Marijuana and the developing brain

Marijuana and the developing brain

More states are legalizing marijuana, but concerns remain about its long-term effects on the adolescent brain.

Marijuana is the most widely used illicit drug in the United States — but the term “illicit” may not apply much longer. Twenty-three states have legalized Cannabis sativa for medical use since 1996. Alaska, Colorado, Oregon, Washington and Washington, D.C., now allow recreational use of the drug for people over 21. Acceptance of marijuana is growing (ahem) like a weed.

Those laws are not without controversy. Among the critics’ concerns is the worry that, despite age limits, legalization might make marijuana more accessible to young people. And adolescents’ developing brains may be particularly vulnerable to lasting damage from the drug.

“There are a lot of open questions” about the long-term effects of marijuana, says Susan Weiss, PhD, director of the division of extramural research at the National Institute on Drug Abuse (NIDA). “But there’s a growing literature, and it’s all pointing in the same direction: Starting young and using frequently may disrupt brain development.”

Brain under construction

Marijuana shows considerable promise for treating medical conditions including pain, muscle spasms, seizure disorders and nausea from cancer chemotherapy. At least some of those benefits are thought to come from cannabidiol, a chemical component of the marijuana plant not thought to produce mind-altering effects. But there’s a lot left to learn about this and other chemical compounds in marijuana. Recently, the Senate recommended $800,000 for an Institute of Medicine study on medical marijuana, and has also encouraged the National Institutes of Health to support more research on cannabidiol.

What’s clear, however, is that marijuana’s signature high comes from a psychoactive component known as tetrahydrocannabinol (THC). And evidence is mounting, says Weiss, that THC is not risk-free.

In the short term, marijuana use has been shown to impair functions such as attention, memory, learning and decision-making. Those effects can last for days after the high wears off. Heavy marijuana use in adolescence or early adulthood has been associated with a dismal set of life outcomes including poor school performance, higher dropout rates, increased welfare dependence, greater unemployment and lower life satisfaction.

But it’s not clear that marijuana deserves the bulk of the blame. Some researchers have suggested that factors such as peer influence, emotional distress or a tendency toward problem behavior could predispose people to drug use as well as poor life outcomes. “Is marijuana the causal agent in these outcomes, or is it part of a variety of vulnerability factors?” Weiss asks.

Few longitudinal studies have been conducted to follow the trajectories of young people before and after they take their first hit of marijuana. But one long-term prospective study from New Zealand showed worrisome findings.

Duke University psychologist Terrie Moffitt, PhD, and colleagues collected data from the Dunedin Multidisciplinary Health and Development Study, longitudinal research that has followed 1,000 New Zealanders born in 1972. Participants answered questions about marijuana use at 18, 21, 26, 32 and 38. They also underwent neuropsychological testing at ages 13 and 38.

The team found that persistent marijuana use was linked to a decline in IQ, even after the researchers controlled for educational differences. The most persistent users — those who reported using the drug in three or more waves of the study — experienced a drop in neuropsychological functioning equivalent to about six IQ points (PNAS, 2012). “That’s in the same realm as what you’d see with lead exposure,” says Weiss. “It’s not a trifle.”

There are some reasons to think that adolescents may be uniquely susceptible to lasting damage from marijuana use. At least until the early or mid-20s, “the brain is still under construction,” says Staci Gruber, PhD, a neuroscientist and director of the Cognitive and Clinical Neuroimaging Core and the Marijuana Investigations for Neuroscientific Discovery (MIND) Program at McLean Hospital/Harvard Medical School. During this period of neurodevelopment, the brain is thought to be particularly sensitive to damage from drug exposure. And the frontal cortex — the region critical to planning, judgment, decision-making and personality — is one of the last areas to fully develop, Gruber says.

Also immature in teens is the endocannabinoid system. As its name implies, this system comprises the physiological mechanisms that respond to THC. That system is important for cognition, neurodevelopment, stress response and emotional control, and it helps to modulate other major neurotransmitter systems, says Krista Lisdahl, PhD, director of the Brain Imaging and Neuropsychology Laboratory at the University of Wisconsin, Milwaukee.

