Polypharmacology Shakes Hands with Complex Aetiopathology

Chronic diseases are due to deviations of fundamental physiological systems, with different pathologies being characterised by similar malfunctioning biological networks. The ensuing compensatory mechanisms may weaken the body's dynamic ability to respond to further insults and reduce the efficacy of conventional single target treatments. The multitarget, systemic, and prohomeostatic actions emerging for plant cannabinoids exemplify what might be needed for future medicines. Indeed, two combined cannabis extracts were approved as a single medicine (Sativex (R)), while pure cannabidiol, a multitarget cannabinoid, is emerging as a treatment for paediatric drug-resistant epilepsy. Using emerging cannabinoid medicines as an example, we revisit the concept of polypharmacology and describe a new empirical model, the 'therapeutic handshake', to predict efficacy/safety of compound combinations of either natural or synthetic origin.