Raphael Mechoulam, Ph.D., is the Lionel Jacobson Professor of Medicinal Chemistry at the Hebrew University of Jerusalem, where he has been working on cannabinoid chemistry (a term he coined) for over forty years. Throughout this time Dr. Mechoulam and colleagues have made some of the most important contributions to the field of cannabinoid research. His lab was the first to identify and synthesize delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis. This discovery in 1964 (with Dr. Yehiel Gaoni) opened the door to a whole new field of medical research that began exploring, not only the therapeutic potential of THC (marketed as Marinol in America), but other natural and synthetic cannabinoids as well, and offered exciting new insights into how the brain functions.
Dr. Mechoulam, along with pharmacologist Dr. Habib Edery and colleagues, went on to isolate and elucidate the structures of most members of the cannabinoid group of compounds in the cannabis plant. Twenty-eight years after discovering THC, in 1992, Dr. Mechoulam, along with Dr. William Devane and Dr. Lumir Hanus, identified the brain’s first endogenous cannabinoid (or endocannabinoid)—the brain’s natural version of THC—which they called “anandamide,” from the Sanskrit word “ananda,” which means “eternal bliss” or “supreme joy.”
It turns out that the brain actually has a whole family of cannabinoid neurotransmitters and receptors. Just as the active compound in opium (morphine) led to the discovery of the endorphin (endogenous morphine) system in the brain, the active compound in cannabis (THC) led to the discovery of the brain’s endocannabinoid system. Later Dr. Mechoulam and colleagues identified the THC metabolites and, more recently, along with Dr. Lumir Hanus and Dr. Shimon Ben-Shabat, he discovered a second endocannabinoid known as 2-arachidonylglycerol (2-AG). These findings have profoundly advanced our understanding of cannabinoid systems.
Endocannabinoids function as neuroprotective agents. They are part of the brain’s reward system, and they help with the reduction of pain.
Vigorous exercise stimulates the release of anandamide, and the sense of euphoric well-being that comes with a healthy workout—what jogging enthusiasts refer to as a “runner’s high”—is due to elevated levels of endocannabinoids. The endocannabinoid system in the brain is also believed to help mediate emotions, consolidate memory, and coordinate movement. In fact, cannabinoid receptors are found in higher concentrations than any other receptor in the brain, and the endocannabinoid system acts essentially in just about every physiological system that people have looked into.
While the political controversy over medical marijuana continues in America, pharmaceutical companies—such as G.W. Pharmaceuticals in the United Kingdom and Sanofi-Synthélabo Recherché in France—are busy researching and developing a wealth of new medications based on compounds found in the cannabis plant. Controlled studies have revealed therapeutic utility of cannabinoids in the treatment of multiple sclerosis and other spasticity ailments, asthma, rheumatoid arthritis, cancer chemotherapy side-effects, glaucoma, AIDS wasting syndrome, and seizure disorders such as epilepsy. Analgesic action and tumor retardation have also been shown.
But even more exciting is the wave of new drugs that are currently being developed from cannabinoid analogs—both agonists and antagonists, meaning drugs that both activate and deactivate cannabinoid receptors in the brain. From new types of pain killers and neuroprotective agents for head trauma and stroke victims, to appetite stimulants and appetite suppressants. Most recently, one of the synthetic compounds (HU-211) from Dr. Mechoulam’s lab has completed phase 2 clinical trials against head trauma with evidence of a neuroprotective effect. The pace of cannabinoid research has certainly been accelerating over the past few years, and Dr. Mechoulam—who has been at the forefront of this research since the beginning—thinks these new drugs are just the tip of the iceberg.
Below is an excerpt from “National Geographic Explorer: Marijuana Nation” documentary featuring commentary by Dr. Raphael Mechoulam
Dr. Mechoulam is recognized as one of the world’s experts on cannabinoid-based medicine. In addition to his groundbreaking discoveries, he has written hundreds of scientific papers on his cannabinoid research, and he is the author of the book Cannabinoids as Therapeutic Agents, an early review of the research in this area. Dr. Mechoulam has received numerous honors and awards for his outstanding contributions to the field, and he was the president of the International Cannabinoid Research Society. Dr. Mechoulam is a member of the Israel Academy of Sciences, and among the numerous prizes that he has received for his work, is the highest national scientific prize in Israel—the Israel Prize.
Dr. Mechoulam is mentally energetic, kind, and generous. We spoke about how he came to discover THC and anandamide, the role that endocannabinoids play in the brain, natural ways to increase the brain’s production of anandamide, and the vast array of new cannabinoid-based drugs that are being developed.
