The preclinical animal study, led by researchers at the University of Maryland School of Medicine, was published in the journal Science Advances. It found that prenatal exposure to THC causes a rewiring of the fetal brain. THC caused certain brain cells, called dopamine neurons, to respond in a hyperactive way, causing a heightened increase in dopamine release. This was accompanied by heightened neuronal responsiveness to cues associated with rewards like a light turning on to indicate that food or an opioid drug was available.

“Doctors are contending with an explosion of cannabis use, and the THC content has quadrupled from what it was a generation ago,” said study corresponding author Joseph Cheer, PhD, a Professor of Neurobiology and Psychiatry at the University of Maryland School of Medicine. “It demonstrates the enduring consequences that prenatal cannabis exposure exerts on the brain’s reward system, which ultimately results in a neurobiological vulnerability to opioid drugs.”

The American College of Obstetricians and Gynecologists recommends that doctors counsel patients on concerns about potential adverse health consequences of continued use of cannabis during pregnancy. Dr. Cheer and others doing research on THC exposure during pregnancy are racing to learn more about the health consequences on developing fetuses to help doctors better counsel their patients on the drug’s effects.

This illustration shows that male animals exposed to THC in the womb experience a greater surge in the “reward-seeking” brain chemical dopamine when exposed to opioid drugs as adolescents compared to those that were never exposed to THC.

To conduct this new study, he and his colleagues found that fetuses exposed to a moderately low dose of THC (equivalent to their mothers smoking one to two joints per day) developed changes in how their reward system functioned, causing them to develop an at-risk phenotype for opioid seeking. Animals previously exposed to THC in utero display a dramatically increased motivation to press a lever that would deliver a dose of opioid drugs compared to those that were not previously exposed to THC.

When THC-exposed animals reached early adulthood, they were more likely to show enhanced opioid-seeking and were more likely to relapse upon opioid-associated environmental cues compared to those animals who were not exposed to THC in the womb. They were also more likely to develop persistent addiction-like behaviors.

In a follow-up experiment, the researchers implanted tiny sensors in the animals’ brains and measured heightened dopamine release, accompanied by activity in neurons that over-represented opioid-related cues, in the rats exhibiting strong addiction-like behaviors.

“These observations support the hypothesis of a hypersensitized ‘wanting’ system that develops in the brain after exposure to THC during prenatal development,” said Dr. Cheer. “Interestingly, we found that this opioid-seeking phenotype occurs significantly more in males compared to females, and we are currently performing research with our colleagues at UMSOM, to determine why this is the case.”

Dr. Cheer’s previous work published in the journal Nature Neuroscience found prenatal exposure to THC makes the brain’s dopamine neurons hyperactive, which may contribute to an increased risk of psychiatric disorders like schizophrenia. His work has been independently verified by three independent laboratories throughout the world.

Along with his colleague Mary Kay Lobo, PhD, Professor of Neurobiology at UMSOM, Dr. Cheer serves as the co-director of the Center for Substance Use in Pregnancy, which is part of UMSOM’s Kahlert Institute for Addiction Medicine. The two are working with a team of researchers to investigate the enduring effects of drug and alcohol exposure in the womb.

“We need to more fully understand the enduring effects of THC exposure in the womb and whether we can reverse some of the deleterious effects through CRISPR-based gene therapies or repurposed drugs,” said UMSOM Dean Mark T. Gladwin, MD, who is the John Z. and Akiko K. Bowers Distinguished Professor and vice president for medical affairs at the University of Maryland, Baltimore. “We also need to provide better advice to pregnant patients, many of whom are using cannabis to help control anxiety because they think this drug is safer for their baby than traditional anti-anxiety medications.”

The study was funded by the National Institute on Drug Abuse (Grant: R01 DA022340) (Grant: K99 DA060209). UMSOM faculty member Miguel A. Lujan, PhD, a research associate in Neurobiology, was the first author of the paper.