Cannabinoids, endocannabinoids, and epilepsy: Dr. Raphael Mechoulam

Dr. Raphael Mechoulam was an organic chemist at the Hebrew University of Jerusalem, and the father of cannabis research. His team was the first to elucidate the structure of cannabidiol, or CBD. 

Dr. Mechoulam passed away in March 2023. This episode is a remastering of a conversation between Dr. Mechoulam and Dr. Meir Bialer, held in 2018 at the 13th European Congress on Epileptology. They spoke about CBD, THC, the endocannabinoid system, and the effects of cannabinoids in epilepsy and other conditions.

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Transcript

ILAE: Dr. Raphael Mechoulam was an organic chemist at the Hebrew University of Jerusalem, and the father of cannabis research. His team was the first to elucidate the structure of cannabidiol or CBD. Dr. Mechoulam passed away in March 2023. This episode is a remastering of a conversation between Dr. Mechoulam and Dr. Meir Bialer, held in 2018 at the 13th European Congress on Epileptology. They spoke about the endocannabinoid system and the effects of cannabinoids in epilepsy and other conditions.

Here's Dr. Meir Bialer. 

[00:00:39] Dr. Meir Bialer: Cannabis in general, and cannabidiol, has become in recent years a very hot potato in CNS area, and in particularly in the field of epilepsy. Can you please tell us, how did you start, almost, you know, more than 50 years ago? What triggered your research, extensive research, and well known research in cannabis pharmacology and chemistry, please.

[00:01:07] Dr. Raphael Mechoulam: I'm a natural products chemist. I'm interested in the chemistry of natural products, mostly from plants, and I was surprised to find out in reading  the literature that while morphine had been isolated from opium 150 years previously more or less and cocaine had been isolated again more or less 100 years previously, the chemistry of cannabis was not well known.

And although some very distinguished chemists had worked on it, the compound, the actual active compound or compounds had never been isolated in pure form and the structure was not known. So therefore, in order to go ahead and do the pharmacology, the physiology and the clinical trials, one had to have a strong chemical basis.

So that's why we started,  my group, I started looking at the chemistry of cannabinoids, and that was in 1963, 1964. Our first paper was on the structure of cannabidiol. We established the structure of cannabidiol, and a little bit later, we isolated for the first time, I believe, THC in pure form, and elucidated its structure.

Now, it turned out that there are a lot of compounds of the same type. Today we know that there are about 100 compounds of the same type. We isolated most of the major ones, but they didn't turn out to be psychoactive. The only one that was psychoactive was tetrahydrocannabinol, THC. 

The second compound I was talking about is cannabidiol, which is found at high levels in most cannabinoid mixtures. This compound turned over the years to be of extreme interest. We found a few years later, after a lot of preclinical work in rats and mice, that it has, amongst other things, anti-epileptic properties. 

Both compounds, both THC and cannabidiol, have anti-epileptic activity.

However, cannabidiol can be given at very high doses because it causes no side effects. It does not cause any undesirable effects. THC above a certain dose, and initially, for people that have never used cannabis, five milligrams can cause side effects. And therefore, we're not interested in THC as an anti-epileptic drug because above a certain level, there are too many side effects, too many effects that we're not interested in.

Cannabidiol, by comparison, which is at least as active as THC, probably much more, can be given at very high doses. And we know that the activity in animals, at least, is certainly dose dependent.

Now, usually the research that was done in the U.S. and in the U. K. was done on material that had been left aside. It had been found by the police or through other means. The material had been laid aside and THC had slowly oxidized to cannabinol. So cannabinol was discovered, but it's not a natural product. 

Cannabidiol actually had been isolated by Roger Adams in the U.S. in the 1930s, and by Alex Todd, Lord Todd, at the same time, more or less, but the structure was not known. So we elucidated the structure of cannabidiol, and we also isolated THC in a pure form for the first time. So there is a somewhat of a difference between these two compounds. 

[00:05:16] Dr. Meir Bialer: And also, I think it's worth emphasizing that in the Cannabis sativa, the natural herb itself, all those cannabinoids, we are talking cannabidiol, THC, are existing as their analogous carboxylic acids, right? And  what happens? How does this decarboxylation of the formation of the cannabidiol, the THC, that are used medically occurs? Does it occur upon storage? Or in a chemical reaction? 

[00:05:43] Dr. Raphael Mechoulam: Well, the plant, Cannabis sativa, actually does not produce either THC or cannabidiol. It produces their precursors. These are acids, phenolic acids, but these compounds are not stable. Just by staying on the plant or in the extract, they slowly convert into CBD, if one starts from cannabidiol acid, or from THC acid into THC. Now, this is the reason that these acids, which are actually the natural products, have not been investigated thoroughly is because they break down.

