Overview

Cannabis containing cannabinoids has been used for centuries for its medicinal properties to reduce inflammation and pain and relax muscles.¹ However, the science behind the effect of cannabinoids on relieving pain and spasms was only discovered in the 20^th century.

Tetrahydrocannabinol (THC), one of the two main cannabinoids, is responsible for the antispasticity effect.^1,2 THC binds to cannabinoid type 1 receptors (CB1) in the central nervous system. THC binding to CB1 receptors reduces the release of glutamate neurotransmitters, thereby reducing spasticity, where skeletal muscle suffer from combination of increased reflex neuron activity in tendons and paralysis.

This article simplifies the science behind cannabinoids' effectiveness on muscle spasticity by introducing and breaking down the concepts.

Understanding spasticity: An overview on causes and symptoms

Involuntary muscle contractions with spasms or jerking movements, constant muscle tightness (increased muscle tone), resistance to stretching, and limited motion are nothing less than pain, disabling, and discomforting. These symptoms are the hallmarks of spasticity.

Spasticity is a condition caused by injury within the spinal cord or the brain, regions that control muscle and stretch reflexes. An injury can disrupt the muscle contraction-relaxation mechanism (Figure 3), leading to spasticity.

The tightness or stiffness of muscles in spasticity prevents normal, unrestricted movement.³ 

The spectrum of spasticity varies from subtle neurological disorders to immobility and dependency.^3,4 Spasticity is a symptom in stroke, cerebral palsy (CP), anoxia, traumatic brain injury (TBI), spinal cord injury (SCI), multiple sclerosis (MS), and neurodegenerative diseases.^3,4

Approved medications available: Is there a need for cannabinoids in treating spasticity?

The course of treating spasticity is decided considering the cause, other medical comorbidities, patient support system, and overall goals of management.³ Treatments for individuals with spasticity aim at relieving symptoms and improving the quality of life.

Treatment options for spasticity

Traditional treatment methods, usually implemented in combination with one another, include physiotherapy, occupational therapy, casting or bracing, and approved medications. Invasive surgical procedures are employed only in cases of severe spasticity.^3,4

Medications approved by the regulatory bodies, including baclofen, tizanidine, dantrolene, and diazepam, work as muscle relaxants, thereby reducing muscle spasms.^3,4 

Botulinum toxin A (Botox), a natural bacterial toxin, is also approved to ease localised spasticity by temporarily paralysing the overactive contracting muscles.³ Access the leaflet with more information on botulinum toxin injections for the treatment of spasticity in adults.

Approved medications for spasticity treatment: What are the limitations?

Conventional medications may provide relief from mild to moderate spasticity, reduce muscle tone, and decrease pain and discomfort.^3,5 However, very rarely do these medications provide complete relief and significantly improve one’s functioning.^3,5

According to their users, the intolerable limitations and side effects of conventional medications are nausea, drowsiness, and weakness.⁵

Individuals with SCI, spinal cord injury or MS, multiple sclerosis, who sought relief through marijuana (parts or products from the cannabis plant), expressed decreased muscle spasms and pain, relief from nausea, and peaceful sleep.⁵ 

Additionally, decreased noticeable spasticity symptoms, enhanced daily activities, and improved quality of life from cannabinoid spray have been reported.⁶ 

Cannabinoids explained: Why do they affect humans?

Hundreds of chemical compounds have reportedly been isolated from the cannabis plant (Cannabis sativa), called cannabinoids.⁷ Cannabinoids are known to have physiological and psychological effects. But how does a plant secondary metabolite elicit a response in humans?

Endocannabinoids: How it revealed cannabinoids' mechanism of action

In the 1960s, phytochemicals (plant bioactive compounds with physiological effects) from the cannabis plant, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), were discovered.⁷ 

The study of THC and CBD, two of the many phytocannabinoids (Phyto- means plant in Greek), led to a chain of ground-breaking discoveries:⁷

• Synthetic cannabinoid compounds were designed
• These ‘synthetic cannabinoids’ during research bound to and revealed the presence of specific cannabinoid binding sites (receptors) in the human brain
• The receptors were named cannabinoid receptors type 1 (CB1) and type 2 (CB2)

The discovery of receptors CB1 and CB2 aroused curiosity about their need in the human body. Thereafter, two cannabinoids produced naturally in the human system (endocannabinoids) and structurally similar to phytocannabinoids, were found to target the receptors CB1 and CB2.⁷

Therefore, phytocannabinoids (from plants) and synthetic cannabinoids (lab-made) can elicit functions similar to endocannabinoids (produced naturally by the body) because they interact with the same receptors, CB1 and CB2.

Cannabinoid binding sites: Critical to the body's functions

Our body comprises several chemical messengers that, upon binding specific receptors (like a key to a lock), unlock a cascade effect that drives various functions. 

