Advances in the management of multiple sclerosis spasticity: recent clinical trials.

“Most patients with multiple sclerosis (MS) experience spasticity as the clinical course evolves. Associated symptoms include (often painful) spasms, urinary dysfunction and sleep disturbances. THC:CBD oromucosal spray (Sativex®) is approved for symptom improvement in adult patients with moderate to severe MS-related spasticity who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.


In pivotal clinical trials of THC:CBD oromucosal spray, a meaningful proportion of patients with treatment-resistant MS spasticity achieved clinically relevant improvement with active treatment versus placebo. The utility of a 4-week trial of therapy to identify patients who respond to treatment was demonstrated in an enriched-design study.

THC:CBD oromucosal spray was well tolerated in these studies, with no evidence of effects typically associated with recreational cannabis use.

In a subsequent post approval clinical trial, THC:CBD oromucosal spray had no statistically significant effect on cognition and mood compared with placebo.

Moreover, after 50 weeks’ treatment, approximately two-thirds of patients, physicians and caregivers reported improvement from baseline in spasticity based on global impressions of change.

In phase III clinical trials, approximately one-third of MS patients with treatment-resistant spasticity had a clinically relevant and statistically significant response to THC:CBD oromucosal spray.

In addition to a reduction in spasticity, responders experienced meaningful relief from associated symptoms.

THC:CBD oromucosal spray was generally well tolerated and efficacy was maintained over the longer term.

A post-approval clinical trial indicated no effect of THC:CBD oromucosal spray on cognition or mood after 50 weeks of use.”

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Advances in the management of multiple sclerosis spasticity: multiple sclerosis spasticity nervous pathways.

“Involvement of the endocannabinoid system in pathophysiological mechanisms responsible for spasticity has been demonstrated in animal models of MS…

Evidence indicates that the antispasticity effects of THC:CBD oromucosal spray (Sativex®) are associated with enhanced cortical long-term potentiation.

CB1 receptors, which are associated with movement, postural control, and pain and sensory perception, influence glutamatergic pathways.

THC:CBD oromucosal spray was shown to reverse motor cortex plasticity from long-term depression through long-term potentiation of synaptic transmission, thereby restoring, at least in part, effective corticospinal inputs to spinal circuits.”

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A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain.

“Peripheral neuropathic pain (PNP) poses a significant clinical challenge.

The long-term efficacy of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was investigated…

THC/CBD spray was well tolerated for the study duration and patients did not seek to increase their dose with time, with no new safety concerns arising from long-term use.

In this previously difficult to manage patient population, THC/CBD spray was beneficial for the majority of patients with PNP associated with diabetes or allodynia.”

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Effects of cannabidiol in the treatment of patients with Parkinson’s disease: An exploratory double-blind trial.

“Parkinson’s disease (PD) has a progressive course and is characterized by the degeneration of dopaminergic neurons.

… the endocannabinoid system has emerged as a promising target.

…Our findings point to a possible effect of CBD in improving quality of life measures in PD patients with no psychiatric comorbidities…”

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Drug-resistant MS spasticity treatment with Sativex® add-on and driving ability.

“The aim of the present observational study was to determine the effects of a delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) oromucosal spray (Sativex® spray), brand name Sativex® , indicated for drug-resistant MS spasticity, on the driving ability of treated MS patients…

Treatment of MS patients with Sativex® does not negatively impact on driving ability and may improve moderate to severe treatment-resistant MS spasticity.”

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Cannabidiol improves vasorelaxation in Zucker Diabetic fatty rats through cyclooxygenase activation

“Cannabidiol (CBD) decreases insulitis, inflammation, neuropathic pain and myocardial dysfunction in preclinical models of diabetes.

We recently showed that CBD also improves vasorelaxation in the Zucker Diabetic fatty (ZDF) rat, and the objective of the present study was to establish the mechanisms underlying this effect…

CBD exposure enhances the ability of arteries to relax via enhanced production of vasodilator COX 1/2-derived products acting at EP4 receptors.”

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Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington’s disease.

