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. 

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.

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.

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.

Pinene is unique in  that it has two main isomers, alpha and beta, that are both common in the cannabis plant. These isomers have the same molecular composition but different arrangements and are usually notated as α-pinene and β-pinene. As its name suggests, this terpene has a piney aroma and is abundant in most conifers. Pinene can be found in a large variety of plants, including rosemary, parsley, dill and—not surprisingly—pine trees! Various animal studies have demonstrated that pinene may exhibit gastroprotective[1], anxiolytic[2], and anticonvulsant[3] properties, as well as the potential to improve sleep quality[4]. In addition, some animal and in vitro studies have implicated this terpene as a potential treatment for various neurodegenerative diseases[5], including Alzheimer’s[6] and Parkinson’s Disease[7], due to its neuroprotective properties[8]. In vitro research, including studies on essential oils rich in pinene, has shown that pinene may display antioxidant[9], anti-inflammatory[10], antimicrobial[11] effects. Finally, as with several other terpenes, pinene has been linked to anti-tumor[12] and anti-cancer[13] activity.

[1] Pinheiro Mde A, Magalhães RM, Torres DM, Cavalcante RC, Mota FS, Oliveira Coelho EM, Moreira HP, Lima GC, Araújo PC, Cardoso JH, de Souza AN, Diniz LR. Gastroprotective effect of alpha-pinene and its correlation with antiulcerogenic activity of essential oils obtained from Hyptis species. Pharmacogn Mag. 2015 Jan-Mar;11(41):123-30. doi: 10.4103/0973-1296.149725. PMID: 25709221; PMCID: PMC4329611.

[2] Kasuya H, Okada N, Kubohara M, Satou T, Masuo Y, Koike K. Expression of BDNF and TH mRNA in the brain following inhaled administration of α-pinene. Phytother Res. 2015 Jan;29(1):43-7. doi: 10.1002/ptr.5224. Epub 2014 Sep 17. PMID: 25230317.

[3] Felipe CFB, Albuquerque AMS, de Pontes JLX, de Melo JÍV, Rodrigues TCML, de Sousa AMP, Monteiro ÁB, Ribeiro AEDS, Lopes JP, de Menezes IRA, de Almeida RN. Comparative study of alpha- and beta-pinene effect on PTZ-induced convulsions in mice. Fundam Clin Pharmacol. 2019 Apr;33(2):181-190. doi: 10.1111/fcp.12416. Epub 2018 Oct 25. PMID: 30230028.

[4] Yang H, Woo J, Pae AN, Um MY, Cho NC, Park KD, Yoon M, Kim J, Lee CJ, Cho S. α-Pinene, a Major Constituent of Pine Tree Oils, Enhances Non-Rapid Eye Movement Sleep in Mice through GABAA-benzodiazepine Receptors. Mol Pharmacol. 2016 Nov;90(5):530-539. doi: 10.1124/mol.116.105080. Epub 2016 Aug 29. PMID: 27573669.

[5] Porres-Martínez M, González-Burgos E, Carretero ME, Gómez-Serranillos MP. In vitro neuroprotective potential of the monoterpenes α-pinene and 1,8-cineole against H2O2-induced oxidative stress in PC12 cells. Z Naturforsch C J Biosci. 2016;71(7-8):191-9. doi: 10.1515/znc-2014-4135. PMID: 27352445.

[6] Lee GY, Lee C, Park GH, Jang JH. Amelioration of Scopolamine-Induced Learning and Memory Impairment by α-Pinene in C57BL/6 Mice. Evid Based Complement Alternat Med. 2017;2017:4926815. doi: 10.1155/2017/4926815. Epub 2017 Nov 1. PMID: 29234406; PMCID: PMC5687139.

[7] Srivastava R, Choudhury PK, Dev SK, Rathore V. Neuroprotective effect of α-pinene self-emulsifying nanoformulation against 6-OHDA induced neurotoxicity on human SH-SY5Y cells and its in vivo validation for anti-Parkinson’s effect. J Biochem Mol Toxicol. 2021 Nov;35(11):e22902. doi: 10.1002/jbt.22902. Epub 2021 Aug 31. PMID: 34464010.

[8] Khoshnazar M, Parvardeh S, Bigdeli MR. Alpha-pinene exerts neuroprotective effects via anti-inflammatory and anti-apoptotic mechanisms in a rat model of focal cerebral ischemia-reperfusion. J Stroke Cerebrovasc Dis. 2020 Aug;29(8):104977. doi: 10.1016/j.jstrokecerebrovasdis.2020.104977. Epub 2020 Jun 13. PMID: 32689608.

[9] Porres-Martínez M, González-Burgos E, Carretero ME, Gómez-Serranillos MP. In vitro neuroprotective potential of the monoterpenes α-pinene and 1,8-cineole against H2O2-induced oxidative stress in PC12 cells. Z Naturforsch C J Biosci. 2016;71(7-8):191-9. doi: 10.1515/znc-2014-4135. PMID: 27352445.

[10] Rufino AT, Ribeiro M, Judas F, Salgueiro L, Lopes MC, Cavaleiro C, Mendes AF. Anti-inflammatory and chondroprotective activity of (+)-α-pinene: structural and enantiomeric selectivity. J Nat Prod. 2014 Feb 28;77(2):264-9. doi: 10.1021/np400828x. Epub 2014 Jan 23. PMID: 24455984.

[11] Rodrigues KA, Amorim LV, Dias CN, Moraes DF, Carneiro SM, Carvalho FA. Syzygium cumini (L.) Skeels essential oil and its major constituent α-pinene exhibit anti-Leishmania activity through immunomodulation in vitro. J Ethnopharmacol. 2015 Feb 3;160:32-40. doi: 10.1016/j.jep.2014.11.024. Epub 2014 Nov 25. PMID: 25460590.

[12] Chen W, Liu Y, Li M, Mao J, Zhang L, Huang R, Jin X, Ye L. Anti-tumor effect of α-pinene on human hepatoma cell lines through inducing G2/M cell cycle arrest. J Pharmacol Sci. 2015 Mar;127(3):332-8. doi: 10.1016/j.jphs.2015.01.008. Epub 2015 Feb 7. PMID: 25837931.

[13] Jo H, Cha B, Kim H, Brito S, Kwak BM, Kim ST, Bin BH, Lee MG. α-Pinene Enhances the Anticancer Activity of Natural Killer Cells via ERK/AKT Pathway. Int J Mol Sci. 2021 Jan 11;22(2):656. doi: 10.3390/ijms22020656. PMID: 33440866; PMCID: PMC7826552.