Antidepressant-like effects of cannabidiol when combined with temozolomide in adult rats
Laura Gálvez-melero, Sandra Ledesma-Corvi, C. Bis-Humbert, M. García-Fuster
Frontiers in Pharmacology June 29, 2026 DOI: 10.3389/fphar.2026.1873308 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Adult male and female rats |
| Interventions | Temozolomide Cannabidiol Fluoxetine |
| Dose | Temozolomide 25 mg/kg; Cannabidiol 10 or 30 mg/kg; Fluoxetine 5-20 mg/kg |
| Duration | Temozolomide: 2 cycles, 5 days/cycle, 1 dose/day; cannabidiol and fluoxetine: 3 doses within 24 h |
| Measures | Forced-swim test |
| Topics | CBD |
| Key points | Cannabidiol combined with temozolomide produced a sex-dependent antidepressant-like response seen only in male rats, while fluoxetine combined with temozolomide did not differ from either drug alone. All drugs tested induced antidepressant-like responses, with efficacy depending on sex and dose. The authors propose cannabidiol as a candidate adjunct for glioblastoma patients on temozolomide to improve affective-like responses, pending validation in glioblastoma animal models. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on CBD, most cited first.