Overview

Multiple sclerosis, often shortened to MS, is a chronic neurological disorder resulting in progressive loss of nerve cells within the brain, optic nerve and spinal cord. There are an estimated 150,000 people affected with MS in the U.K. Common symptoms that occur around the time of diagnosis are walking difficulties, cognitive impairment, fatigue, and unusual feeling within skin such as burning. As the disease progresses, individuals may experience increasing muscular pain, bladder and bowel problems and body stiffness. Standard treatments are unable to improve the quality of life of individuals affected by MS; driving an interest in alternatives such as cannabis-based therapies. An often overlooked component of cannabis plants, known as terpenes that gives rise to characteristic aroma of cannabis, has shown synergistic and beneficials effects alongside medicinal cannabis use).³ 

Multiple Sclerosis (MS): A neurodegenerative autoimmune disorder

Multiple sclerosis is the most common neurological disorder. Unfortunately, the exact cause of MS is unknown, but is it often classed as an autoimmune disorder.¹

What is autoimmunity?

The immune system is a powerful internal defence mechanism that protects the body from potentially dangerous foreign invaders such as viruses and bacteria. However, autoimmune disorders mean that an individual's immune system attacks it’s own body cells and tissues, mistaking them as ‘foreign’ and dangerous: leading to damage and disease.¹

How does autoimmunity affect nerve cells in MS?

In MS, the protective fatty layer around nerve cells, known as the myelin sheath, starts to progressively deteriorate due to attacks from immune cells. The myelin sheath not only acts to protect nerve cells, but also to optimise the effectiveness of the nerves. This disrupts nerve signal transmission, as well as causing progressive damage to the neuronal axons, which are crucial in enabling communication to other nerve cells.¹

Subtypes and symptoms of multiple sclerosis

No two cases of MS are the same, but can be organised into categories with specific characteristics. With this in mind, multiple sclerosis can be split into four-types. 

• Clinically isolated syndrome (CIS): Occurring in young adults, this stage describes the first episode of MS symptoms. It usually affects the optic nerve (nerve connections between the eyes and brain), the spinal cord, or the brainstem⁴
• Relapsing-remitting MS (RRMS): Affecting ~85% of people with MS, this is the most common type of MS. People experience discrete episodes (i.e., flare ups or relapses) of neurological symptoms lasting at least 24 hours, followed by varying periods of remission. The duration and period of remission varies between individuals⁵. Overtime, it may transition to a progressive form
• Secondary-progressive MS (SPMS):This form typically follows RRMS, where symptoms progressively worsen with or without relapses.If RRMS is not effectively treated in time, approximately half of individuals will develop SPMS within 10 to 20 years⁶
• Primary-progressive MS (PPMS): Affecting 10-15% of individuals with MS, this form of MS is the least common. Unlike other types, PPMS is progressive from the first occurrence of symptoms, meaning the symptoms gradually worsen from the beginning, without any clear relapses or remissions. This form of MS is mostly associated with walking disabilities rather than other symtoms associated with other forms of MS⁷

Due to the progressive loss of nerve cells throughout the brain and spinal cord, a variety of symptoms can arise. However, these can vary between individuals and also on a day-to-day basis.

Introduction to cannabis as a therapeutic option for MS

What is cannabis?

Cannabis, of which cannabis sativa and cannabis indica, are most commonly used for recreation and medicinal purposes It is a plant indigenous to Asia and Western China. This ancient plant’s ‘medicinal’ capabilities have been harnessed by ancient civilisation such as the Chinese, Egyptian, and Greeks. Their capabilities include:⁸

• Pain relief
• Anti-inflammatory 
• Stress/ anxiety relief (dose dependent)

What are the active compounds in cannabis?

The cannabis plant contains over 560 compounds known as phytochemicals (compounds found in plants beneficial to humans) such as alkaloids, flavonoids, phytocannabinoids and terpenoids.⁶ However, since the discovery of the ‘endocannabinoid system’ in humans, the cannabinoid compounds known as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have taken centre stage.

What is the endocannabinoid system and how does cannabis work in the body?

