Welcome members and clients of OMMP PIF. Due to increased costs, our website has moved to this server, Thanks go to our Friend and colleague, Wired57, for making this possible. If you have any questions or concerns, please start a new topic in 
Thank you 
04-16-2012, 10:10 PM
Arthritis
General Reference (not clearly pro or con)
General Reference (not clearly pro or con)
MedlinePlus, the National Library of Medicine's online Medical Encyclopedia, stated as of May 15, 2006: "Arthritis is inflammation of one or more joints, which results in pain, swelling, and limited movement.
Osteoarthritis is a common type of arthritis characterized by a gradual loss of cartilage from the joints. Although osteoarthritis can affect almost any joint, it most often affects the hands, knees, hips, and spine. Common symptoms include pain, stiffness, some loss of joint motion, and changes in the shape of affected joints.
Rheumatoid arthritis is a chronic autoimmune disease, mainly characterized by inflammation of the lining, or synovium, of the joints. It can lead to long-term joint damage, resulting in chronic pain, loss of function and disability"
More">http://medicalmariju...ID=000131">More on Pro's and Cons
01/20/2006
Marijuana Like Drug Shows Promise in Treating Arthritis
by Joel Rutstein M.D.
Could smoking pot or taking marijuana in any form help with rheumatoid arthritis? A recent study in England suggests that it might have benefit. A company in England called GW Pharmaceuticals makes a spray called Saltivex. Saltivex contains two components of marijuana. One is tetrahydrocannabinol and the other is cannabodiol. These are important parts of marijuana that have been shown previously to benefit patients who have pain or inflammation. In this study they looked at a total of fifty-eight patients with rheumatoid arthritis. Thirty-one were treated with Saltivex and twenty-seven were given a placebo spray. The patients took it in the evening with one or two sprays for four weeks, and this was done at night in order to minimize any problems with side effects. Patients were not told ("blinded") as to whether they were getting the real Saltivex or a placebo. It turned out that when patients used the Saltivex spray derived from marijuana components that their pain was less and their sleep was better. Their overall activity of their rheumatoid arthritis also improved. There were some side effects noted. Out of the thirty-one rheumatoid arthritis patients receiving the real spray, eight patients experienced dizziness, four of the thirty-one patients had dry mouth, and three of them had light-hotheadedness. This is a very small study with limited number of patients, but it does suggest that it would be worthwhile to performing a larger study to see if indeed marijuana or a marijuana derivative would truly benefit rheumatoid arthritis patients. Perhaps before you rush down to the nearest college campus to buy your first bag of marijuana, let's wait and see what these longer term studies show.
source: http://www.arthritis...our Medications
Pot-Based Drug Promising for Arthritis
Spray Shows Benefits for Rheumatoid Arthritis in Small British Study
By Miranda Hitti
WebMD Health NewsReviewed by Louise Chang, MDNov. 8, 2005 - A spray containing two chemicals extracted from marijuana improved pain and sleep in rheumatoid arthritis (RA) patients, British researchers report.
The study, which appears in Rheumatology, was small, brief, and likely the first of its kind, note the researchers. They write that the "encouraging" results warrant larger, longer studies.
The spray, called Sativex, is made by GW Pharmaceuticals, the British drug company that funded the study. It is sprayed into the mouth and the medication is absorbed under the tongue or the inside part of the cheek.
One of the researchers is GW Pharmaceuticals' medical director. Two others disclose having received honoraria from GW Pharmaceuticals.
Spray Study
The study included 58 RA patients. They had no history of psychiatric disorders, substance misuse, epilepsy, or severe heart, kidney, or liver problems.
First, patients rated their pain at rest, during movement, and first thing in the morning. They also rated their quality of sleep.
Next, the patients were given one of two sprays to use every evening for about a month. Sativex was one of those sprays. The other was an empty spray (placebo).
Sativex was given to 31 patients. The other 27 patients got the placebo. No one knew which patients had gotten Sativex.
Sativex contains THC (delta-9-tetrahydrocannabinol) and CBD (cannabidiol). Those are key therapeutic compounds in cannabis that have been shown by other studies to produce effects on pain and inflammation, write the researchers.
They included rheumatologist David R. Blake of the Royal National Hospital for Rheumatic Diseases in Bath, England.
Study's Results
Compared with the placebo group, patients taking Sativex had notable improvements in pain (including pain during movement and pain at rest), sleep quality, and RA disease activity, the researchers report.
Morning pain didn't change much but was "surprisingly low" to begin with, write Blake and colleagues.
The sprays were only used in the evening to minimize any intoxication. The most common side effects with Sativex were dizziness (eight patients, or 26% of the Sativex group), dry mouth (four patients, or 13%), and lightheadedness (three patients, or 10% of those taking Sativex).
source: http://www.webmd.com...g-for-arthritis
Cannabis Helps - Arthritis
Arthritis refers to any more than 100 inflammatory joint disorders characterized by pain, swelling, and limited movement. Arthritis involves the inflammation and degeneration of cartilage and bone that make up the joint. Experts estimate that more than 31 million people in the United States alone suffer from various degrees of the disease. Common forms of arthritis are osteoarthritis and rheumatoid arthritis. Emerging evidence implies that cannabis can help alleviate symptoms of both conditions.
Osteoarthritis, the more common disorder, occurs when cartilage in the joints degenerates. It typically strikes the joints that support weight such as the knees, hips, and spine. Main symptoms of the disease are joint stiffness, swelling, and pain, usually in the morning. Rheumatoid arthritis is characterized by painful swelling of the smaller joints with the destruction of the tissue around them. Physicians commonly prescribe analgesics and nonsteroidal anti-inflammatory drugs (NSAIDS) to ease the pain and inflammation associated with arthritis.
Cannabis' pain reducing properties are well documented (1) and emerging evidence indicates that it holds anti-inflammatory qualities. Dale Gieringer, author of the paper "Review of Human Studies on the Medical Use of Marijuana," cites three animal and laboratory studies documenting cannabis' potential anti-inflammatory effects. (2) In addition, a 1988 study by an English research team found the cannabinoid CBD (cannabidiol) ameliorated inflammation in mice. "Our results would suggest that cultivation of cannabis plants rich in CBD and other phenolic substances would be useful for medicinal purposes in the treatment of certain inflammatory disorders," researchers concluded. (3) It is possible that cannabis' anti-inflammatory properties could reduce swelling and improve mobility in some arthritis patients. Research in this area is obviously needed.
References used above
1. R. Callahan, "How Does Marijuana Kill Pain," Associated Press, October 4, 1998. See also [pain]
2. "Review of the Human Studies on the Medical Use of Marijuana," Dale Gieringer, Ph.D. (1996).
