Why are cannabis-based medicines prescribed for Multiple Sclerosis?
This article is intended for whomever does not want or can purchase the published studies off expensive and often very technical peer reviewed studies.
Here are summarized and explained the findings regarding therapeutic uses as well as side effects of cannabinoid products for patients with Multiple Sclerosis.
The criteria of inclusion of studies on this review was that of double-blind, randomized, placebo-controlled, human studies, in order to minimize bias data.
You can also find part 1 of this review here: “Making cannabis-based studies on MS easy: a review”
|Authors||Year||Treatment||Lenght of trial|
|Corey-Bloom, J Wolfson, T et al.||2012||800 mg Cannabis (4% Δ9-THC)||2 weeks|
|Killestein J, Hoogervorst EL et al.||2002||Sativex (THC-CBD ratio 1:1) <10 mg||4 weeks|
|Wade D, Robson P et al.||2003||Sativex (THC-CBD ratio 1:1) 2.5-120 mg||4 weeks|
|Wade DT, Makela P et al.||2004||Sativex (THC-CBD ratio 1:1) 2.5-120 mg||6 weeks|
|Zajicek J, Fox P, Sanders H||2003||15 weeks|
Case studies on Multiple Sclerosis address the utility of cannabis-based medications for the management of spasticity and pain; they also evaluate overall movement control, sense of fatigue and any side effect associated with the treatment, the most significant being cognitive impairment.
In order to rate objectively all data, there are standard tests used; for example, in order to assess a change in spasticity, is used a test developed in 1987 by Bohannon and Smith, the “Modified Ashworth Scale”, which can span from 0 (no increase in muscle tone) to 4 (affected part(s) rigid in flexion or extension ). (1)
Given a result mismatch between the subjective evaluation of antispastic properties and the Modified Ashworth Scale, (which has been discussed in: Making cannabis-based studies on MS easy: a review) it was introduced a Numerical Rating Scale (NRS) and in 2007 a full ethical approval was granted to NRS, ranging 0 to 10 and decided by the patients themselves.
It is also used the Rivermead Mobility Index, a questionnaire on mobility comprising 15 questions such as “From lying in bed, are you able to get up to sit on the edge of the bed on your own? ”
As for the rating of pain, it is usually measured with a visual scale, as other methods are often impractical for human patients. This method, despite sounding of little objectivity, offers a good analysis: pain’s perception is personal and ultimately medically-induced relief can vary vastly between patients. Patients were also asked to rate their feeling of fatigue.
Cognitive performance can be evaluated by the “Paced Auditory Serial Addition Test” or in short, PASAT, firstly developed by Gronwall and Sampson in 1974.
PASAT is a legitimate tool that allows scientists to scale levels of cognitive impairment; the way it works is quiet simple, a series of single digit numbers must be summed over the amount of time allowed, which usually decreases until a minimum of 1.2 seconds. (2)
It is clear that several factors can influence the results of this test, such as stress related to performance, but also mathematical skills, and individual speed of speech.
Note to the reader:
Many of the studies reviewed on here used PASAT test in order to assess cognitive performance of patients immediately following drug administration; it has been demonstrated that the psychotropic component of cannabis, tetrahydrocannabinol (THC) leads to the diminished theta and fast-ripple waves, disrupting the synchronous firing of neurons and negatively impacting on short-term memory generation, meaning that the low PASAT scores are mostly associated with an inability to remember the numbers shown rather than processing their sum. (3)
This is said in order to specify what exactly is meant by cognitive impairment by PASAT.
On the flip side, psychometric approaches that focused on the use of cannabis on other cognitive tasks, such as divergent thinking (DT) tests and remote associations tests (RAT) –which focus on the ability of an individual to generate creative ideas, reported opposite results. In fact, cannabis use has also shown to promote “rare-creative” responses and alpha wave activity (an electromagnetic brain wave activity associated with wakefulness and creativity)(4,5)
In order to establish motor coordination and speed, walks were timed.
Requirements for study participation. (Who was not in the studies)
Each study had a few specific eligibility criteria, but some general features. These are described below; they have been included in this review so that the reader can get a clear understanding that the results discussed are only attributed to the population that collocates within these criteria.
- No participants were allowed the use of benzodiazepines, high doses of narcotic medications for pain or other psychoactive drugs (cocaine-amphetamines etc)
- Other treatments for spasticity were allowed, but a change of medications during the trial period was not allowed.
- Participants whom were not cannabis-naive, were required to refrain from it for at least a month prior and could not use privately during the study.
- Patients whit an history of a psychiatric disorder (other than depression) were excluded
- Patients with a comorbid neurologic, cardiac, immunologic or respiratory disease (in addition to MS) were excluded
- Women who were pregnant or breastfeeding were also excluded.
Demography (Who was in the studies)
Given the nature of the disease, usually studies featured an higher percentage of women (63%) and the age was averaged around 45. In order to obtain linear cognitive performance tests, average education was 15 years of school. 60% of participants required walking aids, and 20% required the use of a wheelchair.
Treatment for Multiple Sclerosis
In cannabis-based trial (6), were administered either pre-rolled cannabis or placebo cigarettes with identical appearances and weight (about 800 mg), provided by the National Institute on Drug Abuse.
