Please could you give a brief introduction to mephedrone?

Mephedrone is a fairly new designer drug which has been around for a few years. It exploded in popularity in Europe (and particularly in the UK) before it started to spread in a major way elsewhere.

Mephedrone is a substituted cathinone. Cathinones are very similar to amphetamines; they are almost identical apart from one small difference in the molecule. Because of this, cathinones have fairly similar effects to their amphetamine equivalents.

But mephedrone is a substituted cathinone, meaning that it has the basic skeleton of the cathinone molecule with some extra parts added on the end. In a similar way, ecstasy (MDMA) is a substituted amphetamine.

With most of the cathinones we can guess what they are going to do by looking at the amphetamine equivalent. But with mephedrone, the amphetamine equivalent (4-methylmethamphetamine) is even more obscure than mephedrone. As we know virtually nothing about either drug, this was an open field where we had very little clue as to what we were going to find before we started looking.

What other names is mephedrone known as?

It has various street names. The most common ones would be “Drone” or “MCat”, but it also has a lot of variant names such as “Bubbles”. Mephedrone is also frequently referred to as “Meow” or “Meow Meow”, but this is more of a media than a street name.

You will also frequently see it as one of the ingredients in the drug mixes sold as “bath salts” or “plant food” (these don’t have anything to do with bathing or plants; the names were originally an attempt to evade product safety laws). Although you will often find mephedrone in these products, any given batch of them could have almost anything in them.

Officially, mephedrone is 4-methylmethcathinone, although that’s only one of many possible “official” names for the same molecule. Chemists have a tendency to be infuriatingly inconsistent in their naming schemes at times.

How does mephedrone act on the brain?

We don’t know in detail, as we have only just started looking. We do know a few things though. In earlier research, we looked at what areas of the brain were activated by the drug and compared those results to methamphetamine and ecstasy.

The patterns of brain activation that you get from methamphetamine and ecstasy have a lot in common, but they also have substantial differences. The pattern you get from mephedrone is as if you’d taken the ecstasy pattern and the methamphetamine pattern and laid them on top of one another: virtually all of the brain regions that are activated by ecstasy are also stimulated by mephedrone, and the regions stimulated by methamphetamine are also fired up by mephedrone. The strength of activation in each region isn’t as simple as the sum of the two patterns, but combining them does give you the list of areas affected, and this fits with what users tell us about the subjective experience of the drug.

We only have a limited understanding of what mephedrone is actually doing when it gets to the brain. We know that it causes a sharp and sudden release of dopamine and serotonin in the nucleus accumbens, which is a region of the brain that is closely involved in addiction. This fits with what we know about the likely addictiveness of mephedrone. We also know that mephedrone is able to interfere with the structures that normally function to remove neurotransmitters from the synapse after they’ve done their thing, which is similar to the mechanism of drugs like cocaine.

Our recent study was divided into two halves. The first half involved giving rats either 1 or 10 doses of mephedrone – once a day over 10 days for the 10-dose guys – and then having a look at their brains one hour after their last dose. We wanted to see what it had done to the dopamine and serotonin levels and the molecules that these break down to in the brain.

What we found was that one hour after their last dose of mephedrone, there were opposing patterns of action of serotonin and dopamine. With serotonin, the neurotransmitter levels were drastically reduced, but the metabolites which serotonin breaks down into were substantially increased. With dopamine the patterns were the other way round: dopamine was up but the metabolites were down.

Serotonin is associated with euphoria – happy feelings. Users say that when they use mephedrone they get a huge wave of euphoria that lasts a fairly short time and then goes away. We think that the drug is causing a sudden surge of serotonin, which then gets metabolized and broken down. So, one hour after the drug you are seeing the aftermath of the serotonin wave – that’s why the metabolites are up and the serotonin down. This might also explain why users report that sustained use of the drug can largely eliminate the euphoric effect. In those cases, it’s likely that they’ve simply exhausted their brain’s supply of serotonin.

