Caryophyllene (/ˌkærioʊˈfɪliːn/), more formally (−)-β-caryophyllene (BCP), is a natural bicyclic
sesquiterpene that is a constituent of many
essential oils, especially clove oil, the oil from the stems and flowers of Syzygium aromaticum (cloves),[3] the essential oil of Cannabis sativa,
copaiba,
rosemary,[4] and
hops.[5] 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 notable for having a
cyclobutane ring, as well as a trans-double bond in a 9-membered ring, both rarities in nature.
Caryophyllene is one of the chemical compounds that contributes to the
aroma of
black pepper.[6]
Pharmacology
β-Caryophyllene acts as a full agonist of the
cannabinoid receptor type 2 (CB2 receptor) in rats.[7] β-Caryophyllene has a binding affinity of Ki = 155 nM at the CB2 receptors in mice.[8] β-Caryophyllene has been shown to have anti-inflammatory action linked to its CB2 receptor activity in a study comparing the pain killing effects in mice with and without CB2 receptors with the group of mice without CB2 receptors seeing little benefit compared to the mice with functional CB2 receptors.[7] β-Caryophyllene has the highest cannabinoid activity compared to the ring opened isomer α-caryophyllene
humulene which may modulate CB2 activity.[9] To compare binding,
cannabinol (CBN) binds to the CB2 receptors as a partial agonist with an affinity of Ki = 126.4 nM,[10] while delta-9-
tetrahydrocannabinol binds to the CB2 receptors as a partial agonist with an affinity of Ki = 36 nM.[11]
Caryophyllene helps to improve cold tolerance at low ambient temperatures. Wild giant pandas frequently roll in horse manure, which contains β-caryophyllene/caryophyllene oxide, to inhibit
transient receptor potential melastatin 8 (TRPM8), an archetypical cold-activated ion channel of mammals.[12]
In an in vitro human colorectal adenocarcinoma study, β-caryophyllene used alone did not inhibit cancer cell growth, but a combination of β-caryophyllene 10 μg/mL and
paclitaxel 0.025 μg/mL resulted in 189% cancer cell growth inhibition (compared to paclitaxel used alone).[13]
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.[14][15] Rats given up to 700 mg/kg daily for 90 days did not produce any significant toxic effects.[16] Caryophyllene has an
LD50 of 5,000 mg/kg in mice.[17][18]
14-Hydroxycaryophyllene oxide (
C15H24O2) was isolated from the urine of
rabbits treated with (−)-caryophyllene (C15H24). The
X-raycrystal structure of 14-hydroxycaryophyllene (as its
acetate derivative) has been reported.[20]
The
metabolism of caryophyllene progresses through (−)-caryophyllene oxide (C15H24O) since the latter compound also afforded 14-hydroxycaryophyllene (C15H24O) as a
metabolite.[21]
Caryophyllene oxide,[22] in which the
alkene group of caryophyllene has become an
epoxide, is the component responsible for cannabis identification by
drug-sniffing dogs[23][24] and is also an approved food additive, often as flavoring.[15] Caryophyllene oxide may have negligible cannabinoid activity.[25]
Natural sources
The approximate quantity of caryophyllene in the
essential oil of each source is given in square brackets ([ ]):
^Baker, R. R. (2004). "The pyrolysis of tobacco ingredients". Journal of Analytical and Applied Pyrolysis. 71 (1): 223–311.
doi:
10.1016/s0165-2370(03)00090-1.
^
abGhelardini, C.; Galeotti, N.; Di Cesare Mannelli, L.; Mazzanti, G.; Bartolini, A. (2001). "Local anaesthetic activity of beta-caryophyllene". Farmaco. 56 (5–7): 387–389.
doi:
10.1016/S0014-827X(01)01092-8.
hdl:2158/397975.
PMID11482764.
^
abOrmeño, E.; Baldy, V.; Ballini, C.; Fernández, C. (September 2008). "Production and diversity of volatile terpenes from plants on calcareous and siliceous soils: effect of soil nutrients". Journal of Chemical Ecology. 34 (9): 1219–1229.
Bibcode:
2008JCEco..34.1219O.
doi:
10.1007/s10886-008-9515-2.
PMID18670820.
S2CID28717342.
^Tinseth, G. (January–February 1993).
