Introduction

Multiple sclerosis (MS), a chronic autoimmune inflammatory disease, is characterised by demyelination, inflammation and neuronal death, disrupting the nervous system.¹ The condition manifests as neurological defects as well as physical and cognitive disabilities; in particular, it causes bladder and bowel dysfunction, vision impairment and numbness. The specific cause of MS remains unclear as of yet; however, the condition is multifactorial, with a genetic predisposition playing a role in addition to environmental factors. Together, this can trigger a cascade of events in the immune system, resulting in nerve demyelination and neuronal dysfunction.² It has been estimated that over 1.8 million people worldwide have been diagnosed with MS, with young adults, particularly people assigned female at birth (AFAB) being the most vulnerable.³ 

MS can be categorised into several types, including relapsing-remitting, primary progressive and secondary progressive. Understanding these subtypes is not only important for predicting the prognosis and the course of the condition, but also for deciding which treatment plan is the most suitable for the individual. Primary progressive multiple sclerosis (PPMS) continually progresses from its initial symptoms with no relapses or remission. It mainly affects the nerves of the spinal cord, making up approximately 15% of MS cases.⁴ PPMS patients tend to have fewer brain lesions but more spinal cord lesions, with symptoms involving stiffness, weakness and balancing difficulties.

 MS has no clear causation but has great disease variability, making it a difficult condition to treat. This is particularly the case for PPMS due to its progressive nature and irreversible damage to nerve cells. Currently, Ocrelizumab, which is a disease-modifying drug⁵, is the only approved drug treatment available for PPMS. While the drug’s mechanisms are not fully understood, it is thought that it plays a role in decreasing the amount of B cells attacking the myelin sheath surrounding nerves. Despite this, studies have shown the results of Ocrelizumab to wear off as early as a week after administration, with symptoms of fatigue, cognitive disability, and sensory symptoms returning even after treatment.⁶ Although current treatments may be effective in modulating immunity and reducing relapses, they perform poorly in limiting disease progression, a fundamental component of PPMS.⁷ 

Due to the challenges of treating PPMS, attention has shifted to the therapeutic role cannabis may have. Cannabis has shown promising results in managing chronic pain, bone loss and inflammation, making it an ideal potential candidate for treating neurological conditions, particularly PPMS. 

PPMS and the role of the endocannabinoid system 

The main hallmark of PPMS is inflammation resulting in plaques and injury to the blood-brain barrier, in addition to neurodegeneration to the CNS involving synapses, neurons and axons. Other features also include myelin breakdown and oligodendrocyte injury.¹ 

The neuromodulatory system, also known as the endocannabinoid System (ECS), plays a role in synaptic plasticity, development and the response to endogenous and environmental factors.⁸ Recent clinical trials have shown that endocannabinoids and cannabinoids can effectively reduce neurological disability in MS patients. This is due to the therapeutic effects endocannabinoids possess, acting as a neuroprotectant to control the level of neurodegeneration and reduce inflammatory responses, in addition to their remyelination-promoting abilities through the activation of specific cannabinoid receptors.⁹ Therefore, cannabinoids not only act as a symptom-relief solution, but can also slow down the progression of neurodegeneration, meaning this could be the first potential treatment to specifically target the progressive element of PPMS.¹⁰ 

Medicinal cannabis

Delta-9-Tetrahydrocannabinol (THC) is a medicinal psychoactive component of cannabis, typically used to treat chemotherapy-induced nausea, as well as to stimulate an appetite. In addition, the activation of the CB2 receptor has been associated with mediating THC’s neuroprotective, antispasmodic, and anti-inflammatory effects, highlighting the role it may play in treating or at least alleviating MS symptoms.¹¹ However, due to its potent psychoactive nature, it has been heavily regulated, and has only been legalised in 2018 for medicinal use with a strict criteria for who is allowed to access it.¹² 

Cannabidoil (CBD) is non-intoxicating with no psychoactive activity but with clear pharmacological effects, particularly possessing anti-inflammatory properties as it downregulates the expression of immune cells.¹³ However, products such as CBD oils have shown no evidence in improving PPMS symptoms, although they have shown effectiveness when CBD is combined with THC.

