CHAPTER 12
MECHOULAM'S LEGACY
“It sounds like a snake oil to save the world,” Martin Lee says. “CBD is great, everybody should take it. It’s going to fix every thing in your life. Make everything better. Fix your kitchen sink. Your car will run better. But the thing is that there is real science underpinning the utility of cannabis in multiple different ways and multiple different contexts. And I think that’s unique.”
Lee is the co-founder and director of Project CBD, an educational cannabis science organization and the author of the outstanding book Smoke Signals: A Social History of Marijuana, which won the American Botanical Council’s James A. Duke Award for Excellence in Botanical Literature. He’s also the co-founder of the media watch group FAIR (Fairness & Accuracy in Reporting). He knows how far we’ve come since Dr. Raphael Mechoulam and his research team discovered the endocannabinoid system, and he knows that we still have a long way to go.
“You know, you have these conflicting perceptions,” he explains. “A lot of the discussion has been about whether medical cannabis really works or is just a front for stoners. But once CBD entered the picture that changed the whole discussion. Now, it’s not a question of whether CBD has medical value. The World Health Organization basically gave CBD a clean bill of health.1 The question is: how do we use it for the maximum therapeutic effect?”
Despite all of the barriers there is a shift taking place, and more people are becoming aware of the benefits of CBD and other plant medicines. Let’s start with the World Health Organization (WHO). Based in Geneva, its role is to direct international health within the United Nations’ system and to lead partners in global health responses. It is the world’s arbiter of best practices in health. WHO oversees the implementation of policy through their publication of International Health Regulations and publishes medical reference classifications for governments around the world, including the International Statistical Classification of Diseases; the International Classification of Functioning, Disability and Health; the Global Code of Practice on the International Recruitment of Health Personnel and the International Classification of Health Interventions. They’re also the first port of call for global non-governmental organizations such as the Red Cross and Red Crescent for health care standards for people living in crisis situations.
In 2017, as Lee explained, WHO created a medical reference classification for CBD. This document suggests that governments around the world decriminalize CBD so it can be used in medical contexts. They have also recommended that it be employed in a number of health therapies, a full list of which is in the appendix to this book but includes treatments for Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease, hypoxia-ischemia injury, pain, psychosis, anxiety, depression, cancer, nausea, inflammatory diseases, rheumatoid arthritis, infection, inflammatory bowel and Crohn’s diseases, cardiovascular diseases and diabetic complications. The WHO standards are only the first step, however, in bringing CBD to the forefront of our medical care discourse.
Awareness and change for the better
“A lot of what we’ve learned is connected to anecdotal evidence,” journalist Ricardo Baca explains. It’s not that we don’t have research, but new evidence is coming forward every day from users who find their own path to CBD. “Kids, seniors, parents, using a topical oil or a lotion or a salve . . . they’ve found tremendous medical efficacy. We’ve seen its efficacy and power when it is applied to a senior citizen’s arthritic hand or a child with Dravet syndrome. But we’re coming off of eight decades of propaganda and we just don’t know everything yet. It’s not just about one cannabinoid or one terpene: it’s all these things coming together and creating a specific effect.”
Baca is referring to what is known as the entourage effect, and it’s something that researchers like Dr. Reggie Gaudino are only just starting to explore and capture in terms of their medical applications.
“Cannabinoids are actually a member of a larger family of molecules called terpenoids,” Gaudino explains, talking about a class of organic compounds that are the oldest group of small molecular products synthesized by plants. “It’s a five-carbon chain called an isoprene. Terpenoids, cannabinoids and flavonoids [plant pigments] are all built from the same starting building block. When different enzymes come together, there’s a pathway in this chain, and all of these are likely to be medically important.”
What this means is that we need the whole plant, and not just a single part of it, in order to gain all of the benefits that cannabis medicine has to offer. This doesn’t mean that we have to take THC with our CBD, but when we isolate some molecules from all of the other healthy molecules available in hemp plants, we’re not necessarily going to get the best opportunity to move toward wellness.
Here’s the science. Cannabigerolic acid (CBGA) is actually the first cannabinoid in the pathway. Then, enzymes convert CBGA into tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) and cannabichromenic acid (CBCA).2 CBGA is effective in treating glaucoma,3 Huntington’s disease4 and cancer,5 for example. Taking all of these molecules together maximizes our benefit, and this is the entourage effect in action. But we’re only just scratching the surface of what might be developed in the future.
“Those are the three main cannabinoids,” Gaudino says. “But there actually many, many cannabinoids. We’ve identified between eighteen and twenty-two in distinct cannabinoid synthesis, and we know that there are at least one hundred and forty-four cannabinoids. By that, I mean that these molecules have different sequences so most likely they make different things.”
