Caryophyllene: in the shadow of CBD


Cannabidiol (CBD) is a phytocannabinoid extracted from hemp (Cannabis sativa), that gains more attention from the nutraceutical (and the regulatory) world every day. Available scientific data allow to consider the use of this molecule in a large variety of health areas, but its precise pharmacological activity is not totally understood.
In fact, even if CBD can be considered as a phytocannabinoid due to its affinity for CB1 & CB2 receptors (endocanabinoid receptors involved in numerous physiological mecanisms), this affinity is low and its main impact on "cannabinoid cascades" seems to be indirect. Indeed, CBD negatively modulates FAAH activity leading to the stimulation o anandamide (an endocannabinoid). CBD also inhibits GPR55 receptor (another endocannabinoid pathway) and is an agonist of PPARγ, 5-HT1A and TRPV1 [1-5].
In other words, CBD is a polypharmacological active which made it of great interest for both nutraceutical and pharmaceutical industries. Moreover, CBD booming market and regulatory incertainty has also led the cosmetic industry to wonder if it could be a dermocosmetic ingredient, making it one of the biggest trend in the botanicals, a trend that forecasts a large shadow on a more discrete phytocannabinoid: β-caryophyllene.


β-caryophyllene is also a phytocannabinoid (cannabinoid receptor agonist) present in numerous plants and spices [6-7]. It is widely recognized as a food additive and is also used in cosmetics for its perfume fixative properties. Finally, it is present in multiple essential oils like Copaiba (Copaifera officinalis), Ylang-ylang (Cananga odorata) or Black pepper (Piper nigrum), used in aromatherapy.
Unlike CBD, β-caryophyllene is a specific agonist of CB2 receptors. The absence of activity through CB1 receptors could be considered as a weakness but it is, in fact, a great advantage in some contexts. Indeed, more specificity leads to less risks of side effects. In other words, as long as the purpose of the product is linked to CB2 and not CB1, β-caryophyllene might be a good alternative to CBD. Moreover, β-caryophyllene is safe at an exposure of 2.2 mg/kg/day (to the best of our knowledge, the most restrictive NOAEL is 220 mg/kg/day [8 -12]. Attention should, however, be paid to potential drug interaction [13-14]


β-caryophyllene is a recognized anti-inflammatory agent [6-7], limiting leukocyte endothelial adhesion [15] and Neutrophile migration [16] among other things. It has shown great potential in pain management [17-20] and seems to have positive impact on diverse arthritis models [21-24].
Based on these experimental data, the integration of β-caryophyllene in pain relief topical treatment could be a lead to consider. β-caryophyllene could be combined with other anti-inflammatory botanicals like Salvia miltiorrhiza roots (see the article on topical anti-inflammatory activity of red sage here) to develop a unique natural blend for topical inflammation management.


When CB1 and CB2 are set appart, the last one is usually considered to be more relevant on immune system and PNS, when CB1 is mainly associated with CNS. However, experimental data show that β-caryophyllene is widely active on the neurological area including CNS.
Since this molecule is particularly active on inflammation, neuroprotection is [25-26], unsurprisingly, a field where it showed great potential. Indeed, β-caryophyllene has been tested in numerous models linked to ischaemia [27-33] and seizures [34-36] with significant results. Moreover, it has also been tested in multiple experimental models related to diverse neuropathologies like multiple sclerosis [37-38], Alzheimer's disease [39-40] and Parkinson's disease [41-43].
Surprisingly, β-caryophyllene seems to also have a positive impact in depression and anxiety model [44-46], as well as in addiction behaviour [47-48], opening new health opportunities for the molecule and for the natural extracts that contain it in large quantity like Copaifera officinalis essential oil or specific Piper nigrum extract enriched in β-caryophyllene

CBD has tremendous therapeutical potential. However, its booming market does not mean that it's the best answer to every condition vaguely related to cannabinoids pathways. β-caryophyllene is a well known and safe, food additive and cosmetic ingredient. It is also a CB2 receptor specific agonist with fascinating health potential in a myriad of conditions related to inflammation, but also with positive effect on other aspects like glycemia or lipid metabolism (see next article on β-caryophyllene virtues).

[1] Gaston TE, Szaflarski JP (2018) – “Cannabis for the Treatment of Epilepsy: an Update.” Curr Neurol Neurosci Rep. 2018 Sep 8;18(11):73. doi: 10.1007/s11910-018-0882-y.
