The review, led by Ahmad J. Harahsheh and colleagues spanning institutions in Jordan, Kazakhstan, and Malaysia, systematically searched PubMed, Scopus, and Web of Science from database inception through 22 August 2026. After screening 1,471 records and removing duplicates, retracted publications, and ineligible reports, the team landed on 25 studies: 23 clinical investigations and just 2 preclinical studies. That imbalance itself tells a story. Most of what we know about venlafaxine in cancer comes from patient-facing trials of symptom relief, not from bench experiments probing tumor-killing power. The authors assessed methodological quality using Joanna Briggs Institute checklists for clinical studies and the SYRCLE Risk of Bias tool for animal work, and they deliberately synthesized clinical and preclinical evidence separately to avoid conflating very different tiers of proof.

The strongest signal by far concerns vasomotor symptoms — the hot flashes that torment breast cancer survivors on endocrine therapy and men with prostate cancer undergoing androgen deprivation. In a landmark randomized, double-blind, placebo-controlled trial, Loprinzi and colleagues demonstrated dose-dependent reductions in hot flash scores: within-group drops of 61 percent at both 75 and 150 mg/day, significantly outperforming the 27 percent seen with placebo (P < 0.001 for each venlafaxine dose versus placebo). The review’s authors are careful to flag a common misreading here: those headline percentages describe change from baseline within each arm, not the treatment effect itself, since placebo arms often improve substantially too. The real evidence lies in the between-group comparisons, and those favor venlafaxine at higher doses.

Head-to-head comparisons add texture. Venlafaxine beat clonidine for hot flash frequency in one double-blind randomized trial (a median drop of 7.6 versus 4.85 hot flashes per day, P = 0.025), though clonidine fared better on a severity score in that same study. A crossover trial found the two drugs essentially equivalent, with venlafaxine causing more treatment-limiting side effects. Against gabapentin, venlafaxine matched the 66 percent hot flash score reduction but won the preference contest decisively — 68 percent of patients chose to stay on it. Against acupuncture, benefits were comparable during treatment but faded faster after venlafaxine withdrawal. In men with prostate cancer, the picture dims: one phase III trial found hormonal agents (cyproterone acetate and medroxyprogesterone) substantially outperformed venlafaxine, and a placebo-controlled factorial trial failed to meet its primary endpoint for venlafaxine in androgen-deprived men. Notably, a 2026 prospective study in tamoxifen-treated Japanese breast cancer patients showed venlafaxine cut hot flash scores by nearly 50 percent without altering tamoxifen or its active metabolite levels — a critical pharmacological point, since strong CYP2D6 inhibitors like paroxetine can sabotage tamoxifen’s activation, while venlafaxine does not.

The chemotherapy-induced peripheral neuropathy (CIPN) story is far messier. CIPN affects roughly 19 to 85 percent of patients depending on the chemotherapeutic agent, driving dose reductions, treatment discontinuations, and lasting neurological damage. Venlafaxine’s record here is inconsistent. Its brightest moment came in the EFFOX phase III trial, where 31.3 percent of patients receiving venlafaxine achieved complete relief of acute oxaliplatin-induced neurotoxicity versus just 5.3 percent on placebo (P = 0.03). But a pilot randomized trial failed to show venlafaxine prevented chronic oxaliplatin neuropathy, missing its primary endpoint on the EORTC QLQ-CIPN20 sensory subscale. Comparative trials against duloxetine — the only drug with moderate-quality evidence support in the current ASCO guideline for painful CIPN — generally favored duloxetine, particularly for motor neuropathy and neuropathic pain, though one Iranian trial found the two statistically indistinguishable across overall outcomes. The review concludes that evidence is insufficient to recommend venlafaxine for preventing or routinely treating chronic CIPN, though it may remain a reasonable fallback for patients who cannot tolerate duloxetine.

Other supportive care applications rest on thin ice. A single phase II trial in head and neck cancer found that adding venlafaxine to prophylactic high-dose gabapentin did nothing for oral mucositis pain, opioid use, feeding tube placement, or quality of life beyond gabapentin alone. Improvements in fatigue, sleep quality, and depressive symptoms appeared only as secondary or exploratory outcomes within hot flash trials — sometimes restricted to responder subgroups — and cannot be read as independent evidence for those indications. One small crossover trial in post-surgical neuropathic pain after breast cancer treatment missed its primary endpoint of average daily pain intensity, though secondary measures of pain relief and maximum pain intensity favored venlafaxine. Across the board, venlafaxine was generally well tolerated, with nausea, constipation, appetite loss, and dry mouth the most common complaints, and lower doses (37.5–75 mg/day) gentler than higher ones.

