Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Two of the primary hypotheses underlying motor neuron vulnerability are susceptibility to excitotoxi- city and oxidative damage. There is rapidly emerging evidence that the cannabinoid receptor system has the potential to reduce both excitotoxic and oxidative cell damage. Here we report that treatment with D9- tetrahydrocannabinol (D9-THC) was effective if administered either before or after onset of signs in the ALS mouse model (hSODG93A transgenic mice). Administration at the onset of tremors delayed motor impairment and prolonged survival in D9-THC treated mice when compared to vehicle controls. In addition, we present an improved method for the analysis of disease progression in the ALS mouse model. This logistic model pro- vides an estimate of the age at which muscle endurance has declined by 50% with much greater accuracy than could be attained for any other measure of decline. In vitro, D9-THC was extremely effective at reducing oxidative damage in spinal cord cultures. Additionally, D9-THC is anti-excitotoxic in vitro. These cellular mechanisms may underlie the pre- sumed neuroprotective effect in ALS. As D9- THC is well tolerated, it and other cannabi- noids may prove to be novel therapeutic targets for the treatment of ALS.