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A Complex Link Between Marijuana and Schizophrenia

A. F. Benvenuto Saturday, July 24, 2010 ,
Since the days of Reefer Madness, scientists have sought to understand the complex connection between marijuana and psychosis. Cannabis can cause short-term psychotic experiences, such as hallucinations and paranoia, even in healthy people, but researchers have also long noted a link between marijuana use and the chronic psychotic disorder, schizophrenia.
Repeatedly, studies have found that people with schizophrenia are about twice as likely to smoke pot as those who are unaffected.
Conversely, data suggest that those who smoke cannabis are twice as likely to develop schizophrenia as nonsmokers. One widely publicized 2007 review of the research even concluded that trying marijuana just once was associated with a 40% increase in risk of schizophrenia and other psychotic disorders. 
But here's the conundrum: while marijuana went from being a secret shared by a small community of hepcats and beatniks in the 1940s and '50s to a rite of passage for some 70% of youth by the turn of the century, rates of schizophrenia in the U.S. have remained flat, or possibly declined. For as long as it has been tracked, schizophrenia has been found to affect about 1% of the population. 
One explanation may be that the two factors are coincidental, not causal: perhaps people who have a genetic susceptibility to schizophrenia also happen to especially enjoy marijuana. Still, some studies suggest that smoking pot can actually trigger the disease earlier in individuals who are predisposed, and yet researchers still aren't seeing increases in the overall schizophrenia rate or decreases in the average age of onset. 
In recent months, new research has explored some of these issues. One study led by Dr. Serge Sevy, an associate professor of psychiatry at the Albert Einstein College of Medicine in New York City, looked at 100 patients between the ages of 16 and 40 with schizophrenia, half of whom smoked marijuana. Sevy and colleagues found that among the marijuana users, 75% had begun smoking before the onset of schizophrenia and that their disease appeared about two years earlier than in those who did not use the drug. But when the researchers controlled for other factors known to influence schizophrenia risk, including gender, education and socioeconomic status, the association between disease onset and marijuana disappeared. 
Gender alone accounted for a large proportion of the risk of early onset in Sevy's study, which included 69 men and 31 women. "Males in general have earlier age of onset of schizophrenia," says Sevy. In men, the disease tends to take hold around age 19, while in women it isn't typically seen until 22 - irrespective of marijuana use. But, typically, teenage boys are four times more likely than girls to be heavy pot smokers, which may create an illusory association between the drug and onset of the disease.
Yet past studies limited to males have found exactly such a link, associating marijuana use with earlier development of full-blown psychosis. And other research has found that ongoing cannabis use increases hospitalizations for psychotic symptoms in schizophrenic patients and decreases social and cognitive functioning. A 2008 review of the data found that relapse and failure to take prescribed medication was consistently associated with cannabis use, although, again, controlling for other factors weakened the link.
One explanation could be that the effects of marijuana vary depending on the genetics of the individual patient's schizophrenia. Marie-Odile Krebs, professor of psychiatry at the National Institute of Health and Medical Research (INSERM) laboratory in France, and her colleagues published a study in June that identified two broad groups of people with schizophrenia who used cannabis: those whose disease was profoundly affected by their drug use and those who were not.
Within Krebs's study population of 190 patients (121 of whom had used cannabis), researchers found a subgroup of 44 whose disease was powerfully affected by the drug. These patients either developed schizophrenia within a month of beginning to smoke pot or saw their existing psychosis severely exacerbated with each successive exposure to the drug. Schizophrenia appeared in these patients nearly three years earlier than in other marijuana-users with the disease.
The key difference between the cannabis-sensitive patients and the nonaffected group was a family history of disease: those in the former group had three times the number of close relatives with psychotic disorders, says Krebs. Further, the sensitive group started smoking pot at a younger age - before age 17, compared with 18 in patients without marijuana sensitivity - and Krebs thinks the early exposure may have critically altered the development of brain receptors affected by marijuana.
These receptors, known as endocannabinoid receptors, affect the action of the brain's dopamine systems, fine-tuning the response of the neurons involved. Although this process is not yet completely understood, changing the way endocannabinoids influence dopamine during development could result in a chronically high level of dopamine in some regions of the brain, which may increase the likelihood of psychotic episodes. Stimulant drugs such as amphetamine and cocaine, which increase the action of the dopamine system, for instance, are known to produce psychotic experiences, while antipsychotic drugs work by blocking the brain's dopamine receptors. 
