Cocaine Treatment and the Stroop Test

Treatment dropouts do poorly on color/word match.

It’s commonly used to demonstrate behavioral inhibition, but it’s also a nifty parlor game. It is called the Stroop Test, and it plays off the fact that people are far better at reading words than they are at intentionally ignoring them. To prove it, John Ridley Stroop’s 1935 Ph.D. thesis showed how difficult it is to interfere with the automatic processing of words. In the basic Stroop test, a list of color names is presented. However, the word green might be printed in red ink, and the word red might be printed in blue ink. The task is to quickly name not the word itself, but the color of the word. As an example, for the word “green” printed in red ink, the correct verbal answer is “red.” Because of a phenomenon called directed attention, this is hilariously difficult to do. The subject must actively inhibit the automatic response—reading the word—in order to do something else.

What’s all this got to do with drug addiction?

Psychologists have known for some time that drug craving focuses attention on drug-related stimuli in the environment, and draws attention away from environmental cues unrelated to drugs. Naturally, researchers began to wonder whether the Stroop test could be brought to bear on the matter of addiction, and employed as a tool with which to predict the likelihood of relapse among the addict population. 

As researchers at the University of Wales have pointed out,  “Decisions about drinking and drug use can be highly automatic, with users being unaware of the factors that influence their decisions.” At the same time, addicts are hyper-aware of addiction-related environmental stimuli, compared to non-addicts. As a result, “the automatic processing of addiction-related stimuli might elicit conditioned responses such as withdrawal… or they might invoke automatic patterns leading to substance use.”

In a recent study of treatment dropouts among 74 cocaine-addicted subjects, published in Neuropsychopharmacology, Dr. Chris Streeter and coworkers at the Boston University School of Medicine and Harvard University provide strong evidence for the use of the Stroop Test as a diagnostic tool in addiction treatment.  Variations on the Stroop Test were better predictors of dropout than addiction severity, depression, and other clinical variables.  Dropouts took 24 per cent longer, on average, to finish the tests than cocaine addicts who stuck with treatment, the researchers reported.  “These finding suggest that the Stroop test can be used to identify cocaine-dependent subjects at risk for treatment dropout,” say the researchers, and that it can serve as another instrument with which to “identify and tailor interventions of at risk individuals in the hope of improving treatment compliance.”

Furthermore, other studies suggest that attentional bias may serve as a useful predictor of opiate relapse and smoking cessation failure as well.

Streeter, C., Terhune, D., Whitfield, T., Gruber, S., Sarid-Segal, O., Silveri, M., Tzilos, G., Afshar, M., Rouse, E., Tian, H., Renshaw, P., Ciraulo, D., & Yurgelun-Todd, D. (2007). Performance on the Stroop Predicts Treatment Compliance in Cocaine-Dependent Individuals Neuropsychopharmacology, 33 (4), 827-836 DOI: 10.1038/sj.npp.1301465

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The Cocaine Conundrum

Effective treatment remains elusive.

For addiction to cocaine, amphetamine, and other stimulants, the treatment picture has been complicated by the lack of any truly significant anti-craving medications. (See post, “No Pill for Stimulant Addiction"). The National Institute on Drug Abuse (NIDA) has yet to approve any medications for the treatment of either cocaine or amphetamine addiction.

Take the case of cocaine. Partly the problem stems from the direct effect cocaine has on dopamine transmission.  The hunt for a pharmaceutical approach to blunt that effect is complicated by the problematic nature of dopamine receptors.  Dopamine antagonist drugs like the antipsychotic drug haloperidol do not always block the stimulant rush. And their side effects, such as lethargy, emotional blunting, and tardive dyskinesia, make them unsuitable for ongoing addiction therapy. Conversely, some drugs that act as dopamine agonists turn out to be addictive in their own right. Many designer drugs are like that.

Because of all this, different approaches may be needed. The direct ride to the pleasure pathway provided by stimulants makes it difficult to tamper selectively with their effects. An antibody that would reduce cocaine consumption and sop up cocaine molecules in the brain, a kind of vaccine against cocaine, is one approach being pursued (See post, “Cocaine Vaccine Hits Snag”).

