Of Mice and Methamphetamine

Diabetes drug being tested for addiction.

It’s a mouthful: peroxisome proliferator activated receptor gamma (PPAR-gamma). 

Peroxisomes are specialized subunits inside cells that help metabolize various substances, including fatty acids and certain toxins. A blockbuster member of this drug family—Avandia—is a much disputed but immensely lucrative diabetes medicine that may cause heart failure.

(Partial Agonist Ppar Gamma Cocrystal)--------->

PPAR gamma agonists belong to a class of drugs known as thiazolidinediones. Clinical research has pointed toward additional therapeutic applications for thiazolidinediones in the areas of inflammation and cancer. The only approved use for thiazolidinediones is in the treatment of diabetes, but the drug class has also been studied for treatment of polycystic ovary syndrome, psoriasis, autism—and now drug addictions. A PPAR compound will soon undergo testing under the auspices of the Omeros Corporation, with funding from the National Institute on Drug Abuse (NIDA).

Omeros says it has developed a novel drug “for the prevention and treatment of addiction to substances of abuse, such as opioids nicotine and alcohol, as well as other compulsive behaviors, including eating disorders.” Phase 2 clinical studies on opiate addiction by Dr. Sandra D. Comer and associates at the New York State Psychiatric Institute will begin soon, according to an Omeros press release.

Such claims add up to a tall order for any anti-craving drug. In fact, no drug currently exists for the treatment of so wide a spectrum of addictive disorders. Nonetheless, Omeros claims to have demonstrated a previously unknown link between a variant of this family of diabetes medications and addiction.

The heart problems linked to the PPAR marketed as Avandia may be a special case. According to an article by Gardiner Harris in the New York Times, based on government reports obtained by the newspaper: “If every diabetic now taking Avandia were instead given a similar pill named Actos, about 500 heart attacks and 300 cases of heart failure would be averted every month because Avandia can hurt the heart. Avandia, intended to treat Type 2 diabetes, is known as rosiglitazone and was linked to 304 deaths during the third quarter of 2009.” Actos, another thiazolidinedione, has not been linked to any heart trouble.

 GlaxoSmithKline is disputing the findings. A number of other pharmaceutical houses—AstraZeneca, and Eli Lilly among them—discontinued their first generation PPAR drugs. The derivative marketed as Avandia is not the compound under study by Omeros.

There is little clinical evidence to bolster the PPAR theory. A recent Spanish study suggested the possibility that PPAR gene variants may be associated with higher alcohol consumption in a small sampling of Mediterranean drinkers.

The most comprehensive study may be a 2007 paper in Neuropsychopharmacology by Takehiko and coworkers, demonstrating that PPARs can have an effect on behavioral sensitization to methamphetamine in mice.

Behavioral sensitization is the name for the progressive increase in meth-driven locomotor activity over time. The researchers found that a PPAR variant “plays an inhibitory role in the expression” of sensitization to methamphetamine. The action takes place in the brain’s nucleus accumbens, where repeated hits of meth cause an increase in PPAR expression, according to the researchers: “These results indicate that [an isotope of PPAR] in the reward system is involved in behavioral sensitization to METH.”

What is the mechanism of action? The researchers speculate that upregulation and activation of PPAR in the meth-crazy mice may be due in part to an inflammatory response. PPAR, in theory, exerts anti-inflammatory activity in brain cells.  And psychostimulants, according to the researchers, “upregulate the expression of target genes via activation of inflammatory-responsive transcriptional factors.”

Maeda, T., Kiguchi, N., Fukazawa, Y., Yamamoto, A., Ozaki, M., & Kishioka, S. (2006). Peroxisome Proliferator-Activated Receptor Gamma Activation Relieves Expression of Behavioral Sensitization to Methamphetamine in Mice Neuropsychopharmacology, 32 (5), 1133-1140 DOI: 10.1038/sj.npp.1301213

Graphics Credit: http://www.prostaglandinresearch.com

Alcohol: The Genetic Puzzle (3 of 3)

What about other drugs?

Do the same genetic relationships demonstrated in the alcohol adoption studies prove true for other drugs? Was it conceivable that heroin addiction or cigarette smoking could be traits (disorders, really) that men and women inherited?

“There have been a number of animal studies showing genetic differences in sensitivity to nicotine,” said Dr. Neal Benowitz of the Clinical Pharmacology Unit at San Francisco General Hospital, one of the nation’s premier nicotine research centers. And Professor Ovide Pomerleau, the Director of Behavioral Medicine at the University of Michigan Medical School, who collaborated with Cloninger’s group on genetic studies of nicotine and alcohol, told me: “Some people are drawn to smoking, and some people are not. Everybody pretty much goes through the same kind of peer pressures, the same kind of socialization pressures, and then you have some people who emerge as smokers, and some people who don’t. Some people who start smoking give it up easily, and there are others who can’t. Well, why? My answer is that I think there are innate differences in susceptibility.” 

