Editor's Note: In a recent three-part series, "Alcoholism: Vice or Disease?" (part 1, part 2, part 3), neuroscientist Howard Fields, MD, PhD, a senior researcher at the UCSF-affiliated Ernest Gallo Clinic and Research Center and director of the Wheeler Center for the Neurobiology of Addiction, tabbed the brain's lack of impulsivity control — not lack of willpower — as a central cause of addiction. Peter Banys, MD, director of the substance abuse clinic at the UCSF-affiliated San Francisco Veterans Affairs Medical Center and a clinical professor in the UCSF Department of Psychiatry, now responds with a different perspective on the promise of research and the mystery of recovery.
I enjoyed Howard Fields' recent three-part review of the neuroscience of alcoholism. I, too, believe that in the near future we will have more effective pharmacological interventions for the alcoholisms.
Why do I use the plural? Because alcoholism, like so many seemingly unitary diseases in the past (such as leukemia), is better conceptualized as a group of final, common-pathway disorders with diverse genetic drivers, different biochemical anomalies and different responses to interventions.
We will soon be speaking of the alcoholisms.
As my friends at the Gallo Center know only too well, there is certainly going to be a large family of alcoholism disorders with genetic differences. The national Collaborative Studies on Genetics of Alcoholism (COGA) has identified many gene loci implicated not only in alcohol consumption, but in related phenomena such as impulsivity or sensation seeking.
Decades of clinical work attempting to phenotype alcoholics into behavioral categories (maintenance, binge, periodic) or character structures (impulsive, dogmatic, passive) or age of onset (early, adult, late onset) have mostly failed to show improvement in matching patients to treatments.
Personalized Anti-addiction Drugs
In my opinion, genotyping will lead to better medication matching than phenotyping. The goal is to identify one or more subtypes that respond to one or more medications. For example, patients who respond to naltrexone (an opiate blocker) for alcohol relapse prevention may just have a genetic variant in the mu opiate receptor. I hope for a simple genetic blood test that might be correlated with a good response to naltrexone.
Having said that, to date, most medications for alcoholism (including naltrexone and the European drug acamprosate) tend to wash out in large-scale, controlled trials — maybe, just maybe because we still can't parse alcoholism into workable subcategories. The awkward truth about approved medications for alcoholism is that (a) effect sizes tend to be small and (b) long-term compliance is exceedingly poor.
Enter two cautionary tales. We already have two drugs (Antabuse and naltrexone) in the pharmacy that ought to be perfect interventions for alcoholism and for opiate addiction. Antabuse (disulfiram) was discovered independently in Ohio and Denmark in the 1940s. It blocks an enzyme in alcohol metabolism and causes a nauseating rise in acetaldehyde as an intermediate product. It reliably makes most people seriously nauseated when they consume even a small amount of alcohol. And it is effective for five to seven days after the last daily dose.
Yet, large-scale studies cannot prove it more effective than placebo, and it seems to work only when both legally mandated and compliance-monitored.
Naltrexone is a powerful mu opiate blocker, and virtually no opiate on earth can override its long-acting blockade. Anyone taking it is simply wasting his or her time attempting to get an effect from injected heroin.
It should be capable of halting the heroin epidemic in its tracks, but it isn't.
In this country, the only subgroups that do well on it are medical professionals whose licenses are held hostage to compliance. The gold standard for heroin treatment comes from a different angle: It is methadone, a long-acting, noninjectable opiate replacement or, more recently, buprenorphine, a partial opiate agonist.
Craving Is Misunderstood
What about targeting craving? Everyone talks about craving as if it were a reliable precursor to drinking or using. It is not; many relapses occur much like a lightning strike on a clear day — that is, without warning. Craving is one of those concepts that everyone uses and thinks they understand until they settle down to measure it, at which point it starts to trickle through their fingers.