Cannabinoid binding sites, CB1 and CB2, are the main receptors involved in the endocannabinoid system (ECS). These receptors are found in abundance in our brain and body.⁷ 

Cannabinoid receptors type 1 (CB1)

CB1 receptors are found in our nervous system. Hence, their role in regulating critical body and brain functions:^7,8

• CB1 is present in key locations in the brain like amygdala (emotional regulation), basal ganglia (movement control), and hippocampus (memory formation).
• CB1 receptors are located in the peripheral nervous system and various areas within the spinal cord along the pain pathway.
• The receptors are present throughout the neurons (unit of the nervous system).
• The receptors are also present in organs involved in energy metabolism: muscle, liver, endocrine pancreas, and adipose tissue.

Cannabinoid receptors type 2 (CB2)

In contrast, CB2 receptors are found mainly on the immune cells (defence cells), in and out of the central nervous system.^7,8 

Exposure to external cannabinoids (phyto- or synthetic), has its effects on bodily functions by ‘hijacking’ these receptors from the endocannabinoids (AEA or 2-AG). 

Cannabinoids and spasticity: The science behind the effect

Since the recognition of the medical value of cannabinoids by the United Nations (UN) in 2020, the use of medical cannabinoids is less restricted.⁹

The medical cannabinoids include:⁹

• Synthetic cannabinoids (e.g., dronabinol and nabilone capsules with lab-made THC)
• Cannabis derivatives (e.g., Nabiximols oromucosal spray with equal proportions of THC and CBD)

Since the approval of Nabiximols in 2010, the cannabis-derived extracts have been allowed exclusively for medicinal use, e.g., to treat resistant symptoms of MS, in the United Kingdom.^9,10

Why does the body let external cannabinoids ‘hijack’ cellular machinery (ECS)?

Medical cannabinoids with THC and CBD are the pharmacologically relevant compounds.¹⁰ They are agonists.^7,9,10

Medical cannabinoids are agonists, as they mimic the endocannabinoids, both in structure and action.⁸ By ‘hijacking’ or binding, mainly to the cannabinoid receptors, medical cannabinoids (at a particular dosage) elicit or activate responses within the cells.⁷

However, dronabinol and nabilone, the synthetic THC and the cannabis-derived THC, are partial agonists (elicit partial responses).^7,9

What happens when cannabinoids bind to cannabinoid receptors?

Naturally, small quantities of endocannabinoids (AEA and 2-AG) are produced in different parts of our body and help regulate important functions like pain, mood, and appetite. 

AEA and 2-AG bind to CB1/CB2 to modulate the contraction strength in skeletal muscles. By adjusting the acetylcholine release (Figure 2) and fine-tuning the excitatory (glutamate) and inhibitory (GABA) neurotransmission (Figure 3), AEA and 2-AG control muscle contraction.^11,12

Studies have demonstrated the mechanism by which medical cannabinoids effectively reduce muscle spasticity in adults with disrupted muscle contraction-relaxation machinery (Figure 4) due to MS.^2,7

Partial agonist cannabinoids work alongside endocannabinoids. Studies in non-human models of MS indicated an increase in AEA and 2-AG in the brain and spinal cord.¹³ 

Medical cannabinoids (THC), that mimic the endocannabinoids, bind to CB1 receptors in the CNS (Figure 1). Binding initiates receptor activation, inhibiting the glutaminergic transmission (Figure 2) or reducing glutamate release, thereby modulating muscle tone and reducing spasticity (Figure 4).²

Figure 4. The impact of cannabinoids on spasticity: understanding the science.

FAQs

If your body produces endocannabinoids, why don’t they cause a ‘high’?

Among the endocannabinoids, AEA has a higher affinity for the CB1 receptors in the CNS. However, they don’t cause a ‘high’ due to a partial response, as they are partial agonists. Synthetic THC for therapy (controlled dose) is also a partial agonist without the ‘high’ effect.⁷ 

In addition, endocannabinoids produced in small quantities by the body in an activity-dependent manner are rapidly broken down thereafter.

In contrast, synthetic cannabinoids (e.g., K2 or spice) are full agonists (trigger maximum response), thereby posing a significant risk of toxicity or death by overdose.

How do the anti-spasticity effects of CBD compare to those of THC?

CBD is not established to have the same effect on spasticity as THC. CBD acts on the CB1 receptor to decrease the efficacy and potency of the phytocannabinoid THC or psychotropic effects of THC.⁷ 

Studies have established CBD to aid mobility in individuals with MS by reducing pain and inflammation. However, the reported anti-spasticity effects of CBD could be because of THC used in combination.¹³ 

For example, Sativex®, an oral spray, contains both THC and CBD (1:1). THC could have played a significant part in reducing muscle spasticity, as the impact of CBD on spasticity tends to be less pronounced when used alone.

Summary

• Injury to the spinal cord or brain can impair the mechanism of muscle contraction and relaxation, resulting in spasticity
• Endocannabinoids AEA and 2-AG bind to CB1/CB2 receptors to modulate the contraction strength in skeletal muscles
• Phytocannabinoids and synthetic cannabinoids (THC), when consumed, interact with CB1 and CB2 receptors to elicit functions similar to endocannabinoids
• THC that mimics the endocannabinoids binds to CB1 receptors in the CNS and inhibits glutaminergic transmission, reducing glutamate release
• Cannabinoids reduce noticeable spasticity symptoms, enhance daily functional activities, and improve the quality of life in individuals with debilitating spasticity