17 November 2011

Name your poison: Ecstasy, or MDMA (methylenedioxymethamphetamine)

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Part 2 of our special investigation into the latest research into the effects of recreational drugs.
Name your poison

Credit: Veer Images

ECSTASY – The ‘feel-good’ drug

Despite recent signs it may be starting to lose its appeal, the most widely used illicit drug in Australia after cannabis is ecstasy, a synthetic stimulant with hallucinogenic properties.

Ecstasy, or MDMA (methylenedioxymethamphetamine) – first appeared in Australian nightclubs in the late 1980s and the dance and rave scene has largely propelled its popularity since. This is despite being linked in a blaze of publicity to several deaths in the mid-1990s, both here and overseas.

MDMA was first synthesised in 1912 by a German pharmaceutical company; stemming from research to develop a blood-clotting agent, not an appetite suppressant as has been reported.

In the 1950s, it was assessed for its chemical warfare potential, and during the 1970s used in psychotherapy before emerging in the early 1980s as a recreational drug in the U.S. It was banned there in the mid-1980s but, by then, MDMA and its reputation as a party drug were already spreading throughout Europe.

Its chemical structure shares similarities with both mescaline, a psychedelic alkaloid found in the Mexican peyote cactus, and the stimulant amphetamine. Like other stimulants, ecstasy increases the activity of neurotransmitters dopamine and norepinephrine. But MDMA’s main point of difference is that it causes large releases of the neurotransmitter serotonin, which influences emotions, appetite, mood, pain perception and sleep.

The effects include reduced inhibitions and heightened feelings of empathy, which explains why MDMA users report an increased sense of intimacy. But it can also induce uncomfortable extremes in sensations, cause anxiety and depression and raise the heart rate.

Studies have shown that, post-use, the brain’s serotonin level can plummet and remain low for a period. In high doses it can cause damage to serotonin neurons, says Kelly Clemens, a psychology research fellow at Macquarie University in Sydney.

Some animal studies have shown that the damage can be long-lasting. Although this hasn’t been shown in humans, there have been reports of heavy MDMA users suffering from ongoing confusion, anxiety and memory problems. However, MDMA tends not to be noted for long-term dependence. There are, in fact, very few mentions in the scientific literature of users with the same sorts of addiction problems that can develop with other recreational drugs, such as methamphetamines or cocaine.

What tends to happen is that, over time, the post-high comedown that stems from depleted serotonin levels tends to outweigh the drug’s initial kick. “So, generally after a few years [users will] think it’s not worth it any more and if they have a change in circumstances – [such as] getting married or having kids – they’ll find using it doesn’t fit with their lifestyle any more,” says Clemens.

In 2005, the United Nations Office on Drugs and Crime ranked Australians as the highest per capita users of ecstasy. The most recent assessment of the country’s usage rate was 2007 when the AIHW reported that 8.9% of the over-14 population had tried the drug. However, in May 2011, the Australia Ecstasy and Related Drugs Reporting System (EDRS) reported that “the number of ecstasy users nominating it as their drug of choice had fallen significantly since 2005 and the number using the drug weekly had halved”.

Quality has been an issue for users. Analyses of seized ‘ecstasy’ tablets in Victoria in 2007 found that 60% contained MDMA. About a quarter contained no active drug while about 10% contained other illicit synthetic psychoactives such as MDA or MDEA. Methamphetamine and ketamine, a human and veterinary anaesthetic, are other compounds that have been identified in ecstasy tablets in Australia.

The EDRS also reported this year the detection of emerging low-level use of new ‘designer’ drugs and it’s been widely speculated this group could grow to replace or supplement ecstasy use in Australia.

HEROIN AND THE OPIATES – The painkillers

For Australians, the opiates, which include heroin and methadone, are at the opposite end of the popularity scale to ecstasy. In 2007, just 1.6% of the population over the age of 14 had experimented with this group of drugs during their lifetime.

