Strategies Against Methamphetamine and Cocaine Described at ASAM Meeting

November 1, 2007

Widespread media reports and billboard campaigns decrying a methamphetamine epidemic are drawing attention away from the greater and more entrenched use of cocaine, according to a National Institute of Drug Abuse (NIDA) scientist speaking at the American Society of Addiction Medicine's (ASAM) 38th Annual Medical-Scientific Conference, held in Miami, April 26 to 29.

Widespread media reports and billboard campaigns decrying a methamphetamine epidemic are drawing attention away from the greater and more entrenched use of cocaine, according to a National Institute of Drug Abuse (NIDA) scientist speaking at the American Society of Addiction Medicine's (ASAM) 38th Annual Medical-Scientific Conference, held in Miami, April 26 to 29.

In a symposium sponsored by the NIDA, Wilson Compton, MD, director of the Division of Epidemiology, Services and Prevention Research, said that cocaine remains the recreational stimulant drug of choice, used by 5% to 6% of the US population, compared with 1.5% to 2.5% of the population using methamphetamine.

There are regional and racial differences in use, however, and Compton noted a relatively higher use of methamphetamine among Hawaiian and Native American populations, and an apparent progression of use from Pacific islands and the western United States toward the East Coast.

PERSPECTIVE ON METHAMPHETAMINE EPIDEMIOLOGY

Compton attributed the increasing news coverage, despite relatively stable levels of methamphetamine use, to the means of manufacturing and trafficking the drug, as well as to possible increases in toxicity. In contrast to the concealed transport of cocaine across borders, methamphetamine laboratories have been found and "busted" in residential neighborhoods, with families in proximity to the toxic, unstable compounds. Families are also aware of, and affected by, the nationwide restrictions on pseudoephedrine, an ingredient in popular cold and flu remedies and a principal component in the manufacture of methamphetamine.

In addition, the pattern of use, spreading from the western states toward the East, gives credence to the "gathering threat" of methamphet-amine. Methamphetamine use is also increasingly associated, Compton noted, with both HIV infection and medication-resistant HIV infection, in a manner previously observed with crack cocaine. There has also been an increase in the number of methamphetamine users seeking treatment for medical complications and for detoxification, Compton indicated. "There is a distinction between the public health--the population-based survey showing, if anything, a decrease in meth use overall--and the tremendous increase in the problems associated with [it], with the admission rates."

He suggested that some increase in the presented complications from methamphetamine use may be the result of a shift in the preferred route of administration from oral and injection to inhalation by smoking. An increase in toxicity may also correspond to an increase in purity, Compton said, with imports from Mexico replacing the products from domestic laboratories that are closed or are unable to obtain the pseudoephedrine base or other manufacturing components.

Domestic producers persist, however, as reflected in a July news report in the Des Moines Register of Iowa farmers securing their fertilizer tanks against the pilfering of anhydrous ammonium nitrate for use in manufacturing meth-amphetamine. More than 4000 locks for the tanks have been distributed in the state, and there are plans to add calcium nitrate to render the mixture unsuitable for the methamphetamine labs. These measures were characterized in a news conference by Lt Gov Patty Judge as "one more success in Iowa's fight against the substance."

NEURAL TARGETS FOR STIMULANT ADDICTION Glutamatergic pathways

Kathleen Brady, MD, PhD, professor of psychiatry and director of the Clinical Neurosciences Program at the Med- ical University of South Carolina in Charleston, described several neurotransmitter targets for research in developing medications to treat methamphetamine, cocaine, and other stimulant drug addictions. She said that the excitatory glutamate pathways to the mesolimbic dopaminergic cell groups of the nucleus accumbens and ventral tegmental area (VTA) have been associated with mechanisms for associative learning. Glutamate helps in forming memories and associations via long-term potentiation through stimulating dopamine release in the VTA, Brady explained.

These pathways, she suggested, are "laying the tracks for the context, memory, and emotional valence that's associated with drug use and drug cues."

Although Brady considers topiramate (Topamax) to be one of the more promising agents to affect the glutamatergic system for this purpose, she notes that it is not easy to use in this population because it requires gradual dose titration to avoid cognitive dysfunction and other adverse effects. When the daily dose is raised to 200 mg, however, there are promising data on reduced cocaine use compared with placebo, with more subjects maintaining urine test evidence of drug abstinence for 3 consecutive weeks.

Other agents affecting the glutamatergic system that are being assessed as applications for stimulant substance abuse include N-acetyl-l-cysteine (NAC), an antidote for acetaminophen overdose, which interferes with the cysteine-glutamine exchange, increasing glutamate and, in early testing, appears to reduce cue-induced craving; and D-cycloserine (DCS), an antituberculosis agent and N-methyl-d-aspartate agonist that has been used to facilitate exposure-based extinction therapies in anxiety disorders and for which there is preliminary evidence that it facilitates extinction of response to cocaine cues.

