High hopes for new marijuana drug

Marijuana

“Researchers have developed a synthetic compound which gives the benefits of marijuana without the high.

US researchers are developing a marijuana-derived synthetic compound to relieve pain and inflammation without the mood-altering side effects associated with other marijuana based drugs.

Professor Sumner Burstein, from the University of Massachusetts Medical School in Worcester, presented his team’s findings at last week’s national meeting of the American Chemical Society in Boston.

He is hopeful about the potential of the synthetic compound to treat a variety of conditions, including chronic pain, arthritis and Multiple Sclerosis.

The synthetic compound is called ajulemic acid, and has a formula based on that of THC. It has already produced encouraging results in animal studies of pain and inflammation, and is currently being tested on humans.

Exactly how ajulemic acid works is still under investigation but it appears to suppress chemical mediators, such as prostaglandins and cytokines, known to cause inflammation.

“We believe the compound will replace aspirin and similar drugs in most applications because of its lack of toxic side effects”, said Professor Burstein, referring to extensive animal studies, as well as a safety trial of the compound conducted in France last year among 15 healthy volunteers.

No clinically adverse effects were reported, including gastrointestinal ulcers, which have been associated with other non-steroidal anti-inflammatory compounds such as aspirin and ibuprofen.

But most significantly, no mood-altering side effects were reported. With an increasing number of medically beneficial compounds being found in marijuana, such as THC and CBD, researchers have been searching for years for ways to utilise these therapeutically without their associated “high”. They have had little success until now.

“Some people want the high,” admits Professor Burstein. “But the medical community wants efficacy without this effect.”

As well as animal studies of their own that show the compound is as potent a painkiller as morphine, Professor Burstein notes other promising animal studies that have been published. In rodent models of rheumatoid arthritis, the compound prevented joint damage. Tests of MS in rats showed the drug relieves muscle stiffness associated with the disease.

It is now undergoing tests in Germany in a group of 21 patients with chronic pain who take ajulemic acid orally twice daily, in capsule form.

Depending on these results, which will be available in about six weeks, the researchers predict the synthetic compound could be on offer by prescription within two years.

It could also be a promising alternative to current drugs used to treat arthritis, such as COX-2 inhibitors. These have been linked to adverse side effects, including heart attacks and stroke.”

http://www.abc.net.au/science/articles/2002/08/26/656786.htm?fb_action_ids=460011707368809&fb_action_types=og.likes&fb_source=aggregation&fb_aggregation_id=288381481237582

Cannabis drug ‘fights pain without high’

   “Scientists have developed a cannabis-based medicine which relieves chronic pain without any of the “high” normally associated with the drug.

They believe the discovery could pave the way for cannabis-based medication to become available by prescription within two years.

Much of the controversy surrounding the medicinal use of cannabis has centred on fears that it would be used solely for its mood-altering effects.

However, scientists at the University of Massachusetts in the United States say their discovery should help authorities to overcome these fears.

Dr Sumner Burstein and colleagues say early trials of the medication in animals and healthy patients have been promising.

The medication, called ajulemic acid or CT3, has been manufactured in laboratories.

It maximises the medicinal effects of tertrahydrocannabinol – the key ingredient of cannabis – without any of the mind-altering effects.

‘More effective’

In animal tests, this compound was found to be between 10 to 50 times more effective at reducing pain than tetrahydrocannabinol.

Those tests showed that ajulemic acid was very effective at preventing the joint damage associated with arthritis and relieving the muscle stiffness associated with multiple sclerosis.”

Read more: http://news.bbc.co.uk/2/hi/health/2207478.stm

Marijuana-Derived Compound Targets Pain, Inflammation

   “Researchers are developing a marijuana-derived synthetic compound to relieve pain and inflammation without the mood-altering side effects associated with other marijuana based drugs.

  They say the compound could improve treatment of a variety of conditions, including chronic pain, arthritis and multiple sclerosis. Their findings were presented at the 224th national meeting of the American Chemical Society, the world’s largest scientific society.

   The compound, called ajulemic acid, has produced encouraging results in animal studies of pain and inflammation. It is undergoing tests in a group of people with chronic pain and could be available by prescription within two to three years, the researchers say.

 “We believe that [the compound] will replace aspirin and similar drugs in most applications primarily because of a lack of toxic side effects,” says Sumner Burstein, Ph.D., lead investigator in the study and a professor in the department of biochemistry and molecular pharmacology at the University of Massachusetts Medical School in Worcester. “The indications so far are that it’s safe and effective,” he added.”

Read more: http://www.sciencedaily.com/releases/2002/08/020822071026.htm

Suppression of human monocyte interleukin-1beta production by ajulemic acid, a nonpsychoactive cannabinoid.

