Penn-Nursing

Research Points to Omega-3 as a Nutritional Intervention for Childhood Behavioral Problems

At the forefront of a field known as “neurocriminology,” Adrian Raine of the University of Pennsylvania has long studied the interplay between biology and environment when it comes to antisocial and criminal behavior. With strong physiological evidence that disruption to the emotion-regulating parts of the brain can manifest in violent outbursts, impulsive decision-making and other behavioral traits associated with crime, much of Raine’s research involves looking at biological interventions that can potentially ward off these behavioral outcomes.

A new study by Raine now suggests that omega-3, a fatty acid commonly found in fish oil, may have long-term neurodevelopmental effects that ultimately reduce antisocial and aggressive behavior problems in children.

He is a Penn Integrates Knowledge Professor with appointments in the School of Arts & Sciences and the Perelman School of Medicine.

Along with Raine, the study featured Jill Portnoy a graduate student in the Department of Criminology, and Jianghong Liu, an associate professor in the Penn School of Nursing. They collaborated with Tashneem Mahoomed of Mauritius’ Joint Child Health Project and Joseph Hibbeln of the National Institute on Alcohol Abuse and Alcoholism.

It was published in the Journal of Child Psychology and Psychiatry.

When Raine was a graduate student, he, his advisor and colleagues conducted a longitudinal study of children in the small island nation of Mauritius. The researchers tracked the development of children who had participated in an enrichment program as 3-year-olds and also the development of children who had not participated. This enrichment program had additional cognitive stimulation, physical exercise and nutritional enrichment. At 11 years, the participants showed a marked improvement in brain function as measured by EEG, as compared to the non participants. At 23, they showed a 34 percent reduction in criminal behavior.

Raine and his colleagues were interested in teasing apart the mechanisms behind this improvement. Other studies suggested the nutritional component was worth a closer look.

“We saw children who had poor nutritional status at age 3 were more antisocial and aggressive at 8, 11 and 17,” Raine said. “That made us look back at the intervention and see what stood out about the nutritional component. Part of the enrichment was that the children receiving an extra two and a half portions of fish a week.”

Other research at the time was beginning to show that omega-3 is critical to brain development and function.

“Omega-3 regulates neurotransmitters, enhances the life of a neuron and increases dendritic branching, but our bodies do not produce it. We can only get it from the environment,” Raine said.

Research on the neuroanatomy of violent criminals suggested this might be a place to intervene. Other brain-imaging researchers have shown that omega-3 supplementation increases the function of the dorsolateral prefrontal cortex, a region Raine found to have higher rates of damage or dysfunction in criminal offenders.

Raine’s new study featured a randomized controlled trial where children would receive regular omega-3 supplements in the form of a juice drink. One hundred children, aged 8 to 16, would each receive a drink containing a gram of omega-3 once a day for six months, matched with 100 children who received the same drink without the supplement. The children and parents in both groups took a series of personality assessments and questionnaires at the start.

After six months, the researchers administered a simple blood test to see if the children in the experimental group had higher levels of omega-3 than those in the controls. They also had both parents and children take the personality assessments. Six months after that, the researchers had parents and children take the assessment again to see if there were any lasting effects from the supplements.

The assessments had parents rate their children on “externalizing” aggressive and antisocial behavior, such as getting into fights or lying, as well as  “internalizing” behavior, such as depression, anxiety and withdrawal. Children were also asked to rate themselves on these traits.

While the children’s self-reports remained flat for both groups, the average rate of antisocial and aggressive behavior as described by the parents dropped in both groups by the six-month point. Critically, however, those rates returned to the baseline for the control group but remained lowered in the experimental group, at the 12-month point.

“Compared to the baseline at zero months,” Raine said, “both groups show improvement in both the externalizing and internalizing behavior problems after six months. That’s the placebo effect.

“But what was particularly interesting was what was happening at 12 months. The control group returned to the baseline while the omega-3 group continued to go down. In the end, we saw a 42 percent reduction in scores on externalizing behavior and 62 percent reduction in internalizing behavior.“

At both the six- and 12-month check-ins, parents also answered questionnaires about their own behavioral traits. Surprisingly, parents also showed an improvement in their antisocial and aggressive behavior. This could be explained by the parents taking some of their child’s supplement, or simply because of a positive response to their child’s own behavioral improvement.

The researchers caution that this is still preliminary work in uncovering the role nutrition plays in the link between brain development and antisocial behavior. The changes seen in the one-year period of the experiment may not last, and the results may not be generalizable outside the unique context of Mauritius.

Beyond these caveats, however, there is reason to further examine omega-3’s role as a potential early intervention for antisocial behavior.  

“As a protective factor for reducing behavior problems in children,” Liu said, “nutrition is a promising option; it is relatively inexpensive and can be easy to manage.”

Follow-up studies will include longer-term surveillance of children’s behavioral traits and will investigate why their self-reports did not match the parental reports. 