Regular users probably account for no more than 0.1% of the adult population. And yet these compounds are annually linked to about a third of all deaths in Australia directly related to the toxic effects of drugs, including legal drugs.

Heroin – considered to be the world’s most powerful painkiller – has legendary powers of addiction. A semi-synthetic compound based on the resin secreted by the opium poppy, Papaver somniferum, it was first produced in the 1890s by a chemist working for German pharmaceutical company Bayer, who was looking for a painkiller without morphine’s addictive properties.

Within a decade, however, heroin addiction was already becoming a problem in Europe. By the 1930s, Australia had the developed the world’s highest per capita rate of heroin consumption. The scale of heroin use and addiction began to climb here from the mid-1980s, peaking in the late 1990s when deaths from the drug reached an unprecedented level. Just over 1,100 people died from opioid overdose in Australia in 1999, more than three times as many killed as was by these drugs in 2005.

In its pure form, heroin is a white crystalline powder. But the drug sold on the streets can be varying shades of off-white to pink or brown. Like any illicit drug with a synthetic component, it’s usually produced in unsterile, illegal operations and cut with adulterants at various stages on its journey to users.

The human body produces its own opiate-like neurotransmitters known as endogenous opioids. These include endorphins and are natural painkillers. But they’re also involved with the control of basic body functions such as hunger and thirst as well as mood and immune response.

Heroin and the other opiates bind to the same receptors in the brain as our endogenous opioids. The process dulls the activity of the neurons to which some of these receptors are attached and it’s this process that’s believed to underpin the euphoria that heroin-users report experiencing when they start using the drug. The process also indirectly stimulates dopamine production, adding to the high.

Users experience an initial rush of intense pleasure and a sense of wellbeing for the first 30 minutes or so after taking heroin, followed by as much as four hours of lethargy. Heart rate, respiration, blood pressure and general metabolism are slowed down – in the case of an overdose, to a fatal degree. Constipation and a loss of appetite and sex drive are common with long-term use.

Not surprisingly, it’s the endogenous opioid system that’s involved in slowing the metabolisms of mammals, such as bears, during winter hibernations.

Repeated use of these drugs reduces the production of a compound known as cAMP (cyclic adenosine monophosphate), a so-called ‘second messenger’ chemical that relays signals from the cell surface to target molecules inside the cell, and is important in transferring information about many fundamental biological processes. When the opiates eventually clear from the body, cAMP production capacity increases, causing neural hyperactivity and the infamous craving of more of the drug that often steers users towards physical dependence.

Drug researchers prefer not to rank the addictive capacities of drugs, as individual responses and circumstances certainly play a powerful role. But most concede that, for individuals, the extraordinary power to induce physical dependency, coupled with its long-term impacts on basic biological functions, put heroin near the top of the list.

NICOTINE AND ALCOHOL – Social drugs

When it comes to societal costs and long-term health implications, however, the drugs with the biggest impact aren’t the illicit ones. Not by a long shot. And that’s a matter of recurring incredulity among drug addiction researchers.

“We’re always astounded that tobacco and alcohol are legal when they do the most damage to your body compared to other drugs!” laments Clemens, a neuroscienctist focussed on the science of nicotine addiction. “People think of tobacco, in particular, as a soft drug, but when you look at the stats related to it, smoking and its consequences are a huge public health concern.”

The statistics for tobacco truly are staggering. In Australia, as is the case worldwide, tobacco smoking is the single largest and most preventable cause of ill health and death. Each year it kills about five million people worldwide.

There’s no question that many of the health problems, including cardiovascular disease and many cancers, caused by tobacco relate to the way it’s used – through smoking. But the compound within the plant that’s roundly blamed for much of the addictive nature of tobacco and many of its toxic and disease-causing attributes is nicotine. This alkaloid, the main psychoactive compound in tobacco, was first isolated in 1828 by German chemists. From a natural history perspective, it evolved in the plant to function as a pesticide, protecting the leaves from insect damage.

