cannabis constituent cannabidiol is an oral anti-arthritic therapeutic

[Sequoiacrone]

The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis

<LI id=contrib-1>A. M. Malfait (http://www.pnas.org/search?author1=A.+M.+Malfait&sortspec=date&submit=Submit)* (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#aff-1),† (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#fn-1), <LI id=contrib-2>R. Gallily (http://www.pnas.org/search?author1=R.+Gallily&sortspec=date&submit=Submit)† (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#fn-1),‡ (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#aff-1), <LI id=contrib-3>P. F. Sumariwalla (http://www.pnas.org/search?author1=P.+F.+Sumariwalla&sortspec=date&submit=Submit)* (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#aff-1), <LI id=contrib-4>A. S. Malik (http://www.pnas.org/search?author1=A.+S.+Malik&sortspec=date&submit=Submit)* (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#aff-1), <LI id=contrib-5>E. Andreakos (http://www.pnas.org/search?author1=E.+Andreakos&sortspec=date&submit=Submit)* (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#aff-1), <LI id=contrib-6>R. Mechoulam (http://www.pnas.org/search?author1=R.+Mechoulam&sortspec=date&submit=Submit)‡ (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#aff-1), and
M. Feldmann (http://www.pnas.org/search?author1=M.+Feldmann&sortspec=date&submit=Submit)* (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#aff-1),§ (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#fn-2)
+ (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#)Author Affiliations

*Kennedy Institute of Rheumatology, 1 Aspenlea Road, Hammersmith, London W6 8LH, United Kingdom; and ‡Hebrew University, Hadassah Medical School, P.O.B. 12272, Jerusalem 91120, Israel

Edited by Anthony Cerami, The Kenneth S. Warren Laboratories, Tarrytown, NY, and approved June 2, 2000 (received for review March 10, 2000)

Abstract

The therapeutic potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis, was explored in murine collagen-induced arthritis (CIA). CIA was elicited by immunizing DBA/1 mice with type II collagen (CII) in complete Freund's adjuvant. The CII used was either bovine or murine, resulting in classical acute CIA or in chronic relapsing CIA, respectively. CBD was administered after onset of clinical symptoms, and in both models of arthritis the treatment effectively blocked progression of arthritis. CBD was equally effective when administered i.p. or orally. The dose dependency showed a bell-shaped curve, with an optimal effect at 5 mg/kg per day i.p. or 25 mg/kg per day orally. Clinical improvement was associated with protection of the joints against severe damage. Ex vivo, draining lymph node cells from CBD-treated mice showed a diminished CII-specific proliferation and IFN-γ production, as well as a decreased release of tumor necrosis factor by knee synovial cells. In vitro effects of CBD included a dose-dependent suppression of lymphocyte proliferation, both mitogen-stimulated and antigen-specific, and the blockade of the Zymosan-triggered reactive oxygen burst by peritoneal granulocytes. It also was found that CBD administration was capable of blocking the lipopolysaccharide-induced rise in serum tumor necrosis factor in C57/BL mice. Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect in CIA.

Footnotes


↵ (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#xref-fn-1-1) † A.M.M. and R.G. contributed equally to this work.
↵ (http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46#xref-fn-2-1) § To whom reprint requests should be addressed. E-mail: m.feldmann@ic.ac.uk (m.feldmann@ic.ac.uk).
This paper was submitted directly (Track II) to the PNAS office.
See commentary on page 9363 (http://www.pnas.org/lookup/volpage/97/9363).
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.160105897.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.160105897
Abbreviations: CBD, cannabidiol; CIA, collagen-induced arthritis; CII, type II collagen; LNC, lymph node cell; TNF, tumor necrosis factor; RA, rheumatoid arthritis; LPS, lipopolysaccharide
Copyright © The National Academy of Sciences



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Commentary:

Stephen E. Straus
Immunoactive cannabinoids: Therapeutic prospects for marijuana constituentsPNAS 2000 97:9363-9364; published ahead of print August 8, 2000

Extract (http://www.pnas.org/content/97/17/9363.extract)
Full Text (http://www.pnas.org/content/97/17/9363.full)
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find the full text here:
http://www.pnas.org/content/97/17/9561.abstract?sid=71b59767-261a-42bc-aae8-2cc73ea58e46

Also find my comments on the trials and tribulations of researching an OLD PNAS abstract about whole cannabis use in mice injected with Arthritis

[Sequoiacrone]

