Antidepressant-like effects of cannabidiol when combined with temozolomide in adult rats

There is a need for characterizing more efficacious therapeutic strategies for glioblastoma multiforme to overcome treatment resistance to the standardized use of temozolomide as well as to better treat its debilitating comorbidities like depression. In this context, combination therapies, particularly cannabidiol with temozolomide exhibited additive or synergistic anti-tumor effects, capable of improving temozolomide's resistance over the course of treatment. Beyond its antitumoral properties and given the promising antidepressant-like profile of cannabidiol, we aimed at evaluating the pharmacological interaction of a combined therapy with cannabidiol and temozolomide as a potential novel antidepressant-like strategy, in comparison with temozolomide's combination with fluoxetine, the goal treatment standard for depressive-like symptomatology. To do so, adult male and female rats received (i.p.) temozolomide (25 mg/kg, 2 cycles, 5 days/cycle, 1 dose/day), cannabidiol (10 or 30 mg/kg, 3 doses within 24 h), fluoxetine (5-20 mg/kg, 3 doses within 24 h) alone and/or in combination. Antidepressant-like responses were scored under the stress of the forced-swim test. The results proved that all drugs induced antidepressant-like responses, although efficacy was related to sex and the dose administered. Moreover, the combination of fluoxetine with temozolomide was not different than the response induced by each drug separately. However, combining cannabidiol with temozolomide exhibited a sex-dependent antidepressant-like response solely observed in male rats, offering a potential therapeutic avenue to address depression in glioblastoma, where current antidepressants remain largely ineffective. Therefore, we propose that cannabidiol might be a good option to be administered in glioblastoma patients treated with temozolomide for improved affective-like responses, although not before its future validation in animal models of glioblastoma. Moreover, upcoming studies should center in personalizing the doses needed for this combinational approach to be also effective in females.