As with most decision points around pregnancy, cannabis use is a fraught subject. Researchers can’t assess it in randomized trials because dosing pregnant people with the psychoactive substance is unethical. The next best thing is studies with enough participants who use cannabis on their own, allowing for comparisons with those who do not.

The findings of one such study, published on November 15 in the Proceedings of the National Academy of Sciences USA, highlight symptoms of increased anxiety, hyperactivity and aggression in children whose parents used cannabis during pregnancy. And its analysis of placental tissue points to changes in the activity of immunity-related genes.

Today pregnant people “are being bombarded with a lot of ads to treat nausea and anxiety during pregnancy” with cannabis, says the paper’s senior author Yasmin Hurd, director of the Addiction Institute at Mount Sinai. “Our studies are about empowering them with knowledge and education so that they can make decisions.”

The results are “very striking, very much a first,” says Daniele Piomelli, a professor and director of the Center for the Study of Cannabis at the University of California, Irvine, who was not involved in the work. Pregnancy studies in rodents and even in sheep, which have a placenta more like ours, have required cautious interpretations of findings that show effects on offspring behavior and function, he says. The new study is one of the first to tackle the question in people “in a systematic way,” Piomelli adds.

Hurd and her colleagues worked with 322 parent-child pairs, beginning with profiles of genetic activity in placental samples taken at birth. When the children reached about three years of age, samples of their hair were tested for levels of stress hormones. From ages three to six, they also underwent recordings of their heart-rate variability, another indicator of stress response, and evaluations for anxiety, aggression and hyperactivity. The researchers used statistical methods to exclude effects from cigarette smoking, parental anxiety and other factors that could confuse associations with cannabis use.

In the placental tissues, gene activity was altered with cannabis exposure during pregnancy: genes related to the inflammatory response showed decreased function. Anxiety and hyperactivity levels were higher in children from cannabis-exposed pregnancies and were associated with the placental gene patterns. The researchers speculate that a decline in the activity of immune-related genes in the placenta might explain the behavioral findings.

“We always have to interpret human studies with a grain of salt,” Piomelli says, because factors other than cannabis could still be the true cause of the behavioral outcomes, including experiences after birth. Although the researchers in this study “did a really good job” of controlling for these factors, he says, “there is only so much one can do.”

Anxiety is an example of a potential confounding factor, says Mitch Earleywine, a professor of psychology at the University at Albany, State University of New York, who was not involved in the study. Anxiety has some genetic underpinning, which parents can pass to children. For this reason, he says, “I’m not sure that cannabis is really the issue” instead of genetics. Earleywine is also an advisory board member of the National Organization for the Reform of Marijuana Laws (NORML), which advocates for the legalization of cannabis.

Hurd agrees that human studies will always involve elements that can muddy the findings. “Yes, genetics plays a role, maternal anxiety plays a role, their postnatal environment plays a role,” she says. But even with all of that, the associations her group found with cannabis are results that “I don’t think we can ignore.”

For parents who used cannabis during pregnancy and find these results potentially unsettling, “the human organism is very resilient,” Piomelli says. “Appropriate care and love and attention to your kid can certainly reduce any potential harm.” Hurd says that one strategy to reduce harm is to be alert to signs of anxiety or hyperactivity in children and get them help right away.