As Gaudino explains, cannabidivarin (CBDV) and tetrahydrocannabivarin (THCV) are CBD derivatives that may not only treat nausea6 but also Parkinson’s7 and Alzheimer’s.8 Gaudino is exploring these molecules in his work for a very specific reason. His mother was a nurse, and his father was a surgeon, so he comes from his own health care legacy. But when his father had a stroke, Gaudino immediately gave him CBD and CBG. If stroke patients receive CBD and CBG, with their neuro-regenerative properties, within a few weeks they’ve been shown to have fewer long-term symptoms.9
But, for Gaudino, future research has to shift the status quo for cannabis if we’re going to be successful at fully taking advantage of this plant. “We focused on THC,” he says. “Chances are if we had a more diverse approach to research, rather than focusing on the recreational use of cannabis, we may have seen plants with other cannabinoids as well. Unless we go back out there and find the original plants we might not ever know what we’ve lost. CBD is one of the things that managed to be saved. We found something and people jumped on the bandwagon. All of these cannabinoids have a medical efficacy that we have been missing for the last eighty years.”
A new world of health care: Patients leading the way
Veterinary science is another one of the growing areas of influence in cannabis medicine, and yet it’s mired in the same kind of social, legal and political challenges that affect human treatments using CBD.
Holistic veterinarian and scientist Dr. Gary Richter is the author of the bestselling book The Ultimate Pet Health Guide, and he can’t advocate for CBD’s use. If he does, he risks having his license taken away. What he does do, however, is support animal owners through their CBD process. He does this because, in recent years, there has been a definitive increase in the number of requests he has had for cannabis medicine for dogs, cats and other animals at his California practice.
“My veterinary practice is really surrounded by and defined by integrative medicine,” Richter says, which is related to what we call CAM for human health care. “I practice both conventional Western medical care as well as what some people might call holistic alternative care, acupuncture, herbal therapy, these sorts of things. So you know, for me as a veterinarian, I’m always looking for new ways I can help my patients. Looking at cannabis as medicine was a natural progression.”
Richter has had some first-hand experience observing what happens when his patients turn to CBD to treat their pets. Changing demographics, new lifestyle trends and a shift in American attitudes toward pets have led to a significant increase in pet health care spending in the last few years. Expanding disposable incomes, higher educational levels and more awareness of a range of lifestyle options has resulted in a new kind of pet owner who views their pet as a close member of the family.10 This has created a new world of pet care in which CBD becomes an option, especially for intractable diseases such as cancer.
“One of my patients was a dog diagnosed with lymphoma. This dog had cancer and received all manner of care: supplements, medications, chemotherapy,” Richter explains. “With cannabis therapy, this dog has lived well past anybody’s expectation of how long it should have lived with lymphoma. The dog lives a great life. When our expectations are so far exceeded, and when we see it happen over and over and over again and cannabis is involved, it’s hard not to connect those two dots.”
Dr. Sari Prutchi-Sagiv is the director of technology transfer, pharma and diagnostics at Mor Research in Tel Aviv. As one of Dr. Raphael Mechoulam’s legacy scholars, she’s the first to say that patients have led the way to one of the most important breakthroughs in CBD care. Prutchi-Sagiv’s work centers on what is called graft versus host disease (GVHD), and it’s one of the most serious and deadly conditions in the world, affecting the most vulnerable patients: those who have received bone marrow transplants to treat aggressive forms of cancer like leukemia and lymphoma. In GVHD, donor blood cells attack the recipient, which can eventually lead to internal bleeding, liver failure and likely death. It’s an autoimmune disorder and it is the most common cause of long-term complications and rejection of new organs after a transplant.
“In my work, I manage pharmaceutical inventions,” she says. “We’re the biggest HMO here in Israel. We have 5 million patients in fourteen hospitals. One doctor approached me because he had an idea. Some of his patients undergoing bone marrow transplant felt better with medical marijuana, and he wanted to see if cannabidiol would help. So he approached Mechoulam and he called me, and I started managing this project.”
Running four different clinical trials with ninety patients with acute or chronic GVHD, which has an 80 to 100 percent mortality level, Prutchi-Sagiv was astonished when she found how quickly and easily CBD, taken every day for a month, had an effect.
“We had excellent results. In one trial, we reduced incidence of GVHD from fifty to seventy percent to twelve percent of patients,” Prutchi-Sagiv shares. “In another pre-transplant trial, when patients took CBD seven days before transplant and thirty to one hundred days afterwards, zero patients acquired GVHD. I have never seen such a significant result before. It’s incredible.”
Mechoulam’s legacy, and his call to action, extends far outside of Israel, as more people hear about his work. Steve DeAngelo, the American medical cannabis leader, recently felt called to meet the man himself in Tel Aviv. DeAngelo asked, given what we know about the role of the endocannabinoid system in maintaining homeostasis and how widespread the endocannabinoid system is in the human body, whether it would be reasonable to assume that cannabis will be effective for every medical condition known to humankind.
