multiple sclerosis is one of the diseases where a therapeutic role for cannabinoids has been investigated for a long time. Preclinical studies and clinical trials have tested cannabinoid extracts and THC (alone or in combination with CBD) for their potential to treat MS or relieve its symptoms with varying results. Overall, the results seem positive, but more research is necessary.
In a mouse study, plant cannabinoid CBD and endocannabinoid PEA each individually reduced inflammation and neuronal demyelination (Rahimi et al., 2015). However, co-administration of both cannabinoids reduced the anti-inflammatory and anti-demyelinating effects suggesting antagonism between both cannabinoid pathways. In a mouse model of MS (Theiler's murine encephalomyelitis), Sativex (50/50% THC/CBD oromucoso spray was compared with CBD-enriched or THC-enriched cannabis extract. Motor deterioration and inflammation (astrogliosis) were equally reduced by Sativex and CBD-enriched extract but THC-enriched extract was less effective. The effects of CBD were PPARγ-mediated whereas THC signaling was CB1/2 dependent (Feliú et al., 2015). In the rat MOG35-55 model of experimental autoimmune encephalitis / multiple sclerosis 5 μM CBD upregulated CD69 and Lag3 on CD4+CD25- T-cells and anti-inflammatory markers IL-10 and STAT5 promoting T-cell anergy and cell-cycle arrest. CBD also reduced MHC2, CD25 and CD69 on CD19+ cells reducing their antigen-presenting and pro-inflammatory potential (Kozela et al., 2015). Gene profiling showed that CBD generally suppresses pro-inflammatory genes, T-cell proliferation and potentially T-cell memory while enhancing anti-inflammatory genes (affected genes listed in article) (Kozela et al., 2016). In the Experimental Autoimmune Encephalitis (EAE) mouse model of multiple sclerosis, daily application of a 1% CBD cream on the skin (Giacoppo et al., 2015):
- Reduces the clinical symptoms of EAE such as weight loss
- Reduces hind limb paralysis
- Reduces demyelination
- Completely prevents inflammatory lymphocyte infiltration in white matter
- Reduces the amount of CD4 and CD8 positive T cells
- Reduces Glial Fibrillary Acidic Protein, indicative of reactive astrogliosis
- Reduces pro-inflammatory markers IL-6, TGFβ and IFNγ
- Increases anti-inflammatory marker IL-10
Feliú, A., Moreno-Martet, M., Mecha, M., Carrillo-Salinas, F.J., de Lago, E., Fernández-Ruiz, J., and Guaza, C. (2015). A sativex-like combination of phytocannabinoids as a disease-modifying therapy in a viral model of multiple sclerosis.Br. J. Pharmacol.
Giacoppo, S., Galuppo, M., Pollastro, F., Grassi, G., Bramanti, P., and Mazzon, E. (2015). A new formulation of cannabidiol in cream shows therapeutic effects in a mouse model of experimental autoimmune encephalomyelitis. Daru J. Fac. Pharm. Tehran Univ. Med. Sci. 23, 48.
Kozela, E., Juknat, A., Kaushansky, N., Ben-Nun, A., Coppola, G., and Vogel, Z. (2015). Cannabidiol, a non-psychoactive cannabinoid, leads to EGR2-dependent anergy in activated encephalitogenic T cells. J. Neuroinflammation 12, 52.
Kozela, E., Juknat, A., Gao, F., Kaushansky, N., Coppola, G., and Vogel, Z. (2016). Pathways and gene networks mediating the regulatory effects of cannabidiol, a nonpsychoactive cannabinoid, in autoimmune T cells. J. Neuroinflammation 13, 136.
Rahimi, A., Faizi, M., Talebi, F., Noorbakhsh, F., and Naderi, N. (2015). Interaction between the protective effects of cannabidiol and palmitoylethanolamide in experimental model of multiple sclerosis in C57BL/6 mice. Neuroscience.
In several clinical trials, cannabis extracts or Sativex, a 50/50% mixture of synthetic THC and CBD were successfully used to treat spasticity, muscle stiffness, neuropathic pain etc. in patients that were not responsive to conventional treatment (Rog et al., 2007; Zajicek et al., 2012). In one study, the THC/CBD mixture produced symptomatic relief in 75% of patients (Flachenecker et al., 2014). However, not every clinical trial found a therapeutic effect of cannabinoids on symptoms of MS (Ball et al., 2015; Centonze et al., 2009). Typical side-effects of THC treatment, such as dizziness or nausea, and in extreme cases even seizures, have been reported (Wade et al., 2006).
One meta-study assessed the effect of cannabinoids on multiple MS symptoms (Koppel et al., 2014). Their conclusions were that cannabinoids (particularly THC and CBD) effectively reduced muscle spasms and central pain but are ineffective in treating tremors associated with MS.
Ball, S., Vickery, J., Hobart, J., Wright, D., Green, C., Shearer, J., Nunn, A., Gomez Cano, M., MacManus, D., Miller, D., et al. (2015). The cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis. Health Technol. Assess. Winch. Engl. 19, 1–188.
Centonze, D., Mori, F., Koch, G., Buttari, F., Codecà, C., Rossi, S., Cencioni, M.T., Bari, M., Fiore, S., Bernardi, G., et al. (2009). Lack of effect of cannabis-based treatment on clinical and laboratory measures in multiple sclerosis. Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol. 30, 531–534.
Flachenecker, P., Henze, T., and Zettl, U.K. (2014). Nabiximols (THC/CBD oromucosal spray, Sativex®) in clinical practice--results of a multicenter, non-interventional study (MOVE 2) in patients with multiple sclerosis spasticity. Eur. Neurol. 71, 271–279.
Koppel, B.S., Brust, J.C.M., Fife, T., Bronstein, J., Youssof, S., Gronseth, G., and Gloss, D. (2014). Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders Report of the Guideline Development Subcommittee of the American Academy of. Neurology 82, 1556–1563.
Rog, D.J., Nurmikko, T.J., and Young, C.A. (2007). Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin. Ther. 29, 2068–2079.
Wade, D.T., Makela, P.M., House, H., Bateman, C., and Robson, P. (2006). Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult. Scler. Houndmills Basingstoke Engl. 12, 639–645.
Zajicek, J.P., Hobart, J.C., Slade, A., Barnes, D., Mattison, P.G., and MUSEC Research Group (2012). multiple sclerosis and extract of cannabis: results of the MUSEC trial. J. Neurol. Neurosurg. Psychiatry 83, 1125–1132.