Multiple Sclerosis and Cannabis
By Diana Hahn and Stacey Marie Kerr, MD
Multiple sclerosis (MS) is a chronic disease of the central nervous system--the brain and spinal cord. Cannabis has been identified as a promising treatment option for MS because it addresses symptoms as well as aspects of disease progression.
Many preliminary studies have shown benefits of treating MS with cannabinoids, though some studies have had mixed results. With approximately 15% of patients with MS in the United States already using cannabis, more research is warranted on the role of the endocannabinoid system (ECS) in MS as well as the potential benefits and risks of cannabinoid therapy for these patients. 
The Immune System and Central Nervous System
While the exact cause of MS is unknown, science has shown that immune system dysfunction plays a large role and ultimately leads to inflammation causing neurodegeneration (damage and death of nerve cells).
There are several pathways for neurodegeneration, and these pathways may change over the course of MS. As the central nervous system (CNS) accumulates damage, changes in activity occur that include altered conduction across nerve cells, some loss of nutritional support for nerves, and the formation of compensatory alternative nerve pathways.
These changes can lead to further degeneration that is independent of the original insults from the immune system and inflammation. Thus, in later phases of MS, neurodegeneration may continue even in the absence of immune system dysfunction. 
from inflammation to nerve damage
Many conventional MS treatments focus on modulation of the immune system, trying to prevent inflammation that cascades into nerve damage. Two of the main causes of inflammatory damage are cytokine release and glutamate excitotoxicity.
Cytokines are signaling molecules that stimulate the movement of cells towards sites of inflammation. Glutamate responds by efficiently pulling calcium into the cells to fight the inflammation. But if the inflammation causes excessive activity from these, with too many cells and too much calcium, the excess causes damage to nerves. Once nerves are damaged, they become even more vulnerable to pro-inflammatory agents as well as to oxidative stress. 
Axons, slender projections coming off nerve cells, conduct electrical impulses. The axons are covered in a protective sheath called myelin, and it is this sheath that is damaged by inflammation in MS. Demyelination (damage to the myelin) causes axonal loss, which leads to the inhibition of normal neural transmission.
While axonal loss often occurs early in MS, it only becomes apparent later in the disease when the damage has reached a threshold beyond which the central nervous system can no longer compensate.  Autoimmunity, inflammation, and nerve damage result in a variety of MS symptoms including spasticity, incontinence, neuropathic pain, and a decline in cognitive function.
The Endocannabinoid System
The ECS plays a vital role in modulating and maintaining homeostasis in the immune system as well as in the central nervous system. While it is possible that MS may affect the ECS, it is also possible that abnormalities in the ECS may make certain people more susceptible to MS, to more aggressive symptoms, or to disease progression. 
Studies have shown that cannabinoid receptors play a significant role in managing MS, as well as showing that cannabinoids may also function outside the cannabinoid receptor system to reduce inflammation.
Most research regarding cannabinoid receptors and MS has focused on CB1 receptors. Activation of CB1 receptors may help at many levels of disease mechanism and progression:
- Neuroprotective—plays a role in preventing and/or limiting neurodegeneration during inflammation. Patients with reduced CB1 expression suffered from more neurodegeneration than those with normal CB1 receptor expression; [2, 3]
- Anti-inflammatory—inhibits calcium influx and glutamate release while reducing neuronal excitability; [4, 5]
- Anti-spasticity; 
- Plays a role in neuroplasticity and nerve development; 
- Presence in the basal ganglia area of the brain suggests it may mediate motor performance and movement control; 
- Presence in nociceptive (pain perception) pathways of brain and spinal cord suggest they are part of a natural analgesic system.
As an agonist of both CB1 and CB2, the endocannabinoid anandamide activates cannabinoid receptors. Interestingly, higher levels of anandamide are associated with more inflammation. It is possible that elevated levels of anandamide in the CNS in MS may be coming from inflammatory cells invading the brain from peripheral areas of the body.  No changes in 2-AG levels have been recorded in MS patients, suggesting that AG-2 is not as significant as anandamide in MS. 
Both THC and CBD have been shown to be beneficial in addressing symptoms of MS. Although preclinical research suggests that cannabinoids may also be effective in treating the disease, THC and CBD’s neuroprotective capacity in MS has yet to be proven in humans. It appears, however, that regular low doses of cannabinoids may provide neuroprotective effects.  In mice, studies have shown that CBD promotes neuronal survival and restoration.  THC and CBD may offer benefits by acting as cannabinoid receptor agonists as well as by providing anti-inflammatory effects outside of the ECS. 
CBD for MS
While THC has been shown to be effective in treating MS symptoms, its psychoactive effects can be undesirable or intolerable for patients, especially those also experiencing cognitive deterioration. CBD, when taken with THC, can counteract some of THC’s psychoactive effects while also providing its own benefits. Formulations with high CBD and low THC, or even pure CBD, may also be beneficial for MS patients. In animal studies, CBD has been shown to limit the release of pro-inflammatory agents, as well as limit their migration into the central nervous system. 