3. E. Formukong et al., "Analgesic and Antiinflammatory Activity of Constituents of Cannabis Sativa L.," Inflammation 12 (1988): 361.
source: http://www.budbuddie...s/arthritis.htm
For results in this study go to: http://www.pnas.org/...97/17/9561.full
The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis
A. M. Malfait*,, R. Gallily,, P. F. Sumariwalla*, A. S. Malik*, E. Andreakos*, R. Mechoulam, and M. Feldmann*,
+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)
Next SectionAbstract
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- 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.
Cannabidiol (CBD) is one of the major components of Cannabis sativa, marijuana (1). Marijuana contains approximately 80 constituents, termed cannabinoids (2, 3). CBD is not psychoactive, unlike the other major component of cannabis, 9-tetrahydrocannabinol (9THC) (4, 5). A vast literature documents the immune modulating effects of cannabinoids, in vivo and in vitro, mainly of 9THC and synthetic analogues such as CP55,940 (reviewed in ref. 6). A nonexhaustive list of in vitro effects includes inhibition of the proliferative responses of T lymphocytes (7), inhibition of cytotoxic T cell activity (8), suppression of macrophage function and antigen presentation (9, 10), and inhibition of NO production by macrophages (11). Reports on the in vitro effects of CBD on immune cells are scarce and include the modulation of tumor necrosis factor (TNF), IL-1, and IFN- by human peripheral blood mononuclear cells (12, 13) and the suppression of chemokine production by a human B cell line (14). These potentially anti-inflammatory properties of CBD, together with the lack of psychotropic effect and low toxicity (15), prompted us to test the potential of CBD as a therapeutic agent in collagen-induced arthritis (CIA).
CIA, a murine model for rheumatoid arthritis (RA), is elicited by immunizing DBA/1 mice with type II collagen (CII) in complete Freund's adjuvant (16). The immune response to CII involves both humoral and cellular mechanisms (17, 18), and the cellular response is T helper 1-mediated (19). CIA is characterized by rapid onset of clinical joint inflammation, resulting in destruction of joint tissues and cartilage/bone erosions. Suppression of the inflammatory process by blocking TNF with mAbs has proven an effective treatment of CIA (20, 21), and these findings led to the successful use of TNF blockade in multiple phase I, II, and III clinical trials with RA patients (reviewed in ref. 22), thus validating the predictive value of CIA as a model for RA. In the present study, we report that CBD has a beneficial therapeutic action on established CIA, and we explore its mode of action.
Previous SectionNext SectionMaterials and Methods
Purification of CBD.CBD was purified from hashish as reported (23). Its purity was established on the basis of melting point (6667), optical rotation (aD = 125), and single peak on gas chromatography (23).
Induction and Monitoring of Heterologous CIA.Bovine CII was purified from hyaline cartilage (21). Male DBA/1 mice (812 weeks old) were immunized with 100 g of CII emulsified in complete Freund's adjuvant (Difco) by intradermal injection at the base of the tail. From day 15 after immunization onward, mice were examined daily for onset of clinical arthritis. Assessment of arthritis included monitoring of clinical scores where 0 = normal; 1 = slight swelling and erythema; 2 = pronounced edema; 3 = joint rigidity. Each limb was graded, resulting in a maximal clinical score of 12 per animal. The arthritis was monitored over 10 days, after which the mice were killed (21).
Induction and Monitoring of Homologous CIA.Mouse CII was purified from sternal cartilage from female DBA/1 mice, as described for bovine CII. For the chronic experiments, 6-week-old mice were immunized with mouse CII (100 g) in complete Freund's adjuvant. The animals were boosted 15 days later with 100 g CII i.p. From day 30 after immunization onward, 80% of the mice developed a chronic relapsing arthritis, which was monitored for 5 weeks as described above.
Administration of CBD.CBD treatment commenced at the first clinical signs of arthritis and was administered i.p. daily until day 10 of arthritis. The CBD concentrations used were 20 mg/kg (n = 12), 10 mg/kg (n = 17), 5 mg/kg (n = 15), and 2.5 mg/kg (n = 9). CBD was dissolved in ethanol/cremophor (Sigma) (1:1, vol/vol) and further diluted in saline, so that the final solution was ethanol/cremophor/saline (1:1:18). Mice injected with vehicle alone (ethanol/cremophor in saline) served as controls (n = 23).
For the oral treatment protocol, CBD was dissolved in olive oil and administered by oral gavage, daily, from the onset of arthritis for 10 days. The doses used were 10 mg/kg, 25 mg/kg, and 50 mg/kg (n = 6 per group). Control mice were fed olive oil (n = 6).
For the chronic experiments, mice were treated from the first symptoms of arthritis for 5 weeks. For the i.p. route, CBD was injected daily at 10 mg/kg (n = 7) or 5 mg/kg (n = 7). Again, mice injected with vehicle alone served as controls (n = 7). For the oral route, the treatment was administered daily (Monday to Friday) at a dose of 25 mg/kg (n = 6) and control mice were fed olive oil (n = 6).
Histological Analysis.At the end of each experiment, hind paws were removed postmortem, fixed in formalin, and decalcified in 5% EDTA. The paws were embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Arthritic changes in the foot joints were scored as mild (mild synovial hyperplasia), moderate (pannus formation and erosions limited to the cartilage-pannus junction), or severe (extended bone and cartilage erosions with loss of joint architecture). All assessments were performed by an observer blinded to the treatment received.
Lipopolysaccharide (LPS) Induction of Serum TNF in Mice.Female C57BL/6 mice were injected i.p. with a sublethal dose of LPS (100 g, Escherichia coli O55:B5, Difco). CBD was injected simultaneously, either i.p. or s.c., at a dose of 10 mg/kg. Ninety minutes later, the mice were bled and serum TNF levels were determined by bioassay (24).
Reactive Oxygen Intermediate Production by Mouse Granulocytes.C57BL/6 mice were injected i.p. with 1.5 ml thioglycollate (Difco), and 18 h later the cells were harvested by sterile lavage with PBS. The cells were washed and resuspended in Hanks' balanced salt solution without phenol red, and 0.5 ml of the cell suspension was added into luminometer tubes. CBD (dissolved in ethanol) was added at this point at a final concentration of 6 g/ml. Finally, 10 l Luminol (Sigma) and 30 l Zymosan (Sigma) were added, and the chemiluminescence was measured immediately in a luminometer (Biolumate LB 95, Berhold, Wildbad, Germany).
