PET was first described in 1994 by the Japanese phytochemist, Yoshinori Asakawa. But it wasn’t until Jürg Gertsch from the Institute of Biochemistry and Molecular Medicine at the University of Bern, evaluated the similarity of this compound in structure and activity to THC in the brains of mammals that the significance became more relevant.Several years ago, Gertsch noticed that liverworts were being promoted online as “legal highs”, used by recreational and medicinal users in Switzerland, New Zealand, as well as other areas of the world. But no research had been done to evaluate the pharmacological properties of the cannabinoids contained in the plant. Gertsch joined forces with his colleague, Erick Carreira, from the Department of Chemistry at the ETH Zürich, and proceeded to compare THC and PET.
Using an animal model (mice), the team demonstrated that PET reaches the brain relatively easily, but activates cannabinoid receptors– CB1 and CB2 receptors–to a much weaker degree compared with THC. As a result, a key difference between the two compounds is that PET is much less psychoactive compared with THC, making it more attractive for medicinal as opposed to recreational purposes. But PET’s more potent anti-inflammatory effects, compared with THC, based on initial studies, certainly became a point of further interest.
Gertsch believes that PET’s more robust anti-inflammatory effect in the brain compared with THC, makes it noteworthy, especially if you consider its potential medical applications.
“It’s astonishing that only two species of plants, separated by 300 million years of evolution, produce psychoactive cannabinoids,” said Gertsch in apress release.
And it turns out that the Maori people, indigenous to New Zealand, have utilized the liverwort plant for centuries as a traditional medicine for treating abnormalities of the liver or digestive issues.
“The work of Jürg Gertsch and colleagues is a prominent advance in understanding the role of plants beyond cannabis on the endocannabinoid system,” said Ethan Russo M.D., a neurologist, and Director of Research and Development for International Cannabis and Cannabinoids Institute (ICCI). “Perrottetinene from the liverwort, Radula marginata, has proven to stimulate weakly the CB1 receptor where THC and the endocannabinoids, anandamide (ANA) and 2-arachidonyl glycerol (2-AG) also bind.
“Although this activity was proven via positive effects on the mouse tetrad of hypothermia (lowered temperature), catalepsy (frozen behavior), hypolocomotion (decreased movement) and analgesia (pain reduction), and was demonstrated to enter the brain, it is unlikely to become a major target of recreation users because of its relatively low potency and especially since liverworts are very slow growing and difficult to cultivate.” added Russo.
Russo also explained that “perrottetinene differs from THC in a key way that makes it potentially useful medically, in that it reduces levels of prostaglandins D2 and E2 in the brain without producing COX inhibition, and thus may provide an effective anti-inflammatory and pain killer with a low risk of intoxication, formation of ulcers, or production of heart attacks or strokes.
Russo explained that this finding should prompt additional biochemical prospecting in other liverwort species in this frequently overlooked group of “primitive” plants.
Jeffrey C. Raber, Ph.D., a chemist with expertise in cannabinoid physiology and CEO of The Werc Shop, an independent testing laboratory in Southern California, also sees the potential upside of perrottetinene from a clinical standpoint as well, but realizes that cultivating and extraction of the compound may be challenging, but could be overcome with creativity and ingenuity.
“The stereochemistry of this compound suggests it may possess interesting clinical potential with minimized psychoactive side effect,” explained Raber. “Obtaining significant quantities of pure compound may be challenging initially, but viable natural based or synthetic routes may both be developed should it prove of interest to do so.”
PET less psychoactive compared with THC
It’s well known that low doses of THC may offer therapeutic potential when it comes to treating various chronic illnesses. But THC is limited from a therapeutic standpoint due to a strong psychoactive effect at higher doses, other than being illegal at this time.
As previously mentioned, in contrast to THC, PET inhibits the production of inflammatory prostaglandins in the brain. As a result, PET likely has an effect on cannabinoid receptors which interact with our endogenous endocannabinoids. Certainly more preclinical studies of various models of chronic and inflammatory pain will be necessary to better understand its role in this setting.
To obtain adequate amounts of PET from the liverwort plant, Gertsch collaborated with his colleague, Erick Carreira, whose team developed a new synthetic way to preserve the 3-D structure of the compound on a molecular level.
“The present study is a prime example of how new synthetic concepts can make a contribution towards enriching our pharmacological knowledge of biologically-active natural substances”, said Michael Schafroth, PhD, who studied and worked under the direction of Dr. Carreira, in a press release.
“Both solid fundamental research in the field of biochemical and pharmacological mechanisms as well as controlled clinical studies are required to carry out cannabinoid research”, added Gertsch.
With recent legalization of Cannabis in Canada helping to support ongoing support for research and patient interest in using combinations of CBD and THC to treat common conditions such as endometriosis, fibromyalgia and IBS, it’s becoming more apparent that the endocannabinoid system and its associated deficiencies may hold the key to relieving pain and alleviating bothersome symptoms that are difficult to treat.
Use of CBD (Epidiolex, GW Pharmaceuticals) to treat intractable seizures associated with Dravet syndrome and Lennox Gastaut Syndrome, along with THC (2.7 mg) and CBD (2.5 mg) per spray (nabiximols, Sativex, GW Pharmaceuticals) to treat spasticity associated with MS is supported by published research and has emerged as a viable way to manage these difficult-to-treat conditions when available and standard approaches yield minimal improvement.
As clinicians seek less harmful modalities than opioids for treating chronic pain, PTSD, gastrointestinal, and autoimmune disorders, liverwort and its derivatives may hold promise as a safer therapy. The road to get there will involve not only refining methods of extraction and purification, but a significant amount of preclinical studies in animal models, before it’s ever tested in humans.
“2018 has seen the phenomenal rise of Cannabis and hemp (CBD) as an alternative therapy to alleviate the symptoms of pain, epilepsy, PTSD, MS, fibromyalgia, endometriosis, GI disorders, and many other chronic conditions,”said Rich Able, a medical device consultant based in Seattle.
“This is a very exciting time as big liquor and big pharma companies have invested billions of dollars into Cannabis ventures and clinical labs throughout the year,” offered Able. “This trend will continue as clinicians potentially investigate safer plant-based alternative therapies such as liverwort.”
“Known plant-based compounds like this one [PET] can be challenging to protect with patents, which is one reason why they may not be prioritized by industry,” said Greg Wesner, Chair of Lane Powell’s Intellectual Property Litigation Team, based in Seattle. “Nevertheless, even if the active pharmaceutical ingredient (API) itself is not patentable as a chemical entity, it may be possible to obtain patent protection for a drug candidate that combines the API with an effective, patentable drug delivery technology.”
“Moreover, the API could be the subject of a method of treatment patent if the API is discovered to be a novel treatment for a disease indication,” added Wesner.