Beta-caryophyllene: the terpene that binds to CB2 receptors

Terpenes are the volatile molecules responsible for the smell of plants. Beta-caryophyllene, often shortened to BCP, carries peppery and woody notes. It is found in black pepper, whose seed essential oil contains more than a third of it, and in clove, hops, rosemary and basil. It is also present in hemp flowers: the 2008 article that made it famous notes that it can account for up to 35 % of the essential oil of Cannabis sativa. The authors put ordinary daily dietary intake at between 10 and 200 mg.

Its structure sets it apart from most of its neighbours: it is a bicyclic sesquiterpene, heavier and less volatile than myrcene or limonene. For the wider picture, our article on the role and chemistry of hemp terpenes places BCP among the other compounds of the aromatic profile, and the simple guide to terpenes explains how to spot them on a label.

In June 2008, Jürg Gertsch and his colleagues published an article in the Proceedings of the National Academy of Sciences under a direct title: "Beta-caryophyllene is a dietary cannabinoid". Their demonstration had several strands.

(E)-beta-caryophyllene binds selectively to the type 2 cannabinoid receptor, with an affinity constant measured at 155 nanomolar, and behaves as a functional agonist of that receptor. It does not activate the CB1 receptor, the one whose stimulation produces the psychotropic effects of THC: BCP is therefore not psychoactive. In mice, an oral dose of 5 mg per kilogram strongly reduced an inflammatory response induced by carrageenan. That effect is absent in mice lacking CB2 receptors, which ties the observation to the proposed mechanism.

The authors' conclusion is cautious and worth repeating as it stands: BCP is a non-psychoactive functional ligand of the CB2 receptor found in the diet. The important word is diet.

Beta-caryophyllene is registered as an authorised flavouring substance in the European Union under number FL 01.007, under Regulation (EC) No 1334/2008 on flavourings. It has been the subject of safety assessments by EFSA within the flavouring group evaluations, for aliphatic and alicyclic hydrocarbons. Those assessments draw on genotoxicity data and 90-day studies in rats. The joint FAO-WHO committee evaluated it in 2004 under number JECFA 1324. It concluded that there was no safety concern at the intake levels observed for use as a flavouring agent. Its entry in the Union list nevertheless carries a note stating that its evaluation is not closed: it is authorised for use, not definitively classified without reservation.

That status has two practical consequences. The first: its presence in a food or aromatic product is unremarkable, and does not turn that product into a cannabinoid preparation. The second: no claim of a health benefit relating to beta-caryophyllene is authorised in the European Union. A manufacturer writing that a BCP product acts on inflammation would step outside the framework, whatever the preclinical literature says.

Most of the work published since 2008 concerns animal models and cell systems: anti-inflammatory signals, effects in neuropathic models, work on neuroprotection models. These results justify further research. They say nothing reliable about what a hemp flower containing BCP produces in a person.

Three limits are worth knowing. The doses used in animals, expressed by body weight, bear no comparison with what inhaling or ingesting a natural terpene profile delivers. The oral bioavailability of BCP is low and variable. Finally, no clinical trial of sufficient size has assessed isolated beta-caryophyllene in humans against a clinical endpoint. The same caution applies to the entourage effect hypothesis, which remains a working hypothesis and not an established mechanism.

In practice, not much. A rich terpene profile is an indicator of freshness and of care taken over drying: terpenes evaporate with time, heat and light. On that basis, the presence of beta-caryophyllene on an analysis tells you more about how well a batch has been kept than about any expected effect.

On vaporisation, one error circulates widely. Tables of "terpene boiling points" give beta-caryophyllene a value of around 120 to 130 °C. That value comes from a measurement made under reduced pressure, at 14 mm Hg, that is to say under vacuum. At atmospheric pressure, the pressure inside a vaporiser, chemical databases such as PubChem give, after JECFA, a boiling point of 256 °C. A heavy sesquiterpene is released gradually well before its boiling point, but the figure of 120 °C does not carry the meaning attributed to it. Our guide to vaporisation temperatures sets out the useful steps.

And as with everything else, the only document that commits anyone is the batch analysis: at Phytogrammes, the certificate is published before purchase.