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Name your poison: marijuana


From our brains to our prospects of longevity, just what do recreational drugs do to the body? Shifting from the intricacies of a 'high' in the brain to the effects of withdrawal, addiction and long-term use (and abuse), here is the latest medical research on some of society's biggest vices. By Karen McGhee.


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CANNABIS – THE NOT-SO-MILD HIGH

Cannabis use was common among Nadia Solowij’s circle of friends and acquaintances during her late teens and twenties.

“It was the 1980s, and probably half the people I knew were smoking it,” recalls Solowij, now a senior lecturer at University of Wollongong’s school of psychology. “I watched as some grew out of it, while others continued to use [it] for many years.”

At the time, the drug’s short-term mood altering effects were well known, as they had been for thousands of years. And the potential damage to lungs from smoking cannabis was becoming a concern.

But there wasn’t much consideration given to potential long-term or permanent effects on the body. Solowij became intrigued that some people could use the drug for many years and appear to live reasonably normal lives. “But others didn’t seem to be functioning well and you’d see them deteriorate,” she says.

Solowij is now one of the world’s leading researchers into the effects of cannabis on behaviour and the brain. One of her team’s studies, published in 2008 in the Archives of General Psychiatry, documented significant structural changes in the brains of long-time cannabis users.

Notably, MRI scans showed that the hippocampus and amygdala – regions thought to be involved in memory – were markedly reduced. And, while the cannabis users in the study had an average age of 39, their memory abilities were equivalent to those of people almost 20 years older.

IT WAS A SIGNIFICANT contribution to an ever-growing body of evidence that has, for the past two decades, been steadily overturning the drug’s benign image. Study after study in animals and humans has found that long-term exposure to cannabis can have marked impacts on brain structure and function, impairing learning and a range of other cognitive capabilities.

A major focus of recent research – anecdotally raised by scientists as long ago as early the 20th century – has been the potential link between cannabis use and the debilitating mental illness schizophrenia.


Slightly more than 1% of the global population – 285,000 people in Australia – suffer from schizophrenia, making it more prevalent than Alzheimer’s disease, multiple sclerosis or insulin-dependent (type I) diabetes.

The current scientific literature falls short of identifying cannabis as a causal agent for the disease. “But there’s now strong evidence of a clear association between cannabis use and schizophrenia,” says Jan Copeland, founding professor and director of the National Cannabis Prevention and Information Centre (NCPIC) at the University of New South Wales in Sydney.

There’s been a particular focus in the research on teenage users, largely because cannabis tends to be an experimental drug of choice among many adolescents. And studies show that people who try it first as adolescents – rather than as adults – are more likely to become dependent and long-term users. It’s a phenomenon that’s also been documented in rats, the usual laboratory animal studied for substance abuse and dependence because their physiological – most notably neurological – responses to drugs are similar to those of humans.

Researchers find it relatively easy to get rats hooked on most psychotropic drugs – from alcohol to heroin. But it’s very hard to make rats dependent on cannabis when they try it first as an adult. “We’re now getting very good and specific information about the effects of cannabis on the adolescent brain, and how absolutely vital a window that is,” says Copeland.

A major part of normal brain development during adolescence involves the natural ‘pruning’ of neural connections and pathways that aren’t efficient or being used, while reinforcing those that are. It’s thought that the use of cannabis in adolescence may interfere with this crucial process. And while scientists still don’t know what does cause schizophrenia, it’s believed people with the disease have too many connections in their brain, which probably accounts for the overwhelming and debilitating hallucinations sufferers typically experience. It’s also highly likely there is some underlying genetic component to the disease, although the relevant genes are yet to be identified.

When it comes to illicit substance abuse, cannabis is by far the drug of choice. In Australia and throughout the developed world it’s the most widely used of all the illicit psychotropics. Australian Institute of Health and Welfare (AIHW) figures, published in 2008 and based on a 2007 survey, indicate that almost six million Australians older than 14 have tried cannabis at least once. About 600,000 had used it in the week before the survey, while 1.6 million had used it during the previous 12 months.

The drug comes from a plant, Cannabis sativa, which probably originated in India and has been used by humans for more than 4,000 years. Its leaves, resin and flowers, all of which can be smoked or eaten, contain hundreds of different chemicals, including more than 60 known as cannabinoids. Just one of these is largely responsible for the ‘high’ the drug gives users: delta-9-tetahydrocannabinol (THC).

ONE OF THE HUMAN BRAIN’S many neural networks is known as the endocannabinoid system, so named because this is where cannabis initiates many of its effects on the body. The key areas of impact of this system include motor control, cognition, motivated behaviour and emotional responses.

