Chapter 4. The Chemistry of Behavior: Neurotransmitters and Neuropharmacology
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By MIKE STOBBE / AP Medical Writer ATLANTA (AP) — Can’t get enough shuteye? Nearly 9 million U.S. adults resort to prescription sleeping pills — and most are white, female, educated or 50 or older, according to the first government study of its kind. But that’s only part of the picture. Experts believe there are millions more who try options like over-the-counter medicines or chamomile tea, or simply suffer through sleepless nights. ‘‘Not everyone is running out to get a prescription drug,’’ said Russell Rosenberg, an Atlanta-based sleep researcher. The Centers for Disease Control and Prevention study was based on interviews with about 17,000 adults from 2005 through 2010. Study participants were even asked to bring in any medicines they were taking. Overall, 4 percent of adults said they'd taken a prescription sleeping pill or sedative in the previous month. The study did not say whether use is increasing. But a CDC researcher calculated that use rose from 3.3 percent in 2003-2006 to 4.3 percent in 2007-2010. That echoes U.S. market research — as well as studies in some other countries — that indicate an increase in insomnia in recent decades. ‘‘Sleep disorders overall are more prevalent than what they were,’’ said Dr. Ana Krieger, medical director of New York’s Weill Cornell Center for Sleep Medicine. © 2013 NY Times Co.
Link ID: 18588 - Posted: 08.31.2013
As the debate about legalizing marijuana heats up in Canada, a new study suggests the drug might be riskier for teens to consume than had been previously thought. Researchers from the Université de Montréal and New York's Icahn School of Medicine at Mount Sinai Hospital conducted a review of 120 studies examining cannabis and teenage brain development, and concluded there is strong evidence early cannabis use puts some teens at risk of developing addiction and mental health problems as adults. Dr. Didier Jutras-Aswad, with the Université de Montréal's psychiatry department, is a co-author of the review, which was published this month in the journal Neuroparmacology. He says that in adolescence, the brain is still fine-tuning how different areas, such as learning and memory, interact and it appears that marijuana use alters that process. "When you disrupt this, actually, development, during adolescence, notably through cannabis use, you can have very pervasive, very negative effects in the long-term, including on mental health and addiction risk," he told CBC News. Some studies have also found links between early cannabis use and schizophrenia, but Jutras-Aswad says it seems clear there is a wide risk profile that includes genetics and behavioural traits in addition to age. "For me, the question is not about whether cannabis is good or bad, but who is more likely to suffer from problems in cannabis, because we know for most people that will not happen," he said. © CBC 2013
By Stephen L. Macknik A new study in the Journal of Neuroscience suggests that a part of the brain critical to motivation, the substantia nigra, which is famous for its role as a primary culprit in Parkinson’s Disease, is central to the relationship between feeding and drug seeking behavior. Neuroscientists have known for some time that acquisition of drug seeking behavior is higher in people whose food supply is restricted. But nobody knew why. Neuroscientist Sarah Branch and her colleagues at the University of Texas Health Science Center in San Antonio have now discovered a critical neural mechanism that links food restriction to enhanced drug efficacy. They mildly restricted the diet of mice and found that it caused certain neurons in the substantia nigra burst in activity. These neurons, called dopamine neurons, are implicated in the feeling of pleasure felt with drugs of abuse. It’s as if the neurons are preparing to reward their owner the moment that food is found, perhaps to reinforce food acquisition. When the mice were given cocaine as well, the bursty effect in food restricted mice was enhanced even further, which leads to increased drug seeking behavior too. Interestingly, they found that the effects could persist up to ten days after the food restriction ended. The results suggest that there may be a way to enhance drug efficacy in patients with chronic pain. But it also serves as a cogent reminder that the substantia nigra is central to how the brain generates motivational behavior. When the substantia nigra dies, you get Parkinson’s, and you find it difficult to motivate yourself to even pass through a doorway. © 2013 Scientific American