Dopamine, on the other hand, is more to do with the addictive potential of a drug. With dopamine, we think what it might be doing is inhibiting the metabolism of dopamine so it doesn’t break down as fast; therefore it hangs around in the system for longer. This would explain why the dopamine was up while the metabolites were down, although it remains just an interesting hypothesis until it can be confirmed by further research.

What damage can mephedrone have on the brain?

In terms of actual physical damage, i.e. dead neurons and so forth, we don’t have any solid evidence to date. Almost all of the studies so far that were looking at mephedrone induced damage to the brain came back with nothing. One study did find some changes in serotonin systems; however, that particular study used quite high doses of mephedrone and also kept their rats in a rather warm environment throughout (nothing extreme, but equivalent to a moderately hot day). We know that these sorts of drugs often interact in a nasty way with hyperthermia. Although there were results suggestive of possible damage there, it is possible that it was caused by the hyperthermia rather than by the drug directly.

So we don’t have convincing evidence for actual physical damage of the brain. What we do have, however, is evidence for behavioural and cognitive impairment. Human studies suggested that regular mephedrone users had impaired memory. That has now been followed up and confirmed by the second half of my recent study. In this part, we gave rats the drug for 10 days and then sent them home for five weeks of drug-free living.

We then gave them behavioural tests to see if the drugs had done any damage; for example, to see if the drugs had made our rats more anxious or less social and so forth. All of the anxiety and social tests came back negative (so far), but where we did find something was with memory.

There’s a particular behavioural test that you can run on a rat called the novel object recognition test. It is a memory test that relies on the rats’ natural instincts. Rats are omnivores; their survival depends on them exploring their surroundings and exploiting every potential source of food. Because of this, rats like new stuff. If you put something new in their enclosure they will go and investigate it, and you can take advantage of this to test their memory.

For the novel object recognition test, you put the rats in an environment with two identical new objects in it. You then leave them in there long enough to explore and get used to the objects, before taking them back to the home cage for however long you want to test their memory over. You then bring them back to the same enclosure with one of the previous objects and one different object.

If their memory is intact, they will spend nearly all their time checking out the new object – because they like new things. On the other hand, if their memory is damaged, they will regard both objects as new and they will spend equal time on each.

With our higher dose mephedrone animals this is exactly what we found. We got a textbook novel object recognition impairment that gave good evidence, especially because it agrees with the suggestion from the human study, that mephedrone can damage your memory in a way that persists. The rats had been off the drug for a month and a half and their memory was still damaged. A month and a half is quite a long time for a rat, so anything hanging around for that long is quite possibly permanent.

Was it previously known that mephedrone could affect memory?

No. Until very recently, we knew absolutely nothing about this. There was the suggestion of memory impairment from the recent human study, but that was actually published after our research was completed (but before ours made it into print).

Cathinones have been traditionally used for thousands of years. For example, “Khat” twigs, which contain cathinone, are frequently chewed in East Africa for their relatively mild stimulant effect. Synthetic cathinones, like methcathinone and methylmethcathinone, first started to appear in Eastern Europe and Israel over the last couple of decades.

It looks like mephedrone as a drug probably originated in Israel, where it was briefly being developed as an experimental pesticide. Mephedrone is not a particularly good pesticide, so they stopped doing that, but a few people started taking it recreationally before it was banned there.

A few years ago it started to show up in the UK and Western Europe. This was probably driven by the fact that European authorities had been so successful in cracking down on cocaine and ecstasy supplies at the time. For a few years there was a period where the cocaine and ecstasy available in the UK was of dreadful quality, was very expensive and extremely hard to get. This created a market for an alternative, and mephedrone stepped into the gap. It appears that most of the mephedrone being sold at the moment is being manufactured on an industrial scale in China, but it could be produced by any reasonably competent lab.

What precisely did your research find?

There were two major findings from the latest paper. The first is the contrasting patterns of action we found with dopamine and serotonin when we looked at the rats shortly after they’d had their drug. Getting a handle on the basic neurochemistry of the drug is essential to understanding how it works in the brain.

