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Raphael Mechoulam

cancers using several different mechanisms, not just one.

David: 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?

Raphael: 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-Aventis 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 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’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.

David: What are some of the new drugs and treatments that you foresee being developed from cannabinoid analogs in the future?

Raphael: 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 a 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 seem 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.

David: They just started studies here in America treating post-traumatic stress disorder with MDMA.

Raphael: Yes, I know that. There is a group that is pushing MDMA quite a bit. They’ve been here many times, and they’re close friends of mine. I don’t know whether it’s useful or not, but chances are that it may be. Let’s see the result.

David: 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?

Raphael: 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.

David: Why is that?

Raphael: The laws have changed. I can not 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.

David: But it’s an endogenous substance.

Raphael: 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 a 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.

David: Why do you think that there has been so much political resistance to the notion of cannabinoids as medicine?

Raphael: 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-Aventis 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-Aventis 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.

David:  Besides weight loss, what other uses would there be for a cannabinoid antagonist?

Raphael: One of them is nicotine withdrawal, which has some nasty symptoms. Mark Twain once said “It’s easy to stop smoking; I’ve done it many times.” (laughter) So apparently this antagonist may help with that. That’s one things, and I’m not sure that there are many others. Possibly, it may help with some of the withdrawal symptoms for other drug abuse agents, like heroin perhaps, or maybe cocaine. I’m not sure, because not enough work has been done. But those are the two major things that I can see.

Another big field will be agonists specific to the CB-2 receptor. The CB-2 receptor is in the periphery. We synthesized a CB-2 specific agonist that has nothing to do with the CB-1, which is present in the brain. It is very good for all kinds of digestive system disorders. THC is excellent for treating Crohn’s disease and things of that sort. It’s not on the market yet, but quite a few groups are working on it. So it will definitely be very useful in those cases.

There are other things. For example, many years ago we elucidated the structure of a compound called cannabidiol, which is present in very large amounts in cannabis. It’s more than THC, and it is anti-inflammatory. It is excellent against rheumatoid arthritis, at least in animals . We worked together with a London group–real top of the field people in rheumatoid arthritis–and they have never seen anything as good as that. So chances are that this particular compound, cannabidiol, can be used in rheumatoid arthritis. And it has no psychotropic effects, as a matter of fact, because it does not bind to the receptors. Maybe it has something to do with the metabolism of anandamide. Maybe it blocks the anandamide breakdown. Maybe. 

This is something we saw, but whether it’s relevant to its activity, frankly I don’t know. So this compound possibly will be used for rheumatoid arthritis. A company is already working on that, so it is not only the endocannabinoids as such, but also other compounds which are in the vicinity. There is also another receptor that we haven’t fully

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