*Review* β**-Caryophyllene: A Sesquiterpene with Countless Biological Properties**

**Fabrizio Francomano 1,**†**, Anna Caruso 1,**†**, Alexia Barbarossa 1, Alessia Fazio 1,\*, Chiara La Torre 1, Jessica Ceramella 1, Rosanna Mallamaci 2, Carmela Saturnino 3, Domenico Iacopetta 1 and Maria Stefania Sinicropi 1**


Received: 18 November 2019; Accepted: 9 December 2019; Published: 11 December 2019

**Abstract:** β-Caryophyllene (BCP), a natural bicyclic sesquiterpene, is a selective phytocannabinoid agonist of type 2 receptors (CB2-R). It isn't psychogenic due to the absence of an a ffinity to cannabinoid receptor type 1 (CB1). Among the various biological activities, BCP exerts anti-inflammatory action via inhibiting the main inflammatory mediators, such as inducible nitric oxide synthase (iNOS), Interleukin 1 beta (IL-1β), Interleukin-6 (IL-6), tumor necrosis factor-alfa (TNFα), nuclear factor kapp a-light-chain-enhancer of activated B cells (NF-κB), cyclooxygenase 1 (COX-1), cyclooxygenase 2 (COX-2). Peroxisome proliferator-activated receptors alpha (PPARα) e ffects are also mediated by the activation of PPARα and PPAR-γ receptors. In detail, many studies, in vitro and in vivo, sugges<sup>t</sup> that the treatment with β-caryophyllene improves the phenotype of animals used to model various inflammatory pathologies, such as nervous system diseases (Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke), atherosclerosis, and tumours (colon, breast, pancreas, lymphoma, melanoma and glioma cancer). Furthermore, pre-clinical data have highlighted that BCP is potentially useful in *Streptococcus* infections, osteoporosis, steatohepatitis, and exerts anticonvulsant, analgesic, myorelaxing, sedative, and antidepressive e ffects. BCP is non-toxic in rodents, with a Lethal dose, 50% (LD50) greater than 5000 mg/kg. Nevertheless, it inhibits various cytochrome P450 isoforms (above all, CYP3A4), which metabolise xenobiotics, leading to adverse effects, due to drug levels over therapeutic window. All the reported data have highlighted that both pharmacological and toxicological aspects need to be further investigated with clinical trials.

**Keywords:** sesquiterpene; inflammatory pathologies; nutraceuticals