Abstract

   “Oral administration of ajulemic acid (AjA), a cannabinoid acid devoid of psychoactivity, reduces joint tissue damage in rats with adjuvant arthritis. Because interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNFalpha) are central to the progression of inflammation and joint tissue injury in patients with rheumatoid arthritis, we investigated human monocyte IL-1beta and TNFalpha responses after the addition of AjA to cells in vitro… Reduction of IL-1beta by AjA may help explain the therapeutic effects of AjA in the animal model of arthritis. Development of nonpsychoactive therapeutically useful synthetic analogs of Cannabis constituents, such as AjA, may help resolve the ongoing debate about the use of marijuana as medicine.”

http://www.ncbi.nlm.nih.gov/pubmed/12566094

Ajulemic acid, a synthetic cannabinoid acid, induces an antiinflammatory profile of eicosanoids in human synovial cells.

“AIMS:

To better understand mechanisms whereby Ajulemic acid (AjA), a synthetic antiinflammatory cannabinoid, promotes resolution of acute and chronic inflammation in animal models, we investigated its influence on cyclooxygenase 2 (COX2) expression and eicosanoid production in human fibroblast-like synovial cells (FLS).”

“KEY FINDINGS:

AjA increased the steady state levels of COX2 mRNA in and arachidonic acid release from FLS. Treatment of FLS with AjA increased 15-deoxy-delta(12,14)-PGJ(2) (15d-PGJ(2)) production in a concentration dependent manner, but did not affect PGE(2) production significantly.”

“SIGNIFICANCE:

The capacity of AjA to increase selectively and markedly 15d-PGJ(2), an eicosanoid which facilitates resolution of inflammation, suggests that AjA may have value as a therapeutic agent for the treatment of rheumatoid arthritis (RA) and other diseases characterized by acute and chronic inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/18840450

Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid.

Abstract

   “Production of matrix metalloproteinases (MMP) in joint tissue of patients with inflammatory arthritis facilitates cartilage degradation and bone erosion, and leads to joint deformities and crippling. Thus, MMPs are important targets for agents designed to treat inflammatory arthritis. Oral administration of ajulemic acid (AjA), a synthetic, nonpsychoactive cannabinoid acid, prevents joint tissue injury in rats with adjuvant arthritis. AjA binds to and activates PPARgamma directly. Therefore, we investigated the influence of AjA on MMP production in human fibroblast-like synovial cells (FLS), and examined the role of PPARgamma in the mechanism of action of AjA. FLS, treated or not with a PPARgamma antagonist, were treated with AjA then stimulated with TNFalpha or IL-1alpha. Release of MMPs-1, 3, and 9 was measured by ELISA. The influence of AjA on MMP-3 release from stimulated PPARgamma positive (PPAR+/-) and PPARgamma null (PPAR-/-) mouse embryonic fibroblasts (MEF) was also examined. Addition of AjA to FLS suppressed production of MMPs whether or not PPARgamma activation was blocked. Secretion of MMP-3 was also suppressed by AjA in both TNFalpha- and IL-1alpha-stimulated PPARgamma+/- and PPARgamma-/- MEF. Suppression of MMP secretion from FLS by AjA appears to be PPARgamma independent. Prevention by AjA of joint tissue injury and crippling in the rat adjuvant arthritis model may be explained in large part by inhibition of MMPs. These results suggest that AjA may be useful for treatment of patients with rheumatoid arthritis and osteoarthritis.”

http://www.ncbi.nlm.nih.gov/pubmed/16927387

Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw.

Abstract

“Cannabidiol, the major non-psychoactive component of marijuana, has various pharmacological actions of clinical interest. It is reportedly effective as an anti-inflammatory and anti-arthritic in murine collagen-induced arthritis.

The present study examined the anti-inflammatory and anti-hyperalgesic effects of cannabidiol, administered orally (5-40 mg/kg) once a day for 3 days after the onset of acute inflammation induced by intraplantar injection of 0.1 ml carrageenan (1% w/v in saline) in the rat. At the end of the treatment prostaglandin E2 (PGE2) was assayed in the plasma, and cyclooxygenase (COX) activity, production of nitric oxide (NO; nitrite/nitrate content), and of other oxygen-derived free radicals (malondialdehyde) in inflamed paw tissues. All these markers were significantly increased following carrageenan. Thermal hyperalgesia, induced by carrageenan and assessed by the plantar test, lasted 7 h. Cannabidiol had a time- and dose-dependent anti-hyperalgesic effect after a single injection. Edema following carrageenan peaked at 3 h and lasted 72 h; a single dose of cannabidiol reduced edema in a dose-dependent fashion and subsequent daily doses caused further time- and dose-related reductions. There were decreases in PGE2 plasma levels, tissue COX activity, production of oxygen-derived free radicals, and NO after three doses of cannabidiol. The effect on NO seemed to depend on a lower expression of the endothelial isoform of NO synthase.

 In conclusion, oral cannabidiol has a beneficial action on two symptoms of established inflammation: edema and hyperalgesia.”

http://www.ncbi.nlm.nih.gov/pubmed/14963641

Cannabinoids for the treatment of inflammation.

“Cannabinoids are effective at suppressing immune and inflammation functions in leukocytes in vitro, and in animal models of acute inflammation, such as the mouse hind paw, ear and air pouch models, as well as gastrointestinal, pulmonary, myocardial, vascular, periodontal, neural, hepatic, pancreatic and arthritic inflammation models.

