Introduction 

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s or motor neuron disease

(MND) is a fatal neurodegenerative disease that causes muscle weakness and paralysis that get worse over time due to progressive loss of nerve cells in the brain and spinal cord (central nervous system) that dampens neuromuscular communication, ultimately leading to respiratory failure. Despite gradual physical function decline as diseases advances, there is unfortunately currently no cure to stop or reverse ALS progression. Recent research into alternative therapies thus has raised interests in cannabinoids, the bioactive compounds among cannabis plants. Given cannabinoids, especially tetrahydrocannabinol (THC) and cannabidiol (CBD), with their potential benefits of muscle relaxation, pain relief, anti-inflammatory, and neuroprotective properties. Cannabinoids, with reported potentiality in delaying ALS symptoms by managing muscle stiffness, pain, and neuroinflammation. This article is going to walk you through how the cannabinoids mechanisms would benefit individuals with ALS to offer a new way of potential symptomatic management and disease progression delay to improve quality of life among the ALS population. 

Understanding ALS 

Pathophysiology 

Amyotrophic Lateral Sclerosis (ALS) is the progressive neurodegenerative disease that affects motor neurons in the brain and spinal cord, responsible for voluntary muscle control. With the development of ALS as a gradual death of upper motor neurons (UMNs) in the brain and lower motor neurons (LMNs) in the spinal cord. The ongoing neuronal loss would disrupt neuromuscular communication between the brain, spinal cord and voluntary muscles, resulting in progressive muscle weakness 

While the exact cause of ALS remains unclear, a combination of genetic, molecular, and environmental factors is thought to be causative.^1,2 Cellular mechanisms, such as protein misfolding, RNA metabolic abnormalities, mitochondrial dysfunction, glutamate excitotoxicity, and neuronal material transport obstruction are all contributing factors of ALS neurodegeneration.²

Symptoms and disease progression

Each ALS occurrence is unique with varied symptoms among individuals, where there is not necessarily a clear-cut disease progression that symptoms may appear gradually or rapid deterioration with plateau. It often begins with subtle muscle weakness, typically from arms or legs (limb-onset), causing difficulties in walking, grasping objects, or speech and swallowing muscles (bulbar-onset) that make speech become slurred or swallowing become challenging. Symptoms such as weaknesses, spasticity, muscle cramps, and twitches would become more widespread as ALS advances. Eventually, result in complete paralysis of voluntary muscles even locked in syndrome associated with respiratory challenges, with preservation of sensations, involuntary bodily function, and often cognitive abilities.^3,4

Regarding the relentless progression of ALS, it typically starts from limb weakness to severe motor impairment widespread across the body, eventually taking away one’s ability to move, speak, eat, or breathe independently, requiring full-time care and assistance. As there is currently no way to halt or slow the motor neuron deterioration, despite the duration of disease course, respiratory failure is often the primary cause of death, mostly after 2-5 years or more after diagnosis.^3,4

What are cannabinoids and how do they work? 

Cannabinoids are bioactive chemical compounds that join cannabinoid receptors in the human body, produced from the plant, Cannabis Sativa. 

There are two main subtypes; tetrahydrocannabinol (THC) and cannabidiol (CBD). 

• Tetrahydrocannabinol (THC), the primary psychoactive component responsible for dopamine release, creates euphoria (“high”) sensation
• Cannabidiol (CBD), as a non-psychoactive, essential component of medical marijuana

These cannabinoids, along with several others, interact upon the body’s endocannabinoid system (ECS), a complex, cellular-signalling network that is vital for various physiological process regulation including skeletal muscle functioning, pain sensation, inflammation, and neuronal growth.^5,6,7 

Consisting of endocannabinoids, the two (CB1 and CB2) receptors, and enzymes that synthesize and degrade these compounds among the ECS. 

Two cannabinoid receptor subtypes 

• CB1 receptors are primarily found in the CNS that regulate the release of gamma-aminobutyric acid (GABA) and glutamate for motor control, pain perception, appetite, brain development and neuroplasticity
• CB2 receptors are mainly located in immune or glial cells among the peripheral nervous system(PNS) for immunity and inflammatory modulation

When cannabinoids bind to these receptors, a variety of effects are produced.

THC is highly affinized with CB1 receptors, resulting in its psychoactive effects for mood regulation, plus the potential pain relief and appetite stimulation through CNS regulation. 

CBD, conversely, with a lower binding affinity, yet interacts with both CB1 and CB2 receptors in modulating the ECS indirectly by inhibiting FAAH enzyme that breaks down and sustains anandamide levels, to improve mood, reduce inflammation and ease chronic pain without psychoactive effects. 

Mechanisms of cannabinoids in slowing ALS progression 

Targeting inflammation, oxidative stress, mitochondrial function, and various symptom management, cannabinoids are shown to potentially delay ALS symptom progression, in view of its underlying neuroinflammation, oxidative damage, and progressive neuronal degeneration. 

