Multiple sclerosis: treatment with medical cannabis

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Multiple Sclerosis (MS) usually occurs between the ages of 20 and 40. The neurological disease progresses episodically, and symptoms may vary. While standard therapies can reduce the frequency and duration of relapses, drug therapies are not free of severe side effects. Medical cannabis provides a complementary therapy option low on side effects, to alleviate various MS symptoms, with different studies supporting the theory.

Multiple sclerosis (poly sclerosis) is an autoimmune or chronic inflammatory disease of the central nervous system (CNS) in which inflammatory processes in the brain and spinal cord destroy parts of the nerve fibers. In the process, the defense cells, which usually attack pathogens and foreign substances, damage the body’s own tissue. In simple terms, this means that the immune system turns against its own body.

Multiple sclerosis: What are the causes?

The exact causes have not yet been conclusively clarified. Although it has been proven that the disease is caused by the inflammatory processes in the brain and spinal cord, it is unclear why it occurs. Different factors seem to come into play, such as the autoimmune process.

Infections with viruses (e.g., herpes viruses, chlamydia, or the Eppstein-Barr-Virus) that resemble the body’s own structures may be a possible cause. These could also be the case in the development of other autoimmune diseases, such as rheumatoid arthritis or systemic lupus erythematosus (SLE).

Furthermore, hereditary factors also play an important role. Relatives of MS patients are 30 times more likely of also developing the disease.

What are the symptoms of multiple sclerosis?

Typical MS-related symptoms include:

Sensory disturbances:

  • tingling (formication) and/or numbness in the arms and legs.
  • Poor temperature perception
  • Tightness sensations around the joint and hip region.
  • Sudden jerking along the spine when the head is bent forward (neck flexion sign) 

Visual disturbances:

  • sore eyes
  • haze in front of the eyes
  • impairment of color recognition
  • double vision and/or flashes of light 

Muscle paralysis:

  • muscles that tire quickly and lack strength
  • tense or stiff muscles
  • spastic paralysis in arms and/or legs
  • facial paralysis (facial nerve palsy).

In addition, other symptoms such as taste, balance, and speech disorders may occur. Likewise, there may be disturbances in bladder and bowel emptying. The psyche may suffer equally from the disease. Many affected patients develop depression, suffer from mood swings or insomnia.

As varied as the symptoms are, numerous triggers can also lead to an acute episode. Particular risk factors can be stress, infections, certain vaccinations or hormone fluctuations. Immune system influencing medications can also trigger an acute attack.

Diagnosis and therapy in Multiple Sclerosis

If MS is suspected, an anamnesis interview and a comprehensive neurological examination are usually the consequence, during which muscle strength, reflexes and sensations are tested, among other things. To confirm the diagnosis, a cerebrospinal fluid (CSF) sample is taken. Furthermore, electroencephalography (EEG) and magnetic resonance imaging (MRI) can also confirm the diagnosis, as these imaging techniques can detect the abnormal inflammatory lesions.

Since multiple sclerosis cannot be cured, the goal of any therapy is to alleviate acute symptoms (symptomatic therapy) and to treat acute relapses. In addition, drugs can be used to try to reduce the inflammatory processes.

MS patients receive immunotherapeutics for this purpose. Therefore, active substances such as interferon-beta are used in the basic therapy if the disease is mild to moderate. Basic therapy can reduce the frequency and duration of relapses, but immunotherapeutics can have severe side effects, such as:

  • Gastrointestinal distress
  • Fever
  • Pain in the limbs
  • Headache
  • Fatigue

In case of a patient not responding to therapy or in occurrence of highly active phase, immunotherapeutics, with the active ingredients natalizumab or alemtuzumab, are normally prescribed. These drugs contain targeted antibodies.

Other drugs such as high-dose glucocorticoids (anti-inflammatory drugs) are additionally used in acute relapses. However, an acute flare cannot always be relieved with cortisone therapy. Moreover, treatment with cortisone is also associated with side effects, from which the patients suffer additionally.

Course of the disease and prognosis

MS is initially relapsing and later progresses chronically. The exact course of the disease cannot be predicted. It varies from person to person. About one third of all patients in the advanced stage live without a major severe disability. Another third experience only partial restrictions in their daily lives and occupations. The disease is accompanied by occupational disability and need for care in another third.

Cannabis as medicine for multiple sclerosis

Since the discovery of the endocannabinoid system in the human body over 20 years ago, cannabis-based medicines have been intensively researched. Endocannabinoids are substances that bind with cannabinoid receptors (CB1 and CB2 receptors) and modulate the information flow of neurons in the CNS. Therefore, they can influence various functions such as pain perception, appetite and sleep. In multiple sclerosis, changes in the endocannabinoid system have been demonstrated, so that the previously mentioned functions can be impaired.