[2] Mandolini GM, Lazzaretti M, Pigoni A, Oldani L, Delvecchio G, Brambilla P (2018) – “Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical overview.” Epidemiol Psychiatr Sci. 2018 Aug;27(4):327-335. doi: 10.1017/S2045796018000239. Epub 2018 May 23.
[3] Fogaça MV, Campos AC, Coelho LD, Duman RS, Guimarães FS (2018) – “The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling.” Neuropharmacology. 2018 Jun;135:22-33. doi: 10.1016/j.neuropharm.2018.03.001. Epub 2018 Mar 3.
[4] Gaston TE, Friedman D (2017) – “Pharmacology of cannabinoids in the treatment of epilepsy.” Epilepsy Behav. 2017 May;70(Pt B):313-318. doi: 10.1016/j.yebeh.2016.11.016. Epub 2017 Jan 10.
[5] Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS (2012) – “Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders.” Philos Trans R Soc Lond B Biol Sci. 2012 Dec 5;367(1607):3364-78. doi: 10.1098/rstb.2011.0389.
[6] Sharma C, Al Kaabi JM, Nurulain SM, Goyal SN, Kamal MA, Ojha S. (2016) “Polypharmacological Properties and Therapeutic Potential of β-Caryophyllene: A Dietary Phytocannabinoid of Pharmaceutical Promise.” Curr Pharm Des. 2016;22(21):3237-64.
[7] Jürg Gertsch, Marco Leonti, Stefan Raduner, Ildiko Racz, Jian-Zhong Chen, Xiang-Qun Xie, Karl-Heinz Altmann, Meliha Karsak and Andreas Zimmer (2008) « Beta-caryophyllene is a dietary cannabinoid » Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9099-104. doi: 10.1073/pnas.0803601105. Epub 2008 Jun 23.
[8] Schmitt D, Levy R, Carroll B. (2016) “Toxicological Evaluation of β-Caryophyllene Oil: Subchronic Toxicity in Rats.” Int J Toxicol. 2016 Sep;35(5):558-67. doi: 10.1177/1091581816655303. Epub 2016 Jun 29.
[9] Oliveira GLDS, Machado KC, Machado KC, da Silva APDSCL, Feitosa CM, de Castro Almeida FR. (2018) “Non-clinical toxicity of β-caryophyllene, a dietary cannabinoid: Absence of adverse effects in female Swiss mice.” Regul Toxicol Pharmacol. 2018 Feb;92:338-346. doi: 10.1016/j.yrtph.2017.12.013. Epub 2017 Dec 16.
[10]Bastaki M, Api AM, Aubanel M, Bauter M, Cachet T, Demyttenaere JCR, Diop MM, Harman CL, Hayashi SM, Krammer G, Lu V, Marone PA, Mendes O, Renskers KJ, Schnabel J, Tsang SY, Taylor SV (2020) – “Dietary administration of β-caryophyllene and its epoxide to Sprague-Dawley rats for 90 days.” Food Chem Toxicol. 2020 Jan;135:110876. doi: 10.1016/j.fct.2019.110876. Epub 2019 Oct 11.
[11] Di Giacomo S, Mazzanti G, Di Sotto A. (2016) “Mutagenicity of cigarette butt waste in the bacterial reverse mutation assay: The protective effects of β-caryophyllene and β-caryophyllene oxide.” Environ Toxicol. 2016 Nov;31(11):1319-1328. doi: 10.1002/tox.22136. Epub 2015 Mar 2.
[12] Alvarez-González I1, Madrigal-Bujaidar E, Castro-García S. (2014) “Antigenotoxic capacity of beta-caryophyllene in mouse, and evaluation of its antioxidant and GST induction activities.” J Toxicol Sci. 2014;39(6):849-59.
[13] Nguyen LT, Myslivečková Z, Szotáková B, Špičáková A, Lněničková K, Ambrož M, Kubíček V, Krasulová K, Anzenbacher P, Skálová L. (2017) « The inhibitory effects of β-caryophyllene, β-caryophyllene oxide and α-humulene on the activities of the main drug-metabolizing enzymes in rat and human liver in vitro » Chem Biol Interact. 2017 Dec 25;278:123-128. doi: 10.1016/j.cbi.2017.10.021. Epub 2017 Oct 23.
[14] Katsuyama S, Mizoguchi H, Kuwahata H, Komatsu T, Nagaoka K, Nakamura H, Bagetta G, Sakurada T, Sakurada S (2013) – “Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception.” Eur J Pain. 2013 May;17(5):664-75. doi: 10.1002/j.1532-2149.2012.00242.x. Epub 2012 Nov 9.