By James Gallagher Health and science reporter, BBC News Taking cocaine can change the structure of the brain within hours in what could be the first steps of drug addiction, according to US researchers. Animal tests, reported in the journal Nature Neuroscience, showed new structures linked to learning and memory began to grow soon after the drug was taken. Mice with the most brain changes showed a greater preference for cocaine. Experts described it as the brain "learning addiction". The team at University of California, Berkeley and UC San Francisco looked for tiny protrusions from brain cells called dendritic spines. They are heavily implicated in memory formation. The place or environment that drugs are taken plays an important role in addiction. In the experiments, the mice were allowed to explore freely two very different chambers - each with a different smell and surface texture. Once they had picked a favourite they were injected with cocaine in the other chamber. A type of laser microscopy was used to look inside the brains of living mice to hunt for the dendritic spines. More new spines were produced when the mice were injected with cocaine than with water, suggesting new memories being formed around drug use. The difference could be detected two hours after the first dose. BBC © 2013
Keyword: Drug Abuse
Link ID: 18561 - Posted: 08.26.2013
I HAVE been struggling with an addiction to opiates for the past three years. It started with prescription painkillers and progressed to full-blown heroin dependence. In an attempt to kick the habit I signed up for a traditional 30-step inpatient treatment that involved individual and group counselling, and which cost about $30,000. That was a year ago, and it didn't work. I felt unable to stay away from heroin. Now I am at a small clinic in Baja California, Mexico, where I am taking part in the first trial to investigate the effectiveness of treating heroin addiction with a single dose of ibogaine – a psychoactive substance derived from the rainforest shrub Tabernanthe iboga. "Ibogaine can take you many places, causing you to experience a range of emotions, memories and visions. If any of these images become too frightening, just open your eyes." I am reassured by the words of the director of the clinic, Jeff Israel, but the drug's history is not all rosy. Several clinical trials have shown that low doses of ibogaine taken over the course of a few weeks can greatly reduce cravings for heroin and other drugs. There was extensive research on it in the 1990s, with good evidence of safety in animals and a handful of studies in humans. The US National Institute on Drug Abuse invested over $1 million, but then abandoned the project in 1995. A study had shown that at high doses, ibogaine caused some brain cell degeneration in rats. Lower doses similar to those used in human addiction trials showed no such effect, however. © Copyright Reed Business Information Ltd.
Keyword: Drug Abuse
Link ID: 18552 - Posted: 08.24.2013
Posted by Dr. Sushrut Jangi The child's family and physician were making decisions about how to treat this disease. Many readers voted that starting an ADHD medication and behavioral therapy together might be a good way forward. Her doctor agrees with this approach. "A lot of judgement happens the day I talk about starting medicines for young children," Dr. Chan says. Most parents have already tried numerous other routes, such as behavioral therapy which is frequently recommended first. But behavioral therapy alone is hard to implement. "It's hard to access and there's not too many families who can actually carry it out," Chan says. "If you're a single parent working multiple jobs, its really hard to fit the time to take your child regularly. It's a huge time investment." J's parents tried the behavioral therapy route and they worked hard at it. But he wasn't improving. Dr. Chan is more than familiar with the culture of fear that surrounds ADHD medications, but she feels these fears are overinflated. Consequently, children who might benefit from being on medicine get delayed treatments, which can have harmful social effects. "Children in his class already know that he's different, so they react to him differently. Children with ADHD start getting negative feedback from their peers early on." Dr. Chan feels that this is one potential justification for starting medications early. "These medicines can help children get out of cycles of negative-feedback. And we're not condemning children to medicine for the rest of their lives. They can be started as a trial, and then stopped down the line." © 2013 NY Times Co.
