Phytomolecules

Caryophyllene: in the shadow of CBD

1. CBD: A GIANT IN THE PHYTOVCANNABINOID WORLD

Cannabidiol (CBD) is a phytocannabinoid extracted from hemp (Cannabis sativa), that gains more attention from the nutraceutical (and the regulatory) world every day. Available scientific data allow to consider the use of this molecule in a large variety of health areas, but its precise pharmacological activity is not totally understood.

In fact, even if CBD can be considered as a phytocannabinoid due to its affinity for CB1 & CB2 receptors (endocanabinoid receptors involved in numerous physiological mecanisms), this affinity is low and its main impact on "cannabinoid cascades" seems to be indirect. Indeed, CBD negatively modulates FAAH activity leading to the stimulation o anandamide (an endocannabinoid). CBD also inhibits GPR55 receptor (another endocannabinoid pathway) and is an agonist of PPARγ, 5-HT1A and TRPV1 [1-5].

In other words, CBD is a polypharmacological active which made it of great interest for both nutraceutical and pharmaceutical industries. Moreover, CBD booming market and regulatory incertainty has also led the cosmetic industry to wonder if it could be a dermocosmetic ingredient, making it one of the biggest trend in the botanicals, a trend that forecasts a large shadow on a more discrete phytocannabinoid: β-caryophyllene.
2. β-CARYOPHYLLENE : DISCRETE BUT FASCINATING

β-caryophyllene is also a phytocannabinoid (cannabinoid receptor agonist) present in numerous plants and spices [6-7]. It is widely recognized as a food additive and is also used in cosmetics for its perfume fixative properties. Finally, it is present in multiple essential oils like Copaiba (Copaifera officinalis), Ylang-ylang (Cananga odorata) or Black pepper (Piper nigrum), used in aromatherapy.

Unlike CBD, β-caryophyllene is a specific agonist of CB2 receptors. The absence of activity through CB1 receptors could be considered as a weakness but it is, in fact, a great advantage in some contexts. Indeed, more specificity leads to less risks of side effects. In other words, as long as the purpose of the product is linked to CB2 and not CB1, β-caryophyllene might be a good alternative to CBD. Moreover, β-caryophyllene is safe at an exposure of 2.2 mg/kg/day (to the best of our knowledge, the most restrictive NOAEL is 220 mg/kg/day [8 -12]. Attention should, however, be paid to potential drug interaction [13-14]
3. β-CARYOPHYLLENE : FOR INFLAMMATION AND PAIN ?

β-caryophyllene is a recognized anti-inflammatory agent [6-7], limiting leukocyte endothelial adhesion [15] and Neutrophile migration [16] among other things. It has shown great potential in pain management [17-20] and seems to have positive impact on diverse arthritis models [21-24].

Based on these experimental data, the integration of β-caryophyllene in pain relief topical treatment could be a lead to consider. β-caryophyllene could be combined with other anti-inflammatory botanicals like Salvia miltiorrhiza roots (see the article on topical anti-inflammatory activity of red sage here) to develop a unique natural blend for topical inflammation management.
4. β-CARYOPHYLLENE : NEUROGICALLY ACTIVE

When CB1 and CB2 are set appart, the last one is usually considered to be more relevant on immune system and PNS, when CB1 is mainly associated with CNS. However, experimental data show that β-caryophyllene is widely active on the neurological area including CNS.
Since this molecule is particularly active on inflammation, neuroprotection is [25-26], unsurprisingly, a field where it showed great potential. Indeed, β-caryophyllene has been tested in numerous models linked to ischaemia [27-33] and seizures [34-36] with significant results. Moreover, it has also been tested in multiple experimental models related to diverse neuropathologies like multiple sclerosis [37-38], Alzheimer's disease [39-40] and Parkinson's disease [41-43].

Surprisingly, β-caryophyllene seems to also have a positive impact in depression and anxiety model [44-46], as well as in addiction behaviour [47-48], opening new health opportunities for the molecule and for the natural extracts that contain it in large quantity like Copaifera officinalis essential oil or specific Piper nigrum extract enriched in β-caryophyllene
5. CONCLUSION

CBD has tremendous therapeutical potential. However, its booming market does not mean that it's the best answer to every condition vaguely related to cannabinoids pathways. β-caryophyllene is a well known and safe, food additive and cosmetic ingredient. It is also a CB2 receptor specific agonist with fascinating health potential in a myriad of conditions related to inflammation, but also with positive effect on other aspects like glycemia or lipid metabolism (see next article on β-caryophyllene virtues).
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