Preparation of CBD for in Vitro Experiments. CBD was dissolved in ethanol at a stock concentration of 10 mg/ml and stored at 4C for up to 2 months. CBD stock was further diluted in warm medium immediately before use. All tissue culture media, vehicle control, and CBD preparations were shown to contain less than 0.1 unit/ml endotoxin, as assessed by the chromogenic Limulus Amebocyte Lysate assay (BioWhittaker). At the end of all in vitro experiments described below, viability of the cells was assessed with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test (25).
Splenic Lymphocyte Culture.Pooled spleens from 10-week-old DBA/1 mice were pushed through a sieve and a single cell suspension was prepared. The cells were washed, layered over a Lympholyte-M density gradient (Cedarlane Laboratories), and spun at 2,000 rpm for 45 min. The buffy coat containing lymphocytes was washed three times and then plated at 2 105 cells/100 l per well in complete medium comprising DMEM supplemented with 10% heat-inactivated FCS, 1% glutamine, 100 units/ml penicillin, 100 mg/ml streptomycin, and 2 105 M 2-mercaptoethanol. Cells were stimulated with 5 g/ml Con A in the presence of 010 g/ml CBD. After 72 h, cells were pulsed with 0.5 Ci/well [3H]thymidine (Amersham Pharmacia) overnight, harvested, and assessed for incorporation of radioactivity.
Draining Lymph Node Cell (LNC) Culture.Mice (controls or CBD-treated) were killed at day 3 after disease onset, and inguinal LNCs were cultured as described (26). Cells were cultured with or without bovine CII (50 g/ml) in Tris-buffered saline, pH 7. Supernatants were collected after 72 h and stored at 20C until cytokine measurement. Alternatively, after 72 h, cells were pulsed with [3H]thymidine overnight and assessed for incorporation of radioactivity.
Culture of Murine Synovial Cells.Mice (control mice or CBD-treated) were killed at day 10 of arthritis and the knee joints were removed. Synovial cell cultures were performed as described (27). Briefly, synovial membranes were excised under a dissecting microscope and digested with 1 mg/ml collagenase A and 0.15 mg/ml DNase type IV in the presence of 33 g/ml polymyxin B. The cells then were washed extensively and cultured in 96-well plates at a density of 2 106 cells/ml (100 l/well) in complete medium with or without CBD at specified concentrations. Supernatants were collected after 24 h and stored at 20C until measured for TNF.
Cytokine Assays.For determination of bioactive TNF levels, an assay was performed by using the WEHI 164 cell line (28), as described (29), or BALB/c CL.7 cells, as described (24). IFN- levels were measured by sandwich ELISA. The capture/detection antibody pair used was R46A2 (obtained from the American Type Culture Collection, courtesy of J. Abrams) and hamster mAb 122200 (Genzyme).
Discussion
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; Table 1). 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, 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).
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- release (Table 3). 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). This finding suggests that the therapeutic actions of CBD include the suppression of TNF-a, a proinflammatory cytokine known to be a major mediator of arthritis (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). 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 exp<b></b>ression 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). 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 and ref. 34). We also observed the blockade of NO production by peritoneal macrophages (not shown), as reported in the literature (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). Recent research in vitro and in animal models has led to increasing evidence that cannabinoids are also important modulators of the immune system (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). 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, 38). Moreover, clinical trials with CBD have been conducted in humans with epilepsy (39) and Huntington's disease (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), 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).
The results presented here leave a number of questions to elucidate in the future. First, is CBD solely responsible for the anti-arthritic effects in vivo or is there an active metabolite involved? Second, via which receptor does CBD exert its effects? Two receptors for cannabinoids have been identified, the brain receptor, CB1 (42), and the peripheral cannabinoid receptor, CB2 (43), which is present on T and B lymphocytes, natural killer cells, and macrophages (6). The affinity of CBD for the cannabinoid receptors is very low, lower than that of the other cannabinoids (43, 44). The possibility that CBD, because of its lipophilicity interferes with cell membranes, thus altering their functions, or that a metabolite acts on the CB2 receptor, cannot be ruled out. These questions should be the subject of future studies.
Previous SectionNext SectionAcknowledgments
We thank Paul Warden and the staff of the Kennedy Institute of Rheumatology Biological Services Unit, Professor R. N. Maini for helpful advice, and Philip Connolly for preparation of the histological sections. The work was funded by the Arthritis Research Campaign of Great Britain.
source: http://www.pnas.org/...97/17/9561.full
Rheumatoid arthritis, cannabis based medicine eases pain and suppresses disease
The first study to use a cannabis-based medicine (CBM) for treating rheumatoid arthritis has found that it has a significant effect on easing pain and on suppressing the disease.
Writing in the medical journal Rheumatology [1], the researchers say that although the differences were small and variable in the group of 56 patients they studied, the results are statistically significant and a larger trial is needed to investigate in more detail the effects of CBM on the disease which affects approximately 600,000 people in the UK (1 in 100 of the population).[2]
There is anecdotal evidence that cannabis can provide pain relief for people with rheumatoid arthritis (RA), and in a recent survey 155 (16%) of 947 people who obtained cannabis on the black market for medicinal reasons said they did so to obtain relief from symptoms of RA. However, this study in Rheumatology journal, led by David Blake, Professor of Bone and Joint Medicine at the Royal National Hospital for Rheumatic Diseases (RNHRD), Bath, and the University of Bath, UK, is the first randomised controlled trial to investigate the effect of a CBM on RA. It is published online today (Wednesday 9 November).
In the double-blind trial, the researchers randomised 31 patients to receive the CBM and 27 the placebo. The CBM (brand name: Sativex) was in the form of an easy-to-use mouth spray that patients could administer themselves up to a maximum of six doses a day. The CBM consisted of a blend of whole plant extracts, standardised for content, that delivered approximately equal amounts of two key therapeutic constituents from the cannabis plant: delta-9-Tetrahydrocannabinol (THC) and cannabidiol (CBD). Mouse studies have shown that THC and CBD have anti-inflammatory effects, and that CBD blocked progression of RA and produced improvements in symptoms.
Dr Ronald Jubb, Consultant Rheumatologist, at the University Hospital Birmingham NHS Foundation Trust, UK, said: "Patients had a baseline assessment at the beginning of the trial and then were randomised to receive either the CBM or placebo. Patients only took the doses in the evening in order to minimise possible intoxication-type reactions. The starting dose was one actuation within half an hour of retiring, and this was increased by one actuation every two days to a maximum of six doses according to individual response over a period of two weeks. Stable dosing was then maintained for a further three weeks."
