Pubdate: Sat, 26 Mar 2005
Source: New Scientist (UK)
Page: 44
Copyright: New Scientist, RBI Limited 2005
Contact:  http://www.newscientist.com/
Details: http://www.mapinc.org/media/294
Author: Graham Lawton
Graph: Prevalence of cannabis use http://www.mapinc.org/images/bycountry.jpg
Graph: Youthful enthusiasm http://www.mapinc.org/images/everused.jpg
Bookmark: http://www.mapinc.org/topics/psychosis
Bookmark: http://www.mapinc.org/find?420 (Cannabis - Popular)

CANNABIS: TOO MUCH, TOO YOUNG

AT THE end of Jim van Os's street in the pleasant Dutch city of Maastricht 
there is a coffee shop. As with many such establishments in the 
Netherlands, "coffee shop" is something of a euphemism: most of its 
customers go there not to drink coffee but to buy and smoke dope. Van Os 
isn't too keen on the place. He doesn't like the shady characters it 
attracts. He doesn't like the fact that his children have to walk past it. 
And most of all he doesn't like that fact that the place breaks the law and 
sells marijuana to under-18s.

Van Os's fears are rooted in more than the usual parental angst. He is a 
psychiatrist at the University of Maastricht who investigates the effect of 
marijuana on people's brains - particularly adolescents' brains. And the 
findings of his research make him worry about the effects of all this dope 
smoking on the kids in his neighbourhood.

Over the past couple of years van Os and several others have been building 
the case that, for some teenagers, smoking cannabis leads to serious mental 
health problems in later life, including schizophrenia. Van Os claims that 
marijuana is responsible for up to 13 per cent of schizophrenia cases in 
the Netherlands. And with cannabis use among teenagers on the rise, the age 
at first use falling (see Graphic), and the strength of cannabis on the up, 
he says the figure can only increase.

It is a frightening conclusion, and one that is already starting to shape 
the debate over the legal status of cannabis. In the UK, van Os's findings 
have been seized upon by politicians, tabloid newspapers and mental-health 
lobby groups who want drug laws tightened up. But their case is far from 
made. Some researchers say there are potentially fatal flaws in the 
research, and that it would be a serious mistake to change the law based on 
an as-yet unproven theory. So who is right? The answer, it turns out, is 
more complex than it first appears.

Compared with substances like heroin and crack cocaine, cannabis is seen by 
many people as relatively harmless. Several European countries take a 
lenient view of its use, and in the UK marijuana was downgraded from a 
class B to a class C drug last year, meaning people caught with small 
quantities are not usually arrested.

But doctors have long known that taking a lot of cannabis over a short 
period can occasionally cause temporary symptoms of psychosis, one of the 
hallmarks of schizophrenia (see "Psychosis explained"). The question of 
whether the drug has long-term mental health consequences, however, is much 
more contentious.

The first hints of possible long-term harm came from Jamaica in the 1960s, 
where doctors noticed that Rastafarians who were heavy dope smokers seemed 
unusually prone to psychotic illnesses. The suspicion grew in the 1980s, 
when studies led by Robin Murray of the Institute of Psychiatry in London 
showed that patients with schizophrenia or some other kind of psychosis, 
were twice as likely as those without mental illness to be regular cannabis 
users.

But it wasn't until a major Swedish study was published in 1987 that a link 
between cannabis and long-term mental health problems was established. A 
team from the Karolinska Institute in Stockholm analysed the records of all 
the young men who had done national service in the Swedish army in 1969 and 
1970 - 50,087 in total, representing about 97 per cent of the male 
population aged 18 to 20. The records included details of the men's 
experiences with drugs before being called up, including age at first use, 
what they had taken and how often.

The team then checked out each man's medical history up to the mid-1980s. 
They found that those who had smoked cannabis before being called up were 
six times as likely to end up in hospital with schizophrenia as non-users. 
This, the team concluded, provided clear evidence that smoking cannabis was 
a risk factor for psychosis.

Case closed? Not at all. The study certainly showed a correlation between 
cannabis use and psychosis, but, as many people pointed out, it by no means 
proved that the former caused the latter. For one thing, the analysis 
ignored several possible "confounding factors" - other differences between 
users and non-users of cannabis that could be the real explanation for the 
link with schizophrenia. For example, dope smokers could plausibly be more 
likely to take other drugs such as LSD, which is a hallucinogen. Perhaps it 
was these drugs that were actually causing schizophrenia. Another 
possibility was that there was some hidden factor - possibly genetic - that 
predisposed people both to smoking cannabis and developing psychosis.

