https://www.biospace.com/article/cbd-perils-promise-and-development-for-neuropathic-pain/
Published: Dec 18, 2019 By Mark Terry
Cannabidiol, or CBD, is one of several compounds extracted from the cannabis (marijuana) plant. In recent years, CBD has become enormously popular, and its market is believed to be hundreds of millions of dollars. Believers and users of CBD extoll its benefits for inflammation, muscle soreness, pain, anxiety and a whole host of other things, including cancer.
It is, however, very understudied. There is little if any information on appropriate dosing, let alone the efficacy or safety of CBD.
Recently, the U.S. Food and Drug Administration (FDA) issued warning letters to 15 companies for illegally selling products that contain CBD in ways that violate the Federal Food, Drug, and Cosmetic Act (FD&C Act). It also published a revised Consumer Update describing its safety concerns over CBD products in general. One of the conclusions of the report is that the agency “cannot conclude that CBD is generally recognized as safe (GRAS) among qualified experts for its use in human or animal food.”
Douglas Brenneman, who spent much of his career at the National Institute of Child Health and Human Development at the National Institutes of Health (NIH) and who was a senior research fellow at Johnson & Johnson, spoke with BioSpace about CBD and his scientific advisory work for Kannalife, which is developing CBD analogs for clinical use. Brenneman is also founder and chief scientific officer of Advanced Neural Dynamics.
In terms of CBD, Brenneman notes, “That whole area has changed dramatically in the last year. The real game-changer was when Epidiolex went on the market.”
In November 2018, GW Pharmaceuticals, with offices in London, UK and Carlsbad, California, announced the FDA had approved Epidiolex (cannabidiol) for seizures associated with Lennox-Gastaut syndrome (LGS) or Draven syndrome, which are severe forms of childhood epilepsy. The drug, a form of cannabidiol, is marketed in the U.S. by a GW subsidiary, Greenwich Biosciences.
Brenneman notes that people have had a tendency to anecdotally claim that CBD was safe, “but when they actually went and tested it in a clinical trial, they found a number of toxicities that were of significant concern. The number one concern is liver toxicity. In terms of Epidiolex, what they found was that almost 15% of the patients had elevated levels of serum transaminases. There were several enzymes that were elevated that were indicative of liver toxicity. That was one red flag that came up.”
Another was the danger of Epidiolex and CBD in developing organisms, which is another way of saying fetuses.
“One of the hats I wear is a developmental biologist. They found no safe dose has been found for any organism that is in the developing system. In other words, anyone who is pregnant or even thinking of getting pregnant should be nowhere close to this drug,” Brenneman said. “There is no safe dose of CBD for someone who is pregnant in terms of fetal exposure.”
He says that when you’re discussing drugs, you’re talking about risk-benefit ratio. “And when you’re talking about these desperately ill children who had epilepsy, the FDA decided it’s probably okay because these kids were having huge numbers of seizures a day and Epidiolex really did help. It was a very effective anti-convulsant in these children, despite the fact there were these concerns about liver toxicity.”
One hopeful aspect of this was that when they stopped taking the drug, the liver symptoms went away, so there was a clear cause and effect, which was also dose dependent—the higher the doses, the higher the liver toxicity.
Moving on to a little broader understanding of cannabinoids, Brenneman said, “If you’re taking these drugs, you’d better watch your liver enzymes. You’d better watch out. Not everyone responds that way, a majority don’t, but it’s one of the confounding aspects of giving cannabinoids. We are not all created equal. We vary the number of receptors and characteristics of how people respond to cannabinoids.”
Which brings us to Kannalife. The company was founded in 2010 and all of its patents are co-invented by Brenneman. Kannalife is developing proprietary CBD and CBD-like molecules for neurodegenerative disorders, including chemotherapy-induced peripheral neuropathy (CIPN). This is a chronic nerve pain caused by the toxic aspects of chemotherapy drugs. It is also working on other neurodegenerative disorders that can potentially be treated with CBD analogs.
The lead compound is KLS-13019.
“One of the confounding aspects of CBD is that it interacts with many, many targets, at least a dozen,” Brenneman said. “And at least four of them are in areas we’re interested in, which is neuroprotection. The compounds we’re developing protect the nerve cells from clinically relevant toxins.”
In developing KLS-13019, the compound lost its anti-convulsant properties, but dramatically increased the pharmacological focus in the nervous system.
Brenneman said, “Now we have a potent neuroprotective molecule. We’re getting some understanding of properties it can elicit that CBD cannot.”
So far the drug is been tested in culture and animals, treating the nerve damage that elicits nerve pain from use of a chemotherapeutic called paclitaxel. Much of the toxicology work has been conducted by Sara Jane Ward at Temple University.
Brenneman presented data on KLS-13019 in June 2019 at the 29th Annual International Cannabinoid Research Society Symposium on Cannabinoids. The research was in collaboration with Ward’s work at Temple and funded by a grant from the National Institute on Drug Abuse.
“Interestingly enough, you have to realize that neuropathic pain has several components, several phases. One of the initial ones is just a reaction to the drug itself, which is basically an oxidative stressor,” Brenneman said. “It starts damaging the neurons. This happens within hours. It’s this initial phase we’re trying to protect from. CBD and KLS-13019 both do a great job there. But this is only the initial phase when we’re trying to protect the nerve cells.”
He adds that you need hundreds of times more CBD than KLS-13109 for the same effect, but they both work.
But the real differentiator, Brenneman said, is what they’re currently working on. It’s an actual reversal of neuropathic pain. And this appears to be a major difference between CBD and KLS-13109, at least in animal models.
“It’s night and day. CBD has no effect in terms of reversing the neuropathic pain,” Brenneman said. “But our compound, at reasonably low doses, is able to completely reverse the neuropathic pain in these animals.”
One of their control substances is morphine, which is used to ameliorate neuropathic pain associated with chemotherapy. Brenneman points out that morphine does the job quite well, but because of the addictive quality, and the current opioid epidemic, there are numerous reasons to not use morphine in this context. However, KLS-13109 has no effect on the reward pathways in the brain and doesn’t interact with any opiate receptor. “Here we have a clear difference between CBD and our compound, which is what we’re excited about.”
At this time, Kannalife is looking to complete its animal toxicology studies in the next year and then hopes to get into the clinic sometime in 2021. “We have a lot of boxes to check for the FDA,” he said.
Although Kannalife is currently focused on neuropathic pain, KLS-13109 and potentially other analogs under development, may be effective in other areas, particularly when you consider the non-opiate qualities and neuroprotective effects.
“There’s a whole other array of neurodegenerative disease we’re potentially interested in and looking at,” Brenneman said. “It’s not just a matter of differentiating ourselves from CBD, but also expanding our therapeutic interest to see what this compound can do.”
