Bringing New Medications to the Treatment of Addiction

Kampman et al. (1998) reported on the validity of the Cocaine Selective Severity Scale (CSSA), which maps the intensity of cocaine withdrawal signs and symptoms at treatment entry and during the treatment process. The investigators found that this scale, in combination with baseline urine results, predicts ability to attain three weeks of cocaine abstinence in 87% of the cases analyzed (Kampman et al., 2002). In addition to demonstrating the obvious merit of identifying patients who might need additional attention and more intense treatment, the researchers also showed that patients with high CSSA scores responded better to amantadine(Drug information on amantadine) (Symmetrel) (Kampman et al., 2000) and propranolol(Drug information on propranolol) (Inderal) (Kampman et al., 2001) in placebo-controlled trials. Follow-up studies are in progress.

Building on knowledge gained from animal studies suggesting that cocaine's blockade of the dopamine(Drug information on dopamine) transporter plays a key role in producing its addictive and reinforcing effects, NIDA has been studying the compound GBR 12909 (Vanoxerine) as a potential medication for cocaine addiction.

Studies show that GBR 12909 (Vanoxerine) has a strong affinity for the dopamine transporter, greater than that of cocaine. Unlike cocaine, however, which produces a dramatic spike of dopamine, causing a burst of euphoria, GBR 12909 binds more slowly to the transporter and produces a relatively modest and long-lasting increase in dopamine (Tsukada et al., 2000), an indication that it could be used as a medication to dampen cocaine's euphoric effects and be especially useful in reducing cocaine craving. A self-administration study in monkeys using GBR 12909 as a pretreatment showed an elimination of cocaine self-administration (Glowa et al., 1995a, 1995b). More recent studies showed the effect of GBR 12909 was enhanced in conditions where lower unit doses of cocaine were available or response requirements for cocaine were high (Stafford et al., 2000). The drug is currently being tested in a cocaine-experienced population to determine its effects in this population, including subjective effects. An interaction study testing the effects of GBR 12909 on the subjective and cardiovascular effects of cocaine will then precede any outpatient studies.

Another compound NS2359 also known for its ability to modulate the dopamine transporter is being tested in a cocaine-dependent population as part of a Phase I safety study. Both compounds (GBR 12909 and NS2359) may restore the brain's neurotransmitter homeostasis, and, as a result, these potential medications may help cocaine addicts overcome negative mood symptoms and loss of energy.

Recognizing that the dopamine system appears to be the critical substrate for both the reinforcing effects and the psychomotor stimulant effects of cocaine and amphetamines, much work is being done at all three dopamine receptor subtypes: D₁, D₂ and D₃. For example, researchers are using high throughput screening procedures to screen vast libraries of chemical compounds with potential for use as D₁ receptor agonists. These compounds have been shown to block cocaine priming, and NIDA has already screened three libraries containing some 65,000 compounds.

Several D₃ receptor partial agonist compounds are being looked at for their potential in preventing relapse to cocaine. Tests in rats by two different groups have found that D₃ compounds suppress cocaine self-administration (Pilla et al., 1999; Vorel et al., 2002). Researchers are particularly interested in how the compound can suppress the "conditioned cueing" phenomena, wherein cocaine users react to conditioned prompts that they relate to their previous pleasures and experiences with cocaine use.

Additionally, NIDA is supporting the development of an anti-cocaine vaccine. Preclinical tests show the vaccine can block a significant percentage of cocaine from reaching the brain by preventing it from passing through the body's protective blood-brain barrier (Kosten et al., 2002). An outpatient study of this vaccine is scheduled to begin in spring 2003.

Building on the knowledge gained from developing medications for cocaine addiction, NIDA is making progress on treatments for methamphetamine. It has initiated a number of activities to stimulate more research on this particular drug, including launching the Methamphetamine Treatment Discovery Program to identify, evaluate and recommend potential treatments to manage methamphetamine addiction. Several medications are under development for treating different consequences of methamphetamine abuse. Many of the drugs under development target the brain's dopamine system. For example, two FDA-approved drugs, selegiline(Drug information on selegiline) (Elderpryl) and bupropion (Wellbutrin), are being tested in Phase I interactions studies in methamphetamine users before proceeding to Phase II evaluations for safety and efficacy. Bupropion has already been shown to be effective in treating nicotine(Drug information on nicotine) addiction (and is approved for that indication under the brand name Zyban) and may be helpful in treating methamphetamine addiction as well. There are approximately a dozen other medications that are currently under development for methamphetamine addiction.