By JULIE TURKEWITZ Samantha Dittmeier was the youngest of Karen Allar’s four children. “She was very loving, very compassionate,” said Ms. Allar, 51, an employment counselor who lives on Long Island. “Unfortunately, the addiction got to her.” Ms. Dittmeier, 23, died of a heroin overdose in January, leaving behind her 3-year-old son, Aiden. Ms. Allar is haunted, she said, not just by her daughter’s tumble into addiction, but also by the circumstances of her death. She wonders if her life might have been saved if the emergency workers who treated her had been armed with naloxone, a powerful drug that can reverse the effects of an overdose. “You start to get that sick feeling again,” Ms. Allar said, recounting a frantic race to the hospital just before Ms. Dittmeier’s death. “I’m back at work. I’m trying to think positive about such a horrible situation.” On Long Island and across New York State, drug overdoses are taking an increasing toll. The most common killers are opioids, a class of painkillers that includes prescription drugs like Vicodin, OxyContin and Percocet, as well as illegal narcotics like heroin. In Suffolk and Nassau Counties, the two that make up Long Island, 338 people died of opioid overdoses in 2012, up from 275 in 2008, according to county records. Statewide, opioid overdoses killed 2,051 people in 2011, more than twice the number that they killed in 2004. The spate of deaths is spurred, in part, by the easy access to prescription drugs. As a result, the state has begun several efforts to stem access to prescription drugs. A new law aims to stop addicts from gaining access to multiple rounds of medication by requiring doctors to consult an Internet database that tracks prescriptions. © 2013 The New York Times Company
Keyword: Drug Abuse
Link ID: 18548 - Posted: 08.22.2013
Moheb Costandi Exposure to nicotine in the womb increases the production of brain cells that stimulate appetite, leading to overconsumption of nicotine, alcohol and fatty foods in later life, according to a new study in rats. Smoking during pregnancy is known to alter fetal brain development and increase the risk of premature birth, low birth weight and miscarriage. Prenatal exposure to nicotine also increases the likelihood of tobacco use and nicotine addiction in later life, but exactly how is unclear. To understand the mechanisms behind this effect, Sarah Leibowitz, a behavioural neurobiologist at the Rockefeller University in New York, and her colleagues injected pregnant rats with small doses of nicotine — which the researchers say are comparable to the amount a pregnant woman would get from smoking one cigarette a day — and then examined the brains and behaviour of the offspring. In a paper published today in Journal of Neuroscience1, they found that nicotine increased the production of specific types of neurons in the amygdala and hypothalamus. These cells produce orexin, enkephalin and melanin-concentrating hormone, neuropeptides that stimulate appetite and increase food intake. Rats exposed to nicotine in the womb had more of these cells and produced more of the neuropeptides than those that were not, and this had long-term consequences on their behaviour. As adolescents, they not only self-administered more nicotine, but also ate more fat-rich food and drank more alcohol. © 2013 Nature Publishing Group
By James Gallagher Health and science reporter, BBC News A lifetime of too much copper in our diets may be contributing to Alzheimer's disease, US scientists say. However, research is divided, with other studies suggesting copper may actually protect the brain. The latest study in Proceedings of the National Academy of Sciences showed high levels of copper left the brain struggling to get rid of a protein thought to cause the dementia. Copper is a vital part of our diet and necessary for a healthy body. Tap water coming through copper pipes, red meat and shellfish as well as fruit and vegetables are all sources of dietary copper. Barrier The study on mice, by a team at the University of Rochester in New York, suggested that copper interfered with the brain's shielding - the blood brain barrier. Mice that were fed more copper in their water had a greater build-up of the metal in the blood vessels in the brain. The team said this interfered with the way the barrier functioned and made it harder for the brain to get rid of a protein call beta amyloid. One of the hallmarks of Alzheimer's disease is the formation of plaques of amyloid in the dying brain. Lead researcher Dr Rashid Deane said: "It is clear that, over time, copper's cumulative effect is to impair the systems by which amyloid beta is removed from the brain." BBC © 2013
By RICHARD A. FRIEDMAN, M.D. Fully 1 in 5 Americans take at least one psychiatric medication. Yet when it comes to mental health, we are facing a crisis in drug innovation. Sure, we have many antidepressants, antipsychotics, hypnotic medications and the like. But their popularity masks two serious problems. First, each of these drug classes is filled with “me too” drugs, which are essentially just copies of one another; we have six S.S.R.I. antidepressants that essentially do the same thing, and likewise for the 10 new atypical antipsychotic drugs. Second, the available drugs leave a lot to be desired: patients with illnesses like schizophrenia, major depression and bipolar disorder often fail to respond adequately to these medications or cannot tolerate their side effects. Yet even though 25 percent of Americans suffer from a diagnosable mental illness in any year, there are few signs of innovation from the major drug makers. After a series of failed clinical trials in which novel antidepressants and antipsychotics did little or no better than placebos, the companies seem to have concluded that developing new psychiatric drugs is too risky and too expensive. This trend was obvious at the 2011 meeting of the American Society for Clinical Pharmacology and Therapeutics, where only 13 of 300 abstracts related to psychopharmacology and none related to novel drugs. Instead, they are spending most of their research dollars on illnesses like cancer, heart disease and diabetes, which have well-defined biological markers and are easier to study than mental disorders. © 2013 The New York Times Company