The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis

Based on the reported analgesic and anti-inflammatory properties of cannabinoids, it was considered that these compounds might have anti-arthritic potency. The aim of the present study was to assess the therapeutic efficacy of CBD, a nonpsychoactive component of marijuana, in murine CIA as a model for RA. In the initial experiments, CBD was administered i.p. after the onset of clinical arthritis. It was found that CBD exerted a dose-dependent suppressive action, both on the clinical arthritis and joint damage (Fig. 1 (http://www.pnas.org/content/97/17/9561.full#F1); Table 1 (http://www.pnas.org/content/97/17/9561.full#T1)). The dose dependency showed a bell-shaped curve, with the 5 mg/kg dose exerting an optimal therapeutic effect, whereas both the lowest dose (2.5 mg/kg) and the highest dose (20 mg/kg) were inactive. Interestingly, the therapeutic action also was observed when CBD was administered orally and 25 mg/kg, not the highest dose tested, was most effective. The same therapeutic protocols subsequently were performed in homologous CIA, a chronic relapsing form of CIA with a disease pattern that resembles human disease better (30 (http://www.pnas.org/content/97/17/9561.full#ref-30), 31 (http://www.pnas.org/content/97/17/9561.full#ref-31)). Again, we found an optimal amelioration of clinical disease and joint damage for CBD, 5 mg/kg i.p. or 25 mg/kg orally. The clinical anti-inflammatory effect with 5 mg/kg i.p. was not statistically significant, but histological evaluation showed a significant protection of the joints. We do not have an explanation for the bell-shaped dose dependency, but such behavior has been repeatedly described for cannabinoids (32 (http://www.pnas.org/content/97/17/9561.full#ref-32)).
CBD was found to exert a potent immunosuppressive effect both in vivo and in vitro. LNCs from mice treated with CBD showed a diminished CII-specific proliferation and markedly diminished IFN-γ release (Table 3 (http://www.pnas.org/content/97/17/9561.full#T3)). In independent in vitro experiments, it was found that CBD suppressed the CII-specific proliferation of LNCs from arthritic mice in a dose-dependent manner, and it also suppressed Con A-induced proliferation of purified lymphocytes.
Synovial cells from mice that had been treated with an optimal dose of CBD (5 mg/kg per day i.p. for 10 days) released significantly less TNF when cultured in vitro than synovial cells from control animals (Fig. 3 (http://www.pnas.org/content/97/17/9561.full#F3)). This finding suggests that the therapeutic actions of CBD include the suppression of TNF-α, a proinflammatory cytokine known to be a major mediator of arthritis (22 (http://www.pnas.org/content/97/17/9561.full#ref-22)). This was corroborated by the finding that CBD, when injected i.p. or s.c at a concentration of 10 mg/kg, blocked LPS-induced serum TNF in C57BL/6 mice (Table 5 (http://www.pnas.org/content/97/17/9561.full#T5)). Nevertheless, we could not find suppression of TNF release by arthritic synovial cells when CBD was added in vitro (not shown), nor could we demonstrate in multiple attempts that CBD suppressed TNF release by mouse bone marrow-derived macrophages or RAW cells (data not shown). This discrepancy between in vivo and in vitro results suggests that the TNF suppression, which is observed in vivo after administration of CBD, might be mediated by an active metabolite of CBD. Another possibility is that the decreased TNF expression in vivo is an indirect consequence of a suppressed T helper 1 response.
Thus, the anti-arthritic potency of CBD seems to be the result of a combination of immunosuppression, especially of a T helper 1 response and an anti-inflammatory action by way of reducing TNF in the synovium, a combination that has proven successful in the past when anti-IL-12 and anti-TNF were combined to treat CIA (33 (http://www.pnas.org/content/97/17/9561.full#ref-33)). Apart from these major effects, we also have demonstrated other in vitro anti-inflammatory actions of CBD that may contribute to its anti-arthritic potency, such as the inhibition of the release of reactive oxygen species by Zymosan-stimulated neutrophils (Table 4 (http://www.pnas.org/content/97/17/9561.full#T4) and ref. 34 (http://www.pnas.org/content/97/17/9561.full#ref-34)). We also observed the blockade of NO production by peritoneal macrophages (not shown), as reported in the literature (11 (http://www.pnas.org/content/97/17/9561.full#ref-11)).
Cannabis has a long history as a medicinal preparation, mainly for properties such as analgesia, antiemesis, ocular hypotension, and anticonvulsion (reviewed in ref. 35 (http://www.pnas.org/content/97/17/9561.full#ref-35)). Recent research in vitro and in animal models has led to increasing evidence that cannabinoids are also important modulators of the immune system (6 (http://www.pnas.org/content/97/17/9561.full#ref-6)) and thus could have a role in the treatment of chronic inflammatory diseases, were the development of clinical trials not hampered by legal obstacles. It is therefore important to find out whether nonpsychoactive cannabinoids are suitable for treating chronic inflammatory disease. A recent report describes the effect of a nonpsychoactive synthetic derivative from tetrahydrocannabinol (THC), dimethylheptyl-THC-11-oic acid, in adjuvant arthritis in rats (36 (http://www.pnas.org/content/97/17/9561.full#ref-36)). The authors found that the compound reduced the severity of arthritis when administered from immunization onward (i.e., in a preventive protocol). The present study shows that CBD, a natural constituent of marijuana, is effective as an anti-arthritic therapeutic in established CIA. Its efficacy when given orally renders it an attractive candidate for the treatment of RA. The experiments in the chronic CIA model show that prolonged treatment with CBD does not induce tolerance, a phenomenon often observed with cannabinoids (37 (http://www.pnas.org/content/97/17/9561.full#ref-37), 38 (http://www.pnas.org/content/97/17/9561.full#ref-38)). Moreover, clinical trials with CBD have been conducted in humans with epilepsy (39 (http://www.pnas.org/content/97/17/9561.full#ref-39)) and Huntington's disease (40 (http://www.pnas.org/content/97/17/9561.full#ref-40)), and it was found that chronic oral administration of CBD, up to 10 mg/kg per day for 6 weeks, had no side effects. Interestingly, one paper describes that feeding 300 or 600 mg CBD to healthy human volunteers resulted in elevated plasma cortisol levels (41 (http://www.pnas.org/content/97/17/9561.full#ref-41)), yet another factor that may contribute to its anti-inflammatory/immunosuppressive actions. All of this suggests that CBD may be valuable in the treatment of other chronic inflammatory diseases as well. Indeed, preliminary studies indicate that CBD is able to delay and attenuate experimental allergic encephalomyelitis in mice (R.G. and H. Ovadia, unpublished observations) as well as inflammatory bowel disease in IL-10 knockout mice (T. Sheinin and M.F., unpublished observations).


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