The Cadoret group looked into the question and reported in the Archives of General Psychiatry that alcohol problems in biological relatives appeared to correlate highly with drug abuse in siblings. “Some theorists have suggested that multiple addictions to a wide variety of substances constitute evidence against a genetic interpretation of addiction,” wrote Cadoret. “The present data appear to refute that position, suggesting instead some underlying biochemical foundation involved in all of the substances abused….” 

Dr. Janice Keller Phelps, the drug treatment specialist from Seattle, maintained that “a large number of addicted people I have treated over the years had strong family histories of addiction. Time and again I encountered heroin addicts, cocaine addicts, or speed addicts with one or both parents addicted to alcohol, for example, or with one or more brothers or sisters also addicted—though not necessarily to the same drug. It is known and acknowledged that many alcoholics have one or more alcoholic parents; the large number of children of alcoholics who are not alcoholic but instead are addicted to other substances, however, is not so well recognized.”

In many ways, the genetic findings by Goodwin, Cloninger, and others were as far from the old problems-in-living approach, the Freudian approach, as it was possible to get. As Dr. Edward Sellers, who directed the psychopharmacological research program at the University of Toronto’s Addiction Research Foundation during the 1990s, explained to me: “One simplified way of looking at it is that every cell, every hormone, every membrane in the body has got genetic underpinnings, and while many of the genetic underpinnings are similar in people, in fact there are also huge differences. So on one level, the fact that there is a genetic component to addiction is not very surprising. What is surprising is that you could ever have it show up in a dominant enough way to be something that might be useful in anticipating risk.”

If there existed a set of genes that predisposed people to alcoholism, and possibly other addictions, then these genes had to control the expression of something specific. That’s what genes did. 

However, addiction researchers could not even agree on the matter of where they should be looking for such physical evidence of genetic difference. In the brain? Among the digestive enzymes? Blood platelets? A gene, or a set of genes, coding for…what? Substance H? Production of certain neurotransmitters? What was it they were supposed to be looking for?

What set of genes coded for happiness?

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008.

Graphics Credit: http://www.drugabuse.gov

Alcoholism: The Genetic Puzzle (Cont.)

Type 1s and Type 2s

The alcoholics in the Cloninger-Bohman studies fell into two distinct categories. Type 1, the more common form, developed gradually, later in life, and did not necessarily require structured intervention. Type 1 alcoholic men did not always experience the dramatic declines in health and personal circumstances so characteristic of acute alcoholism. These people sometimes straddled the line between alcoholism and “problem drinking.” For Type 1 alcoholics, the genetic inheritance was more like a latent tendency; a propensity that did not automatically show up in every case. It was as if some environmental triggering mechanism, some outside set of circumstances, was required for the inheritance to express itself.

Type 2 alcoholism was a different story altogether. It was bad business from the start; a very unlucky roll of the dice indeed. Type 2 alcoholics were in serious trouble starting with their first taste of liquor during adolescence. Their condition worsened with horrifying speed. They frequently had a history of violent and antisocial behavior, and they often ended up in prison. They were rarely able to hold down normal jobs or sustain workable marriages for long. Type 2s, also known as “familial” or “violent” alcoholics, were even more likely to have had an alcoholic parent. They were, in short, severely addicted to alcohol.

Almost 20 per cent of children born to Type 2 alcoholics became alcoholics themselves. At first glance, this rate does not seem particularly high. The numbers are not as neat and clean as classic Mendelian genetics would have it. But recessive traits are like that. In the case of a recessive gene, inheritance rates are much lower. “Most behaviors,” writes Tabitha Powledge in Bioscience, “do not wend their way through generations in the manner of Mendel’s smooth and wrinkled peas.”  Viewed in that light, 20 per cent is a very high number, and the Stockholm Adoption Study constituted strong evidence for the inheritability of the condition known as alcoholism.

Goodwin’s Danish studies and the Cloninger-Bohman studies were not the only evidence for a genetic connection in at least some cases of alcoholism. In the United States, Remi Cadoret and a team at the University of Iowa studied Iowa adoptees, and came up with similar results. In fact, more than a dozen major studies of twins pointed to the same conclusion:  In alcoholic families, there is a marked difference in alcoholism rates when identical twins (who share the same genes) are compared with fraternal twins (whose genetic makeup differs). If one identical twin is alcoholic, the likelihood that the other identical twin is also alcoholic turns out to be nearly twice as high as it is with fraternal twins. Alcoholism begets alcoholism, even when the alcoholic parent is nowhere on the scene.

