Australasian Science Magazine

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By By Craig Motbey

Euphoric and highly addictive, a popular party drug also causes long-term memory loss.

A popular new “party” drug has been attracting some attention lately. You may know it as Drone, M-Cat, Bubbles or Meow. The pharmaceutical name is mephedrone, and its impact is something like a mix between ecstasy and cocaine or methamphetamine.

We’ve been studying it to see what the long-term effects of use might be. The early signs are that, although not up there with the worst of the worst, mephedrone is by no means benign. It appears to be highly addictive and evidence is beginning to mount that it may cause substantial damage to memory.

Unfortunately, by the time we get mephedrone all worked out, another dozen new party drugs will be doing the rounds in its place.

Mephedrone is a part of a family of drugs called cathinones. Human use of cathinones for their psychoactive properties traces back to prehistory. Known as “khat” by the people of eastern Africa, the leaves and twigs of the Catha edulis shrub have been chewed for centuries in traditional cultures.

The effects could be described as somewhere between a serious coffee habit and mild amphetamine use. This is un­surprising to chemists because the cathinone and amphetamine molecules are almost identical. Although not entirely free of negative consequences, traditionally managed khat chewing has a relatively mild impact on most users.

However, one cathinone in particular has attracted a lot of interest of late. Mephedrone (4-methylmethcathinone) is a fairly new party drug that has exploded in popularity over the past few years. It has a variety of names on the street: Drone, M-Cat, Bubbles and Meow. It’s also a frequent ingredient in the drug mixes sold as “bath salts” or “plant food”.

Mephedrone is not just normal cathinone: it’s a “substituted cathinone”. This means it’s a molecule with the same backbone as the basic cathinone, but with some extra bits stuck on the ends. In a similar way, MDMA (“ecstasy”) is a substituted amphetamine. Just as the effects of an ecstasy pill are very different to the effects of straight amphetamines, the impact of mephedrone is quite different from traditional khat.

Mephedrone users enjoy euphoria, mental and physical stimulation, an enhanced sense of touch and empathy and a bit of sensory distortion. The subjective experience of the drug is something like a mix between MDMA and methamphetamine or cocaine. It’s stimulating, euphoric, touch-enhancing and appears to be very, very addictive.

One of the big problems with newly-emerging drugs is that we know virtually nothing about them. Many thousands of people are regularly consuming mephedrone, but until now the scientific community has had no idea about whether or not this might be causing damage to people.

This is particularly worrying because it’s possible for a tiny change to the structure of a molecule to drastically alter the impact it has on the brain. One of the clearest examples of this was demonstrated in California in the early 1980s.

A group of illicit chemists there had been trying to make a synthetic painkiller called MPPP so that they could sell it to heroin addicts. Unfortunately, this team of underground pharmacists weren’t quite up to the job: they made a mistake. As a result, their batch of MPPP was contaminated with a closely related chemical called MPTP. While MPPP is merely a strong painkiller, MPTP is just plain poisonous.

MPTP destroys the dopamine neurons in a region of the brain known as the substantia nigra. This is a part of the brainstem closely involved in controlling body movement, and it’s the bit that goes wrong in Parkinson’s disease. Thus MPTP poisoning gives you the symptoms of advanced Parkinson’s disease – permanently and almost instantly. It does it so well that medical researchers deliberately use MPTP to create animal models of Parkinson’s disease.

But in the early 1980s nobody knew anything about MPTP poisoning. They had no reason to suspect that it might be dangerous: after all, the MPTP molecule is almost identical to the not-particularly-harmful MPPP. The first clue anyone had that MPTP might be hurting people was when a wave of young drug users started to appear in hospitals with a mysterious illness that resembled Parkinson’s disease.

The world of illicit drugs has changed since the 1980s. Waves of novel designer drugs are now appearing every year. European authorities identified 41 new psychoactive drugs entering the market in 2010 alone. With the vast majority of these drugs, we know absolutely nothing about their potential to cause damage to the brain. Although most of these new drugs are molecules that closely resemble existing drugs, the MPTP case demonstrates that this is no guarantee of safety.

It is entirely possible for a tiny molecular change to transform a completely innocuous substance into a totally lethal one. It’s also the case that neurological injuries are often subtle and progressive in their nature: the damage to the brain precedes the damage to the mind, and by the time an injury has become behaviourally obvious it is often too late to do anything about it.

While the MPTP situation was tragic for the people directly affected, the dramatic and sudden nature of MPTP poisoning was actually a blessing in disguise. Obviously toxic drugs can be detected and avoided relatively easily, but drugs with subtle and cumulative effects have the potential to harm huge numbers of people before anybody knows that it’s happening.

Because of this situation, it is very important that psycho­pharmacologists work as fast and as hard as they can to investigate the effects of new drugs on the brain. If some of them do turn out to be very dangerous, then a lot of harm can be prevented by discovering and publicising these dangers as quickly as possible. And this is where I come in.

Along with a team of researchers based at the University of Sydney, I have spent the past few years attempting to lay the groundwork for an investigation of mephedrone. There are some basic questions that need to be answered. How does this drug work in the brain? Is it addictive? Does it cause damage?

When you’re investigating a drug that you don’t know is safe, there are fairly tight restrictions on the circumstances in which you can give that drug to people. This is especially so when it’s a drug that you have good reason to suspect might be harmful. For that and other reasons, the early research on these questions tends to be conducted with non-human animals, typically rats or mice.

That is what we did. To begin with, we gave some mephedrone to a group of rats before looking at their brains to see what brain regions were activated by the drug. When a neuron is working hard it will begin to physically alter itself in response, much like what happens when you exercise a muscle. There are some particular genes that are activated and proteins that are reliably produced by neurons as a part of this process.