Given that an estimated 50% of the risk for schizophrenia is attributable to genes and family history, disseminating the results of research like Krebs's could help delay the onset of disease in thousands of people and prevent years of severe disability in those with a family history of schizophrenia. Although the disease itself affects only 1% of the population, about 10% of healthy people have personality features that, when intensified, may characterize schizophrenia - such as paranoia - meaning that the proportion of the population who may be sensitive to marijuana could be larger than expected, Krebs says. 
However, discouraging marijuana use in patients who have schizophrenia or are at high risk of developing it is a complicated task, not least because the drug is extremely popular with this group. Their affinity for the drug may be related to a phenomenon recently described in a study published in the British Journal of Psychiatry: The research tracked the moods of 80 marijuana smokers, 42 of whom had psychotic disorders like schizophrenia. Participants were asked to record their moods at various points over the course of six days, determined by a watch that beeped periodically to signal the volunteers. All participants, not surprisingly, reported feeling happier when they were high, but the mood-lifting effect of marijuana was stronger among smokers with schizophrenia. Unlike people without the disease, schizophrenia patients also reported a reduction in negative feelings after smoking marijuana. "Everyone feels better," explains lead author Cecile Henquet, an assistant professor of psychology and psychiatry at Maastricht University in Holland. "But [schizophrenia] patients also have less anxiety and are less socially withdrawn."
But which is the chicken and which is the egg? In another study by Sevy at Albert Einstein College of Medicine, researchers interviewed adults with schizophrenia (and their families) who smoked marijuana, and found that they reported being better adjusted during childhood than those who did not indulge. It makes sense when you consider the practicalities and social nature of drug use. Being at least somewhat socially connected is necessary to be able to obtain an illegal drug - if you appear too "crazy," people are less likely to befriend you and dealers may be too wary to sell to you. Many people with schizophrenia exhibit odd behavior that puts them at risk for social rejection years before they develop full-blown delusions and hallucinations in adulthood. 
The access issue may also help explain why some studies find better - not worse - cognitive functioning in people with schizophrenia who smoke marijuana. That's what Pamela DeRosse, a research scientist at Long Island's Feinstein Institute for Medical Research, and her colleagues found in a study of 455 people with schizophrenia published in Schizophrenia Research in July. The research showed that patients who smoked marijuana had faster brain processing speed, greater verbal ability and better memory than patients who didn't smoke - not attributes usually associated with being high. "I can't really tell you why they aren't doing worse," says DeRosse. "But in order to go out to even find cannabis, enough to become dependent or abuse it, requires that you be more cognitively intact than the average patient with schizophrenia."
Indeed, many schizophrenia patients who smoke pot smoke enough to become addicted. As Henquet's study showed, the drug's mood-boosting effects appear immediately after smoking, as do some hallucinations, but the bulk of negative marijuana-related effects appear later on, as an increased rate of hallucination that affects patients even when they are not high. This is the exact type of drug effect that raises addiction risk: The user's experience is one of short-term gain associated with the drug, with long-term pain that seems unrelated. "This is what explains why patients with schizophrenia use cannabis for longer and more frequently than controls," says Henquet. "They are apparently more sensitive to the addictive potential than other people."
That marijuana can have such incompatible effects in schizophrenia patients - enhancing mood while exacerbating hallucinations and delusions - is not surprising, when its chemical makeup is considered. One chemical called delta-9 tetrahydocannabinol (THC) is known to cause hallucinations and in high doses can even make healthy people feel paranoid or suffer brief attacks of psychosis. But another component of marijuana called cannabidiol (CBD) has anti-psychotic effects.
Consequently, researchers who study the knotty relationship between drug use and schizophrenia hope that patients may one day benefit from cannabis-derived drugs. The key is to replicate the antipsychotic properties of CBD without triggering the risks carried by THC. But in the meantime, scientists are still trying to identify which patients, based on genes and family history, may be most helped by potential new pharmaceutical drugs and who may be spared harm by avoiding illicit drug use now.


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