‘Endo’ is a prefix used in latin to denote inner, thus the endocannabinoid system refers to our own internal system, which uses ‘in house’ made cannabinoid to regulate brain and spinal cord function, as well as the immune system. The body produced N-arachidonoylethanolamine (AEA and also called anandamide) second endogenous molecule named 2-arachidonoylglycerol (2-AG).⁹ 

The actions of the endocannabinoid system are predominantly undertaken by two receptors: cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). For specifics on these receptors and their mechanisms check out this article. Since these receptors are distributed and located on different regions of the body it can have different results depending on which is activated.⁹

• CB1: These receptors are in high numbers in the central nervous system, as well as the liver, skin and adipose tissue. (fat cells)
• CB2: mostly found on immune cells, but also found in the brain. (under disease-states)

How does THC and CBD affect the body?

THC, the psychoactive component of cannabis, partially binds to CB1 and to CB2. Due to the location of CB1 in the brain, the binding of THC causes psychoactive effects (aka “high”). These includek:⁸

• Pain relief
• Anti-anxiety (in low doses) or heightened anxiety/paranoia (high doses)
• Increased appetite (“munchies”)
• Drowsiness
• Reduced body coordination
• Euphoria
• Anti-nausea 

Since THC also binds to CB2, which is located on immune cells, it can also have an anti-inflammatory effect on users. 

CBD, a non-psychoactive compound that does not cause a “high”, has a broad range of effects. Unlike THC, it binds less strongly to CB1 and CB2. The effects may include:

• Pain relief
• Reduce symptoms of anxiety and depression
• Reduce muscle spasticity in MS and improve cognition in other neurological disorders
• Possible sleep aid

Mostly, the focus of medical and recreational cannabis use has been on THC and BD. However, evidence is emerging that other compounds such as terpenes may enhance the effects of THC and CBD, and/or have benefits on their own. 

What are terpenes?

In recent years, the phytocannabinoid-terpenoid interaction has sparked interest in the potential benefits of the enhanced effects terpenoids can have on medicinal cannabis, alongside THC and CBD. Terpenoids are largely responsible for the characteristic aroma of cannabis. For the plant, these molecules serve as an ‘insecticide’: repelling potential insects that wish to consume the leaves and cause damage to the plant. The bitter state associated with terpenoids also repels grazing animals.¹⁰

Cannabis terpenoids is made up of several terpenes found commonly in the plant, with over 200 compounds being categorised. Examples include: 

• Limonene 
• Myrcene
• Α-pinene
• Linalool
• β-caryophyllene
• Caryophyllene oxide
• Nerolidol 
• Phytol. 

Pharmacologically, terpenoids have shown great versatility and usability due to their ability to interact with human receptors and their ability to cross layers of fat: a highly sought after feature in drug design since it allows access to the brain, which is highly protected. Furthermore, approval by the American Food and Drug Administration (FDA) has found terpenes to be ‘confidently safe for human use’.¹¹

Understanding MS and its treatment needs

THC is a powerful anti-inflammatory by itself: shown to be 20 times more powerful, and twice as much as hydrocortisone (a common steroid used for MS to reduce severity of flare ups). THC also avoids the pitfalls associated with these drugs, such as ulcers associated with chronic aspirin use, and risk of increased infection with the use of hydrocortisone. 

CBD is also shown to be a pain-reliever with potent neuro-protective effects, with high enough concentrations (16uM) showing improvement in cognitive function in animal research models. 

Current treatment options used for MS:

The first line treatment options used for MS are known as disease-modifying therapies (DMTs). The commonly used are:¹²

• Interferon-β (IFN-β): reduces the inflammatory response that would otherwise worsen and damage nerves, worsening symptoms
• Glatiramer acetate (GA): similar to IFN-β, modulates the activity of the immune system to reduce damage

Though these therapies are well tolerated and their safety is extensively studied, they do not control all disease aspects of individuals with MS. 