The endocannabinoid system can be therapeutically influenced not only with endogenous cannabinoids (endocannabinoids), but also with the help of cannabinoids (phytocannabinoids) from the cannabis plant such as tetrahydrocannabinol (THC) and cannabidiol (CBD).

Cannabis therapy for spastic symptoms

Around 80 percent of patients suffer from spastic disorders that cause pain. Various studies have already shown that cannabinoids can have a positive effect on spasticity.

In 2004, Swiss researchers found in their double-blind crossover study that in 37 out of 50 subjects with MS, the frequency of muscle spasms was reduced by treatment with an orally administered standardized cannabis extract [1].

In 2007, another clinical trial from the United Kingdom also showed that medical cannabis was more effective than a placebo [2]. A standardized Oro-mucosal medication (oral spray) containing THC and CBD was used in this case.

Also, US researchers investigated the effect of cannabis extracts on spasticity and muscle spasms in MS and confirmed a positive effect [3].

More recent studies also show that MS patients may benefit from cannabis-based medications. In April 2017, New Zealand researchers reported on patients with MS who had an inadequate response to treatment with standard medications. After having been treated with the oral spray Sativex (THC/CBD) for 12 weeks, their spastic symptoms improved [4].

Important information: The oral spray Sativex is approved for MS therapy. Therefore, health insurance companies are obligated to cover the costs, no prior authorization or application is required. 

Medical cannabinoids against pain

The majority of patients suffer from severe pain – whether due to spasticity or inflammation of nerve tissue. It is well known that cannabis as a medicine can have a beneficial effect on chronic pain. Even for pain associated with multiple sclerosis, studies have shown that medicinal cannabis can be effective in the form of ready-to-use or prescription medicines, or dried medical cannabis flowers [5].

Cannabidiol (CBD) against inflammation

Research hypothesizes that the reason cannabis is medicinally effective for MS-related spasms and muscle spasms is the assumption that the non-psychoactive cannabinoid CBD is be able to reduce nerve inflammation. In a 2011 Israeli study, researchers used mice with an MS-like condition to show that they were able to move their stiff legs again and had less inflammation after receiving highly concentrated CBD [6].

In 2017, the same Israeli researchers reported that pro-inflammatory astrocytes (star-shaped neurons) are involved in almost all brain functions and that they interact with the endocannabinoid system. After analyzing collected data, researchers stated that astrocyte activity can possibly be reduced by administering CBD [7]. This could have a positive effect on disease progression in MS, Alzheimer’s disease, and epilepsy. However, clinical research is still lacking to confirm these assumptions.

MS patients with severe spasticity achieved therapeutic success with Sativex

In 2010, a team of researchers studied the efficacy of Sativex or placebo in 337 patients with therapie-resistent spasticity due to multiple sclerosis. Sativex is an oral spray containing THC and CBD. Participants rated the severity of spasticity using a numerical rating scale (NRS) ranging from 0 to 10 points. The researchers defined a response to therapy as a reduction in spasticity of at least 30 percent. They found that using the oral spray reduced the severity of symptoms by -1.3 points compared to -0.8 points for those in the placebo group. Thirty-six percent of those in the Sativex group responded to the therapy. In the placebo group, this figure was only 24 percent. The drug was well tolerated. Only mild to moderate side effects occurred.

The results show that Sativex is an effective add-on therapy for MS patients with severe spasticity [8]. Based on the positive results of this and other large clinical trials in MS patients*, Sativex was approved in Germany in July 2011. A 2019 market report showed that Sativex is now available in 21 European countries, making it the most approved cannabinoid-based medicine [9].

Placebo-controlled study: Sativex spray effective as add-on therapy

In 2019, an international team of researchers from the Czech Republic, Spain and Germany published a placebo-controlled study (Salvant Study: Sativex as Add-on therapy Vs. Further optimized first-line ANTispastics) of cannabinoid therapy in patients with MS with moderate to severe spasticity. The efficacy of Sativex as add-on therapy to conventional antispasmodic medications was investigated. The study consisted of two phases: During the first 4-week phase, 191 participants received the cannabinoid spray to identify patients who would benefit. The cannabinoid spray reduced spasticity by at least 20 percent in these individuals as measured by a numeric rating scale (NRS) of 0-10. Slightly more than half (106 people) responded to Sativex and began the double-blind study phase: 53 people each took either Sativex or a placebo for 12 weeks in addition to optimizations of the other antispastic medications.

After 12 weeks, the study investigated which patients benefited clinically significantly, i.e., spasticity decreased by at least 30 percent: Under Sativex, spastic symptoms decreased significantly in about three-quarters (77.4 percent), compared to only one-third (32.1 percent) in the placebo group. Sativex also improved other symptoms: average scores for spasticity, graded using the Ashworth scale, and pain were significantly reduced while being treated with the spray. Side effects of cannabis therapy were mild to moderate.

