Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cannabinoids for the treatment of rheumatic diseases — where do we stand?

Nature Reviews Rheumatology volume 14, pages 488–498 (2018)Cite this article

Subjects

Abstract

As medical use of cannabis is increasingly legalized worldwide, a better understanding of the medical and hazardous effects of this drug is imperative. The pain associated with rheumatic diseases is considered a prevalent indication for medicinal cannabis in various countries. Thus far, preliminary clinical trials have explored the effects of cannabis on rheumatoid arthritis, osteoarthritis and fibromyalgia; preliminary evidence has also found an association between the cannabinoid system and other rheumatic conditions, including systemic sclerosis and juvenile idiopathic arthritis. The potential medicinal effects of cannabis could be attributable to its influence on the immune system, as it exerts an immunomodulatory effect on various immune cells, including T cells, B cells and macrophages. However, the available evidence is not yet sufficient to support the recommendation of cannabinoid treatment for rheumatic diseases.

Key points

  • Cannabinoids can affect the proliferation, apoptosis and cytokine production of immune cells, acting as possible immune modulators.

  • Preclinical data suggest that cannabinoids possess therapeutic potential in the following rheumatic diseases: rheumatoid arthritis, osteoarthritis, systemic sclerosis and fibromyalgia.

  • Clinical data regarding cannabinoid treatment for rheumatic diseases are scarce; therefore, recommendations concerning cannabinoid treatment cannot be made.

  • Cannabinoid treatment should not be taken lightly; special consideration and advise are required regarding adverse effects and drug interactions.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Endocannabinoid signalling via cannabinoid receptor 1.
Fig. 2: Adverse effects of cannabinoids.
Fig. 3: Interactions of cannabinoids and other drugs.

References

  1. Warf, B. High points: an historical geography of cannabis. Geogr. Rev. 104, 414–438 (2014).

    Article  Google Scholar 

  2. Zuardi, A. W. History of cannabis as a medicine: a review. Revista Brasileira Psiquiatria 28, 153–157 (2006).

    Article  Google Scholar 

  3. Pain, S. A potted history. Nature 525, S10–S11 (2015).

    Article  PubMed  CAS  Google Scholar 

  4. Katchan, V., David, P. & Shoenfeld, Y. Cannabinoids and autoimmune diseases: a systematic review. Autoimmun. Rev. 15, 513–528 (2016).

    Article  PubMed  CAS  Google Scholar 

  5. Gaoni, Y. & Mechoulam, R. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86, 1646–1647 (1964).

    Article  CAS  Google Scholar 

  6. Devane, W. A., Dysarz, F. A., Johnson, M. R., Melvin, L. S. & Howlett, A. C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34, 605–613 (1988).

    PubMed  CAS  Google Scholar 

  7. Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).

    Article  PubMed  CAS  Google Scholar 

  8. Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83–90 (1995).

    Article  PubMed  CAS  Google Scholar 

  9. Maccarrone, M. et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol. Sci. 36, 277–296 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Mechoulam, R. Cannabis - the Israeli perspective. J. Basic Clin. Physiol. Pharmacol. 27, 181–187 (2016).

    Article  PubMed  Google Scholar 

  11. Iversen, L. Cannabis and the brain. Brain 126, 1252–1270 (2003).

    Article  PubMed  Google Scholar 

  12. Mackie, K. Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength. Int. J. Obes. 30 (Suppl. 1), S19–S23 (2006).

    Article  CAS  Google Scholar 

  13. Pagotto, U., Marsicano, G., Cota, D., Lutz, B. & Pasquali, R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr. Rev. 27, 73–100 (2006).

    Article  PubMed  CAS  Google Scholar 

  14. Guindon, J. & Hohmann, A. G. The endocannabinoid system and pain. CNS Neurol. Disord. Drug Targets 8, 403–421 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Sido, J. M., Nagarkatti, P. S. & Nagarkatti, M. Role of endocannabinoid activation of peripheral CB1 receptors in the regulation of autoimmune disease. Int. Rev. Immunol. 34, 403–414 (2015).