An FDA-approved Alzheimer’s Drug Could Help Smokers Quit

Despite several safe drug therapies available to help smokers quit, three-quarters report relapsing within six months of a quit attempt. University of Pennsylvania researchers Rebecca Ashare and Heath Schmidt saw potential for a permanent cessation solution in a class of FDA-approved medications used to improve cognitive impairments from Alzheimer’s disease.

In a study consisting of a rat trial and a human trial, Ashare and Schmidt studied the effects of two acetylcholinesterase inhibitors, or AChEIs, called galantamine and donepezil on overall nicotine intake. The rat component showed that pretreating the rodents with an AChEI decreased their nicotine consumption. Consistent with these effects, clinical trial participants taking the AChEI, not the placebo, smoked 2.3 fewer cigarettes daily, a 12 percent decrease, and noted feeling less satisfied with the cigarettes they did smoke.

“We’re very interested in screening potential efficacy of anti-addiction medications in our models,” said Schmidt, a professor in Penn’s School of Nursing and Perelman School of Medicine. “For this study, we looked at potential smoking-cessation medications.”

The research itself took a translational approach, what Ashare, a professor in Penn Medicine’s psychiatry department, calls bi-directional. In other words, the preclinical data informed the clinical study and vice versa.

At Penn’s Center for Interdisciplinary Research on Nicotine Addiction, work on smoking cessation has been ongoing since 2001. Specifically, research from Caryn Lerman, CIRNA’s director and the Mary W. Calkins Professor in Psychiatry, concluded that people who quit smoking often report a decrease in what’s commonly called their executive functions.

“They feel fuzzy. They’re forgetful,” Ashare said. “Those deficits are related to their ability to quit smoking. It was this clinical aspect of smoking cessation we thought would be useful to take further.”

That’s when they turned to the acetylcholinesterase inhibitors.

In the brain, the neurotransmitter called acetylcholine is important to cognitive functions like learning and short-term memory. When nicotine enters the body, it binds to the same receptors in the brain that acetylcholine binds to, resulting in smoking’s rewarding and reinforcement effects. Acetylcholinesterase inhibitors increase acetylcholine levels in the brain and, in effect, substitute nicotine’s effects.

Schmidt had successfully employed such a model with other addictive substances like cocaine. He divided a group of rats into galantamine and donepezil cohorts. To mirror voluntary drug taking in humans, the rats self-administered nicotine using a lever pushed at will. Once nicotine-taking stabilized, the rats were pretreated with one of the two AChEIs.

For both drugs, “we were able to show a reduction in total nicotine self-administered,” Schmidt said; however, there was a caveat.

“We know from the literature that upward of 30 percent of patients will report nausea and vomiting [when taking these drugs], and this will limit their compliance,” he said. “We had seen that these drugs reduced nicotine self-administration, but we wanted to make sure it wasn’t because the rats were sick.”

Unlike humans who can verbally report when they don’t feel well and whose bodies react to nausea, rats lack the reflex to vomit. In previous research, Matthew Hayes, who has appointments in Penn Medicine and Penn Nursing, had shown that in rats kaolin clay consumption coats the stomach like an antacid and quells any ill effects. Collaborating with Hayes, Schmidt offered the animals kaolin clay, then compared how much they ate normally and with the addition of the AChEIs.

“At the doses shown to reduce nicotine self-administration, the AChEIs did not make our animals sick,” Schmidt said. The findings sparked the CIRNA clinical trial, which has to date studied 33 smokers ages 18 to 60.

People who were interested in quitting smoking signed on for 23 days. For the first two weeks, they continued to smoke but also took either galantamine or a placebo. Before the trial began, researchers assessed the smokers’ cognitive function to get a baseline. Participants followed the regimen for two weeks and then were asked to not smoke for one full day. Two more assessments took place: after the two weeks on the cigarette-drug combination and again after that initial smoke-free day. Finally, the researchers asked the study subjects to do their best to not smoke for seven straight days, a time during which the participants still took either galantamine or a placebo.

“That week-long period is a proxy for longer-term cessation. The ability to quit smoking the first week after you make a quit attempt is highly predictive of long-term success,” Ashare said.

She’s still actively recruiting for the trial, with an aim of 80 people total. Once the trial reaches that number, she’ll dig into overall quit data. What she’s learned so far — that smokers who used the FDA-approved galantamine smoked fewer cigarettes per day and enjoyed them less — is promising, particularly given that those who don’t smoke during that first crucial week are 32 times more likely to quit smoking permanently.

“Our goal in investigating these different repurposed medications is not to replace the medications that are already available,” she said. “We know that they’re effective. Our goal is to target different populations of smokers who may be more likely to experience these cognitive deficits.”

There’s no data to suggest that a clinician treating a smoker should prescribe one of these AChEIs now. But Ashare and Schmidt are forging a path, and, if it leads where they think it might, it could provide smokers yet another option to help them quit.

Ashare and Schmidt published their work in the Nature journal Translational Psychiatry.