“There was a not-too-long silence and Dr. Mechoulam said, ‘Yes, I think that would be a fair statement,’” DeAngelo says. “Cannabis isn’t just the most important medical breakthrough since the discovery of germ theory. Cannabis is the most important medical breakthrough since the discovery of medicine. There is no other medicine that we know of on the planet that is effective for such a wide range of medical conditions, that has so few and such gentle side effects to it. I don’t think it’s an exaggeration to consider that cannabis may be the most valuable medicine that we have on the planet today.”
Mechoulam shared a new story with DeAngelo about the effects of CBD on the residents of an Israeli nursing home. “All of them reported an improvement in mood. All of them reported a reduction in nightmares. So there’s some very consistent effects. But then there were some different effects that varied from patient to patient, from person to person. People who were overweight dropped weight and came closer to their ideal body mass index. Nursing home residents who were underweight gained weight and came closer to their ideal body mass index. It didn’t do the same thing in everybody’s body, but what it did do was restore everybody’s body to its state of natural balance.”
Our roles, our lives
It’s really important for people to understand themselves and understand the plant so they can do the best job of representing themselves to physicians and researching their own needs, Gaudino recommends.
CBD is the master regulator, and using it is all about finding and maintaining balance, that essential homeostasis that allows us to thrive and survive. Using the whole plant can allow us to gain access to the entourage effect. There is no one-size-fits-all fix with CBD, however, and we have just as much research to do on what cannabis won’t help fix as we do on determining where it will lead to better health. As Gaudino explains, for example, some people have allergic reactions to CBD. There are also those whose systems will react badly for other reasons. As Janie Maedler shares, some children with epilepsy react badly to certain forms of CBD, and therefore it’s really important to work with a trained doctor or cannabis consultant to know exactly what is right for each person and each disease trajectory. Everyone’s endocannabinoid system is based on their own genetics and their own physical response.
We can’t just rely on researchers to find all of these answers for us. As Mechoulam’s legacy shows, researchers need our help in bringing these ideas forward and moving CBD research in the right direction. Mechoulam was the first person to ask questions. I believe that the future that we’re seeking is one where we can continue his conversation. The more that we ask questions, the more that we can slowly shift the status quo. The more that we ask questions, the more that we can decrease the legal, physical and social barriers to effective plant medicines. The more that we ask questions, the more that we can increase access to CBD.
We may not always have the right answers, but we always need to be on the lookout for better questions to find the route to health and happiness.
1. [World Health Organization. (2017, November 6–10). CANNABIDIOL (CBD) PreReview Report. Geneva: Expert Committee on Drug Dependence.]↩
2. [Havelka, J. (2018). What is CBG and what are the benefits of this cannabinoid? Leafly. Retrieved from https://www.leafly.com/news/cannabis-101/what-is-cbg-cannabinoid]↩
3. [Nadolska, K. & Goś, R. (2008). Possibilities of applying cannabinoids’ in the treatment of glaucoma. Klinika Oczna, 110(7–9), 314–317.]↩
4. [Valdeolivas, S., Navarrete, C., Cantarero, I., Bellido, M.L., Muñoz, E. & Sagredo, O. (2015). Neuroprotective properties of cannabigerol in Huntington’s disease: studies in R6/2 mice and 3-nitropropionate-lesioned mice. Neurotherapeutics, 12(1), 185–199.]↩
5. [Borrelli, F., Pagano, E., Romano, B., Panzera, S., Maiello, F., Coppola, D. , . . . & Izzo, A.A. (2014). Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a cannabis-derived non-psychotropic cannabinoid. Carcinogenesis, 35(12), 2787–2797.]↩
6. [Rock, E.M., Sticht, M.A., Duncan, M., Stott, C. & Parker, L.A. (2013). Evaluation of the potential of the phytocannabinoids, cannabidivarin (CBDV) and Δ9-tetrahydrocannabivarin (THCV), to produce CB1 receptor inverse agonism symptoms of nausea in rats. British Journal of Pharmacology, 170(3), 671–678.]↩
7. [Ojha, S., Javed, H., Azimullah, S. & Haque, M.E. (2016). β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease. Molecular and Cellular Biochemistry, 418(1–2), 59–70.]↩
8. [Karl, T., Garner, B. & Cheng, D. (2017). The therapeutic potential of the phytocannabinoid cannabidiol for Alzheimer’s disease. Behavioural pharmacology, 28(2), 142–160.]↩
9. [Russo, E.B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology, 163(7), 1344–1364.]↩
10. [Pirsich, W., von Hardenberg, L.M. & Theuvsen, L. (2017). The pet food industry: an innovative distribution channel for marketing feed products from welfare friendly production to consumers? International Journal on Food System Dynamics, 8(3), 250–261.]↩