Cannabidiol (CBD), a major non-psychotropic component of cannabis, is receiving growing attention as a potential anticancer agent. CBD suppresses the development of cancer in both in vitro (cancer cell culture) and in vivo (xenografts in immunodeficient mice) models. For critical evaluation of the advances of CBD on its path from laboratory research to practical application, in this review, we wish to call the attention of scientists and clinicians to the following issues: (a) the biological effects of CBD in cancer and healthy cells; (b) the anticancer effects of CBD in animal models and clinical case reports; (c) CBD’s interaction with conventional anticancer drugs; (d) CBD’s potential in palliative care for cancer patients; (e) CBD’s tolerability and reported side effects; (f) CBD delivery for anticancer treatment.

Cytotoxic effects of cannabidiol (CBD) and tamoxifen (TAM) have been observed in several cancer types. We have recently shown that CBD primarily targets mitochondria, inducing a stable mitochondrial permeability transition pore (mPTP) and, consequently, the death of acute lymphoblastic leukemia (T-ALL) cells. Mitochondria have also been documented among cellular targets for the TAM action. In the present study we have demonstrated a synergistic cytotoxic effect of TAM and CBD against T-ALL cells. By measuring the mitochondrial membrane potential (ΔΨm), mitochondrial calcium ([Ca²⁺]_m) and protein-ligand docking analysis we determined that TAM targets cyclophilin D (CypD) to inhibit mPTP formation. This results in a sustained [Ca²⁺]_m overload upon the consequent CBD administration. Thus, TAM acting on CypD sensitizes T-ALL to mitocans such as CBD by altering the mitochondrial Ca²⁺ homeostasis.

Kv4.2 channels are the principal mediators of the fast transient outward K⁺ current (I_tof) in the heart and the A-type current (I_A) in the nervous system, both of which play a relevant role in shaping cardiac action potentials and neuronal excitability. This review focuses on how interactions with ancillary subunits, such as potassium channel interacting proteins (KChIPs) and dipeptidyl peptidase-like proteins (DPPs), beyond regulating trafficking, membrane expression, and gating properties of Kv4.2 channels, significantly influence channel drug response, demonstrating that Kv4.2 does not represent a fixed pharmacological entity but rather a dynamic macromolecular complex whose drug responsiveness depends on its subunit composition. Understanding this accessory subunit-dependent modulation is important, as the pharmacological profile of Kv4.2-containing channels may differ depending on the predominant accessory subunit composition in each tissue.