Anti-inflammatory effects

Cannabinoids, typically CBD, helps to regulate inflammatory response in the context of ALS⁷. By modulating the ECS through pro-inflammatory cytokines and chemokine release inhibition to suppress neurological inflammatory response, cannabinoids can help to reduce neuroinflammation, a significant progression contributor of ALS that accelerates neuronal damage.⁸

Neuroprotection

Cannabinoids, CBD in particular, are shown to have neuroprotective properties in various neurodegenerative diseases. Through excitotoxicity reduction, neuronal survival pathways enhanced, and neurogenesis promotion, cannabinoids can protect neurons from damage and death. Thereby, delaying ALS symptom progression.⁹

Glutamate signaling modulation

While excessive glutamate signalling has been a contributing factor of neurodegeneration in ALS.² Cannabinoids capabilities in modulating glutamate release, thus signaling, could possibly decrease excitotoxicity and protect neurons from damage.⁹

Mitochondrial function 

Mitochondrial dysfunction has been a contributing factor of ALS.² While cannabinoids are found to improve mitochondrial function, vital for energy metabolism and neuronal health. The enhanced mitochondrial energy metabolism that secure cellular processes could protect motor neurons and slow down symptoms in ALS.¹⁰

Reduction of oxidative stress

Given oxidative stress exists as a hallmark of ALS, contributing to neuronal damage.¹¹ Cannabinoids have antioxidant properties that help to lower oxidative stress and protect neurons from oxidative damage to possibly slow down ALS symptoms progress.⁹

Regulation of microglial activationWhile microglial activation and neuroinflammation are known contributing to ALS progression. With cannabinoids' ability in modulating microglial activation, the degenerative process of ALS can potentially be hampered through inflammatory reduction.^9,12,13

Autophagy enhancement 

Autophagic dysregulation is implicated among ALS pathogenesis.¹⁴ where cannabinoids are shown to enhance autophagy, as the ability of cells in removing damaged components for cellular homeostasis maintenance. Cannabinoids, by protecting neurons from degeneration, are thereby possibly helpful to slow down ALS progression.¹⁵

Overall management of symptoms

Other than delaying ALS progression, cannabinoids are found to be valuable in managing ALS symptoms. While cannabinoids interact with CB1 offers prominent relief to the muscle stiffness, spasticity, and pain commonly seen in ALS. THC, could reduce muscle spasticity, alleviate pain and stimulate appetite.^16,17,18 Furthermore, diminishes the ALS-related sleep disruptions caused by pain, respiratory muscles spasms and muscle cramps.¹⁹ By relieving these ALS symptoms, in improving individual comfort, maintain adequate nutrition intake, reduce excessive energy expenditure by supporting muscle health, and benefiting sleep quality. Thus, enhancing ALS individuals’ overall well-being, energy level, and daily activities tolerance. 

Important considerations for application/usage 

Due to motor neuronal vulnerability, applying cannabinoids like THC and CBD in ALS management to potential slowing down disease course is not without risk. It requires careful consideration of safety, potential side effects, legal restrictions, personalized dosing and administration methods. 

Safety and side effects

Depending on various individual differences, as well as the amount, strength, forms, and frequency of cannabinoids consumption, a wide range of short-term effects such as dizziness, dry mouth, nausea, cognitive, sensory, and perceptual impairments, with psychoactive effects like hallucination, delusion, and psychosis that potentially impair daily cognitive functioning triggered at an even higher dose. However, as ALS patients are often already having respiratory challenges, where cannabinoids exacerbate shortness of breath, nocturnal awakenings and sputum production. Continuous monitoring of potential respiratory declineare vital for timely treatments and interventions. Nonetheless, adopting a gradual dosage increase under medical guidance to adjust when tolerance and dependence occurs when using cannabinoids long-term.²⁰

Legal concerns, dosage and administration

As ALS occurrence is highly varied among individuals, doses recommended for delaying ALS are still under development due to diverse individual responses. While non-psychoactive CBD can be taken at higher doses, more careful and cautious dosing is typically needed in THC to avoid psychoactive reactions. 

Concerning the diverse administration methods, while oils, capsules, and sublingual tinctures (cannabinoid drops to be used under the tongue) are preferred to be used in a consistent dosing, while aerosolized inhaled form offers rapid relief yet may irritate the respiratory system and intensify respiratory distress.²¹ Hence, individuals with ALS should still work closely with their multidisciplinary healthcare professionals to figure out an optimal dosage and administer method tailoring to their needs and symptom profile, to optimize effectiveness in delaying disease progression whilst minimizing adverse effects. 

Summary 

Cannabinoids like THC and CBD has shown promises potential in slowing down the disease progression of ALS through anti-inflammation and neuroprotection that mitigates neuroinflammation, protect motor neurons for death through reducing oxidative stress, improve mitochondrial function, modulate glutamate transmission, and symptom relief. However, as the supporting evidence of efficacy are still indirect, only upon animals on the current stage, further human trials are still needed to validate findings, figure out optimal dose, understand and minimize the potential adverse effects. Further research is crucial to explore the full therapeutic potential of cannabinoids in ALS to offer hope for improved treatments and prognosis among this devastating neurodegenerative condition.