Who Discovered THC??

at the Weizmann Institute of Science in Rehovot, Israel, Dr. Raphael  Mechoulam – along with his colleagues, Dr. Yehiel Gaoni and Dr. Haviv  Edery – succeeded in the very first isolation and elucidation of the  active constituent of cannabis, D9-tetrahydrocannabinol, also known as  THC. The discovery of the THC compound – now almost 50 years ago –  started a revolution in thinking about cannabis that carries on to this  day.

Dr. Mechoulam is currently a professor of medicinal chemistry  and natural products at the Hebrew University of Jerusalem. His total  synthesis of THC, as well as other cannabinoids such as cannabidiol  (CBD), is the cornerstone of the burgeoning medical-cannabis industry.  Furthermore, his major contributions in the field of organic chemistry  and the interaction of human and plant biology have led to the discovery  of cannabinoid receptors in the human brain and the endocannabinoid  system in the human body.

Dr. Mechoulam was kind enough to give  his time for an exclusive interview with High Times at his university  laboratory in Jerusalem. It is very plausible that Dr. Mechoulam may one  day win a Nobel Prize for his work and contributions in these fields.  But it is his courage in introducing a previously little-researched  plant to the world – a plant that is rapidly proving itself as nothing  short of miraculous – that make Dr. Raphael Mechoulam The Man.

Let’s start at the beginning. Tell us a little bit about what the marijuana scene was like when you began working with cannabis.

It  was a South American problem, really. Nobody was smoking it in the US  except for a few musicians – a few black musicians, you know.  Incidentally, it seems to have something to do with – well, ah, how can I  explain that? Maybe understanding the music better, or hearing the  music better. Especially jazz musicians. But that was it.

So then how did your research with cannabis come about exactly?

Well,  when my friend [Dr. Yehiel Gaoni] and I started working on it, I was 32  years old. And when I initially asked for a grant, I sent it out to the  NIH [National Institutes of Health] in the US. I asked for a research  grant, but they said, “No, no, no. It is not in our interest. Let us  know when you have something more relevant for us.” But then, soon after  we isolated THC, they decided it was relevant work.

And  so, when we started working, essentially nobody was working on that –  and the reasons were probably legal. You couldn’t really do it in the  US, at least, and the US was, at that time, the only place that there  was any serious research going on … and the UK. The laws were such that  you had to have guards all over the place. You can’t see an American  professor with graduate students and having three guards around him.

So  we had just isolated THC and, to the world’s surprise, they [NIH] came  over to see our work. We had 10 grams of THC isolated from hashish, so  they took it back with them, and most of the initial research in the US  was done with our THC.

And so here [in Israel] we had no problem  working because, you know, here – well, the laws are the same, but the  application of the law is a little bit different. They knew I was not  going to go outside and start selling marijuana; they didn’t assume that  I will do that. We were able to work on it for a couple of years,  though essentially nobody else was around, so we published quite a bit –  and that was in the mid-’60s. So that was it.

We know that  your interest lies in the connection between chemistry and biology, but  what was the intent for you with cannabis? Did you think back then that  there was medicinal value in cannabis? 

No, no, it’s a  natural product. If you look at the other illicit drugs that are  throughout the world, morphine came out of opium or poppy plants, and  cocaine came out of cocoa leaves – and these were discovered 150 years  ago. Morphine was isolated in the early 19th century, and cocoa and  cocaine in the middle 19th century. And surprisingly, THC – the active  component of cannabis – was not known, which seemed very strange.

And  I know why it was not isolated: because the techniques were very  complicated. See, morphine and cocaine are so-called alkaloids, namely a  natural product that contains a nitrogen [atom] on the molecule, and it  can give us salt; it precipitates as a salt. And so you have salt:  Cocaine is a salt, morphine is a salt – very easy to prepare. It turned  out that THC does not have a nitrogen, and it is present in a mixture of  compounds – we know that there are about 60 of them now. And they  didn’t have the techniques to isolate them in the past. So a few people  tried here and there, actually some very good people – one of them [Lord  Alexander Todd] got the Nobel Prize for something else. But they never  succeeded in isolating the pure substance, and so they never knew whether they had one compound or many compounds, and so on.

So  the impetus was really that cannabis was being used and you knew of its  use, yet there was no real research? I’m trying to figure out why it  was cannabis that you guys went to instead of, say, boswellia or some  other plant. 

Well, my interest is in natural products  that have some biological activity, and there are a huge number of  natural products and plants that have activities. I probably have the  best library, at least in Israel, with books and publications on natural  products, on plants – you name it, we can find it. And let’s say, just  for the fun of it, here is this dictionary of plants found in southern  and eastern Africa – all plants with medicinal properties. So you can  pick out any one of them and just open it – say buchu. Okay, it is a  natural product. It lists some of the known herbal remedies. It’s also  used for relief of rheumatism.