More importantly, even if there were a causal relationship between cannabis 
use and psychosis, the researchers failed to establish in which direction 
it lay. Sure, it was possible that cannabis led to schizophrenia. But it 
was just as likely that schizophrenia was causing people to smoke cannabis. 
Perhaps they were "self-medicating" - taking the drug to alleviate their 
symptoms.

The self-medication hypothesis has proved a popular one, and was virtually 
orthodoxy in the 1980s. For one thing, patients with psychosis often report 
that cannabis makes them feel better. And recent research suggests that one 
of the chemical ingredients of cannabis, cannabidiol, exerts a powerful 
antipsychotic effect. Indeed the UK firm GW Pharmaceuticals, which is 
awaiting approval for an under-the-tongue cannabis spray for multiple 
sclerosis patients, plans to investigate cannabidiol as a treatment for 
schizophrenia.

But the idea that cannabis caused psychosis didn't go away. One prominent 
sceptic of the self-medication idea was Don Linszen, a psychiatrist at the 
University of Amsterdam, the Netherlands, who, as a mental-health 
practitioner in the cannabis capital of Europe, was in daily contact with 
dope-smoking schizophrenia patients. He noticed that the patients who used 
cannabis usually fared much worse than those who didn't. Studies by Murray 
and others confirmed Linszen's observations. If people with psychosis were 
self-medicating, it wasn't working very well.

Meanwhile, several research groups were busy setting up long-term studies 
that followed large groups of young people over many years, keeping track 
of their drug use as teenagers and testing them for signs of psychosis 
later in life. They were similar in principle to the Swedish study, but 
were carefully designed to avoid its mistakes, particularly on the question 
of self-medication.

In the past couple of years results from a number of these studies have 
been reported, and together they make a decent case that the Swedish 
research got it right first time. "I don't think we can deny it any 
longer," says epidemiologist Mary Cannon of the Royal College of Surgeons 
in Ireland, based in Dublin. "Cannabis is part of the cause of schizophrenia."

Cannon helped carry out a study that followed 759 people born in Dunedin, 
New Zealand, in 1972 and 1973 (British Medical Journal, vol 325, p 1212). 
After carefully controlling for self-medication and other confounding 
factors, the researchers found that those who had smoked cannabis three 
times or more before the age of 15 were much more likely to suffer symptoms 
of schizophrenia by the time they were 26 - they had a 10 per cent chance 
compared with 3 per cent for the general population. The team concluded 
that there is a vulnerable minority of teenagers for whom cannabis is 
harmful. "We're not saying that cannabis is the major cause of 
schizophrenia," says Murray, who led the study. "But it's a risk factor."

Similar results have recently come in from a Greek study as well as a 
re-analysis of the original Swedish research. And late last year van Os and 
his team brought out further results. They followed a group of nearly 2500 
14 to 24-year-olds living in and around Munich, Germany, over four years. 
After correcting for all the confounders they could think of, they found 
that, overall, smoking cannabis as an adolescent moderately raised the risk 
of developing signs of psychosis later on, from 16 per cent to 25 per cent. 
But when they focused on individuals who were known to be susceptible to 
psychosis - those who were showing signs of disturbed thought processes by 
age 11 - they found a much stronger link. Susceptible individuals who 
avoided cannabis had a 25 per cent chance of developing psychosis. 
Susceptible individuals who smoked it had a 50 per cent risk. And the more 
cannabis they smoked, and the earlier they smoked it, the worse the outcome.

According to van Os, Murray and others, there can no longer be any doubt 
that there is a small but significant minority of people who have a 
predisposition to psychosis and who would be well advised to steer clear of 
cannabis.

This message is already starting to filter out into society. In the 
Netherlands, the findings have fuelled a growing clamour for reform of the 
laws regulating drug use. In the UK, the mental-health charity Sane has 
called for the reclassification of cannabis to be reversed. And the British 
government recently acknowledged the link in its strongest terms yet, when 
it said in a press release that cannabis was an "important causal factor" 
in mental illness.

But for some researchers, such pronouncements are premature. "I'm not 
convinced," says Les Iversen, professor of pharmacology at the University 
of Oxford and a member of the UK Home Office's Advisory Council on the 
Misuse of Drugs. "I think the jury is still out on this one."

He points out that epidemiological studies are notoriously bad at proving 
cause and effect, in part because it is hard to identify all the 
confounding factors. Scientists are particularly wary of such research when 
the conclusions are based on small statistical differences - as in this 
case. In the New Zealand study, the number of people who had smoked dope on 
three occasions by the age of 15 was just 29, and only three went on to 
develop psychosis. "I can't help thinking that the conclusion is rather 
thin," says Iversen. "It makes you wonder. If they found another 
confounder, where would that leave them?" Van Os himself admits that his 
study does not eliminate all the confounding factors.