By ANAHAD O'CONNOR Nationwide, roughly a third of all visits to emergency rooms for injuries are alcohol related. Now a new study suggests that certain beverages may be more likely to be involved than others. The study, carried out over the course of a year at the Johns Hopkins Hospital in Baltimore, found that five beer brands were consumed most often by people who ended up in the emergency room. They were Budweiser, Steel Reserve, Colt 45, Bud Ice and Bud Light. Three of the brands are malt liquors, which typically contain more alcohol than regular beer. Four malt liquors accounted for nearly half of the beer consumption by emergency room patients, even though they account for less than 3 percent of beer consumption in the general population. Previous studies have found that alcohol frequently plays a role in emergency room admissions, especially those stemming from car accidents, falls, homicides and drownings, said the lead author of the study, David H. Jernigan of the Johns Hopkins Bloomberg School of Public Health. The new study, published in the journal Substance Use and Misuse, is the first to look at whether certain brands or types of liquor are overrepresented. Dr. Jernigan said that the breakdown of liquor consumption in the study may be particular to Baltimore, and that he and his colleagues are hoping to study other cities as well. The findings could have policy implications, potentially influencing labeling requirements and marketing for higher-alcohol beers, Dr. Jernigan said. Copyright 2013 The New York Times Company
By SABRINA TAVERNISE BALTIMORE — At Everest Greenish Grocery, a brightly lit store on a faded corner of this city, nothing is more popular than a chocolate-flavored little cigar. They are displayed just above the Hershey bars along with their colorful cigarillo cousins — white grape, strawberry, pineapple and Da Bomb Blueberry. And they were completely sold out by 9 one recent evening, snapped up by young people dropping by for a snack or stopping in during a night of bar hopping. “Sorry, no more chocolate,” the night clerk, Qudrad Bari, apologetically told a young woman holding a fruit drink. In 2009, Congress passed a landmark law intended to eliminate an important gateway to smoking for young people by banning virtually all the flavors in cigarettes that advocates said tempted them. Health experts predicted that the change would lead to deep reductions in youth smoking. But the law was silent on flavors in cigars and a number of other tobacco products, instead giving the Food and Drug Administration broad discretion to decide whether to regulate them. Four years later, the agency has yet to assert that authority. And a rainbow of cheap flavored cigars and cigarillos, including some that look like cigarettes, line the shelves of convenience stores and gas stations, often right next to the candy. F.D.A. officials say they intend to regulate cigars and other tobacco products, but they do not say how or when. Smoking opponents contend that the agency’s delay is threatening recent progress in reducing smoking among young people. © 2013 The New York Times Company
Keyword: Drug Abuse
Link ID: 18523 - Posted: 08.19.2013
By Cristy Gelling Repairing a faulty communication line between the gut and the brain can quell the urge to overeat, an experiment that cured chubby mice of their junk food addiction indicates. A similar strategy might be used to treat compulsive eating in people. Some scientists have proposed that, in both mice and humans, overeating can resemble drug addiction; the more food a person consumes, the less responsive the brain becomes to the pleasure of eating. By restoring normal communication between the gut and brain, researchers were able to resensitize overfed rodents to the pleasures of both fatty and healthy foods. "The therapeutic implications are huge,” says neuroscientist Paul Kenny of the Scripps Research Institute in Jupiter, Fla., who was not involved in the study. In the brain, a chemical called dopamine surges in response to pleasurable experiences like eating, sex and taking drugs. But brain-scanning studies suggest that obese individuals have muted dopamine reponses to food. These changes could lead overeaters to seek more and more food to satisfy their cravings, suggests study leader Ivan de Araujo of Yale University. De Araujo and his colleagues looked for ways to restore the dopamine response of overfed mice by studying the signals sent by their guts. In previous work, the researchers found that mice get a dopamine rush when fat is introduced directly into the small intestine via catheters. This shows that the gut communicates with the brain’s reward center even when the mouse can’t taste food. © Society for Science & the Public 2000 - 2013