[15] Zhang Z, Yang C, Dai X, Ao Y, Li Y. (2017) « Inhibitory effect of trans-caryophyllene (TC) on leukocyte-endothelial attachment.” Toxicol Appl Pharmacol. 2017 Aug 15;329:326-333. doi: 10.1016/j.taap.2017.06.016. Epub 2017 Jun 15.
[16] Andrade-Silva M, Correa LB, Candéa AL, Cavalher-Machado SC, Barbosa HS, Rosas EC, Henriques MG. (2016) « The cannabinoid 2 receptor agonist β-caryophyllene modulates the inflammatory reaction induced by Mycobacterium bovis BCG by inhibiting neutrophil migration.” Inflamm Res. 2016 Nov;65(11):869-879. Epub 2016 Jul 5.
[17] Paula-Freire LI, Andersen ML, Gama VS, Molska GR, Carlini EL. (2014) “The oral administration of trans-caryophyllene attenuates acute and chronic pain in mice.” Phytomedicine. 2014 Feb 15;21(3):356-62. doi: 10.1016/j.phymed.2013.08.006. Epub 2013 Sep 20.
[18] Klauke AL, Racz I, Pradier B, Markert A, Zimmer AM, Gertsch J, Zimmer A. (2014) “The cannabinoid CB₂ receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain.” Eur Neuropsychopharmacol. 2014 Apr;24(4):608-20. doi: 10.1016/j.euroneuro.2013.10.008. Epub 2013 Oct 22.
[19] Quintans-Júnior LJ, Araújo AA, Brito RG, Santos PL, Quintans JS, Menezes PP, Serafini MR, Silva GF, Carvalho FM, Brogden NK, Sluka KA. (2016) “β-caryophyllene, a dietary cannabinoid, complexed with β-cyclodextrin produced anti-hyperalgesic effect involving the inhibition of Fos expression in superficial dorsal horn.” Life Sci. 2016 Mar 15;149:34-41. doi: 10.1016/j.lfs.2016.02.049. Epub 2016 Feb 13.
[20] Segat GC, Manjavachi MN, Matias DO, Passos GF, Freitas CS, Costa R, Calixto JB. (2017) “Antiallodynic effect of β-caryophyllene on paclitaxel-induced peripheral neuropathy in mice.” Neuropharmacology. 2017 Oct;125:207-219. doi: 10.1016/j.neuropharm.2017.07.015. Epub 2017 Jul 18.
[21] Ames-Sibin AP, Barizão CL, Castro-Ghizoni CV, Silva FMS, Sá-Nakanishi AB, Bracht L, Bersani-Amado CA, Marçal-Natali MR, Bracht A, Comar JF (2018) – “β-Caryophyllene, the major constituent of copaiba oil, reduces systemic inflammation and oxidative stress in arthritic rats.” J Cell Biochem. 2018 Dec;119(12):10262-10277. doi: 10.1002/jcb.27369. Epub 2018 Aug 21.
[22] Irrera N, D'Ascola A, Pallio G, Bitto A, Mazzon E, Mannino F, Squadrito V, Arcoraci V, Minutoli L, Campo GM, Avenoso A, Bongiorno EB, Vaccaro M, Squadrito F, Altavilla D (2019) – “β-Caryophyllene Mitigates Collagen Antibody Induced Arthritis (CAIA) in Mice Through a Cross-Talk between CB2 and PPAR-γ Receptors.” Biomolecules. 2019 Jul 31;9(8). pii: E326. doi: 10.3390/biom9080326.
[23] Ames-Sibin AP, Barizão CL, Castro-Ghizoni CV, Silva FMS, Sá-Nakanishi AB, Bracht L, Bersani-Amado CA, Marçal-Natali MR, Bracht A, Comar JF. (2018) – “β-Caryophyllene, the major constituent of copaiba oil, reduces systemic inflammation and oxidative stress in arthritic rats.” J Cell Biochem. 2018 Dec;119(12):10262-10277. doi: 10.1002/jcb.27369. Epub 2018 Aug 21.
[24] El-Sheikh SMA, Abd El-Alim AEF, Galal AAA, El-Sayed RG, El-Naseery NI. (2019) – “Anti-arthritic effect of β-caryophyllene and its ameliorative role on methotrexate and/or leflunomide-induced side effects in arthritic rats.” Life Sci. 2019 Sep 15;233:116750. doi: 10.1016/j.lfs.2019.116750. Epub 2019 Aug 10.
