The brain on legal highs.

25 April 2013

Interview with

Dr. Colin Davidson, St. George's University of London

Hannah - Colin Davidson from St. George's University of London has the role of finding out what legal high substances actually do in the brain. So, how do you do that?

Colin - I work quite close with John. He's just along the corridor and I used to work on just methamphetamine and cocaine, and then met John and he started giving me all these completely new compounds. I test them out on pieces of rat brains, so we want to see whether they have stimulant effects, whether it looks like cocaine, whether it looks like amphetamine.

Hannah - When you say that you're looking at a rat brain, how exactly are you doing that?

Colin - Without going into too many details, we kill a rat as quickly and as humanely as possible and we take what's called brain slices. So they're 0.4 mm thick and I try and incorporate parts of the brain that I'm interested in. In this case, it's usually a part called the nucleus accumbens which is the main brain reward pathway where your listeners have probably heard of dopamine as a neurotransmitter.  That's the neurotransmitter most involved in addiction and any rewarding activity like eating or sex. So, I've got my little brain slice that I can keep alive in an artificial cerebrospinal fluid and it get oxygen, it gets glucose. It can stay alive for up to 12 hours or more. And I give a small electrical stimulation to mimic an action potential which is what happens in the brain and the small electrical activities cause release of transmitters. So, I mimic that in this little piece of brain and measure transmitter release and then obviously, I'll take a few measurements, add the drug, whatever drug I'm looking at and see if it increases or sometimes decreases the amount of transmitter I'm getting out and that's a very good indication of whether it's got addictive liability.

Hannah - So, what kind of thing would you see if you added for example illegal drugs like cocaine or amphetamine?

Colin - Well, cocaine would increase the amount of transmitter that comes out by about 4-fold so that the actual amount that comes out is higher and it hangs around for a lot longer. One of the first legal highs I tested was something called Ivory Wave that I got from John Ramsey. I actually found that to have a larger effect than cocaine. I wasn't really expecting that. Cocaine is such a great compound at doing this. Amphetamine and amphetamine-like drugs and we haven't mentioned methadrone yet which is the most famous legal high. It seems to be a bit like amphetamine and ecstasy, but they can cause transmitter release without action potentials which potentially makes them more dangerous ,I think, because it's been shown that amphetamine and methamphetamine, these types of compounds actually cause neurotoxicity in animals. There's a lot of animal studies on that and I did some of those when I worked in America. But also, it's been shown quite recently that human methamphetamine, amphetamine addicts do have problems with their brain such as brain lesions and very long term problems after using them.

Hannah - So, it's causing cell death - these nerve cells - to actually die.

Colin - Especially in the dopamine system and a long time ago it was hypothesized that this cell death might lead to early onset Parkinson's, and recent research has suggested that that is true, that the people who were taking amphetamines or methamphetamine 10 or 20 years ago are getting early onset Parkinson's more often than you may expect.

Hannah - And what about drugs like for example, benzo fury, has I believe been on the scene for quite some time now and it seems to be very popular, and it's legal at the moment?

Colin - Yeah, I was at a conference yesterday in Bath actually, one that John Ramsey was organising, the "Sew Prof," the Sewage Profiling Conference and someone gave a talk there and mentioned that benzo fury is actually one of the most popular drugs at the moment. It has been actually associated with 2 or 3 deaths quite recently. It seems to have both stimulant properties like cocaine or amphetamine, but also has LSD- or trippy-like properties, so you get a double effect from it. My colleague, James Moffatt, has shown us that it's a very potent vasoconstrictor, so it's going to give you hypertension and potentially cause other cardiovascular problems.

Chris - You mentioned that that agent has this hallucinogenic property, but obviously, you can't tell that from a slice in a dish.

Colin - We know that LSD works on the 5HT-2A receptor, so a little bit of protein in the cell membranes which has obviously got a normal physiological function but this is the small protein that LSD and these hallucinogenic drugs actually attach to very strongly and stimulate and cause things to happen inside the cell. So, we've shown and I've got a colleague at Roehampton University, Jolanta Opacka-Juffry, who's shown that benzo fury binds quite strongly to the 5HT-2A receptors. I'd also say that you can also get hallucinogenic effects from these psycho-stimulants and back in the '60s, a lot of people who took amphetamine were misdiagnosed as being schizophrenic. So, if you get massive releases of dopamine, it can cause you to have hallucinations and act like a schizophrenic. So, these drugs like the one I mentioned earlier, desoxypipradrol which is fairly potent has actually caused these sort of effects in abusers, and they've done some crazy things recently.

Chris - What about working out whether or not these drugs are toxic because by measuring the nerve transmitters coming out, that tells you something about what they're doing to the brain, but what about going back to your earlier point about the fact that they will do damage potentially? How can you tell that from your slice experiments? Can you?

Colin - Yeah, I've got a method to measure mitochondrial activities. So, one of their ideas is that some of these drugs might mess up their mitochondria and  mitochondria are the small things inside your cells that produce energy, ATP.  So, if you run out energy, the cell dies and that's been shown for amphetamine and methamphetamine. It can cause damage to neurons, probably by destructing mitochondria. So, I've been looking at some of these new legal highs using this mitochondrial stain in brain slices, but the ideal thing to do would be to try some long term studies where you may dose an animal with one of these drugs for a few weeks then see what effect it's had. That's the best way to do it.

Hannah - So Colin, once you have this data about how these compounds might affect the brain in terms of causing cell death, addiction and also have psychoactive properties, then what do you do with this data? Who do you tell and then what happens? What's the next step?

Colin - Well typically, we try and publish it in a good journal, but that's quite a long process. So, we always try and disseminate the data to the appropriate people and I have given some talks to the ACMD, Advisory Council on the Misuse of Drugs who would inform the government whether they thought something was dangerous or not. I give talks to various scientific meetings and so on, and get the data out there to the people that need to know.

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