By Laura Sanders Pregnant mice buzzed on caffeine gave birth to pups with brain changes and lasting memory deficits, a new study shows. The results, published Aug. 7 in Science Translational Medicine, leave unclear whether caffeine causes a similar effect in people. The study convincingly shows that caffeine changes the brains of exposed pups, says child neurologist Barry Kosofsky of Weill Cornell Medical College in New York. But he cautions that mouse and human brains develop very differently, so direct comparisons are impossible. The study has no immediate message for pregnant women, Kosofsky says. “We are totally at a loss about what to say for caffeine.” For a mouse mother, though, the experiment’s story is clearer: Moderate caffeine intake during pregnancy changes baby brains, and not for the better. While pregnant and later lactating, mice drank water laced with caffeine — an amount comparable to that in three to four cups of coffee a day. In offspring, cells in a memory center in the brain called the hippocampus fired off too many messages, an abnormal behavior that could lead to seizures, Carla Silva, of the French National Institute of Health and Medical Research and the University of Coimbra in Portugal, and colleagues found. As adults, the caffeine-exposed mice performed worse than nonexposed mice on memory tests. Usually, mice ignore familiar objects and spend lots of time investigating something new. But mice exposed to caffeine while developing weren’t keen on exploring new objects, suggesting that they couldn’t remember which object was new. What’s more, these mice had fewer neurons in parts of the hippocampus than normal mice. © Society for Science & the Public 2000 - 2013
Drinking cocoa every day may help older people keep their brains healthy, research suggests. A study of 60 elderly people with no dementia found two cups of cocoa a day improved blood flow to the brain in those who had problems to start with. Those participants whose blood flow improved also did better on memory tests at the end of the study, the journal Neurology reported. Experts said more research was needed before conclusions could be drawn. It is not the first time cocoa has been linked with vascular health and researchers believe that this is in part due to it being rich in flavanols, which are thought to have an important role. In the latest study, researchers asked 60 people with an average age of 73 to drink two cups of cocoa a day - one group given high-flavanol cocoa and another a low-flavanol cocoa - and consume no other chocolate. Ultrasound tests at the start of the study showed 17 of them had impaired blood flow to the brain. There was no difference between those who drank flavanol-rich cocoa and those who had flavanol-poor cocoa. But whichever drink they were given, 88% of those with impaired blood flow at the start of the study saw improvements in blood flow and some cognitive tests, compared with 37% of people whose blood flow was normal at the beginning of the study. BBC © 2013
By Scicurious Most current treatments for depression target the serotonin system, a chemical messenger that plays a role in mood (though it also plays a role in many, many other things). Most of the antidepressant drugs on the market (such as Prozac, Celexa, and Zoloft) that target serotonin do it by blocking the recycling of serotonin, keeping it in the spaces between neurons and allowing it to be active for far longer than it might otherwise. The problem is, these drugs take a long time to work. Often many weeks. In that time, patients may grow frustrated as side effects happen and the needed effects don’t. Patients may be in very desperate straights when they first go on medication, and any extra time before the drugs work becomes that much more dangerous. The drugs may not work at all, causing doctors and patients to have to go through the entire, weeks long process over and over again. Scientists are looking for new antidepressant mechanisms, and trying to create more effective drugs. But there are various ways to go about it. You can go looking for an entirely new way of working, but you can also look at ways to make the current drugs work faster. One target that might help antidepressant drugs work faster is one of the many receptors for serotonin, the 5-HT1A receptor. Receptors are proteins that sit on cell surfaces, and bind chemicals. When they bind a chemical, they cause change, maybe by opening a channel, or starting a signal to make a neuron fire more, or less. What a receptor does depends on its type, but also where in the brain it is located and on what type of cell. © 2013 Scientific American
Link ID: 18463 - Posted: 08.06.2013
