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A new study reports that a diet rich in omega-3 fatty acids during pregnancy can prevent some of the lasting neuropsychiatric effects of prenatal THC exposure in rats. The findings, published in Molecular Psychiatry, suggest these protective effects are much more pronounced in male offspring, highlighting a significant sex-based difference in the outcomes.
The rationale behind the investigation stems from the increasing use of cannabis during pregnancy, coupled with a public perception that it is relatively safe. Scientific evidence, however, suggests that prenatal exposure to THC, the main psychoactive component in cannabis, can pose risks to a developing fetus. THC can cross the placenta and directly affect the fetal brain, interfering with the endocannabinoid system, a complex network of signals that helps guide proper brain formation.
This natural signaling system is built from fatty acids, which are lipids. The authors behind the new study hypothesized that since THC disrupts this lipid-based system, a dietary intervention focused on beneficial lipids like omega-3 fatty acids might offer a protective effect. Omega-3s are known to be fundamental for building healthy brain cells and circuits, making them a logical candidate for counteracting some of THC’s disruptive influence.
“Cannabis use during pregnancy is rising and there are misperceptions about its safety for the developing fetal brain. There is also a big knowledge gap about how prenatal cannabis use can impact critical brain developmental systems like the omega-3 fatty acid pathway, which is critical for healthy brain development and mental health outcomes,” said study author Steven R. Laviolette, a professor and director of the Addiction Research Group at the University of Western Ontario.
To explore this, the research team used a rat model. Pregnant rats were divided into four groups. Two groups received a standard control diet, and two received a diet enriched with omega-3 fatty acids. Within each dietary group, half of the dams were given daily injections of THC during gestation, while the other half received a harmless vehicle injection. This created four experimental conditions for the offspring: a control group, a group exposed only to omega-3s, a group exposed only to THC, and a group exposed to both THC and the omega-3 diet.
The researchers then followed the offspring into adulthood, conducting a comprehensive series of tests to assess their behavior, brain function, and brain chemistry. The first observation was related to birth weight. Offspring exposed to THC had significantly lower birth weights, but this effect was prevented in the pups whose mothers were on the omega-3 diet.
Behavioral testing in adulthood revealed clear, sex-specific outcomes. Males exposed to THC showed heightened anxiety-like behaviors in various tests. This anxiety was absent in the THC-exposed males that also received the omega-3 diet, suggesting the diet had a preventative effect. Females did not show the same anxiety-like behaviors from THC exposure.
The researchers also examined cognitive function through tests of social interaction, spatial working memory, and the ability to recognize objects in a specific order. In these tasks, prenatal THC exposure led to deficits in both male and female offspring. The omega-3 diet successfully prevented these cognitive problems in males. For females, the benefits were limited; the diet helped restore social motivation but did not improve their performance on the other memory tasks.
“We were surprised by 1) how severe the THC-induced abnormalities in omega-3-6 levels were in the brain and 2) how males and female offspring were differentially impacted by these effects, demonstrating that male vs. female offspring show differential sensitivity to maternal cannabis exposure,” Laviolette told PsyPost.
To understand the brain activity behind these behaviors, the team recorded electrical signals from neurons in three interconnected brain regions: the prefrontal cortex, the nucleus accumbens, and the hippocampus. They found that THC altered the normal firing patterns of brain cells differently in males and females. In the prefrontal cortex, THC caused hyperactivity in both sexes. The omega-3 diet restored normal activity in males but was less effective in females.
In the hippocampus, a region important for memory and mood, THC had opposite effects on activity in the two sexes. It made neurons in males underactive, while making neurons in females overactive. The omega-3 diet successfully corrected this imbalance in both sexes, returning neuronal activity to normal levels. The communication patterns between brain regions, which rely on coordinated rhythmic electrical waves, were also disrupted by THC. Again, the omega-3 diet helped normalize these communication rhythms more effectively in males than in females.
The deepest level of analysis looked at the molecular makeup of the brain, focusing on the lipids and proteins that are the building blocks of brain function. The results here were particularly revealing. THC exposure caused widespread disruptions in the balance of fatty acids and other lipid molecules in all three brain regions studied.
Even in the males whose behavior and brain activity appeared to be normalized by the omega-3 diet, these fundamental lipid imbalances persisted into adulthood. This suggests that while the dietary intervention could prevent outward symptoms, it did not completely fix the underlying chemical disruption caused by THC.
“While our dietary intervention prevented some of the negative impacts of fetal cannabis exposure, it did not fully restore normal fatty acid levels in the brain,” Laviolette said. “Thus, further research is needed to determine the precise balance of omega-3 (e.g. DHA vs. EPA) in order to block these negative outcomes.”
“Our findings are not to suggest that adding omega-3 supplements during pregnancy can prevent the negative effects of maternal cannabis exposure. Cannabis use during pregnancy is always dangerous and can have unintended negative effects on the developing child’s brain.”
Similarly, THC altered the levels of important proteins involved in brain cell communication and structure. The omega-3 diet helped correct many of these protein changes in males, but the effects were far less consistent in females. The findings collectively point to a scenario where the omega-3 diet provides a substantial buffering effect against THC-induced damage in the male brain, but the female brain seems to respond very differently to both the initial THC exposure and the dietary intervention.
“The major finding is that we found that exposure to THC during fetal brain development can strongly disrupt the normal balance between the omega-3 and omega-6 fatty acid pathways in the developing brain,” Laviolette explained. “These pathways need to be balanced in order to control processes like inflammation and oxidative stress, which are linked to increased risk for many cognitive and psychiatric problems in children.”
“We found that if we intervened with a high omega-3 dietary intervention during pregnancy, we were able to prevent many of the negative outcomes from maternal cannabis use. Importantly, this is not to suggest that taking omega-3 along with cannabis is a safer option, rather, it demonstrates that cannabis can strongly interfere with the developing brains normal balance of the omega-3-6 signaling pathways and that it would be necessary to restore healthy omega-3 fatty acid levels to block some of these dangerous side-effects of maternal cannabis use.”
“We also found that maternal cannabis use impacts three major brain areas, the hippocampus, prefrontal cortex and striatum, all of which had disruptions in normal fatty acid signaling levels and male and female offspring showed cognitive deficits in later life that were associated with pathology in these brain areas,” Laviolette said.
The study has some limitations. The research was conducted in rats, and while these models are informative for understanding basic neurobiology, the findings do not automatically translate to humans. The specific mechanisms, such as the diet’s effect on inflammation in the placenta, were not directly measured and require more investigation.
Looking ahead, researchers plan to further explore the biological reasons for the profound differences between male and female responses. They also hope to investigate whether providing omega-3 supplementation later in life, such as during childhood or adolescence, could help reverse or prevent problems that emerge long after birth.
The study, “Perinatal omega-3 sex-selectively mitigates neuropsychiatric impacts of prenatal THC in the cortico-striatal-hippocampal circuit,” was authored by Mohammed H. Sarikahya, Samantha L. Cousineau, Marta De Felice, Hanna J. Szkudlarek, Kendrick Lee, Aleksandra Doktor, Amanda Alcaide, Marieka V. DeVuono, Anubha Dembla, Karen Wong, Mathanke Balarajah, Sebastian Vanin, Miray Youssef, Kuralay Zhaksylyk, Madeline Machado, Haseeb Mahmood, Susanne Schmid, Ken K.-C. Yeung, Daniel B. Hardy, Walter Rushlow & Steven R. Laviolette.
