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 combinations. Biochemical modifications s ...

that occurs widely in nature. 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 is commercially available as a liquefied gas. Derivatives of cyclobutane are called cyclobutanes. Cyclobutane itself is of no commerc ...

ring, as well as a ''trans''-double bond in a 9-membered ring, both rarities in nature.

Production

Caryophyllene can be produced synthetically, but it is invariably obtained from natural sources because it is widespread. It is a constituent of many

essential oil An essential oil is a concentrated hydrophobic liquid containing volatile (easily evaporated at normal temperatures) chemical compounds from plants. Essential oils are also known as volatile oils, ethereal oils, aetheroleum, or simply as the ...

s, 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 plant, herbaceous flowering plant. The species was first classified by Carl Linnaeus in 1753. The specific epithet ''Sativum, sativa'' means 'cultivated'. Indigenous to East Asia, Eastern Asia, the pla ...

'',

copaiba Copaiba is an oleoresin obtained from the trunk of several pinnate-leaved South American leguminous trees (genus ''Copaifera''). The thick, transparent exudate varies in color from light gold to dark brown, depending on the ratio of resin to esse ...

rosemary ''Salvia rosmarinus'' (), commonly known as rosemary, is a shrub with fragrant, evergreen, needle-like leaves and white, pink, purple, or blue flowers. It is a member of the sage family, Lamiaceae. The species is native to the Mediterranean r ...

, 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 whic ...

. 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 An odor (American English) or odour (Commonwealth English; see spelling differences) is a smell or a scent caused by one or more volatilized chemical compounds generally found in low concentrations that humans and many animals can perceive v ...

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

Basic research

β-Caryophyllene is under

basic research Basic research, also called pure research, fundamental research, basic science, or pure science, is a type of scientific research with the aim of improving scientific theories for better understanding and prediction of natural or other phenome ...

for its potential action as an agonist of the

cannabinoid receptor type 2 The cannabinoid receptor 2 (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 1 (CB1), which is largely responsible for ...

(CB₂ receptor). In other basic studies, β-caryophyllene has a binding affinity of K_i = 155 nM at the CB₂ receptors. β-Caryophyllene has the highest cannabinoid activity compared to the ring opened isomer α-caryophyllene

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 b ...

which may modulate CB₂ activity. To compare binding, cannabinol binds to the CB₂ receptors as a partial agonist with an affinity of K_i = 126.4 nM, while delta-9-

tetrahydrocannabinol Tetrahydrocannabinol (THC) is a cannabinoid found in cannabis. It 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) de ...

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

Safety

Caryophyllene has been given

generally recognized as safe Generally recognized as safe (GRAS) is a United States Food and Drug Administration (FDA) designation that a chemical or substance added to food is considered safe by experts under the conditions of its intended use. An ingredient with a GRAS d ...

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

Metabolism and derivatives

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

rabbit Rabbits are small mammals in the family Leporidae (which also includes the hares), which is in the order Lagomorpha (which also includes pikas). They are familiar throughout the world as a small herbivore, a prey animal, a domesticated ...

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

X-ray An X-ray (also known in many languages as Röntgen radiation) is a form of high-energy electromagnetic radiation with a wavelength shorter than those of ultraviolet rays and longer than those of gamma rays. Roughly, X-rays have a wavelength ran ...

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

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 ''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 cellular processes; the co ...

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, c ...

. :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, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or at the terminal position. Terminal alkenes are also known as Alpha-olefin, α-olefins. The Internationa ...

group of caryophyllene has become an

epoxide In organic chemistry, an epoxide is a cyclic ether, where the ether forms a three-atom ring: two atoms of carbon and one atom of oxygen. This triangular structure has substantial ring strain, making epoxides highly reactive, more so than other ...

, is the component responsible for cannabis identification by drug-sniffing dogs and is also an approved food additive, often as flavoring. Caryophyllene oxide may have negligible cannabinoid activity.

Natural sources

The approximate quantity of caryophyllene in the

of each source is given in square brackets ('' '): *

Cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae that is widely accepted as being indigenous to and originating from the continent of Asia. However, the number of species is disputed, with as many as three species be ...

(''

'') .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'') [5.1–14.5%] *

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

(''

Ocimum ''Ocimum'' is a genus of aromatic annual and perennial herbs and shrubs in the family Lamiaceae, native to the tropical and warm temperate regions of all 6 inhabited continents, with the greatest number of species in Africa. Its best known spe ...

'' 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 verum'') [6.9–11.1%] *Malabathrum (''Cinnamomum tamala'') [25.3%] * Cananga odorata, Ylang-ylang (''Cananga odorata'') .1–10.7%*

Copaiba Copaiba is an oleoresin obtained from the trunk of several pinnate-leaved South American leguminous trees (genus ''Copaifera''). The thick, transparent exudate varies in color from light gold to dark brown, depending on the ratio of resin to esse ...

oil (''

Copaifera ''Copaifera'' is a genus of tropical plants in the legume family Fabaceae. It includes 40 species native to the tropical Americas (Nicaragua to northeastern Argentina), west and central tropical Africa, and Borneo.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 combinations. Biochemical modifications s ...

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 ≥ 2. Terpenes are major biosynthetic building blocks. Comprising more than 30,000 compounds, these unsaturated hydrocarbons are produced predomi ...

precursors dimethylallyl pyrophosphate (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 linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate () and tetrasodium pyrophosphate (), among others. Often pyrophosphates a ...

, catalyzed by the enzyme GPPS2, to form geranyl pyrophosphate (GPP). This further reacts with a second unit of IPP, also via an S_N1-type reaction catalyzed by the enzyme IspA, to form

farnesyl pyrophosphate Farnesyl pyrophosphate (FPP), also known as farnesyl diphosphate (FDP), is the precursor to all sesquiterpenes, which comprises thousands of compounds. These include all sesquiterpenes as well as sterols and carotenoids. It is also used in the syn ...

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

Compendial status

Food Chemicals Codex The Food Chemicals Codex (FCC) is a collection of internationally recognized standards for the purity and identity of food ingredients. Scope The FCC features more than 1,250 monographs, including food-grade chemicals, processing aids, foods (suc ...

Notes and references

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