Appendix B: Taming Inflammatory Cytokines


Inflammatory cytokines may be of short-term benefit in fighting injury and infection. But inflammation comes at a cost and can have negative consequences.

Cannabis compounds are well-known for controlling inflammatory cytokines, which is what accounts for much of their value in treating conditions such as arthritis, inflammatory pain, and many cancers.

This support article enumerates key cytokines and what's known about the cannabis compounds that are able to inhibit them.

Lowering IL-6

CBD, THC, perillyl alcohol, α-terpineol, 4-terpineol, eucalyptol, and apigenin may all be useful in lowering IL-6. ⮛ RESEARCH ⮛

CBD lowers IL-6 in ischemic rat hearts and in chemically stressed mouse microglial cells[Durst_2007][Kozela_2009]. THC lowers IL-6 in chemically stressed macrophages and in mouse microglial cell lines[Kozela_2009][Chang_2001][Puffenbarger_2000]. BCP lowers IL-6, IL-1β, and TNF-α in an immortalized microglial cell line used to study neuroinflammation[Guo_2014].

Perillyl alcohol, a metabolite of d-limonene lowers IL-6, IL-1β, and TNF-α in a rat model of stroke[Tabassum_2014]. α-Terpineol lowers IL-6 in human cheek cells stressed with desiccated orange juice[Held_2007]. α-Terpineol and 4-terpineol (aka terpinen-4-ol) lower both IL-6 and IL-1β in chemically stressed human macrophages[Nogueira_2014][Trinh_2011]. Eucalyptol has lowerd IL-6, IL-1β, and TNF-α in various in vitro and animal models of inflammation[Caceres_2017][Lima_2013][Yadav_2017][Li_2016][Kennedy-Feitosa_2016][Yu_2018][Khan_2013][Trinh_2011]. The flavonoid apigenin lowers IL-6 in chemically stressed mice[Smolinski_2003].

Lowering IL-1

CBD, THC, BCP (β-caryophyllene), nerolidol, perillyl alcohol (and thus d-limonene), eucalyptol, α-Humulene, and geraniol may all be useful in lowering IL-1. ⮛ RESEARCH ⮛

CBD and THC lower IL-1β in chemically stressed mouse microglial cells. CBD lowers IL1-β and TNF-α in a mouse model of multiple sclerosis[Mecha_2013]. BCP (β-caryophyllene) lowers IL-1β and TNF-α in in vitro tests[Gertsch_2008][Guo_2014][Medeiros_2007].

Nerolidol inhibits IL1-β and TNF-α in mouse periotinitis[Fonsêca_2015]. As noted above, perillyl alcohol reduced IL-1β and TNF-α in a rat model of stroke, and eucalyptol lowerd IL-1. α-Humulene lowerd IL-1β and TNF-α in rat paw edema[Medeiros_2007]. Geraniol lowerd IL-1β and TNF-α in rat tongue cancer[Madankumar_2017].

Lowering TNF-α

CBD, BCP (β-caryophyllene), nerolidol, perillyl alcohol, α-humulene, eucalyptol, α-terpineol, geraniol and apigenin may all be useful in lowering TNF-α. ⮛ RESEARCH ⮛

As noted above, CBD, BCP, nerolidol, perillyl alcohol, α-humulene, eucalyptol, α-terpineol, and geraniol all lower TNF-α.

The flavonoid apigenin lowerd TNF-α in an experiential model of mouse pancreatitis[Charalabopoulos_2019]. Apigenin lowerd TNF-α and upregulated the anti-inflammatory cytokine IL-10 in mouse leukemia macrophages[Palacz-Wrobel_2017].

Lowering IL-17

CBD, THC, and BCP (β-caryophyllene) may be useful in lowering IL-17. ⮛ RESEARCH ⮛

CBD lowers IL-17[Giacoppo_2016][Harvey_2013], as does THC[Kozela_2013]. JWH‐133 lowers IL-17 in macrophages[Guillot_2013][Norooznezhad_2016], so the same is likely to be true of the stronger CB2 agonist BCP[Gertsch_2008].

Lowering IL-8

THCA inhibits IL-8 in inflamed colon tissues[Nallathambi_2017].

Lowering GM-CSF and CCL3

CBD lowers GM-CSF and CCL3 in triple-negative breast cancer[Elbaz_2015].

