The UCI professor utilizes the endocannabinoid system to tackle pain management, anxiety, inflammation and much more.
Everyone has one and, despite the name, it’s far from green and does not show up on a drug test.
Enter: the body’s endocannabinoid system.
This signaling system is found in the brain and throughout the body, and is responsible for regulating and balancing many processes, including neurotransmission, immune response, hunger and metabolism, and memory.
Since 1992, Daniele Piomelli, Ph.D., UC Irvine (UCI) distinguished professor of anatomy and neurobiology and Louise Turner Arnold Chair in the Neurosciences, has worked toward unlocking the full potential of the complex endocannabinoid system while simultaneously searching for the right business partner who will apply his long list of endocannabinoid-related technologies and research to their full potential.
For Piomelli, success involves solving a biological problem, advancing health through the discovery of new medicines and improving the economy by creating new jobs. His lab at UCI’s Gillespie Neuroscience Research Facility uses the endocannabinoid system to solve medical problems such as chronic pain and post-traumatic stress disorder (PTSD).
“We know that the endocannabinoid system, both in the central nervous system and outside the central nervous system, plays very important roles in regulating stress and pain perception,” said Piomelli.
The Roots
In 1992, while still fresh out of his postdoc, Piomelli read about the discovery of the first endocannabinoid and quickly changed his lab’s focus to understanding how this molecule was produced and destroyed in the body. He soon discovered that molecular probes may help understand the endocannabinoid system and possibly be used as a starting point for the creation of safe and effective therapies.
“It was a fascinating molecule because it did not resemble any other transmitter in the brain, but it did resemble a class of molecules that I had been studying before,” said Piomelli. “It was different enough that I could tell that the whole biochemistry, the whole physiology had to be figured out.” 
Fast forward to present-day UCI and one will see Piomelli’s office decorated with antique posters, including a hand drawn anatomy of the pancreas from 1940s France. A fake python sits in a terrarium, a sword in its sheath lay across his couch and, as one might expect from a professor studying cannabis and the endocannabinoid system, a burlap poster depicting a woman with large green leaves fanning behind her head adorns the door to his office. It’s hard not to ignore the obvious.
“There is evidence that cannabis alleviates chronic pain in adults,” said Piomelli. “How does it work exactly? We know that its active constituent, tetrahydrocannabinol (THC), combines with cannabinoid receptors in pain-sensing pathways inside and outside the brain. These receptors are normally activated by endocannabinoids. This is an important value of cannabis that is often underestimated: it opened a window on the endocannabinoid system, which has clear medicinal potential.” said Piomelli. “But there are also a lot of problems with cannabis.”
Cannabis, as Piomelli puts it, is a sledgehammer because THC has strong psychoactive effects. And with 11 U.S. states now legalizing the recreational use of marijuana and 21 U.S. states for medicinal use, the market is now overgrown with products of all types stemming from a widely under-regulated drug.
“You eat it, you smoke it, you vape it, it gets to your brain, activates all cannabinoids receptors,” said Piomelli. “But the endocannabinoid system is much more subtle. You can tweak it, you can block the receptor, you can modulate the receptor using endogenous molecules.”
Learning to regulate the body’s endocannabinoid system for therapeutic potential is what now drives most of his research, and cannabis helps his lab understand how the system works.
“There is literally no organ system in the body that does not have it and there are very few organ systems in the body where it’s not important,” said Piomelli.
Working the System
In the Center for the Study of Cannabis at UCI, the lab is discovering that endocannabinoids are fundamental to energy and metabolism. According to Piomelli’s research, the endocannabinoid system is an extremely important controller of body weight and metabolic health.
“The problem is that when you block the endocannabinoid system in the brain, you become anxious, you become aggressive, you start having pains and aches, and you may even have suicidal ideations and stuff like that, because of the role it plays in mood,” said Piomelli.
However, the opposite is true if the system is boosted.
“If we find a new anti-anxiety medicine, that would be really important, particularly for conditions like post-traumatic stress disorder, which are currently not treated at all,” said Piomelli.
Piomelli received grants from the National Institutes of Health to study the potential of endocannabinoid boosting drugs for pain relief and reduce the use of opiate-based drugs.
Piomelli is currently focused on three specific enzymes that can be reconfigured with the help of molecules to act as inhibitors, fatty acid amide hydrolase (FAAH), N-acylethanolamine-hydrolyzing acid amidase (NAAA) and acid ceramidase. From these three classes of inhibitors, Piomelli has created pharmaceuticals that are tweaked within the endocannabinoid system to help suppress pain, inflammation, appetite, anxiety and depression.
Commercialize It
Piomelli’s FAAH inhibitor technology is utilized through a Canadian startup company he co-founded, Exxel Pharma, where he is also the chief scientific officer, primarily consulting for the company.
Exxel Pharma focuses on the development of small-molecule therapeutics for safe, non-addictive treatment of pain, PTSD and substance use disorders, such as opioid addiction.
“I’ve gotten to work closely with Dr. Piomelli since we co-founded Exxel and have very much enjoyed our partnership,” said Soren Mogelsvang, Exxel co-founder and CEO. “Daniele is great scientist, and a passionate and eloquent advocate of our therapeutics. He gets the bigger picture of drug development and has done a terrific job of de-risking the therapeutics, which speeds up the commercialization process.”
Exxel Pharma plans to focus on the clinical development of pain management therapeutics and will begin phase one of human clinical trials in fall 2020.
Piomelli has also licensed another group of inhibitors to a company that focuses on chemotherapy-induced neuropathic pain and has additionally licensed another technology to a company that is interested in treating Parkinson’s disease.
Each of the three inhibitors represent endocannabinoid-boosting drugs for pain relief. They play a vital role in discovering how the endocannabinoid system can be tweaked, and have led to the discovery of other molecules that affect neurological diseases.
“The enzyme inhibitors destroy one of the ancillary endocannabinoid molecules and has profound anti-inflammatory effects, so we made a bunch of molecules that block it,” said Piomelli.
These molecules were licensed to a company that was funded and run by a venture capitalist group based in Boston that utilized only a small portion of this technology’s potential.
“It’s like they went into a watermelon field, destroyed the entire watermelon field and just ate a few bites of the reddest part,” said Piomelli.
Although he was disappointed in this particular company’s use of his technology, Piomelli has received the patents and is seeking ways to move this technology back into the marketplace.
Looking for the Green Light
The growing market trends toward utilizing cannabis and cannabidiol (CBD) for profit has left Piomelli frustrated and wary of finding a business partner who is not interested in getting a quick buck from his technology.
Piomelli is not interested in being first-to-market within cannabis spaces; instead, he is more focused on finding the right business partner who, like Piomelli, has a more thoughtful approach to creating a business with his technology and understands the importance of research translation and regulations.
“What matters is that you need to learn how to navigate those regulations,” said Piomelli. “You need to learn how to translate what you find in the lab into something that can be used in people. That translational component is the hardest to find and is also very hard because you would like to have a business partner who actually is on your side.”
For now, Piomelli aims to find a trustworthy company who will utilize his technologies to their fullest potential. And all the while, Piomelli continues to cook up more uses from the body’s endocannabinoid system in his lab and supports Exxel Pharma in their steps toward human clinical trials.
“Engineering investments are what they are and the return is a lot more predictable,” said Piomelli. “But if we don’t invest more in pharma, we’re not going to have medicines to help with gigantic problems like pain, PTSD, addiction and depression. Do we want to be that society? I don’t think so.”
Learn more about UCI’s Center for the Study of Cannabis.
*Illustrations: Julie Kennedy, UCI Beall Applied Innovation
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