Modafinil (Provigil) also affects the glutamatergic system, Brady said. Charles Dackis, MD, chief of psychiatry at the Penn Presbyterian Medical Center in Philadelphia, commented that it was originally considered for trials with cocaine because its therapeutic effects appear to be the opposite of symptoms that occur in cocaine detoxification. "It relieves nearly all of the symptoms of cocaine withdrawal," Dackis said, "over-sleeping, over-eating, decreased energy, and poor concentration."

A surprising finding from the modafinil trials is that the agent also blunts the euphoric effects of cocaine. In one trial, not yet published, the degree of blunting was assessed by whether chronic cocaine users would opt for $10 rather than for another line of cocaine. Those with modafinil pretreatment took the $10, Dackis said, because of the unsatisfactory effect of subsequently administered cocaine.

Targeting GABA and dopamine

The g-aminobutyric acid-ergic (GABA-ergic) system was described by Brady as a counterbalance to the excitatory glutamate system, with dopamine release in the nucleus accumbens under strong GABA-ergic inhibitory controls. "So, you can try to manipulate either side of this equation, and impact dopamine release without necessarily targeting dopamine receptors," Brady said.

The prospect of an indirect mechanism to affect mesolimbic dopamine levels in treating stimulant drug abuse is attractive in part, Brady said, because of unimpressive trials to date with directly active dopaminergic agents, such as methylphenidate (Concerta, Metadate, Methylin, Ritalin), amantadine (Symmetrel), selegiline (Eldepryl, Zelapar), and bromocriptine (Parlodel). She noted, however, that early studies with aripiprazole (Abilify), which exerts mixed effects on dopamine, suggest potential for blunting subjective stimulant effects.

One novel and promising agent affecting dopamine is the alcohol consumption deterrent, disulfiram (Anta-buse), which Brady described as "probably the one with the most potential." Although principally used to inhibit the metabolism of ethanol by aldehyde dehydrogenase, Brady explained that disulfiram also increases central dopamine transmission by inhibiting dopamine b-hydroxylase.

"The efficacy in cocaine dependence is really not based on decreasing alcohol use," Brady said. "It looks like there is a specific cocaine effect."

Kyle M. Kampman, MD, of the University of Pennsylvania Center for Studies of Addiction, noted that disulfiram is being used in combination with naltrexone in clinical trials for codependency on cocaine and alcohol. "These patients tend to have significantly more psychosocial problems, and they also have significantly worse outcomes," he said. "Specifically, these patients are harder to retain in treatment and harder to get abstinent, either from cocaine or alcohol."

Kampman concurred with Brady on the potential benefit of disulfiram to reduce cocaine use. "Whatever the mechanism of action, there are few medications that we've tested for cocaine dependence that have the track record that disulfiram has," Kampman declared. "There are actually, now, 3 double-blind, placebo-controlled trials of disulfiram for cocaine dependence that have been positive."

Frank Vocci, PhD, director of NIDA's Division of Pharmacotherapies and Medical Consequences of Drug Abuse and moderator of the symposium, commented that the dopamine D3 receptor antagonists have shown greater promise for this application than agents affecting D2. In animal model testing, there are indications of a "trifecta" success, Vocci declared, with D3 antagonist investigational agents reducing reinstatement of cue-induced, priming-induced, and stress-induced stimulant drug consumption.

Vocci noted that the neurobiological basis for using D3 antagonists is also dramatic: within 8 hours of a single dose of methamphetamine or cocaine, there is a 25% increase in D3 receptors in several sites in the rat brain, including the shell of the nucleus accumbens, where these receptors are most prominent at baseline. "I can't say that nothing else in neurobiology would happen like this, but this is an extremely robust response," Vocci said.

Agents affecting the GABA-ergic system that have shown promise include baclofen (Lioresal), a GABAb agonist indicated for spasticity, which has demonstrated some ability to reduce cue-induced cocaine craving. Brady noted that this agent appears more effective with higher levels of cocaine use at baseline.

An antiepileptic that inhibits GABA transaminase, vigabatrin (Sabril), is used outside the United States as a second- or third-line agent, but it was not approved by the FDA because of relatively rare but serious visual field defects developing with long-term use. Short-term use of this drug to reduce stimulant drug abuse is currently being evaluated by the manufacturer with NIDA collaboration, Brady said.

"The data in animals with this agent are very, very compelling in terms of decreasing cocaine use and other drug use," Brady said. "I think this is going to be a really promising agent, and I think we're going to be hearing a lot more about it."

This sentiment was echoed at the conclusion of the symposium by Vocci. "This drug [vigabatrin], I think, is going to have a more robust effect than the other drugs you've heard about today."

Other agents affecting the GABA-ergic system and being assessed for their usefulness to treat stimulant abuse include tiagabine (Gabitril), for which there are preliminary data showing reduced cocaine craving, and progesterone, which affects the GABA-ergic system in addition to endocrinological sites. Brady is currently studying pro-gesterone for this application, observing that it has "a lot of implications for the menstrual cycle phase and cocaine use cessation."

Brady anticipates that several of these research directions will yield useful medications for the treatment of stimulant addiction. "While we still have no FDA-approved medications for the treatment of cocaine dependence," Brady concluded, "there are, I think, a number of very exciting new strategies under development with really exciting pilot data."