How to Study Cannabis | Interview with Dr. Allyn Howlett

0:00:12.4Pfizer

Jed: Hi, this is Dr. Jed Macosko at Wake Forest University and Academic Influence, and today, we have an old friend of mine, Professor Allyn Howlett, from Wake Forest University too. So Professor Howlett is here because she is an expert in the cannabis area, and in particular, the cannabinoid receptor.

So in the 1980s, people didn’t even know that there was a cannabinoid receptor, but you were the one who figured it out, is that true?

Allyn Howlett: Well, that is true, but I wouldn’t say it was all me, because I collaborated with some chemists from Pfizer, and at the time, these chemists were no longer working on the cannabinoid pain relieving project because their board of directors had decided that that probably wasn’t going to be something that Pfizer wanted to work with.

I think at the time, part of their thinking was that the side effects of sedation and muddled thinking would mean that you wouldn’t be able to use this kind of compound for pain relief and use it at home.

It would be fine to use in the hospital where people were bedridden, muddled thinking, sedation might actually keep you so that your healing process could continue, but if you were to have a chronic, neurogenic, pathogenic kind of pain at home, then that would not be the kind of drug that they wanted to have on the market.

And I think they also felt that, for the hospital-based pain relief, the opioids were doing just fine, and so it wouldn’t be in their best interest to compete with cannabinoid compounds, but I think a third thing...

Jed: So after Pfizer... Yeah, the third thing, go ahead. Go ahead, tell us the third thing.

Allyn: Well, you know, back in the 1970s was when the drug scheduling went through Congress. Up until then, drugs were not labelled as being highly addictive or highly abused.

And it wasn’t until the late ’70s that the DEA was given the role of identifying compounds as to whether they had a good medicinal use, or whether they were going to be highly liable in substance use.

So cannabis, smoking pot, is not a good way to deliver a drug, so it had no medicinal use, but it was something that could be abused, so it landed in Schedule I.

And so now, Pfizer has a compound that they’ve modified from THC’s structure, but it’s still a cannabinoid compound, and I think that entered into their thinking about whether they wanted to have that kind of a drug on the market.

Jed: Yeah, I certainly can see why Pfizer would wanna drop the project like a hot potato, but that left you all by yourself, and originally, you said you were collaborating with them.

Allyn: Well, no, actually, as a researcher, that left me in a better position.

Jed: Oh.

Allyn: Because Pfizer’s company line was, There is no good therapeutic use for cannabinoids. And that meant that the compounds that these chemists had developed, they could share with researchers, because they were not going to be taken by the drug down the pipeline to market.

So the company didn’t care about them anymore, the chemists were very excited to have a collaborator who could work to figure out how they worked.

Jed: Oh, that’s good.

Allyn: Yes. So as a result, they gave me 60 compounds, and at the time, all I had to do was write them a letter and ask for them, and drug companies were very good about sharing their compounds with researchers, as long as they were legitimate researchers.

And of course, someone who works for a medical school doing biochemistry is a legitimate researcher. So I was able to use those compounds in order to identify what we call structure activity relationships. So the better these drugs were at pain relief, according to the Pfizer studies, the better they were in my cell culture model at causing the cell signalling.

So already, we knew that there was... As you change the structure and they didn’t work so well, the same thing happened in the cell culture model. So we had a very good model that could mimic what would be a much more complex behaviour in the models that Pfizer was using. So that was a good thing, because now, we had some cell signalling and we could figure out how it works in the cell.

Jed: Fascinating. So you used your little petri dishes with little neurons growing inside, you squirted in one of these great compounds that you were getting for free from Pfizer, and every time you used one of their powerful pain-killing ones, it had a powerful effect on those neurons.

Allyn: That’s right.

Jed: Every time you used a weaker one, it had a weaker effect, so you knew you were on to something.

Allyn: That’s right. That’s right.

0:06:06.6Spice and K2

Jed: And from the 1980s till today, how much more do we know about what’s the receptor, what does it do? Can you bring us up to speed with what we know now that things are becoming more legalised?

Allyn: Well, actually, we knew a lot before legalisation, because that’s when... We share our information as researchers with other scientists by writing up our experiments and putting them in research journals.

That way, not only drug companies can see what we’re doing, but all the other researchers in the world can see what we’re doing. And if they’re interested, then they can read what I did, and they can say, Aha, I wonder if this works in my system.

So that’s where we can go from one set of ideas to somebody else’s pet projects and look at their sets of ideas. So that can include animal models for behaviors, but it can also include people who are studying cardiovascular disease who want to know if these same compounds are working in blood vessels or in the heart, it can involve people studying the liver, and we can study those.

So at that point, we could, along with many, many labs throughout the entire world, ask questions not only about how it’s working in the brain, but how these things are working in other cell types throughout the entire body.

So all of that was done, and it wasn’t done in the United States as much, because of the difficulties that it takes to be able to keep THC in the lab, because it’s Schedule I.

Now that doesn’t mean it’s prohibitive, what that means is every year I have to send money to the DEA and to the North Carolina Department of Health in order to keep a license.

And then when I get compounds, I get them from a legitimate source like the National Institute of Drug Abuse, that gives researchers compounds for free, and I have to keep track of how much I have in the lab and how much I use for all of my experiments, so that it doesn’t get lost.