Iversen also points out problems with how psychosis is defined in each 
study. Van Os's results, for example, seem to show that psychosis is 
relatively common in cannabis smokers. But he chose a very broad definition 
- - a single psychotic symptom, such as hearing voices or a paranoid belief. 
That's not the same as schizophrenia. About 20 per cent of the general 
population live with these symptoms: only 1 in 20 of them ever require 
treatment.

Iversen isn't the only doubter. Last year John Macleod of the University of 
Birmingham, UK, carried out a systematic review of the 16 high-quality 
long-term studies that have looked at cannabis and mental health and 
concluded that there was "no strong evidence" of a link with psychosis (The 
Lancet, vol 363, p 1579). "I'm not saying there is no causal association, 
but at the moment, by the conventional standards of epidemiology, the 
evidence is not particularly strong," he says.

There are other reasons to doubt the reality of a link. If it were genuine, 
schizophrenia should be becoming more common as teenage cannabis 
consumption goes up. But it isn't. In 2003 researchers at the University of 
New South Wales in Sydney found that, despite a steep rise in cannabis use 
among Australian teenagers over the past 30 years, there had been no rise 
in the prevalence of schizophrenia.

In the Genes

The only study to find a rise in schizophrenia was carried out in the inner 
London district of Camberwell, where continual demographic changes make 
interpreting the result almost impossible.

It seems the question of whether cannabis use can indeed lead to 
schizophrenia will be unresolved for some time yet. One research avenue 
that may shed further light on the matter is to look at whether genes are 
involved. One of the members of Cannon's group, Avsahlom Caspi of King's 
College London, is an authority on gene-environment interactions. A couple 
of years ago he made a splash by showing that a genetic predisposition to 
depression could interact with a traumatic experience such as bereavement 
to trigger the illness (New Scientist, 26 July 2003, p 15). "We thought, 
let's put this model to work on cannabis and psychosis," says Cannon.

She and her colleagues reanalysed the data from the New Zealand study, this 
time adding in another variable - genetic predisposition to schizophrenia. 
The gene they investigated, called COMT, encodes an enzyme 
(catechol-O-methyl transferase) that breaks down a signalling chemical in 
the brain called dopamine. COMT comes in two forms, one of which is 
marginally more common in people with schizophrenia and is thought to be a 
risk factor for the disease.

The results were crystal clear. The team found that in people with two 
copies of the "normal" version of COMT, smoking cannabis had little effect 
on their mental health. In people with one normal and one "bad" form of the 
gene, smoking cannabis slightly increased their risk of psychosis. But for 
people with two copies of the bad gene, cannabis spelled trouble: smoking 
it as a teenager increased their likelihood of developing psychosis by a 
factor of 10. The results have not yet been published, and Cannon warns 
that they need replicating, but even so she says "this is a very large 
effect, similar to the size of smoking and lung cancer. This is a very 
significant finding." Case, perhaps, closed.

What should be done about it, however, remains an open question. Van Os 
advocates that teenagers with a personal or family history of mental 
illness be urged to steer clear of the drug. He also advocates legal 
changes: governments should focus on keeping cannabis out of the hands of 
teenagers and outlawing extra-strong varieties of cannabis, such as skunk 
and white widow.

For Iversen though, this is still stretching the evidence. "What the data 
show is that the risk applies to a small minority of young people who start 
smoking cannabis at a very young age," he says. "Are we going to change the 
law for the benefit of a vulnerable minority? A small minority of people 
are vulnerable to liver damage if they drink even a small amount of 
alcohol, but we haven't changed the law to protect them."

[sidebar]

PSYCHOSIS EXPLAINED

What Is Psychosis

A symptom of mental health problems, not an illness in its own right.

What Do the Symptoms Involve

Psychotic people often have delusional beliefs, such as that someone is 
reading their mind or that they are immensely wealthy, powerful or famous. 
Extreme disorganisation and auditory and visual hallucinations are also 
common. Sufferers are usually unable to cope with daily life yet most are 
unaware that their behaviour is abnormal.

What Causes It

The main cause of psychosis is mental illness, principally schizophrenia 
and manic depression but also depression and dementia. Symptoms can follow 
infections, head injury, brain tumours, intoxication, poisoning and even 
traumatic events. Some psychotic episodes have no obvious cause.

What's The Outlook

Some people have only one episode, others struggle with psychosis their 
entire life. 
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MAP posted-by: Richard Lake