Neurons in the endocannabinoid system have attachment sites known as cannabinoid receptors. Under normal conditions these receive and respond to a neurotransmitter called anandamide, which relays chemical messages relating to the regulation of appetite, memory and emotions.

THC affects the body because it mimics anandamide and replaces it on the cannabinoid receptors, altering the normal functioning of the endocannabinoid system. This creates a sense of relaxation, even euphoria. Short-term memory and the ability to judge time and distance are often affected. By locking onto the cannabinoid receptors, THC also – indirectly – triggers the production of the neurotransmitter dopamine, a fundamental impact of all mood-altering drugs.

As well as THC, there’s another cannabis chemical that’s been of increasing interest to researchers in the past decade – cannabidiol (CBD). It’s sometimes referred to as the ‘good’ cannabinoid because it seems to naturally counter some of the negative effects of THC. In drug research circles, it’s widely known that users in Australia believe cannabis has been getting stronger and increasingly associated with unpleasant side effects, including hallucinations and paranoia.

TESTS CARRIED OUT ON cannabis samples in Britain, New Zealand and the U.S. have identified that THC levels have certainly been increasing due to breeders selectively breeding plants that are high in THC and low in CBD. Australian cannabis hasn’t been subjected to the same testing, but it’s likely the phenomenon has also occurred here. The NCPIC estimates the potency of cannabis in Australia has doubled in the last decade.

There have been anecdotal reports out of Amsterdam, in the Netherlands – where a tolerance policy is applied to marijuana – of dealers now promoting high-CBD cannabis as users seek a more mellow product.

CBD has also attracted the attention of pharmaceutical companies because of its potential to treat a range of conditions, from nausea to inflammation. And Solowij, like many cannabis experts, is particularly interested in evidence that CBD improves memory impairment and other negative effects of THC. “It sort of balances out the THC, and there is a lot of interest now in looking at the proportions of THC versus CBD in cannabis,” she explains. “Some studies have even shown CBD to have anti-anxiety and anti-psychotic-like effects when given to humans.

“There are, of course, millions of cannabis users who don’t suffer psychosis … cannabis does not cause psychosis, but it can trigger it in a vulnerable individual,” she says. “So we’re trying to understand by what mechanisms the different components of the plant are important. How do they interact with a genetic predisposition to mental illness?”

According to research, about one in 10 people who begin using cannabis will become dependent on it – physiologically as well as psychologically. Drug agencies believe there are currently more than 200,000 people in Australia with a cannabis dependency.

While the term addiction is used in animal models for the repetitive use and seeking of a drug, the same condition – or disease, as researchers increasingly call it – is termed dependence in humans. Cannabis dependence is medically defined, in the same way as alcohol, cocaine, heroin or methamphetamine dependence, as: “When an individual persists in use of alcohol or other drugs despite problems related to use of the substance, substance dependence may be diagnosed. Compulsive and repetitive use may result in tolerance to the effect of the drug and withdrawal symptoms when use is reduced or stopped.”

People trying to break their dependence on cannabis might not experience the same physiological symptoms or behaviours as the stereotypical ‘addict’ giving up heroin or even alcohol. But cannabis withdrawal can certainly be an unpleasant experience; and agencies in Europe, the U.S. and Australia have all reported recent rises in the number of people requesting help to quit cannabis. “When you’re withdrawing [from cannabis] your [natural] endocannabinoid system is resetting,” explains Copeland. “And so it affects all of the things that cannabis influences, such as sleeping and mood.”

In a world-first, the organisation will soon begin human trials in Sydney and Newcastle to test, ironically, a new cannabis-based drug to help shake cannabis dependence. The drug being trialled, Sativex, is a botanical extract of whole cannabis, originally developed by a British-based GW Pharmaceuticals to alleviate multiple sclerosis symptoms. “You get a controlled dose of both CBD and THC in almost equal amounts [via an] oral spray,” says Copeland.

The hope is it will allow people wanting to break a cannabis dependence to be given a tapered dose of both CBD and THC, so they can experience a gradual withdrawal without enduring excessively unpleasant symptoms: essentially weaning them off cannabis while allowing their endocannabinoid system to reset.

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METHAMPHETAMINE – THE STIMULANT

Methamphetamine, unlike cannabis, has never had a reputation as a soft drug. The powerful synthetic stimulant first appeared on Australian streets in the mid-1990s and is often called ‘speed’. More potent forms of the drug – known as ‘base’ and ‘ice’ – surfaced a few years later.

Its rise since then has been truly meteoric. Methamphetamine, is now one of the most pervasive illicit drugs in Australia, with around 1 in 10 people over the age of 14 having used it at least once. In line with the drug’s party image, that figure is highest in the 20-29 age bracket.