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“Cannabinoid agonists might serve as neuroprotective agents in neurodegenerative disorders… Cannabinoids may also offer neuroprotection in Huntington’s disease (HD)…

Here, we examined this hypothesis in a rat model ofHuntington’s disease (HD)…

Our results showed that only compounds able to activate CB2 receptors were capable of protecting striatal projection neurons from malonate-induced death. That CB2 receptor agonists are neuroprotective was confirmed…

…neuroprotection was attained exclusively with antioxidant cannabinoids like Δ9-tetrahydrocannabinol (Δ9-THC; or cannabidiol (CBD)…

In summary, our results demonstrate that stimulation of CB2 receptors protect the striatum against malonate toxicity, likely through a mechanism involving glial cells, in particular reactive microglial cells in which CB2 receptors would be upregulated in response to the lesion. Activation of these receptors would reduce the generation of proinflammatory molecules like TNF-alpha.

Altogether, our results support the hypothesis that CB2 receptors could constitute a therapeutic target to slowdown neurodegeneration in HD.”

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Cannabis-Based Medicine Reduces Multiple Pathological Processes in AβPP/PS1 Mice.

“Several recent findings suggest that targeting the endogenous cannabinoid system can be considered as a potential therapeutic approach to treat Alzheimer’s disease (AD).

The present study supports this hypothesis demonstrating that delta-9-tetrahydrocannabinol (THC) or cannabidiol (CBD) botanical extracts, as well as the combination of both natural cannabinoids, which are the components of an already approved cannabis-based medicine, preserved memory in AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage.

Moreover, THC + CBD reduced learning impairment in AβPP/PS1 mice.

…suggesting a cannabinoid-induced reduction in the harmful effect of the most toxic form of the Aβ peptide.

Among the mechanisms related with these positive cognitive effects, the anti-inflammatory properties of cannabinoids may also play a relevant role…

In summary, the present findings show that the combination of THC and CBD exhibits a better therapeutic profile than each cannabis component alone and support the consideration of a cannabis-based medicine as potential therapy against AD.”

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Delta-9-tetrahydrocannabinol + cannabidiol. A reasonable option for some patients with multiple sclerosis.

“Conventional drugs have only a limited impact on spasticity associated with multiple sclerosis and are rarely satisfactory. A solution for oral transmucosal delivery (spray) containing a mixture of cannabis extracts (2.7 mg of delta-9-tetrahydrocannabinol + 2.5 mg of cannabidiol per spray) has been granted marketing authorisation in France for patients who are inadequately relieved by standard treatments. Three double-blind, placebo-controlled trials in a total of about 300 patients tested this combination, in addition to ongoing treatment, for periods of 6 to 14 weeks. Individually, none of these trials showed any tangible anti-spastic efficacy, but two combined analyses showed “response rates” of about 35% with the mixture versus about 25% with placebo. In a trial with 572 patients, the 241 patients who “responded” after 4 weeks of treatment were randomised to either continue using the cannabis extract or receive placebo. Twelve weeks later, 75% of patients using the extract were still “responders”, versus 51% of patients switched to placebo. The principal adverse effects of the cannabis extracts consist of neuropsychiatric disorders that resolve on treatment withdrawal. The potential for abuse increases with the dose and is tangible from 16 sprays per day. Pharmacokinetic interactions due to P-glycoprotein inhibition are likely. Treatment during pregnancy may lead to neonatal withdrawal symptoms. In practice, about 10% of patients in whom standard anti-spastic medications are unsatisfactory benefit from a specific effect of the cannabis extracts contained in this oral spray.”

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“Cannabinoids have been shown to promote the expression of the intercellular adhesion molecule 1 (ICAM-1) on lung cancer cells as part of their anti-invasive and antimetastatic action…

Cannabidiol (CBD), a non-psychoactive cannabinoid, enhanced the susceptibility of cancer cells to adhere to and subsequently lysed by LAK cells, with both effects being reversed by a neutralizing ICAM-1 antibody…

ICAM-1-dependent pro-killing effects were further confirmed for the phytocannabinoid Δ9-tetrahydrocannabinol (THC) and R(+)-methanandamide, a stable endocannabinoid analogue…

Altogether, our data demonstrate cannabinoid-induced upregulation of ICAM-1 on lung cancer cells to be responsible for increased cancer cell susceptibility to LAK cell-mediated cytolysis.

These findings provide proof for a novel antitumorigenic mechanism of cannabinoids.”

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