Repeated exposure to marijuana can dial down cellular activity in the endocannabinoid system. Such interference might be a bigger problem for immature brains, says Lisdahl. “That sets the stage for why adolescents may be more sensitive to the effects of repeated marijuana exposure, from a neuroscience perspective.”

Altered brains

Indeed, a number of studies have found evidence of brain changes in teens and young adults who smoke marijuana. In 2013, Rocío Martín-Santos, MD, PhD, at the University of Barcelona, and colleagues reviewed 43 studies of chronic cannabis use and the brain. They found consistent evidence of both structural brain abnormalities and altered neural activity in marijuana users. Only eight of those studies focused on adolescents, but the findings from those studies suggested that both structural and functional brain changes emerge soon after adolescents start using the drug. Those changes may still be evident after a month of abstaining from the drug, the researchers reported (PLOS ONE, 2013).

Some of those brain abnormalities have been linked to cognitive differences. Gruber found that regular, heavy marijuana users — those who reported smoking five of the last seven days, and more than 2,500 times in their lives — had damage to their brains’ white matter, which helps enable communication among neurons. Those white matter changes were correlated with higher impulsivity, she found, particularly in people who began smoking before age 16 (Psychopharmacology, 2013).

Much of Gruber’s work compares heavy, regular marijuana users who began before and after age 16. Her results suggest there’s greater risk in starting young. Compared with users who began after 16, early-onset smokers made twice as many mistakes on tests of executive function, which included planning, flexibility, abstract thinking and inhibition of inappropriate responses. As adults, those who started using before 16 reported smoking nearly 25 times per week, while those who started later smoked half as often, about 12 times per week. The early-onset smokers also reported smoking an average of nearly 15 grams each week, versus about 6 grams for their late-onset counterparts (Psychology of Addictive Behaviors, 2012).

Gruber’s participants had reported using marijuana at least five times in the past week. But other labs have found structural differences in the brains of less frequent users. Jodi Gilman, PhD, at Massachusetts General Hospital/Harvard Center for Addiction Medicine, and colleagues used MRI to look for brain changes in 18- to 25-year-olds who smoked marijuana at least once per week, but were not dependent on the drug.

Compared with nonusers, the smokers had changes in the shape, volume and gray matter density of two brain regions associated with addiction: the nucleus accumbens (which plays a role in motivation, pleasure and reward processing) and the amygdala (a region involved in memory, emotion and decision-making). Participants who smoked more often had more significant differences (Journal of Neuroscience, 2014).


Open questions

But the case against marijuana isn’t closed. Other studies have failed to turn up evidence that marijuana use results in brain abnormalities. In one recent example, Barbara Weiland, PhD, at the University of Colorado at Boulder, and colleagues attempted to replicate Gilman’s study in adolescents and adults who smoked marijuana daily. But Weiland’s team argued that previous studies, including Gilman’s, failed to adequately control for alcohol use by the participants. After carefully matching for alcohol intake in the control and experimental subjects, the researchers failed to find physical differences in the nucleus acumbens or the amygdala of daily marijuana smokers (Journal of Neuroscience, 2015).

On the other hand, says Lisdahl, Weiland’s subjects were primarily male — and some research suggests females might be more sensitive to marijuana’s effects during adolescence.

In other cases, too, the evidence against marijuana is frustratingly mixed. While some studies have found increased risk for mood disorders and psychotic symptoms among marijuana users, for instance, a new study by Jordan Bechtold, PhD, at the University of Pittsburgh Medical Center, and colleagues found that chronic use among teenage boys did not raise the risk of later depression, lung cancer, asthma or psychotic symptoms (Psychology of Addictive Behaviors, 2015).

In hopes of painting a clearer picture of marijuana’s potential risks to youth, NIDA plans to launch the Adolescent Brain and Cognitive Development (ABCD) study later this year. The prospective longitudinal study will follow 10,000 individuals across the United States over a decade, starting when they’re 9 or 10. “The idea is to look at what these kids are like before they start using substances, and then follow over time what happens to their brains,” Weiss says.

Other important questions remain to be answered. Much of the research on the long-term cognitive effects of cannabis has focused on heavy users. It’s not clear whether there’s a safe level of use, Lisdahl says. Nor is it known whether the brain changes associated with marijuana use are permanent, or if the brain can recover with time. “A lot of people have used marijuana for a few years during adolescence,” says Lisdahl. “Have they done damage that’s irreversible?”

