How ecstasy can kill brain neurons by cutting their power supply

The work to be published in the Journal of Neuroscience[1] also reveals that a drug used in Parkinson’s disease is capable of prevent this damage. By showing how ecstasy can directly compromise such a crucial cellular process the research might help an eventual resolution of the two decade-long debate over whether or not ecstasy use is dangerous.

MDMA (the main component of ecstasy) leads to the production and accumulation of serotonin, a feel-good chemical, which is behind the pleasant effects of the drug. But scientists also know that ecstasy leads to excessive, and most probably toxic quantities of serotonin accumulating in the nerve endings. How this affected ecstasy users, however, was until now not known..

But the Portuguese researchers Ema Alves, Teresa Summavielle, Félix Carvalho and colleagues from the University of Porto and the Porto Polytechnic Institute.

It was known that neurons that produce serotonin eliminate its excess by using monoamine oxidase (MAO), a type of enzyme (enzymes are proteins that mediate chemical reactions) that as it destroys serotonin produces hydrogen peroxide (H2O2). And H2O2 can lead to the formation of free radicals – toxic molecules that when in high quantities can damage the cell components, including DNA, by oxidising them in the same reaction that leads iron to rust. What Alves, Summavielle, Carvalho and colleagues also realised is that in serotonin-producing neurons the existing MAO – which is called MAO-B – is found on the membrane of mitochondria, the structures where nutrients are converted into the energy used by the cell.

Alves and colleagues’ hypothesis was that in these neurons MAO-B, while eliminating the excessive serotonin released in response to ecstasy consume, would produced toxic quantities of free radicals on the mitochondrial membrane. This toxic accumulation could, by affecting the cell energy-producing machine, result in neural death as affected neurons would be incapable of performing basic cellular reactions..

In order to test this hypothesis the team of researchers used four groups of adolescent rats: a group was treated with MDMA, another with MDMA and selegiline – a drug known to block MAO-B activity – and the remaining two served as control. The control groups included one set treated with selegiline alone in order to assure that selegiline had no effect beside MAO-B blocking, and another with an innocuous substance. After some time the animals’ brains were removed and the mitochondria of serotonin-producing neurons analysed. Adolescent rats were used since teenager abusers – ecstasy main users –have particularly vulnerable cerebral and hormonal systems in result of not being yet fully mature.

As hypothesised MDMA-treated rats showed serious damage in their mitochondria including the loss of entire pieces of DNA – mitocondrial DNA codes for proteins involved in the energy-producing process –compromising the whole energetic machine.

On the other hand, animals treated with MDMA and selegiline did not have any signs of mitochondrial problems confirming the importance of MAO-B in MDMA-induced damage. Interestingly, it was seen that MDMA also increase the rats’ body temperature– a hallmark effect of ecstasy – but this was not associated with the mitochondrial damage suggesting that ecstasy was toxic at other levels too.

Ecstasy, or 3,4 methylenedioxymethamphetamine appeared in the raves of the 1980s and although much studied in the last two decades its dangerousness continues to be debated due to the lack of conclusive results. The drug seems to be toxic for neurons (at least in non-humans laboratory models) and has been shown to kill animals but then, relatively few people have died from taking it and those that did it was mostly due to the heatstroke induced by the drug causing respiratory failure. Nevertheless, several studies have suggested that long-term ecstasy users seem to present serious memory loss.

Alves, Summavielle, Carvalho and colleagues’ results reveals a mechanism by which ecstasy leads to “power-cuts” in the brain neurons, compromising their activity and survival. Not only that but this effect was seen in the serotonin-produced neurons and serotonin is known to be involved in memory, which is believed can be compromised by the drug. As consequence the researchers are now investigating if those long-time users of the drug with signs of memory loss show alterations in their mitochondria/serotonin-producing neurons.

Teresa Summavielle, one of the researchers says “We hope that this findings can help convince ecstasy' users, mainly adolescents, that ecstasy really affects the way our brain functions.”