Epigraph Vol. 21 Issue 1, Winter 2019

Raphael Mechoulam and the history of cannabis research

At the 13th European Congress on Epileptology, held in Vienna in August 2018, Meir Bialer talked with Raphael Mechoulam, an organic chemist at the Hebrew University of Jerusalem and arguably the father (and grandfather) of cannabis research.

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Transcript of interview

Meir Bialer: Cannabis in general, and cannabidiol, has become a very “hot potato” in the central nervous system area and particularly in the field of epilepsy. Tell us, how did you start, more than 50 years ago, what triggered your extensive research in cannabis pharmacology?

Raphael Mechoulam and Meir Bialer
Raphael Mechoulam and Meir Bialer

Raphael Mechoulam - I’m a natural products chemist, so I am focused on the chemistry of natural products, mostly from plants. [In the early 1960s] I was surprised to find out that while morphine had been isolated from opium 150 years previously, and cocaine had been isolated 100 years previously, the chemistry of cannabis was not well known. Some distinguished chemists had worked on it, but the active compound or compounds had never been isolated in pure form, and the structures were not known.

In order to understand the pharmacology and do clinical trials, you need a strong chemical basis. That’s why my group started looking at the chemistry of cannabinoids. That was in 1963 and 1964. Our first paper was on the structure of cannabidiol, and a bit later we isolated for the first time THC in pure form and elucidated its structure.

It turns out 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 THC. The other compound, cannabidiol (CBD), is found at high levels in most cannabinoid mixtures. Most plants produce cannabidiol or its precursor. This compound turned out to be of extreme interest. We found a few years later, after a lot of preclinical work in rats and mice, that CBD had antiepileptic properties.

Both THC and CBD have antiepileptic activity; however, CBD can be given at very high doses because it has no side effects. THC above a certain dose can cause side effects; for people who have never used cannabis, that dose can be 5 milligrams.  So we’re not interested in THC as an antiepileptic drug because above a certain dose, there are too many side effects. Cannabidiol, by comparison, can be given at very high doses. And we know that the activity, in animals at least, is certainly dose dependent.

Now cannabinol, another cannabinoid, is not really a natural product. It’s formed by oxidation of THC. The research that was done in the United States and United Kingdom was done on cannabis that had been set aside, found by the police or through other means, and THC had slowly oxidized to cannabinol. So cannabinol was discovered, but it’s not a natural product.

CBD had been isolated by Roger Adams in the US in the 1930s and by Alexander Todd at about the same time, but the structure wasn’t known. So we elucidated the structure of CBD, and we isolated THC in pure form for the first time.

Meir Bialer: In the Cannabis sativa plant itself, all those cannabinoids exist as analogues of carboxylic acid. How does decarboxylation occur to form CBD and THC—does it occur during storage or is it a chemical reaction?

Raphael Mechoulam: The plant Cannabis sativa does not produce either THC or CBD. It produces their precursors—these are phenolic acids, but these compounds are not stable. They slowly convert into CBD from cannabidolic acid, or from THC acid to THC. This is why the acids, which are actually the natural products, have not been investigated thoroughly—because they break down. 

Over the last few years, we’ve been looking at these acids. It is possible through chemical modification to make them stable, and we found that these acids are active. We don’t know yet whether they’re active in epilepsy because we haven’t looked at epilepsy models, but now that we have these compounds we will look to see if they are potent or more potent than CBD or THC. So far we’ve found that cannabidiolic acid methyl ester, the stable precursor to CBD, is an anti-anxiety compound, and that it works for pain.

Meir Bialer: How do you explain that the chemical structures of CBD and THC were elucidated in the early 60s, but the two known endocannabinoids were discovered 30 years after. Did people not look for them, or was it difficult to isolate these compounds, which exist in every human being?

Raphael Mechoulam: There was no conception [of endocannabinoids]. The mechanism of THC action was not known. People thought it had a general effect, so it was thought that the cannabinoids, particularly THC, do not act through a specific mechanism. The theory was that THC solubilizes in the cell membrane or something of that sort. It turns out that was wrong.

We did some work and found that most probably the plant cannabinoids act through a specific mechanism, and indeed Allyn Howlett in the United States in the mid-80s discovered a receptor (CB1), and later a second (CB2) was discovered.

Now, receptors don’t exist because there’s a plant out there; receptors exist because we, through compounds made in our body, activate them. So we went looking for the endogenous compounds that activate the cannabinoid receptors. We managed to identify a compound, in 1992, and we called it anandamide.

Meir Bialer: Why did you call it that?

Raphael Mechoulam: It’s based on the word “ananda” in Sanskrit, which means “supreme joy”.

From a chemical point of view, anandamide and THC are completely different, but they have the same activity. A second compound was found by our group a couple of years later. It turned out to be closely related to anandamide but it was an ester, and it is known as 2-AG (2-arachidonoylglycerol).

These are cannabinoids made by our body. These two compounds activate the receptors—there are two types of receptors—and all the effects we know of THC, THC mimics their activity.

The activity of these two endocannabinoids [anandamide and 2-AG] is very large. There are more cannabinoid receptors in the brain than any other receptor known. These compounds are very important. They aren’t formed and then wait for something to happen to activate them—they are formed when and where needed, and then they activate the receptors.

There are many groups throughout the world discovering many types of effects caused by these endogenous cannabinoids. In a recent review, two eminent scientists at the NIH published that the endocannabinoid system is involved in essentially all human disease. This is a very strong statement, but it seems to be correct. Today we know that the endocannabinoid system—the receptors, the endocannabinoids, the enzymes that form and break down the endocannabinoids—are involved in many physiological reactions, and therefore in many disease states.

Meir Bialer: We have Sativex on the market, which is a combination of THC and CBD, but now that Epidiolex has approval, what do you see as the next discipline where we can have cannabinoid – synthetic or phytocannabinoid – in epilepsy or related areas?

Raphael Mechoulam: Many of the natural products that are known to be active are not sold for a long period time as such. In many cases derivatives are made. For example, you cannot buy penicillin anymore, but you can buy a derivative of penicillin. You cannot buy cortisone – you can buy a derivative of it. So chances are, over the next decade, derivatives of CBD will be found that are more active, so one does not have to use very high doses, and such compounds will enter the market. But I’m not aware of any synthetic CBD in clinical tests as an anti-epilepsy drug.

Meir Bialer: Do you have a final statement to neurologists?

Raphael Mechoulam: I believe over the next decade to 15 years we will have a lot of cannabinoid drugs, for a variety of diseases and certainly for epilepsy. Probably the epilepsy drugs will be the first. They may be natural products like CBD, which is an excellent product because it does not have side effects, but also derivatives, and I have no doubt this field will expand to a very large extent as a major field of therapeutics. As we speak today of corticosteroids, we will probably speak in 10 years about cannabinoids and cannabinoid derivatives.

Meir Bialer: Thank you very much for speaking with us.