Clinical trial studies have shown the beneficial effects of cannabinoids in reducing MS symptoms, with greater improvements in spasticity compared to control groups. Nabiximol, an oromucosal spray consisting of a 1:1 THC: CBD combination and approved for the treatment of spasticity, has been shown to alleviate MS symptoms effectively with regards to pain and muscle stiffness.¹⁴ However, secondary symptoms of MS such as poor sleep, bladder function and quality of life did not improve upon the assistance of cannabinoids, with study findings being mixed.¹⁵ 

Challenges and considerations in cannabis use for PPMS

There are strict regulations in place with medical cannabis only being prescribed to moderate-severe PPMS patientsif all other treatments have failed, with it being regarded almost as a ‘last resort’ treatment option. The administration has been associated with a narrow therapeutic window for cannabinoid benefits, reinforcing the importance of taking a medically safe dosage, which should only be prescribed by medical healthcare professionals.^16,17 

Patients with PPMS should remain mindful that cannabis is illegal to buy or grow, even if the purpose is for medicinal use. Smoking cannabis can be extremely harmful, particularly with PPMS patients having a greater vulnerability to neurodegeneration. This is due to cannabis tending to be mixed with tobacco, which has been associated with increased lesions and greater damage to the brain and spinal cord.

Even if cannabis has been medically prescribed, patients should be aware that the activation of certain receptors in cannabis has both positive and negative effects; as a result, the therapy may be associated with undesirable psychoactive effects and risks. Side effects may involve reduced cognitive abilities, particularly attention, memory and executive functions; for example, studies have shown that smoking cannabis reduces hippocampal volumes and density, a region in the brain associated with memory. In addition, patients may become dependent on cannabis; it was found that up to 10% of users meet the criteria for lifetime cannabis dependence due to its addictive components.¹⁸ This highlights the necessity of patient education and stringent regulations for prescribing, and the importance of understanding the psychological side effects so the patient can make an informed decision. 

Future directions

An effective treatment for PPMS remains unclear as of yet, with a lack of well-designed, large-scale clinical trials. Despite having identified cannabis as a novel target for neuroprotection and inflammation, it is still not used as a widespread treatment option for PPMS. This is perhaps due to the lack of validity, with clinical trials showing modest results compared to control groups. However, it could also be due to cannabis being considered a recreational drug, and the taboo associated with it. There may be future developments on minimising the psychoactive elements of the medicine to balance out the therapeutic effects it has. Although cannabis is seen as an alternative pseudomedicine, there is a demand for it amongst PPMS patients, with 1 in 5 patients saying they would be willing to try cannabis to help alleviate their symptoms.¹² 

Summary

Primary progressive multiple sclerosis is a chronic inflammatory condition, continually progressing from its initial symptoms with no remission. There is no cure for MS and current treatment options tend to focus on reducing relapses. However, this would not be effective in treating PPMS due to the nature of it being progressive, making it difficult to treat. Therefore, in recent years, attention has shifted to cannabis being used as a potential therapeutic treatment for PPMS. Cannabis, specifically THC and CBD combined, has shown improvements in spasticity, properties of neuroprotection, and reducing inflammation, making it an ideal potential treatment option. In 2018, the medicine Nabiximol became available in the UK; however, patient accessibility is low due to the strict regulations in place to prevent dependency, and the potential for addiction or for it to be used recreationally. In addition, clinical trial results using cannabis as a treatment for PPMS have shown limited validity, with modest results compared to control groups. Cannabis is a promising novel treatment for PPMS as it specifically targets the progressive nature of the condition; however, more evidence-based research is needed for it to be used on a widespread scale as a treatment of PPMS.