Caryophyllene (), more formally (−)-β-caryophyllene, (BCP), is a natural bicyclic

sesquiterpene Sesquiterpenes are a class of terpenes that consist of three isoprene units and often have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be cyclic or contain rings, including many unique combinations. Biochemical modifica ...

that is a constituent of many essential oils, especially clove oil, the oil from the stems and flowers of ''

Syzygium aromaticum Cloves are the aromatic flower buds of a tree in the family Myrtaceae, ''Syzygium aromaticum'' (). They are native to the Maluku Islands (or Moluccas) in Indonesia, and are commonly used as a spice, flavoring or fragrance in consumer products, ...

'' (cloves), the essential oil of ''

Cannabis sativa ''Cannabis sativa'' is an annual herbaceous flowering plant indigenous to Eastern Asia, but now of cosmopolitan distribution due to widespread cultivation. It has been cultivated throughout recorded history, used as a source of industrial fiber ...

'',

rosemary ''Salvia rosmarinus'' (), commonly known as rosemary, is a shrub with fragrant, evergreen, needle-like leaves and white, pink, purple, or blue flowers, native to the Mediterranean region. Until 2017, it was known by the scientific name ''Rosma ...

, and

hops Hops are the flowers (also called seed cones or strobiles) of the hop plant '' Humulus lupulus'', a member of the Cannabaceae family of flowering plants. They are used primarily as a bittering, flavouring, and stability agent in beer, to wh ...

. It is usually found as a mixture with isocaryophyllene (the ''cis'' double bond isomer) and

α-humulene Humulene, also known as α-humulene or α-caryophyllene, is a naturally occurring monocyclic sesquiterpene (C15H24), containing an 11-membered ring and consisting of 3 isoprene units containing three nonconjugated C=C double bonds, two of them be ...

(obsolete name: α-caryophyllene), a ring-opened isomer. Caryophyllene is notable for having a

cyclobutane Cyclobutane is a cycloalkane and organic compound with the formula (CH2)4. Cyclobutane is a colourless gas and commercially available as a liquefied gas. Derivatives of cyclobutane are called cyclobutanes. Cyclobutane itself is of no commercia ...

ring, as well as a ''trans''-double bond in a 9-membered ring, both rarities in nature. β-Caryophyllene acts as a full agonist of the

Cannabinoid receptor type 2 The cannabinoid receptor type 2, abbreviated as CB2, is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the ''CNR2'' gene. It is closely related to the cannabinoid receptor type 1 (CB1), which is la ...

(CB2 receptor) in rats. β-Caryophyllene has a binding affinity of Ki = 155nM at the CB2 receptors in mice. 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. β-Caryophyllene has the highest cannabinoid activity compared to the ring opened isomer α-caryophyllene which may modulate CB2 activity. To compare binding,

Cannabinol Cannabinol (CBN) is a mildly psychoactive cannabinoid that acts as a low affinity partial agonist at both CB1 and CB2 receptors. This activity at CB1 and CB2 receptors constitutes interaction of CBN with the endocannabinoid system (ECS). CBN w ...

(CBN) binds to the CB2 receptors as a partial agonist with an affinity of CB2 Ki = 126.4 nM while Delta-9-

Tetrahydrocannabinol Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC' ...

binds to the CB2 receptors as a partial agonist with an affinity of Ki = 36nM. The first

total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes i ...

of caryophyllene in 1964 by

E. J. Corey Elias James Corey (born July 12, 1928) is an American organic chemist. In 1990, he won the Nobel Prize in Chemistry "for his development of the theory and methodology of organic synthesis", specifically retrosynthetic analysis. Regarded by many a ...

was considered one of the classic demonstrations of the possibilities of synthetic organic chemistry at the time. Caryophyllene is one of the chemical compounds that contributes to the

aroma An odor (American English) or odour (Commonwealth English; see spelling differences) is caused by one or more volatilized chemical compounds that are generally found in low concentrations that humans and animals can perceive via their sense ...

black pepper Black pepper (''Piper nigrum'') is a flowering vine in the family Piperaceae, cultivated for its fruit, known as a peppercorn, which is usually dried and used as a spice and seasoning. The fruit is a drupe (stonefruit) which is about in di ...

. Caryophyllene has been given GRAS (generally regarded as safe) designation by the FDA and is approved by the FDA for use as a food additive, typically for flavoring. Caryophyllene helps to improve cold tolerance at low ambient temperatures. Wild giant pandas frequently roll in horse manure, which contains beta-caryophyllene/caryophyllene oxide, to inhibit transient receptor potential melastatin 8 (TRPM8), an archetypical cold-activated ion channel of mammals.

Metabolism and derivatives

14-Hydroxycaryophyllene oxide ( C₁₅ H₂₄ O₂) was isolated from the urine of

rabbit Rabbits, also known as bunnies or bunny rabbits, are small mammals in the family Leporidae (which also contains the hares) of the order Lagomorpha (which also contains the pikas). ''Oryctolagus cuniculus'' includes the European rabbit s ...

s treated with (−)-caryophyllene (C₁₅H₂₄). The

X-ray X-rays (or rarely, ''X-radiation'') are a form of high-energy electromagnetic radiation. In many languages, it is referred to as Röntgen radiation, after the German scientist Wilhelm Conrad Röntgen, who discovered it in 1895 and named it ' ...

crystal structure In crystallography, crystal structure is a description of the ordered arrangement of atoms, ions or molecules in a crystalline material. Ordered structures occur from the intrinsic nature of the constituent particles to form symmetric patterns t ...

of 14-hydroxycaryophyllene (as its

acetate An acetate is a salt formed by the combination of acetic acid with a base (e.g. alkaline, earthy, metallic, nonmetallic or radical base). "Acetate" also describes the conjugate base or ion (specifically, the negatively charged ion called ...

derivative) has been reported. The

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...

