Experimental Agent Shows Promise for Alcohol Dependence

Megan Brooks

October 29, 2015

An experimental dopamine stabilizer (OSU6162) can reduce the craving for alcohol in dependent adults by normalizing the level of dopamine in the brain, a small phase 2 study from Sweden suggests.

"The compound OSU6162 is unique from available drugs on the market for the treatment of alcohol dependence in that it acts directly on the dopamine system," study investigator Pia Steensland, PhD, of the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, told Medscape Medical News.

"Dopamine is a core neurotransmitter involved in the development and progression of alcohol dependence," Dr Steensland explained. The researchers tested the effects of OSU6162 on cue- and priming-induced craving in 56 alcohol-dependent, treatment-seeking adults in a phase 2 exploratory placebo-controlled human laboratory study.

The study was published online October 6 in the journal European Neuropsychopharmacology.

Less "Liking for Drinking"

For 14 days, participants took either OSU6162 or matching placebo tablets and were instructed not to drink alcohol. On day 15, they participated in three sessions in which craving for alcohol was induced by active (alcohol-specific) cues, neutral stimuli, and priming (drinking an alcoholic beverage containing ethanol, 0.20 g/kg body weight).

Treatment with OSU6162 did not significantly attenuate subjective ratings of cue-induced alcohol craving but did significantly ease subjective ratings of priming-induced craving. OSU6162, compared with placebo, decreased the "liking" of alcohol after the first sip of alcohol and also attenuated the craving for alcohol after drinking one glass of an alcoholic beverage, Dr Steensland said.

Patients with the poorest impulse control, who are thought to be most at risk for relapse after a period of abstinence, were those who responded best to OSU6162.

OSU6162 was safe and well tolerated over the short 14-day treatment period. There were no reports of serious side effects, the authors note.

"OSU6162 has an important and unique advantage compared to other dopamine agents in that it has a beneficial side effect profile. This is potentially due to OSU6162's ability to mildly stabilize, or normalize, the disturbed dopamine activity in contrast to traditional dopamine agents that fully block or stimulate the dopamine system," Dr Steensland said.

OSU6162's ability to target the dopamine system in brain regions relevant for alcohol dependence is supported by a human neuroimaging study that showed that the agent preferentially binds to D2/D3-receptors in the striatum.

Not a Quick Fix

A study of OSU6162 in rats published simultaneously in Addiction Biology adds to the understanding of how OSU6162 works. Rats that voluntarily consumed alcohol for nearly a year had lower levels of dopamine in the brain than did nondrinking rats. Treating the rats that had been drinking long term with OSU6162 counteracted the low concentrations of dopamine in the brain.

"Based on our present results in long-term drinking rats, our hypothesis is that OSU6162 can reduce the alcohol craving in dependent people by returning the downregulated levels of dopamine in their brain reward system to normal," Dr Steensland said.

Larger clinical efficacy trials with larger patient groups and a longer treatment period (3 to 6 months) are needed to determine whether OSU6162 also can help alcohol-dependent people drink less alcohol and reduce the risk for relapse, the researcher say.

"We do not believe that one pill is a quick fix out of a complex disorder such as addiction. However, if we, through medication with a compound such as OSU6162, can help these individuals to control their craving for alcohol, we can give them an increased ability to assimilate other, eg, psychological treatments necessary to recover or control their drinking," Dr Steensland noted.

The study is "certainly interesting, and with only modestly efficacious pharmacotherapies to date, any potentially efficacious one is noteworthy, even if its effect is modest and applies only to some," Richard Saitz, MD, MPH, chair and professor, Department of Community Health Sciences, Boston University School of Public Health, in Massachusetts, told Medscape Medical News.

"This study finds an effect on one symptom in some people. This, at best, if it is proven safe and efficacious in the future (which the authors point out was not done in this study), would impact some subset of people with alcohol disorders, may still be worth pursuing, but it won't be a miracle cure," added Dr Saitz, who was not involved in the research.

The study also shows that what is recognized clinically as alcohol use disorder is not one thing.

"In other words, people with these disorders have a range of causes and manifestations, and depending on which are more important in an individual case, might determine which specific treatment is best. That is speculation and a direction in which future research likely needs to go. An analogy: we never talk about treatments for 'heart disease' and instead talk about treatments for specific types of heart disease with specific etiologies and characteristics. For alcohol use disorders, we are at a relatively primitive stage of understanding the disorder and its treatments," Dr Saitz said.

Ethical Issues?

Petros Levounis, MD, vice-chair of the American Psychiatric Association's Council on Addiction Psychiatry, called the study "interesting with potentially promising results. Cutting down on cravings is of primary importance. That's what naltrexone does. It cuts down the craving and makes alcohol less exciting, so I would very much want to know how this drug compares with naltrexone."

Dr Levounis, who was not involved with this research, is chair of the Department of Psychiatry at Rutgers New Jersey Medical School, in Newark. He noted, however, that the design of the study gave him "pause."

"These are treatment-seeking alcoholics. They are given medication and instructed not to drink for 14 days, and we don't know how many did or did not drink. Then on day 15, they were given alcohol as part of the study. How ethical is that? I know that it passed the IRB [institutional review board] in Sweden, but I think you'd have some problems in the United States passing the IRB. I fully understand the scientific benefit of this kind of design, but it raises a significant ethical issue for me," Dr Levounis said.

The research was financed with grants from several organizations, including the Swedish Brain Foundation, the Swedish Research Council, the Torsten Söderberg Foundation, Systembolaget's alcohol research council, and the Swedish Research Council for Health, Working Life and Welfare. The rights to OSU6162 are owned by Nobel Laureate Arvid Carlsson, coauthor of the study and professor emeritus at the Sahlgrenska Academy, whose team also invented the substance.

Eur Neuropsychopharmacol. Published online October 6, 2015. Abstract

Addiction Biol. Published online October 6, 2015. Full text

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