Skip to main content
Top

08-06-2018 | Pain | Review | Article

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

Journal: Nature Reviews Rheumatology

Authors: Daphna Katz-Talmor, Itay Katz, Bat-Sheva Porat-Katz, Yehuda Shoenfeld

Publisher: Nature Publishing Group UK

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.
Literature
1.
Warf, B. High points: an historical geography of cannabis. Geogr. Rev. 104, 414–438 (2014).CrossRef
2.
Zuardi, A. W. History of cannabis as a medicine: a review. Revista Brasileira Psiquiatria 28, 153–157 (2006).CrossRef
3.
Pain, S. A potted history. Nature 525, S10–S11 (2015).PubMedCrossRef
4.
Katchan, V., David, P. & Shoenfeld, Y. Cannabinoids and autoimmune diseases: a systematic review. Autoimmun. Rev. 15, 513–528 (2016).PubMedCrossRef
5.
Gaoni, Y. & Mechoulam, R. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86, 1646–1647 (1964).CrossRef
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
7.
Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).PubMedCrossRef
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).PubMedCrossRef
9.
Maccarrone, M. et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol. Sci. 36, 277–296 (2015).PubMedPubMedCentralCrossRef
10.
Mechoulam, R. Cannabis - the Israeli perspective. J. Basic Clin. Physiol. Pharmacol. 27, 181–187 (2016).PubMedCrossRef
11.
Iversen, L. Cannabis and the brain. Brain 126, 1252–1270 (2003).PubMedCrossRef
12.
Mackie, K. Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength. Int. J. Obes. 30 (Suppl. 1), S19–S23 (2006).CrossRef
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).PubMedCrossRef
14.
Guindon, J. & Hohmann, A. G. The endocannabinoid system and pain. CNS Neurol. Disord. Drug Targets 8, 403–421 (2009).PubMedPubMedCentralCrossRef
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).PubMedCrossRef
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).PubMedPubMedCentralCrossRef
17.
Castillo, P. E., Younts, T. J., Chávez, A. E. & Hashimotodani, Y. Endocannabinoid signaling and synaptic function. Neuron 76, 70–81 (2012).PubMedPubMedCentralCrossRef
18.
Howlett, A. C. et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 54, 161–202 (2002).PubMedCrossRef
19.
Howlett, A. C., Blume, L. C. & Dalton, G. D. CB1 cannabinoid receptors and their associated proteins. Curr. Med. Chem. 17, 1382–1393 (2010).PubMedPubMedCentralCrossRef
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).PubMedPubMedCentralCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
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).PubMedPubMedCentralCrossRef
24.
Beltramo, M. et al. CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur. J. Neurosci. 23, 1530–1538 (2006).PubMedCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
28.
Barrie, N. et al. Endocannabinoids in arthritis: current views and perspective. Int. J. Rheum. Dis. 20, 789–797 (2017).PubMedCrossRef
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).PubMedPubMedCentralCrossRef
30.
Irving, A. et al. Cannabinoid receptor-related orphan G protein-coupled receptors. Adv. Pharmacol. 80, 223–247 (2017).PubMedCrossRef
31.
Katz, D., Katz, I. & Shoenfeld, Y. Cannabis and autoimmunity–the neurologic perspective: a brief review. J. Neurol. Neuromed. 1, 11–15 (2016).
32.
Pertwee, R. G. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol. Ther. 74, 129–180 (1997).PubMed
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).PubMedPubMedCentralCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
36.
Russo, E. B. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br. J. Pharmacol. 163, 1344–1364 (2011).PubMedPubMedCentralCrossRef
37.
Russo, E. B. & Marcu, J. Cannabis pharmacology: the usual suspects and a few promising leads. Adv. Pharmacol. 80, 67–134 (2017).PubMedCrossRef
38.
Jiang, C.-P. et al. Anti-rheumatoid arthritic activity of flavonoids from Daphne genkwa. Phytomedicine 21, 830–837 (2014).PubMedCrossRef
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).CrossRef
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).PubMedCrossRef
41.
Wang, T., Collet, J.-P., Shapiro, S. & Ware, M. A. Adverse effects of medical cannabinoids: a systematic review. CMAJ 178, 1669–1678 (2008).PubMedPubMedCentralCrossRef
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).CrossRef
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).PubMedPubMedCentralCrossRef
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).PubMedPubMedCentralCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
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).PubMedPubMedCentralCrossRef
49.
Curran, H. V. et al. Keep off the grass? Cannabis, cognition and addiction. Nat. Rev. Neurosci. 17, 293–306 (2016).PubMedCrossRef
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).PubMedCrossRef
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).CrossRef
52.
Agrawal, A. & Lynskey, M. T. Candidate genes for cannabis use disorders: findings, challenges and directions. Addiction 104, 518–532 (2009).PubMedPubMedCentralCrossRef
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).PubMedPubMedCentralCrossRef
54.
Smith, A. M. et al. Prenatal marijuana exposure impacts executive functioning into young adulthood: an fMRI study. Neurotoxicol. Teratol. 58, 53–59 (2016).PubMedCrossRef
55.
Kerbrat, A. et al. Acute neurologic disorder from an inhibitor of fatty acid amide hydrolase. N. Engl. J. Med. 375, 1717–1725 (2016).PubMedCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
58.
Anderson, G. D. & Chan, L. N. Pharmacokinetic drug interactions with tobacco, cannabinoids and smoking cessation products. Clin. Pharmacokinet. 55, 1353–1368 (2016).PubMedCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
61.
Hartman, R. L. et al. Controlled cannabis vaporizer administration: blood and plasma cannabinoids with and without alcohol. Clin. Chem. 61, 850–869 (2015).PubMedCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
64.
Shapira, Y., Agmon-Levin, N. & Shoenfeld, Y. Geoepidemiology of autoimmune rheumatic diseases. Nat. Rev. Rheumatol. 6, 468–476 (2010).PubMedCrossRef