- Cannabis cigarettes contained about 4% Δ9-tetrahydrocannabinol (delta-9-THC) by weight.
- Placebo cigarettes had the same base material but with the Δ9-THC removed.
The trial lasted for 2 weeks, with 8 visits. The effects were assessed after 45 minutes of treatment. Urine for baseline tox-screen was collected before each visit.
- In orally sprayed cannabis studies (7) (8) (10), the amount of THC-CBD (1:1) mix administered daily was <10 mg daily and 2.5-120 mg/24 hours respectively.
- Two studies (7,8) lasted for a total amount of 4 weeks
- The participants were administered either oromucosal sprays of matched placebo, or whole plant cannabis-based medicinal extract (CBME) containing equal amounts of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) at a dose of 2.5-120 mg of each daily, in divided doses for a total of 6 weeks. (10)
In a larger study, (9) were compared the effects of cannabis extracts (THC:CBD) vs THC only (Marinol) (the route of administration was oral-capsules)
- The duration time of this study was up to 15 weeks;(9) and 16-to 75 weeks in the follow up study
- The amounts of THC-CBD administered daily were 2.5 mg THC +1.25 mg CBD + 5% other cannabinoids, first the contents were tritated and doses were adjusted depending on side effects, up to a max of 25 mg of THC daily (depending on body weight)
- Treatment with smoked cannabis resulted in a reduction in patient scores on the modified Ashworth scale by an average of 2.74 points more than placebo. (p < 0.0001)*
- Treatment with oral cannabis resulted in a reduction in patient scores on the modified Ashworth scale by an average of 3 points more than placebo (7), no change (8), 1.2 and 4 (p=0.29 ) (9).
For all active groups examined, treatment reduced pain scores on a visual analogue scale by an average of 5.28 points more than placebo. (p = 0.008).
3) QUALITATIVE RATINGS
Bladder function and mood were improved in all studies as well as an overall reduction in severity (2.1) and frequency (1.9) of symptoms (p=0.05)
Scores for the timed walk did not differ significantly between treatment and placebo.
RMI scores improved as well of 0.45 scores (p=0-01)
Scores on the Paced Auditory Serial Addition Test decreased by 8.67 points more with treatment than with placebo (p = 0.003)
The other studies that have used different delivery systems (pills, oral mucosal sprays such as Sativex) and evaluated participants at study completion, rather than within one hour of smoking have reported no or limited adverse effects on cognition .
* p identifies the probability that the data analysed have occurred for statistical accident. The lower the value of p, the higher statistical significance of the data. Usually, values at =0.01 are accepted as “significant” and =0.001 are “highly significant”
Smoked cannabis was found beneficial in symptoms and pain reduction by patients affected by MS, whom are otherwise resistant to anti-spasticity treatments.
It was generally well-tolerated, but in 1 case the participant did not like the psychoactive effect of cannabis, which was vastly recognised by the patients versus placebo, due to the acute cognitive effects.
Moreover, smoking cannabis did not significantly affect patient perceptions of fatigue or deficits, and the feeling of “highness” was perceived at a lower extent with the passing of time.
Several studies demonstrated the increased efficacy of whole cannabis extract versus THC extract capsules. The cited studies above concluded that oromucosal administration of THC and CBD in a 1:1 ratio is well tolerated by patients with Multiple Sclerosis who respond poorly to conventional antispastic drugs.
Despite the technical difficulties on assessing change in spasticity, the current studies data support the position that the beneficial effects of Sativex outweigh the adverse pharmaceutical effects, accordingly both with personal patients ratings as well as objective ones.
If you are interested in reading more about Sativex, check our “A guide on Sativex“.
Moreover, you can continue reading about Multiple Sclerosis & Cannabis in this other article.
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List of references
1) Bohannon, R. and Smith, M. (1987). “Interrater reliability of a modified Ashworth scale of muscle spasticity.” Physical Therapy 67(2): 206.
2) Tombaugh, T N. (2006). A comprehensive review of the Paced Auditory Serial Addition Test (PASAT). Archives of Clinical Neuropsychology. 21 (1), 53–76.
3) Maier, N., Morris, G., Schumann, S., et al. 2012. Cannabinoids disrupt hippocampal sharp wave-ripples via inhibition of glutamate release. Hippocampus, 22, 1350-62.
4) Morgan, C. J., Rothwell, E., Atkinson, H., et al. 2010. Hyper-priming in cannabis users: a naturalistic study of the effects of cannabis on semantic memory function. Psychiatry Res., 176, 213-8.
5) Gruzelier, J. 2009. A theory of alpha/theta neurofeedback, creative performance enhancement, long distance functional connectivity and psychological integration. Cogn Process., 10, S101-9.
6) Corey-Bloom, J Wolfson, T et al.. (2012). Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ. 184 (10), 1143-1150.
7) Killestein J, Hoogervorst EL, Reif M, Kalkers NF, Van Loenen AC,Staats PG, Gorter RW, Uitdehaag BM, Polman CH: Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology 2002, 58:1404-1407
8) Wade D, Robson P, House H, Makela P, Aram J: A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil 2003, 17:21-29.
9) Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, Thompson A, UK MS Research Group: Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003, 362:1517-1526.
10) Wade DT, Makela P, Robson P, et al. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler 2004;10:434-41.
11) Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry 2005;76:16649.