[25] Machado KDC, Islam MT, Ali ES, Rouf R, Uddin SJ, Dev S, Shilpi JA, Shill MC, Reza HM, Das AK, Shaw S, Mubarak MS, Mishra SK, Melo-Cavalcante AAC (2018) – “A systematic review on the neuroprotective perspectives of beta-caryophyllene.” Phytother Res. 2018 Dec;32(12):2376-2388. doi: 10.1002/ptr.6199. Epub 2018 Oct 3.
[26] Askari VR, Shafiee-Nick R (2019) – “The protective effects of β-caryophyllene on LPS-induced primary microglia M1/M2 imbalance: A mechanistic evaluation.” Life Sci. 2019 Feb 15;219:40-73. doi: 10.1016/j.lfs.2018.12.059. Epub 2019 Jan 5.
[27] Chang HJ, Kim JM, Lee JC, Kim WK, Chun HS. (2013) “Protective effect of β-caryophyllene, a natural bicyclic sesquiterpene, against cerebral ischemic injury.” J Med Food. 2013 Jun;16(6):471-80. doi: 10.1089/jmf.2012.2283. Epub 2013 Jun 4.
[28] Guo K, Mou X, Huang J, Xiong N, Li H. (2014) “Trans-caryophyllene suppresses hypoxia-induced neuroinflammatory responses by inhibiting NF-κB activation in microglia.” J Mol Neurosci. 2014 Sep;54(1):41-8. doi: 10.1007/s12031-014-0243-5. Epub 2014 Feb 4.
[29] Lou J, Cao G, Li R, Liu J, Dong Z, Xu L. (2016) “β-Caryophyllene Attenuates Focal Cerebral Ischemia-Reperfusion Injury by Nrf2/HO-1 Pathway in Rats.” Neurochem Res. 2016 Jun;41(6):1291-304. doi: 10.1007/s11064-016-1826-z. Epub 2016 Jan 22.
[30] Tian X, Peng J, Zhong J, Yang M, Pang J, Lou J, Li M, An R, Zhang Q, Xu L, Dong Z. (2016) “β-Caryophyllene protects in vitro neurovascular unit against oxygen-glucose deprivation and re-oxygenation-induced injury.” J Neurochem. 2016 Dec;139(5):757-768. doi: 10.1111/jnc.13833. Epub 2016 Sep 19.
[31] Zhang Q, An R, Tian X, Yang M, Li M, Lou J, Xu L, Dong Z. (2017) « β-Caryophyllene Pretreatment Alleviates Focal Cerebral Ischemia-Reperfusion Injury by Activating PI3K/Akt Signaling Pathway.” Neurochem Res. 2017 May;42(5):1459-1469. doi: 10.1007/s11064-017-2202-3. Epub 2017 Feb 24.
[32] Yang M, Lv Y, Tian X, Lou J, An R, Zhang Q, Li M, Xu L, Dong Z. (2017) » Neuroprotective Effect of β-Caryophyllene on Cerebral Ischemia-Reperfusion Injury via Regulation of Necroptotic Neuronal Death and Inflammation: In Vivo and in Vitro.” Front Neurosci. 2017 Oct 26;11:583. doi: 10.3389/fnins.2017.00583. eCollection 2017.
[33] Assis LC, Straliotto MR, Engel D, Hort MA, Dutra RC, de Bem AF. (2014) “β-Caryophyllene protects the C6 glioma cells against glutamate-induced excitotoxicity through the Nrf2 pathway.” Neuroscience. 2014 Oct 24;279:220-31. doi: 10.1016/j.neuroscience.2014.08.043. Epub 2014 Sep 4.
[34] Liu H, Song Z, Liao D, Zhang T, Liu F, Zhuang K, Luo K, Yang L. (2015) “Neuroprotective effects of trans-caryophyllene against kainic acid induced seizure activity and oxidative stress in mice.” Neurochem Res. 2015 Jan;40(1):118-23. doi: 10.1007/s11064-014-1474-0. Epub 2014 Nov 23.
[35] de Oliveira CC, de Oliveira CV, Grigoletto J, Ribeiro LR, Funck VR, Grauncke AC, de Souza TL, Souto NS, Furian AF, Menezes IR, Oliveira MS. (2016) - “Anticonvulsant activity of β-caryophyllene against pentylenetetrazol-induced seizures.” Epilepsy Behav. 2016 Mar;56:26-31. doi: 10.1016/j.yebeh.2015.12.040. Epub 2016 Jan 29.