There is a large and unsatisfying literature on craving (something actually very hard to measure and of only limited importance in relapse). In my clinical opinion, Fields is right to focus on deep reward mechanisms in the brain (even harder to measure, but probably the key mechanism to addiction). So far, the drugs we have (a) only work for some, but not all, alcoholics, and (b) have unclear impacts on craving. They probably work (when they do) on more basic reward/payoff mechanisms deep in the brain.
Craving is a more important concept in addiction to stimulants (cocaine and methamphetamine) and opiates. This, I think, is because there is a more simple (almost Pavlovian) conditioned response going on.
A major part of treatment for stimulant addicts is in relapse prevention, often consisting of careful cue identification and avoidance. I had a patient who had profound cocaine craving at one particular intersection in the Mission District, near a coffee shop in which he purchased drugs. The intervention was not to desensitize him or talk him out of it. It was instead to avoid driving through the neighborhood. Expose a cocaine addict in recovery to a crystalline white powder, and interesting things happen on functional brain imaging.
There is no a priori reason why some medications might not reduce craving, but more fundamental mechanisms will likely be found. Craving is simply insufficient as a lone concept to understand why someone can suddenly relapse, as a veteran I see just did after more than eight years of sobriety. He had no craving to warn him. It just seemed "right" to accept a drink after all this time.
What remains the Holy Grail of all this research? It is to find fundamental reward mechanisms that can be so modified by medication that alcohol returns to being a mere beverage (as it is for nine out of 10 American men). For a brief, shining moment, we thought we had it in naltrexone. We thought we had found the opiate reward hidden deep inside the alcoholic drinking. Then a large, multisite, placebo-controlled trial in the VA (Krystal et al., New England Journal of Medicine) dashed that overly simple hope.
Does "Recovery" Work?
What about recovery, the psychological side of the equation? I do think that recovery remains in great measure a psychological process of coming to terms with one's problem, be that personal weakness, human frailty or whatever we choose to call it. It takes time and outside help.
Books have been written about recovery. But what is essential is that most people cannot do it on their own; they have tried for decades to "control" themselves and failed. Recovery starts when one person asks another for help. In this respect, this is an entirely human process, although we can dress it up in various fancier kinds of language, from Alcoholics Anonymous and sociology to psychiatry. Recovery is not about willpower, to be sure, and it is also about more than neurochemistry.
A career in addiction does a lot of damage to one's family and social nexus. Recovery brings with it the inescapable confrontation with the damage one has done to others. In this regard, it shifts the work away from mere reward to entirely more complex questions, such as what it takes to gain personal redemption and forgiveness from those who have been harmed. It is why, perhaps, only the first step of AA's 12 steps even mentions alcohol. The rest are concerned with questions of personal integrity, making amends and eventually helping others less fortunate along the way.
Recovery is not as simple as the restitution of abstinence (an abnormal condition for most Americans) or the blockade of craving. The mystery of recovery is that it necessarily faces one with questions of how one is to live a life of integrity.
Biochemical and genetic progress is around the corner. But the genetics of the alcoholisms will necessarily force clearer thinking about public policy, lest we discover that our children are uninsurable due to genetic profiling of risks.
I do agree with Fields that incarceration for addiction is a proven failure as public policy. Over 30 years of the "war on drugs" have taught us that. This is why the passage of Proposition 36 (treatment rather than incarceration) in 2000 was so important. But California still has the highest drug incarceration rate in the nation (and thus, the world), and we continue to jail more citizens for possession than we do for trafficking or manufacture. Despite the temporary setback of Prop. 36, some in the powerful incarceration industry are still advocating two new prisons for California. They know how to keep them filled.
- Collaborative Studies on Genetics of Alcoholism (COGA)
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health
- Naltrexone in the Treatment of Alcohol Dependence
- New England Journal of Medicine 345;1734-1739, December 13, 2001
- Participation in Alcoholics Anonymous: Intended and Unintended Change Mechanisms
- Alcoholism: Clinical and Experimental Research, March 2003;27(3):524
- Twelve-step Program
- Alcoholics Anonymous
- California Proposition 36: The Substance Abuse and Crime Prevention Act of 2000