Paucity of studies documenting the anti-inflammatory effects of cannabis in man

There is a lot of talk about how cannabis can reduce inflammation. I decided to see how many studies have actually tested this hypothesis in humans. It seems we know very little about whether cannabis is effective at reducing inflammation in humans – at least when it comes to measuring that inflammation by accepted lab tests.

The easiest-to-test and most sensitive biomarkers of inflammation are C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR). Other commonly-tested biomarkers of inflammation are IL-1, IL-6, and TNF-alpha.

I did a PubMed search for studies that mention any combination of CRP, ESR, IL-1, IL-6, or TNF. I also did another search for any studies that mention cannabis. Then I combined the two data sets to find the studies that might have looked for an effect of cannabis on any of these biomarkers of inflammation. Here was the search strategy: ((((((((il-1 AND Humans[Mesh])) OR (il-6 AND Humans[Mesh])) OR (tnf AND Humans[Mesh])) OR (c-reactive protein AND Humans[Mesh])) OR (sedimentation rate AND Humans[Mesh])) AND Humans[Mesh])) AND (cannabis AND Humans[Mesh])  

Amazingly, in all of the world’s medical literature, and despite the popularity of cannabis, and despite all the claims of its anti-inflammatory power, only 30 studies could be identified in this search. As you look at the titles, you’ll find that even fewer papers actually address the question of whether cannabis can reduce inflammation. By my count, only about half of these are relevant.  Here is the complete list of titles that represent the totality of medical knowledge about the effects of cannabis on markers of inflammation in man.

1: Kafil TS, Nguyen TM, MacDonald JK, Chande N. Cannabis for the treatment of Crohn’s disease. Cochrane Database Syst Rev. 2018 Nov 8;11:CD012853. doi:10.1002/14651858.CD012853.pub2. PubMed PMID: 30407616.

2: Kafil TS, Nguyen TM, MacDonald JK, Chande N. Cannabis for the treatment of ulcerative colitis. Cochrane Database Syst Rev. 2018 Nov 8;11:CD012954. doi:10.1002/14651858.CD012954.pub2. PubMed PMID: 30406638.

3: Juncal-Ruiz M, Riesco-Dávila L, de la Foz VO, Ramírez-Bonilla M, Martínez-García O, Irure-Ventura J, Leza JC, López-Hoyos M, Crespo-Facorro B. The effect of excess weight on circulating inflammatory cytokines in drug-naïve first-episode psychosis individuals. J Neuroinflammation. 2018 Feb 28;15(1):63. doi: 10.1186/s12974-018-1096-6. PubMed PMID: 29490673; PubMed Central PMCID: PMC6389043.

4: Abidi AH, Presley CS, Dabbous M, Tipton DA, Mustafa SM, Moore BM 2nd. Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts. Arch Oral Biol. 2018 Mar;87:79-85. doi: 10.1016/j.archoralbio.2017.12.005. Epub 2017 Dec 6. PubMed PMID: 29274621.

5: Zaka M, Sehgal SA, Shafique S, Abbasi BH. Comparative in silico analyses of Cannabis sativa, Prunella vulgaris and Withania somnifera compounds elucidating the medicinal properties against rheumatoid arthritis. J Mol Graph Model. 2017 Jun;74:296-304. doi: 10.1016/j.jmgm.2017.04.013. Epub 2017 Apr 19. PubMed PMID: 28472734.

6: Naftali T, Mechulam R, Marii A, Gabay G, Stein A, Bronshtain M, Laish I, Benjaminov F, Konikoff FM. Low-Dose Cannabidiol Is Safe but Not Effective in the Treatment for Crohn’s Disease, a Randomized Controlled Trial. Dig Dis Sci. 2017 Jun;62(6):1615-1620. doi: 10.1007/s10620-017-4540-z. Epub 2017 Mar 27. PubMed PMID: 28349233.

7: Fond G, Berna F, Andrianarisoa M, Godin O, Leboyer M, Brunel L, Aouizerate B, Capdevielle D, Chereau I, D’Amato T, Denizot H, Dubertret C, Dubreucq J, Faget C, Gabayet F, Llorca PM, Mallet J, Misdrahi D, Passerieux C, Richieri R, Rey R, Schandrin A, Urbach M, Vidailhet P, Boyer L, Schürhoff F; FACE-SZ (FondaMental Academic Centers of Expertise for Schizophrenia) group. Chronic low-grade peripheral inflammation is associated with severe nicotine dependence in schizophrenia: results from the national multicentric FACE-SZ cohort. Eur Arch Psychiatry Clin Neurosci. 2017 Aug;267(5):465-472. doi: 10.1007/s00406-017-0771-4. Epub 2017 Feb 25. PubMed PMID: 28238173.