The researchers found that in comparison with the placebo, patients who had taken the CBM had statistically significant improvements in pain on movement, pain at rest, quality of sleep, inflammation (measured by a Disease Activity Score involving 28 joints - DAS 28) and intensity of pain (measured by the Short-Form McGill Pain Questionnaire SF-MPQ).
For instance, on a score of 0-10 where 0 is no pain, CBM patients on average moved from 7 to 4.8 for pain on movement (placebo patients moved from 6.7 to 5.3), 5.3 to 3.1 (placebo 5.3 to 4.1) for pain at rest, and 5.7 to 3.4 (placebo 5.8 to 4.6) for quality of sleep. On the DAS 28 score of 0-10, the CBM patients moved from 5.9 to 5 (placebo 6 to 5.9), and on the SF-MPQ score of 0-100 for intensity of pain at present, the CBM patients moved from 48 to 33, while the placebo patients remained unchanged at 50.
Adverse side effects were mostly mild or moderate (e.g. dizziness, light-headedness, dry mouth, nausea). Of the eight patients who experienced mild dizziness, in four patients this occurred during the initial two-week period when they were gradually increasing the doses, and two occurred two days after this initial period, so these were probably due to patients getting used to the correct dose. No patients taking the CBM had to withdraw from the trial due to adverse side effects, but three did from the placebo group.
Dr Philip Robson, Senior Research Fellow and Consultant Psychiatrist at the Oxford University Department of Psychiatry and Director of the Cannabinoid Research Institute within GW Pharmaceuticals (the manufacturer of Sativex), explained: "Withdrawals from the placebo group were probably due to a psychological effect, a spontaneous occurrence, or a reaction with another medicine."
Dr Jubb said: "The results from the first controlled study of CBM in rheumatoid arthritis are encouraging, with overall improvements in pain on movement and at rest, improvement in the quality of sleep and improvement in the overall condition of the patients' arthritis. Whilst the differences are small and variable across the patient group, they represent benefits of clinical relevance and indicate the need for more detailed investigation through larger trials to see exactly where CBM could be best used with minimum side effects."
If further trials are run, researchers will probably extend the dosing period over the full 24-hour period. Dr Robson said: "The beneficial effects in this study occurred in the context of a dosing regime restricted to evening dosing in order to minimise any possible intoxication-type reactions. However, 24-hour dosing with Sativex, using a self-titration regime, in trials for multiple sclerosis resulted in only minimal intoxication scores."
He continued: "The element that can cause the 'high' in cannabis - THC - also has valuable pharmacological activity. It is thought to be an essential therapeutic component and therefore it can't be removed from the medicine. However, the method of giving the doses, via the mouth spray, and the principle of self-titration, where each patient gradually determined their own optimal dose level up to a maximum of six doses a day, minimised the risk of intoxication."
Dr Robson said that fears that the CBM could be abused by patients hoping to get a "high" were probably unfounded. "It seems that in practice this is a very rare event. More than 1,000-patient years of treatment with Sativex in clinical trials have been accumulated and to date there has not been a single documented case of abuse. The fact is that the motivation of medicinal users of cannabis-based medicine is entirely different from recreational users: the former simply want symptom relief and the ability to go about their normal lives, and for them intoxication would be a distinct disadvantage; for the latter, smoking marijuana is infinitely more intoxicating than Sativex and is still easily available."
[1] Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology Advance Access published on November 9, 2005.
doi:10.1093/rheumatology/kei183
[2] Rheumatoid arthritis affects three times as many women as men. Prevalence in the UK is approximately 0.5% in men and 1.8% in women, increasing after the age of 64 to 2% in men and 5% in women. There are many more people with less severe forms of RA that do not meet the diagnostic criteria for definite or classical disease.
source: http://www.medicalne...icles/33376.php
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is an inflammatory disease of the joints characterized by pain, stiffness, and swelling, as well as an eventual loss of limb function. Rheumatoid arthritis is estimated to affect about one percent of the population, primarily women.
Use of cannabis to treat symptoms of RA is commonly self-reported by patients with the disease. In a 2005 anonymous questionnaire survey of medicinal cannabis patients in Australia, 25 percent reported using cannabinoids to treat RA.[1] A survey of British medicinal cannabis patients found that more than 20 percent of respondents reported using cannabis for symptoms of arthritis.[2] Nevertheless, few clinical trials investigating the use of cannabis for RA appear in the scientific literature.
In January 2006, investigators at the British Royal National Hospital for Rheumatic Disease reported successful treatment of arthritis with cannabinoids in the first-ever controlled trial assessing the efficacy of natural cannabis extracts on RA.[3] Investigators reported that administration of cannabis extracts over a five week period produced statistically significant improvements in pain on movement, pain at rest, quality of sleep, inflammation, and intensity of pain compared to placebo. No serious adverse effects were observed. Similar results had been reported in smaller, Phase II trials investigating the use of orally administered cannabis extracts on symptoms of RA.[4]
Preclinical data also indicates that cannabinoids can moderate the progression of RA. Writing in the August 2000 issue of the Journal of the Proceedings of the National Academy of Sciences, investigators at Londons Kennedy Institute for Rheumatology reported that cannabidiol (CBD) administration suppressed progression of arthritis in vitro and in animals.[5] Administration of CBD after the onset of clinical symptoms protected joints against severe damage and effectively blocked [the] progression of arthritis, investigators concluded. Daily administration of the synthetic cannabinoid agonist HU-320 has also been reported to protect joints from damage and to ameliorate arthritis in animals.[6]
Summarizing the available literature in the September 2005 issue of the Journal of Neuroimmunology, researchers at Tokyos National Institute for Neuroscience concluded, Cannabinoid therapy of RA could provide symptomatic relief of joint pain and swelling as well as suppressing joint destruction and disease progression.[7]
source: http://www.norml.org...m?Group_ID=7015
Cannabis for Rheumatoid Arthritis
Question
I've had bad arthritis (rheumatism) for years, and I've just heard that cannabis can help. Is that true? Can I get some without a doctor's prescription?
Answer
People have been claiming for years that cannabis can help the pain of rheumatoid arthritis (RA). But there haven't been any good clinical studies to prove the point - until recently. In the November 9 issue of the medical journal Rheumatism doctors report on a study of Sativex, a cannabis-based medicine. Given as a spray into the mouth, Sativex was compared with a dummy spray (placebo) in 58 RA patients over a 5-week period.
Sativex produced statistically significant improvements in main on movement, pain at rest, a joint disease score, and the quality of sleep. There was no effect on morning stiffness. Side effects were only mild or moderate dizziness, light-headedness, and dry mouth.