Rachel Seifert Over 40 years ago President Richard Nixon declared war on "public enemy No 1" in the US – drug abuse. Since then, aggressive US anti-drug policies have continued unabated, with over $1 trillion spent on law enforcement and over 45 million people arrested on drugs charges. However, the numbers remain relatively unchanged, with over 20 million users of illegal drugs in the US today. Many voices on the international stage are starting to speak out against not only the failure of these policies but the harm they are causing. Yet the PR machine created around the war on drugs still exerts a huge influence over public opinion. In High Price, Dr Carl Hart joins the growing number of professionals breaking with conventional thinking as he debunks myths and misconceptions associated with illegal drugs. Hart brings two very different but complementary perspectives to the debate: his experience of growing up in a poor African-American community in Miami, and his scientific learning as a neuroscientist studying the effects of drugs. Although the two are not always joined seamlessly, they give him a rare insight into the often deep misunderstanding of illegal drugs, with which he attempts to turn sensationalist, stereotypical views on their head. By telling his own life story, Hart gives us a fascinating insight into the cultural mores of his community, growing up on the streets, and the racism he has faced throughout his life. Now a distinguished scientist, he reflects on his childhood with a new understanding, applying his scientific knowledge to reassess the path that led him to a career in academia, while avoiding the circle of drugs, addiction and prison in which many of his family and friends got caught up. © 2013 Guardian News and Media Limited
Keyword: Drug Abuse
Link ID: 18462 - Posted: 08.06.2013
An experimental treatment for alcohol dependence works better in individuals who possess specific combinations of genes that regulate the function and binding of serotonin, a brain chemical affected by the treatment, according to a study supported by the National Institutes of Health. A report of the finding appears online in the American Journal of Psychiatry. “This study is another important step toward personalized treatments for alcohol dependence,” says Kenneth R. Warren, Ph.D., acting director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), which funded the study. “A personalized approach based on a person’s genetic makeup is increasingly being investigated for delivering optimum treatment to the ‘right’ patient.” Ondansetron is a medication currently used to treat nausea and vomiting, often following chemotherapy. It works by blocking serotonin-3 receptors, and has shown potential as a treatment for defined subpopulations with alcohol dependence. In previous studies, Professor Bankole Johnson, D.Sc., M.D., and his team at the University of Virginia, Charlottesville, have shown that variations in genes that encode the serotonin transporter, a protein that regulates the concentration of serotonin between nerve cells, can significantly influence drinking intensity. They have also shown that the effectiveness of ondansetron therapy among people with alcohol dependence is influenced by variations of the serotonin transporter gene.
by Michael Slezak Could the US government be losing support in the global war on drugs? A year after some Latin American countries officially discussed alternatives to prohibition, Uruguay has moved to allow the production, sale and distribution of cannabis. The new legislation, which has made it through one house of parliament in Uruguay, has been described by President José Mujica as a "cutting-edge experiment". If passed by the upper house, the laws will allow registered users to buy up to 40 grams a month from a pharmacist, grow up to six plants at home, or grow up to 99 plants as part of a "cannabis club" made up of between 15 and 45 members. Uruguay has seen increases in crime associated with illegal drugs, particularly cocaine. According to the US Department of State, the drug problem continues there despite "concerted and consistent government efforts to combat these trends", including increased arrests and drug seizures. Mujica says the legislation aims to bring an existing market into the "light of day" and stop it from "corrupting everything". "They are doing it for the same reason the US stopped alcohol prohibition [in the 1930s]," says David Nutt at Imperial College London. "To reduce organised crime and achieve tax revenue for the country." The move comes hot on the heels of two US states legalising the production and distribution of cannabis and New Zealand creating a legal market for new designer drugs. © Copyright Reed Business Information Ltd.
Keyword: Drug Abuse
Link ID: 18451 - Posted: 08.03.2013
Andrew M. Seaman, Reuters Children with an autism spectrum disorder spend about twice as much time playing video games as kids who don't have a developmental disability, according to a new study. Researchers also found that children with an autism spectrum disorder or attention deficit/hyperactivity disorder (ADHD) are at an increased risk of gaming addictions, compared to children without the disabilities. "What we found is that it looks like (addictive gaming) was largely driven by inattention," Christopher Engelhardt, one of the study's authors from the University of Missouri in Columbia, told Reuters Health. Previous studies have found that children with an autism spectrum disorder or ADHD spend more time playing video games and are at increased risk for gaming addictions than other children, write the researchers in the journal Pediatrics. No single study, however, has looked at the three groups to see whether shared features of autism and ADHD - such as inattention or hyperactivity - seem to drive video game use. For the new study, Engelhardt and his colleague surveyed the parents of 141 boys between the ages of 8 and 18 years old. Of those, 56 had an autism spectrum disorder, 44 had ADHD and 41 were developing normally. Overall, they found that kids with an autism spectrum disorder played - on average - 2.1 hours of video games per day. Children with ADHD spent about 1.7 hours per day playing video games and normally developing kids played about 1.2 hours per day.