Known pharmacologically as N-methyl-1-phenylpropan-2-amine, methamphetamine was first synthesised by a Japanese chemist in 1893 from ephedrine – a natural stimulant and appetite suppressant originally isolated from a desert shrub in central Asia. It had a complicated and chequered history of military and pharmaceutical use and abuse throughout much of the 20th century.

And following a string of worrying medical and scientific reports, including concerns about its link to psychosis, it became increasingly controlled from the 1970s onwards.

It remains available for restricted pharmaceutical use in some countries, but its use is now illegal in much of the world. And its manufacture is largely clandestine and uncontrolled in ‘backyard’ laboratories using chemicals such as pseudoephedrine, the decongestant in some cold and flu medications.

IN ITS PUREST FORM, methamphetamine is a bitter, odourless, white, crystalline powder. It’s most often sold and used in Australia in this form, although dealers cut it with adulterants to improve profit margins.

Contrary to popular belief and urban myths, these are usually innocuous ingredients such as sucrose, but the powder can become laced with toxic contaminants during the manufacturing process.

The drug – which can be taken orally, snorted, smoked or injected – is also sold in tablet and liquid form and is often an ingredient in pills traded as ‘ecstasy’.

Methamphetamine works directly on the brain’s reward system in two ways; it blocks the clearance of dopamine from nerve pathways while also stimulating excessive production of the neurotransmitter. Animal experiments have shown the drug causes massive spikes in dopamine levels – as much as 10 times higher than surges detected during sex in the same animals.

Methamphetamine users report that the drug gives them feelings of intense pleasure and exhilaration while increasing energy levels and enhancing confidence. If injected, smoked or snorted, these sensations initially hit in a rush, but if the drug is taken orally, they take hold more gradually. Regardless of how it’s taken, the high can last for more than six hours and the drug remains in the user’s body for up to two days.

The drug is considered highly addictive, with research on methamphetamine use showing that between 10% and 20% of people who use the drug will develop a dependence.

COCAINE – THE HEART STRESSOR

Unlike Methamphetamine, pure cocaine has a botanical origin. It’s extracted from the leaves of the coca bush, Erythroxylon sp., which originally grew mostly in Peru and Bolivia, in South America. But neighbouring Colombia is now, famously, the biggest producer for the illicit trade.

Indigenous South Americans have chewed the leaves for at least 2,000 years, reportedly to stimulate the central nervous system, increase stamina, ease pain and suppress hunger. It wasn’t until the mid-19th century that cocaine hydrochloride, one of more than a dozen alkaloids contained in the plant, was first extracted pharmaceutically. And it’s true that the American soft drink Coca-Cola originally contained it, as did many elixirs and tonics of the late 19th century.

Like methamphetamine, cocaine also directly increases dopamine levels – but not to the same extent as methamphetamine. It works a little differently, blocking the body’s natural reabsorption and recycling of dopamine but not stimulating production of the neurotransmitter.

Its effects are similar to those of methamphetamine, but, because it breaks down more rapidly and completely in the body, the sensations of pleasure it brings are considerably shorter-lived – measured in minutes, rather than hours.

The pleasure and heightened alertness that come from both drugs are due to the action of dopamine on the peripheral nervous system – the part of the nervous system outside of the brain and central nervous system.

BOTH OF THESE stimulant drugs are vasoconstrictors – they cause spasms and tightening of the muscles lining the walls of arteries and veins. This leads to narrowing of the blood vessels, and cocaine is also known to cause blood clotting. In heavy users, vasoconstriction can be so intense it restricts blood flow to the tissues and muscles in some parts of the body – which is why the skin and other external features of heavy methamphetamine users appear to age so rapidly.

It is also vasoconstriction that contributes in heavy users of both methamphetamine and cocaine to the condition known as ‘formication'; the hallucinated sensation that insects are crawling beneath the skin, which addicts will scratch and gnaw at, creating sores.

Research has shown the effects of both cocaine and methamphetamine on the cardiovascular system significantly elevate the risk of both heart attack and stroke. “When you increase monoamines [such as dopamine] in the peripheral nervous system … it increases your arousal level, and that’s effectively like a stressor,” explains Rebecca McKetin, an expert on these drugs from the Centre for Mental Health Research at the Australian National University in Canberra. “And that, in the long term, increases the risk of stroke and cardiovascular disease in the same way any stress would.”

Increased heart attack and stroke risks might not be surprising for methamphetamine, with its hard drug image. But there’s been growing concern among Australia’s emergency doctors and drug workers that a significant proportion of ‘recreational’ cocaine users may underestimate the risk of a drug that was once widely known as ‘pop star powder’.

