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When S.K. Dey, PhD, talks about fertility, he speaks in terms of windows.
The early stages of embryonic development, he says, involve a series of narrow windows of opportunity – critical timeframes that define when an egg can be fertilized, when a blastocyst can successfully implant into the lining of the uterus, when a healthy placenta can form, and so on.
Dey, director of the Division of Reproductive Sciences at Cincinnati Children’s, says these windows can be affected by a wide range of environmental factors – what the mother eats, whether she suffers infections, what sorts of chemicals she may ingest – accidentally or not.
For two decades, he has been studying one particular source of disruption to these reproductive windows – marijuana use. Dey is among the pioneers worldwide in understanding the many functions of the endocannabinoid system, a complex set of signaling molecules discovered in the early 1990s. This signaling system helps regulate neurotransmission in the brain and throughout the body.
Our bodies naturally produce endocannabinoids on an as-needed basis. However, the active ingredient in marijuana – tetrahydrocannabinol (THC) – also activates this system. This stimulation of the endocannabinoid system helps explain why people get “high” from marijuana use. However, the effects go beyond mere sensation. Research in animal models shows that marijuana use can harm reproduction in several ways.
“Any disturbance during the window of implantation leads to adverse ripple effects throughout the course of pregnancy,” Dey says. “This is a very dynamic phase. Things move rapidly. If anything goes wrong, if a window shifts out of sync, you have a problem.”
Previous studies have linked aberrant endocannabinoid signaling to increased risk of ectopic pregnancy, preeclampsia, miscarriages and preterm labor. In addition, babies that survive prenatal exposure to marijuana face potential deficits in growth and brain development.
Dey joined Cincinnati Children’s in 2008 to launch the Division of Reproductive Sciences. But he has been studying this emerging field since 1990, when he received the first of several grants from the National Institute on Drug Abuse (NIDA).
His work helps explain how endocannabinoids function during reproduction. Understanding what happens when this signaling system goes awry may eventually lead to new ways to enhance fertility and possibly treat other diseases.
Endocannabinoids are lipid molecules produced by the body that activate two specific G-protein-coupled receptors. Cannabinoid receptor type 1 (CB1) is found primarily in the brain, but also in many peripheral tissues including the uterus. Cannabinoid receptor type 2 (CB2) is typically found in the cells of the immune system and in the testis.
Endocannabinoids react with nerve cells differently than traditional neurotransmitters. They tend to play a down-regulating role, often opposing the activity of other neurotransmitters. This has generated interest in using these compounds to develop improved pain relievers, anti-obesity medications and other treatments. During pregnancy, endocannabinoid signaling plays significant roles throughout development.
In men, chronic marijuana use has been associated with lower testosterone levels, reduced sperm counts and impotency. In women, its habitual use is linked to fetal abnormalities and miscarriages.
However, only recently have the mechanisms involved been more fully understood. Studies in pregnant mice have demonstrated
that endocannabinoid signaling is involved in egg transport, implantation and other stages of fetal development. An excessive influx of THC from marijuana consumption can disrupt these processes.
“You have to have the right balance of endocannabinoid signaling,” Dey says. “We have shown that CB1 is expressed in the preimplantation embryo. We also have shown that either high levels of CB1 activation, or its absence, can influence implantation and pregnancy outcome.”
In September 2010, Dey and his group published a paper in the Proceedings of the National Academy of Sciences (PNAS) that reported a new connection between endocannabinoids and placenta formation. Defective signaling at this stage can interfere with placental development, which in turn can lead to recurrent miscarriages and preterm labor. The paper concludes that these findings in mouse models could be clinically relevant to humans, but more research is needed to confirm the connection.
One challenge to demonstrating the potential harmful effects of marijuana during pregnancy is the lack of human data. More research is needed to connect animal study findings to the human world, says Maurizio Macaluso, MD, DPH, director of the Division of Biostatistics and Epidemiology at Cincinnati Children’s.
“Most of the data we have about how many pregnant women use marijuana are very unreliable,” he says. “When illegal or illicit substances are involved, it is hard to get truthful responses to questions.”
Yet gathering better data is vital.
“There are hundreds of chemicals that are potentially interfering with our reproductive potential. We are built to be resilient, but these environmental exposures are taking a toll,” Macaluso says. “Environmental exposures are definitely a concern, both in women and men. There is evidence that tobacco smoking, alcohol consumption and recreational drug use all have adverse impact on fertility. There are solid data worldwide that the quality of semen is decreasing. This too may be an effect of environmental exposures.”
Dey often lectures on the science of endocannabinoid signaling, most recently in July 2011 at the Annual Symposium of the International Cannabinoid Research Society.
He continues his early pregnancy studies using a continuing grant from NIDA. His group is also working with Senad Divanovic, PhD, and Christopher Karp, MD, at Cincinnati Children’s to seek funding from the March of Dimes to further study how endocannabinoid signaling affects immune responses in the context of preterm birth.
“A lot of people want to believe marijuana is a harmless drug. That’s wrong,” Dey says. “If you are going to be pregnant, don’t smoke marijuana. The risks are very real.”
S.K. Dey, PhD, is the director of the Division of Reproductive Sciences at Cincinnati Children's.
Rebalancing the Endocannabinoid System May Help Treat Several Conditions
As Dey and other researchers gain deeper insights into the endocannabinoid system, potential clinical applications are emerging.
For example, fetal growth can be severely retarded when pregnant mice have overactive endocannabinoid systems. Dey and colleagues recently published findings that show administering a CB1 antagonist can reverse such growth retardation in mice.
Meanwhile, researchers worldwide are exploring whether re-balancing the endocannabinoid system can treat conditions unrelated to fertility, such as anxiety disorders, pain, nausea, obesity, brain injury, multiple sclerosis, epilepsy, Parkinson’s disease, Huntington’s disease, depression, and substance addiction.
“People are exploring a number of approaches,” Dey says. “But most of these are in early stages and await extensive human clinical trials.”
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