Abstract
Background Venlafaxine, a serotonin–norepinephrine reuptake inhibitor, has been investigated in oncology for several supportive care indications and, more recently, for potential anticancer activity. However, the available evidence remains fragmented across clinical and preclinical studies. Objective This systematic review aimed to synthesize the available evidence regarding the role of venlafaxine in oncology, including established supportive care applications and emerging anticancer potential. Methods A systematic literature search was conducted in PubMed, Scopus, and Web of Science from database inception to 22 August 2026. Original clinical and preclinical studies evaluating venlafaxine in cancer populations or experimental cancer models were eligible. Clinical and preclinical evidence was synthesized separately using a narrative approach. Methodological quality was assessed using Joanna Briggs Institute tools for clinical studies and the SYRCLE Risk of Bias tool for animal studies. Results 25 studies were included, comprising 23 clinical studies and 2 preclinical studies. The strongest clinical evidence supported venlafaxine for treatment-related hot flashes, particularly among breast cancer survivors receiving endocrine therapy, with the strongest randomized, placebo-controlled trial evidence showing significantly greater reductions with venlafaxine than placebo (P < 0.0001 for higher doses); within-group percentage reductions are also reported but should not be interpreted as treatment effects. Evidence for chemotherapy-induced peripheral neuropathy was inconsistent, with potential benefit for acute oxaliplatin-related neurotoxicity but insufficient support for prevention or routine treatment of chronic CIPN. Evidence for other supportive care outcomes, including oral mucositis-associated pain, fatigue, sleep quality, depressive symptoms, and quality of life, was limited. Venlafaxine was generally well tolerated, although adverse effects varied by dose and comparator. Preclinical studies investigated anticancer activity, but not equivalently: one in melanoma models showed direct antiproliferative/pro-apoptotic effects of venlafaxine via JNK1/2–Nur77 signaling, whereas a colorectal cancer study showed only context-dependent antagonism of norepinephrine-driven tumor progression, with no significant effect of venlafaxine alone. No clinical evidence currently supports venlafaxine as a direct anticancer treatment. Conclusion Venlafaxine has an established evidence-based role in supportive oncology for treatment-related hot flashes, whereas its role in CIPN and other supportive care indications remains uncertain. Emerging anticancer findings are limited to preclinical models and should be considered hypothesis-generating. Further randomized clinical trials are needed for supportive care indications, while additional mechanistic and preclinical validation is required before venlafaxine can be considered for clinical evaluation as an anticancer therapy.