It looks as if this cannabis-based drug is going to be a useful addition to the range of pain drugs for RA, once it's been approved for marketing in the USA. For that to happen, further, larger, trials will be necessary. Until then, stick to the drugs that your doctor can prescribe now.
source: http://www.healthand...891;jsessionid=
General Reference (not clearly pro or con)
General Reference (not clearly pro or con)
MedlinePlus, the National Library of Medicine's online Medical Encyclopedia, stated as of May 15, 2006: "Arthritis is inflammation of one or more joints, which results in pain, swelling, and limited movement.
Osteoarthritis is a common type of arthritis characterized by a gradual loss of cartilage from the joints. Although osteoarthritis can affect almost any joint, it most often affects the hands, knees, hips, and spine. Common symptoms include pain, stiffness, some loss of joint motion, and changes in the shape of affected joints.
Rheumatoid arthritis is a chronic autoimmune disease, mainly characterized by inflammation of the lining, or synovium, of the joints. It can lead to long-term joint damage, resulting in chronic pain, loss of function and disability"
More">http://medicalmariju...ID=000131">More on Pro's and Cons
01/20/2006
Marijuana Like Drug Shows Promise in Treating Arthritis
by Joel Rutstein M.D.
Could smoking pot or taking marijuana in any form help with rheumatoid arthritis? A recent study in England suggests that it might have benefit. A company in England called GW Pharmaceuticals makes a spray called Saltivex. Saltivex contains two components of marijuana. One is tetrahydrocannabinol and the other is cannabodiol. These are important parts of marijuana that have been shown previously to benefit patients who have pain or inflammation. In this study they looked at a total of fifty-eight patients with rheumatoid arthritis. Thirty-one were treated with Saltivex and twenty-seven were given a placebo spray. The patients took it in the evening with one or two sprays for four weeks, and this was done at night in order to minimize any problems with side effects. Patients were not told ("blinded") as to whether they were getting the real Saltivex or a placebo. It turned out that when patients used the Saltivex spray derived from marijuana components that their pain was less and their sleep was better. Their overall activity of their rheumatoid arthritis also improved. There were some side effects noted. Out of the thirty-one rheumatoid arthritis patients receiving the real spray, eight patients experienced dizziness, four of the thirty-one patients had dry mouth, and three of them had light-hotheadedness. This is a very small study with limited number of patients, but it does suggest that it would be worthwhile to performing a larger study to see if indeed marijuana or a marijuana derivative would truly benefit rheumatoid arthritis patients. Perhaps before you rush down to the nearest college campus to buy your first bag of marijuana, let's wait and see what these longer term studies show.
source: http://www.arthritis...our Medications
Pot-Based Drug Promising for Arthritis
Spray Shows Benefits for Rheumatoid Arthritis in Small British Study
By Miranda Hitti
WebMD Health NewsReviewed by Louise Chang, MDNov. 8, 2005 - A spray containing two chemicals extracted from marijuana improved pain and sleep in rheumatoid arthritis (RA) patients, British researchers report.
The study, which appears in Rheumatology, was small, brief, and likely the first of its kind, note the researchers. They write that the "encouraging" results warrant larger, longer studies.
The spray, called Sativex, is made by GW Pharmaceuticals, the British drug company that funded the study. It is sprayed into the mouth and the medication is absorbed under the tongue or the inside part of the cheek.
One of the researchers is GW Pharmaceuticals' medical director. Two others disclose having received honoraria from GW Pharmaceuticals.
Spray Study
The study included 58 RA patients. They had no history of psychiatric disorders, substance misuse, epilepsy, or severe heart, kidney, or liver problems.
First, patients rated their pain at rest, during movement, and first thing in the morning. They also rated their quality of sleep.
Next, the patients were given one of two sprays to use every evening for about a month. Sativex was one of those sprays. The other was an empty spray (placebo).
Sativex was given to 31 patients. The other 27 patients got the placebo. No one knew which patients had gotten Sativex.
Sativex contains THC (delta-9-tetrahydrocannabinol) and CBD (cannabidiol). Those are key therapeutic compounds in cannabis that have been shown by other studies to produce effects on pain and inflammation, write the researchers.
They included rheumatologist David R. Blake of the Royal National Hospital for Rheumatic Diseases in Bath, England.
Study's Results
Compared with the placebo group, patients taking Sativex had notable improvements in pain (including pain during movement and pain at rest), sleep quality, and RA disease activity, the researchers report.
Morning pain didn't change much but was "surprisingly low" to begin with, write Blake and colleagues.
The sprays were only used in the evening to minimize any intoxication. The most common side effects with Sativex were dizziness (eight patients, or 26% of the Sativex group), dry mouth (four patients, or 13%), and lightheadedness (three patients, or 10% of those taking Sativex).
source: http://www.webmd.com...g-for-arthritis
Cannabis Helps - Arthritis
Arthritis refers to any more than 100 inflammatory joint disorders characterized by pain, swelling, and limited movement. Arthritis involves the inflammation and degeneration of cartilage and bone that make up the joint. Experts estimate that more than 31 million people in the United States alone suffer from various degrees of the disease. Common forms of arthritis are osteoarthritis and rheumatoid arthritis. Emerging evidence implies that cannabis can help alleviate symptoms of both conditions.
Osteoarthritis, the more common disorder, occurs when cartilage in the joints degenerates. It typically strikes the joints that support weight such as the knees, hips, and spine. Main symptoms of the disease are joint stiffness, swelling, and pain, usually in the morning. Rheumatoid arthritis is characterized by painful swelling of the smaller joints with the destruction of the tissue around them. Physicians commonly prescribe analgesics and nonsteroidal anti-inflammatory drugs (NSAIDS) to ease the pain and inflammation associated with arthritis.
Cannabis' pain reducing properties are well documented (1) and emerging evidence indicates that it holds anti-inflammatory qualities. Dale Gieringer, author of the paper "Review of Human Studies on the Medical Use of Marijuana," cites three animal and laboratory studies documenting cannabis' potential anti-inflammatory effects. (2) In addition, a 1988 study by an English research team found the cannabinoid CBD (cannabidiol) ameliorated inflammation in mice. "Our results would suggest that cultivation of cannabis plants rich in CBD and other phenolic substances would be useful for medicinal purposes in the treatment of certain inflammatory disorders," researchers concluded. (3) It is possible that cannabis' anti-inflammatory properties could reduce swelling and improve mobility in some arthritis patients. Research in this area is obviously needed.
References used above
1. R. Callahan, "How Does Marijuana Kill Pain," Associated Press, October 4, 1998. See also [pain]
2. "Review of the Human Studies on the Medical Use of Marijuana," Dale Gieringer, Ph.D. (1996).