Jed: Did somebody ever take any of your stash?

Allyn: Yeah, that’s right. Now, it turns out that most of what I do is not done with THC itself, it’s done with compounds that drug companies made.

Because I can work with drug companies, and I can work with synthetic organic chemists labs throughout the world, and then we can test those compounds and see how they work. And that’s how we work together with other kinds of disciplines. As a pharmacologist, I can work with a chemist, and we can say, I wonder if we can find a compound that can block the effects, because when I got started, there were no blockers.

So it’s very handy to have a blocker. Because if you said... Let’s suppose that these compounds are working in the heart. Well, one way to test that is to give a blocker and say, You see, my effect went away, because I gave a blocker to the cannabinoid receptor, and now I don’t see that effect on the heart any more. Well, there wasn’t one. So a number of chemists had a holy grail, it was their goal to try to develop a modification on that chemistry, so that it could block the responses, and no one ever found that.

So we had four or five chemistry labs throughout the world that were making compounds, hoping that a little modification in the chemistry could make it a blocker.

And instead, they either got something that was a better mimic of THC itself, or maybe it just didn’t work at all. And I’ll tell you where that’s gotten us into trouble, because as researchers, we all share our information, and we do it by writing up our experiments in journals that are published.

Chemists do the same thing, except the kinds of things they write are how they did the modifications on the drugs. Well, there’s always that evil entrepreneur out there someplace, who can read these same journals and say, Aha, I can make this in my garage, or, In my basement, or, All I need is... and then they read the recipe that was written in the journals by the chemists, and they make it. And that’s how we end up with Spice or K2, is those are compounds that somebody made someplace, somewhere in the world, that they advertise on websites or put them in fancy packages and sell them at stores that sell interesting things and fancy packages, and people buy those. But they’re really quite dangerous, because they have used some of the compounds that are maybe extremely potent.

And someone who doesn’t know what they’re doing can get very sick. And there have been a number of emergency room cases of people coming in, and their friends who find them totally distraught in their dorm rooms don’t know what they took. They take their friends to the emergency room, and the doctor says, What did they take? I don’t know.

And the reason is that when this happens, chemists find out what it was that was in the product, and then it gets made illegal. And then the entrepreneurs make something different, put it in their compounds, they spray it onto plant products so it looks a lot like marijuana but it isn’t, and then they sell something else. So every year, there may be different compounds in those packages. So the physicians don’t know how to treat it.

0:12:57.7THC and compounds that are similar

Jed: That’s terrible.

Now, is the motivation for the entrepreneurs, obviously to make money, but is it to avoid it being illegal or to make it more potent, or is it a little bit of both?

Allyn: Well, I think it’s to avoid being illegal.

Jed: Okay.

Allyn: Because it goes back to the scheduling. THC when it’s packaged for Food and Drug Administration-approved medicines, it is a generic name called Dronabinol and a brand name called Marinol, and it has been used in the United States as a medicine, but it’s not smoked.

It’s used as a medicine, like we take other capsules as medicine, and it was originally used when people took cancer drugs that made them vomit all the time. And it helped prevent the vomiting. And then when we had the AIDS epidemic, it helped people who were dying, to be able to feel better, to eat more, so that their bodies didn’t waste away, because they were starving themselves to death.

And so it has its Food and Drug Administration approved use. Smoking pot is not an approved use, because you get a lot of tars and plant products in your lungs. We don’t smoke our medicines.

So in this case, THC and compounds that were like THC had been scheduled as Schedule I, and that’s what we call as illegal. And that’s why I have to have a license in order to study it in the lab. It’s not illegal like breaking into somebody’s house and stealing something. I mean, that’s a law, but the DEA scheduling is like a law, and it says that you cannot use this compound unless you’re using it for medicinal purposes, and that’s what the DEA scheduling is about.

Jed: So has any of your stash gone missing at all? Has anybody taken your chemicals?

Allyn: Oh, no, no, and again it’s because I don’t use very much THC.

Jed: Okay, good.

Allyn: And many of the compounds that we get from the plant don’t have those kinds of effects in the brain. But I use compounds that have drug company code names, because many years ago, the drug companies were very interested in making these as pain relievers, and for those purposes that I just told you about, the AIDS and other kinds of aspects.

And as a result, their chemist modified their compounds, they never took them to market, so they never got a brand name that you would recognize. What they had was the chemical company’s code number and their initials at the beginning.

So I’ve got vials of things in my freezer that have drug company names and code numbers on, and that’s not just cannabinoids. This is what drug companies do when they’re trying to develop compounds, and then they release them to scientists who can study how they work. And so before they take them to market, they just leave them with these code numbers.

So almost all of us, if you open up our refrigerators and our freezers, you’re going to see little vials that come from drug companies that have code numbers on. And no matter what neurotransmitters you’re studying in the brain, there are probably gonna be some drugs that are gonna either work just like them or either block them.

0:17:09.8Sign off

Jed: Fascinating. Well, thank you so much Dr. Howlett for coming on this show and talking about it. Allyn, it’s just been fun to see you again and we look forward to having this air and helping people understand what’s going on with all of these receptors. So thank you very much.

Allyn: Good. Thank you for having me.