Overall, the scientific team concluded that Sativex for resistant spasticity in MS – in addition to treatment optimization of standard antispastic therapy – leads to better and more significant symptom relief than adjustment of standard medication alone [10].

Significant improvement of severe spasticity

In 2020, German and Spanish scientists published a so-called post-hoc analysis, a statistical evaluation of the SALVANT study. The goal of the research team was to clarify how patient-specific differences – disability status, severity, and duration of spasticity – might have influenced the therapeutic success of Sativex or placebo. The severity of spasticity and pain, as measured by the Numeric Rating Scale, were assessed throughout the course of therapy.

Patients were divided into different subgroups, which were statistically analyzed separately:

  • EDSS (Expanded disability status scale): disability status due to MS.
  • Severity of spasticity: less severe (NRS 4 – 6), severe (NRS above 6)
  • Duration of spasticity: less than 5 years, at least 5 years.

Statistical data confirmed the effectiveness of Sativex: in all participants, the cannabinoid spray was able to halve the average NRS scores for spasticity and pain. The researchers concluded that Sativex relieved severe spastic symptoms across all subgroups.

The prospects of success with cannabinoid treatment were statistically higher, the more a patient was affected: For moderate spasticity, more participants numerically benefited from Sativex than placebo in the SALVANT trial. Statistically significant improvements were seen in those with severe spasticity. Pain associated with spasticity often improved similarly across subgroups [11].

Cannabinoids effective and safe in long-term therapy

An open-label follow-up study published in 2012 evaluated the long-term safety and tolerance of Sativex in 146 MS patients with spasticity. The English research team recorded frequency and severity of side effects. The average duration of use was 334 days, ranging from one day to 2.2 years. A total of 59 patients (40%) took Sativex for more than one year.

Mild to moderate side effects were observed most frequently, with dizziness (24.7%), fatigue (12.3%), and headache being the most common. Serious side effects were reported by five individuals (3.4%). One of the participants suffered psychiatric adverse effects. Most adverse effects resolved after treatment discontinuation within 30 days, without withdrawal symptoms. Also, symptomatology did not worsen after discontinuation of Sativex in comparison to the original condition.

The individual cannabinoid dose required varied among subjects but remained approximately constant once optimally adjusted. Therefore, most patients did not develop tolerance and the dosage of other antispastic medication remained approximately unchanged. Overall, the results show that cannabinoids can be used safely and effectively in the long-term treatment of MS. In contrast, other oral antispasticity drugs such as baclofen, benzodiazepines, tizanidine, or dantrolene often have limited use due to therapy-limiting side effects [12]. They often must be dosed relatively high, which may cause side effects such as muscle weakness [13].

Placebo-controlled study: dronabinol safe for long-term treatment of nerve pain

Many MS patients suffer from neuropathic pain. Antineuropathic medications (e.g. tricyclic antidepressants, calcium channel blockers, opioids) often bring severe side effects and often relieve the pain insufficiently. Many studies are therefore investigating cannabis as another drug therapy option for nerve pain.

In a double-blind study published in 2017, a German research team investigated the risk-benefit ratio of long-term treatment of neuropathic pain with dronabinol (synthetically produced THC). 240 patients with MS with central neuropathic pain participated in the study conducted between June 2007 and March 2010. At random, 124 patients received dronabinol and 116 received a placebo.

The study consisted of three sections:

  • Placebo-controlled study phase: 16 weeks, including 4-week dose adjustment.
  • Open-label study phase: 32 weeks
  • Follow-up phase: 96 weeks with a subgroupt of patients, with 100 patients continuing the study up to 119 weeks

Researchers examined the change in pain intensity as measured by a numeric rating scale (NRS) of 0 to 10 during the 16-week double-blind study. In addition, the safety profile of dronabinol (adverse effects, abuse, and dependence) was examined.

This clinical trial demonstrates a clinically relevant decrease of pain during the dronabinol and placebo treatment (dronabinol ca. 1,92 and placebo ca. 1,81), without reaching a statistical significant difference between both groups. Pain intensity also remained consistently low at 2.5 to 3.8 during the follow-up phase with dronabinol. In the double-blind phase, quality of life increased significantly in both treatment groups.

Patients taking dronabinol reported increased side effects: The most common were drowsiness, dizziness, fatigue, and dry mouth. Serious side effects were rare: Three subjects experienced dysphoria, constipation, and pain intensification. Tolerance to many adverse side effects builds with longer-term use, therefore, dronabinol is well tolerated in the long term. Most side effects occurred during the 4-week-dose-finding period. Tolerability of dronabinol was rated good by most patients: In the double-blind phase, 84.5 percent and in the open-label phase, 85.2 percent of participants rated cannabinoid therapy as well tolerated. This percentage increased to 93 percent in the follow-up phase. On average, dronabinol was taken for 382 days, or just over a year.

