Epigenetics and Addiction

Turning off the genes for substance abuse.

If psychiatric disorders, including depression and addiction, are rooted in nature, but modified by nurture, some better way of viewing the interaction between genes and the environment is desperately needed.

Enter "epigenetics," defined as the study of how gene expression can be modified without making direct changes to the DNA. Writing in Science News, Tina Hesman Saey explains that "epigenetic mechanisms alter how cells use genes but don't change the DNA code in the genes themselves.... The ultimate effect is to finely tune to what degree a gene is turned on or off. Often the fine tuning is long-lasting, setting the level of a gene's activity for the lifetime of the cell."

A common form of epigenetic modification involves adding molecules to the DNA structure. Adding molecules from a methyl group or an acetyl group can change the manner in which genes interact with a cell's transcribing system. Cells can "mark" specific genes by attaching a methyl group consisting of three hydrogen atoms and one carbon atom to cytosine in the DNA base, effectively turning genes on or off without making major alterations to genetic structure. (Gene mutations or insertions, on the other hand, are capable of fundamentally altering the DNA protein structure.)

Scientists have learned that epigenetic changes can be caused by environmental impacts, but the details are not well understood. We have not yet reached the point of being able to link a specific experience of stress or infection or chemical exposure to specific epigenetic alterations.

What does any of this have to do with drug addiction or depression? One of the environmental impacts researchers have linked to epigenetic changes is drug addiction. The DNA double helix is packaged in proteins collectively called chromatin. One set of proteins, the histones, is a frequent site of epigenetic modification. In a study published in Neuron, Eric Nestler and co-workers in the Southwestern Medical Center at the University of Texas found that alterations in chromatin packaging were tied up with the dopamine release caused by cocaine addiction. The researchers concluded that chronic cocaine use was influenced by "chromatin remodeling." Specifically, modulating histone activity "alters locomotor and rewarding responses to cocaine."

How does this work? As Saey writes in Science News: "Another gene, known as delta-FosB, also switches on when a wave of dopamine washes over the nucleus accumbens.... Delta-FosB teams up with other transcription factors and recruits enzymes that acetylate histones and remodel control regions of some genes..... Such findings suggest that medicines that interrupt or reverse epigenetic changes caused by drugs of abuse could one day prevent or cure addiction."


Image Credit: Science in School

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Annals of Addiction: Richard Lewis

From The Harder They Fall

"It's hard to know exactly when I became an alcoholic. What I do know is that growing up I felt misunderstood, not appreciated, and needing validation. I didn't feel I was getting it from important people in my life. They had their problems, their own concerns. I felt sort of invisible....

"Drinking made me feel not as miserable. It was a great Band-Aid. It progressed, but it didn't stop me in my career. I've done well, and I was an alcoholic at the height of my career, when I really hit. When alcohol really got me by the throat, I quit stand-up comedy. Acting was easier. Easier to stay sober most of the time, do my work, and know I'm off for three days.....

"There were tip-offs, even way early. I remember getting some sort of sexually transmitted disease that was going to last for a week. I had to take certain antibiotics, and I remember the doctor very nonchalantly saying, 'Oh, by the way, you can't drink for five days.' I was going to New York to appear on the Letterman show, and all I thought about was, 'Oh my God, there I am in first class, five-and-a-half hours in an airplane, without booze. There I am in New York with my friends and no booze. I can't even have a couple of glasses of wine in my hotel room to relax before the show.' That's all I thought about. I wasn't thinking of my career. I wasn't thinking about anything but 'I can't believe I can't drink.' It was horrifying. And that was thirteen years before I bottomed.

"I was hallucinating. I was emaciated. Holed up doing coke for six nights.... I was ashamed to waste my life, given all the blessings I had. That I would throw away my life needlessly. To have a disease that I could stop giving myself, if I surrendered, finally.....