Then comes the provocative part: the anticancer signals. Two preclinical studies, both rated moderate quality by SYRCLE criteria, investigated venlafaxine’s direct effects on tumors — but they are not equivalent, and the review treats them accordingly. In melanoma models, Niu and colleagues showed that venlafaxine inhibited proliferation of MV3 human melanoma cells, induced apoptosis, and shrank xenograft tumors in immunodeficient mice by roughly 64 percent. The mechanism runs through activation of the JNK1/2–Nur77 signaling pathway, triggering mitochondrial translocation of Nur77, elevated reactive oxygen species, and activation of the caspase-3/PARP apoptotic cascade. In colorectal cancer, by contrast, Zhang and colleagues found venlafaxine alone did nothing to tumor growth, viability, or angiogenic markers. Its effect was purely contextual: it blocked norepinephrine-driven tumor progression by inhibiting the norepinephrine transporter (NET/SLC6A2), suppressing the downstream NET–PPP2R1A–Akt–VEGF axis. When norepinephrine was present, adding venlafaxine cut tumor volume to 25.1 percent and tumor weight to 28.7 percent of norepinephrine-alone levels. That is antagonism of a stress-hormone-driven pathway, not standalone cytotoxicity.

A sobering translational pharmacology analysis undercuts any temptation to extrapolate these findings to the clinic. Both preclinical studies used roughly 10 micromolar venlafaxine in vitro, yet at the standard 150 mg/day clinical dose, steady-state plasma concentrations of parent venlafaxine reach only about 0.54 micromolar total — roughly 0.39 micromolar free — a gap of more than an order of magnitude. The major active metabolite, O-desmethylvenlafaxine, circulates at higher levels but was never tested in the anticancer experiments and cannot simply be assumed to reproduce the same mechanisms. Murine doses of 20 and 10 mg/kg convert to approximate human-equivalent doses of 114 and 57 mg, but these are crude scaling approximations, not proof of equivalent systemic or tumor exposure. No data exist on venlafaxine concentrations within human tumor tissue. The safety database covers only supportive-care and psychiatric dosing ranges (37.5–225 mg/day); the exposures that might be needed for antitumor activity are entirely uncharacterized.

The broader context of drug repurposing makes this inquiry more than academic curiosity. Repositioning approved drugs offers well-characterized pharmacokinetics, established safety records, lower costs, and faster clinical translation than de novo discovery. Epidemiological evidence adds fuel: a propensity score-matched cohort study of over 420,000 UK Biobank participants associated antidepressant use with lower overall cancer morbidity and mortality, though causality remains unproven. Medicinal chemists have even built Nuc01, a venlafaxine-derived compound that pairs antidepressant activity with inhibition of LSD1, an epigenetic regulator implicated in tumor proliferation, metastasis, and immune escape — though the review stresses this is a structurally modified derivative, not venlafaxine itself. Parallel work on sertraline suggests these translational bottlenecks are common across antidepressant repurposing.

Where does this leave patients and clinicians? Venlafaxine holds a legitimate, guideline-consistent place in supportive oncology — The North American Menopause Society’s 2023 position statement rates SNRIs as Level I recommended for vasomotor symptoms, and newer agents like the neurokinin-3 receptor antagonist fezolinetant have yet to face venlafaxine in head-to-head oncology trials. Everything beyond hot flash control — CIPN, mucositis pain, fatigue, mood — demands better-designed randomized trials with standardized outcomes. And the anticancer dream, however tantalizing, requires independent replication of the JNK1/2–Nur77 and NET pathway findings, oral-dosing pharmacokinetic studies, biomarker development, and testing across tumor types before any phase I trial could be justified. The review’s authors are unambiguous: no clinical evidence currently supports venlafaxine as a direct anticancer treatment, and the leap from symptom management to tumor therapy remains a long, unproven road. For now, the drug’s real value in oncology lies in making survival more livable — one hot flash at a time.

Subject of Research: Systematic review of venlafaxine's supportive-care uses and preclinical anticancer potential in oncology

Article Title: Venlafaxine in oncology: supportive-care evidence and emerging preclinical anticancer signals: a systematic review

Article References: Harahsheh, A. J., Myrzabay, Z., Askambayeva, N., Ishak, R., & Aljofan, M. (2026). Venlafaxine in oncology: supportive-care evidence and emerging preclinical anticancer signals: a systematic review. Frontiers in Pharmacology, 17, Article 1945568. https://doi.org/10.3389/fphar.2026.1945568

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1945568

Keywords: venlafaxine, oncology, hot flashes, chemotherapy-induced peripheral neuropathy, drug repurposing, SNRI, supportive care, breast cancer, JNK1/2-Nur77 pathway, norepinephrine transporter, preclinical studies, systematic review