As far as marijuana is concerned, most of the attention has recently focused on the start of commercial sales of the drug. But this week, the mediator of pot's mind-altering effects, the chemical THC, also graced the pages of Science, and not simply because it's easier to obtain in Colorado. As with many other illicit drugs, THC can be used to tell us about how the brain works. And, in this case, it has identified an entirely new bit of signaling that normally helps limit the drug's intoxicating effects.

The study came about because some scientists were curious as to whether drugs altered steroid signaling in the brain. We tend to think of steroids as muscle-building molecules, but things like testosterone also affect behavior in both men and women. And the brain also produces a specialized set of hormones that regulate behavior and cognition.

So, to find out whether drug use altered the brain's steroid signaling, a large international team of researchers started feeding a variety of drugs to mice and rats: cocaine, morphine, nicotine, alcohol—and THC. They then looked at whether a variety of steroids in the brain had altered concentrations. Just about every drug caused some changes, but most of these were relatively minor. In contrast, one steroid, pregnenolone, went up by 3,000 percent.

That's a somewhat surprising result, given that pregnenolone isn't thought to be very exciting. As far as anyone knew, it was a precursor that enzymes modified into a number of different active steroids, but pregnenolone itself didn't seem to do anything. Yet tests with several chemicals that also activate the cannabinoid receptor that THC binds to showed that all of them boosted the level of pregnenolone. And the authors showed that activating the cannabinoid receptor boosted the levels of the enzyme that synthesizes the steroid.

To find out whether pregnenolone might have a previously unidentified function, the team obtained a chemical that blocked its synthesis. Then the researchers injected it along with THC and tested the animals for what they termed the "cannabinoid tetrad": slow movement, poor regulation of body temperature, reduced sensitivity to pain, and catalepsy (a specific type of loss of consciousness). They also tested for symptoms normally seen in humans, like memory loss and the munchies.

Normally, you'd expect (or at least I'd expect) that a signaling molecule induced by a drug might mediate a subset of its effects. So, injecting an inhibitor that blocked the signaling should selectively eliminate some of those effects—stopping the munchies while leaving animals lethargic and indifferent to pain. Instead, the exact opposite occurred. The inhibitor of pregnenolone synthesis enhanced every single one of the effects the authors tested. Thus, animals without the hormone seem to respond to THC even more strongly than they normally do.

The authors conclude that pregnenolone actually binds to the cannabinoid receptor that THC activates and, in doing so, inhibits its activity. Thus, it appears that the active ingredient in pot creates a feedback loop that limits its effects: THC increases pregnenolone, which in turn blocks the response to THC. These sorts of feedback loops aren't uncommon and tend to be used to keep a signaling event from causing an excessive response. It also suggests that the intoxicating effects of marijuana would be even stronger if it weren't for this bit of brain chemistry.

The authors suggest that the hormone could have a role in treating anyone who became dependent upon THC. But, until any side effects are characterized, it's probably not a good idea to try to use this to sober up before driving.

Science, 2013. DOI: 10.1126/science.1243985 (About DOIs).