8: Hengartner MP, Kawohl W, Haker H, Rössler W, Ajdacic-Gross V. Big Five personality traits may inform public health policy and preventive medicine: Evidence from a cross-sectional and a prospective longitudinal epidemiologic study in a Swiss community. J Psychosom Res. 2016 May;84:44-51. doi: 10.1016/j.jpsychores.2016.03.012. Epub 2016 Mar 24. PubMed PMID: 27095158.

9: Bonnet U. Abrupt Quitting of Long-term Heavy Recreational Cannabis Use is Not Followed by Significant Changes in Blood Pressure and Heart Rate. Pharmacopsychiatry. 2016 Jan;49(1):23-5. doi: 10.1055/s-0035-1565242. Epub 2016 Jan 13. PubMed PMID: 26761126.

10: Fond G, Godin O, Brunel L, Aouizerate B, Berna F, Bulzacka E, Capdevielle D, Chereau I, Dorey JM, Dubertret C, Dubreucq J, Faget C, Gabayet F, Le Strat Y, Micoulaud-Franchi JA, Misdrahi D, Rey R, Richieri R, Passerieux C, Schandrin A, Schürhoff F, Tronche AM, Urbach M, Vidalhet P, Llorca PM, Leboyer M; FACE-SZ (FondaMental Academic Centers of Expertise for Schizophrenia) group. Peripheral sub-inflammation is associated with antidepressant consumption in schizophrenia. Results from the multi-center FACE-SZ data set. J Affect Disord. 2016 Feb;191:209-15. doi: 10.1016/j.jad.2015.11.017. Epub 2015 Nov 26. PubMed PMID:26674214.

11: Patsenker E, Sachse P, Chicca A, Gachet MS, Schneider V, Mattsson J, Lanz C, Worni M, de Gottardi A, Semmo M, Hampe J, Schafmayer C, Brenneisen R, Gertsch J, Stickel F, Semmo N. Elevated levels of endocannabinoids in chronic hepatitis C may modulate cellular immune response and hepatic stellate cell activation. Int J Mol Sci. 2015 Mar 27;16(4):7057-76. doi: 10.3390/ijms16047057. PubMed PMID: 25826533; PubMed Central PMCID: PMC4425004.

12: Alshaarawy O, Anthony JC. Cannabis smoking and serum C-reactive protein: a quantile regressions approach based on NHANES 2005-2010. Drug Alcohol Depend. 2015 Feb 1;147:203-7. doi: 10.1016/j.drugalcdep.2014.11.017. Epub 2014 Nov 28. PubMed PMID: 25529540; PubMed Central PMCID: PMC4297696.

13: Grace MH, Yousef GG, Esposito D, Raskin I, Lila MA. Bioactive capacity, sensory properties, and nutritional analysis of a shelf stable protein-rich functional ingredient with concentrated fruit and vegetable phytoactives. Plant Foods Hum Nutr. 2014 Dec;69(4):372-8. doi: 10.1007/s11130-014-0444-7. PubMed PMID: 25359555.

14: Jonker I, Klein HC, Duivis HE, Yolken RH, Rosmalen JG, Schoevers RA. Association between exposure to HSV1 and cognitive functioning in a general population of adolescents. The TRAILS study. PLoS One. 2014 Jul 1;9(7):e101549. doi: 10.1371/journal.pone.0101549. eCollection 2014. PubMed PMID: 24983885; PubMed Central PMCID: PMC4077793.

15: Stojanovic A, Martorell L, Montalvo I, Ortega L, Monseny R, Vilella E, Labad J. Increased serum interleukin-6 levels in early stages of psychosis: associations with at-risk mental states and the severity of psychotic symptoms. Psychoneuroendocrinology. 2014 Mar;41:23-32. doi:10.1016/j.psyneuen.2013.12.005. Epub 2013 Dec 14. PubMed PMID: 24495605.

16: Ismail AM, Dubrey SW, Patel MC. Recurrent headaches: a case of neurological Behçet’s disease. Br J Hosp Med (Lond). 2013 Oct;74(10):592-3. PubMed PMID: 24105316.