3. E. Formukong et al., "Analgesic and Antiinflammatory Activity of Constituents of Cannabis Sativa L.," Inflammation 12 (1988): 361.
source: http://www.budbuddie...s/arthritis.htm
For results in this study go to: http://www.pnas.org/...97/17/9561.full
The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis
A. M. Malfait*,, R. Gallily,, P. F. Sumariwalla*, A. S. Malik*, E. Andreakos*, R. Mechoulam, and M. Feldmann*,
+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)
Next SectionAbstract
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- 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.
Cannabidiol (CBD) is one of the major components of Cannabis sativa, marijuana (1). Marijuana contains approximately 80 constituents, termed cannabinoids (2, 3). CBD is not psychoactive, unlike the other major component of cannabis, 9-tetrahydrocannabinol (9THC) (4, 5). A vast literature documents the immune modulating effects of cannabinoids, in vivo and in vitro, mainly of 9THC and synthetic analogues such as CP55,940 (reviewed in ref. 6). A nonexhaustive list of in vitro effects includes inhibition of the proliferative responses of T lymphocytes (7), inhibition of cytotoxic T cell activity (8), suppression of macrophage function and antigen presentation (9, 10), and inhibition of NO production by macrophages (11). Reports on the in vitro effects of CBD on immune cells are scarce and include the modulation of tumor necrosis factor (TNF), IL-1, and IFN- by human peripheral blood mononuclear cells (12, 13) and the suppression of chemokine production by a human B cell line (14). These potentially anti-inflammatory properties of CBD, together with the lack of psychotropic effect and low toxicity (15), prompted us to test the potential of CBD as a therapeutic agent in collagen-induced arthritis (CIA).
CIA, a murine model for rheumatoid arthritis (RA), is elicited by immunizing DBA/1 mice with type II collagen (CII) in complete Freund's adjuvant (16). The immune response to CII involves both humoral and cellular mechanisms (17, 18), and the cellular response is T helper 1-mediated (19). CIA is characterized by rapid onset of clinical joint inflammation, resulting in destruction of joint tissues and cartilage/bone erosions. Suppression of the inflammatory process by blocking TNF with mAbs has proven an effective treatment of CIA (20, 21), and these findings led to the successful use of TNF blockade in multiple phase I, II, and III clinical trials with RA patients (reviewed in ref. 22), thus validating the predictive value of CIA as a model for RA. In the present study, we report that CBD has a beneficial therapeutic action on established CIA, and we explore its mode of action.
Previous SectionNext SectionMaterials and Methods
Purification of CBD.CBD was purified from hashish as reported (23). Its purity was established on the basis of melting point (6667), optical rotation (aD = 125), and single peak on gas chromatography (23).
Induction and Monitoring of Heterologous CIA.Bovine CII was purified from hyaline cartilage (21). Male DBA/1 mice (812 weeks old) were immunized with 100 g of CII emulsified in complete Freund's adjuvant (Difco) by intradermal injection at the base of the tail. From day 15 after immunization onward, mice were examined daily for onset of clinical arthritis. Assessment of arthritis included monitoring of clinical scores where 0 = normal; 1 = slight swelling and erythema; 2 = pronounced edema; 3 = joint rigidity. Each limb was graded, resulting in a maximal clinical score of 12 per animal. The arthritis was monitored over 10 days, after which the mice were killed (21).
Induction and Monitoring of Homologous CIA.Mouse CII was purified from sternal cartilage from female DBA/1 mice, as described for bovine CII. For the chronic experiments, 6-week-old mice were immunized with mouse CII (100 g) in complete Freund's adjuvant. The animals were boosted 15 days later with 100 g CII i.p. From day 30 after immunization onward, 80% of the mice developed a chronic relapsing arthritis, which was monitored for 5 weeks as described above.
Administration of CBD.CBD treatment commenced at the first clinical signs of arthritis and was administered i.p. daily until day 10 of arthritis. The CBD concentrations used were 20 mg/kg (n = 12), 10 mg/kg (n = 17), 5 mg/kg (n = 15), and 2.5 mg/kg (n = 9). CBD was dissolved in ethanol/cremophor (Sigma) (1:1, vol/vol) and further diluted in saline, so that the final solution was ethanol/cremophor/saline (1:1:18). Mice injected with vehicle alone (ethanol/cremophor in saline) served as controls (n = 23).
For the oral treatment protocol, CBD was dissolved in olive oil and administered by oral gavage, daily, from the onset of arthritis for 10 days. The doses used were 10 mg/kg, 25 mg/kg, and 50 mg/kg (n = 6 per group). Control mice were fed olive oil (n = 6).
For the chronic experiments, mice were treated from the first symptoms of arthritis for 5 weeks. For the i.p. route, CBD was injected daily at 10 mg/kg (n = 7) or 5 mg/kg (n = 7). Again, mice injected with vehicle alone served as controls (n = 7). For the oral route, the treatment was administered daily (Monday to Friday) at a dose of 25 mg/kg (n = 6) and control mice were fed olive oil (n = 6).
Histological Analysis.At the end of each experiment, hind paws were removed postmortem, fixed in formalin, and decalcified in 5% EDTA. The paws were embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Arthritic changes in the foot joints were scored as mild (mild synovial hyperplasia), moderate (pannus formation and erosions limited to the cartilage-pannus junction), or severe (extended bone and cartilage erosions with loss of joint architecture). All assessments were performed by an observer blinded to the treatment received.
Lipopolysaccharide (LPS) Induction of Serum TNF in Mice.Female C57BL/6 mice were injected i.p. with a sublethal dose of LPS (100 g, Escherichia coli O55:B5, Difco). CBD was injected simultaneously, either i.p. or s.c., at a dose of 10 mg/kg. Ninety minutes later, the mice were bled and serum TNF levels were determined by bioassay (24).
Reactive Oxygen Intermediate Production by Mouse Granulocytes.C57BL/6 mice were injected i.p. with 1.5 ml thioglycollate (Difco), and 18 h later the cells were harvested by sterile lavage with PBS. The cells were washed and resuspended in Hanks' balanced salt solution without phenol red, and 0.5 ml of the cell suspension was added into luminometer tubes. CBD (dissolved in ethanol) was added at this point at a final concentration of 6 g/ml. Finally, 10 l Luminol (Sigma) and 30 l Zymosan (Sigma) were added, and the chemiluminescence was measured immediately in a luminometer (Biolumate LB 95, Berhold, Wildbad, Germany).
