Endocannabinoid System Found to Play a Role in Chemotherapy-Caused Hearing Loss | Research

The takeaway

Cisplatin chemotherapy disrupts the endocannabinoid system in hearing cells, and blocking the CB2 receptor may actually protect against this damage.

Cancer patients on cisplatin, oncologists, and researchers studying hearing loss prevention.

CB2 receptor blockade protected hearing cells from cisplatin damage

What the researchers found

Cisplatin treatment downregulated CB2 receptors and disrupted the 2-AG metabolic pathway in auditory hair cells. Counterintuitively, pharmacological blockade of CB2 receptors with SR144528 protected hair cells from cisplatin damage by inhibiting caspase-3 cleavage (a cell death marker).

Why it matters

Cisplatin-induced hearing loss affects many cancer patients and has no treatment. Identifying the endocannabinoid system as involved opens an entirely new avenue for protective therapies during chemotherapy.

The numbers in context

Both major endocannabinoids (AEA and 2-AG) were present in auditory hair cells. Cisplatin downregulated CB2R, DAGLb, and ABHD6. CB2 receptor blockade via SR144528 reduced caspase-3 cleavage, a marker of cell death.

How the study worked

Researchers profiled the endocannabinoid system in mouse auditory hair cell lines, established an in vitro cisplatin toxicity model, validated findings in an in vivo mouse model, and tested whether CB2 receptor blockade could protect against damage.

What this study cannot tell us

Primarily an in vitro study with some in vivo validation. The cell line (UB/OC1) is derived from mouse tissue and may not perfectly replicate human auditory cells. Translating CB2 blockade to clinical hearing protection requires extensive further research.

How to read the evidence

Early-stage mechanistic study combining in vitro and in vivo mouse models. Novel finding but far from clinical application.

When this study was published

2026 study.

The bigger picture

The counterintuitive finding that blocking (not activating) CB2 receptors protects hearing cells challenges simple assumptions about cannabinoid pharmacology. It suggests the endocannabinoid system role in hearing is more nuanced than in other tissues.

Questions still open

Could cannabis use during chemotherapy affect hearing loss risk? Would CB2 receptor antagonists need to be administered locally to the ear, or could systemic treatment work?

Common questions

Can cannabinoids prevent chemotherapy hearing loss?

This study found that blocking (not activating) the CB2 cannabinoid receptor protected hearing cells from cisplatin damage in mice. This is a very early finding that needs much more research before any clinical application.

Why is this counterintuitive?

Most cannabinoid research focuses on activating receptors for therapeutic benefit. Here, blocking a cannabinoid receptor was protective, suggesting the endocannabinoid system plays an unusual role in hearing cell biology.

Read the original research

Unraveling Endocannabinoid Signaling Pathways in Cisplatin-Induced Ototoxicity.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 40(4), e71568

View on PubMed ↗Publisher’s paper ↗

Citation

Palaniappan, Sakthimala; Tisi, Annamaria; Di Meo, Camilla; Urbano, Cristina; Fenton, Georgina E; Della Valle, Francesco; Fanti, Federico; Compagnone, Dario; Nazarè, Marc; Versnel, Huib; Aramini, Andrea; Allegretti, Marcello; Maccarrone, Mauro. (2026). Unraveling Endocannabinoid Signaling Pathways in Cisplatin-Induced Ototoxicity.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 40(4), e71568. https://doi.org/10.1096/fj.202502888RR