    Article  PubMed  CAS  Google Scholar 

  16. Dunn, S. L., Wilkinson, J. M., Crawford, A., Bunning, R. A. D. & Le Maitre, C. L. Expression of cannabinoid receptors in human osteoarthritic cartilage: implications for future therapies. Cannabis Cannabinoid Res. 1, 3–15 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Castillo, P. E., Younts, T. J., Chávez, A. E. & Hashimotodani, Y. Endocannabinoid signaling and synaptic function. Neuron 76, 70–81 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Howlett, A. C. et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 54, 161–202 (2002).

    Article  PubMed  CAS  Google Scholar 

  19. Howlett, A. C., Blume, L. C. & Dalton, G. D. CB1 cannabinoid receptors and their associated proteins. Curr. Med. Chem. 17, 1382–1393 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Pertwee, R. G. et al. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol. Rev. 62, 588–631 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Aghazadeh Tabrizi, M., Baraldi, P. G., Borea, P. A. & Varani, K. Medicinal chemistry, pharmacology, and potential therapeutic benefits of cannabinoid CB 2 receptor agonists. Chem. Rev. 116, 519–560 (2016).

    Article  PubMed  CAS  Google Scholar 

  22. Gui, H. et al. Expression of cannabinoid receptor 2 and its inhibitory effects on synovial fibroblasts in rheumatoid arthritis. Rheumatology 53, 802–809 (2014).

    Article  PubMed  CAS  Google Scholar 

  23. Malfitano, A. M., Basu, S., Maresz, K., Bifulco, M. & Dittel, B. N. What we know and do not know about the cannabinoid receptor 2 (CB2). Semin. Immunol. 26, 369–379 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Beltramo, M. et al. CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur. J. Neurosci. 23, 1530–1538 (2006).

    Article  PubMed  CAS  Google Scholar 

  25. Katz, D., Katz, I., Porat-Katz, B. & Shoenfeld, Y. Medical cannabis: another piece in the mosaic of autoimmunity? Clin. Pharmacol. Ther. 101, 230–238 (2016).

    Article  PubMed  Google Scholar 

  26. Bellini, G. et al. Association between cannabinoid receptor type 2 Q63R variant and oligo/polyarticular juvenile idiopathic arthritis. Scand. J. Rheumatol. 44, 284–287 (2015).

    Article  PubMed  CAS  Google Scholar 

  27. Engler, A. et al. Expression of transient receptor potential vanilloid 1 (TRPV1) in synovial fibroblasts from patients with osteoarthritis and rheumatoid arthritis. Biochem. Biophys. Res. Commun. 359, 884–888 (2007).

    Article  PubMed  CAS  Google Scholar 

  28. Barrie, N. et al. Endocannabinoids in arthritis: current views and perspective. Int. J. Rheum. Dis. 20, 789–797 (2017).

    Article  PubMed  Google Scholar 

  29. Lowin, T. & Straub, R. H. Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis. Arthritis Res. Ther. 17, 226 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Irving, A. et al. Cannabinoid receptor-related orphan G protein-coupled receptors. Adv. Pharmacol. 80, 223–247 (2017).

    Article  PubMed  Google Scholar 

  31. Katz, D., Katz, I. & Shoenfeld, Y. Cannabis and autoimmunity–the neurologic perspective: a brief review. J. Neurol. Neuromed. 1, 11–15 (2016).

    Google Scholar 

  32. Pertwee, R. G. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol. Ther. 74, 129–180 (1997).

    PubMed  CAS  Google Scholar 

  33. Thomas, A. et al. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br. J. Pharmacol. 150, 613–623 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Ligresti, A., De Petrocellis, L. & Di Marzo, V. From phytocannabinoids to cannabinoid receptors and endocannabinoids: pleiotropic physiological and pathological roles through complex pharmacology. Physiol. Rev. 96, 1593–1659 (2016).

    Article  PubMed  CAS  Google Scholar 

  35. Ben-Shabat, S. et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol. 353, 23–31 (1998).

    Article  PubMed  CAS  Google Scholar 

  36. Russo, E. B. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br. J. Pharmacol. 163, 1344–1364 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Russo, E. B. & Marcu, J. Cannabis pharmacology: the usual suspects and a few promising leads. Adv. Pharmacol. 80, 67–134 (2017).

    Article  PubMed  Google Scholar 

  38. Jiang, C.-P. et al. Anti-rheumatoid arthritic activity of flavonoids from Daphne genkwa. Phytomedicine 21, 830–837 (2014).

