Now, in the beginning it was not clear what the basics of the action was. We knew a lot about the actual physiological effects and the pharmacology. All these things could be investigated with pure THC, and there were thousands of papers on THC. We had isolated it, and as we had a synthesis, it was not very difficult to work with it. But the basics of the metabolic action were completely unknown, and there was some real reasons for that. The reason for this lack of clarity arose when we synthesized a mirror-image of the THC molecule. The THC molecule has two asymmetric centers, and therefore it is available in both positive and negative forms. Now, the negative form is the active one, so, supposedly, the positive form should have been inactive. But, actually, it was. People said that they had repeated our synthesis and tested the compounds, and they were active.
Now, if you have a compound which has two forms–called enantiomers–and they’re both active, then chances are that it doesn’t bind to a receptor, to a enzyme, or anything like that because these receptors are also asymmetric, and therefore only one of the symmetric compounds should act, or should bind to them. Well, it turned out that this was wrong, that people were mistaken. We took some THC, synthesized both compounds in completely pure form, and it turned out that only the negative form was active. So it was just a technical error by many groups who tested both enantiomers, because we found that this is not true, that only one form was active. Therefore, there was an asymmetric molecule in the body, and this led quite shortly thereafter to the discovery of the first receptor, which, of course, is asymmetric as well. That was done by Allyn Howlett at the St. Louis University Medical School in 1988. She did some excellent work, and her student was Bill Devane.
I invited Bill Devane to join my group in the late ‘80s, early ‘90s, and he came and stayed with us for about two years. He came here to study some chemistry, but I had some other ideas for him. I thought that, if there is a receptor, then the receptor is not in our brain just because there is a plant out there, but because there is, obviously, a compound synthesized in the brain which activates this particular receptor. Because Bill had experience with the receptors–it was the subject of his Ph.D. thesis–that meant that we could chemically identify a compound which will bind to this receptor in the brain.
So I had Bill, and there was a Czech fellow who joined me just about that time. He also came for six months, and he’s still with me ten years later, Lumir Hanus. They worked very hard indeed. We had to separate and separate brain extracts, and test them on binding, and then we tested them in the U.K. on some physiological activities. And ultimately we got an extremely small amount of material. But that was enough to be able to show the structure, to elucidate the structure of that. So we were glad. We synthesized it immediately, and that compound turned out to be anandamide.
David: What was the reason that you named it “anandamide?”
Raphael: We assumed it has to do with joy. After all, people normally use marijuana to feel better, to be happy–and we were certainly happy, having succeeded after so much work to identify the compound. It was completely unexpected that the compound would be a fatty acid derivative. The compound in the cannabis plant is a tricyclic compound and here we had a fatty acid, which is completely different from a chemical point of view. But they had more or less exactly the same actions, both in vitro and in vivo. We called it “anandamide” because “ananda” means “supreme joy” in Sanskrit, and “amide” comes from its structure, because it has an amide bond. So together it sounded okay. We called it “anandamide.”
We also knew that there are a different type of endocannabinoid receptors in the periphery that are not present in the brain. So we looked in the periphery, in the spleen, and we found a second compound, very closely related to anandamide, called 2-arachidonylglycerol. Anandamide is arachidonyl ethanolamide. So these are the endogenous cannabinoids–the endocannabinoids. It has turned out by the work of hundreds of groups now, including my own. Obviously there is a lot of interest in this group of compounds.
David: What do you think the function of anandamide and other endocannabinoids are in the brain?
Raphael: 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.
David: 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.” 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?
Raphael: 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.
David: What are your thoughts about using cannabinoids as a treatment to help prevent cancer or retard tumor growth?
Raphael: 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