"One reason I love being sober is that I thought about this guy I saw who slipped last week, who I spoke to this morning.... I wouldn't have been able to do that if I was drinking. I couldn't have helped this guy.... If I'm going to leave any kind of legacy, making people laugh is fine, but to help somebody get the darkness from out of their eyes and to turn their life around, it's the most important aspect of my life."

Excerpted from:

The Harder They Fall, by Gary Stromberg and Jane Merrill. Center City, MN: Hazelden.


Photo Credit: Pearlies of Wisdom

Annals of Addiction: Grace Slick

From The Harder They Fall

"There's a whole bunch of alcoholics on both sides of my family, but they function in the sense that everybody kept their jobs. There were no divorces, except for my grandmother, but she's not an alcoholic. She was just a wild child like I was. Our alcoholics all kept their jobs and stayed married....

"The Airplane became famous as the original psychedelic band, but personally, I was more of a drinker. Anything that was around and easy I took--marijuana was very easy to score, but alcohol was my drug of choice. That's the genetic deal going on, where I'm an addict in the sense that anything I like I'm all over. Like flies on shit! And sometimes that works out fine. Right now I'm a painter. That's how I make my living and pay the mortgage....

"In 1970, when I became pregnant with China, I wasn't conscious of addiction. My life was all just sex, drugs and rock and roll. But I'm not a moron, so I knew that what you put into your face goes into your body, and part of your body is what's living in there--the child....

"Life is now fine. My daughter is sober. China came in a couple of weeks after me. Into the same rehab. My sponsor was amused. She had never seen a mother-daughter combination in the same rehab....

"I always felt very close to the story of Alice in Wonderland for a real good reason. If you remember what happened to her, she came from a very straight-laced Episcopalian Republican background, and at some point between twelve and twenty-four--mine at about eighteen or so--you go down the rabbit hole."

Excerpted from:
The Harder They Fall, by Gary Stromberg and Jane Merrill. Center City, MN: Hazelden.

Photo Credit: Donna E. Natale Planas/Miami Herald

Annals of Addiction: Malcolm McDowell

From The Harder They Fall

"My father was an alcoholic, so I never really drank much. I kept away from it, but I didn't realize that cocaine was really the same thing. Alcohol eventually started getting a little out of control, but in the form of 'fine wine.' That was my excuse....

"So I didn't consider wine a problem, but cocaine was a problem, and that got out of hand quite fast. It had a very bad effect on my marriage. The lies and deceit and everything that goes with addiction. I went from snorting it occasionally to now smoking it, doing freebase. Doing as much as I could. Finish a batch at four in the morning. Driving around the San Fernando Valley looking for some more of it. Driving while completely stoned, of course. How I was never in an accident, I just don't know....

"The using ended because I went down to the Betty Ford Center.... I didn't thank God at the time time, however. I felt I'd lost a great friend or mistress, that I'd lost the one thing that I could totally trust--all that bullshit! It wasn't until I started to work on myself at Betty Ford, which is a wonderful place as is any place that gets you sober....And, of course, it's hard work, recovery. Less and less hard as the years have gone by, but you know, the way we live our lives is all recovery in one sense or another. We go through a shattering experience like that, and everything we do in life from then on is in a way influenced by what we've been through."

Excerpted from:
The Harder They Fall, by Gary Stromberg and Jane Merrill. Center City, MN: Hazelden.

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The Chemistry of Cocaine Addiction

Crack, free-base, and powder

The cocaine high is a marvel of biochemical efficiency. Cocaine works primarily by blocking the reuptake of dopamine molecules in the synaptic gap between nerve cells. Dopamine remains stalled in the gap, stimulating the receptors, resulting in higher dopamine concentrations and greater sensitivity to dopamine in general.

Since dopamine is involved in moods and activities such as pleasure, alertness and movement, the primary results of using cocaine--euphoria, a sense of well being, physical alertness, and increased energy—are easily understood. Even a layperson can tell when lab rats have been on a cocaine binge. The rapid movements, sniffing, and sudden rearing at minor stimuli are not that much different in principle from the outward signs of cocaine intoxication among higher primates.

