Original article
Safety and efficacy of low-dose medical cannabis oils in multiple sclerosis

https://doi.org/10.1016/j.msard.2020.102708Get rights and content

Highlights

  • Medical cannabis treatment at low dose was safe and well tolerated in MS.

  • Treatment resulted in a reduction in pain intensity, spasticity and sleep disturbances.

  • Treatment showed no impairment in ambulation, dexterity or processing speed.

  • Medical cannabis can be used as an alternative to treat spasticity and pain in MS.

ABSTACT

Introduction

The use of cannabis as medical therapy to treat chronic pain and spasticity in patients with multiple sclerosis (MS) is increasing. However, the evidence on safety when initiating treatment with medical cannabis oils is limited. The aim of this study was to investigate the safety of sublingual medical cannabis oils in patients with MS.

Methods

In this prospective observational safety study 28 patients with MS were treated with medical cannabis oils (THC-rich, CBD-rich and THC+CBD combined products) and were followed during a titration period of four weeks. Patients were evaluated at treatment start (Visit 1) and after four weeks treatment (Visit 2). At each visit neurological examination (Expanded Disability Status Scale – EDSS), ambulation (Timed 25-Foot Walk Test - T25FWT), routine blood tests, plasma cannabinoids, dexterity (9-Hole Peg Test - 9-HPT) and processing speed (Symbol Digit Modalities Test - SDMT) were tested. Adverse events (AEs) and tolerability were reported at Visit 2. Secondary, efficacy of medical cannabis on pain, spasticity and sleep disturbances were measured by numeric rating scale (NRS-11) each day during the 4-week treatment period.

Results

During treatment with cannabis preparations containing 10-25 mg/mL THC, the most common AEs were dry mouth, drowsiness, dizziness and nausea of mild to moderate degree. Two patients experienced pronounced symptoms with excessive dreaming and drowsiness, respectively, which led to treatment stop during the titration. Three serious adverse events (SAE) were reported but were not associated with the treatment. Mean doses of THC and CBD were 4.0 mg and 7.0 mg, respectively, and primarily administered as a once-daily evening dose. Furthermore, pain decreased from a median NRS score of 7 to 4, (p = 0.01), spasticity decreased from a median NRS score of 6 to 2.5 (p = 0.01) and sleep disturbances decreased from a median NRS score of 7 to 3 (p < 0.001). No impairment in disability, ambulation, dexterity or processing speed was observed.

Conclusion

Treatment with medical cannabis oils was safe and well tolerated, and resulted in a reduction in pain intensity, spasticity and sleep disturbances in MS patients. This suggests that medical cannabis oils can be used safely, especially at relatively low doses and with slow titration, as an alternative to treat MS-related symptoms when conventional therapy is inadequate.

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,

References (33)

  • EG Celius et al.

    The influence of THC:CBD oromucosal spray on driving ability in patients with multiple sclerosis-related spasticity

    Brain Behav

    (2018)
  • C Carcieri et al.

    Cannabinoids concentration variability in cannabis olive oil galenic preparations

    J. Pharm. Pharmacol.

    (2018)
  • Danish Medicines Agency, Guidelines for doctors. Available at: https://www.retsinformation.dk/eli/retsinfo/2018/9000...
  • B Fischer et al.

    Lower-risk cannabis use guidelines: A comprehensive update of evidence and recommendations

    Am. J. Public Health.

    (2017)
  • MA Huestis

    Human cannabinoid pharmacokinetics

    Chem. Biodivers.

    (2007)
  • Pharmacokinetics of cannabinoids

    Pain Res. Manag.

    (2005)
  • Cited by (7)

    View all citing articles on Scopus
    View full text