CANALS Trial (2019) — Nabiximols for Spasticity in Motor Neuron Disease
CANALS is the first and still the only randomized placebo-controlled trial of a pharmaceutical cannabinoid for spasticity in motor neuron disease. Its central finding — that nabiximols produces a modest but statistically significant reduction in spasticity over six weeks — opened the door for cannabinoids as a legitimate option in the MND spasticity toolkit. Although small and short in duration, CANALS remains the anchor of the MND-specific cannabinoid evidence base and the reason clinicians take the question seriously at all.
What they did
The CANALS Study Group — an Italian multicentre consortium led by Nilo Riva at Ospedale San Raffaele in Milan — enrolled 60 adult patients with motor neuron disease. The cohort was intentionally heterogeneous to reflect real-world MND: most participants had amyotrophic lateral sclerosis, but the study also included patients with primary lateral sclerosis and progressive muscular atrophy, all with spasticity sufficient to interfere with daily function.
Participants were randomized 1:1 to receive either nabiximols (brand name Sativex) or a matched placebo. Nabiximols is a standardised oromucosal spray containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a roughly 1:1 ratio. Each actuation of the spray delivers 2.7 mg of THC and 2.5 mg of CBD. Patients self-titrated up to a maximum of 12 sprays per day according to symptom response and tolerability, which is the same titration schedule used in the MS spasticity approval.
The treatment period was six weeks, and both patients and investigators were blinded to allocation. The primary endpoint was the change in patient-reported spasticity on a 0-10 Numeric Rating Scale (NRS), a standard measure used in prior MS spasticity trials. Secondary endpoints included the modified Ashworth scale (an examiner-rated spasticity measure), pain scores, sleep quality, ALSFRS-R functional score, and adverse events.
What they found
The primary analysis found that nabiximols produced a statistically significant reduction in spasticity compared with placebo. On the 0-10 NRS scale, nabiximols-treated patients reduced their spasticity scores by 0.11 points more than placebo-treated patients (95% confidence interval for the difference in change: -0.54 to -0.32; p = 0.013). Expressed as a between-group effect, the NRS reduction was modest in absolute terms, but statistically robust given the small sample size.
Secondary outcomes broadly supported the primary finding. Modified Ashworth scores showed a trend toward improvement with nabiximols, and pain scores improved modestly. Sleep quality and ALSFRS-R functional scores were not significantly different between groups over the 6-week period — which is expected given the short duration and the fact that ALSFRS-R measures overall function, not spasticity specifically.
Safety was the other critical finding. Nabiximols was well tolerated. The overall rate of adverse events was higher in the nabiximols group than in the placebo group, but the events were mostly mild and expected: dizziness, fatigue, dry mouth, and mild cognitive effects. No serious adverse events were attributed to the drug. Crucially for a population with motor neuron disease, there was no signal that nabiximols accelerated muscle weakness or functional decline — a concern that had limited earlier willingness to test cannabinoids in this population.
Why it matters
CANALS did three things that the MND community has been working with ever since. First, it provided direct MND-specific evidence for a cannabinoid intervention, which until 2019 did not exist. Before CANALS, any discussion of cannabis for MND spasticity had to be extrapolated from multiple sclerosis, where the evidence is much stronger but the disease is different. CANALS collapsed part of that gap — at least for the six-week horizon it covered.
Second, it established a safety profile in a vulnerable population. Prior to CANALS, clinicians had legitimate concerns that cannabinoids might worsen cognition, weaken muscles further, or interact badly with respiratory function in MND patients. CANALS did not show those signals at the doses and duration tested. That does not mean long-term use is safe — there are no long-term MND data — but it does mean that short-term pharmaceutical cannabinoid use in MND is not obviously dangerous, which is a meaningful starting point.
Third, and most importantly for PLS specifically, CANALS included PLS patients in the cohort. The subgroup was small — the trial was not powered to detect disease-specific effects — but the inclusion matters. It means that nabiximols has been tested, even at a low statistical power, in exactly the patient population most likely to benefit from cannabinoid-mediated spasticity relief. PLS is pure upper motor neuron disease, so spasticity is the dominant symptom, and the motor reserve available for other medications to compromise is often already stretched thin. A cannabinoid that reduces spasticity without adding weakness — the way baclofen and tizanidine can — is a genuinely different option in the toolkit.
Limitations
CANALS is a Phase 2 trial, and it shows. The sample size (60 patients) was too small to detect subgroup effects or to reliably compare ALS, PLS, and PMA. The six-week treatment period is short — shorter than the horizon on which spasticity usually becomes a major functional problem in MND, and far too short to assess long-term safety, tolerance, dependence, or effects on disease progression. The primary endpoint (patient-reported NRS) is subjective, and while the blinding was rigorous, patients could likely detect whether they were receiving active drug from the mild intoxicating effects of THC, which introduces some risk of unblinding.
Nabiximols itself is not the same as smoked cannabis, vaporized cannabis, edible cannabis, or isolated CBD. CANALS therefore tells us about a standardized 1:1 pharmaceutical product at therapeutic doses, not about recreational cannabis use. Conclusions about the latter require careful extrapolation and are addressed separately in the cannabis and PLS page.
What has happened since
No follow-up Phase 3 trial of nabiximols in MND has yet been completed as of early 2026, despite the promising Phase 2 signal. The MS spasticity approval remains the primary regulatory home for nabiximols, and off-label use in MND spasticity is reported anecdotally in several European centres. The absence of a Phase 3 MND trial is partly a commercial decision — the MND market is small — and partly a reflection of how difficult cannabinoid trials are to run, given the blinding challenge and the regulatory burden.
For patients and clinicians reading CANALS today, the practical takeaway is that pharmaceutical cannabinoids are a reasonable, evidence-supported option to discuss for MND spasticity — particularly in patients who cannot tolerate baclofen or tizanidine, or who have reached the limit of those drugs without adequate symptom control. CANALS does not make that decision for anyone, but it creates the evidence base on which such a decision can legitimately be made.
How this connects
CANALS is the primary evidence source for the Cannabis and PLS page, which translates the trial findings into practical guidance for patients and families. For the broader spasticity evidence base — including the tizanidine vs baclofen RCT, the long-term intrathecal baclofen follow-up, and the PLS-specific ITB case series — see the Spasticity Research Hub. The main spasticity management page is where most PLS patients should start.
Citation
Riva N, Mora G, Sorarù G, Lunetta C, Ferraro OE, Falzone Y, Leocani L, Fazio R, Quattrini A, Comi G; CANALS Study Group. Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurology. 2019 Feb;18(2):155-164. doi: 10.1016/S1474-4422(18)30406-X.