Borgonetti and colleagues investigated whether Cannabis sativa L. extract (CSE) and its main chemical components, β-caryophyllene, and cannabidiol, bear neuroprotective effects. An in vitro model of glutamate-induced neuronal excitotoxicity using SH-SY5Y cells was optimized. ERK levels, brain-derived neurotrophic factor release, glutamate-impaired cell viability, CB1 protein expression, and how CSE influenced them were studied. The role of CB1 modulation was confirmed using AM4113, a CB1 antagonist. CSE, through ERK modulation, counteracted the changes in brain-derived neurotrophic factor level and significantly protected SH-SY5Y from glutamate-impaired cell viability. CSE entirely reversed CB1 receptor expression, and the use of AM4113 reduced the efficacy of CSE, suggesting the involvement of CB1 in neuro-excitotoxicity modulation. The investigation, thus,  showed that CSE harbors neuroprotective effects. As a result, it can be proposed that the whole cannabis Phytocomplex could be a more effective strategy than its primary constituents alone, and suggested further investigations using more complex cellular and animal models. Fitoterapia (2022) DOI: 10.1016/j.fitote.2022.105315.