Over the last few years, we have been looking at these acids by making them stable by a small chemical modification. It is possible to make them stable, which we published. And we found out that these acids, or their stable products, are active. We don't know yet whether they're active in epilepsy because we haven't looked at epileptic models.

Now that we have these compounds, we shall try to see whether these natural products, the actual natural products of the cannabinoids, are potent or more potent than cannabidiol itself or THC. So far, we have found that cannabidiolic acid methyl ester, the stable precursor of cannabidiol, is an anti-anxiety compound. And we have seen also that it works in pain. 

[00:07:29] Dr. Meir Bialer: How do you explain that cannabidiol and THC were discovered or their chemical structure was elucidated by you and your co worker in the early 60s, while the endocannabinoid, the two known endocannabinoids were discovered only 30 years ago?

People did not look in a target way for that or it was difficult to isolate. Was it a conception or the idea to isolate this endocannabinoid that exists in every human being? 

[00:08:03] Dr. Raphael Mechoulam: Well, there was no conception really. The mechanism of THC action was not known. And people thought that maybe it's a general thing, and therefore it was generally believed that cannabinoids, the plant cannabinoids, in particular THC, does not act in the body through a specific mechanism, but it's kind of a general, a compound that has general effects by solubilizing the membranes or something of that sort.

Well, it turned out that this is wrong. We did some work on that aspect and we found that most probably the cannabinoids, the plant cannabinoids or THC, act on a specific, through a specific mechanism. And indeed Allyn Howlett in the U.S. in the mid-eighties discovered a receptor (CB1), and later a second receptor was discovered.

Now receptors don't exist because there is a plant out there. Receptors exist because we, through compounds that are made in our body, activate it. So we went ahead looking for the compounds that activate the cannabinoid receptors. And we managed to identify a compound which activates these receptors in 1992. We called it anandamide. 

[00:09:34] Dr. Meir Bialer: Why did you call it anandamide? 

[00:09:36] Dr. Raphael Mechoulam: Well, based on the word "ananda" in Sanskrit, meaning supreme joy. And so we called it ananda-amide--the amide is part of the structure. Now, from a chemical point of view, anandamide and THC are completely different, but they have the same activity. But a completely different chemical structure.

A second compound was found by our group a couple of years later, and it turned out to be very closely related to anandamide, but it was an ester, and it is known today as 2-AG. So these two compounds are actually cannabinoids in our body. And THC mimics their effects. These two compounds activate the receptors, there are two types of receptors, and all the effects that we know of THC, THC actually mimics their activity.

And the activity of these two compounds is very large. As a matter of fact, the receptors in the brain, the cannabinoid receptors in the brain, are probably at higher levels, there are more cannabinoid receptors in the brain than any other receptor known, and these compounds are of extreme importance.

They are not formed and then wait for something to happen in order to activate the receptors. They are formed when and where needed, they activate the receptors, and this is how they act. And we have discovered quite a large number of effects. There are many, many groups throughout the world that are working and are discovering many types of effects that are caused by the endogenous cannabinoids.

And indeed, in a recent review , eminent scientists at the NIH published that the endocannabinoid system is involved in essentially all human diseases. This is a very, very strong statement, but it seems to be correct, and today we know that the endocannabinoid system, namely the receptors, the endogenous cannabinoids, the enzymes that form these endogenous cannabinoids, the enzymes that break down these endogenous cannabinoids, they are involved in many, many physiological reactions and therefore in many disease states.

[00:12:19] Dr. Meir Bialer: We know that we have Sativex on the market, which is a combination of THC and cannabidiol in a very low dose, 2. 5, 2. 4 milligrams. But now that cannabidiol just got FDA approval, hopefully we'll get the correct scheduling of four or five that will allow its free marketing. What do you see the next discipline where we can have cannabinoids, either synthetic or phytocannabinoids, in epilepsy or related areas?

[00:12:54] Dr. Raphael Mechoulam: Well, many of the natural products that are known to be active are not sold for a long period of time as such. In many cases, derivatives are made and they are sold. For example, penicillin. You cannot buy penicillin anymore. You can buy a derivative of penicillin. You cannot buy corticosteroids, cortisone. You can buy a derivative of cortisone. 

So chances are that over the next decade, derivatives of cannabidiol will be found which are more active. One doesn't have to use very high doses and chances are that such compounds will be on the market. But at the moment, I'm not aware of any synthetic cannabidiol which is in clinical tests as an anti-epilepsy drug, 

I believe that over the next decade or maybe 15 years, we shall have quite a lot of new cannabinoid drugs for a variety of diseases, certainly for epilepsy. Probably the epileptic drugs will be the first one. Whether they are natural products like cannabidiol, which is an excellent product because it does not have side effects, but maybe also derivatives, and I have no doubt that this field will expand to a very large extent as a major field of therapeutic properties.

And as we speak today of corticosteroids, we shall probably speak in 10 years to the same extent about endocannabinoids and endocannabinoid derivatives.