Scientists at Indiana University have found that significant amounts of the two main components of cannabis, THC and CBD, enter the embryonic brain of mice in utero and impair the mice's ability as adults to respond to fluoxetine, a drug commonly used to treat anxiety and depression and known by the brand name Prozac.

The study suggests that when the developing brain is exposed to THC or CBD, normal interactions between endocannabinoid and serotonin signaling may be diminished as they become adults.

"Hemp-derived CBD is a legal substance in the U.S., and we are in a time of increasing state-level legalization of cannabis. Therefore, use of cannabis components have increased across most levels of society, including among pregnant women," said Hui-Chen Lu, author of the study, director of the Linda and Jack Gill Center and a professor in the Department of Psychological and Brain Sciences in the IU Bloomington College of Arts and Sciences. "The study marks the beginning of an effort to understand the effects of THC and CBD on the endogenous cannabinoid system in the developing brain and body."

The study was published in Cannabis and Cannabinoid Research and will be a part of the upcoming 2021 Gill Symposium, which will focus exclusively on the topic of cannabis.

Researchers studied four groups of pregnant mice. Some received daily moderate doses of either THC, CBD, or a combination of equal parts THC and CBD; a control group was given placebo injections throughout pregnancy. Using mass spectrometry, IU psychological and brain sciences professor Heather Bradshaw tested embryos and found that CBD and THC both could reach the embryonic brain, determining that the drug was making it past the placenta.

"The surprising part is that maternal exposure to CBD alone—a drug that is often considered as safe and harmless and is a popular 'natural' therapy for morning sickness—resulted in a lasting impact on adult mice offspring," Lu said. "Both prenatal THC and CBD exposure impaired the adult's ability to respond to fluoxetine. The results suggest taking a cautious approach to using CBD during pregnancy."

There is some evidence for CBD's effectiveness in treating chronic pain and anxiety, though the only FDA-approved indication for CBD to date is the treatment of severe seizure disorders.

"We still know very little about the effects of CBD on the developing brain," Lu said.

The new paper is one of the first studies to see the potential negative impact of CBD on the developing brain and later behaviors.

Study co-author Ken Mackie, Gill Chair of Neuroscience at IU Bloomington, said researchers know that prenatal cannabis exposure may increase the risk for anxiety and depression, so it is important to evaluate the response to a class of drug used to treat anxiety and depression.

While many of the tests reflected normal mouse behaviors, one test—to determine their response to stress—stood out strongly as atypical. The mice in all groups responded normally to a stressful situation. As expected, fluoxetine increased stress resilience in mice whose mothers had received the placebo. However, the drug was ineffective in mice whose mothers had received THC, CBD or their combination.

Fluoxetine works by increasing the amount of serotonin available at brain synapses, an effect known to require the endocannabinoid system. This internal system of receptors, enzymes and molecules both mediates the effects of cannabis and plays a role in regulating various bodily systems, such as appetite, mood, stress and chronic pain.

To test if maternal exposure to THC and/or CBD impaired endocannabinoid signaling in the adult offspring, the researchers tested whether giving a drug to boost the endocannabinoid system would restore fluoxetine's effectiveness. They found that enhancing the endocannabinoid system restored normal fluoxetine responses in mice that had received THC or CBD while their brains were developing.

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