Indiana University Research & Creative Activity


Volume 30 Number 2
Spring 2008

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Kenneth Mackie
Ken Mackie
Photo © Tyagan Miller

brain neuron
CB-1 cannabinoid receptors (in green)
Photo courtesy Ken Mackie

Your Brain on Drugs

by Steve Hinnefeld

Undergraduates typically ask the same question when they learn about Ken Mackie's research: "Dude, can I be one of your subjects?"

Mackie is a professor in the Department of Psychological and Brain Sciences at Indiana University Bloomington and one of the university's Linda and Jack Gill Chairs in Neuroscience.

For almost two decades, he has studied the effects of marijuana on the brain and a host of related questions that arise from that topic.

While not well known to the general public, Mackie's field of study has produced new information about the functioning of the brain. And work is under way to turn those research findings into new therapies for treating pain, obesity, seizure disorders, and the symptoms of multiple sclerosis, Parkinson's disease, and other disorders.

Equally compelling to Mackie and his colleagues, their laboratory is helping solve the puzzle of how the brain works at the molecular level, demonstrating that the same neurochemical system that responds to active ingredients in marijuana may play an important role in memory, learning, and sensation.

"Our question is really focused on how does it work? How does it interact with other systems?" says Mackie, who came to IU Bloomington from the medical school at the University of Washington in Seattle.

As for the would-be research subjects hoping for a chance to get stoned--no, Mackie does not use human research subjects. He and his colleagues do most of their work with neurons and other cells, cultured and tended in a laboratory on the fourth floor of the IU Bloomington Psychology Building.

Not Your Father's Psychology

Mackie moved to Indiana in January 2007. By the fall, he had relocated his lab, bringing along three co-workers: Alex Straiker, a research scientist and a co-author with Mackie of a number of journal articles; Jim Wager-Miller, the lab's lead technician for the past seven years; and Brady Atwood, a graduate student in the neurobiology program at the University of Washington.

IU also recruited Mackie's wife, Yvonne Lai, who is a research scientist in IUB Department of Psychological and Brain Sciences. Mackie and Lai have two children: Michelle, 16, and Ian, 13. Lanky and soft-spoken, Mackie says he and his family enjoy downhill skiing, hiking, and bicycling in their spare time--all the more reason that it took a strong pull from IU and Bloomington to get them to leave the Pacific Northwest.

"It was a difficult decision," he says. "The attractions [here] included the endowed chair, good colleagues, and an opportunity to participate in the further strengthening of the neuroscience program at IU."

The Gill Chairs were endowed by Linda and Jack Gill, higher-education philanthropists who divide their time between Houston and Indianapolis. Jack Gill, a high-tech entrepreneur and venture capitalist, earned a Ph.D. in organic chemistry from Indiana University in 1963 and has, since last July, been a member of the IU Board of Trustees. In addition to the Gill Center and its endowed chairs, the Indiana Metabolomics and Cytomics Initiative, funded in 2004 with a $53 million gift from the Lilly Endowment, supports research in the life sciences, including neuroscience. And the Multidisciplinary Science II building, now under construction just north of the Psychology Building, will provide state-of-the-art space for researchers--including Mackie and his laboratory.

Linda B. Smith, professor and chair of the Department of Psychological and Brain Sciences, says Mackie's research provides a perfect example of the breadth and depth of research that caused the former Psychology Department to rename itself two years ago.

"As a department, we are committed to explaining behavior--and mind--from the molecular and cellular level through neural systems to cognition to the social behavior of individuals," Smith says. IU Bloomington had trailed some peer universities in neuroscience research, she says, but "with the Gill Center, we plan to catch up by hiring top scientists whose work integrates with work at other levels of analysis in the department.

"Integrative research like this is our future," Smith says. "It's not your father's psychology any more."

Bliss from Within

Saying that Mackie and his colleagues study marijuana and the brain only begins to suggest the scope of their research. They study the brain's endogenous cannabinoids, or endocannabinoids. These signaling chemicals occur naturally in the brain and are similar to the active ingredients in cannabis, or marijuana. The brain's endocanna-binoid system includes receptor proteins and the enzymes involved in synthesizing and breaking down the endocannabinoids.

