Drugs like psilocybin, the active ingredient in hallucinogenic mushrooms, play all sorts of tricks on the mind. They distort the perception of time, space, and self, and even untether the senses. Some researchers thought these strange effects might result from the drugs overexciting the brain. But the first study to use functional magnetic resonance imaging (fMRI) to examine brain activity in people who've taken psilocybin finds that the drug reduces neural firing in key communication hubs, essentially disconnecting some brain regions from each other.

In Central America and elsewhere, hallucinogenic drugs have been used for centuries in healing and religious ceremonies. Recent years have seen renewed interest in exploiting them to explore the neural basis of spirituality and potentially to treat depression, anxiety, and other mental illnesses. Yet neuroscientists know little about how these compounds act on the brain to cause such intensely altered experiences. Hallucinogenic drugs are tightly regulated, and few previous studies have tried to gauge their effects on the human brain. One study, using positron emission tomography (PET), found that psilocybin increases brain metabolism, especially in the frontal cortex.

In the new work, published this week in the Proceedings of the National Academy of Sciences, researchers led by psychopharmacologists Robin Carhart-Harris and David Nutt of Imperial College London used a different method, fMRI, to scan the brains of 30 people who were under the influence of psilocybin. The tight confines and loud noises of the scanner could be scary for someone on psilocybin, Nutt says. To minimize the chances of anyone having a bad trip, the researchers recruited people who'd taken hallucinogens previously, and they delivered the drug intravenously so that it would have a faster—and shorter—effect than, say, eating magic mushrooms.

The researchers performed two different types of MRI scans, one that measured blood flow throughout the brain and one that determined blood oxygenation, which neuroscientists generally assume is an indicator of neural activity. Contrary to the previous study, the scans showed that psilocybin reduces blood flow and neural activity in several brain regions, including the posterior cingulate cortex and medial prefrontal cortex. The researchers quizzed the volunteers after the psilocybin had worn off and found that people in which these regions were most inhibited tended to report the most intense hallucinatory experiences. Nutt says he's not sure why the findings differ from those of the PET study, but he speculates that it could be due to the different time courses of the injectable drug his team used and the oral tablets used in the other research.

The posterior cingulate and medial prefrontal cortices are hubs in the so-called default mode network, a web of interconnected brain regions that becomes active when people allow their minds to wander. Some researchers have proposed that the default mode network is crucial for introspective thought and even for generating the sense of consciousness, and Nutt thinks the finding that psilocybin inhibits this network could help explain the surreal experiences the drug causes. "What I think is going on is that this network in the brain that pulls together a sense of self becomes less active," he says, "and you get this fragmented or dissipated sense of being."

"It's a very interesting study that raises lots of new questions," says Roland Griffiths, a psychopharmacologist at Johns Hopkins University in Baltimore, Maryland. He says the possibility that the drugs work by interfering with the default mode network is an appealing hypothesis that deserves further investigation.

Nutt and Griffiths are interested in the therapeutic potential of hallucinogenic drugs. Griffiths is involved in a pilot study testing whether psilocybin and psychotherapy can ease end-of-life anxiety in cancer patients. Nutt's group is looking into using the drug to treat depression, and this week in The British Journal of Psychiatry, he and colleagues report that psilocybin can increase neural activity in brain regions related to memory when people recall events from their past. The drug also improved people's ability to access personal memories and related emotions, which the researchers say could be helpful during psychotherapy.