The non-psychoactive cannabinoid receptor CB2 is emerging as a critical target for cannabinoid regulation of inflammation, and thus CB2-selective agonists are undergoing intense investigation and research. This review discusses the evidence for cannabinoid regulation of inflammation across a range of models and highlights the most promising drug candidates.”

http://www.ncbi.nlm.nih.gov/pubmed/17520866

Cannabinoid-based drugs as anti-inflammatory therapeutics.

“In the nineteenth century, marijuana was prescribed by physicians for maladies ranging from eating disorders to rabies. However, as newer, more effective drugs were discovered and as the potential for abuse of marijuana was recognized, its use as a therapeutic became restricted, and only recently has its therapeutic potential been re-evaluated.

 

 Recent studies in animal models and in humans have produced promising results for the treatment of various disorders – such as obesity, cancer, and spasticity and tremor due to neuropathology – with drugs based on marijuana-derived cannabinoids.

 

 Moreover, as I discuss here, a wealth of information also indicates that these drugs have immunosuppressive and anti-inflammatory properties; therefore, on the basis of this mode of action, the therapeutic usefulness of these drugs in chronic inflammatory diseases is now being reassessed.”

 

http://www.ncbi.nlm.nih.gov/pubmed/15864274

Cannabinoids as novel anti-inflammatory drugs

Figure 1

“Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors. The discovery of Δ9-tetrahydrocannabinol (THC) as the major psychoactive principle in marijuana, as well as the identification of cannabinoid receptors and their endogenous ligands, has led to a significant growth in research aimed at understanding the physiological functions of cannabinoids. Cannabinoid receptors include CB1, which is predominantly expressed in the brain, and CB2, which is primarily found on the cells of the immune system. The fact that both CB1 and CB2 receptors have been found on immune cells suggests that cannabinoids play an important role in the regulation of the immune system. Recent studies demonstrated that administration of THC into mice triggered marked apoptosis in T cells and dendritic cells, resulting in immunosuppression. In addition, several studies showed that cannabinoids downregulate cytokine and chemokine production and, in some models, upregulate T-regulatory cells (Tregs) as a mechanism to suppress inflammatory responses. The endocannabinoid system is also involved in immunoregulation. For example, administration of endocannabinoids or use of inhibitors of enzymes that break down the endocannabinoids, led to immunosuppression and recovery from immune-mediated injury to organs such as the liver. Manipulation of endocannabinoids and/or use of exogenous cannabinoids in vivo can constitute a potent treatment modality against inflammatory disorders. This review will focus on the potential use of cannabinoids as a new class of anti-inflammatory agents against a number of inflammatory and autoimmune diseases that are primarily triggered by activated T cells or other cellular immune components.”

“Cannabis, commonly known as marijuana, is a product of the Cannabis sativa plant and the active compounds from this plant are collectively referred to as cannabinoids. For several centuries, marijuana has been used as an alternative medicine in many cultures and, recently, its beneficial effects have been shown in: the treatment of nausea and vomiting associated with cancer chemotherapy; anorexia and cachexia seen in HIV/AIDS patients; and in neuropathic pain and spasticity in multiple sclerosis. Cannabinoid pharmacology has made important advances in recent years after the discovery of the cannabinoid receptors (CB1 and CB2). Cannabinoid receptors and their endogenous ligands have provided an excellent platform for the investigation of the therapeutic effects of cannabinoids. It is well known that CB1 and CB2 are heterotrimeric Gi/o-protein-coupled receptors and that they are both expressed in the periphery and the CNS. However, CB1 expression is predominant in the CNS, especially on presynaptic nerves, and CB2 is primarily expressed on immune cells.”

“Cannabinoids are potent anti-inflammatory agents and they exert their effects through induction of apoptosis, inhibition of cell proliferation, suppression of cytokine production and induction of T-regulatory cells (Tregs).”

“Executive summary

  • Cannabinoids, the active components of Cannabis sativa, and endogenous cannabinoids mediate their effects through activation of specific cannabinoid receptors known as cannabinoid receptor 1 and 2 (CB1 and CB2).
  • The cannabinoid system has been shown both in vivo and in vitro to be involved in regulating the immune system through its immunomodulatory properties.
  • Cannabinoids suppress inflammatory response and subsequently attenuate disease symptoms. This property of cannabinoids is mediated through multiple pathways such as induction of apoptosis in activated immune cells, suppression of cytokines and chemokines at inflammatory sites and upregulation of FoxP3+ regulatory T cells.
  • Cannabinoids have been tested in several experimental models of autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, colitis and hepatitis and have been shown to protect the host from the pathogenesis through induction of multiple anti-inflammatory pathways.
  • Cannabinoids may also be beneficial in certain types of cancers that are triggered by chronic inflammation. In such instances, cannabinoids can either directly inhibit tumor growth or suppress inflammation and tumor angiogenesis.”                      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/