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

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

. :Caryophyllene (C₁₅H₂₄) → caryophyllene oxide (C₁₅H₂₄O) → 14-hydroxycaryophyllene (C₁₅H₂₄O) → 14-hydroxycaryophyllene oxide ( C₁₅ H₂₄ O₂). Caryophyllene oxide, in which the

alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...

group of caryophyllene has become an

epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...

, is the component responsible for cannabis identification by drug-sniffing dogs and is also an approved food additive, often as flavoring.

Natural sources

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

Cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: '' Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternativel ...

(''

'') .8–37.5% of cannabis flower essential oil">cannabis_flower_essential_oil.html" ;"title=".8–37.5% of cannabis flower essential oil">.8–37.5% of cannabis flower essential oil*Black caraway (''Carum nigrum'') [7.8%] *Cloves (''Syzygium aromaticum'') [1.7–19.5% of Oil of cloves, clove bud essential oil] *Hops (''Humulus lupulus'') .1–14.5%ref name="issn02357216"> *

Basil Basil (, ; ''Ocimum basilicum'' , also called great basil, is a culinary herb of the family Lamiaceae (mints). It is a tender plant, and is used in cuisines worldwide. In Western cuisine, the generic term "basil" refers to the variety also ...

('' Ocimum'' spp.) O. gratissimum''; 4.0–19.8% ''Ocimum micranthum">O. micranthum''">Ocimum gratissimum">O. gratissimum''; 4.0–19.8% ''Ocimum micranthum">O. micranthum''ref name="issn14246376"> *Oregano (''Origanum vulgare'') [4.9–15.7%] *Black pepper (''Piper nigrum'') [7.29%] *Lavandula angustifolia, Lavender (''Lavandula angustifolia'') .62–7.55% of lavender oil">lavender_oil.html" ;"title=".62–7.55% of lavender oil">.62–7.55% of lavender oil*Rosemary (''Rosmarinus officinalis'') [0.1–8.3%] *Cinnamomum zeylanicum, True cinnamon (''Cinnamomum zeylanicum'') [6.9–11.1%] *Malabathrum (''Cinnamomum tamala'') 5.3%*

Ylang-ylang ''Cananga odorata'', known as ylang-ylang ( ) or cananga tree, is a tropical tree that is native to the Philippines, Malaysia, Indonesia, New Guinea, the Solomon Islands, and Queensland, Australia. It is also native to parts of Thailand and Viet ...

(''Cananga odorata'') .1–10.7%* Copaiba oil ('' Copaifera'')

Biosynthesis

Caryophyllene is a common

among plant species. It is biosynthesized from the common

terpene Terpenes () are a class of natural products consisting of compounds with the formula (C5H8)n for n > 1. Comprising more than 30,000 compounds, these unsaturated hydrocarbons are produced predominantly by plants, particularly conifers. Terpenes ar ...

precursors

dimethylallyl pyrophosphate Dimethylallyl pyrophosphate (DMAPP; or alternatively, dimethylallyl diphosphate (DMADP); also isoprenyl pyrophosphate) is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosynt ...

(DMAPP) and

isopentenyl pyrophosphate Isopentenyl pyrophosphate (IPP, isopentenyl diphosphate, or IDP) is an isoprenoid precursor. IPP is an intermediate in the classical, HMG-CoA reductase pathway (commonly called the mevalonate pathway) and in the ''non-mevalonate'' MEP pathway of i ...

(IPP). First, single units of DMAPP and IPP are reacted via an S_N1-type reaction with the loss of

pyrophosphate In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among o ...

, catalyzed by the enzyme GPPS2, to form

geranyl pyrophosphate Geranyl pyrophosphate (GPP), also known as geranyl diphosphate (GDP), is the pyrophosphate ester of the terpenoid geraniol. Its salts are colorless. It is a precursor to many natural products. Occurrence GPP is an intermediate in the isoprenoid ...

(GPP). This further reacts with a second unit of IPP, also via an S_N1-type reaction catalyzed by the enzyme

IspA ISPA may refer to: * Indian Space Association (ISpA) * Institute of Space and Planetary Astrophysics * Instrument for Structural Policies for Pre-Accession, part of the European Union Regional policy * International Sleep Products Association * I ...

, to form

farnesyl pyrophosphate Farnesyl pyrophosphate (FPP), also known as farnesyl diphosphate (FDP), is an intermediate in the biosynthesis of terpenes and terpenoids such as sterols and carotenoids. It is also used in the synthesis of CoQ (part of the electron transport ch ...

(FPP). Finally, FPP undergoes QHS1 enzyme-catalyzed intramolecular cyclization to form caryophyllene. : Wiki Project - Caryophyllene 1

Compendial status

* Food Chemicals Codex

Notes and references

{{Authority control Flavors Cannabinoids Sesquiterpenes Alkene derivatives Hydrocarbons CB2 receptor agonists Cyclobutanes