Chemically, cocaine and amphetamine are very different compounds. Psychoactively, however, they are very much alike. Of all the addictive drugs, cocaine and speed have the most direct and most devastatingly euphoric effect on the dopamine systems of the brain. Writing in the November 2004 issue of Synapse, Jonathan D. Brodie and colleagues at the New York University School of Medicine reported that “A rapid elevation in nucleus accumbens dopamine characterizes the neurochemical response to cocaine, methamphetamine, and other drugs of abuse."

In the late 1990s, scientists at Johns Hopkins and NIDA had shown that opiate receptors play a role in cocaine addiction as well. PET scans demonstrated that cocaine addicts showed increased binding activity at mu opiate receptors sites in the brain during active cocaine addiction. Take away the cocaine, and the brain must cope with too many empty dopamine and endorphin receptors.

Cocaine and amphetamine produce rapid classical conditioning in addicts, demonstrated by the intense cravings touched off by such stimuli as the sight of a building where the user used to buy or sell. Environmental impacts of this nature can produce marked blood flow increases to key limbic structures in abstinent addicts.

When the crack "epidemic" first became news, it was clear that the old specialty of free-basing was now within reach of existing cocaine users. No paraphernalia needed except for a small pipe; no more butane and mixing; no muss, no fuss. Like basing, smoking crack was a drug dealer’s dream. The “rush” from smoking crack was more potent, but even more transient, than the short-lived high from nasal ingestion

Both the cocaine high and the amphetamine high are easily augmented with cigarettes or heroin. These combinations result in “nucleus accumbens dopamine overflow,” a state of neurochemical super saturation similar to the results obtained with the notorious “speedball”—heroin plus cocaine.

It has been clear for more than a decade that most cocaine treatment programs are failures. In the case of the newly arrived crack cocaine, relapse rates after formal treatment sometimes approach one hundred per cent. Clearly, a piece of the puzzle has been missing. If receptors were the sites that controlled how drugs affected the mind, and if genes controlled how receptors were grown, then one implication of all the receptor theories was that sensitivity to addictive drugs could conceivably have a genetic basis. It was a large step in the right direction, because there were already good reasons for seeing alcoholism and other addictions as inherited dysfunctions in brain chemistry.

--Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.

Photo Credit: Legal Drug Alternatives

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Take the Alcohol Test

CAGE questionnaire still a useful tool

Despite the time, labor, and expense that have gone into the search for a better way to diagnose alcoholism, researchers have yet to outdo what may be the simplest, most accurate test for alcoholism yet devised. A set of four simple, relatively non-controversial questions, first devised in 1970 by Dr. John A. Ewing, still serve as a useful predictive tool for alcoholism.

Neurobiology has taught us that addictive drugs cause long-lasting neural changes in the brain. The problems start when sustained, heavy drinking forces the brain to accept the altered levels of neurotransmission as the normal state of affairs. As the brain struggles to adapt to the artificial surges, it becomes more sensitized to these substances. It may grow more receptors at one site, less at another. It may cut back on the natural production of these neurotransmitters altogether, in an effort to make the best of an abnormal situation. In effect, the brain is forced to treat alcoholic drinking as normal, because that is what the drinking has become.

The likelihood that many alcoholics and other drug addicts have inherited a defect in the production and distribution of serotonin and other neurotransmitters is a far-reaching finding. While it is difficult to measure neurotransmitter levels directly in brains, there are indirect ways of doing so. One such method is to measure serotonin’s principle metabolic breakdown product, a substance called 5-HIAA, in cerebrospinal fluid. From these measurements, scientists can make extrapolations about serotonin levels in the central nervous system as a whole.