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008.

Graphics Credit: http://brainlink.org/

Alcoholism: The Genetic Puzzle

Fathers and Sons.

The hunt for genetic influences on alcoholism derives largely from the work of Dr. Donald W. Goodwin, chair of the Department of Psychiatry at the University of Kansas Medical Center. Starting in the early 1970s, Dr. Goodwin and co-workers, using computer technology and a detailed database of Scandinavian health records, scrutinized the results of 5,000 adoption cases in Copenhagen. The results of the initial study stunned alcoholism experts around the world. The sons of alcoholics were more likely to become alcoholics themselves, as many had expected. But the relationship held true even when the children of alcoholics were separated from their natural parents shortly after birth, and subsequently raised by foster parents.

In Phase 2 of the Danish studies, Goodwin selected only alcoholic families in which one son had been raised by his biological parents, while the other son had been adopted away early in life. Raised in separate environments, twins of this sort are highly prized for genetic research. Goodwin compared the sons who had been raised by their alcoholic birth parents to their adopted-away brothers. It didn’t seem to make any difference: Rates of alcoholism were roughly the same. Environmental factors alone did not seem to account for it.

“By their late twenties or earlier,” Goodwin wrote, “the offspring of alcoholics had nearly twice the number of alcohol problems and four times the rate of alcoholism as the children whose parents had no record of hospitalization for alcoholism.” It did not look like family environment was the primary determinant.

Perhaps some of the children simply ended up with less effective foster parents, detractors pointed out. Alternatively, some unknown trauma might have been inflicted in the womb. Maybe the pregnant mother drank. Environmental factors can never be ruled out. Nonetheless, the basic implications of Goodwin’s work could not be shaken off. The Danish adoption studies were the first major scientific papers to establish a firm link between heredity and alcoholism.

Beginning in the 1980s, Dr. C. Robert Cloninger, professor of psychiatry and genetics at Washington University in St. Louis, and Michael Bohman, a Swedish pediatrician, began a broader series of adoption studies. The Stockholm Adoption Study scrutinized the records of more than 3,000 adopted individuals, and confirmed the Danish studies: The children of alcoholics, when compared with the children of non-alcoholic parents, were far more likely to become alcoholics themselves—even if they were adopted away. 

Moreover, “Alcohol abuse in the adoptive parents was not associated with an increased risk of abuse in the children they reared,” Cloninger later reported in the journal Science, “so there was no evidence that alcoholism is familial because children imitate their [non-biological] parents.”  

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008.

Graphics Credit: http://www.3dscience.com/

A Seaside Story of Love and Junkies

Documentary airs today on VBS.TV

A reminder that drug addiction is always, at bottom, about real people in the real world: The online video service VBS.TV is offering the first of a 6-part documentary on the underreported heroin epidemic in South Wales.

“Swansea Love Story,” according to its promoters, “follows the lives of a community of young heroin addicts living in an economically ravaged city of South Wales.”

Co-director Andy Kapper said in a press release: “I wanted to make this film because we were tired of seeing homeless young people being portrayed as little more than statistics. Documentaries about drug use often come out pious and fail to really get to know the people behind the drug usage. We wanted to show what it was like to live on the street, under the grip of heroin, as realistically as possible.”

The London Evening Standard called it “stunning, shocking, touching,  and deeply moving.”

I watched Part One. It's only seven minutes long, but it will sit you up straight.

The Nucleus Accumbens

Final destination for addictive drugs.

The release of dopamine and serotonin in the nucleus accumbens lies at the root of active drug addiction. The pattern of neural firing that results from this surge of neurotransmitters is the “high.” It is the chemical essence of what it means to be addicted. Part of the medial forebrain bundle (MFB), which mediates punishment and reward, the nucleus accumbens is the ultimate target for the dopamine released by the ingestion of cocaine, for example.

The release of dopamine and serotonin in the nucleus accumbens appears to be the final destination of the reward pathway—the last act in the pleasure play. If you think about a drug, take a drug, or crave a drug, you are lighting up the nucleus accumbens with a surge of electrochemical activity. These are essentially the same pathways that regulate our food and water-seeking behavior. By directly or indirectly influencing the molecules of pleasure, drugs and alcohol trigger key neurochemical events that are central to our feelings of both reward and disappointment. In this sense, the reward pathway is a route to both pleasure and pain.