The tobacco plant, Nicotiana tabacum, is a relative of the humble potato and native to the Americas, where its leaves were used for thousands of years by the indigenous population as a painkiller and for a range of other purposes. Sailors brought seeds back to Europe after Columbus voyaged to the New World late in the 15th century and, for the next few hundred years, tobacco was widely promoted for its ‘health-giving’ properties.

Alarm bells began ringing as early as the 19th century but, by the mid-20th century, strong links between smoking and deadly diseases were being made and the evidence has been mounting ever since.

“Nicotine is really interesting compared to the other drugs of abuse,” Clemens says. “Something like cocaine, for example, acts in the brain in quite a specific and targeted way, but nicotine binds to nicotine receptors that are throughout the brain, not just in the reward system.”

The receptor sites to which nicotine binds are meant for acetylcholine, the most prevalent neurotransmitter in the body. It is involved with arousal levels – exerting an influence on heart and breathing rates, influencing memory and learning and stimulating muscle cells. Repeated stimulation of acetylcholine receptor sites by nicotine also increases the release of dopamine.

“I think people assume we know everything there is to know about nicotine addiction but that’s not the case,” says Clemens. “And that’s [illustrated] by the fact [current] treatments for tobacco addiction are really poor: between 80 and 90% of people trying to quit will relapse within six months to a year.”

Clemens is now steering her work towards looking at ‘cues’ related to smoking and how these might increase the addictive pull of nicotine. “With nicotine and other drugs, the cues are important but the context is really important too,” she says. “So, you can go to rehab and successfully stop taking drugs there. But as soon as you come back to where you started [your addiction] and where you were taking [the drug], you’re going to relapse straight away. So we’re now [exploring] how important the context of drug-taking and relapse are.”

Research in animals and humans increasingly suggests it’s not only nicotine addiction that’s influenced by cues but also dependence on other recreational drugs, including cocaine and, most significantly, alcohol.

Cues and context on alcohol use go back millennia in human culture and are now intricately connected with most modern societies. The product of fermenting sugar, ethanol is the psychotropic drug present in all alcoholic drinks and the component responsible for so much damage to human bodies and brains.

The effects of excess alcohol consumption have been clear for many decades in heavy and dependent users. Brain damage that impairs the ability to reason, plan or remember, liver disease, strokes and foetal alcohol syndrome in the children of mothers who drink heavily while pregnant are just a few of the long list of afflictions that alcoholics and binge drinkers face.

And since the 1990s, when the development of highly sensitive brain imaging technologies shed new light on how the human brain develops, it’s become increasingly clear that alcohol can cause serious, long-lasting damage to the developing adolescent brain.

But the scientific and medical literature has wrestled more earnestly with identifying a safe, or healthy, level of use for adults. The issue has been complicated by research suggesting there may be some health benefits, such as a decreased risk of cardiovascular disease with moderate alcohol use. More recently there have been claims that a compound found in red wine, resveratrol, has increased life spans and reduced cancers in animal studies.

In 2011, however, following a comprehensive analysis of cancer research and statistics published in the Medical Journal of Australia, Cancer Council Australia clarified what a healthy level of alcohol consumption should be for adult Australians.

According to the council, an estimated 5% of all cancer in Australia is caused by long-term, chronic alcohol use – that’s 5,000-plus cases annually. And there is now convincing evidence that alcohol causes 41% of mouth, pharynx and larynx cancers in Australia, 51% of oesophageal cancer, 22% of breast cancer in women and 7% of bowel cancer in men.

The council issued a position statement on alcohol and cancer risk that left no doubt about the level of ethanol exposure that could be considered safe for the human body – zero: “Any level of alcohol consumption increases the risk of developing an alcohol-related cancer; the level of risk increases in line with the level of consumption.”

For a country with one of the world’s highest per capita rates of alcohol consumption, it’s sobering advice.

Karen McGhee is a science writer based in Sydney.
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