In Australia, there are three broad groups of cocaine users. “There’s the more hardcore drug users who inject it and inject other drugs as well,” explains Sharlene Kaye, a research fellow with the National Drug & Alcohol Research Centre (NDARC), at the University of New South Wales. Then there’s a substantial group of younger, better educated, 20-somethings using cocaine as a party drug in conjunction with ecstasy and alcohol. “And then we’ve got … what we call this hidden population,” says Kaye. “They’re professionals and people in a high socio-economic status group that we aren’t able to access through our research. We know they’re out there because [anecdotally] they keep appearing … certainly in the media.”

A recent NDARC study of cocaine-related fatalities suggests this otherwise hidden group is aged in the mid-thirties, about half are employed, mainly in professional occupations. It’s thought they use cocaine recreationally and may assume that, perhaps because it’s used by celebrities who don’t fit the stereotypic image of a desperate addict, the drug must be physiologically harmless. “But it’s a classic cardio-toxic drug,” says Kaye. Even in first-time users, and small amounts, the drug can initiate vasoconstriction and vasospasm that can cause heart attacks and heart arrhythmias.

“SO THAT’S THE short-term risks. Then you’ve got chronic effects, from long-term use. It can cause longer term changes in the heart muscle – [such as] ventricular hypertrophy, where the [heart’s] ventricle walls actually become enlarged and thickened,” says Kaye.

“And we’ve seen in the studies of fatalities that it accelerates coronary artery disease progression. So [we’re] seeing younger people that have got serious artery disease [due to cocaine use].” This includes severe narrowing of the arteries in people of an age group where such damage would not normally be seen.

In the emergency unit at Royal North Shore Hospital in affluent Sydney suburbia, there’s been an anecdotal rise in young, well-educated, cocaine users presenting with heart attacks. It’s exactly the group Kaye and her colleagues believe they haven’t been able to study.

A cardiac specialist at the hospital and senior lecturer at the University of Sydney’s medical school, Gemma Figtree, says she’s noticed the trend during the past two years.

So far it’s been young professional men, aged in their early-to-mid thirties, who have presented with heart attacks. “But I certainly know they have a lot of friends who are females who are users as well, and they all say they didn’t know this could happen,” says Figtree. “And suddenly their young friend has irreversible damage to their heart and it comes as a big shock.”

Figtree is now involved in an anonymous study of regular recreational cocaine users to investigate whether there has been any silent damage to their heart muscle.

“WE’RE LOOKING AT whether they’ve had previous little heart attacks, but weren’t aware that’s what they were having,” says Figtree, explaining that a lot of users have told her chest pain was often accepted as part of a normal and benign side effect of using cocaine. “But it’s actually a serious health risk. And in my experience [these users] are completely shocked by the fact that [this drug] can have such devastating effects on their heart, even from first-time use.” Her advice to cocaine users with chest pain is to go straight to a hospital. And the potential for long-term damage to the brain is also of growing concern. It’s now understood the brain changes in an adaptive way to all mood-altering drugs.

“What you see are ‘plastic’ [structural and functional] changes in the brain that occur in response to a drug and, in the case of methamphetamine, you also see toxicity,” says McKetin, one of the world’s foremost authorities on methamphetamine abuse. “So you’ve got your acute drug effects and that [involves] increases in the neurotransmission of dopamine, but then you’ve got these plastic changes [at the neural level] that occur as an habituation, or reaction, to having the drug around all the time in the [brain’s] environment.”

This changes the sensitivity of neurons and their receptors. “It’s a little like plants: expose them to constant wind and they will [stay bent] one way,” explains McKetin. “What you see is toxicity where the actual ends of the neurons degenerate.”

While this toxic response can potentially occur with all of the psychotropic drugs, it can be particularly severe with methamphetamine. The ends of the neurons can recover – although the process is not completely reversible and it may take many months, even years.

So how does the adaptation by the brain to the state of being bathed in methamphetamine or cocaine manifest itself when the user isn’t taking the drugs? “Off the drugs they’re really low, really depressed, they don’t feel pleasure in things, they feel lethargic, their sleep patterns get disturbed,” says McKetin. “And they also get psychotic symptoms – paranoia and hallucinations.”

For long-time heavy users trying to quit, it can take weeks and even months for dopamine levels to readjust in the brain. And the process can be harrowing. “They’re climbing the walls because they’re screaming inside, and they’re teary and they can’t do anything but want the drug,” says McKetin. “They’re completely out of sorts: yes, it’s a psychological craving of the drug, it’s paranoia, it’s depression and mood swings. But it’s such a strong phenomenon and it certainly has a biological basis.”

STAY TUNED: PART 2 OF “NAME YOUR POISON”, FEATURING ECSTASY, HEROIN AND THE OPIATES AND NICOTINE AND ALCOHOL WILL BE PUBLISHED TOMORROW.

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Karen McGhee is a contributor to Cosmos Magazine
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