Limonene is a terpene commonly found in the peels of citrus fruits like lemons, limes, and oranges, as well as in cannabis flowers, spruce trees, and other plants. It is commonly used in foods, beverages, fragrances, cleaners, and cosmetics due to its pungent sweet citrusy aroma. It has been identified in peer-reviewed research as inducing anti-stress[1], anti-anxiety,[2] anti-depressant,[3] and anti-inflammatory (in the airways)[4]^,[5] effects in mouse models. It has also been identified as having antioxidant[6] and anti-cancer[7] properties in human trials and has been identified as a potential muscle relaxant[8] and relaxation aid[9]. When combined, these properties may implicate limonene as being helpful in the treatment of those suffering from related symptoms due to Qualifying Conditions.

[1] Komiya, M., Takeuchi, T. & Harada, E. “Lemon oil vapor causes an anti-stress effect via modulating the 5-HT and DA activities in mice.” Behavioural Brain Research 172, 240–249, DOI:10.1016/j.bbr.2006.05.006 (2006)

[2] Song Y, Seo S, Lamichhane S, Seo J, Hong JT, Cha HJ, Yun J. Limonene has anti-anxiety activity via adenosine A2A receptor-mediated regulation of dopaminergic and GABAergic neuronal function in the striatum. Phytomedicine. 2021 Mar;83:153474. doi: 10.1016/j.phymed.2021.153474. Epub 2021 Jan 21. PMID: 33548867.

[3] Lorigooini Z, Boroujeni SN, Sayyadi-Shahraki M, Rahimi-Madiseh M, Bijad E, Amini-Khoei H. Limonene through Attenuation of Neuroinflammation and Nitrite Level Exerts Antidepressant-Like Effect on Mouse Model of Maternal Separation Stress. Behav Neurol. 2021 Jan 29;2021:8817309. doi: 10.1155/2021/8817309. PMID: 33564342; PMCID: PMC7864762.

[4] Ryoji Hirota, Hiroyuki Nakamura, Sabah Asif Bhatti, Nlandu Roger Ngatu, Basilua Andre Muzembo, Narongpon Dumavibhat, Masamitsu Eitoku, Masayoshi Sawamura & Narufumi Suganuma (2012)“Limonene inhalation reduces allergic airway inflammation in Dermatophagoides farinaetreated mice.”Inhalation Toxicology 24:6, 373-381, DOI:10.3109/08958378.2012.675528 (2012)

[5] Patel, M., Narke, D., Kurade, M. et al. Limonene-induced activation of A2A adenosine receptors reduces airway inflammation and reactivity in a mouse model of asthma. Purinergic Signalling 16, 415–426 (2020). https://doi.org/10.1007/s11302-020-09697-z

[6] Crowell, P. L. & Gould, M. N. “Chemoprevention and Therapy of Cancer by d-Limonene.” Critical Reviews™ in Oncogenesis 5,1–22, DOI:10.1615/CritRevOncog.v5.i1.10 (1994).

[7] Chebet JJ, Ehiri JE, McClelland DJ, Taren D, Hakim IA. Effect of d-limonene and its derivatives on breast cancer in human trials: a scoping review and narrative synthesis. BMC Cancer. 2021 Aug 6;21(1):902. doi: 10.1186/s12885-021-08639-1. PMID: 34362338; PMCID: PMC8349000.

[8] do Vale TG, Furtado EC, Santos JG Jr, Viana GS. Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) n.e. Brown. Phytomedicine. 2002 Dec;9(8):709-14. doi: 10.1078/094471102321621304. PMID: 12587690.

[9] Joung, D., et al. “Physiological and Psychological Effects of Olfactory Stimulation with D-Limonene.” Advances in Horticultural Science, vol. 28, no. 2, 2014, pp. 90–94. JSTOR, http://www.jstor.org/stable/24586803. Accessed 1 Nov. 2022. 

Caryophyllene (also known as β-Caryophyllene or BCP) is a terpene found in several common herbs and spices like cloves, black pepper, cinnamon, basil, and oregano. In cannabis, caryophyllene often contributes to a peppery, earthy flavor profile. Animal models have demonstrated a possible interaction of caryophyllene with the endocannabinoid system[1] as well as pain relief via CB2 activation[2]. Other animal studies have identified this terpene as a potential treatment for several conditions, including anxiety[3], depression[4], inflammation[5], and overall pain relief[6]. In addition, in vitro studies have evaluated the antioxidant[7] and sedative[8] effects of this terpene. Finally—and perhaps most noteworthy—both in vitro[9] and animal[10] studies have implicated caryophyllene as a potential treatment for cancer, with human trials demonstrating its potential to treat nausea[11].

