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Ecstasy in a crystal form contained within a capsule.

Crystals of the psychedelic drug MDMA, also called ecstasy, which restores the ability of mice to learn from certain aspects of their environment.Credit: Police Scotland/Contraband Collection/Alamy

Psychedelic drugs are promising treatments for many mental-health conditions, but researchers don’t fully understand why they have such powerful therapeutic effects. Now, a study in mice suggests that psychedelics all work in the same way: they reset the brain to a youthful state in which it can easily absorb new information and form crucial connections between neurons1.

The findings raise the prospect that psychedelic drugs could allow long-term changes in many types of behavioural, learning and sensory system that are disrupted in mental-health conditions. But scientists caution that more research needs to be done to establish how the drugs remodel brain connections.

The study was published on 14 June in Nature.

Short trip, long benefits

Psychedelics such as MDMA (also known as ecstasy), ketamine and psilocybin — the active ingredient in magic mushrooms — are known for producing mind-altering effects, including hallucinations in some cases. But each compound affects a different biochemical pathway in the brain during the short-term ‘trip’, leaving scientists to wonder why so many of these drugs share the ability to relieve depression2, addiction and other difficult-to-treat conditions in the long term.

Gül Dölen, a neuroscientist at Johns Hopkins University in Baltimore, Maryland, and her colleagues sought answers by studying how psychedelics affect social behaviour in mice. Mice can learn to associate socializing with positive feelings, but only during an adolescent ‘critical period’, which closes as they become adults.

The scientists trained mice to associate one ‘bedroom’ in their enclosure with mousy friends and another room with solitude. They could then examine how psychedelics affected the rodents’ room choices — a proxy for whether the drug affects the critical period.

Sociable mice

Dölen’s team had previously found3 that giving MDMA to adult mice in the company of other mice reopened the critical period, making the MDMA-treated animals more likely to sleep in the social room than were untreated mice. This was not surprising: MDMA is well known for promoting bonding in some animals and in humans.

For their new paper, the researchers gave adult mice either MDMA or one of four psychedelic drugs not known to promote sociability: ibogaine, LSD, ketamine and psilocybin. Mice that received any of the psychedelic drugs were more likely to choose the social room than untreated mice, suggesting that each of the drugs could reopen the critical period.

But mice did not prefer the social room if given enough ketamine to make them unconscious and therefore unaware of their companions. This suggests that the drugs only open the social critical period if they are taken in a social context. Each drug opened the critical period for a different length of time, ranging from one week for ketamine to more than four weeks for ibogaine.

Next, the team looked at the animals’ brains. They found that in certain brain regions, neurons had become more sensitive to the ‘love hormone’ oxytocin. Dölen suspects that the drugs confer a state called metaplasticity on the neurons, making the cells more responsive to a stimulus such as oxytocin. This state makes them more likely to rewire and form new connections that would indicate the neurons were responding. The neurons also started expressing genes involved in regulating a protein matrix on their surface. Modifying this matrix, Dölen says, could free the neurons’ branches to grow and find new connections.

Drugs that hold the key?

Dölen argues that psychedelics function as a master key that can unlock many kinds of critical period — not just one for sociability — by bestowing metaplasticity on neurons. The end result depends on the context in which the drugs were taken: the level of social engagement, in this case. The results indicate, she says, “that there’s some mechanistic relationship between critical period opening and that altered state of consciousness that’s shared by all psychedelics”.

Takao Hensch, a neurologist at Harvard University in Cambridge, Massachusetts, says the paper is “pioneering” in finding biological mechanisms for how psychedelic drugs work. “It gives hope that [critical periods] are not irreversible and a very careful cellular understanding of psychedelic drugs might hold the key to reopening brain plasticity,” he says. He adds that social behaviour is very complex and that the drugs’ effects should be studied in other brain regions.

David Olson, a biochemist at the University of California, Davis, is sceptical. The drugs, he says, could be changing physical connections between neurons in certain parts of the brain, rather than inducing metaplasticity that makes the neurons more open to influence by environmental stimuli.

Dölen is now testing whether the psychedelic drugs can reopen other types of critical period, including those for the motor system. Reopening it, she says, could lengthen the amount of time that people who have had strokes can benefit from physical therapy, which currently works only in the first few months after a stroke.

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