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).PubMedPubMedCentralCrossRef
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).CrossRef
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).PubMedCrossRef
68.
Fukuda, S. et al. Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis. BMC Musculoskelet. Disord. 15, 275 (2014).PubMedPubMedCentralCrossRef
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).PubMedCrossRef
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).CrossRef
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).PubMedPubMedCentralCrossRef
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).PubMedCrossRef
73.
Bannuru, R. R. et al. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis. Ann. Intern. Med. 162, 46 (2015).PubMedCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
76.
Gõmez, R. et al. Endogenous cannabinoid anandamide impairs cell growth and induces apoptosis in chondrocytes. J. Orthop. Res. 32, 1137–1146 (2014).PubMedCrossRef
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).PubMedCrossRef
78.
La Porta, C. et al. Role of the endocannabinoid system in the emotional manifestations of osteoarthritis pain. Pain 156, 2001–2012 (2015).PubMedPubMedCentralCrossRef
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).PubMedCrossRef
80.
Rossi, D. et al. How I treat patients with systemic sclerosis in clinical practice. Autoimmun. Rev. 16, 1024–1028 (2017).PubMedCrossRef
81.
Marquart, S. et al. Inactivation of the cannabinoid receptor CB1 prevents leukocyte infiltration and experimental fibrosis. Arthritis Rheum. 62, 3467–3476 (2010).PubMedCrossRef
82.
Akhmetshina, A. et al. The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis. Arthritis Rheum. 60, 1129–1136 (2009).PubMedCrossRef
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).PubMedPubMedCentralCrossRef
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).PubMedPubMedCentralCrossRef
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).PubMedCrossRef
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).PubMedPubMedCentralCrossRef
87.
Garcia-Gonzalez, E. et al. Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts. Rheumatology 48, 1050–1056 (2009).PubMedCrossRef
88.
Wolfe, F. et al. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin. Arthritis Rheum. 46, 319–329 (2016).PubMedCrossRef
89.
Fitzcharles, M.-A. & Jamal, S. Expanding medical marijuana access in Canada: considerations for the rheumatologist. J. Rheumatol. 42, 143–145 (2015).PubMedCrossRef
90.
Walsh, Z. et al. Cannabis for therapeutic purposes: patient characteristics, access, and reasons for use. Int. J. Drug Policy 24, 511–516 (2013).PubMedCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
93.
Walitt, B., Klose, P., Fitzcharles, M. A., Phillips, T. & Häuser, W. Cannabinoids for fibromyalgia. Cochrane Database Syst. Rev. 7, CD011694 (2016).PubMed
94.
Skrabek, R. Q., Galimova, L., Ethans, K. & Perry, D. Nabilone for the treatment of pain in fibromyalgia. J. Pain 9, 164–173 (2008).PubMedCrossRef
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).PubMedCrossRef
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).PubMedPubMedCentralCrossRef
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).PubMedPubMedCentralCrossRef
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).PubMedPubMedCentralCrossRef
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).PubMedCrossRef
100.
Whiting, P. F. et al. Cannabinoids for medical use. JAMA 313, 2456 (2015).PubMedCrossRef
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).PubMedCrossRef
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
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).PubMedPubMedCentralCrossRef
104.
Hall, W. & Degenhardt, L. The adverse health effects of chronic cannabis use. Drug Test. Anal. 6, 39–45 (2014).PubMedCrossRef
105.
Schrot, R. J. & Hubbard, J. R. Cannabinoids: medical implications. Ann. Med. 48, 128–141 (2016).PubMedCrossRef
106.
Silins, E. et al. Young adult sequelae of adolescent cannabis use: an integrative analysis. Lancet Psychiatry 1, 286–293 (2014).PubMedCrossRef
107.
Solowij, N. Adolescent cannabis use: what is the evidence for functional brain alteration? Curr. Pharm. Des. 22, 6353–6365 (2016).PubMed
108.
Chabarria, K. C. et al. Marijuana use and its effects in pregnancy. Am. J. Obstet Gynecol. 215, 506.e1–506.e7 (2016).CrossRef
109.
Vaucher, J. et al. Cannabis use and risk of schizophrenia: a Mendelian randomization study. Mol. Psychiatry 23, 1287–1292 (2017).PubMedPubMedCentralCrossRef
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).PubMedCrossRef
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).CrossRef
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).PubMedCrossRef
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).PubMedCrossRef
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
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).PubMedPubMedCentralCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
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
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).PubMedCrossRef
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).PubMedCrossRef
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).PubMedCrossRef
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).PubMedPubMedCentralCrossRef
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).PubMedCrossRef
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).
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).PubMedCrossRef
127.
Parker, J. et al. Suppression of human macrophage interleukin-6 by a nonpsychoactive cannabinoid acid. Rheumatol. Int. 28, 631–635 (2008).PubMedCrossRef
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).PubMedCrossRef
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).PubMedPubMedCentralCrossRef
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
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).PubMedCrossRef