALS
Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice
https://www.ncbi.nlm.nih.gov/pubmed/16571781

2006: In a mouse model of ALS, a synthetic CB1 agonist delays disease progress
AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis
https://www.ncbi.nlm.nih.gov/pubmed/16781706

2005: In a mouse model of ALS, CBN delayed disease onset
Cannabinol delays symptom onset in SOD1 (G93A) transgenic mice without affecting survival
https://www.ncbi.nlm.nih.gov/pubmed/16183560

2004: In a mouse model of ALS, THC delayed motor impairment and prolonged survival as well as attenuating excitotoxic and oxidative cell damage
Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid
https://www.ncbi.nlm.nih.gov/pubmed/15204022

2004: A survey of 13 cannabis users found it might be helpful for ALS
Survey of cannabis use in patients with amyotrophic lateral sclerosis
https://www.ncbi.nlm.nih.gov/pubmed/15055508