Photo by rafael-castillo, via Flickr
Photo by rafael-castillo, via Flickr

Weed: A Gateway Drug Across Generations?

If you haven’t seen marijuana in the news lately then you haven’t been paying attention. This week lawmakers in Maryland, Maine, Massachusetts, Colorado, WashingtonKentucky, and Georgia are all talking about weed. Some doctors are using the drug to treat epilepsymultiple sclerosis, and chronic pain. Journalists are finding stories of marijuana lobbyists and marijuana job fairs and multi-day cannabis tours.

Most of these news stories mention that little is known about the long-term effects of marijuana use. But I bet the average Joe is much more likely to make jokes about weed than fret about its potential harms. I was in the joking camp last week. My perspective is beginning to shift, however, thanks to a new rat study suggesting that steady marijuana exposure causes brain and behavioral problems not only in the animals exposed, but in their future ratlets.

“When I was in school you were taught that the only thing you pass on to your kids is your DNA sequence. Now we know that what you do in your lifetime impacts the next generation more than we thought,” says lead investigator Yasmin Hurd, a neuroscientist at the Mount Sinai School of Medicine in New York. “It’s important for people to think about that as we have these public discussions about marijuana.”

Marijuana is the most commonly used illicit drug in the United States, and seems to be getting more popular by the day. An estimated 18.9 million people have used it sometime in the past month, according to a 2012 survey done by the U.S. Department of Health and Human Services. That’s up from 14.5 million in 2007. As more people use it, more people seem to think it’s safe. That same survey showed that, in 2007, 55 percent of kids between 12 and 17 perceived “great risk” in smoking pot. In 2012, only 44 percent did.

But just how risky is it? Scientists are only beginning to figure that out.

Several years ago, Hurd and her colleagues showed that adolescent rats exposed to THC (the molecule primarily responsible for pot’s mind-altering effects) are more likely to self-administer heroin as adults than are rats not exposed to THC. This pointed to weed as a “gateway” into other kinds of addictive drugs.

The new study aimed to see whether any of these effects carried into the next generation. Over the past decade or so, many researchers have reported that a wide variety of environmental exposures leave chemical marks on DNA that stick around in the germ line, sometimes for several generations. (I just wrote a feature for Naturefeature for Nature about this avenue of research.) To give one well-known example, a 2002 study of Swedish historical records found that men who had experienced famine in childhood were less likely to have grandsons with heart disease or diabetes than those who were well fed.

Just as they did in previous studies, Hurd’s team gave male and female rats periodic injections of THC throughout their adolescent period. This pattern of exposure is meant to mimic the typical pot-smoking teen. “Every few days they got about a joint’s worth of THC,” Hurd says.

Several weeks after the exposure ends (enough time for all traces of THC to disappear), the researchers allowed the animals to mate. Immediately after delivery, their pups were transferred to another cage to be raised by a female rat who had never been exposed to THC.

When those babies reached adulthood, even though they themselves had never been exposed to THC, their brains showed a range of molecular abnormalities. They had unusually low expression of the receptors for glutamate and dopamine, two important chemical messengers, in the striatum, a brain region involved in compulsive behaviors and the reward system. What’s more, brain cells in this region had abnormal firing patterns, the study found.

“I really didn’t expect such significant differences,” Hurd says. “The fact that you see significant changes, molecular changes, in how the neurons communicate with each other — that’s very significant to me.”

This second generation had altered behaviors as well. Compared with controls, rats whose parents had been exposed to THC were more sensitive to novelty in their environment and were more likely to self-administer heroin by repeatedly pressing a lever. All of this would suggest, as the authors wrote in the paper, that marijuana has a “cross-generational gateway” effect.

“It’s always important to recognize that animal models are just that, and not always perfect predictors of human behavior. That said, these data are striking,” says Chris Pierce, a neuroscientist at the University of Pennsylvania, who was not involved in the new study. Last year Pierce’s team reported a similar kind of epigenetic inheritance: Male offspring of rats that had been exposed to cocaine showed increased resistance to cocaine addiction compared with controls.

As is true of so many epigenetic studies, the researchers don’t know much about the biological mechanism that might allow THC exposure to carry over to the next generation. Pierce points out that because both the mother and father were exposed to THC, it’s unclear whether one or both parents must be exposed in order for the offspring to be affected.

Hurd’s team is now analyzing the sperm of the exposed males to see whether it carries abnormal patterns of DNA methylation, a common epigenetic marker. The researchers also also investigating whether some of these effects extend to a third generation.

Epigenetic influences may seem scary — it’s awful to think that dumb choices I made in college might one day mess up my kid’s brain. But Hurd puts a more optimistic spin on it. Just as drug exposures can leave harmful marks on the genome, our other experiences or behaviors may be able to undo the damage, or have other positive effects. “Some things could counter it, and others could exacerbate it,” she says. “We don’t appreciate this plasticity enough.”

This kind of scientific research, in Hurd’s views, too often gets left out of the public debate over the legalization of marijuana. “If anyone brings any science into the discussion you’re seen as this negative group trying to stop the freedom of individuals, and that’s not the case,” she says. “I think we need to have the debate, with science being a huge part of that.”