17: Costello EJ, Copeland WE, Shanahan L, Worthman CM, Angold A. C-reactive protein and substance use disorders in adolescence and early adulthood: a prospective analysis. Drug Alcohol Depend. 2013 Dec 1;133(2):712-7. doi: 10.1016/j.drugalcdep.2013.08.027. Epub 2013 Sep 10. PubMed PMID: 4099969; PubMed Central PMCID: PMC4106409.

18: Kozela E, Juknat A, Kaushansky N, Rimmerman N, Ben-Nun A, Vogel Z. Cannabinoids decrease the th17 inflammatory autoimmune phenotype. J Neuroimmune Pharmacol. 2013 Dec;8(5):1265-76. doi: 10.1007/s11481-013-9493-1. Epub 2013 Jul 28. PubMed PMID: 23892791.

19: Naftali T, Bar-Lev Schleider L, Dotan I, Lansky EP, Sklerovsky Benjaminov F, Konikoff FM. Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clin Gastroenterol Hepatol. 2013 Oct;11(10):1276-1280.e1. doi: 10.1016/j.cgh.2013.04.034. Epub 2013 May 4. PubMed PMID: 23648372.

20: Di Nicola M, Cattaneo A, Hepgul N, Di Forti M, Aitchison KJ, Janiri L, Murray RM, Dazzan P, Pariante CM, Mondelli V. Serum and gene expression profile of cytokines in first-episode psychosis. Brain Behav Immun. 2013 Jul;31:90-5. doi: 10.1016/j.bbi.2012.06.010. Epub 2012 Jun 28. PubMed PMID: 22749891; PubMed Central PMCID: PMC3675681.

21: Igue R, Potvin S, Bah R, Stip E, Bouchard RH, Lipp O, Gendron A, Kouassi E. Soluble interleukin-2 receptor levels correlated with positive symptoms during quetiapine treatment in schizophrenia-spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Aug 15;35(7):1695-8. doi: 10.1016/j.pnpbp.2011.05.011. Epub 2011 May 24. PubMed PMID: 21627977.

22: Borrelli F, Aviello G, Romano B, Orlando P, Capasso R, Maiello F, Guadagno F, Petrosino S, Capasso F, Di Marzo V, Izzo AA. Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis. J Mol Med (Berl). 2009 Nov;87(11):1111-21. doi: 10.1007/s00109-009-0512-x. Epub 2009 Aug 20. PubMed PMID: 19690824.

23: Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, Altmann KH, Karsak M, Zimmer A. 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. PubMed PMID: 18574142; PubMed Central PMCID: PMC2449371.

24: Mach F. New anti-inflammatory agents to reduce atherosclerosis. Arch Physiol Biochem. 2006 Apr;112(2):130-7. Review. PubMed PMID: 16931455.

25: Verhoeckx KC, Korthout HA, van Meeteren-Kreikamp AP, Ehlert KA, Wang M, van der Greef J, Rodenburg RJ, Witkamp RF. Unheated Cannabis sativa extracts and its major compound THC-acid have potential immuno-modulating properties not mediated by CB1 and CB2 receptor coupled pathways. Int Immunopharmacol. 2006 Apr;6(4):656-65. Epub 2005 Nov 7. PubMed PMID: 16504929.

26: Katona S, Kaminski E, Sanders H, Zajicek J. Cannabinoid influence on cytokine profile in multiple sclerosis. Clin Exp Immunol. 2005 Jun;140(3):580-5. PubMed PMID: 15932522; PubMed Central PMCID: PMC1809378.

27: Killestein J, Hoogervorst EL, Reif M, Blauw B, Smits M, Uitdehaag BM, Nagelkerken L, Polman CH. Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis. J Neuroimmunol. 2003 Apr;137(1-2):140-3. PubMed PMID: 12667658.

28: Zurier RB, Rossetti RG, Burstein SH, Bidinger B. Suppression of human monocyte interleukin-1beta production by ajulemic acid, a nonpsychoactive cannabinoid. Biochem Pharmacol. 2003 Feb 15;65(4):649-55. PubMed PMID: 12566094.

29: Masset D, Bourdon JH, Arditti-Djiane J, Jouglard J. [Impact of delta-9-tetrahydrocannabinol and its metabolites on the immune system]. Acta Clin Belg. 1999;53 Suppl 1:39-43. Review. French. PubMed PMID: 10216981.

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