Mackie grew up in New Hampshire, earned his M.D. degree from Yale University, and then studied with Paul Greengard, who shared the 2000 Nobel Prize in Medicine for research in signal transduction in the nervous system. With clinical training in anesthesiology, Mackie says, he was drawn naturally to research that that wrestled with questions of how and why chemical substances work in the brain to reduce pain.

As he was beginning his research career--at about the same time that the Partnership for a Drug-Free America was preaching that "your brain on drugs" resembled a fried egg--scientists were asking, in their curious and nonjudgmental way: What really is going on in the brains of people who smoke marijuana?

Researchers had learned in the 1970s that opiate drugs such as morphine and heroin activated receptor proteins in the brain, and that they mimicked the effects of naturally occurring opioids called endorphins. Reasoning that a similar mechanism might be at work for marijuana, scientists looked for receptors that would be stimulated by the main active ingredient in cannabis, called delta-9-tetrahydrocannabinol, or THC. Eventually they found and were able to clone two receptors, which they called CB1 and CB2.

"What was missing," Mackie says, "was, why does the brain have this receptor? The body doesn't make receptors so people can go get stoned."

The presence of receptors targeted by marijuana suggested that the brain was producing chemicals that would interact with them--that is, endogenous cannabinoids--and, in 1992, they were found. The first was named anandamide by its discoverers, from the Sanskrit word ananda, meaning "the bliss that comes from within." Later, researchers found another endocannabinoid, designated 2-AG, for 2-arachidonoyl glycerol.

"But what was still missing," Mackie says, "was what these chemicals do in the brain." Hundreds of research studies later, the answer turns out to be: Quite a lot.

Researchers mapped cannabinoid receptors in the brain and showed they were present at high levels in regions involved with memory, cognition, reward, sensory perception, emotions, and motor control, suggesting the endocannabinoid system plays a role in those processes. Moreover, learning how the system operates has created opportunities to develop medications that precisely target the symptoms of ailments ranging from multiple sclerosis and epilepsy to depression and addiction.

Mackie explains one example: "A well-documented side effect of smoking cannabis is that people get hungry for brownies and potato chips--for rich, not very healthy foods," he says.

Scientists speculated that if THC caused "the munchies" by stimulating cannabinoid receptors, a chemical that had the opposite effect could be an effective diet drug. And sure enough, a drug called rimonabant, which blocks CB1 cannabinoid receptors, has been shown in clinical trials to produce weight loss and reverse some of the deleterious metabolic changes associated with obesity. It also has shown promise for smoking cessation and treatment of addictions.

Using drugs to block receptor molecules is one way to manipulate the endocannabinoid system for medical purposes. Another approach is to chemically interfere with enzymes that are part of the system. For example, targeting enzymes that break down cannabinoids can magnify their effectiveness--potentially helping reduce pain or anxiety, as examples. That appears to be the case with drugs called FAAH inhibitors, which target the enzyme known as fatty acid amide hydrolase (FAAH). Pharmaceutical companies are following such research closely and funding their own studies, looking for ways to modulate the endocannabinoids that Mackie is working on.

Open Questions

Mackie says that students who joke about wanting to be his research subjects often follow up with a serious question: Is smoking marijuana bad for me? "That's an impossible question to answer," he says.

As an anesthesiologist who spent time working in hospital emergency departments, Mackie can say from experience that marijuana does not cause the same public-health problems as abuse of alcohol, tobacco, and hard drugs. "We saw many more people who wrapped their cars around trees on alcohol than on marijuana," he says. On the other hand, his research shows in detail that using marijuana does alter the normal functioning of the brain. "On general principle, you think that is something to avoid," he says.

Another question that Mackie often gets asked is: Should marijuana be legal, if not for recreational use, then as medicine? "People come with strongly formed opinions, pro and con, and they try to slant our work to fit those opinions," he says.

In Washington, state law now permits doctors to suggest cannabis as a "drug of last resort" for patients with certain terminal or debilitating medical conditions, including cancer, HIV, and intractable pain.

"It clearly works for some people, without a doubt," Mackie says. But whether that means doctors will some day be able to prescribe cannabis, he says, is a public policy question that will have to be answered through coordinated legislation at the state and federal levels, not in research labs.

Steve Hinnefeld is a media specialist for IU's Office of University Communications in Bloomington.