Lowering Nitric Oxide

α-Humulene, α-terpinene, α-pinene, and β-pinene neutralize the free radical nitric oxide[Coté_2017][Rufino_2015]. d-Limonene also lowers nitric oxide levels[Rufino_2015].
⮛ MORE ⮛

Nitric oxide is of course not a cytokine, but it may be worth tamping down due to its role in inflammatory processes. Caution may be merited, however. It functions as a neurotransmitter at neuron synapses. It induces vasodilatation in the cardiovascular system. And it plays a role in immune response where cytokine-activated macrophages release nitric oxide in high concentrations[Sharma_2007].


Rendered according to the Citations Online architecture

Coté_2017. Anti-Inflammatory, Antioxidant, Antibiotic, and Cytotoxic Activities of Tanacetum vulgare L\. Essential Oil and Its Constituents. Full text. Coté H, Boucher M-A, Pichette A, Legault J. Medicines. Online 2017 May 25.

Rufino_2015. Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis. Abstract, full text. Rufino A T, Ribeiro M, Sousa C, et al. European Journal of Pharmacology. Published 2015 March 5.

Elbaz_2015. Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: Novel anti‐tumor mechanisms of Cannabidiol in breast cancer. Full text. Elbaz M, Nasser M W, Ravi J, et al. Molecular oncology. Online 2015 January 19.

Sharma_2007. Role of nitric oxide in inflammatory diseases [literature review]. Abstract. Sharma J N, Al-Omran A, Parvathy S S. Inflammopharmacology. Published 2007 December.

Durst_2007. Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury[Animal study]. Full text. Durst R, Danenberg H, Gallily R, et al. American Journal of Physiology. Online 2007 December 1.

Kozela_2009. Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells. Full text. Kozela E, Pietr M, Juknat A, et al. Journalof Biological Chemistry. Online 2009 November 12.

Chang_2001. Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of eicosanoids[animal study]. Abstract. Chang Y, Lee S, Lin W. Journal of Cellular Biochemistry. Online 2001 April 23.

Puffenbarger_2000. Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Abstract. Puffenbarger R, Boothe A, Cabral G. Glia. Published 2000 January.

Guo_2014. Trans-caryophyllene suppresses hypoxia-induced neuroinflammatory responses by inhibiting NF-κB activation in microglia. Abstract. Guo K1, Mou X, Huang J, Xiong N, Li H. Journal of Mocular Neuroscience. Online 2014 February 4.

Tabassum_2014. Perillyl alcohol improves functional and histological outcomes against ischemia-reperfusion injury by attenuation of oxidative stress and repression of COX-2, NOS-2 and NF-κB in middle cerebral artery occlusion rats. Abstract. Tabassum R, Vaibhav K, Shrivastava P, et al. European Journal of Pharmacology. Online 2014 September 18.

Held_2007. Characterization of alpha-terpineol as an anti-inflammatory component of orange juice by in vitro studies using oral buccal cells. Abstract. Held S, Schieberle P, Somoza V. Journal of Agricultural and Food Chemistry. Online 2007 September 1.

Nogueira_2014. Terpinen-4-ol and alpha-terpineol (tea tree oil components) inhibit the production of IL-1β, IL-6 and IL-10 on human macrophages. Abstract. Nogueira M, Aquino S, Rossa Junior C, Spolidorio D. Inflammation Research. Online 2014 June 20.

Caceres_2017. Transient Receptor Potential Cation Channel Subfamily M Member 8 channels mediate the anti-inflammatory effects of eucalyptol[animal study]. Full text. Caceres A, Liu B, Jabba S, et al. British Journal of Pharmacology. Online 2017 March 23.

Lima_2013. 1,8-cineole (eucalyptol) ameliorates cerulein-induced acute pancreatitis via modulation of cytokines, oxidative stress and NF-κB activity in mice. Abstract. Lima P R, de Melo T S, Carvalho K M M B, et al. Life Sciences. Online 2013 May 20.

Yadav_2017. Suppression of inflammatory and infection responses in lung macrophages by eucalyptus oil and its constituent 1,8-cineole: Role of pattern recognition receptors TREM-1 and NLRP3, the MAP kinase regulator MKP-1, and NFκB. Full text. Yadav N, Chandra H. PloS One. Online 2017 November 15.

Li_2016. 1, 8-Cineol Protect Against Influenza-Virus-Induced Pneumonia in Mice. Abstract. Li Y, Lai Y, Wang Y, et al. Inflammation. Online 2016 June 28.

Kennedy-Feitosa_2016. Eucalyptol attenuates cigarette smoke-induced acute lung inflammation and oxidative stress in the mouse. Abstract. Kennedy-Feitosa E, Okuro R, Pinho-Ribeiro V, et al. Pulmonary Pharmacology & Theraputics. Online 2016 September 4.

