09 Oct COMT; another “wrong” result for the reefer madness hype

Peter Reynolds posted a short comment earlier this week about some new research into the COMT gene and its claimed role in cannabis induced psychosis. This is a more in-depth look at what’s happened and why it’s important – not to say very good – news.

One of the great “reefer madness V2.0” claims has been dealt a serious blow this week, probably enough to kill it off altogether with luck. To read the comment from the study which put the knife in though, you would never guess.

In the abstract to a paper called “Cannabis, COMT and psychotic experiences” (abstract here – to read the full paper you’ll have to cough up $15) Prof Stan Zammit and others put their names to this dire sounding warning:

Cannabis increases risk of psychosis irrespective of underlying COMT genotypes. These findings argue against the widely held belief that the relative risk of developing psychosis following use of cannabis is dependent upon variation within COMT. The public health message about the potential increase in risk of psychotic disorders following cannabis use should not be tempered by reports that this harm is subgroup specific in the absence of robust evidence of replication.

It’s almost as if they sat up very late at night trying to think of a way of saying this which would not undermine the reefer madness scare and they obviously tried very hard. A cynic might put this down to not wanting to upset the Daily Mail, but if it was the case they needn’t have bothered because the study got absolutely no press coverage at all in the mainstream media, probably because its results are just so “off message”.

How is it possible to claim that such an apparently obvious “cannabis causes psychosis” comment is in reality so damaging to the reefer madness hype of the last decade? To understand why it’s important to rewind a little to the origins of the ‘reefer madness’ scare, which most certainly did get a lot of press coverage – oh, and to remember that genetic science is really, really scary.

COMT is the name of a specific gene called ‘catechol-methyl-transferase’ and, like all genes, it comes in two halfs (one from each parent) which can be of two forms; ‘val’ (valine) and ‘met’ (methionine). Both variations exist in about equal amounts and so any individual person can have COMT genes of either the val-val type, the met-val or val-met type (which is the same thing), or the met-met variety and in most situations it makes no difference to the person concerned.

However, one of the things psychiatrists think they have noticed is a correlation between people carrying one version of the gene and an increased risk of psychosis. Mover, they had a reason to suspect this link in that the COMT gene’s job is to moderate the amount of dopamine in the prefrontal cortex – the bit of your brain where “you” are and which is the bit that goes wrong when you get psychosis.

Quite a few researchers then set out to demonstrate that this combination of the COMT gene was at the root of ‘cannabis psychosis’. OK, perhaps that’s not fair, but it did seem like that at one point. Certainly what happened is that some researchers looked for an effect they expected to see and perhaps as a result, they saw it. Take for example this report in Schizophrenia.com which was widely covered back in 2005 which references an article in New Scientist which is also sadly also behind a pay wall

In the original New Zealand study used by researchers, people who had smoked cannabis on three occasions by the age of 15 had a 10 per cent chance of developing the condition by the age of 26.

Dr Mary Cannon’s research team recently re-analysed the data from from this study, adding another variable – genetic predisposition to schizophrenia. The gene they investigated, called COMT (catechol-O-methyl transferase), encodes an enzyme that breaks down a signalling chemical dopamine in the brain. 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 New Zealanders 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 the drug as a teenager increased their likelihood of developing psychosis by a factor of 10.

Notice how the term “bad gene” is used here, implying a genetic fault of some kind, and that the results were “clear” – beyond doubt, this was true!

This whole issue can probably be traced back to the work of (now sir) Robin Murray and other well respected scientists who advanced this theory with great enthusiasm through the middle of the 2000’s and it played well with the prohibition lobby who made great mileage from it.

The reason it was a very potent issue for the prohibition lobby is easy to understand:

1: Madness frightens people. Perhaps understandably psychosis is something most of us don’t really want think about, it still ranks as one of those taboo subjects we close our collective minds to, which goes some way to explaining why a large number of ill people are “cared” for by being locked up in prison. It is, in short, a very emotive subject.

2: COMT provided a mechanism to pin cannabis psychosis on – not only that but it concerned genetics, with all the connotations of genetic engineering and other dark arts that play well on the public fear index.

But most importantly:

3: It meant 25% of the population were at a high risk from cannabis; a quarter of us are walking around with this ‘faulty’ gene which opens the door to psychosis through cannabis use and as no-one can know what type of COMT gene they have, anyone who used cannabis was playing a form of Russian roulette.

All this was great Daily Mail fodder and it was played for all its worth. COMT provided the scientific basis for presenting Reefer Madness V2 as undeniable fact. As recently as March this year the Daily Mail stated

Previous research has shown that a quarter of the population has a genetic predisposition which makes them ten times more likely to develop psychosis and other schizophrenia-like symptoms after smoking cannabis.

It wasn’t only the Daily Mail, just about every cannabis scare story has been dominated by the COMT claim. The Independent on Sunday comment piece in May this year by Patrick Cockburn warned:

Not everybody taking it is vulnerable to the same degree, but numerous studies show that cannabis can be the precipitating factor for a sizeable minority of the population, perhaps 20 per cent, with a genetic predisposition to psychosis.

Make no mistake, the COMT gene theory has been used to great effect by the prohibition campaign to fight against cannabis law reform. However, the results of Stan Zammit’s latest work, which set out to examine this claimed link are quite clear:

There was no evidence of an interaction under multiplicative models between cannabis use and COMT on the risk of developing psychotic experiences in our primary analyses. In sensitivity analyses we observed highly variable evidence of interaction, whereby psychotomimetic effects of cannabis were greater in methionine homozygotes under some scenarios, but in valine homozygotes under others.

And in a puff the COMT gene scare is gone… Apologies for the flippant sounding comment, but that is what has happened with the study from Stan Zammit and associates, it is a big blow to the reefer madness hype.

So what of their very scary sounding comments regarding cannabis and psychosis which come in the conclusions of this study? Just how much of a danger does Stan Zammit think cannabis represents in terms of psychosis? In a paper published in 2009 entitled “If cannabis caused schizophrenia—how many cannabis users may need to be prevented in order to prevent one case of schizophrenia England and Wales calculations” (abstract here – again it’s behind a paywall and if it comes up with some kind of error, do a search for “cannabis psychosis” with “zammit” as the author) he concluded that if cannabis did cause schizophrenia – itself an assumption – then to prevent just one case in adults over 20 or so, we would have to prevent around 3,000 heavy cannabis users, or 150,000 light users. So to be honest the risk isn’t very high at all, and now, it seems, it isn’t concentrated in a sub-group of genetically vulnerable people either.

Most importantly the failure of the COMT gene theory means there isn’t a sub group of people at especially high risk from cannabis. The risk for adults is, in truth very, very low – if it exists at all.

Now of course there is still an issue with kids using cannabis for reasons unconnected with faulty genes and there is a very good case to be made for a properly regulated regime for commercial cannabis sales that would include age limits. As Stan Zammit concluded in his 2009 paper

More attention should be given to testing the hypothesis that cannabis is related causally to psychotic outcomes, and to considering what strategies will be the most effective in reducing heavy cannabis use among young people.

It’s hard to see how spending vast amounts of money preventing adults from using cannabis is going to do that and one of the key arguments used to defend doing so has been blown away.