Palmitoylethanolamide: A Potential Alternative to Cannabidiol

The endocannabinoid system (ECS) is a widespread cell signaling network that maintains homeostasis in response to endogenous and exogenous stressors. This has made the ECS an attractive therapeutic target for various disease states. The ECS is a well-known target of exogenous phytocannabinoids derived from cannabis plants, the most well characterized being Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). However, the therapeutic efficacy of cannabis products comes with a risk of toxicity and high abuse potential due to the psychoactivity of THC. CBD, on the other hand, is reported to have beneficial medicinal properties including analgesic, neuroprotective, anxiolytic, anticonvulsant, and antipsychotic activities, while apparently lacking the toxicity of THC. Nevertheless, not only is the currently available scientific data concerning CBD's efficacy insufficient, there is also ambiguity surrounding its regulatory status and safety in humans that brings inherent risks to manufacturers. There is a demand for alternative compounds combining similar effects with a robust safety profile and regulatory approval. Palmitoylethanolamide (PEA) is an endocannabinoid-like lipid mediator, primarily known for its anti-inflammatory, analgesic and neuroprotective properties. It appears to have a multi-modal mechanism of action, by primarily activating the nuclear receptor PPAR-α while also potentially working through the ECS, thus targeting similar pathways as CBD. With proven efficacy in several therapeutic areas, its safety and tolerability profile and the development of formulations that maximize its bioavailability, PEA is a promising alternative to CBD.