Researchers are offering new ammunition to worried parents trying to dissuade their teens from smoking marijuana: Evidence is mounting that for some adolescents whose genes put them at added risk, heavy marijuana use could increase the chances of developing severe mental illness -- psychosis or schizophrenia.
This week, the marijuana-psychosis link gained ground when two major medical journals reviewed the research to date and concluded that it was persuasive. In PLOS Medicine, an Australian public health policy specialist wrote that genetically vulnerable teens who smoke marijuana more than once a week ''appear at greater risk of psychosis," while the British medical journal BMJ cited estimates that marijuana use could contribute to about 10 percent of cases of psychosis.
The new research has little hint of ''Reefer Madness" alarmism. Rather, a half-dozen long, careful studies published in the last several years have tried to determine whether marijuana-smoking is a cause rather than an effect of mental illness. And groundbreaking research has begun to try to pinpoint which genes and brain chemicals could do the damage.
The conclusions remain controversial, in part because it would be unethical to randomly assign teens to smoke or not smoke marijuana -- which would be necessary to perform a gold-standard study to definitively show that adolescent marijuana use causes mental illness. It could be the other way around, or some other factor could put teens at risk of both.
But the recent research has attempted to get around these hurdles by controlling for factors such as the presence of psychosis before the use of marijuana, family income, education, other drug use, and childhood traumas.
''No single study is perfect," Wayne Hall, author of the PLOS Medicine essay and a professor at the University of Queensland, said in an e-mail interview. ''But the fact that so many individually imperfect studies so consistently find this relationship adds confidence to the conclusion that the relationship is causal."
The recent research points to adolescence as a particularly risky time to smoke marijuana heavily for those genetically predisposed to mental illness. Brain scientists theorize that marijuana may induce temporary changes in brain chemistry that, when reinforced over time, become permanent.
Among the research cited by both papers appearing this week was an intriguing study published last year that followed a group of more than 800 New Zealanders from birth until age 26. The study looked at people with a gene variant that apparently predisposes them to developing psychosis, and people without it. The variant was carried by 25 percent of the study's participants.
The study found that among those with this variant, smoking marijuana as teens increased their risk of psychosis in young adulthood nearly tenfold compared with those who did not smoke as teens. Those who smoked marijuana but did not have the gene variant incurred little or no added risk.
No test of such gene variants is widely available. Dr. Robin Murray, a psychiatry professor at Kings College London and an author of the New Zealand paper, said he and other researchers like to joke that they should set up a DNA-test tent at rock concerts and tell customers whether it is safe to get stoned. In reality, however, the gene research is at too early and tentative a stage to justify offering a test, he said.
Other studies cited in the BMJ article found that teens and young adults who smoked marijuana had roughly double the risk of later developing psychotic symptoms, but these studies did not distinguish between carriers and noncarriers of the gene variant.
Still, even among marijuana smokers, the absolute risk of developing schizophrenia was low, Murray said -- about 2 percent. And the added risk from smoking marijuana was small compared to, say, cigarette smoking, which multiplies a person's chances of lung cancer by 15, he noted.
Overall, schizophrenia affects about one in every 100 people, and two more in every 100 experience a lesser form of psychosis.
This week's PLOS Medicine essay suggests that teens should be considered vulnerable if they have psychosis in the family, an indication their genes may predispose them to it, or have had ''unusual psychological experiences after using cannabis."
In recent months, the White House has emphasized a causal link between marijuana and schizophrenia as part of an antimarijuana campaign, but the National Institute on Drug Abuse does not list psychosis as a marijuana risk on its informational website.
The evidence for a link is becoming more convincing, said Dr. Wilson Compton, who directs the institute's public health research program. But he said the agency wants ''to make sure we don't overblow" the risk, because that would make teenagers likelier to discount the warnings.
The controversy stems in part from the challenges of the research. Consider a boy who has shown early signs of schizophrenia since childhood, lacking friends and seeking isolation. In his early teens, he starts hanging out with marijuana-smokers, gets increasingly withdrawn, and is finally diagnosed with schizophrenia at 19.
In a case like that, it is likely that the early symptoms of the disease led to the marijuana-smoking rather than vice versa, said Dr. Harrison Pope, director of the Biological Psychiatry Laboratory at Harvard's McLean Hospital.
''I'm not saying the studies are wrong," he said. ''I'm saying this is a caveat you have to bear in mind even when you see six studies all in agreement -- it's very, very difficult in retrospect to tease apart the chain of causality."
But even marijuana advocates allow that there could be a link, at least for a small minority of marijuana smokers.
Marijuana has an excellent safety record when used in moderation by adults, emphasized Paul Armentano, senior policy analyst for the National Organization for the Reform of Marijuana Laws. But ''I would not rule out that heavy use of marijuana at a young age, particularly combined with other drugs, could precede onset of some symptoms of mental illness."
The New Zealand study, published last year in the journal Biological Psychiatry, looked at a gene called COMT, which is involved in the breakdown of dopamine, a chemical known to play a role in psychosis.
Though the researchers found a dramatically higher risk when teenagers with the wrong variant of the gene regularly smoked marijuana, they cautioned that even so, that combination accounted for only one-fifth of the people in the study who became psychotic.
''People who smoke pot don't [automatically] go on to become schizophrenic -- boom boom boom," said Alan Budney, a professor and federally funded addiction researcher at the University of Arkansas for Medical Sciences. ''There's an intricate level of risk factors that don't apply to Tom, Dick, and Harry -- it just applies to, say, Jim."
At least, said Murray of London, he now has better answers for schizophrenic patients who ask, ''Why is it you're telling me that cannabis contributed to my going psychotic when all my mates smoked more than me and nothing ever happened to them?"
Carey Goldberg can be reached at firstname.lastname@example.org