"Hop Aroma and Flavor". Brewing Techniques. Retrieved July 21, 2010.
^
abJirovetz, L.; Buchbauer, G.; Ngassoum, M. B.; Geissler, M. (November 2002). "Aroma compound analysis of Piper nigrum and Piper guineense essential oils from Cameroon using solid-phase microextraction–gas chromatography, solid-phase microextraction–gas chromatography–mass spectrometry and olfactometry". Journal of Chromatography A. 976 (1–2): 265–275.
doi:
10.1016/S0021-9673(02)00376-X.
PMID12462618.
^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.
doi:
10.1021/ja01057a040.
• Asakawa, Y.; Taira, Z.; Takemoto, T.; Ishida, T.; Kido, M.; Ichikawa, Y. (June 1981). "X-Ray Crystal Structure Analysis of 14-Hydroxycaryophyllene Oxide, a New Metabolite of (—)-Caryophyllene, in Rabbits". Journal of Pharmaceutical Sciences. 70 (6): 710–711.
doi:
10.1002/jps.2600700642.
PMID7252830.
S2CID38358882.
^Yang, Depo; Michel, Laura; Chaumont, Jean-Pierre; Millet-Clerc, Joëlle (1999). "Use of caryophyllene oxide as an antifungal agent in an in vitro experimental model of onychomycosis". Mycopathologia. 148 (2): 79–82.
doi:
10.1023/a:1007178924408.
PMID11189747.
S2CID24242933.
^Stahl, E.; Kunde, R. (1973). "Die Leitsubstanzen der Haschisch-Suchhunde" [The tracing substances of hashish search dogs]. Kriminalistik (in German). 27: 385–389.
^Wiley, Jenny L.; Marusich, Julie A.; Blough, Bruce E.; Namjoshi, Ojas; Brackeen, Marcus; Akinfiresoye, Luli R.; Walker, Teneille D.; Prioleau, Cassandra; Barrus, Daniel G.; Gamage, Thomas F. (June 2024). "Evaluation of cannabimimetic effects of selected minor cannabinoids and Terpenoids in mice". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 132: 110984.
doi:
10.1016/j.pnpbp.2024.110984.
PMID38417478.
S2CID267941924.
^Singh, G.; Marimuthu, P.; De Heluani, C. S.; Catalan, C. A. (January 2006). "Antioxidant and biocidal activities of Carum nigrum (seed) essential oil, oleoresin, and their selected components". Journal of Agricultural and Food Chemistry. 54 (1): 174–181.
doi:
10.1021/jf0518610.
hdl:11336/99544.
PMID16390196.
^Zheljazkov, V. D.; Cantrell, C. L.; Tekwani, B.; Khan, S. I. (January 2008). "Content, composition, and bioactivity of the essential oils of three basil genotypes as a function of harvesting". Journal of Agricultural and Food Chemistry. 56 (2): 380–5.
doi:
10.1021/jf0725629.
PMID18095647.
^Calvo Irabién, L. M.; Yam-Puc, J. A.; Dzib, G.; Escalante Erosa, F.; Peña Rodríguez, L. M. (July 2009). "Effect of postharvest drying on the composition of Mexican oregano (Lippia graveolens) essential oil". Journal of Herbs, Spices & Medicinal Plants. 15 (3): 281–287.
doi:
10.1080/10496470903379001.
S2CID86208062.
^Umezu, T.; Nagano, K.; Ito, H.; Kosakai, K.; Sakaniwa, M.; Morita, M. (December 2006). "Anticonflict effects of lavender oil and identification of its active constituents". Pharmacology Biochemistry and Behavior. 85 (4): 713–721.
doi:
10.1016/j.pbb.2006.10.026.
PMID17173962.
S2CID21779233.
^Kaul, Pran N; Bhattacharya, Arun K; Rajeswara Rao, Bhaskaruni R; Syamasundar, Kodakandla V; Ramesh, Srinivasaiyer (1 January 2003). "Volatile constituents of essential oils isolated from different parts of cinnamon (Cinnamomum zeylanicum Blume)". Journal of the Science of Food and Agriculture. 83 (1): 53–55.
Bibcode:
2003JSFA...83...53K.
doi:
10.1002/jsfa.1277.