[1] Poddighe L, Carta G, Serra MP, Melis T, Boi M, Lisai S, Murru E, Muredda L, Collu M, Banni S, Quartu M. Acute administration of beta-caryophyllene prevents endocannabinoid system activation during transient common carotid artery occlusion and reperfusion. Lipids Health Dis. 2018 Feb 5;17(1):23. doi: 10.1186/s12944-018-0661-4. PMID: 29402275; PMCID: PMC5799897.

[2] Klauke AL, Racz I, Pradier B, Markert A, Zimmer AM, Gertsch J, Zimmer A. 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. PMID: 24210682.

[3] Bahi A, Al Mansouri S, Al Memari E, Al Ameri M, Nurulain SM, Ojha S. 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. PMID: 24930711.

[4] Hwang ES, Kim HB, Lee S, Kim MJ, Kim KJ, Han G, Han SY, Lee EA, Yoon JH, Kim DO, Maeng S, Park JH. Antidepressant-like effects of β-caryophyllene on restraint plus stress-induced depression. Behav Brain Res. 2020 Feb 17;380:112439. doi: 10.1016/j.bbr.2019.112439. Epub 2019 Dec 17. PMID: 31862467.

[5] Gushiken LFS, Beserra FP, Hussni MF, Gonzaga MT, Ribeiro VP, de Souza PF, Campos JCL, Massaro TNC, Hussni CA, Takahira RK, Marcato PD, Bastos JK, Pellizzon CH. Beta-caryophyllene as an antioxidant, anti-inflammatory and re-epithelialization activities in a rat skin wound excision model. Oxid Med Cell Longev. 2022 Feb 3;2022:9004014. doi: 10.1155/2022/9004014. PMID: 35154574; PMCID: PMC8831077.

[6] Paula-Freire LI, Andersen ML, Gama VS, Molska GR, Carlini EL. 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. PMID: 24055516.

[7] Jayaprakasha GK, Jagan Mohan Rao L, Sakariah KK. Volatile constituents from Cinnamomum zeylanicum fruit stalks and their antioxidant activities. J Agric Food Chem. 2003 Jul 16;51(15):4344-8. doi: 10.1021/jf034169i. PMID: 12848508.

[8] Rabbani M, Sajjadi SE, Vaezi A. Evaluation of anxiolytic and sedative effect of essential oil and hydroalcoholic extract of Ocimum basilicum L. and chemical composition of its essential oil. Res Pharm Sci. 2015 Nov-Dec;10(6):535-43. PMID: 26779273; PMCID: PMC4698864.

[9] Mannino F, Pallio G, Corsaro R, Minutoli L, Altavilla D, Vermiglio G, Allegra A, Eid AH, Bitto A, Squadrito F, Irrera N. Beta-Caryophyllene Exhibits Anti-Proliferative Effects through Apoptosis Induction and Cell Cycle Modulation in Multiple Myeloma Cells. Cancers (Basel). 2021 Nov 16;13(22):5741. doi: 10.3390/cancers13225741. PMID: 34830893; PMCID: PMC8616110.

[10] Dahham SS, Tabana Y, Asif M, Ahmed M, Babu D, Hassan LE, Ahamed MBK, Sandai D, Barakat K, Siraki A, Majid AMSA. β-Caryophyllene Induces Apoptosis and Inhibits Angiogenesis in Colorectal Cancer Models. Int J Mol Sci. 2021 Sep 29;22(19):10550. doi: 10.3390/ijms221910550. PMID: 34638895; PMCID: PMC8508804.

[11] Shim, Hyun & Song, Dong & Shin, Cheol & Yoon, Hyuk & Park, Young & Kim, Nayoung & Lee, Dong. (2019). Inhibitory Effects of β-caryophyllene on Helicobacter pylori Infection: A Randomized Double-blind, Placebo-controlled Study. The Korean Journal of Gastroenterology. 74. 199. 10.4166/kjg.2019.74.4.199.

Linalool is a naturally occurring terpene found most commonly in lavender and basil. Due to its sweet, floral aroma, it is often used as an additive in several household products like soap and perfume. Several animal studies have implicated this terpene in the potential treatment of various conditions, including depression[1], anxiety[2], stress[3], inflammation[4]^,[5], and pain[6]. In addition, animal models have demonstrated that linalool may possess anti-convulsant[7], anti-asthma[8], and sedative[9] properties. Human trials have even linked the usage of linalool-rich essential oils to menstrual pain relief[10]. Further research is warranted to fully investigate the health benefits of this terpene.

[1] Guzmán-Gutiérrez SL, Bonilla-Jaime H, Gómez-Cansino R, Reyes-Chilpa R. Linalool and β-pinene exert their antidepressant-like activity through the monoaminergic pathway. Life Sci. 2015 May 1;128:24-9. doi: 10.1016/j.lfs.2015.02.021. Epub 2015 Mar 11. PMID: 25771248.