    Article  PubMed  CAS  Google Scholar 

  39. Parmar, J. R., Forrest, B. D. & Freeman, R. A. Medical marijuana patient counseling points for health care professionals based on trends in the medical uses, efficacy, and adverse effects of cannabis-based pharmaceutical drugs. Res. Soc. Adm. Pharm. 12, 638–654 (2016).

    Article  Google Scholar 

  40. Adams, A. J. et al. ‘Zombie’ outbreak caused by the synthetic cannabinoid AMB-FUBINACA in New York. N. Engl. J. Med. 376, 235–242 (2017).

    Article  PubMed  CAS  Google Scholar 

  41. Wang, T., Collet, J.-P., Shapiro, S. & Ware, M. A. Adverse effects of medical cannabinoids: a systematic review. CMAJ 178, 1669–1678 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Tait, R. J., Caldicott, D., Mountain, D., Hill, S. L. & Lenton, S. A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment. Clin. Toxicol. 54, 1–13 (2015).

    Article  CAS  Google Scholar 

  43. National Academies of Sciences, Engineering and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research (The National Academies Press, 2017).

  44. Auer, R. et al. Association between lifetime marijuana use and cognitive function in middle age. JAMA Intern. Med. 176, 352 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Batalla, A. et al. Structural and functional imaging studies in chronic cannabis users: a systematic review of adolescent and adult findings. PLoS ONE 8, e55821 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Rocchetti, M. et al. Is cannabis neurotoxic for the healthy brain? A meta-analytical review of structural brain alterations in non-psychotic users. Psychiatry Clin. Neurosci. 67, 483–492 (2013).

    Article  PubMed  Google Scholar 

  47. Meier, M. H. et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc. Natl Acad. Sci. USA 109, E2657–E2664 (2012).

    Article  PubMed  Google Scholar 

  48. Volkow, N. D., Baler, R. D., Compton, W. M. & Weiss, S. R. B. Adverse health effects of marijuana use. N. Engl. J. Med. 370, 2219–2227 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Curran, H. V. et al. Keep off the grass? Cannabis, cognition and addiction. Nat. Rev. Neurosci. 17, 293–306 (2016).

    Article  PubMed  CAS  Google Scholar 

  50. Meier, M. H. et al. Associations between adolescent cannabis use and neuropsychological decline: a longitudinal co-twin control study. Addiction 113, 257–265 (2017).

    Article  PubMed  Google Scholar 

  51. Anthony, J. C., Warner, L.a. & Kessler, R. C. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Exp. Clin. Psychopharmacol. 2, 244–268 (1994).

    Article  Google Scholar 

  52. Agrawal, A. & Lynskey, M. T. Candidate genes for cannabis use disorders: findings, challenges and directions. Addiction 104, 518–532 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Verweij, K. J. H. et al. Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studies. Addiction 105, 417–430 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Smith, A. M. et al. Prenatal marijuana exposure impacts executive functioning into young adulthood: an fMRI study. Neurotoxicol. Teratol. 58, 53–59 (2016).

    Article  PubMed  CAS  Google Scholar 

  55. Kerbrat, A. et al. Acute neurologic disorder from an inhibitor of fatty acid amide hydrolase. N. Engl. J. Med. 375, 1717–1725 (2016).

    Article  PubMed  CAS  Google Scholar 

  56. Lindsey, W. T., Stewart, D. & Childress, D. Drug interactions between common illicit drugs and prescription therapies. Am. J. Drug Alcohol Abuse 38, 334–343 (2012).

    Article  PubMed  Google Scholar 

  57. Stout, S. M. & Cimino, N. M. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab. Rev. 46, 86–95 (2014).

    Article  PubMed  CAS  Google Scholar 

  58. Anderson, G. D. & Chan, L. N. Pharmacokinetic drug interactions with tobacco, cannabinoids and smoking cessation products. Clin. Pharmacokinet. 55, 1353–1368 (2016).

    Article  PubMed  CAS  Google Scholar 

  59. Geffrey, A. L., Pollack, S. F., Bruno, P. L. & Thiele, E. A. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia 56, 1246–1251 (2015).