However, testing for serotonin levels is imprecise and impractical in the real world of the doctor's office and the health clinic. Despite all the promising research on neurotransmission, what can physicians and health professionals do today to identify alcoholics and attempt to help them? For starters, physicians could look beyond liver damage to the many observable “tells” that are characteristic patterns of chronic alcoholism—such manifestations as constant abdominal pain, frequent nausea and vomiting, numbness or tingling in the legs, cigarette burns between the index and middle finger, jerky eye movements, and a chronically flushed or puffy face. Such signs of acute alcoholism are not always present, of course. Many practicing alcoholics are successful in their work, physically healthy, don’t smoke, and came from happy homes.

The CAGE test takes less than a minute, requires only paper and pencil, and can be graded by test takers themselves. It goes like this:

1. Have you ever felt the need to (C)ut down on your drinking?

2. Have you ever felt (A)nnoyed by someone criticizing your drinking?

3. Have you ever felt (G)uilty about your drinking?

4. Have you ever felt the need for a drink at the beginning of the day—an “(E)ye opener?

People who answer “yes” to two or more of these questions should seriously consider whether they are drinking in an alcoholic or abusive manner.

--Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.

Neuroaddiction and the Reward Pathway

How addictive drugs fool Mother Nature

"The addicted brain is distinctly different from the nonaddicted brain,” writes Alan Leshner, the former director of the National Institute of Drug Abuse (NIDA). “Changes in brain structure and function is what makes it, fundamentally, a brain disease. A metaphorical switch in the brain seems to be thrown as a result of prolonged drug use.”

Addiction is both a cause and a consequence of these fundamental alterations in brain function. If physical abnormalities in the brain are at the root of the problem, then any treatment program worth its weight ought to be dealing—directly or indirectly--with these differences in brain state. Writing in Lancet, researcher Charles O’Brien has suggested a similar orientation: “Addiction must be approached more like other chronic illnesses--such as diabetes and chronic hypertension--than like an acute illness, such as a bacterial infection or a broken bone."

All of this suggests that we are not likely to win a war on drugs, achieve zero tolerance, or become chemical-free any time soon. The drug problem is an artifact of the basic design of the mammalian brain. Humankind is extraordinarily susceptible to drug abuse anywhere and everywhere certain drugs are widely available—and all because of a “design quirk” in the reward pathways of the central nervous system.

Any sufficiently powerful receptor-active drug is, in its way, fooling Mother Nature. This deceit means, in a sense, that all such drugs are illicit. They are not natural, however organic they may be. Yet, the human drive to use them is all-pervasive. We have no real built-in immunity to drugs that directly target specific receptors in the limbic and cortical pleasure pathways. The act of “liking” something is controlled by the forebrain and brain stem. If you receive a pleasant reward, your reaction is to “like” it.

If, however, you are anticipating a reward, and are, in fact, engaging in behaviors motivated by that anticipation, it can be said that you “want” it. The wholly different act of wanting something strongly is a mesolimbic dopamine-serotonin phenomenon. We like to receive gifts, for example, but we want food, sex, and drugs. As Nesse and Berridge put it, “The ‘liking’ system is activated by receiving the reward, while the ‘wanting’ system anticipates reward and motivates instrumental behaviors. When these two systems are exposed to drugs, the “wanting” system motivates persistent pursuit of drugs that no longer give pleasure, thus offering an explanation for a core paradox in addiction."

Under the biochemical paradigm, a runaway appetite for non-stop stimulation of the reward pathway is a prescription for disaster. The harm is physical, behavioral, and psychological--as are the symptoms. Peer pressure, disciplinary difficulties, contempt for authority--none of these conditions is necessary for drug addiction to blossom. What the drug itself does to people who are biologically vulnerable is enough. No further inducements are required.

Even this brief summation of the ways in which addictive drugs alter neurotransmission should serve to demonstrate that these substances have more in common than we ordinarily assume. All these drugs are of course rewarding, so it is perhaps not too surprising, for all their differences, that they work the limbic reward pathways. All these drugs share common mechanisms of action, which is why they are addictive.

--Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.


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