[2] Linck VM, da Silva AL, Figueiró M, Caramão EB, Moreno PR, Elisabetsky E. Effects of inhaled Linalool in anxiety, social interaction and aggressive behavior in mice. Phytomedicine. 2010 Jul;17(8-9):679-83. doi: 10.1016/j.phymed.2009.10.002. Epub 2009 Dec 3. PMID: 19962290.

[3] Nakamura A, Fujiwara S, Matsumoto I, Abe K. Stress repression in restrained rats by (R)-(-)-linalool inhalation and gene expression profiling of their whole blood cells. Journal of Agricultural and Food Chemistry. 2009 Jun;57(12):5480-5485. DOI: 10.1021/jf900420g. PMID: 19456160.

[4] Huo M, Cui X, Xue J, Chi G, Gao R, Deng X, Guan S, Wei J, Soromou LW, Feng H, Wang D. Anti-inflammatory effects of linalool in RAW 264.7 macrophages and lipopolysaccharide-induced lung injury model. J Surg Res. 2013 Mar;180(1):e47-54. doi: 10.1016/j.jss.2012.10.050. Epub 2012 Dec 4. PMID: 23228323.

[5] Ma J, Xu H, Wu J, Qu C, Sun F, Xu S. Linalool inhibits cigarette smoke-induced lung inflammation by inhibiting NF-κB activation. Int Immunopharmacol. 2015 Dec;29(2):708-713. doi: 10.1016/j.intimp.2015.09.005. Epub 2015 Oct 1. PMID: 26432179.

[6] Peana AT, D’Aquila PS, Chessa ML, Moretti MD, Serra G, Pippia P. (-)-Linalool produces antinociception in two experimental models of pain. Eur J Pharmacol. 2003 Jan 26;460(1):37-41. doi: 10.1016/s0014-2999(02)02856-x. PMID: 12535857.

[7] Elisabetsky E, Brum LF, Souza DO. Anticonvulsant properties of linalool in glutamate-related seizure models. Phytomedicine. 1999 May;6(2):107-13. doi: 10.1016/s0944-7113(99)80044-0. PMID: 10374249.

[8] Kim MG, Kim SM, Min JH, Kwon OK, Park MH, Park JW, Ahn HI, Hwang JY, Oh SR, Lee JW, Ahn KS. Anti-inflammatory effects of linalool on ovalbumin-induced pulmonary inflammation. Int Immunopharmacol. 2019 Sep;74:105706. doi: 10.1016/j.intimp.2019.105706. Epub 2019 Jun 26. PMID: 31254955.

[9] Linck VM, da Silva AL, Figueiró M, Piato AL, Herrmann AP, Dupont Birck F, Caramão EB, Nunes DS, Moreno PR, Elisabetsky E. Inhaled linalool-induced sedation in mice. Phytomedicine. 2009 Apr;16(4):303-7. doi: 10.1016/j.phymed.2008.08.001. Epub 2008 Sep 27. PMID: 18824339.

[10] Ou MC, Hsu TF, Lai AC, Lin YT, Lin CC. Pain relief assessment by aromatic essential oil massage on outpatients with primary dysmenorrhea: a randomized, double-blind clinical trial. J Obstet Gynaecol Res. 2012 May;38(5):817-22. doi: 10.1111/j.1447-0756.2011.01802.x. Epub 2012 Mar 22. PMID: 22435409.

Previously known as α-caryophyllene, humulene is an isomer of the more commonly known terpene, β-caryophyllene. Not only do these terpenes share a molecular composition, but they also create similar earthy, peppery aromas and are often found together in nature. Some in vitro studies have shown that humulene may act as an anti-cancer agent[1], perhaps potentiated with the presence of β-caryophyllene[2]. Using essential oils rich in humulene, researchers have been able to demonstrate the potential anti-inflammatory[3] and antibacterial[4] effects of this terpene. Another study, using mouse models, concluded that humulene may also be able to treat allergic asthmatic airway inflammation[5]. Humulene is also often invoked as an appetite suppressant, although research supporting this claim is limited and warrants further investigation.

[1] Chen H, Yuan J, Hao J, Wen Y, Lv Y, Chen L, Yang X. α-Humulene inhibits hepatocellular carcinoma cell proliferation and induces apoptosis through the inhibition of Akt signaling. Food Chem Toxicol. 2019 Dec;134:110830. doi: 10.1016/j.fct.2019.110830. Epub 2019 Sep 25. PMID: 31562948.