Q: What do you think the function of anandamide and other endocannabinoids are in the brain?
Dr. Mechoulam: The endocannabinoid system acts essentially in just about every physiological system that people have looked into, so it appears to be a very central system. Actually, the cannabinoid receptors are found in higher concentrations than any other receptor in the brain, and they are found in very specific areas. They are not found all over, but rather in those places that one would expect them to be—such as areas that have to do with the coordination of movement, emotions, memory, reduction of pain, reward systems, and reproduction. So I believe that this is a very central and essential system that works together and communicates with many other systems.
Exercise has been shown to elevate endocannabinoid levels in the brain, and this probably accounts for what jogging enthusiasts refer to as the “runner’s high.”
Q: Do you think that increasing the amount of natural cannabinoids in the brain has any health benefits, and if so, what are some other ways that you think might increase the brain’s natural production of endocannabinoids?
Dr. Mechoulam: A good friend of mine was involved in that research. The results were a little bit on the marginal side, not tremendously high.
They saw a little bit more anandamide than normal. I would have expected much more. There was just this one paper, so people have not gone into that very thoroughly. It’s probably true, but I think that we have to do a little bit more work on that. I talked to Dr. Piomelli, who was one of the people on that paper, and I believe he also thinks one should see a little bit higher levels.
But there are many ways in which the endocannabinoid levels go up, and this is something quite specific for endocannabinoids. Generally, they are present in very low amounts. They are just not there. If you take a mouse and put it in a very low temperature (around one hundred degrees below zero) the mouse dies, the brain stops functioning immediately, and you’ll find essentially no anandamide. The anandamide is formed on demand when needed, and in only those areas that need that particular compound at the moment.
For example, during pain it will be produced in certain areas. The endocannabinoids are not produced all over, and they will not go into the bloodstream like hormones. They will stay around that particular area where they are supposed to be formed. One of the functions is neuroprotection. Now, I’m speaking about mice because I’m not sure what happens with humans. I’m not working with humans and, obviously, it’s not ethical to do that. If you take a mouse and cause slight damage to the skull of the mouse, or even to the brain, and if you leave the mouse it will recover within thirty days. But if you look at the brains of the mice you find that at least one of the endocannabinoids goes up one thousand percent, so we thought that maybe they have a neuroprotective role.
So we took mice of this type, that had been injured, and we injected them with synthetic endocannabinoids—2-AG, the second compound—and we saw that the damage went down very significantly. And there has been a lot of work on that. There has been some excellent work in California by Greenberg, and they find the same thing in other models. So everybody now believes that these compounds play a role in neuroprotection.
Q: What are your thoughts about using cannabinoids as a treatment to help prevent cancer or retard tumor growth?
Dr. Mechoulam: There are several groups that have found it effective in reducing tumor growth. This is probably due to the same mechanism as before with the neuroprotection. It’s probably not only neuroprotective; it’s probably a protective agent in general. So, to a certain extent, the endocannabinoid system can be compared with the immune system. Now, the immune system obviously guards us against protein effects, viruses, and microbes, but not all damages. So just as our body protects itself with the immune system against microbes or viruses, it also tries to protect itself with other systems—and the endocannabinoid system is one of them. So I believe that it certainly acts against cancer cells. There is a very important group in Spain that has done some excellent work on that, and they’re actually going into human work now with some cancers found in the brain. We have also done a little bit on that, and there is an Italian group that has done a lot of work on that. So, basically, it seems that this is one of the routes that our body uses to try and protect itself with—by acting on cancers using several different mechanisms, not just one.
Q: Can you talk a little about the research that’s currently going on with cannabinoid analogs and the development of new pharmaceutical drugs, such as in the areas of neuroprotection and pain management?
Dr. Mechoulam: THC itself is approved in the U.S. by the FDA, and it is used in many other countries for the prevention of vomiting during cancer chemotherapy, and for appetite enhancement. We, and many others, have found that not only THC does that, but also the endocannabinoids. This is one of the main reasons for high endocannabinoid levels during hunger and so on. Now, THC can be used, and is being used, for these two things.
Sanofi-Synthélabo Recherché in France is doing some interesting work. They have a compound, which is an antagonist of the cannabinoid system, and they have tested it in about eight thousand obese people. They have found that it is extremely useful. Their appetite goes down slowly, as it should, and they lose weight. They plan to introduce the compound in twelve months time, I think. They’re doing a lot of work in the field, and they expect huge sales.
