Oral cannabinoids for spasticity in multiple sclerosis: will attitude continue to limit use?

Oral cannabinoids for spasticity in multiple sclerosis: will attitude continue to limit use? See page 1517 Spasticity is a distressing and disabling symptom that many people with multiple sclerosis face daily because there is inadequate treatment. As one part of an upper motor-neuron syndrome, spasticity manifests as muscle stiffness, spasms, and pain. It also contributes to limited mobility and impaired sleep. The hypothesis that cannabis derivatives (eg, ⌬-9-tetrahydrocannabinol [⌬-9 THC], cannabidiol) relieve spasticity and other symptoms of multiple sclerosis has received increasing attention in recent years. Identification and characterisation of cannabinoid receptors (eg, CB1, CB2), recognition of endogenous cannabinoid ligands, and evidence that activation of the CB1 receptor in the brain leads to inhibitory influences on neurotransmitter release 1 supports this hypothesis. The benefit of cannabinoids in animal models of spasticity 2 and the results of small clinical trials 3–7 have led to investigation of cannabinoids as symptomatic therapy in multiple sclerosis. The potential role of cannabinoids as neuroprotective agents is also intriguing. 1 Although off-label use of a large variety of approved drugs is probably done every day by physicians for every condition, use of cannabinoids has remained limited. Concern about treatment risk, lack of a safe, accessible, and reliable cannabis supply, unclear dosing of smoked cannabis, and lack of social and legal acceptance of cannabinoids as legitimate treatment contribute to this limited use. 8 The study by John Zajicek and colleagues in this issue of The Lancet is the first large multicentre randomised placebo-controlled trial of cannabinoid therapy in multiple sclerosis and is thus an important step forward. Although this trial failed to detect a significant treatment effect of any cannabinoid on the primary outcome, spasticity as measured by the Ashworth scale, 9 use of ⌬-9 THC decreased timed walk (median 12%, 95% CI 6% to 21%) compared with 4% for placebo and cannabis extract (Ϫ2% to 7%, and 0% to 10%, respectively). Subjective improvement of spasticity-related symptoms (spasticity, pain, sleep, spasms) occurred more frequently with cannabinoids than with placebo, whereas there was no treatment effect on symptoms less specifically related to spasticity (irritability, depression, tiredness, tremor, energy). In previous studies 3–7 subjective reports of improvement in various symptoms of multiple sclerosis were almost universal, whereas comparison with a placebo group in Zajicek's study suggests a fairly specific effect on spasticity. Although failing to achieve an effect on the primary outcome suggests Kajicek and colleagues' trial is negative …