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Caryophyllene , more formally (−)-β-caryophyllene (BCP), is a natural bicyclic sesquiterpene that occurs widely in nature. Caryophyllene is notable for having a cyclobutane ring, as well as a trans-double bond in a 9-membered ring, both rarities in nature.

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Production

Caryophyllene can be produced synthetically,2 but it is invariably obtained from natural sources because it is widespread. It is a constituent of many essential oils, especially clove oil, the oil from the stems and flowers of Syzygium aromaticum (cloves), the essential oil of Cannabis sativa, copaiba, rosemary, and hops.3 It is usually found as a mixture with isocaryophyllene (the cis double bond isomer) and α-humulene (obsolete name: α-caryophyllene), a ring-opened isomer.

Caryophyllene is one of the chemical compounds that contributes to the aroma of black pepper.4

Basic research

β-Caryophyllene is under basic research for its potential action as an agonist of the cannabinoid receptor type 2 (CB2 receptor).5 In other basic studies, β-caryophyllene has a binding affinity of Ki = 155 nM at the CB2 receptors.6

β-Caryophyllene has the highest cannabinoid activity compared to the ring opened isomer α-caryophyllene humulene which may modulate CB2 activity.7 To compare binding, cannabinol binds to the CB2 receptors as a partial agonist with an affinity of Ki = 126.4 nM,8 while delta-9-tetrahydrocannabinol binds to the CB2 receptors as a partial agonist with an affinity of Ki = 36 nM.9

Safety

Caryophyllene has been given generally recognized as safe (GRAS) designation by the FDA and is approved by the FDA for use as a food additive, typically for flavoring.1011 Rats given up to 700 mg/kg daily for 90 days did not produce any significant toxic effects.12 Caryophyllene has an LD50 of 5,000 mg/kg in mice.1314

Metabolism and derivatives

14-Hydroxycaryophyllene oxide (C15H24O2) was isolated from the urine of rabbits treated with (−)-caryophyllene (C15H24). The X-ray crystal structure of 14-hydroxycaryophyllene (as its acetate derivative) has been reported.15

The metabolism of caryophyllene progresses through (−)-caryophyllene oxide (C15H24O) since the latter compound also afforded 14-hydroxycaryophyllene (C15H24O) as a metabolite.16

Caryophyllene (C15H24) → caryophyllene oxide (C15H24O) → 14-hydroxycaryophyllene (C15H24O) → 14-hydroxycaryophyllene oxide (C15H24O2).

Caryophyllene oxide,17 in which the alkene group of caryophyllene has become an epoxide, is the component responsible for cannabis identification by drug-sniffing dogs1819 and is also an approved food additive, often as flavoring.20 Caryophyllene oxide may have negligible cannabinoid activity.21

Natural sources

The approximate quantity of caryophyllene in the essential oil of each source is given in square brackets ([ ]):

Biosynthesis

Caryophyllene is a common sesquiterpene among plant species. It is biosynthesized from the common terpene precursors dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP). First, single units of DMAPP and IPP are reacted via an SN1-type reaction with the loss of pyrophosphate, catalyzed by the enzyme GPPS2, to form geranyl pyrophosphate (GPP). This further reacts with a second unit of IPP, also via an SN1-type reaction catalyzed by the enzyme IspA, to form farnesyl pyrophosphate (FPP). Finally, FPP undergoes QHS1 enzyme-catalyzed intramolecular cyclization to form caryophyllene.40

Compendial status

Further reading

Notes and references

References

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  2. Corey, E. J.; Mitra, R. B.; Uda, H. (1964). "Total Synthesis of d,l-Caryophyllene and d,l-Isocaryophyllene". Journal of the American Chemical Society. 86 (3): 485–492. Bibcode:1964JAChS..86..485C. doi:10.1021/ja01057a040. /wiki/Bibcode_(identifier) ↩

  3. Sell, Charles S. (2006). "Terpenoids". Kirk-Othmer Encyclopedia of Chemical Technology. doi:10.1002/0471238961.2005181602120504.a01.pub2. ISBN 0471238961. 0471238961 ↩

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