A recent study published in Molecular Psychiatry provides evidence that exposure to cannabis during pregnancy may alter the trajectory of brain development in offspring from the fetal stage through adulthood. The findings indicate that high concentrations of the drug can lead to sustained reductions in brain volume and anxiety-like behaviors, particularly in females. This research utilizes advanced imaging techniques in mice to track these developmental changes over time.
Cannabis contains delta-9-tetrahydrocannabinol, commonly referred to as THC. This compound is the primary psychoactive ingredient responsible for the effects associated with the drug. It works by interacting with the endocannabinoid system, a biological network that plays a role in regulating various physiological processes. This system helps guide how the brain grows and organizes itself before birth. It influences essential mechanisms such as the creation of new neurons and the formation of connections between them.
Public perception regarding the safety of cannabis has shifted alongside legal changes in many regions. As the drug becomes more accessible, usage rates among pregnant individuals have increased. Some use it to manage symptoms such as morning sickness, anxiety, or pain. However, modern cannabis products often contain significantly higher concentrations of THC than those available in previous decades.
Medical professionals need to understand how these potent formulations might influence a developing fetus over the long term. Existing data has been limited, often relying on observational studies in humans that cannot fully isolate the effects of the drug from other environmental factors. Most previous research has also looked at the brain at a single point in time rather than following its growth continuously.
“As cannabis is legalized in more countries around the world and U.S. States, it is also increasingly being viewed as natural and safe. More people, including pregnant people, are using cannabis, and the concentration of delta-9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, is increasing too,” said study author Lani Cupo, a postdoctoral researcher at McGill University and member of the Computational Brain Anatomy Laboratory.
“Pregnant people may use cannabis for a variety of reasons, either because they don’t know they are pregnant, to help manage mood changes, or to help treat symptoms associated with early pregnancy, such as nausea and vomiting accompanying morning sickness. People should be able to make their own informed decisions about what they do during pregnancy, but there is still a major gap in the scientific understanding of some of the long-term effects of cannabis exposure during pregnancy on brain development.”
The research team employed a mouse model to simulate prenatal exposure. Pregnant mice received daily injections of THC at a dose of 5 milligrams per kilogram from gestational day 3 to 10. This period corresponds roughly to the first trimester in human pregnancy. The dosage was intended to model moderate-to-heavy use, comparable to consuming high-potency cannabis products daily. A control group of pregnant mice received saline injections to provide a baseline for comparison.
To observe brain development, the scientists used magnetic resonance imaging, or MRI. They scanned the offspring at multiple time points to create a longitudinal dataset. The first set of images came from embryos extracted on gestational day 17. A second cohort of pups underwent scanning on alternate days from postnatal day 3 to 10. A third group was imaged during adolescence and adulthood, specifically on postnatal days 25, 35, 60, and 90. This approach allowed the team to track the growth curves of individual subjects throughout their lives.
Analysis of the embryonic images revealed that exposure to the drug affected physical development in the womb. Embryos exposed to THC had smaller overall body volumes compared to the control group. Despite the smaller body size, their brains showed enlargement in specific areas. The lateral ventricles, which are fluid-filled cavities within the brain, were significantly larger in the THC-exposed group. The corpus callosum, a bundle of nerve fibers connecting the brain’s hemispheres, also appeared larger at this stage.
As the mice entered the neonatal period, the pattern of growth shifted. The THC-exposed pups experienced a period of “catch-up” growth regarding their body weight. However, their brain development followed a different path. The rate of brain growth decelerated compared to the unexposed mice. This slowing of growth affected multiple regions, including the hippocampus, amygdala, and striatum.
By the time the animals reached adulthood, the structural differences remained evident. The reduction in brain volume persisted in regions such as the hippocampus and the hypothalamus. The data indicated a sex-dependent effect in the long-term outcomes. Female mice exposed to THC tended to show more pronounced volume reductions in adulthood compared to males. While male mice did exhibit some volume loss, they showed less severe reductions in specific areas like the cerebellum and olfactory bulbs compared to females.
“I was surprised by the apparent vulnerability in female mice compared to male mice when it came to effects in adulthood,” Cupo told PsyPost. “It is very clear from previous studies that sex as a biological variable is important in considering the impact of prenatal cannabis exposure, but the literature shows mixed results depending on the domain being investigated and the timing of outcomes and exposures.”
“Sometimes males are more impacted, sometimes females are more impacted. I think this highlights how critical it is to consider both biological sex and, in humans, gender, when studying prenatal exposures like cannabis. Unfortunately, some research still ignores this important consideration.”
