Pregnancy and pot don't mix.

"Even though marijuana (Cannabis sativa) is the most widely used illegal drug among women of reproductive age, reports dealing with the effects of prenatal exposure to this substance of abuse on length of gestation, fetal growth and offspring behavior are still controversial." So observed research pharmacologist Vincenzo Cuomo at La Sapienza University in Rome.

Cuomo added, "The scenario concerning possible long-term consequences of in utero exposure to cannabis derivatives on cognitive functions is not well understood. These inconclusive results may depend on ethical, practical and interpretive difficulties surrounding research with human subjects."

Which is why Cuomo turned from human mothers and their offspring to rats. He is president of the Society of Italian Pharmacology and senior author of a paper in the current Proceedings of the National Academy of Sciences (PNAS) released online March 25, 2003. Its title tells virtually all: "Prenatal exposure to a cannabinoid agonist produces memory deficits linked to dysfunction in hippocampal long-term potentiation and glutamatergic release."

"The message of this article," Cuomo told BioWorld Today, "is that we know from a few evidences in the literature that children of mothers smoking marijuana during pregnancy exhibit alterations later in their activities or in their cognitive functions. We demonstrate this," he continued," by giving pregnant rats a cannabinoid receptor agonist - a substance that mimics the effects of marijuana.

"We have found in the offspring of these rodent mothers," Cuomo continued, "two main effects. The first one is hyperactivity in the young, which disappeared when they reached maturity. But there remained a long-lasting impairment of their memory capacities. This is the first evidence to my knowledge that can explain the mechanisms underlying the memory impairment caused by exposure to cannabinoids. This cognitive impairment was accompanied by two alterations. One was a decrease of glutamine levels in the hippocampus."

Potentiation: An Electrophysiological Endpoint

"This decline in glutamatergic function may be responsible for another effect we noted - alteration and maintenance of long-term potentiation. This is an electrophysiological endpoint, which is a cellular model of learning and memory. Both effects could explain the memory modification.

"We have to be very careful," Cuomo cautioned, "in extrapolating animal data to human data. But these animal models we now have can be predictive for human offspring of pregnant mothers. For example, some clinicians recently demonstrated that the children of mothers who took cocaine during pregnancy exhibited alteration in their psychology. In other words, those children did not readily recognize their new toys from old toys. We saw similar effects in our rats that were exposed to cocaine during pregnancy.

"As for marijuana, I think there are some active principles, like tetrahydrocannabinol, which cross over to the milk. These results," he suggested, "should convince a pregnant woman not to take marijuana during pregnancy or during lactation."

Is this a prevalent problem in Italy? In Europe? In the world?

"In Italy," Cuomo said, "we don't have precise data on how many women use marijuana during pregnancy. But looking at the literature, it seems that this phenomenon has increased in the past few years And one reason," he surmised, "is that among the various substances of abuse, marijuana is considered, perhaps, not so dangerous as cocaine or heroin.

"Then there is alcohol, ethanol, which produces the classical fetal alcohol syndrome. We know that this syndrome is characterized by morphological changes, somatic alterations and central nervous system modifications. Of course, in this case, the message is clear: No alcohol intake at all during pregnancy. As far as tobacco smoking is concerned, also in this case we know that nicotine can produce in the children of mothers smoking cigarettes during pregnancy effects that resemble neural functional disturbances. They can go so far as to decrease body weight, at least at birth."

Cuomo made the point, "There are more than 2,000 compounds in smoking tobacco. Nicotine, of course, is the main neurotoxic compound, but there is also carbon monoxide, which is the product of combustion. The data for marijuana suggest that this poisonous gas can also be responsible for some postpartum alterations."

Cuomo and his co-authors did not tempt their pregnant rats with straight marijuana. Instead, they administered a synthetic cannabis agonist called "WIN."

Pups Tasked With Behavioral Reproductive Tests

The pups birthed by the expectant rodent dams go through a battery of tasks, from passive avoidance to motor neuron behavior to reproductive capacity, and were monitored from infancy to old age. "Motor activity," Cuomo recounted, "was recorded in an apparatus consisting of a cage 42 by 42 by 30 centimeters equipped with 15 infrared emitters. Each interruption of a beam generated an electric impulse scored by a digital counter. Vertical activity was measured by recording the number of horizontal beams that were broken by the rearing of the animal.

"Passive avoidance behavior tasks gave us an idea of an animal's retention time. Each one was placed in an illuminated compartment and time taken for it to enter the adjacent dark compartment [approach latency] was taken as an index of emotional, nonassociative behavior. For reproductivity, we measured several reproduction parameters, like term weight gain, pregnancy length, size at birth. But we didn't find any change in these parameters. The newborn rats looked normal, as often happens in humans. The children whose mothers took marijuana during pregnancy looked normal at birth. But when they reached 4 or 5 years, school age, they exhibited salient impairment of their cognitive parameters. They were more impulsive, more hyperactive than normal human children.

"This concept is important," he pointed out, "in the sense that even if we exclude that WIN does not produce morphological changes - that is, the classical teratology - I think we have evidence that even in the absence of gross malformations, or overt neurotoxic changes, children of mothers exposed to drugs of abuse but also to psychopharmacological drugs," Cuomo concluded, "can exhibit subtle changes in their cognition capacities and emotional abilities."