Using a technique called “immunohistochemistry”, it’s possible to trick the immune system into highlighting particular types of protein. This allows us to then have a look through a microscope and work out where that protein is appearing and in what quantities.

This is what we did with our mephedrone-dosed rats. By getting the immune response to show us where the proteins associated with neural “exercise” were being produced, we were able to tell which bits of the brain had been working hard in the recent past. We also had a look at the brains of rats that hadn’t been dosed with mephedrone in order to see which bits were just normal brain activity. Comparing the two things allowed us to identify those parts of the brain that are activated or suppressed by mephedrone, and gives us a rough idea of how strongly it might be affecting things.

What we found wasn’t particularly unexpected. People were describing the mephedrone experience as something like a cross between MDMA and methamphetamine, and that’s what we saw in the brain. When you compare the patterns of brain activation induced by MDMA and methamphetamine, they have a lot in common but also many differences. The mephedrone pattern isn’t identical to either of those patterns alone, but it does look a lot like what you’d get if you took the parts they have in common and then added both the MDMA- and methamphetamine-specific regions to that. It strongly activates brain areas associated with stimulation and addiction, as well as those connected to social behaviour.

While figuring out how the drug works is undoubtedly useful, it’s also important to discover if it’s doing any harm to people. So that’s what we did next. First, we gave a daily dose of mephedrone to two groups of rats for 10 days.

With the first group, we looked at their brains shortly after their final dose of drug in order to get some more information about how mephedrone works and to see if it causes inflammation in the brain. This gave us some useful clues about the interaction of mephedrone with the dopamine and serotonin systems, but it didn’t turn up any signs of inflammation.

Dopamine is associated with addiction, whereas serotonin is more connected to euphoria. What we found was that an hour after their last dose of mephedrone there were opposing patterns of action with serotonin and dopamine. With serotonin, the neurotransmitter levels were drastically reduced, but there was a substantial increase in the metabolites that serotonin breaks down into. With dopamine the patterns were the other way round: dopamine was up but its metabolites were down.

We therefore think that mephedrone is causing a sudden surge of serotonin, which then gets rapidly metabolised. What we think mephedrone might be doing with dopamine is inhibiting metabolism so it doesn’t break down as fast.

The exact details of how neurotransmitters affect our thoughts and behaviour tend to be complex and subtle, but in simple terms the serotonin surge probably drives the short-lived euphoria that provides the initial appeal of the drug, while the dopamine effect contributes to its strong addictive “hook”.

With the second group, after the drug treatment we sent them back to their home cages for a month and a half of healthy drug-free living. The idea with these guys was to see if there was any lasting damage caused by the drug.

We did this in two ways. First, we put the rats through every sort of behavioural test we could think of. Then, after the testing was done, we looked at the brains of these guys as well.

Most of the behavioural tests came back negative. Our mephedrone-dosed rats, tested during their drug-free period, didn’t appear to be highly anxious or show other obvious signs of disturbed behaviour. But there was one interesting thing...

Rats are naturally inquisitive little critters due to their lifestyle in the wild – they’re scavengers whose survival depends on making use of every food source available. Because of this they have a natural tendency to explore and investigate new things. Scientists call this “neophilia”, but all that really means is this: rats like new stuff.

If you do it right, you can use this to test their memories. First, you put your rats in a space with two identical things that they haven’t seen before. It doesn’t matter much what you use, just so long as you’re careful to balance out any effects you might get if one object is intrinsically more interesting to the rats than the other.

After you’ve let your rats explore the first pair of objects, you send them back to their home cage for however long it is that you want to test their memory. Then you bring them back to the test arena, which again contains two different things: one of them is something they saw earlier, while the other is new.

If their memory is good they’ll spend most of their time checking out the new thing. But if their memory is gone then both objects will seem “new”, and they’ll split their time 50/50 between the two. If you have a test where the drug-treated rats forget but the control rats remember, then you’ve got evidence that the drug is damaging their memory.

That’s exactly what we found with mephedrone. The rats that had been on the highest dose of the drug split their time equally between the new and old objects, showing clear signs of memory damage. The dose involved was designed to be roughly equivalent to what human users might consume over a night out, once you adjust for the differences between human and rat metabolism.

This result confirms some earlier hints of memory damage in human mephedrone users, and is the first time that a laboratory experiment has shown that mephedrone-induced damage can persist for more than a few days. But it came accompanied by an unanswered question.

When we looked at the brains of the memory-impaired rats, we didn’t find any changes in the levels of neurotransmitters or the rate of transmitter metabolism. Although we know that mephedrone must be doing something to damage our rats’ memories, we don’t know how it does it. All we know is that it doesn’t appear to relate to persistent adaptations in neurotransmitter levels, and that the lack of inflammation in the brains of the animals we tested just after drug dosing suggests that it isn’t a matter of acute injury either.

So the next questions are obvious: how does mephedrone damage memory? Is this damage permanent and/or cumulative? And can we do anything to fix it?

But while those questions are important to answer, and teams of scientists around the world are on the job, the underlying problem is not one that can be solved by research alone.

The emergence of novel psychoactive drugs has accelerated to a point where it is simply not possible for the research community to keep up. Even if we had unlimited resources and easy access to novel drugs as soon as they appear (which we most certainly don’t), it just isn’t possible to investigate long-term and cumulative effects in a timeframe this rapid.

Effects that require years to occur cannot be discovered without years of investigation. Even with regard to short-term effects, by the time the research community has acquired an adequate understanding of the toxicity of any particular drug, a dozen new drugs will have already hit the market.

Unless we do something to address the underlying forces driving drug users to continually seek out new variations of recreational chemistry, it is merely a matter of time before we see the recurrence of something analogous to the MPTP tragedy.