The researchers also assessed behavior to see if these structural changes corresponded to functional differences. In the neonatal phase, researchers recorded ultrasonic vocalizations when pups were separated from their mothers. These high-frequency sounds serve as a form of communication for the young mice. Female pups exposed to THC produced fewer calls, which the authors suggest could indicate deficits in social communication. Conversely, male pups exposed to THC made more calls, potentially signaling increased anxiety or distress.
Later in adolescence, the mice underwent an open-field test to measure anxiety-like behavior. This test involves placing a mouse in a large box and observing its movement patterns. Animals that are anxious tend to stay near the walls and avoid the open center of the arena. The offspring exposed to THC moved less overall and spent significantly less time in the center of the box. This behavior is interpreted as an anxiety-like phenotype. The results provide evidence that the structural brain changes were accompanied by lasting behavioral alterations.
To investigate the cellular mechanisms behind these changes, the researchers used scanning electron microscopy. They examined brain tissue from the hippocampus at a very high resolution. In the embryonic stage, the THC group showed an increased number of dividing cells. This suggests that the drug might trigger premature cell proliferation. However, in the neonatal stage, they did not find a significant difference in the number of dying cells. This implies that the reduced brain volume observed later was likely not caused by mass cell death but perhaps by altered developmental timing.
“In short, we found that exposure to a high concentration of THC early in pregnancy can affect the brain until adulthood,” Cupo explained. “Specifically, we found larger volume of the ventricles, or fluid-filled cavities within the brain, before birth. Then, as the baby mice aged over the first two weeks of life, the brain of THC-exposed pups showed a decreased growth rate compared to the unexposed controls. This smaller volume was sustained until adulthood, especially in female mice.”
“Further, during adolescence the mice showed anxiety-like behavior. Notably, these results are fairly subtle, but they suggest that the trajectory of brain development itself can be impacted by exposure to cannabis early in pregnancy.”
While this study offers detailed insights into brain development, it relies on a rodent model. Mice and humans share many biological similarities, particularly in the endocannabinoid system, which makes them useful for studying basic developmental processes. However, the complexity of the human brain and environmental influences cannot be fully replicated in animal studies. For instance, the study used injections to deliver the drug, whereas humans typically inhale or ingest cannabis. The metabolism and concentration of the drug in the blood can differ based on the method of administration.
Despite these differences, animal models allow scientists to control variables that are impossible to manage in human research. They permit the isolation of a specific chemical’s effect without the confounding variables of diet, socioeconomic status, or other drug use that often complicate human studies. This specific study provided a level of anatomical detail through longitudinal imaging and microscopy that would be unethical or impossible to perform in living humans. The findings serve as a biological proof of principle that prenatal exposure can alter neurodevelopmental trajectories.
The study also utilized a relatively high dose of THC. While this was intended to mimic heavy usage, it may not reflect the effects of occasional or lower-dose use. Additionally, the study focused on THC in isolation. Commercial cannabis products contain a complex mixture of compounds, including cannabidiol (CBD) and terpenes, which might interact with THC to produce different effects.
“It can be easy to put a lot of pressure or even blame on people who use cannabis during their pregnancies, but the reality of the human experience is complex, especially during what can be such a transitional and tumultuous time,” Cupo said. “Although our results do show long-term impacts of cannabis exposure on brain outcomes, the reality of a human choosing to use cannabis or not is much more nuanced than we can recapitulate in a laboratory setting with rodents as a model.”
“In no way do I think these results should be used to shame or blame pregnant people. Instead I hope they can be seen as part of a bigger picture emerging to help supply pregnant people and their care providers with some useful information.”
Future research aims to address some of the current study’s limitations. The authors suggest investigating different methods of administration, such as vaporized cannabis, to better mimic human usage patterns. They also plan to examine the effects of other cannabinoids, such as CBD.
“We would also like to explore the timing of exposure, for example if it begins before conception, or if the father mouse consumes cannabis before conception,” Cupo added. “We would also like to explore more complex models, such as whether early life environmental enrichment can prevent some of the long-term impacts of cannabis exposure.”
“I would just like to re-emphasize that our study is a small piece of a much larger picture that researchers have been approaching from many different angles.”
The study, “Impact of prenatal delta-9-tetrahydrocannabinol exposure on mouse brain development: a fetal-to-adulthood magnetic resonance imaging study,” was authored by Lani Cupo, Haley A. Vecchiarelli, Daniel Gallino, Jared VanderZwaag, Katerina Bradshaw, Annie Phan, Mohammadparsa Khakpour, Benneth Ben-Azu, Elisa Guma, Jérémie P. Fouquet, Shoshana Spring, Brian J. Nieman, Gabriel A. Devenyi, Marie-Eve Tremblay, and M. Mallar Chakravarty.