    Article  PubMed  CAS  Google Scholar 

  60. Abrams, D. I., Couey, P., Shade, S. B., Kelly, M. E. & Benowitz, N. L. Cannabinoid–opioid interaction in chronic pain. Clin. Pharmacol. Ther. 90, 844–851 (2011).

    Article  PubMed  CAS  Google Scholar 

  61. Hartman, R. L. et al. Controlled cannabis vaporizer administration: blood and plasma cannabinoids with and without alcohol. Clin. Chem. 61, 850–869 (2015).

    Article  PubMed  CAS  Google Scholar 

  62. McLeod, A. L., McKenna, C. J. & Northridge, D. B. Myocardial infarction following the combined recreational use of Viagra and cannabis. Clin. Cardiol. 25, 133–134 (2002).

    Article  PubMed  CAS  Google Scholar 

  63. Yamreudeewong, W., Wong, H. K., Brausch, L. M. & Pulley, K. R. Probable interaction between warfarin and marijuana smoking. Ann. Pharmacother. 43, 1347–1353 (2009).

    Article  PubMed  Google Scholar 

  64. Shapira, Y., Agmon-Levin, N. & Shoenfeld, Y. Geoepidemiology of autoimmune rheumatic diseases. Nat. Rev. Rheumatol. 6, 468–476 (2010).

    Article  PubMed  CAS  Google Scholar 

  65. Richardson, D. et al. Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res. Ther. 10, R43 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Lowin, T., Pongratz, G. & Straub, R. H. The synthetic cannabinoid WIN55,212-2 mesylate decreases the production of inflammatory mediators in rheumatoid arthritis synovial fibroblasts by activating CB2, TRPV1, TRPA1 and yet unidentified receptor targets. J. Inflamm. 13, 15 (2016).

    Article  CAS  Google Scholar 

  67. Malfait, A. M. et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc. Natl Acad. Sci. USA 97, 9561–9566 (2000).

    Article  PubMed  CAS  Google Scholar 

  68. Fukuda, S. et al. Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis. BMC Musculoskelet. Disord. 15, 275 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Gui, H., Liu, X., Liu, L.-R., Su, D.-F. & Dai, S.-M. Activation of cannabinoid receptor 2 attenuates synovitis and joint distruction in collagen-induced arthritis. Immunobiology 220, 817–822 (2015).

    Article  PubMed  CAS  Google Scholar 

  70. Blake, D. R., Robson, P., Ho, M., Jubb, R. W. & McCabe, C. S. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology 45, 50–52 (2006).

    Article  CAS  Google Scholar 

  71. Kong, Y. et al. Cannabinoid WIN-55,212–2 mesylate inhibits ADAMTS-4 activity in human osteoarthritic articular chondrocytes by inhibiting expression of syndecan-1. Mol. Med. Rep. 13, 4569–4576 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Ste-Marie, P. A. et al. Survey of herbal cannabis (marijuana) use in rheumatology clinic attenders with a rheumatologist confirmed diagnosis. Pain 157, 2792–2797 (2016).

    Article  PubMed  CAS  Google Scholar 

  73. Bannuru, R. R. et al. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis. Ann. Intern. Med. 162, 46 (2015).

    Article  PubMed  Google Scholar 

  74. Sophocleous, A., Börjesson, A. E., Salter, D. M. & Ralston, S. H. The type 2 cannabinoid receptor regulates susceptibility to osteoarthritis in mice. Osteoarthritis Cartilage 23, 1586–1594 (2015).

    Article  PubMed  CAS  Google Scholar 

  75. Mbvundula, E. C., Bunning, R. A. D. & Rainsford, K. D. Effects of cannabinoids on nitric oxide production by chondrocytes and proteoglycan degradation in cartilage. Biochem. Pharmacol. 69, 635–640 (2005).

    Article  PubMed  CAS  Google Scholar 

  76. Gõmez, R. et al. Endogenous cannabinoid anandamide impairs cell growth and induces apoptosis in chondrocytes. J. Orthop. Res. 32, 1137–1146 (2014).

    Article  PubMed  CAS  Google Scholar 

  77. Huggins, J. P., Smart, T. S., Langman, S., Taylor, L. & Young, T. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Pain 153, 1837–1846 (2012).

