With an increasing number of states approving marijuana for medical and recreational use, it’s easy to think of the drug as relatively harmless. So it’s not surprising that marijuana is the most common illicit drug used in pregnancy.
But despite its perceived safety, there’s growing recognition that maternal marijuana use can cause disruptions in placental function and fetal development, which could have long term health consequences.
Nicole Zürcher, PhD
In a recent position paper in ACS Chemical Neuroscience, researchers from Massachusetts General Hospital and Oregon Health & Science University call for new studies in non-human primates (NHPs) to provide evidence-based recommendations on the risks of maternal marijuana use.
“It’s the right time,” says lead author Nicole Zürcher, PhD, an Assistant Professor at the Martinos Center for Biomedical Imaging at Mass General. “Marijuana is becoming increasingly legalized and more easily taken in pregnancy. There is much to be learned about the crucial role of epigenetics in health and disease and we have a tracer that can measure epigenetic enzymes in the brain.”
Dr. Zürcher notes that prenatal marijuana exposure has already been associated with stillbirth, intrauterine growth restriction and fetal and childhood neurodevelopmental consequences. It has recently been associated with an increased risk of autism spectrum disorder (ASD) as well.
Interactions between genes and environmental factors such as nutrition, exposure to illicit substances and maternal stress are known to play a key role in neurodevelopmental disorders such as ASD. But it is not yet clear which environmental factors present the most risk or how the timing of these exposures affect the developing fetus.
“In adults with ASD, the question that always comes up is, ‘What happened early on?’” explains Zürcher. “In psychiatric disorders that have a neurodevelopmental component, it is important to understand how early events can disrupt typical developmental processes and contribute to disease later in life.”
Epigenetics and Substance Use
Epigenetic modulation—changes in the expression of different genes—during fetal development is essential for normal development and cellular differentiation, including the differentiation of mammalian brain cells for healthy brain function.
However, this process can be disrupted by drug exposure, with long-term health implications for the developing fetus. The most highly implicated drugs in this disruptive process so far have been cocaine, opioids and amphetamines.
Marijuana is also cause for concern because its main psychoactive chemical, Δ9 tetrahydrocannabinol, readily crosses the placenta into the fetus and cannabinoid receptors are widely expressed in both the placenta and the fetal brain, the researchers write.
The placenta plays a key role in fetal growth and development, and placental dysfunction can lead to inadequate fetal nutrition and oxygenation, which can negatively impact growth and cognitive development.
Cannabinoid receptors are part of the endocannabinoid system, neurotransmitters that play an important role regulating cellular functions in different tissues and processes in the body.
The endocannabinoid system was first identified for its role in processing the pharmacological effects of marijuana, but it is active in all individuals regardless of marijuana use.
It is believed to play a role in processes such as mood, memory, movement, motor coordination, learning, emotion, addiction-like behavior and others.
Barriers to Objective Assessment
Gathering objective information about the epigenetic effects of maternal marijuana use in humans is challenging from both a practical and scientific standpoint.
On the practical side, researchers are reliant on mothers to self-report marijuana use during pregnancy, which they may be reluctant to do for fear of social or legal implications.
It is also difficult to determine the potency/amount of marijuana used, the frequency of use or if the mother was taking other illicit substances as well.
Plus, the direct effects of maternal marijuana use cannot currently be assessed in utero, given the inaccessibility of the placenta and fetal organs.
After birth, it is more challenging to separate drug-induced epigenetic effects from those that occur due to other factors such as adverse maternal care or an unhealthy home environment.
How PET Imaging Can Help
Positron emission technology (PET) is an imaging tool that allows researchers to measure the activity of proteins in the body using short lived radioactive tracers that bind to targets of choice.
Two epigenetic enzymes, histone deacetylase 1 and 2 (HDAC1 and HDAC2) are expressed at significantly higher levels in the brain during fetal development when compared to infancy.
HDAC mediates critical brain processes such as learning and memory—and alterations in HDAC expression density and activity have been found in individuals with neurodevelopmental disorders and neuropsychiatric and neurodegenerative diseases.
Zürcher is part of the Chemical Neuroscience Program at the Martinos Center and works closely with the Hooker Research Group, which recently developed and validated a new PET radiotracer, Martinostat, that’s capable of measuring HDAC expression in adult humans.
However, while some prenatal and early postnatal PET imaging has been performed, it is not readily conducted in humans due to risks of radiation exposure.
An Ideal Modeling System
NHPs are the closest proxy to humans when it comes to gestational term, placental structure, the timing of fetal brain development, the researchers write.
Thus they are an ideal model system to help researchers learn more about normal gene expression during development, as well as the impact of environmental exposures including—but not limited to marijuana.
“You can see whether marijuana or other environmental exposure change the level of HDAC expression, and then depending on the brain regions that are affected, you can picture how that could have different consequences on health,” says Zürcher.
“Even the healthy control arm will be super interesting, because it will show us how epigenetics changes naturally in utero.”
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