But other avenues of attack are being exploited.  Scientists in NIDA’s Intramural Research Program are testing compounds that target certain proteins known as dopamine transporters. Transporters move dopamine molecules in and out of the synaptic gap between neurons in the brain. Interfering with that transportation system is another way of altering dopamine uptake, and it represents one active avenue of approach to the treatment of cocaine addiction.

The researchers tested Benztropine Mesylate (BZT), brand name Cogentin, one of a class of drugs known as anticholinergic suppressants commonly used in the management of Parkinson’s disease. What exactly does benztropine do? It possesses both anticholinergic (acetylcholine-blocking) and antihistaminic effects. It has chemical similarities to atropine, which is used for Parkinson’s and for heart disease.

To begin with, the researchers wanted to establish that benztropine itself is non-addictive. By substituting different BZT analogs for cocaine during self-administration testing on addicted rats, “two of the three BZT analogs that were tested significantly reduced drug self-administration… which indicates that those BZT analogs themselves have low potential for abuse.”

Next, the cocaine-addicted rats were given different BZT analogs before they got their cocaine. “When given before rats had access to cocaine in the self-administration chambers,” the researchers reported in the Journal of Pharmacology and Experimental Therapeutics, “two BZT analogs also significantly reduced the number of times the rats would press a lever to receive cocaine.” Monoamine uptake inhibitors were used as a control. The authors conclude that “these compounds are promising candidates for the development of medications for cocaine addiction.”

Hiranita, T., Soto, P., Newman, A., & Katz, J. (2009). Assessment of Reinforcing Effects of Benztropine Analogs and Their Effects on Cocaine Self-Administration in Rats: Comparisons with Monoamine Uptake Inhibitors Journal of Pharmacology and Experimental Therapeutics, 329 (2), 677-686 DOI: 10.1124/jpet.108.145813

Photo credit: http://www.drugabuse.gov

Cocaine Vaccine Hits Snag

Some addicts risk OD to overcome its effects.

The National Institute on Drug Abuse (NIDA) has increasingly placed its bets on treating cocaine addiction with a vaccine rather than an anti-craving medication. And there is reason for this: No prominent candidates for anti-craving drug treatments have yet emerged from the research on cocaine and methamphetamine addiction.

However, there’s a catch: Some cocaine addicts appear willing to risk overdose in order to defeat a new cocaine vaccine, a recent study has shown.

The study, which appeared in the Archives of General Psychiatry, demonstrated that the TA-CD vaccine could blunt the effects of cocaine in some, but not all, patients. The vaccine works by causing the production of antibodies, which attach themselves to cocaine molecules, making the molecules too big too pass effectively through the blood-brain barrier.

Of 115 addicts involved in the study, only 38 % produced sufficient antibodies to dull the effects of cocaine, Rachel Saslow of the Washington Post  reported. And among the high-antibodies group, only 53 % stayed free of cocaine 50 % of the time. “Immunization did not achieve complete abstinence from cocaine use,” said Thomas Kosten of Baylor college of Medicine, one of the authors of the paper.

Moreover, in some of the study participants for whom antibodies made cocaine a disappointing high, researchers found cocaine levels in the body to be as much as ten times higher than previous levels of usage—an obvious attempt to overcome the vaccine’s effectiveness. There were no overdoses, according to Kosten.

No researcher has claimed this as a complete breakthrough, in light of the fact that even those who responded well in the high-antibody group achieved a substantial reduction in cocaine use during the study period--but not abstinence. At this stage the work appears to be aimed more at dose reduction.

Despite the mixed results, NIDA director Nora Volkow characterized the work as “a promising step toward an effective medical treatment for cocaine addiction,” with the proviso that “larger follow-up studies confirm its safety and efficacy.” In an earlier interview with Addiction Inbox, Volkow also expressed excitement about another possible addiction vaccine: “Currently there are anti-nicotine vaccines in clinical testing, which are designed to capture the nicotine molecules while still in the bloodstream, thus blocking their entry in to the brain and inhibiting their behavioral effects. They appear to be effective in helping subjects who develop a high antibody response sustain abstinence over long periods of time. Even those people with a less robust antibody response to the vaccine, decreased their tobacco use. So this approach appears very promising.”

An earlier study by Margaret Haney and others at Columbian University Medical Center, published in Biological Psychiatry, had similar results: “The TA-CD vaccine substantially decreased smoked cocaine's intoxicating effects in those generating sufficient antibody.”