[36] Tchekalarova J, da Conceição Machado K, Gomes Júnior AL, de Carvalho Melo Cavalcante AA, Momchilova A, Tzoneva R. (2018) “Pharmacological characterization of the cannabinoid receptor 2 agonist, β-caryophyllene on seizure models in mice.” Seizure. 2018 Apr;57:22-26. doi: 10.1016/j.seizure.2018.03.009. Epub 2018 Mar 12.
[37] Fontes LBA, Dias DDS, Aarestrup BJV, Aarestrup FM, Da Silva Filho AA, Corrêa JODA. (2017) “β-Caryophyllene ameliorates the development of experimental autoimmune encephalomyelitis in C57BL/6 mice.” Biomed Pharmacother. 2017 Jul;91:257-264. doi: 10.1016/j.biopha.2017.04.092. Epub 2017 May 2.
[38] Alberti TB, Barbosa WL, Vieira JL, Raposo NR, Dutra RC. (2017) « (-)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis.” Int J Mol Sci. 2017 Apr 1;18(4). pii: E691. doi: 10.3390/ijms18040691.
[39] Hu Y, Zeng Z, Wang B, Guo S. (2017) « Trans-caryophyllene inhibits amyloid β (Aβ) oligomer-induced neuroinflammation in BV-2 microglial cells.” Int Immunopharmacol. 2017 Oct;51:91-98. doi: 10.1016/j.intimp.2017.07.009.
[40] Cheng Y, Dong Z, Liu S. (2014) « β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway.” Pharmacology. 2014;94(1-2):1-12. doi: 10.1159/000362689. Epub 2014 Aug 26.
[41] Ojha S, Javed H, Azimullah S, Haque ME. (2016) “β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease.” Mol Cell Biochem. 2016 Jul;418(1-2):59-70. doi: 10.1007/s11010-016-2733-y. Epub 2016 Jun 17.
[42] Javed H, Azimullah S, Haque ME, Ojha SK. (2016) « Cannabinoid Type 2 (CB2) Receptors Activation Protects against Oxidative Stress and Neuroinflammation Associated Dopaminergic Neurodegeneration in Rotenone Model of Parkinson’s Disease.” Front Neurosci. 2016 Aug 2;10:321. doi: 10.3389/fnins.2016.00321. eCollection 2016.
[43] Viveros-Paredes JM, González-Castañeda RE, Gertsch J, Chaparro-Huerta V, López-Roa RI, Vázquez-Valls E, Beas-Zarate C, Camins-Espuny A, Flores-Soto ME. (2017) “ Neuroprotective Effects of β-Caryophyllene against Dopaminergic Neuron Injury in a Murine Model of Parkinson’s Disease Induced by MPTP.” Pharmaceuticals (Basel). 2017 Jul 6;10(3). pii: E60. doi: 10.3390/ph10030060.
[44] Galdino PM, Nascimento MV, Florentino IF, Lino RC, Fajemiroye JO, Chaibub BA, de Paula JR, de Lima TC, Costa EA. (2012) ”The anxiolytic-like effect of an essential oil derived from Spiranthera odoratissima A. St. Hil. leaves and its major component, β-caryophyllene, in male mice.” Prog Neuropsychopharmacol Biol Psychiatry. 2012 Aug 7;38(2):276-84. doi: 10.1016/j.pnpbp.2012.04.012. Epub 2012 Apr 21.
[45] Bahi A, Al Mansouri S, Al Memari E, Al Ameri M, Nurulain SM, Ojha S. (2014) “β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice.” Physiol Behav. 2014 Aug;135:119-24. doi: 10.1016/j.physbeh.2014.06.003. Epub 2014 Jun 13.
[46] Oliveira DR, Silva DM, Florentino IF, de Brito A, Fajemiroye JO, Silva DPB, da Rocha F, Costa EA, De Carvalho PG. (2018) “ Monoamine Involvement in the Antidepressant-Like Effect of β-Caryophyllene.” CNS Neurol Disord Drug Targets. 2018 Apr 20. doi:10.2174/1871527317666180420150249.
[47] Al Mansouri S, Ojha S, Al Maamari E, Al Ameri M, Nurulain SM, Bahi A. (2014) “The cannabinoid receptor 2 agonist, β-caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice.” Pharmacol Biochem Behav. 2014 Sep;124:260-8. doi: 10.1016/j.pbb.2014.06.025. Epub 2014 Jul 3.
[48] He Y, Galaj E, Bi GH, Wang XF, Gardner E, Xi ZX (2019) - "Beta-caryophyllene, a dietary terpenoid, inhibits nicotine-taking and nicotine-seeking in rodents" Br J Pharmacol. 2019 Dec 27. doi: 10.1111/bph.14969.