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Cannabis researcher hopes his discoveries will not be forgotten

Many years after Raphael Mechoulam associated Cannabidiol (CBD) with curing epilepsy, his latest finding may help develop new drugs for anxiety, arthritis, and psoriasis.

Raphael Mechoulam, an Israeli professor of medicinal chemistry (organic chemistry)  at the Hebrew University of Jerusalem, remembers the disillusionment after his groundbreaking discoveries enclosing the structure of the cannabis (marijuana) compounds cannabidiol (CBD) and THC in 1963 and 1964, followed by clinical tests with cannabidiol (CBD) published in 1980.

“Not enough happened,” Mechoulam told, noting that it would take more than thirty years before his clinical effort on using cannabidiol (CBD),  to cure epilepsy became generally accepted. Greenwich Biosciences (owned by GW Pharmaceuticals), was ready to develop the first cannabis-based drug that built on Mechoulam’s study. The medication, Epidiolex, uses seizures associated with 2 rare forms of epilepsy and was approved by the FDA (Food and Drug Administration) just last year.

But even as his job laid the basis for the modern cannabis (marijuana) industry and for recognizing how cannabis (marijuana) interacts with the human body, a white whale eluded study: cannabis acids, which are compounds that are produced in the plant when it is alive and maybe more potent than their better-known derivatives, such as Cannabidiol (CBD) and THC.

That changed, when Mechoulam and a team of Scientists declared at a medical cannabis (marijuana) seminar in Pasadena, California, that they have produced a method for creating synthetic, stable acids that are found within the plant, and that the synthetic acids, which include acid versions of Cannabidiol (CBD) and THC, are now available for licensing to companies for drug development.

The discovery paves the way for drug companies to potentially develop new drugs based on acids for a variety of health issues such as psoriasis, arthritis, anxiety and inflammatory bowel disease.

The study is the product of a startup named EPM, in partnership with six universities in Israel, Mechoulam, Canada and the U.K., a publicly-traded laboratory company and the world’s largest topical cream company.

“I think it’s a big chance,” Dr. Mechoulam, who serves as EPM’s head of research, told, comparing it to his discoveries about Tetrahydrocannabinol (THC) and Cannabidiol (CBD).

In a 2018 British Journal of Pharmacology subject, Mechoulam and his co-authors wrote that their synthetic composite, cannabidiolic acid  ( a major cannabinoid in fiber-type cannabis) methyl ester (called HU-580 in the paper) could be more effective than existing Cannabidiol (CBD) remedies, making it “potential medicine for treating some nausea and anxiety disorders.” Those initial clinical tests found the acids have yielded outcomes on par, and even exceeding, existing therapies, without any side effects.

The naturally occurring but unstable Cannabidiol (CBD) acid (CBDA) is a thousand times more potent than Cannabidiol (CBD) in binding to a particular serotonin receptor thought to be responsible for alleviating nausea and anxiety.

“It’s an attractive molecule that probably doesn’t have side effects,” stated Dan Peer, managing director of the Center for Translational Medicine and head of the Cancer Biology Research Center a Tel Aviv University.

“It works like a steroid. If it doesn’t have adverse effects, then you have a replacement, which is great,” Peer said, discussing testing he did with cannabis (marijuana) acids and inflammatory bowel disease.

Ziva Cooper, research director of the UCLA cannabis (marijuana) Research Initiative, said EPM’s research confirms what many in the field have long suspected about cannabis (marijuana) acids, but have been unable to confirm due to their instability.

“Their work is quite innovative, and it definitely builds on what we know related to the potential therapeutic effects of cannabinoids,” Cooper said, adding that the compound could be particularly effective for pain control.

Cooper told that while more trials will be required to determine the safety and effectiveness  for humans, EPM’s outcome so far are “quite promising.”

As the U.S. government thinks to spend $3 million to study Cannabidiol (CBD), pharmaceutical production veterans still urge attention, while lending some insight regarding why more medications have not been built on cannabis (marijuana) compounds.

“People are always kidding about getting the munchies if they use cannabis (marijuana),” stated David Campbell, an associate at the consulting firm Oliver Wyman and advisor to EPM, who has more than 2 decades of knowledge in the pharmaceutical industry.

Campbell said such anecdotal evidence is a “far cry” from being able to convince a research committee or shareholders about the efficacy of cannabis (marijuana) to treat a condition.

“The medications that are produced are just not vigorous enough,” stated Peer, indicating to THC, Cannabidiol (CBD), and other nonacids.

These factors, in addition to social mores, have all led to a situation where pharmaceutical companies have not been a major presence in cannabis (marijuana) development.

 

“Lilly is not engaged in cannabis (marijuana) research and does not plan on being engaged in cannabis (marijuana) research in the future,” Nicole S. Herbert, a spokeswoman for pharmaceutical giant Eli Lilly, noted in an email.

A Pfizer spokesperson, Sally Beatty, said the company “abandoned” its cannabis-related patents after it ended research into treating cancer and inflammatory pain.

“Years ago we investigated a class of compounds for potential therapeutic value in treating cancer pain and inflammatory pain. Our work in this area was confined to the lab, never tested in patients, and eventually discontinued,” Beatty said. GSK and Sanofi declined to comment and several others did not respond to inquiries on the topic from NBC News.

EPM, which was co-founded by Reshef Swisa, 37, has managed to stabilize the acid version and also standardize the process to maintain consistent output — a key for the pharmaceutical industry, which has heretofore largely kept it distance from the plant despite a surge in popularity in CBD-based products.

EPM, which has one approved patent for its processes along with 13 more under review, is taking a novel business approach to their product, electing to offer their Active Pharmaceutical Ingredient, the key element of a drug, to pharmaceutical companies on a licensing basis. They plan to offer exclusivity for specific medical conditions.

“We are not a drug developer,” Swisa said. “We are a molecule developer.”

Swisa said the first applications will likely be targeted to treat psoriasis in a topical cream. Other promising results suggest the active ingredient could be effective in treating the inflammation that brings on arthritis, anxiety and inflammatory bowel disease.

Swisa and Mechoulam said they hope that the first applications of their compound will enter Phase 1 of FDA testing in six to 12 months, though several business and scientific factors could affect that timeframe.

The developments come at a time when Big Pharma is under siege from state attorneys general over the opioid crisis, which could open the door to exploring alternatives for treating pain.

Though early tests on Mechoulam’s compound are promising, Peer urges caution against expecting an immediate product.

“There is a gap between an interesting molecule and a pharmaceutical product,” Peer said.

The average time for a drug to gain FDA approval is 12 years, according to a 2016 University of Washington study published in Elsevier, though the agency does have four expedited tracks.

While the study is programmed to continue over the long term, Mechoulam pushed for the scientific community to take heed now.

“We could have helped a lot of kids with CBD (cannabidiol) for numerous years,” he said, lamenting the decadeslong delay in acceptance of his discoveries.

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