    Article  PubMed  CAS  Google Scholar 

  78. La Porta, C. et al. Role of the endocannabinoid system in the emotional manifestations of osteoarthritis pain. Pain 156, 2001–2012 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Schuelert, N. et al. Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis. Pain 152, 975–981 (2011).

    Article  PubMed  CAS  Google Scholar 

  80. Rossi, D. et al. How I treat patients with systemic sclerosis in clinical practice. Autoimmun. Rev. 16, 1024–1028 (2017).

    Article  PubMed  Google Scholar 

  81. Marquart, S. et al. Inactivation of the cannabinoid receptor CB1 prevents leukocyte infiltration and experimental fibrosis. Arthritis Rheum. 62, 3467–3476 (2010).

    Article  PubMed  Google Scholar 

  82. Akhmetshina, A. et al. The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis. Arthritis Rheum. 60, 1129–1136 (2009).

    Article  PubMed  Google Scholar 

  83. del Río, C. et al. The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways. Sci. Rep. 6, 21703 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Servettaz, A. et al. Targeting the cannabinoid pathway limits the development of fibrosis and autoimmunity in a mouse model of systemic sclerosis. Am. J. Pathol. 177, 187–196 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Wang, L.-L. et al. Pharmacological activation of cannabinoid 2 receptor attenuates inflammation, fibrogenesis, and promotes re-epithelialization during skin wound healing. Eur. J. Pharmacol. 786, 128–136 (2016).

    Article  PubMed  CAS  Google Scholar 

  86. Li, S. et al. Cannabinoid CB2 receptors are involved in the regulation of fibrogenesis during skin wound repair in mice. Mol. Med. Rep. 13, 3441–3450 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Garcia-Gonzalez, E. et al. Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts. Rheumatology 48, 1050–1056 (2009).

    Article  PubMed  CAS  Google Scholar 

  88. Wolfe, F. et al. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin. Arthritis Rheum. 46, 319–329 (2016).

    Article  PubMed  Google Scholar 

  89. Fitzcharles, M.-A. & Jamal, S. Expanding medical marijuana access in Canada: considerations for the rheumatologist. J. Rheumatol. 42, 143–145 (2015).

    Article  PubMed  Google Scholar 

  90. Walsh, Z. et al. Cannabis for therapeutic purposes: patient characteristics, access, and reasons for use. Int. J. Drug Policy 24, 511–516 (2013).

    Article  PubMed  Google Scholar 

  91. Ware, M. A., Adams, H., Guy, G. W. & Centre, P. The medicinal use of cannabis in the UK: results of a nationwide survey. Int. J. Clin. Pract. 59, 291–295 (2005).

    Article  PubMed  CAS  Google Scholar 

  92. Aggarwal, S. K. et al. Characteristics of patients with chronic pain accessing treatment with medical cannabis in Washington State. J. Opioid Manag. 5, 257–286 (2009).

    Article  PubMed  Google Scholar 

  93. Walitt, B., Klose, P., Fitzcharles, M. A., Phillips, T. & Häuser, W. Cannabinoids for fibromyalgia. Cochrane Database Syst. Rev. 7, CD011694 (2016).

    PubMed  Google Scholar 

  94. Skrabek, R. Q., Galimova, L., Ethans, K. & Perry, D. Nabilone for the treatment of pain in fibromyalgia. J. Pain 9, 164–173 (2008).

    Article  PubMed  CAS  Google Scholar 

  95. Ware, M. A., Fitzcharles, M.-A., Joseph, L. & Shir, Y. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth. Analg. 110, 604–610 (2010).

    Article  PubMed  CAS  Google Scholar 

  96. Fiz, J., Durán, M., Capellà, D., Carbonell, J. & Farré, M. Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life. PLoS ONE 6, e18440 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Fitzcharles, M.-A. et al. Rheumatologists lack confidence in their knowledge of cannabinoids pertaining to the management of rheumatic complaints. BMC Musculoskelet. Disord. 15, 258 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Robinson, R. H. et al. A CB2-selective cannabinoid suppresses T-cell activities and increases Tregs and IL-10. J. Neuroimmune Pharmacol. 10, 318–332 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Gonzalez, E. G. et al. Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis. Ann. Rheum. Dis. 71, 1545–1551 (2012).

