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.

At a safety trial of the compound conducted in France last year among 15 healthy volunteers, no clinically adverse events were reported, including gastrointestinal ulcers, which have been associated with other non-steroidal anti-inflammatory compounds such as aspirin and ibuprofen. No mood-altering effects were reported, Burstein said.

Ajulemic acid is being tested in Germany among a group of 21 patients with chronic severe pain. Results are not yet available.

In animal tests, the compound was 10 to 50 times more potent as a pain-killer than delta-9-tetrahydrocannabinol (THC), the main mood-altering ingredient of marijuana. Laboratory studies indicate that the compound, a synthetic derivative of THC, is more potent than aspirin and ibuprofen, says Burstein.

In rodent models of rheumatoid arthritis, the compound prevented joint damage associated with the disease. It could be a promising alternative to current drugs used to treat arthritis, such as COX-2 inhibitors, the researcher says. These compounds have been linked to adverse side effects, including heart attacks and stroke.

Tests of multiple sclerosis (MS) in rats have shown that the drug relieves muscle stiffness (spasticity) associated with the disease, just as natural marijuana has been shown to have a similar effect. Human studies of the drug's effect on MS are planned.

Other evidence suggests the compound could slow the spread of cancer cells and prolong survival in mice with brain tumors. The U.S. Army is evaluating it as a topical drug to relieve the blistering effects of sulfur mustard gas.

How it works is still under investigation. The compound appears to suppress chemical mediators, such as prostaglandins and cytokines, which are known to cause inflammation, the researcher says.

With an increasing number of medically beneficial compounds being found in marijuana, researchers have been searching for years for ways to utilize these compounds therapeutically without its associated "high." They have had little success, until now.

Marinol(r), the only FDA-approved, marijuana-derived drug, is available by prescription as an appetite stimulant for AIDS patients and for fighting nausea associated with cancer chemotherapy. But this drug, which is also a synthetic derivative of THC, has been reported to cause a "high" in some patients.

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

The original discovery of ajulemic acid was supported by the National Institute on Drug Abuse. Indevus Pharmaceuticals, based in Lexington, Mass., is developing the drug itself under the name CT-3. Burstein owns patents on ajulemic acid.

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The poster on this research, MEDI 333, will be presented at 9:00 a.m., Wednesday, Aug. 21, at the Hynes Convention Center, Hall B, during a general poster session.

Sumner H. Burstein, Ph.D., is a professor in the department of biochemistry and molecular pharmacology at the University of Massachusetts Medical School in Worcester, Mass.

-- Mark T. Sampson

EMBARGOED FOR RELEASE: Wednesday, August 21, 9:00 a.m.; Eastern Time

MEDI 333 Suppression of human monocyte interleukin-1b production by ajulemic acid (CT3): A nonpsychoactive cannabinoidSumner H. Burstein, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, Fax: 508-856-6231, [email protected], Phone: 508-856-2850

Oral administration of ajulemic acid (AjA), a nonpsychoactive cannabinoid, reduces joint tissue damage in rats with adjuvant arthritis*. Because interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) are central to progression of inflammation and joint tissue injury in patients with rheumatoid arthritis (RA), we investigated human monocyte IL-1b and TNF-a responses after addition of AjA to cells in vitro. Peripheral blood and synovial fluid mononuclear cells (PBMC and SFMC) were isolated from healthy subjects and patients with inflammatory arthritis, treated with AjA (0-30 uM) in vitro, then stimulated with lipopolysaccharide. Addition of AjA in vitro to PBMC reduced both steady state levels of pro IL-1b mRNA and secretion of IL-1b in a dose dependent manner. AjA did not influence TNFa gene expression in or secretion from PBMC. Reduction of IL-1b by AjA may help explain the therapeutic effects of AjA in the animal model of arthritis.

EMBARGOED FOR RELEASE: Wednesday, August 21, 9:00 a.m.; Eastern Time

MEDI 333

Suppression of human monocyte interleukin-1b production by ajulemic acid (CT3): A nonpsychoactive cannabinoid

Sumner H. Burstein, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, Fax: 508-856-6231, [email protected], Phone: 508-856-2850

* Briefly explain in lay language what you have done, why it is significant and its implications, particularly to the general public.

The broad goal of our research is to establish that the THC acids such as ajulemic acid, represent a distinct class of cannabinoids which do not bind to either of the known cannabinoid receptors, Although showing no psychotropic activity, they display certain of the pharmacological activities associated with the use of marijuana. The acids occur naturally as metabolites of THC and, as such, can be detected readily in the tissues of marijuana users. The properties of the acids shown in experimental models suggest that they may be of interest as candidates for medicinal agents. These include actions as analgesics and antiinflammatory drugs with a low potential for abuse and a minimum of toxic side effects.

In our research, possible mechanisms for the antiinflammatory effects of the acids are being investigated and compared with the primary cannabinoids such as THC, to look for differences as well as similarities. Experiments will be done to determine their effects on cytokines, eicosanoids and transcription factors in human cell culture systems. Where feasible, in vivo correlates will be examined to show relevance for all of the above studies.

The findings that will be generated from this research might provide a possible solution to the current controversy over the medical use of marijuana. This would be accomplished by the discovery of synthetic analogs of THC, such as ajulemic acid, that would provide the medicinal benefits of Cannabis without the accompanying mood altering effects and abuse potential.

* How new is this work and how does it differ from that of others who maybe doing similar research?

No other labs are currently working on the anti-inflammatory effectsof the cannabinoid acids.