Alcohol, heroin, cigarettes, and other drugs caused a surge of dopamine production, which is then released onto the nucleus accumbens. The result:  Pleasure. When scientists pipe a dopamine-mimicking substance into the nucleus accumbens, targeting dopamine D2 receptors, withdrawal symptoms are blocked in morphine-addicted rats. Similarly, when scientists block dopamine receptors in the accumbens, the morphine-dependent rats exhibit withdrawal symptoms.

When you knock out large slices of the nucleus accumbens, animals no longer want the drugs. So, one cure for addiction has been discovered already—but surgically removing chunks of the midbrain just won’t do, of course.

Dopamine is more than a primary pleasure chemical—a “happy hormone,” as it has been called. Dopamine is also the key molecule involved in the memory of pleasurable acts. Dopamine is part of the reason why we remember how much we liked getting high yesterday. The nucleus accumbens (also known as the ventral striatum) seems to be involved in modulating the emotional strength of the signals originating in the hippocampus. This implicates the hippocampus in relapse, even though this area of the brain does not light up as strongly during actual episodes of craving.

The fact that we know all this is nothing short of amazing, but it is part of a larger perspective afforded by the insights of contemporary neurobiology. We know, for example, that the emotion of fear arises, in large part, through chemical changes in a peanut-sized limbic organ called the amygdala. Does this information make fear any less, shall we say, fearful? It merely locates the substrate upon which the sensation of fear is built.

Studies of the nucleus accumbens have demonstrated abnormal firing rates in scanned addicts who were deep into an episode of craving. The craving for a reward denied causes dopamine levels in the nucleus accumbens to crash dramatically, as they do when users go off drugs. Dopamine, serotonin, and norepinephrine activity soars just as dramatically when a drug user relieves withdrawal symptoms by relapsing. Drug hunger in abstinent addicts is not all in the head, or strictly psychological. Craving has a biological basis.  

Finding a way to override serotonin- and dopamine-mediated mid-brain commands is the essential key to recovery from addiction. One of the aims of a biological understanding of addiction is to tease out the mechanisms by which the reinforcing effects of addictive drugs become transformed into long-term adaptive changes in the brain.

Graphics credit: http://thebrain.mcgill.ca/

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008.

Rethinking the Patch

Quitters do better on 6-month regimen.

It may sound like dream propaganda for the makers of nicotine patches. And it is. Moreover, at least one of the study authors has worked in the past as a consultant for GlaxoSmithKline, maker of Nicoderm CQ, one of the best-selling brands of transdermal nicotine patches.

So there is every reason to dismiss a recent study by researchers at the University of Pennsylvania School of Medicine, published in the Annals of Internal Medicine, which strongly suggests that the currently recommended regimen of two months isn’t long enough. It should be tripled. Which also triples sales.

There’s only one catch: There is reason to believe that the results are legitimate, and that smokers who are trying to quit would be more successful if they stuck with the patch for longer periods than currently recommended on the manufacturer’s box.  For some time now, tobacco addiction researchers, and centers such as Mayo Clinic’s Stop Smoking facilities, have recognized the need for extending the manufacturer’s suggested period of use.

Referring to the patch on its Stop Smoking web site, Mayo Clinic says: “You typically use the nicotine patch for eight to 12 weeks. You may need to use it longer if cravings or withdrawal symptoms continue.”

And from the field come reports of abstaining smokers independently choosing to use the patch longer, often by cutting the patches into eighths or sixteenths in order to accomplish a long, slow taper at the end of the process. By following this route, a nicotine addict need not be aware of the precise day or moment when his nicotine fix from the patch has dropped to placebo levels—further evidence that nicotine addiction is a chronic condition that may not respond to treatments of only two to three months in duration. 

One early development during the marketing of the patch that helped set the short-term use pattern were reports in the 1990s of heart attacks by patch users. Subsequent research showed that rare cardiac problems had arisen in patients who had continued heavy smoking while on the patch, and that there was little evidence of a direct link between nicotine patches and heart attacks. (Recent heart attack victims are advised to wait six weeks and use patches with caution.)

The study concludes: “Transdermal nicotine for 24 weeks increased biochemically confirmed point-prevalence abstinence and continuous abstinence at week 24, reduced the risk for smoking lapses, and increased the likelihood of recovery to abstinence after a lapse compared with 8 weeks of transdermal nicotine therapy.”

One limitation of this particular study, acknowledged as such by the authors, is that “participants were smokers without medical comorbid conditions who were seeking treatment.” In other words, the study cohort consisted of highly motivated smokers.

And another problem is cost: Few health insurance companies cover the full cost of patches, including Medicaid. The additional cost per quitter, the study found, was about $2,400 for the extended regimen.

Nonetheless, any uptick in success rates for smoking cessation programs should be noted and taken under consideration.

Photo Credit: www.drugabuse.gov