    Article  PubMed  CAS  Google Scholar 

  100. Whiting, P. F. et al. Cannabinoids for medical use. JAMA 313, 2456 (2015).

    Article  PubMed  CAS  Google Scholar 

  101. Fitzcharles, M.-A., Baerwald, C., Ablin, J. & Häuser, W. Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): a systematic review of randomized controlled trials. Schmerz 30, 47–61 (2016).

    Article  PubMed  Google Scholar 

  102. Katz, I., Katz, D., Shoenfeld, Y. & Porat-Katz, B. S. Clinical evidence for utilizing cannabinoids in the elderly. Isr. Med. Assoc. J. 19, 71–75 (2017).

    PubMed  Google Scholar 

  103. Gunn, J. K. L. et al. Prenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis. BMJ Open 6, e009986 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Hall, W. & Degenhardt, L. The adverse health effects of chronic cannabis use. Drug Test. Anal. 6, 39–45 (2014).

    Article  PubMed  CAS  Google Scholar 

  105. Schrot, R. J. & Hubbard, J. R. Cannabinoids: medical implications. Ann. Med. 48, 128–141 (2016).

    Article  PubMed  CAS  Google Scholar 

  106. Silins, E. et al. Young adult sequelae of adolescent cannabis use: an integrative analysis. Lancet Psychiatry 1, 286–293 (2014).

    Article  PubMed  Google Scholar 

  107. Solowij, N. Adolescent cannabis use: what is the evidence for functional brain alteration? Curr. Pharm. Des. 22, 6353–6365 (2016).

    PubMed  Google Scholar 

  108. Chabarria, K. C. et al. Marijuana use and its effects in pregnancy. Am. J. Obstet Gynecol. 215, 506.e1–506.e7 (2016).

    Article  Google Scholar 

  109. Vaucher, J. et al. Cannabis use and risk of schizophrenia: a Mendelian randomization study. Mol. Psychiatry 23, 1287–1292 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Mittleman, M. A., Lewis, R. A., Maclure, M., Sherwood, J. B. & Muller, J. E. Triggering myocardial infarction by marijuana. Circulation 103, 2805–2809 (2001).

    Article  PubMed  CAS  Google Scholar 

  111. Weinstein, A., Livny, A. & Weizman, A. Brain imaging studies on the cognitive, pharmacological and neurobiological effects of cannabis in humans: evidence from studies of adult users. Curr. Pharm. Des. 22, 6366–6379 (2017).

    Article  CAS  Google Scholar 

  112. Fitzcharles, M.-A., McDougall, J., Ste-Marie, P. A. & Padjen, I. Clinical implications for cannabinoid use in the rheumatic diseases: potential for help or harm? Arthritis Rheum. 64, 2417–2425 (2012).

    Article  PubMed  Google Scholar 

  113. Wilens, T. E., Biederman, J. & Spencer, T. J. Case study: adverse effects of smoking marijuana while receiving tricyclic antidepressants. J. Am. Acad. Child Adolesc. Psychiatry 36, 45–48 (1997).

    Article  PubMed  CAS  Google Scholar 

  114. Stoll, A. L., Cole, J. O. & Lukas, S. E. A case of mania as a result of fluoxetine-marijuana interaction. J. Clin. Psychiatry 52, 280–281 (1991).

    PubMed  CAS  Google Scholar 

  115. Kokalj, A., Rijavec, N. & Tavčar, R. Delirium with anticholinergic symptoms after a combination of paliperidone and olanzapine pamoate in a patient known to smoke cannabis: an unfortunate coincidence. BMJ Case Rep. 2016, bcr2016214806 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Galiegue, S. et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur. J. Biochem. 232, 54–61 (1995).

    Article  PubMed  CAS  Google Scholar 

  117. Derocq, J.-M., Ségui, M., Marchand, J., Le Fur, G. & Casellas, P. Cannabinoids enhance human B cell growth at low nanomolar concentrations. FEBS Lett. 369, 177–182 (1995).

    Article  PubMed  CAS  Google Scholar 

  118. Schwarz, H., Blanco, F. J. & Lotz, M. Anadamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte proliferation and induces apoptosis. J. Neuroimmunol. 55, 107–115 (1994).