Yu_2018. Treatment with eucalyptol mitigates cigarette smoke-induced lung injury through suppressing ICAM-1 gene expression[animal study]. Full text. Yu N, Sun Y, Su X, et al. Bioscience Reports. Online 2018 July 6.

Khan_2013. 1,8-cineole (eucalyptol) mitigates inflammation in amyloid Beta toxicated PC12 cells: relevance to Alzheimer's disease[animal study]. Abstract. Khan A, Vaibhav K, Javed H, et al. Neurochemical Research. Online 2013 December 31.

Trinh_2011. Artemisia princeps Pamp\. Essential oil and its constituents eucalyptol and α-terpineol ameliorate bacterial vaginosis and vulvovaginal candidiasis in mice by inhibiting bacterial growth and NF-κB activation. Abstract. Trinh H, Lee I, Hyun Y, Kim D. Planta Medica. Online 2011 August 9.

Smolinski_2003. Modulation of lipopolysaccharide-induced proinflammatory cytokine production in vitro and in vivo by the herbal constituents apigenin (chamomile), ginsenoside Rb(1) (ginseng) and parthenolide (feverfew). Abstract. Smolinski A, Pestka J. Food and Chemical Toxicology. Online 2003 July 1.

Mecha_2013. Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors[animal study]. Full text. Mecha M, Feliú A, Iñigo P, Mestre L, Carrillo-Salinas F, Guaza C. Neurobiology of disease. Online 2013 July 11.

Gertsch_2008. β-caryophyllene is a dietary cannabinoid[animal study]. Full text. Gertsch J, Leonti M, Raduner S, et al. Proceedings of the National Academy of Sciences (U.S.). Online 2008 June 23.

Medeiros_2007. Effect of two active compounds obtained from the essential oil of Cordia verbenacea on the acute inflammatory responses elicited by LPS in the rat paw. Full text. Medeiros R, Passos G, Vitor C, et al. British Journal of Pharmacology. Online 2007 April 30.

Fonsêca_2015. Nerolidol exhibits antinociceptive and anti-inflammatory activity: involvement of the GABAergic system and proinflammatory cytokines[animal stuudy]. Abstract. Fonsêca D, Salgado P, de Carvalho F, et al. Fundamental & Clinical Pharmacology. Online 2015 November 2.

Madankumar_2017. Geraniol attenuates 4NQO-induced tongue carcinogenesis through lowering the activation of NF-κB in rats. Abstract. Madankumar A, Tamilarasi S, Premkumar T, et al. Molecular and Cellular Biochemistry. Online 2017 April 10.

Charalabopoulos_2019. Apigenin Exerts Anti-inflammatory Effects in an Experimental Model of Acute Pancreatitis by Down-regulating TNF-α. Full text. Charalabopoulos A, Davakis, Lambropoulou M, et al. In Vivo. Online 2019 July 3.

Palacz-Wrobel_2017. Effect of apigenin, kaempferol and resveratrol on the gene expression and protein secretion of tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) in RAW-264.7 macrophages. Abstract. Palacz-Wrobel M, Borkowska P, Paul-Samojedny M, et al. Biomedicine & Pharmacotherapy. Online 2017 July 20.

Guillot_2013. Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver. Full text. Guillot A, Hamdaoui N, Bizy A, et al. Hepatology. Online 2013 November 19.

Norooznezhad_2016. Cannabinoids: Possible agents for treatment of psoriasis via suppression of angiogenesis and inflammation[essay]. Abstract. Norooznezhad A, Norooznezhad F. Medical Hypotheses. Online 2016 December 14.

Giacoppo_2016. Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis. Abstract. Giacoppo S, Pollastro F, Grassi G, Bramanti P, Mazzon E. Fitoterapia. Online 2016 November 25.

Harvey_2013. Interleukin 17A evoked mucosal damage is attenuated by cannabidiol and anandamide in a human colonic explant model. Abstract. Harvey B, Sia T, Wattchow D, Smid S. Cytokine. Online 2013 November 13.

Kozela_2013. Cannabinoids decrease the th17 inflammatory autoimmune phenotype[in vitro study]. Abstract. Kozela E1, Juknat A, Kaushansky N, et al. Journal of Neuroimmune Pharmacology. Online 2013 July 28.

Nallathambi_2017. Anti-Inflammatory Activity in Colon Models Is Derived from Δ9-Tetrahydrocannabinolic Acid That Interacts with Additional Compounds in Cannabis Extracts. Full text. Nallathambi R, Mazuz M, Ion A, et al. Cannabis and cannabinoid research. 2017 July 1.