We describe two patients with a confirmed diagnosis of high-grade gliomas (grades III/IV), both presenting with O6-methylguanine-DNA methyltransferase (MGMT) methylated and isocitrate dehydrogenase (IDH-1) mutated who, after subtotal resection, were submitted to chemoradiation and followed by PCV, a multiple drug regimen (procarbazine, lomustine, and vincristine) associated with cannabidiol (CBD). Both patients presented with satisfactory clinical and imaging responses at periodic evaluations. Immediately after chemoradiation therapy, one of the patients presented with an exacerbated and precocious pseudoprogression (PSD) assessed by magnetic resonance imaging (MRI), which was resolved in a short period. The other patient presented with a marked remission of altered areas compared with the post-operative scans as assessed by MRI. Such aspects are not commonly observed in patients only treated with conventional modalities. This observation might highlight the potential effect of CBD to increase PSD or improve chemoradiation responses that impact survival. Further investigation with more patients and critical molecular analyses should be performed.