Why cannabis has potential as a complementary therapy

The use of complementary therapies: the use of DMTs alongside cannabis, have been shown to yield beneficial outcomes:

• Muscle spasticity: a common occurrence in MS affecting 60-84% of individuals. The occurrence of this symptom can exacerbate strains and restrictions on daily activities and reduce quality of life. A combination therapy alongside pharmaceutical treatments have shown to increase patient satisfaction. Studies have shown that topical cannabis use, as well as vaping and smoking of THC and THC:CBD has allowed the treatment of spasticity²
• MS-related pain: a frequent and long recognised element of lives affected by MS. This aspect of MS significantly impacts the quality of life of individuals with MS. Though existing therapeutics to treat MS do not address this issue, THC, THC:CBD, or CBD has been shown to have potent analgesic effects (pain relieving)²
• MS-related sleep disorders: one of the most common symptoms amongst individuals affected by MS. This symptoms can be linked to the immunotherapies used in MS, as well as an MS-related symptom. Cannabis has long been recognised as sleep aid in correct doses amongst individuals suffering from insomnia and shown to be well tolerated under medicinal conditions⁸

Nabiximol (generic name for Sativex®) is a oral mucous spray containing 1:1 ratio of THC:CBD. This licensed therapeutic is a therapeutic used in several countries to treat severe spasticity in MS patients. The advent of this licensed therapeutic has opened the door to novel therapy designed to tackle currently untreatable symptoms of MS.²

Mechanisms of terpenes in MS symptom relief

Anti-inflammatory and pain relief effects

• β-Myrcene is a common terpene found in cannabis and has found to be both anti-inflammatory and analgesic (pain relieving). The former effect is via reducing the action of prostaglandin E-2: a principal mediator of inflammation¹³
• α-Pinene, the most widely found terpene in nature, has been shown to have anti-inflammatory effects via reducing the effects of a potent inflammatory pathway known as nuclear factor-kappa B (NF-κB) 
• β-caryophyllene: a predominant terpene in cannabis, it can synergise with THC to have anti-inflammatory and pain relieving effects through similar mechanisms described above^11,13

These terpenes can prove useful in reducing the damage caused by the immune system on nerve cells, hence alleviating the symptoms associated with MS.

Neuroprotective properties

• D-Linalool: Also commonly found in lavender as well as cannabis, this molecules activity on glutamate (the primary excitatory neurotransmitter in the brain) and GABA (the primary inhibitory neurotransmitter in the brain) systems, it has been shown to reduce seizures, anxiety attacks, and have sedative effects in pre-clinical models. Alongside CBD, this terpene can prove neuroprotective against certain symptoms of MS¹¹

Anti-spasticity and Muscle Relaxation

• In addition to its anti-inflammatory benefits, β-Myrcene can also assist in reducing the muscle spasms associated with MS. The effect of this is through its synergistic activity with THC and CBD via the secretion of endogenous opioids (our bodies built-in pain management system)¹¹
• D-Limonene can act alongside CBD to induce sedative states that can help reduce muscle rigidity and spasms associated with MS^3,10

Evidence supporting terpene efficacy and current limitations

Though the potential benefits of terpenes have only recently been uncovered, there are many studies that continue to support this.

• A study published about myrcene found that it can have pain relieving effects in mice believed to be via α₂-adrenoceptor (a receptor found in the central nervous system) stimulated release of endogenous opioids
• Β-caryophyllene discussed earlier was shown by this study to have potential therapeutic effects on inflammation and pain through its binding of the CB2 receptor and synergism with THC

Despite promising research, most of the work so far has been on preclinical cell and animal models, which does not always translate to humans. Continued research is necessary to establish safety, tolerance, effective administration, and exact mechanisms of action. 

Summary

Multiple sclerosis is a devastating disease that can have wide ranging impacts on the quality of life of an individual. Whilst existing pharmaceutical treatments help manage disease progression and are shown to relieve inflammation, they often fall short in treating symptoms related to pain, muscle spasms, and complex neurological dysfunctions. Cannabis, primarily CBD and THC, offer symptom relief, and have made it as licenced therapies in certain countries. Emerging evidence suggests that terpenes, another family of compounds found in cannabis, can enhance the effects of THC and CBD: potentially allowing better treatment of MS and improving quality of life of individuals with this disease. As science progresses, terpene-rich cannabis products could become valuable tools in personalised MS care.