    Article  PubMed  CAS  Google Scholar 

  119. Chen, Y. & Buck, J. Cannabinoids protect cells from oxidative cell death: a receptor-independent mechanism. J. Pharmacol. Exp. Ther. 293, 807–812 (2000).

    PubMed  CAS  Google Scholar 

  120. El-Gohary, M. & Eid, M. A. Effect of cannabinoid ingestion (in the form of bhang) on the immune system of high school and university students. Hum. Exp. Toxicol. 23, 149–156 (2004).

    Article  PubMed  CAS  Google Scholar 

  121. Wu, H.-Y. Y. et al. Cannabidiol-induced apoptosis in primary lymphocytes is associated with oxidative stress-dependent activation of caspase-8. Toxicol. Appl. Pharmacol. 226, 260–270 (2008).

    Article  PubMed  CAS  Google Scholar 

  122. Jan, T.-R., Su, S.-T., Wu, H.-Y. & Liao, M.-H. Suppressive effects of cannabidiol on antigen-specific antibody production and functional activity of splenocytes in ovalbumin-sensitized BALB/c mice. Int. Immunopharmacol. 7, 773–780 (2007).

    Article  PubMed  CAS  Google Scholar 

  123. Cencioni, M. T. et al. Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB2 receptors. PLoS ONE 5, e8688 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Rieder, S. A., Chauhan, A., Singh, U., Nagarkatti, M. & Nagarkatti, P. Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression. Immunobiology 215, 598–605 (2010).

    Article  PubMed  CAS  Google Scholar 

  125. Abo-Elnazar, S., Moaaz, M., Ghoneim, H., Molokhia, T. & El-Korany, W. Th17/Treg imbalance in opioids and cannabinoids addiction: relationship to NF-κB activation in CD4 + T cells. Egypt. J. Immunol. 21, 43–47 (2014).

    Google Scholar 

  126. Maresz, K. et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat. Med. 13, 492–497 (2007).

    Article  PubMed  CAS  Google Scholar 

  127. Parker, J. et al. Suppression of human macrophage interleukin-6 by a nonpsychoactive cannabinoid acid. Rheumatol. Int. 28, 631–635 (2008).

    Article  PubMed  CAS  Google Scholar 

  128. Chang, Y. H., Lee, S. T. & Lin, W. W. Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of eicosanoids. J. Cell. Biochem. 81, 715–723 (2001).

    Article  PubMed  CAS  Google Scholar 

  129. Correa, F., Mestre, L., Docagne, F. & Guaza, C. Activation of cannabinoid CB2 receptor negatively regulates IL-12p40 production in murine macrophages: role of IL-10 and ERK1/2 kinase signaling. Br. J. Pharmacol. 145, 441–448 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Selvi, E. et al. Inhibitory effect of synthetic cannabinoids on cytokine production in rheumatoid fibroblast-like synoviocytes. Clin. Exp. Rheumatol. 26, 574–581 (2008).

    PubMed  CAS  Google Scholar 

  131. Johnson, D. R., Stebulis, J. A., Rossetti, R. G., Burstein, S. H. & Zurier, R. B. Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid. J. Cell. Biochem. 100, 184–190 (2007).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank E. Israeli for his comments on the manuscript.

Author information

Authors and Affiliations

  1. Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Israel

    Daphna Katz-Talmor, Itay Katz, Bat-Sheva Porat-Katz & Yehuda Shoenfeld

  2. Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Daphna Katz-Talmor

  3. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Itay Katz & Yehuda Shoenfeld

  4. Robert H. Smith Faculty of Agriculture, Food and Environment, School of Nutritional Sciences, Hebrew University of Jerusalem, Rehovot, Israel

    Bat-Sheva Porat-Katz

Authors
  1. Daphna Katz-Talmor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Itay Katz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bat-Sheva Porat-Katz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yehuda Shoenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.S., D.K.-T. and I.K. researched data for and wrote the article. D.K.-T. and Y.S. substantially contributed to discussion of content. All authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Yehuda Shoenfeld.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Katz-Talmor, D., Katz, I., Porat-Katz, BS. et al. Cannabinoids for the treatment of rheumatic diseases — where do we stand?. Nat Rev Rheumatol 14, 488–498 (2018). https://doi.org/10.1038/s41584-018-0025-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-018-0025-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing