Monday article #16: Cannabinoids and Multiple Sclerosis
Cannabis is popular for its “high” effects, but do you know that there has been an increasing interest in cannabinoids treatment for multiple sclerosis (MS)? In a recent survey, 47% of respondents showed their interest in taking cannabis to treat their MS symptoms where 26% have already used cannabis, 20% are planning to take cannabis treatment and 16% are currently undergoing cannabis treatments. Here, we will discuss the effectiveness of cannabinoids in treating one of the most disabling MS symptoms: spasticity.
Multiple sclerosis is an autoimmune neuroinflammatory disorder of the central nervous system (CNS) that has affected an estimated 2.5 million people. It is characterised by severe demyelination, inflammation, axonal loss and gliosis in CNS. MS is commonly found in people in their 20 and 30s, but it can also be developed at any stage of your life. Myelin is key for efficient impulses transmission along the nerves. Significant demyelination delays and halts transmission, thereby producing neurological disabilities related to vision, urinary, arm or leg movement, sensation or balance in MS. Though our body can repair the resulted lesions or scars naturally, it is slow and incomplete. Our neurones thereby get damaged progressively and eventually lost. Existing disease-modifying MS treatments revolve around this area of delaying progressive loss by curbing our immune system (adaptive and innate immune system), which appeared to be heavily involved in MS pathogenesis. While autoreactive T lymphocytes underlie MS neuroinflammation, macrophages, microglia and astrocytes are involved in producing inflammatory cytokines, regulating T lymphocytes, as well as engaging in the demyelination process. Unfortunately, there has not been a cure for MS and most MS treatments are not completely effective. Thus, the discovery of cannabinoids as a potential MS treatment caused a surge in interest.
Spasticity is found in 90% of MS patients where at least 50% of them have mild spasticity and 17% have severe spasticity. It is defined as an increase in muscle tone because of hyperexcitability of the stretch reflex. It is often associated with painful manifestations. Most importantly, studies have found that spasticity is the underlying mechanism of motor dysfunction, urological dysfunction and all the painful manifestations in MS. As spasticity is one of the most disabling symptoms and has a huge impact on patients’ quality of life, cannabinoids treatment for spasticity became popular among MS patients, as many have claimed it useful.
Increased usage of cannabis lead to the discovery of the endocannabinoid system (ECS), which is mediated by two G protein cannabinoids receptors in CNS and PNS, cannabinoids receptor 1 (CB1) and cannabinoids receptor 2 (CB2). They involve heavily in retrograde signalling for they locate presynaptically. Their location varies slightly; while CB1 is predominantly found in CNS and less prevalently in PNS and other tissues, CB2 is located in peripheral tissues that are related to the immune system. Hence, CB1 plays a role in neurotransmissions that regulate emotions, stress and peripheral functions (responsiveness), whereas CB2 has an immuno-function e.g role in neuroinflammation. Endocannabinoids (AEA and 2-AG), phytocannabinoids and synthetic cannabinoids can interact with these receptors.
2 phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been studied extensively as they are found to produce huge therapeutic effects. For instance, THC was used to increase the appetite of HIV and cancer patients. While both produce similar effects per the interactions with the same receptors, the difference in affinity, mechanism of actions and additional interactions with other receptors lead to distinct differences in their overall effects. It appears that CBD has anti-tumour, anticonvulsant, anti-psychoactive, anti-inflammatory, neuroprotective, anti-oxidant effects. On the other hand, THC appears to elicit antiemetic, anti-inflammatory, analgesic effects. It also regulates energy homeostasis and acts as a muscle relaxant. THC and CBD are often used in combination as CBD balances out the psychoactive element of THC. Zinah Zamil et al. used the experimental autoimmune encephalomyelitis (EAE) model to illustrate that THC: CBD reduce neuroinflammation significantly by decreasing the amount of pro-inflammatory cytokines (IL-17A and IFN-y) and increasing anti-inflammatory cytokines (TGF-ß and IL-10). In particular, a cannabinoid treatment, Sativex ®, which has a 1:1 ratio of THC and CBD, is undergoing clinical trials to examine its efficacy and safety as an MS anti-spasticity drug. Many clinical trials showed that Sativex generally improved MS spasticity with a significant difference.
However, it appeared that Sativex approached a higher statistical significance when used as an add-on therapy to anti-spasticity drugs such as Baclofen. Further, cannabinoid usage has been limited mainly due to the concerns over tolerability, dependence and long term adverse effects (AEs). While many studies state that AEs were generally well tolerated, a significant amount of people withdrew for the same reason. Importantly, the overall rate of AEs is less than 10% and less than 3% of subjects withdrew from the study due to AEs when cannabinoids are used supplementarily. Therefore, questions arose whereby cannabinoids should be used supplementarily or as a monotherapy.
People also questioned its optimal dosage to achieve maximal effectiveness and minimal adverse effects for many studies utilised a wide range of dosages to prove its effectiveness. Even so, cannabinoids (THC+CBD) is commonly used within the range of 20-40mg/kg. Notably, one of the studies found that in long term, cannabinoids treatment remained effective (6 months) at a slightly lower dosage of 6.3 puffs/ day, thereby can reside the concerns on tolerance and drug misuse. Interestingly, another phase III trial with a shorter period (19 weeks) presented an increase in the dosage trend.
Overall, these areas remain unclear and controversial. Further investigations are required for clarifications, particularly on the long term effectiveness, risk on tolerability and dependence, long term adverse effects and more associated risks. Essentially, cannabinoids have huge therapeutic potential, but a clearer image needs to be drawn for them to be used effectively and safely.
Patti F, Messina S, Solaro C, et al. (2016). Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity. Journal of Neurology, Neurosurgy & Psychiatry. 87, 944-951
Novotna A, Mares J and Ratcliffe S. (2011). A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex®), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol. 18, 1122-1131
This article is prepared by : Lim Tze Yee