Most participants maintained constant dronabinol dosing after dose adjustment was made. This indicates that there is no development of tolerance to therapeutic effects: 63 subjects remained at the same dosage and 24 subjects reduced it during the study. Only 19 subjects temporarily increased the dosage. Fears about dependence and abuse potential of dronabinol are mostly unfounded: Only one person showed mild signs of cannabis dependence during the follow-up period. Abuse cases did not occur. Most participants were able to discontinue dronabinol without problems after the end of the study: Only 6 subjects in the open-label studies and 4 subjects in the long-term study experienced withdrawal symptoms. These included sleep disturbances, nervousness, and an increase in pain after treatment discontinuation.

Overall, the study demonstrates that dronabinol is well tolerated and safe. Neuropathic pain can be relieved over a long period of time, although significant pain relief compared to placebo has not yet been proven. Because other neuropathy medications are often not more effective and carry side effects as well, dronabinol may be a promising treatment option: Due to analgesic, sedative, anticonvulsant, anti-inflammatory, and anti-anxiety effects, dronabinol can alleviate symptoms in a variety of ways. “Overall, the physician should make a case-by-case decision because of the wide range of side effects associated with the various treatment options, especially for combination therapies [14].”

Conclusion

The results of studies to date on the effectiveness of cannabis as a medicine for the symptoms associated with multiple sclerosis, such as spasms, chronic pains, and inflammation, are encouraging for patients. Numerous testimonials from patients seeking cannabis treatment, show that medicinal cannabis can alleviate symptoms. They also often report that their sleep quality improves, as does their overall quality of life. In addition, multiple sclerosis is one of the few established indications for the use of medical cannabis.

Recent studies showed that cannabinoids can provide long-term relief of spasms and pain in MS patients with a good safety profile. However, significant superiority over placebo is currently not proven. Nevertheless, given the limited efficacy and side effects of established anti neuropathic medications such as pregabalin and opioids, cannabinoids may be an important additional therapeutic option to relieve symptoms and increase quality of life.

Sources:

[1] Berner Klinik, Schweiz, 2004, C Vaney et al., „Efficacy, Safety and Tolerability of an Orally Administered Cannabis Extract in the Treatment of Spasticity in Patients With Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study

[2] Department of Neurorehabilitation, UK, Collin C1 et al., 2007, “Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis

[3] Global Neuroscience Initiative Foundation, USA, Shaheen E Lakhan, Marie Rowland1, 2009, “Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review

[4] Springer, Private Bag 65901, New Zealand, Keating GM1, 2017, “Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex®): A Review in Multiple Sclerosis-Related Spasticity

[5] PharmIdeas Research & Consulting Inc., Canada, Iskedjian M1 et al., 2007, “Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain

[6] Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, Kozela E1 et al., 2011, “Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice

[7] Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, Kozela E1 et al.,2017, “Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid

[8] Collin C, Ehler E, Waberzinek G, et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res. 2010;32(5):451-459. doi:10.1179/016164109X12590518685660

[9] Developments in the European cannabis market; EMCDDA, Lisbon, June 2019 doi:10.2810/769499.

[10] Markovà J, Essner U, Akmaz B, et al. Sativex® as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial. Int J Neurosci. 2019;129(2):119-128. doi:10.1080/00207454.2018.1481066

[11] Meuth SG, Henze T, Essner U, Trompke C, Vila Silván C. Tetrahydrocannabinol and cannabidiol oromucosal spray in resistant multiple sclerosis spasticity: consistency of response across subgroups from the SAVANT randomized clinical trial. Int J Neurosci. 2020;130(12):1199-1205. doi:10.1080/00207454.2020.1730832

[12] Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J Neurol. 2013 Jan;260(1):285-95. doi: 10.1007/s00415-012-6634-z. Epub 2012 Aug 10. PMID: 22878432.

[13] Platz T. et al., Therapie des spastischen Syndroms, S2k-Leitlinie, 2018, in: Deutsche Gesellschaft für Neurologie (Hrsg.), Leitlinien für Diagnostik und Therapie in der Neurologie.

[14]  Schimrigk S, Marziniak M, Neubauer C, Kugler EM, Werner G, Abramov-Sommariva D. Dronabinol Is a Safe Long-Term Treatment Option for Neuropathic Pain Patients. Eur Neurol. 2017;78(5-6):320-329. doi:10.1159/000481089

About Minyi Lü

Minyi Lü suffers from chronic pain due to her finger arthritis. She has been treating her complaints very successfully with medicinal cannabis since 2017. As a pharmacist in internship, she now brings her know-how to report on the latest scientific findings around medicinal cannabis.

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