Is it true? Is it not true? I just  opened the book – I have no idea. So there are thousands of them, and  you have to decide what you want to work on, and one has to choose  something that makes sense. And here I know that this [cannabis] is  something that makes sense – namely that it has a compound within the  plant that has obviously active products – and it turned out to be  interesting.

But at that time, you didn’t know about cannabinoid receptors in the human body? 

No,  as a matter of fact, that came much later. You see, there are mistakes  in science, too. People didn’t realize that there were receptors. As a  matter of fact, an excellent group in Oxford with Sir Bill Paton, Sir  William – probably pharmacologist number one in the world, a good friend  of mine – he had said there were no receptors, and for very good  reasons. Those reasons are probably too complicated to explain for a  journal or a magazine ….

Well, try us anyway.

Basically,  the reasons were, you see, when something [like a molecule] binds to a  receptor, it has to have a specific stereochemistry. You have two hands,  they’re identical … well, they’re not identical: If you put one on top of the other, they’re just the opposite – they are mirror images of each other, they are not identical. So it is true for many of the  natural products: They can have two images, mirror images, but only one  of them is the natural product – the other probably doesn’t even exist.  We could synthesize it, but it’s not the natural product. In this  case, the natural product [THC] has the activity. If both of them have  activity, then chances are it does not bind to anything biological like a  receptor, an enzyme or something like that, because the receptor itself  is asymmetric.

So if this is the receptor [holding up one hand], you can have only one thing binding to it, but not its mirror image … only one of them. And it turned out that both of them were active – both mirror  images of THC. One of them was natural; the other one we had  synthesized; both of them worked. So Bill said, “No, it can’t be. There  cannot be a THC receptor.”

Well, it turned out that they were not  very good organic chemists. They were buying the raw material, the  starting material [for their testing], that already had the two  images – with the mirror image being synthetic – and you cannot separate  them at that point. So if you have even 20 percent of the wrong  stereoisomer, then you end up with a completely wrong stereoisomer. So  both compounds tested as active, and thus they thought there would not  be a human receptor.

But then we actually did some better work, I  think, as we found out that it was not true – because only one mirror  image was, in fact, active [laughing]. So, for the 20 years since we  discovered the chemical material [THC], we all went along the wrong  pathway! So when we discovered that only one of them was active, another  good friend of mine in St. Louis finally found the first receptor.

Dr. Howlett?

Yes,  correct, Dr. Allyn Howlett. And so Dr. Howlett found the receptor …  and, basically, if you have a receptor in the body, it’s not because  there is a plant out there. It doesn’t work that way – it works  only because there is something in your body which will activate that  receptor. So we went after those compounds that activated it. And we  found the compound in the brain that activated it.

Anandamide.  

Precisely.

[Also  known as N-arachidonoylethanolamine or AEA, anandamide is a naturally  occurring cannabinoid produced in the human body for use as a  neurotransmitter. It was first isolated and described by the Czech  analytical chemist Lumír Ondřej Hanuš and the American molecular  pharmacologist William Anthony Devane in Dr. Mechoulam’s Hebrew  University laboratory in 1992. 

The name is derived from the Sanskrit  word ananda, which means “bliss” or “delight.”] 

We know there are so many different cannabinoids – THC, CBD, CBN, CBG, etc. Do they all bind with the CB1 and CB2 receptors?

Only  THC – and only THC is psychoactive. So, as it binds to the CB1  receptor, it causes the activities that are known as cannabis  activities. That’s it, period. None of the others – well, at least not  significantly; there are a little bit here and there – but no other  compound out of the 60, or whatever they are, binds.

There is a  lot of interest now in the United States within the medical movement to  find cannabis strains that are high in cannabidiol or CBD.

Well,  this is something that I made a big fuss about. You see, with illicit  cannabis – which is a huge, huge thing in the States – there is no  interest in having anything else but very high levels of THC, because  THC is the compound that attaches [to the brain’s cannabinoid receptors]  and is psychoactive. Nobody’s interested in CBD because it causes no  activity. But it is – from a medical point of view – very  important, because it’s an anti-inflammatory and does all kinds of  interesting things. It even blocks some of the undesirable effects of  THC.

Under THC – of course, you’ve never smoked marijuana [laughing] – but seriously, when you have not  smoked and then do and the doses are high, you may have an acute loss of  memory. I mean, you don’t remember everything as it should be  remembered. And if you have enough CBD, you block that kind of memory  loss.

I was interested in the cannabidiol. But if you look at the  cannabis that’s being grown illicitly in the US – and it’s a small  business [chuckling], probably the number one agricultural product, I’ve  been told, in terms of money – there is little or no CBD in there.

There  was a medical meeting recently in the US, and I went there. I gave the  opening lecture, and I told them you can’t [not have CBD]. You have to have CBD, and that’s it. So they’re trying to get CBD now in medical marijuana, which is the right thing to do.

