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Todd Gould’s lab members couldn’t replicate their experiments. As New Scientist reports, they got different results when testing the antidepressant effects of ketamine in mice depending on which members of the lab conducted the experiment, which involved measuring how long the mice would swim when placed in a tank. Gould, a psychiatry researcher at the University of Maryland School of Medicine, had read a 2014 study that found the presence of men, but not women, dulls mice’s pain, and according to a university news release, his team also heard anecdotes from other labs about experimental results that seemed to be influenced by researcher sex. So they decided to test whether this could explain the inconsistencies they saw. 

The team reported in an August 30 Nature Neuroscience paper that the sex of researchers working with mice did indeed influence outcomes involving ketamine treatment, with the scent of human males triggering the release of a hormone in mice’s brains that enabled the drug to work as an antidepressant. The findings suggest that researcher sex may confound animal research in a variety of experiments—but the team says the work could also point the way toward making antidepressant treatments more effective in humans. 

“Our findings in mice suggests that activating a specific stress circuit in the brain may be a way to improve ketamine treatment,” Gould says in the university announcement. “Our thought is that you may be able to provide a more robust antidepressant effect if you combine the ketamine with activation of this brain region, either a drug that spurs this process in the brain or even some sort of specific stressor.” 

The team confirmed the effect of sex by conducting experiments in which either male or female researchers injected ketamine into the mice, and by testing the animals’ responses to T-shirts and cotton swabs infused with human male or female scent (they were drawn to the materials with female scent but avoided the male-scented items). The researchers also delved into the mechanisms behind that effect, and found that when men administered ketamine to the mice, a hormone called corticotropin-releasing factor (CRF) was released in an area of the mouse hippocampus associated with depression, enabling the ketamine’s antidepressant effect. This didn’t happen when women administered the drug unless they accompanied the ketamine with a dose of CRF. 

“We think that some people may have higher or lower levels of CRF, and we believe that people [who] do not respond well to ketamine antidepressant therapy might respond if we could administer the treatment with some CRF-related chemical that could induce ketamine’s effects,” study coauthor Polymnia Georgiou, a former postdoc in Gould’s lab, says in the university announcement. “Alternatively, we typically see the antidepressant effects of ketamine lasting 1-3 days, but with CRF administration, it is possible that we may be able to extend the effects to last longer with CRF.” 

Beyond the effects of ketamine itself, “What it suggests is that every experiment that’s ever been done with male experimenters has happened with the mice in a different state than experiments that have been done with female experimenters,” Jeffrey Mogil of McGill University in Canada tells New Scientist. Mogil was not involved in the current study but was a coauthor on the 2014 study showing that researcher sex affected mouse pain. 

Gerlinde Metz of the University of Lethbridge in Canada, who was also not involved in the new study, tells New Scientist that researcher sex is just one of many variables that can affect animal experiments; others include their shipment to the lab, diet, and even the season. She says researchers should try to control for the effects of these variables as best they can, although it may be impossible to do so completely. 

The influence of researcher sex on experimental outcomes is “something that we’ve all been ignoring completely because no one thought it was even remotely possible that it could matter,” Mogil tells New Scientist. “But it does.”