The second finding, and the one that is drawing a bit of media attention, is the memory impairment in the rats that had been off the drugs for weeks. Anything that suggests that something that large numbers of people are doing might be damaging to them is of obvious importance.

However, when we looked at the brains of the memory-impaired rats, we didn’t find any long-term changes in their neurochemistry: their dopamine and serotonin levels were the same as the control rats who hadn’t had any drugs. So, whatever it is that is driving the memory impairment it is not something as simple and as obvious as too much serotonin, for example. That’s the next big thing: working out the physical mechanism of the interaction of mephedrone and memory.

Did your research show a correlation between the amount of mephedrone taken and the level of memory loss?

Correlation is too strong a word for it, but the memory impairment was only found with the highest dose used. The two lower dose groups did not show any memory impairment.

Although the subtleties of human to rat dose scaling aren’t always obvious, the memory-impairing dose was chosen in an attempt to find something roughly equivalent to what people might consume over a drug-using session. The fact that the memory impairment was not apparent in the lower dose groups does not imply that lower doses of mephedrone are safe: it is certainly possible that more sustained treatment with the lower doses would have also produced a memory impairment.

What impact do you think your results will have?

Most of what we are trying to do is laying the groundwork for further research. A big problem with mephedrone and similar drugs is that we know almost nothing about them. You can’t do the complicated experiments until someone has done the basic tests such as:

What parts of the brain does it turn on?

Does it damage you? How? Why?

What neurotransmitter systems does it work with and how?

But we also want to provide as much information as possible to the people taking mephedrone. When this drug first arose, the fact that it was briefly legally available in the U.K. led to a perception that it was a relatively innocuous drug. This isn’t the case: while the acute impact of mephedrone isn’t as dramatic as the classical “bad” drugs like heroin or methamphetamine, it does appear to be both highly addictive and able to cause lasting damage. Mephedrone certainly appears to be a higher risk drug than Ecstasy.

Perversely, it seems that a major driving force behind the spread of mephedrone use was the suppression of the ecstasy supply. By prohibiting relatively less harmful drugs, we merely divert demand to more harmful alternatives. If we continue with business as usual, the endless parade of new psychoactive drugs is eventually going to provide something that does a lot of damage to a lot of people, and the damage could be done before the scientific community is even aware that it’s happening.

Do you have any plans for further research into this field?

There are two papers in peer review at the moment which will hopefully be coming out shortly. One of them is looking at the addictive potential of mephedrone and the other is a review paper which also examines the theme of novel psychoactive drugs in a more general sense.

Would you like to make any further comments?

In 2010 alone, the European Union identified 41 new psychoactive drugs. The research community cannot keep up with this. 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 the possibility of long-term and cumulative effects in a timeframe this rapid. Effects that require years to occur cannot be discovered without years of investigation.

We’re still working as fast as we can; research groups around the world are investigating mephedrone and other novel drugs. Other people in my lab are also doing research into this area, looking at the effects of mephedrone on social behaviour and its possible interaction with a variety of physiological and neurochemical systems. But the underlying issues here are not the sorts of things that can be solved with research alone.

Where can readers find more information?

Our most recent research paper was published in PLOS ONE (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045473), while an earlier paper of ours can be found in the journal Addiction Biology (http://onlinelibrary.wiley.com/doi/10.1111/j.1369-1600.2011.00384.x/abstract ).

One of my favourite resources for laypeople on the neuroscience of drugs is a blog called Neurotic Physiology, written by a behavioural neuroscientist who goes by the name of Scicurious (http://scientopia.org/blogs/scicurious/). Her “Science 101” posts in particular give an excellent introduction to the chemistry of the brain.

There isn’t a great deal of information out there on mephedrone, purely because we just don’t know that much yet. However, I’ve published a few basic articles on the subject that can be found at http://theconversation.edu.au/search?q=motbey.

About Craig Motbey

Craig Motbey is a PhD candidate in the final stages of his doctoral studies at the University of Sydney. His studies have been supported by an Australian Postgraduate Award and an AINSE Postgraduate Research Award. His work has been presented at a variety of international neuroscience conferences.