A  lot of the people that we meet around the world are searching for these  CBD-rich strains. Now, with the lab testing going on in the medical  community – you know, with gas-chromotography machines and mass  spectrometers – people are really trying to look closely at it. But  compared to THC, the CBD and CBN results are usually negligible; the CBD  is always less than 1 percent. However, they’ve now found two or three  strains that have around 8 percent CBD.

What do you mean, they have to find the strains? I mean, in Lebanon, they have been growing cannabis for  the last, I don’t know, 300, 400 years or whatever. Lebanese hashish  contains 5 percent THC and about 5 percent CBD. So go to Lebanon, take a  strain from there, period – why make a fuss? We isolate cannabidiol  from hashish. We don’t synthesize it; we isolate it. We do a lot of work on CBD.

So  we go to the police, we pick up a couple of kilos of hashish – not  marijuana. We pick up several kilos of hashish, isolate the cannabidiol  and get a nice crystalline product. THC is an oil; CBD is nicely  crystally. And then we make all kinds of things from CBD. So why make a  fuss? Go to Lebanon and buy a few strains. Or in India – there are a lot  of strains in India.

And where does the CBD bind to if not the CB1 and CB2 receptors?

Oh,  no, it does not bind …. Well, it’s more complicated – it does not bind  to the cannabinoid receptor. It does all kinds of other things. It  prevents adenosine – that’s another compound in the brain – from going  where it should go. It also acts on something else, on serotonin. We  have seen, for example, some work we did here on a disease which has a  nice name, but it’s a sinful disease: hepatic encephalopathy. Now  hepatic encephalopathy, if you are drunk – really seriously drunk – then  you have hepatic encephalopathy. Alcoholics can destroy the liver, and  liver failure then causes central-nervous-system changes. They have  destroyed their liver, and after destroying the liver, they start  destroying the brain. That’s hepatic encephalopathy.

Now, we can  cause hepatic encephalopathy to mice [in lab tests] and then see the  changes that happen in the brain. They can’t walk well and all kinds of  other things. We give them CBD, and it improves their conditions  tremendously. And that was through one of the serotonin receptors. Now,  serotonin is a nice compound – it has 15 or 16 receptors, maybe more.  But this receptor we used was serotonin receptor 1A.

So [CBD]  works in a variety of ways and, surprisingly, it has no side effects.  Very strange. I would have assumed that something that has so many  pathways to it, then it will have some side effects – and it has no side effects. As a matter of fact, it is completely nontoxic. One of  the least toxic compounds that I’ve seen is cannabidiol – very strange.

Many  years ago, NIH thought that they should look at the toxicity of CBD,  because people were smoking both THC and CBD, both of which are present  in marijuana: “Well, we know a little bit about THC; we know nothing  about cannabidiol. Does it cause anything” – I don’t know, destroy the  brain or whatever? And so they did a very thorough study of the toxicity  of CBD and found essentially none … which is very positive.

NIH  is probably one of the best institutions in the world. They really do  excellent work, and I can only admire the people who decided to set up  NIH, I don’t know, 30, 40 years ago.

Then what would be your  guess as to why, with the NIH being in the United States, why the US has  such a hard time getting federal regulation for medicinal cannabis?  Right now it’s only state by state, and the federal government is very  adamant about not allowing marijuana to become legal for medicine. Yet,  like you said, there is all this great research going on over there,  they are at the forefront of a lot of this, so where is the gap here? 

There  is a huge amount of research going on – but I’m not sure, because many  of the states do have regulations for medical marijuana. And the  president actually made some noise that he wants to do it – to allow the  federal government to do it. Now, why didn’t he? Probably he didn’t  have enough power to do it, because chances are that these regulations  have to go through the various committees and so on, and he was not sure  he could get enough support.

Every administration has people  where Mr. A does that and Mr. B does this and then they have a fight.  Mr. B is the person that wins, and that’s it – it’s like all  administrations. I was head of the university many years ago; I know  that that’s the way it works.

Politics ….

Yes, exactly.

But  wasn’t it the politicians who were responsible for all of this? Didn’t  one politician spur the NIH’s decision to give you the research grants  after you first isolated THC?

Yeah, well, they [NIH] didn’t  have a single grant on cannabis at that time, but the National Institute  of Mental Health did, I think. As I said earlier, the NIH wrote me that  they don’t want to, they won’t give me money, because it’s not  interesting or relevant. And then, all of a sudden, I get a phone call  from the head of pharmacology at NIH, and they’re now interested. So I  asked him: “What happened, all of a sudden, that you have great  interest?” Well, it turned out that a senator had called NIH – his son  smoked pot, and he wanted to know whether it would destroy his mind!

And  just like that, the government got NIH to change direction. They don’t  want to fight the senators because they need their support, and they  looked around and [said] “Aha!” – they don’t support grants on  marijuana, so they asked me if I was still working. We had just isolated  THC, and that was it.

Do you remember the name of the senator? We can send him flowers. 

No, but even if I did … I wouldn’t tell you. Anyway, he’s probably dead by now.

https://hightimes.com/culture/people/the-man-who-discovered-thc/