Don't Put That in Your Pipe and Smoke It!

Compared to heroin and cocaine, many people--scientists and teenagers alike--consider marijuana a relatively benign substance. Two new studies in tomorrow's issue of Science* demonstrate, however, that marijuana's effects on the brain are disturbingly similar to those produced by highly addictive drugs. The findings may help scientists devise better strategies for treating marijuana dependence, for which some 100,000 people in the United States alone seek therapy each year.

After previously linking a brain peptide called corticotropin-releasing factor (CRF) to anxiety and stress in people withdrawing from alcohol, cocaine, and opiates, a team of researchers from The Scripps Research Institute in La Jolla, California, along with two visiting scientists from Complutense University of Madrid in Spain, set out to investigate whether CRF might mediate the stressful malaise that some long-term marijuana users experience after quitting.

The active ingredient in marijuana is a cannabinoid known as THC. The researchers injected a synthetic version of the compound into more than 50 rats once a day for 2 weeks to mimic the effects of heavy, long-term marijuana use in people. The researchers produced a dramatic withdrawal syndrome by injecting the rats with a newly developed drug that counteracts THC. The group found the rats' anxiety levels, as measured in a standard behavioral test, shot up, and they displayed exaggerated signs of stress such as compulsive grooming and teeth chattering during withdrawal. What's more, when the scientists measured CRF levels in the rats' brains, they found that rats in withdrawal had two to three times more CRF than controls not given the antagonist.

The results, experts say, provide the first neurochemical basis for a marijuana withdrawal syndrome, and one with a strong emotional component that is shared by other abused drugs. "The work suggests that the CRF system may be a part of a common experience in withdrawal--that is, anxiety," says Alan Leshner, director of the National Institute on Drug Abuse.

But withdrawal is just one component of addiction. Addictive drugs also have immediate rewarding, or reinforcing, effects that keep people and animals coming back for more. The drugs produce these effects, scientists believe, by stimulating the brain's so-called reward system. A key event in the reward pathway is the release of dopamine by a small cluster of neurons in a brain region called the nucleus accumbens. When Gaetano Di Chiara and colleagues at the University of Cagliari in Italy infused THC into a small group of rats, they found that dopamine levels in the nucleus accumbens jumped to double those in control rats infused with an inactive cannabinoid--a surge similar to that seen with heroin.

The studies "send a powerful message that should raise everyone's awareness about the dangers of marijuana use," says David Friedman, a neurobiologist at Bowman Gray School of Medicine in Winston-Salem, North Carolina. But they also suggest avenues for treating marijuana dependence: For instance, chemicals that block the effects of CRF or even relaxation exercises might soothe the miserable moods experienced by people in THC withdrawal.

* For more details, Science Online subscribers can link to the full text of the Tanda and Rodr'guez de Fonseca Reports.

Posted in Brain & Behavior