Preparation of CBD for in Vitro Experiments. CBD was dissolved in ethanol at a stock concentration of 10 mg/ml and stored at 4C for up to 2 months. CBD stock was further diluted in warm medium immediately before use. All tissue culture media, vehicle control, and CBD preparations were shown to contain less than 0.1 unit/ml endotoxin, as assessed by the chromogenic Limulus Amebocyte Lysate assay (BioWhittaker). At the end of all in vitro experiments described below, viability of the cells was assessed with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test (25).
Splenic Lymphocyte Culture.Pooled spleens from 10-week-old DBA/1 mice were pushed through a sieve and a single cell suspension was prepared. The cells were washed, layered over a Lympholyte-M density gradient (Cedarlane Laboratories), and spun at 2,000 rpm for 45 min. The buffy coat containing lymphocytes was washed three times and then plated at 2 105 cells/100 l per well in complete medium comprising DMEM supplemented with 10% heat-inactivated FCS, 1% glutamine, 100 units/ml penicillin, 100 mg/ml streptomycin, and 2 105 M 2-mercaptoethanol. Cells were stimulated with 5 g/ml Con A in the presence of 010 g/ml CBD. After 72 h, cells were pulsed with 0.5 Ci/well [3H]thymidine (Amersham Pharmacia) overnight, harvested, and assessed for incorporation of radioactivity.
Draining Lymph Node Cell (LNC) Culture.Mice (controls or CBD-treated) were killed at day 3 after disease onset, and inguinal LNCs were cultured as described (26). Cells were cultured with or without bovine CII (50 g/ml) in Tris-buffered saline, pH 7. Supernatants were collected after 72 h and stored at 20C until cytokine measurement. Alternatively, after 72 h, cells were pulsed with [3H]thymidine overnight and assessed for incorporation of radioactivity.
Culture of Murine Synovial Cells.Mice (control mice or CBD-treated) were killed at day 10 of arthritis and the knee joints were removed. Synovial cell cultures were performed as described (27). Briefly, synovial membranes were excised under a dissecting microscope and digested with 1 mg/ml collagenase A and 0.15 mg/ml DNase type IV in the presence of 33 g/ml polymyxin B. The cells then were washed extensively and cultured in 96-well plates at a density of 2 106 cells/ml (100 l/well) in complete medium with or without CBD at specified concentrations. Supernatants were collected after 24 h and stored at 20C until measured for TNF.
Cytokine Assays.For determination of bioactive TNF levels, an assay was performed by using the WEHI 164 cell line (28), as described (29), or BALB/c CL.7 cells, as described (24). IFN- levels were measured by sandwich ELISA. The capture/detection antibody pair used was R46A2 (obtained from the American Type Culture Collection, courtesy of J. Abrams) and hamster mAb 122200 (Genzyme).
Discussion
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; Table 1). 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, 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).
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- release (Table 3). 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). This finding suggests that the therapeutic actions of CBD include the suppression of TNF-a, a proinflammatory cytokine known to be a major mediator of arthritis (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). 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 exp<b></b>ression 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). 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 and ref. 34). We also observed the blockade of NO production by peritoneal macrophages (not shown), as reported in the literature (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). Recent research in vitro and in animal models has led to increasing evidence that cannabinoids are also important modulators of the immune system (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). 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, 38). Moreover, clinical trials with CBD have been conducted in humans with epilepsy (39) and Huntington's disease (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), 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).
The results presented here leave a number of questions to elucidate in the future. First, is CBD solely responsible for the anti-arthritic effects in vivo or is there an active metabolite involved? Second, via which receptor does CBD exert its effects? Two receptors for cannabinoids have been identified, the brain receptor, CB1 (42), and the peripheral cannabinoid receptor, CB2 (43), which is present on T and B lymphocytes, natural killer cells, and macrophages (6). The affinity of CBD for the cannabinoid receptors is very low, lower than that of the other cannabinoids (43, 44). The possibility that CBD, because of its lipophilicity interferes with cell membranes, thus altering their functions, or that a metabolite acts on the CB2 receptor, cannot be ruled out. These questions should be the subject of future studies.
Previous SectionNext SectionAcknowledgments
We thank Paul Warden and the staff of the Kennedy Institute of Rheumatology Biological Services Unit, Professor R. N. Maini for helpful advice, and Philip Connolly for preparation of the histological sections. The work was funded by the Arthritis Research Campaign of Great Britain.
source: http://www.pnas.org/...97/17/9561.full
Rheumatoid arthritis, cannabis based medicine eases pain and suppresses disease
The first study to use a cannabis-based medicine (CBM) for treating rheumatoid arthritis has found that it has a significant effect on easing pain and on suppressing the disease.
Writing in the medical journal Rheumatology [1], the researchers say that although the differences were small and variable in the group of 56 patients they studied, the results are statistically significant and a larger trial is needed to investigate in more detail the effects of CBM on the disease which affects approximately 600,000 people in the UK (1 in 100 of the population).[2]
There is anecdotal evidence that cannabis can provide pain relief for people with rheumatoid arthritis (RA), and in a recent survey 155 (16%) of 947 people who obtained cannabis on the black market for medicinal reasons said they did so to obtain relief from symptoms of RA. However, this study in Rheumatology journal, led by David Blake, Professor of Bone and Joint Medicine at the Royal National Hospital for Rheumatic Diseases (RNHRD), Bath, and the University of Bath, UK, is the first randomised controlled trial to investigate the effect of a CBM on RA. It is published online today (Wednesday 9 November).
In the double-blind trial, the researchers randomised 31 patients to receive the CBM and 27 the placebo. The CBM (brand name: Sativex) was in the form of an easy-to-use mouth spray that patients could administer themselves up to a maximum of six doses a day. The CBM consisted of a blend of whole plant extracts, standardised for content, that delivered approximately equal amounts of two key therapeutic constituents from the cannabis plant: delta-9-Tetrahydrocannabinol (THC) and cannabidiol (CBD). Mouse studies have shown that THC and CBD have anti-inflammatory effects, and that CBD blocked progression of RA and produced improvements in symptoms.
Dr Ronald Jubb, Consultant Rheumatologist, at the University Hospital Birmingham NHS Foundation Trust, UK, said: "Patients had a baseline assessment at the beginning of the trial and then were randomised to receive either the CBM or placebo. Patients only took the doses in the evening in order to minimise possible intoxication-type reactions. The starting dose was one actuation within half an hour of retiring, and this was increased by one actuation every two days to a maximum of six doses according to individual response over a period of two weeks. Stable dosing was then maintained for a further three weeks."
The researchers found that in comparison with the placebo, patients who had taken the CBM had statistically significant improvements in pain on movement, pain at rest, quality of sleep, inflammation (measured by a Disease Activity Score involving 28 joints - DAS 28) and intensity of pain (measured by the Short-Form McGill Pain Questionnaire SF-MPQ).