There are compounds that are being tried by many companies. I think that just yesterday a new mixture of THC and CBD [cannabidiol], which is made by a company in England called G.W. Pharmaceuticals as a spray under the tongue, was approved in Canada. So they will be marketing it in Canada for the prevention of all kinds of multiple sclerosis effects, and they will probably get it approved in England. Here we have several things going. There is a compound which was found to be pretty good for prevention of cognition-lowering after heart surgery. After heart surgery, in some cases, there is some cognition lowering, and we found that it certainly does something to that. Initially we found this same compound was very good in the prevention of brain trauma, but large-scale experiments have not been positive. I’m not sure why. I think that it was technical mistake, but that’s another thing.
I’m part of the faculty at the medical school here, and at Hadassah Hospital, and we use THC for a variety of things. It has to be approved in every single case by a committee at the hospital. We have used it for a very wide variety of things. We found it effective in fighting hiccups, for example. You’ll be surprised how if somebody has hiccups constantly for months how terrible it is. And it works fine. We’ve used it for Tourettes Syndrome, which is a very nasty neurological disease.
This was based on work by some colleagues in Hannover, Germany. It works very well indeed. We’ve tried it in cases of multiple sclerosis. We’ve tried it, obviously, with appetite. We gave it four hundred times to children undergoing cancer chemotherapy in order to prevent them from vomiting, and to help with the terrible situation associated with treating children for cancer and so on. They’re happier, and the families are happier, so we’ve been very glad about it. So we try it in various diseases, where there is sufficient literature.
Q: What are some of the new drugs and treatments that you foresee being developed from cannabinoid analogs in the future?
Dr. Mechoulam: First of all, there are those things that have been approved already, such as for improvement of appetite. That’s good for cancer and AIDS, and is widely used. The other one of course is vomiting. The new drugs, I’m sure, will have to do with neuroprotection, and with certain kinds of pain—neuropathic pain, not acute pain. It doesn’t work with acute pain. It works mostly with neuropathic pain, long-term pain.
It may also work in the suppression of memory. This is something that I hope we’ll be able to start shortly. There’s something called post-traumatic stress disorder (PTSD), which is due to upsetting memories that stay around too long. Normally, when there is trauma people slowly forget it. This is true for humans and it’s true for animals. But if the animals do not have an endocannabinoid system, they do not forget bad memories, and this was shown in a paper by a German-Italian group. In collaboration with the Canadian group, we have done some work on that, and in a different model we have seen the same thing. So I expect that the endocannabinoid system is not in good shape in those post-traumatic patients, and chances are that it will work in treating them. We are just about to develop a treatment. People that have PTSD claim that the only thing that helps them is smoking marijuana, so chances are that cannabinoid treatment may help them.
Q: You once said that “Whatever THC does, anandamide does as well.” What is the reason that synthetic anandamide isn’t used therapeutically as an alternative THC?
Dr. Mechoulam: That’s a very touchy subject. Many years ago when insulin was discovered—I think it was in the early twenties—it was in the clinic within six months. When cortisone was discovered fifty years ago it was in the clinic within two years, and it became a very successful drug. We discovered anandamide twelve years ago, and it still has never been officially administered to a human. Neither has anandamide or 2-AG.
Q: Why is that?
Dr. Mechoulam: The laws have changed. I cannot give anandamide to a human because the toxicology research is not there, and the toxicology research is millions of dollars to do. So somebody has to pay for that.
I’ve asked the National Institute of Drug Abuse (NIDA) many times.
Q: But isn’t it an endogenous substance?
Dr. Mechoulam: Yes, but the law is that even a human endogenous substance has to be tested for toxicology and all these things. So I have asked them, I begged them actually, please do it—because a company will not, and obviously an academic person cannot do it. It’s a technical thing. It’s something that’s quite obvious that should be done, yet it has not been done, either with anandamide or with 2-AG. So nobody has ever given anandamide or 2-AG to a human, period.
Q: Why do you think that there has been so much political resistance to the notion of cannabinoids as medicine?
Dr. Mechoulam: I’m not sure that there is that much nowadays. It used to be much more. No company would ever touch anything like that many years ago. If they did, they did it kind of quietly. Now this not so. Sanofi is going to introduce that antagonist on a very wide scale in the states. Actually, most of the major U.S. companies have cannabinoid programs. I know that Smith, Klyne & Beecham has one, and so does Pfizer and Merck. So possibly the other companies are actually waiting for people to come on the market, so they won’t be the first ones. Now that Sanofi is going to be on the market, and THC is already on the market, chances are that the other companies will come too. After all, most of the drugs on the market—the new drugs over the last twenty years let’s say—are based on being agonists or antagonists of receptors of endogenous compounds like dopamine and so on.
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