Effects of Low-Dose Rimonabant on Locomotor Endurance After Spinal Cord Injury: A Translational Proof-of-Concept

Improving locomotor function is a key goal in spinal cord injury (SCI) rehabilitation. CB1 cannabinoid receptor antagonists enhance neuronal excitability and may support motor recovery. To evaluate the safety and efficacy in improving locomotion of short-term, low-dose Rimonabant (a CB1 receptor antagonist/inverse agonist) in moderate/incomplete SCI, we conducted: A) three sequential crossover, randomized, blind, placebo-controlled preclinical experiments in a rat model of moderate contusive thoracic SCI assessing safety and improvements in locomotor endurance after treatment with low doses of Rimonabant (0.062–0.800 mg/kg); and B) a double-blind, randomized, placebo-controlled crossover clinical trial (RIMOFATSCI-1) involving eight individuals with chronic incomplete SCI testing safety and efficacy after 5-day treatment with Rimonabant (2.5 and 5 mg/day). Preclinical analyses did not show treatment-related adverse events but revealed that 0.250 mg/kg Rimonabant significantly improved endurance 24 hours after administration (p < 0.01, Cohen's d = 0.808), with clinically meaningful improvements in 35.7% of responders. The clinical trial confirmed safety, with no psychiatric or severe adverse events. Although functional outcomes improved over time, no significant treatment-specific effects were detected. Thus, low-dose Rimonabant is safe and may acutely enhance locomotor endurance post-SCI. These findings support further investigation in larger trials.