[2] Legault J, Pichette A. Potentiating effect of beta-caryophyllene on anticancer activity of alpha-humulene, isocaryophyllene and paclitaxel. J Pharm Pharmacol. 2007 Dec;59(12):1643-7. doi: 10.1211/jpp.59.12.0005. PMID: 18053325.

[3] Fernandes ES, Passos GF, Medeiros R, da Cunha FM, Ferreira J, Campos MM, Pianowski LF, Calixto JB. Anti-inflammatory effects of compounds alpha-humulene and (-)-trans-caryophyllene isolated from the essential oil of Cordia verbenacea. Eur J Pharmacol. 2007 Aug 27;569(3):228-36. doi: 10.1016/j.ejphar.2007.04.059. Epub 2007 May 22. PMID: 17559833.

[4] Pichette A, Larouche PL, Lebrun M, Legault J. Composition and antibacterial activity of Abies balsamea essential oil. Phytother Res. 2006 May;20(5):371-3. doi: 10.1002/ptr.1863. PMID: 16619365.

[5] Rogerio AP, Andrade EL, Leite DF, Figueiredo CP, Calixto JB. Preventive and therapeutic anti-inflammatory properties of the sesquiterpene alpha-humulene in experimental airways allergic inflammation. Br J Pharmacol. 2009 Oct;158(4):1074-87. doi: 10.1111/j.1476-5381.2009.00177.x. Epub 2009 May 8. PMID: 19438512; PMCID: PMC2785529.

As one of the most common terpenes present in the cannabis plant, myrcene can be found in cultivars worldwide. Often used as an additive in food manufacturing, myrcene can also be found naturally in mangos, lemongrass, and bay leaves. Various studies on animal models have shown some promising applications for this terpene, including sedation[1], muscle relaxation[2], anti-inflammation[3], and overall pain relief[4]. Analyses of essential oils high in myrcene content have also indicated the possible antioxidant[5] and anti-ulcer[6] properties of this terpene. Furthermore, research on mouse models has demonstrated the potential of this terpene to treat ischemic stroke, due to its neuro[7] and cardiac[8] protective effects.

[1] 78. Freitas JC, Presgrave OA, Fingola FF, Menezes MA, Paumgartten FJ. Effect of beta-myrcene on pentobarbital sleeping time. Braz J Med Biol Res. (1993) 26:519–23. [PubMed] [Google Scholar] [Ref list]

[2] do Vale TG, Furtado EC, Santos JG Jr, Viana GS. Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) n.e. Brown. Phytomedicine. 2002 Dec;9(8):709-14. doi: 10.1078/094471102321621304. PMID: 12587690.

[3] McDougall, J.J.; McKenna, M.K. Anti-Inflammatory and Analgesic Properties of the Cannabis Terpene Myrcene in Rat Adjuvant Monoarthritis. Int. J. Mol. Sci. 2022, 23, 7891. https://doi.org/10.3390/ijms23147891

[4] Paula-Freire LI, Molska GR, Andersen ML, Carlini EL. Ocimum gratissimum Essential Oil and Its Isolated Compounds (Eugenol and Myrcene) Reduce Neuropathic Pain in Mice. Planta Med. 2016 Feb;82(3):211-6. doi: 10.1055/s-0035-1558165. Epub 2015 Nov 19. PMID: 26584457.

[5] Ojeda, Adriana & Van Baren, Catalina & Elechosa, Miguel & Juárez, Miguel & Moreno, Silvia. (2013). New insights into antibacterial and antioxidant activities of rosemary essential oils and their main components. Food Control. 31. 189–195. 10.1016/j.foodcont.2012.09.022.

[6] Bonamin F, Moraes TM, Dos Santos RC, Kushima H, Faria FM, Silva MA, Junior IV, Nogueira L, Bauab TM, Souza Brito AR, da Rocha LR, Hiruma-Lima CA. The effect of a minor constituent of essential oil from Citrus aurantium: the role of β-myrcene in preventing peptic ulcer disease. Chem Biol Interact. 2014 Apr 5;212:11-9. doi: 10.1016/j.cbi.2014.01.009. Epub 2014 Jan 27. PMID: 24480520.

[7] Ciftci O, Oztanir MN, Cetin A. Neuroprotective effects of β-myrcene following global cerebral ischemia/reperfusion-mediated oxidative and neuronal damage in a C57BL/J6 mouse. Neurochem Res. 2014 Sep;39(9):1717-23. doi: 10.1007/s11064-014-1365-4. Epub 2014 Jun 28. PMID: 24972849.

[8] Burcu GB, Osman C, Aslı C, Namik OM, Neşe BT. The protective cardiac effects of Β-myrcene after global cerebral ıschemia/reperfusion in C57BL/J6 mouse. Acta Cir Bras. 2016 Jul;31(7):456-62. doi: 10.1590/S0102-865020160070000005. PMID: 27487280.