Original articleSafety and efficacy of low-dose medical cannabis oils in multiple sclerosis
Introduction
Multiple sclerosis (MS) is an immune-mediated neurological disease. A malfunction of the immune system causes destruction of myelin sheets and axons in the central nervous system. MS is the most frequent neurological disease leading to prolonged and progressive physical, psychological and cognitive disability in young adults. With a prevalence of 284/100.000 Denmark has one of the highest prevalence of MS in the world. (The Danish Multiple Sclerosis Registry, 2020) Chronic central neuropathic pain and spasticity are both pronounced symptoms seen among 63% and 80% of people with MS, respectively. (Foley et al., 2013), (Bethoux and Marrie, 2016) Over the last decades cannabis has been suggested as a new treatment option for chronic pain and spasticity.
The cannabis plant, cannabis sativa, produces unique compounds called cannabinoids. (Andre et al., 2016) The predominant compounds are tetrahydrocannabinol (THC), which is psychotropic, and cannabidiol (CBD), which is non-psychotropic. The biological effects of cannabinoids rely on their interaction with the endogenous cannabinoid system (ECS), an important system in modulating and controlling neurotransmitters and immune system activity. (Ullrich et al., 2007) Comprehensive reviews and international guidelines on the efficacy of cannabis-based medicine to alleviate neuropathic pain and spasticity have inconsistent conclusions. (NICE Guidelines, 2019, National Academies of Sciences, Engineering, and Medicine 2017, Mücke et al., 2018) However, a recent systematic review of reviews concluded that cannabinoids may have modest effect in MS in the management of pain and spasticity. (Nielsen et al., 2018)
The acceptance of cannabis as medical therapy to treat chronic pain and spasticity in patients with MS is increasing. In Denmark, cannabis-based medicine includes THC and CBD isolates, synthetic THC (Marinol®), and THC/CBD extract (nabiximols or Sativex®). All products require a prescription, which is a rigorous process. Therefore, only a small fraction of MS patients are treated with cannabis-based medicine. However, patients with MS in Denmark (and many other countries) are aware of the potential beneficial effects of cannabis; therefore, cannabis products are primarily acquired illegally. (Gustavsen et al., 2019)
To unravel this controversy, the Danish government has approved a four-year ’medical cannabis pilot program’ that allows doctors to prescribe medical cannabis products to selected patient groups, which, before now, has been illegal in Denmark (The Danish Ministry of Health, 2018). Medical indications in this program include four groups: nausea after chemotherapy, chronic neuropathic pain, painful spasms caused by MS and painful spasms caused by spinal cord damage. The products are not approved medical products, have usually not been tested in clinical trials and contain no package leaflet or dosage recommendations. The ’medical cannabis pilot program’ became effective January 1, 2018, and included medical cannabis ‘flos’ (whole, dried female flower) and oils.
To our knowledge, no clinical studies have investigated the safety of medical cannabis oils in MS. Therefore, we aimed to examine the safety and titration of sublingual medical cannabis oils among patients with MS.
Section snippets
Study participants and enrollment
Under the umbrella of the national ’medical cannabis pilot program’ medical cannabis treatment could be offered to patients diagnosed with MS, who suffered from refractory neuropathic pain and/or spasticity. In addition, if patients suffered from both pain and spasticity, medical cannabis treatment could be initiated if 1-2 conventional analgesic and antispasmodic drugs have been tried without sufficient effect. Patients were enrolled in the present local project from January 2019 to April 2020
Results
Twenty-eight patients with MS initiated treatment with medical cannabis oils during the recruitment period. Treatments were distributed as follows: THC:CBD 1:2.5 (n=13), THC:CBD 1:1 (n=10), THC-rich (n=1) and CBD-rich (n=4). Two patients discontinued treatment at day 10 and 14 in the titration period. One patient (treated with 1:1 DROPS) stopped the treatment due to unacceptable dizziness and drowsiness and one patient (treated with THC/CBD, 1:2.5) stopped because of lack of efficacy and
Discussion
We found that treatment with medical cannabis oils was safe and well tolerated, and resulted in a reduction in perceived pain intensity, spasticity and sleep disturbances in patients with MS. This matches previous findings: however, these studies primarily included formulations of cannabis medicine as oromucosal spray, dried flowers or oral capsules (Nielsen et al., 2018) and did not address the exact dose when the AEs occurred. Importantly, we observed that AEs also occurred at low doses, e.g.
CRediT author statement
Stefan Gustavsen: Conceptualization-Equal, Data curation-Lead, Formal analysis-Lead, Investigation-Equal, Methodology-Equal, Project administration-Equal, Writing-original draft-Lead
Helle Søndergaard:
Conceptualization-Equal, Project administration-Equal, Writing-original draft-Supporting, Writing-review & editing-Equal
Kristian Linnet: Data curation-Equal, Methodology-Equal, Resources-Equal, Writing-review & editing-Equal
Ragnar Thomsen: Data curation-Equal, Methodology-Equal, Resources-Equal,
Funding
We thank the Torben and Alice Frimodts foundation and Helsefonden for their financial support, e.g. covering the cost of the cannabinoid analyses.
Declaration of Competing Interest
A.B Oturai: has served on scientific advisory boards for Biogen Idec, Novartis and Sanofi Genzyme; has received research support from Novartis and Biogen Idec; has received speaker honoraria from Biogen Idec, Novartis and TEVA; and has received support for congress participation from, Merck, TEVA, Biogen, Roche, Novartis and Sanofi Genzyme. P.S. Sørensen: has received personal compensation for serving on scientific advisory boards, steering committees, independent data monitoring committees or
Acknowledgements
We would like to thank Annette Larsen and Joy Melchert at the Danish Multiple Sclerosis Center, Copenhagen University Hospital, Rigshospitalet for organizing the study visits, and the personnel at the Department of Clinical Biochemistry Copenhagen University Hospital, Rigshospitalet for preparing and sending blood samples for cannabinoid analysis to the Department of Forensic Medicine, Section of Forensic Chemistry, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen,
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