Slowing disease progression and symptom management are the two main goals of MS treatment. Cannabinoids may address both needs. To date, clinical studies have focused on symptom relief. Cannabinoid therapy has been shown to be effective at managing spasticity, incontinence, and pain in MS. One caveat, however, is that it has also been shown to have an adverse effect on cognitive function.
Spasticity is a common symptom of MS that can be difficult to manage. Although there has been inconsistency in the results of clinical trials testing the efficacy of cannabis in treating spasticity, the overall trend suggests that cannabis does help with spasticity and is worth trying, especially for patients who do not respond or cannot tolerate conventional drugs. According to the National Multiple Sclerosis Society, inconsistencies in trials may often be related to poor study design and definition of outcomes. 
Still, there are studies that have found that cannabis lowers spasticity by a statistically significant amount. There is also evidence that CB1 and CB2 receptors may be involved in controlling spasticity, and that anandamide is an ant spasticity agent.  For many patients, smoking appears to be more effective in controlling spasticity than oral delivery, perhaps due to control and predictability of effect and onset time.
Smoked Cannabis Randomized, Placebo-Controlled Crossover Trial
Size: 30 Patients (20 Secondary Progressive MS, 10 Relapsing-Remitting MS)
Test group smoked a 4% THC cannabis cigarette once daily for 3 days. After an 11 day washout period placebo and test groups switched. Primary measured outcome was spasticity, secondary outcomes were pain, timed walk, and cognitive function.
|Performance measure||Before treatment||After Treatment||Before treatment||After Treatment||Cannabis||Placebo||Effect|
|Spasticity, modified Ashworth score, mean (95% CI)*||8.92||8.71||9.13||6.18||2.95||0.21||2.74|
|Pain, visual analogue score, mean (95% CI)†||14.51||11.52||16.61||8.34||8.27||2.99||5.28|
|Physical performance, timed walk, s, mean (95% CI)‡||11.68||11.7||11.66||12.89||1.23||0.03||1.2|
|Cognitive function, PASAT score, mean (95% CI)§||138.08||138.43||140.78||132.46||8.32||-0.35||8.67|
Note: CI = Confidence interval, PASAT = paced auditory serial addition test.
*Scores range from 0 to 24, with higher scores suggesting greater spasticity.
†Scores range from 0 to 100, with higher scores suggesting more severe pain.
‡Times range from 0 to 66 s, with higher scores suggesting a slower pace.
§ Scores range from 0 to 196, with higher scores suggesting better cognitive performance.
Cannabinoids have been shown to be effective in treating pain in general, as well as pain specifically associated with MS. In the results of the study above, smoked cannabis was very effective at treating pain. Many of the anti-inflammatory properties of cannabinoids that may help slow disease progression in MS may also help alleviate pain.
There is a close association between spinal cord damage in MS and lower urinary tract symptoms (LUTS). LUTS appear in 80% of MS patients, with the percentage rising to 96% in patients who have had MS for 10 years or more.  Cannabinoids may help with LUTS through central and peripheral actions related to the spinal cord as well as the smooth muscle of the bladder. 
In a trial done with 630 patients, both THC as well as a CBD-dominant plant-based extract delivered clinically significant improvements in LUTS in MS patients. 
|Improvement in Continence||38%||33%||18%|
|Improved Bladder Function (Subjective)||44%||40%||33%|
|% Better than Placebo||25%||19%||N/A|
Decline in cognitive function is a concern in MS patients, as it affects 40-60% of MS patients. Whether and to what extent cannabis use exacerbates this aspect of the disease is an important consideration, as it can have a significant effect on a patient’s quality of life.
A study done with 50 MS patients on the neuropsychological effects of cannabis showed that cannabis users performed significantly worse than non-users on measures of information processing speed, working memory, executive functions, and visuospatial perception, while not experiencing direct psychoactive effects. Cannabis users were also twice as likely to be classified as globally cognitively impaired, though there were no differences in depression, anxiety, or psychiatric diagnosis. 
While the findings of this study show that there are significant risks in cognitive function associated with cannabis use, it is also important to note that the study was done with patients using “street cannabis,” where the quality, potency, and frequency/amount of consumption was not controlled. It is possible that these adverse cognitive effects could be avoided by using a more controlled cannabis extract. It is also important for patients to weigh the potential benefits against the potential adverse effects when deciding whether or not to use cannabis.
Recommendations Regarding the Use of Cannabis in Multiple Sclerosis. National Multiple Sclerosis Society. http://www.nationalmssociety.org/Treating-MS/Complementary-Alternative-Medicines/Marijuana
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