For instance, on a score of 0-10 where 0 is no pain, CBM patients on average moved from 7 to 4.8 for pain on movement (placebo patients moved from 6.7 to 5.3), 5.3 to 3.1 (placebo 5.3 to 4.1) for pain at rest, and 5.7 to 3.4 (placebo 5.8 to 4.6) for quality of sleep. On the DAS 28 score of 0-10, the CBM patients moved from 5.9 to 5 (placebo 6 to 5.9), and on the SF-MPQ score of 0-100 for intensity of pain at present, the CBM patients moved from 48 to 33, while the placebo patients remained unchanged at 50.
Adverse side effects were mostly mild or moderate (e.g. dizziness, light-headedness, dry mouth, nausea). Of the eight patients who experienced mild dizziness, in four patients this occurred during the initial two-week period when they were gradually increasing the doses, and two occurred two days after this initial period, so these were probably due to patients getting used to the correct dose. No patients taking the CBM had to withdraw from the trial due to adverse side effects, but three did from the placebo group.
Dr Philip Robson, Senior Research Fellow and Consultant Psychiatrist at the Oxford University Department of Psychiatry and Director of the Cannabinoid Research Institute within GW Pharmaceuticals (the manufacturer of Sativex), explained: "Withdrawals from the placebo group were probably due to a psychological effect, a spontaneous occurrence, or a reaction with another medicine."
Dr Jubb said: "The results from the first controlled study of CBM in rheumatoid arthritis are encouraging, with overall improvements in pain on movement and at rest, improvement in the quality of sleep and improvement in the overall condition of the patients' arthritis. Whilst the differences are small and variable across the patient group, they represent benefits of clinical relevance and indicate the need for more detailed investigation through larger trials to see exactly where CBM could be best used with minimum side effects."
If further trials are run, researchers will probably extend the dosing period over the full 24-hour period. Dr Robson said: "The beneficial effects in this study occurred in the context of a dosing regime restricted to evening dosing in order to minimise any possible intoxication-type reactions. However, 24-hour dosing with Sativex, using a self-titration regime, in trials for multiple sclerosis resulted in only minimal intoxication scores."
He continued: "The element that can cause the 'high' in cannabis - THC - also has valuable pharmacological activity. It is thought to be an essential therapeutic component and therefore it can't be removed from the medicine. However, the method of giving the doses, via the mouth spray, and the principle of self-titration, where each patient gradually determined their own optimal dose level up to a maximum of six doses a day, minimised the risk of intoxication."
Dr Robson said that fears that the CBM could be abused by patients hoping to get a "high" were probably unfounded. "It seems that in practice this is a very rare event. More than 1,000-patient years of treatment with Sativex in clinical trials have been accumulated and to date there has not been a single documented case of abuse. The fact is that the motivation of medicinal users of cannabis-based medicine is entirely different from recreational users: the former simply want symptom relief and the ability to go about their normal lives, and for them intoxication would be a distinct disadvantage; for the latter, smoking marijuana is infinitely more intoxicating than Sativex and is still easily available."
[1] Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology Advance Access published on November 9, 2005.
doi:10.1093/rheumatology/kei183
[2] Rheumatoid arthritis affects three times as many women as men. Prevalence in the UK is approximately 0.5% in men and 1.8% in women, increasing after the age of 64 to 2% in men and 5% in women. There are many more people with less severe forms of RA that do not meet the diagnostic criteria for definite or classical disease.
source: http://www.medicalne...icles/33376.php
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is an inflammatory disease of the joints characterized by pain, stiffness, and swelling, as well as an eventual loss of limb function. Rheumatoid arthritis is estimated to affect about one percent of the population, primarily women.
Use of cannabis to treat symptoms of RA is commonly self-reported by patients with the disease. In a 2005 anonymous questionnaire survey of medicinal cannabis patients in Australia, 25 percent reported using cannabinoids to treat RA.[1] A survey of British medicinal cannabis patients found that more than 20 percent of respondents reported using cannabis for symptoms of arthritis.[2] Nevertheless, few clinical trials investigating the use of cannabis for RA appear in the scientific literature.
In January 2006, investigators at the British Royal National Hospital for Rheumatic Disease reported successful treatment of arthritis with cannabinoids in the first-ever controlled trial assessing the efficacy of natural cannabis extracts on RA.[3] Investigators reported that administration of cannabis extracts over a five week period produced statistically significant improvements in pain on movement, pain at rest, quality of sleep, inflammation, and intensity of pain compared to placebo. No serious adverse effects were observed. Similar results had been reported in smaller, Phase II trials investigating the use of orally administered cannabis extracts on symptoms of RA.[4]
Preclinical data also indicates that cannabinoids can moderate the progression of RA. Writing in the August 2000 issue of the Journal of the Proceedings of the National Academy of Sciences, investigators at Londons Kennedy Institute for Rheumatology reported that cannabidiol (CBD) administration suppressed progression of arthritis in vitro and in animals.[5] Administration of CBD after the onset of clinical symptoms protected joints against severe damage and effectively blocked [the] progression of arthritis, investigators concluded. Daily administration of the synthetic cannabinoid agonist HU-320 has also been reported to protect joints from damage and to ameliorate arthritis in animals.[6]
Summarizing the available literature in the September 2005 issue of the Journal of Neuroimmunology, researchers at Tokyos National Institute for Neuroscience concluded, Cannabinoid therapy of RA could provide symptomatic relief of joint pain and swelling as well as suppressing joint destruction and disease progression.[7]
source: http://www.norml.org...m?Group_ID=7015
Cannabis for Rheumatoid Arthritis
Question
I've had bad arthritis (rheumatism) for years, and I've just heard that cannabis can help. Is that true? Can I get some without a doctor's prescription?
Answer
People have been claiming for years that cannabis can help the pain of rheumatoid arthritis (RA). But there haven't been any good clinical studies to prove the point - until recently. In the November 9 issue of the medical journal Rheumatism doctors report on a study of Sativex, a cannabis-based medicine. Given as a spray into the mouth, Sativex was compared with a dummy spray (placebo) in 58 RA patients over a 5-week period.
Sativex produced statistically significant improvements in main on movement, pain at rest, a joint disease score, and the quality of sleep. There was no effect on morning stiffness. Side effects were only mild or moderate dizziness, light-headedness, and dry mouth.
It looks as if this cannabis-based drug is going to be a useful addition to the range of pain drugs for RA, once it's been approved for marketing in the USA. For that to happen, further, larger, trials will be necessary. Until then, stick to the drugs that your doctor can prescribe now.
source: http://www.healthand...891;jsessionid=