Finding answers to these questions may be complicated by the fact that marijuana potency has risen dramatically in recent years. Thirty years ago, THC concentrations were typically well below 10 percent, and even below 5 percent. But a recent analysis of marijuana samples sold in Colorado found THC potency approaching 30 percent, according to results presented at the 2015 meeting of the American Chemical Society.

New methods of administering the drug are also springing up, including smoking new varieties of highly concentrated cannabis resins, which contain even more THC than high-potency pot. Recently popular edible products — think marijuana gummy bears — also present problems. Users might not have a clear sense of what constitutes a reasonable “dose.” And since edible products take longer to be metabolized and produce their psychoactive effects, people can easily overindulge while they’re waiting for a high to kick in. “What’s clearly lacking and sorely needed are studies that look at the effect of increased potency, and different modes and methods of use, on brain-related measures,” Gruber says.

Access and attitudes

Despite these questions, nearly half of U.S. states have already legalized marijuana in some form, and more are likely to follow suit. A number of researchers are now turning their attention to the question of how those laws might affect young people.

Esther K. Choo, MD, MPH, of Brown University, and colleagues used data on more than 11 million high school students from the Centers for Disease Control and Prevention’s national Youth Risk Behavioral Surveillance Survey collected between 1991 and 2011. Marijuana use was common among the students — about one in five reported having smoked marijuana in the last month. But in states that legalized marijuana, the researchers found no increases in teen use following passage of the new laws (Journal of Adolescent Health, 2014).

In a similar study, Deborah Hasin, PhD, at Columbia University Medical Center, and colleagues analyzed survey data from more than one million adolescents collected between 1991 and 2014 as part of NIDA’s Monitoring the Future survey. During that period, 21 states passed laws legalizing cannabis for medical purposes. Hasin and her colleagues found no apparent differences in marijuana use among adolescents before and after the medical marijuana laws were passed (The Lancet, 2015).

Yet Hasin and her colleagues did find that in states where medical marijuana was legal, teen marijuana use was already higher even before the laws were passed. That suggests more permissive attitudes toward marijuana in those states, rather than increased access to the drug, may influence teen use.

Indeed, the Monitoring the Future survey has shown that when perception of marijuana’s risk drops, use of the drug rises in short order. And the perceived risk of marijuana has been declining over the last decade. In 2014, less than 40 percent of high school seniors said they believed regular marijuana use was very risky — the lowest proportion since the 1970s.

Other researchers are exploring how families interpret the new laws. W. Alex Mason, PhD, director of research at the National Institute for Child and Family Studies, Boys Town, and colleagues have studied parents’ perceptions and knowledge of marijuana laws in Washington state. They found that parents often remained uncertain about what was legal or illegal, and only discussed the laws with their children occasionally. “Parents as a theme expressed frustration about not knowing the facts,” Mason says. “In many cases, teenagers are following this more closely than their parents.”

Parents may not be talking to their kids about marijuana often, but retailers seem to be, Lisdahl says. “In Colorado, there are marijuana ads in the free magazines that are clearly marketed to young people.”

Unfortunately, marijuana producers have a strong incentive to hook young users. While about 9 percent of adults who use cannabis become addicted, the rate is 17 percent for people who start smoking in their teens, according to NIDA figures. And as the tobacco and alcohol industries have demonstrated, she says, such companies make the majority of their profits on a relatively small proportion of chronic users. “The minute there’s a profit motive, companies tend to make a product more addictive,” says Lisdahl. “I think legalization is moving ahead prematurely without considering the lessons we’ve learned from nicotine and alcohol prevention policy research.”

Gruber, too, has concerns that marijuana policy is outpacing science. “As we’re on the precipice of all this legislation,” she says, “the take-home message is, there’s a lot that we know, but a lot more we don’t.”

Much of the research on the long-term cognitive effects of cannabis has focused on heavy users. It’s not clear whether there’s a safe level of use. Nor is it known whether the brain changes associated with marijuana use are permanent, or if the brain can recover with time.