In both studies, roughly a quarter of participants made almost no antibodies at all in response to a vaccine injection.

A multi-site clinical trial of the vaccine, headed up by Kosten at Baylor, will begin sometime this spring.

Haney of Columbia told the Washington Post that people “have a mistaken view of how a vaccine might work, thinking of it as magic, where what it’s doing, at best, is blunting the effects. They get very excited, and it’s heartbreaking.” An earlier Addiction Inbox post on cocaine vaccination brought several emails from people asking where they could obtain the vaccine.

DrugMonkey at scienceblogs.com dissected the complicated study, particularly the different levels of antibodies generated in study participants, calling the vaccine “quite obviously not a silver bullet at present.” Furthermore: “Even for the high-responders the outcome was far from overwhelming, a 10 percentage improvement from 35% to 45% cocaine-free urines.” 

Given how intractable to treatment addiction to stimulants has proven, any promising results at all are cause for cautious optimism. DrugMonkey writes: “We need new approaches and this immunopharmacotherapy stuff has potential.”

Photo Credit: http://addictions.about.com/b/2009/10/10/new-cocaine-vaccine.htm

Who are Cocaine’s Primary Victims?

The answer may surprise you.

They are not necessarily the poor, the desperate, or the weak-willed. A National Institute of Drug Abuse (NIDA) study by Dr. Michael Nader and coworkers at Wake Forest University demonstrates that they are likely to be people with innately low levels of dopamine receptor availability. This flaw, possibly genetic, renders them more sensitive to the rewarding effects of cocaine. Put simply: Individuals with less dopamine naturally available in the brain may have an inherited predisposition for cocaine addiction. [Brains Scans at right: Dopamine receptor availability in yellow falls markedly after 6 and 12 months of cocaine self-administration.]

Dopamine D2 receptors, a crucial part of the brain’s primary reward system, are normally occupied by dopamine molecules—although at any given moment, many of the receptors are empty and remain available until a stimulus like cocaine increases dopamine levels and the empty receptors help mop up the excess. Dr. Nader believes that lower D2 receptor availability could be a precursor of addiction to drugs like cocaine. “Perhaps an individual with low availability gets a greater kick from cocaine because the drug-induced dopamine release stimulates a greater percentage of their receptors,” Dr. Nader told staff writer Lori Whitten in a recent edition of NIDA Notes. “Another possibility is that the drug prompts some individuals’ brain cells to release dopamine in particularly high quantities that are sufficient to fill the great majority of vacant D2 receptors, and this augments the high.”

An obvious question hangs over studies of this kind: Are the D2 receptor differences innate, or do they represent changes induced by drug use? To answer this question, Dr. Nader’s team worked with rhesus monkeys in order to take D2 density measurements with PET scans before the animals had ever been exposed to cocaine. Sure enough, the monkeys with the lowest baseline level of D2 receptor availability went on to self-administer cocaine at much higher rates than their D2-normal compatriots. Offering food to the low-dopamine animals did not prove to be a substitute of cocaine, so the effect does not appear to increase all kinds of reward.

There is no doubt that the use of cocaine itself does lead to a rapid reduction of available dopamine receptors, as the brain seeks to achieve a new equilibrium in the face of regular dosings of dopamine-active chemicals. In five monkeys that self-administered cocaine for a year, three of the monkeys showed a strong recovery of receptor availability after only a month of abstinence. However, two of the monkeys showed slower recovery of previous D2 receptor levels. Dr. Cora Lee Wetherington, a neuroscience researcher at NIDA, said that the research thus posed the question of whether people whose dopamine receptor levels recover more slowly during abstinence might prove to be those most likely to relapse.

Medications that increase D2 receptor availability without themselves being highly rewarding represent another promising avenue for treatment. The drugs most likely to help, Dr. Nader thinks, are drugs that act indirectly on dopamine levels through alterations of serotonin and GABA levels in the brain. In addition, researchers are pursuing environmental enrichment experiments in animals and human subjects. Some studies have shown that enriching the environment results in greater D2 receptor levels, Dr. Nader says.

Photo Credit: NIDA

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Drugs for Cocaine Addiction

Researchers target GABA, noradrenaline.

