Much to the joy of many marijuana enthusiasts, cannabis and many of the compounds within it have a number of therapeutic uses — with real hopes they can help replace certain drugs with harsh side effects and treat in places where other medications fail.
However, before they celebrate too much, cannabis has a big problem when it comes to being a truly viable treatment. It’s very unreliable. And even with the best agricultural practices and care, the rotating profile of the different cannabinoids and terpenes from crop to crop — that’s potentially divided up by more than a thousand unique compounds — is seeming unstoppable. With inconstant levels of cannabinoids like THC and CBD from crop to crop, this makes pinpoint accurate dosages very difficult with cannabis plants.
This is not surprising when we look at any of our fruits and vegetables. Most of us don’t expect every tomato we eat to taste exactly the same, and we’re even aware that the different areas of a piece of fruit can taste different. These natural discrepancies in the chemical profile of plants are completely fine for plants we eat and food items we create with them, like ketchup. But when it comes to taking a prescription drug, we expect it to have the same active ingredients in the same ratio every time.
This is one of the main reasons the US Food and Drug Administration has only approved a single prescription medication derived from cannabis. Epidiolex, approved in 2018, is a CBD isolate, which separates the cannabinoid, cannabidiol (CBD), away from a sea of others like it, but slightly — and sometimes not so slightly — different.
Israeli scientists and researchers hope to change that. From plant scientists hoping to teach others how to carefully cultivate cannabis for consistent results. To those such as Reshef Swisa and Asaf Ohana, who in late 2016 started the company EPM (Endless Potential Molecules) to “standardized prescription drugs derived from synthetic cannabinoid acids”.
Israel is no stranger to cannabis, with many hailing their leading work in cannabis research dating back to the renowned research done by Raphael Mechoulam in the 1960s. Raphael and his team were the first to synthesize and name many of the cannabinoids unique to cannabis, succeeding in the total synthesis of the major plant cannabinoids delta-9-THC, CBD, and CBG.
Mechoulam continues his research to this day, partnering with Swisa and Ohana in starting up EPM, who have now patented 14 lab-made molecules which will soon be put to the test in human trials conducted under U.S. FDA guidance.
Research shows medical marijuana can help with everything from common ailments like anxiety to rare seizure disorders. The two disorders EPM are looking to help treat first will be inflammatory bowel disease (IBD) and psoriasis. If things go well, Swisa says acute respiratory distress syndrome (ARDS) will be the next target — a disease sometimes seen in severe COVID-19 cases.
Due to the instability of cannabinoid acids — found in the dried flower — which can easily break down when exposed to heat, Reshef explains this makes large pharmaceutical companies reluctant to turn them into prescription drugs.
“EPM asked, is it possible to create cannabinoid acids in the lab in a way that is stable and suitable for prescription medicine development? That’s the core difference between EPM versus what’s happening in the market today.”
Synthetic cannabinoids may soon be helping many with debilitating chronic diseases
The idea of stabilizing cannabinoids by creating them in a lab is echoed by Prof. Dan Peer, director of the Laboratory of Precision Nano Medicine at Tel Aviv University. He’s is also a member of EPM’s scientific advisory board who presented the positive results of a study on EPM301 for treating IBD, at the International Cannabis Conference hosted virtually by Israel in June.
Talking to ISREAEL21c, Peer says “It’s much smarter to use synthetic molecules because they are highly reproducible and because producing small molecules would be cheaper than creating plants. You can achieve scalability, reproducibility, and robustness,”
“My lab has been studying novel approaches to treat inflammatory bowel diseases such as Crohn’s and ulcerative colitis,”
“I’m a very skeptical guy. Usually, molecules don’t work at the animal level, let alone the clinical level. But when I was approached four years ago by Raphael Mechoulam to check some molecules he synthesized, we discovered that one of them – EPM301 – has unique super anti-inflammatory properties,” Peer says.
When Peer says these EPM301 has super anti-inflammatory effects, he means it with his research showing it works as well and sometimes even better than steroids that are toxic when taken long term. Peer’s three-month study showed no toxic effects from EPM301 on the animals studied.
“This is good news for patients who can receive effective treatment without the severe side effects and risks associated with steroids: damage to liver enzymes, osteoporosis, cataracts, and suppression of the immune system,” Peer says with news that EMP301 could be manufactured at pharma-grade for additional toxicology testing and advanced clinical trials in 2022 — once it completes an initial Phase 1 clinical trial and finalizes the toxicology studies.
For the Phase 1 clinical trial, EPM will be enlisting the help of healthy volunteers for research in psoriasis formulation.
“CBD and THC belong to nature; no one can claim ownership over those patents.”
Performing identically to their cannabinoid counterparts but with none of the instability, EPM’s patented 14 synthetic cannabinoids should bring peace of mind to both proponents of the plant’s therapeutic properties and pharmaceutical companies.
“In the pharma industry, the two elements that do not exist in cannabis that are very much needed for drug development are production consistency so that each pill is exactly the same and ownership of the patent,” says Reshef. “CBD and THC belong to nature; no one can claim ownership over those patents.”
Despite the FDA approving a CBD isolate, Reshef stresses that both the FDA and the pharmaceutical industry as a whole have a fundamental problem working with natural compounds and the inconsistent purity profiles that results from botanical plants.
A tale as old as time and a look at the future
When learning about the origins of many of the medications we take that are synthesized in the lab, it makes perfect sense that the future of medical cannabis could be one devoid of the plant. For example, aspirin is a reliable synthetic analog of salicylic acid found in the bark and leaves of willow and poplar trees.
And while plant scientists — like Israeli’s Nirit Bernstein whose research will help cultivators grow cannabis crops with the best terpene and cannabinoid concentrations – are working diligently to grow plants with identical or nearly identical active chemical profiles, they are finding cannabis is incredibly touchy.
Bernstein is finding that cannabinoid and terpene concentrations are sensitive to overfertilization. In one study, Bernstein found phosphorus enhancement causes a 16% reduction of THCA concentration in the leaves while humic acids reduce THCA and CBDA by 37% and 39%, respectively, at the top of the plant (both leaves and flowers). In another, she saw more than the minimal amount of nitrogen needed to prevent chlorosis caused a reduction in cannabinoid levels — THCA and CBDA, decreased by 69% and 63%, respectively. Cannabinoid concentrations started decreasing well before nitrogen levels induced toxicity.
So, the question remains. What will the future of medical cannabis look like?