Car wrecks may be the most significant and well-documented adverse health effect of smoking marijuana, as clear evidence that it causes schizophrenia or other health problems is largely missing, a literature review showed.

Overall, "the public health burden of cannabis use is probably modest compared with that of alcohol, tobacco, and other illicit drugs," Australian researchers reported in the Oct. 17 issue of The Lancet.

Wayne Hall, PhD, of the University of Queensland in Herston, Australia, and Louisa Degenhardt, PhD, of the University of New South Wales in Sydney, reviewed nearly 100 studies covering acute as well as chronic effects of marijuana, including reports of the prevalence of marijuana use around the world.

Globally, they wrote, about 3.9% of the world's population used marijuana in 2006, according to United Nations statistics.

These data also indicated wide variation from place to place -- North America, Australia, New Zealand, and many nations in western Europe and southern and western Africa have usage rates above 8%, with much lower prevalence in east Asia and certain Muslim countries.

But the data also suggest that marijuana use is stable or falling in nations with high prevalence in the past, while in China, eastern Europe, sub-Saharan Africa, and South America cannabis consumption is increasing.

Hall and Degenhardt said the most common acute effects of cannabis intake are anxiety, panic reactions, and psychotic symptoms, primarily in individuals using the substance for the first time. But the authors moved on to other topics after this assertion and cited no primary sources for it.

They spent more time detailing the psychomotor impairments associated with the marijuana high. "Some experimental studies have shown diminished driving performance in response to emergency situations," Hall and Degenhardt said, findings also corroborated in epidemiological studies.

For example, one study of car crash victims found that they were more likely to have tetrahydrocannabinol (THC), the main psychoactive component of marijuana, in their blood compared with age- and sex-matched controls.

Another study determined that motorists killed in wrecks were 2.5 times as likely to have been responsible for the accident when they had THC in their blood.

On the other hand, it appears that the impairments are less severe than those associated with alcohol, the review authors said, "because cannabis-affected people drive more slowly and take fewer risks."

Few somatic effects of chronic use have been documented, Hall and Degenhardt found, except for several case-control studies suggesting promotion of lung cancer. Also, THC increases heart rate in a dose-dependent way, perhaps increasing risks for people with preexisting cardiovascular disease.

Two studies have indicated that individuals with a history of myocardial infarction were at increased risk for second events or death when they used marijuana, the authors said.

Cognitive effects while high are, of course, well recognized, but their persistence is less clear, Hall and Degenhardt said. Some studies say cognitive impairment remains in chronic heavy users even after they quit, but others indicate that recovery of function is the rule.

Cannabis use has been linked by numerous studies with adverse psychosocial effects including poor school performance and increased likelihood of unemployment, the authors said. But causality has never been proven, they pointed out.

"Whether cannabis use is a contributory cause of poor school performance, is a consequence of poor educational attainment, or poor educational attainment is the result of common factors is unclear," they wrote.

Similar uncertainty clouds the research on whether marijuana fosters use of other, arguably more dangerous, drugs such as cocaine and heroin, the researchers said. People who use marijuana are more likely to use other illicit drugs as well, but causality has been difficult to prove.

Marijuana use has also been linked to increased risk of psychiatric disorders including schizophrenia and, less consistently, depression.

Hall and Degenhardt appeared to be persuaded that the association with schizophrenia is real, citing a series of longitudinal studies that found frequency of marijuana use was correlated with later diagnosis of schizophrenia.

"A meta-analysis [published in The Lancet in 2007] of these longitudinal studies reported a pooled odds ratio of 1.4 (95% CI 1.20 to 1.65) of psychotic symptoms or psychotic disorders in those who had ever used cannabis," Hall and Degenhardt wrote. "Risk of psychotic symptoms or disorders was higher in regular users than in nonusers (OR 2.09, 95% CI 1.54 to 2.84)."

On the other hand, they conceded that a causal relationship remained uncertain. "Evidence is conflicting on whether incidence of schizophrenia increases as cannabis use increases in young adults, as would be expected if the association was causal," they said.

Donald Abrams, MD, chief of hematology-oncology at San Francisco General Hospital, told MedPage Today that the causal direction could actually point the other way.

"One hypothesis suggests that adolescents with schizophrenic tendencies find that cannabis improves their thought disorder and hence tend to be more likely to use cannabis to self-medicate," Abrams, a well-known HIV researcher who has also studied medical uses of marijuana, said in an e-mail.

"Hence, use does not lead to schizophrenia but is associated with amelioration of symptoms," Abrams said.

He also scoffed at the evidence -- which Hall and Degenhardt admitted was weak -- linking marijuana use with depression.

Abrams pointed out that a cannabinoid receptor antagonist, rimonabant (Acomplia, Zimulti), was withdrawn from the market because it was associated with increases in depression and suicide.

"It would seem unlikely that the [receptor] agonist would do the same," he said.

Hall and Degenhardt said a few studies had suggested modest and usually temporary developmental deficits in infants born to mothers who used marijuana, but the evidence was weakened by a lack of controls for other drug use, genetic factors, or simply poor parenting.

Overall, they concluded that marijuana is clearly associated with negative health and psychosocial consequences, but these are not as major as for some other drugs, and the causal relations remain unproven.

"The focus of epidemiological and clinical research should be on clarifying the causative role of cannabis for these adverse health effects," the authors said.

They also cited a recent study estimating that marijuana accounted for about 0.2% of the total disease burden in Australia, a nation with one of the world's highest rates of cannabis use. Its health impact was one-tenth that of alcohol and one-fortieth that of tobacco, the study found.

Abrams called their review balanced on the whole. Hall and Degenhardt, he said, "provide tempering comments in their interpretation of the data that allows for uncertainties that still exist."

But he cautioned against relying exclusively on published studies. "There is a publication bias, in my opinion, towards easier publication of reports of the harmful effects of cannabis" compared with studies finding no adverse consequences, he suggested.