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There’s A ‘Legal High’ You Can Buy Online, And It Isn’t Cannabis

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A recent study by a group of scientists in Bern, Switzerland examining a cannabinoid extracted from a rare moss-like plant–a member of the liverwort family–growing only in Japan, New Zealand, and Costa Rica has revealed potentially useful properties that may be valuable for people suffering with inflammation and chronic pain.

Liverwort (Radula perrottetii)

University of Bern/Stefan Fischer

What’s even more interesting is that this moss is distantly related to a plant we are quite familiar with–Cannabis Sativa which has more recently emerged as a potential approach for treating seizures, multiple sclerosis, inflammation, and many chronic medical conditions.

Thus far, the researchers do not understand why this specific liverwort–which has a different way of living and reproducing compared with Cannabis—would harbor a compound so similar to tetrahydrocannabinol (THC), the psychoactive component found in marijuana. (It was previously believed that the only plant that produces THC was Cannabis Sativa.)

What they do realize is that the cannabinoid isolated from this liverwort, and THC found in Cannabis are chemically similar , but also produce quite similar effects in the brains of mammals.

The study was recently published in the Journal, Science Advances.

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 a press 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.

Market aspects of cannabinoids

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.

A recent study revealed that a moss-like plant known as a liverwort harbors a cannabinoid with remarkable chemical similarities to THC found in Cannabis, and also yields quite similar effects in the brains of mammals.

Healthier Alternatives to Smoking Medical Marijuana

Angela Morrow, RN, BSN, CHPN, is a certified hospice and palliative care nurse.

Anita Chandrasekaran, MD, MPH, is board-certified in internal medicine and rheumatology and currently works as a rheumatologist at Hartford Healthcare Medical Group in Connecticut.

The medicinal use of marijuana is legal in a growing number of U.S. states, and other states might eventually join this list.   Some patients, however, might be unable to smoke medical marijuana because of their illness, disease, symptoms, treatments and/or other factors. This article explores the alternatives to smoking marijuana that might prove healthier or more viable for patients who’ve received a prescription for medical marijuana.

Marijuana Use for Medicinal Purposes

Requiring a doctor’s “recommendation” or referral and secured from legal vendors, medical marijuana can help relieve numerous symptoms, such as pain, glaucoma, migraine headaches,   nausea, and weight loss.

While there are various pros and cons of using medical marijuana, it’s important to understand that the use of marijuana is not without potential side effects. For example, conventional or “street” marijuana might contain harmful fungus and/or pesticides,   which can prove especially dangerous for patients with a compromised immune system.

Moreover, the fact that marijuana is usually smoked—either in cigarette form or through the use of tobacco or water pipes—introduces additional concerns. Patients who have never smoked before, or those receiving other treatments that can interfere with their ability to smoke, might find smoking marijuana difficult or simply impossible.

I found that to be a case with a patient with lung cancer and COPD. He suffered from chronic bone pain, nausea, and severe weight loss. He asked his doctor about medical marijuana and received the necessary prescription. When I came to see him, he held a joint but didn’t know how to use it. It was immediately clear that because of his inexperience and because he was using oxygen and was already suffering from a forceful cough, smoking a marijuana cigarette would not be the best method for him.

Alternative Options

It’s important to again stress that medical marijuana is a physician-referred treatment and should only be used according to a doctor’s instructions. If you or someone you care for receives a prescription for medical marijuana use but cannot smoke marijuana, non-smoking options might include:

Edible Marijuana: Medical cannabis can be heated and made into oils, butters, and tinctures. Many “cannabis clubs” sell pre-made cookies, brownies, lollipops, and teas. Savvy patients—those willing to take the time to empower themselves through research and knowledge—can also find recipes to make their own marijuana tincture, oil, or butter.

Eating or drinking marijuana’s main or active ingredient tetrahydrocannabinol (THC) is certainly preferable for many patients rather than smoking it, but these alternative methods can also create problems. When consumed via food or drink, THC does not absorb into the bloodstream as quickly as when it is smoked.   This can make it more difficult to control the effectiveness of the drug or how much is consumed. In addition, patients who suffer from decreased appetite or nausea might not tolerate eating or drinking marijuana.

Vaporizers: Another option is to inhale marijuana using a vaporizer. This method involves heating the marijuana to a high enough temperature to vaporize the THC but not burn the plant. Patients can then breathe in the vapor from a bag without inhaling the harsh and potentially toxic smoke.

Vaping as it is commonly known, can cause serious lung injury. In 2019, a series of outbreaks across the country of what is called product use associated lung injury (EVALI), have resulted in over 2,291 hospitalizations and caused a reported 48 deaths (as of December 3, 2019).   The Centers for Disease Control and Prevention are conducting studies to analyze the components of the TCH from the vaping products. They recommend that people do not use THC vaporizers and to watch carefully for any symptoms if they continue to vape.  

Finding the Solution That Works for You

Ultimately, it is possible to find healthier or more suitable alternatives to smoking marijuana, as my aforementioned patient did. He experimented with edible marijuana and found that he enjoyed the marijuana brownies he was able to get at a cannabis club, but as his appetite waned, he found it difficult to stomach the rich chocolate taste. He didn’t want to invest in a vaporizer because his life expectancy was short. However, through the people he met at the cannabis club, he was able to strike a deal with another medical marijuana patient and split the cost of a vaporizer—with the agreement that the other patient would inherit the device after his death. It was an unusual arrangement, to be sure, but it allowed him to continue using medical marijuana for several more weeks.

The alternatives to smoking marijuana that might prove healthier or more viable for patients who've received a prescription for medical marijuana.