According to Catalyst Pharmaceutical Partners, a company conducting research on drugs for the treatment of addiction, "The U.S. Food and Drug Administration has recognized that cocaine addiction is a 'serious, life-threatening condition for which there is no current drug treatment,' and the National Institute on Drug Abuse (NIDA) has stated that finding a pharmacological treatment for cocaine addiction is their number one research priority."

Other researchers view it differently, however. Allan Parry, a drug counsellor in Liverpool, U.K., told New Scientist that such work was "only likely to be relevant to a tiny minority of people. People often give up cocaine because their lifestyle changes or they just grow up."

Fighting fire with fire--using drugs to treat drug addiction--will likely remain a controversial approach for years to come.

What is the rationale for the use of drugs in the treatment of drug addiction? There are two basic approaches. Scientists look for medications that help patients initiate abstinence, and they look for drugs that help prevent relapse once the patient has achieved abstinence. The categories are not hard and fast. For example, a drug that effective reduces the reinforcing effects of cocaine by reducing the intensity of withdrawal can theoretically perform both functions at once. On the other hand, a drug that blunts the euphoric effects of cocaine--a drug that takes away the best of the buzz, no matter how much cocaine is ingested--can also succeed at the twin tasks of abstinence initiation and relapse prevention.

The search for medications with which to treat cocaine addiction has been in progress much longer than equivalent efforts aimed at methamphetamine addiction. One research target of long standing is modafinil, an odd-duck drug sold as Provigil for the treatment of narcolepsy. A mild stimulant, modafinil does a little bit of everything, pharmacologically tweaking dopamine, noradrenaline, anandamide and GABA receptor systems. Perhaps for this reason, the drug seemingly has been tried for almost everything, from Alzheimer's to atypical depression to jet lag. The U.S. military has reportedly shown some interest in it.

According to published research by Kyle M. Kampman in the June 2008 Addiction Science and Clinical Practice (PDF), modafinil-treated human subjects used less cocaine than placebo-using counterparts did in several recent small-scale studies. "In a double blind pilot trial with 62 cocaine-dependent patients, those who received modafinil submitted more cocaine-metabolite-free urine samples than placebo-treated patients (42 vs. 22 percent; Dackis et al., 2005)."

Propranolol, better known as the beta-blocker Inderal, works primarily by suppressing adrenaline and noradrenaline levels. In human studies to date, propranolol has shown itself most effective with the most severely cocaine-addicted patients. Studies by Kampman have shown that propanolol-treated patients stay in treatment longer than patients in control groups do.

Specific research on relapse prevention strategies has focused on GABA-enhancing drugs that inhibit cocaine reinforcement by secondarily blocking the dopamine surge characteristic of cocaine intoxication. In addition to vigabatrin, discussed in the previous post, topiramate is another particularly well-suited candidate for relapse prevention. Known as Topamax, and prescribed for seizures and migraines, the drug has shown early promise: "In a 13-week, double-blind, placebo-controlled pilot trial of topiramate involving 40 cocaine-dependent patients.... more of those on topiramate achieved at least 3 weeks of continuous abstinence (59 vs. 26 percent)."

Surprisingly, the granddaddy of all anti-addiction drugs--Antabuse--has made a comeback as a subject of study for cocaine addiction, even though it has never been spectacularly effective in its original application as a relapse prevention drug for alcoholics. Disulfiram, as it is known chemically, causes unpleasant physical sensations, including vomiting, when combined with even small amounts of alcohol. It does so by inhibiting the enzymes responsible for degrading alcohol. Even a little becomes too much. In similar fashion, disulfiram retards the breakdown of cocaine, leading to extremely high levels that induce paranoia and anxiety rather than a pleasurable, if extreme, high. At least four published trials have demonstrated reduced cocaine use in disulfiram-treated patients, according to Kampman's paper . One important downside to using Antabuse for cocaine addiction is that serious complications might occur if alcohol is added to the mix.

Finally, and still well into the future, is the prospect of relapse prevention therapy by means of a vaccine--an entirely different mechanism of approach. Research has shown that it is possible to produce "cocaine-specific antibodies that bind to cocaine molecules and prevent them from crossing the blood-brain barrier, thereby blunting the drug's euphoric and reinforcing effects," Kampman's paper asserts. A vaccine called TA-CD has tested well in preliminary studies.

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.

Photo Credit: MTV News

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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