Where Are All the New Anti-Craving Drugs?

The dilemma of dwindling drug development.

Drugs for the treatment of addiction are now a fact of life. For alcoholism alone, the medications legally available by prescription include disulfiram (Antabuse), naltrexone (Revia and Vivitrol)—and acamprosate (Campral), the most recent FDA-approved entry. A fourth entry, topiramate (Topamax), is currently only approved by the Food and Drug Administration (FDA) for other uses. But none of these are miracle medications, and more to the point, no bright new stars have come through the FDA pipeline for a long time.

New approvals for drugs in this category, like psychiatric drugs in general, have lately been confined to repurposed, “me-too” medications—which, insurance companies complain, are far too expensive. As health insurance giant Cigna explains on its website: “If anticraving medications are not covered by your insurance plan, keep in mind that the price of anticraving medications is usually small compared to the cost of alcohol and/or other drugs.” Perhaps so, but evidently not small enough for the expense to be routinely covered by the prescription portion of insurance policies.

Federal health officials have the same complaints. In a 2004 report entitled “Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products,” the U.S. Food and Drug Administration called for increased public-private collaboration and a “critical development path that leads from scientific discovery to the patient.”

As detailed by Professor Mary Jeanne Kreek, a senior attending physician at the Laboratory of the Biology of Addictive Diseases at Rockefeller University and one of the primary developers of methadone therapy:

Toxicity, destruction of previously formed synapses, formation of new synapses, enhancement or reduction of cognition and the development of specific memories of the drug of abuse, which are coupled with the conditioned cues for enhancing relapse to drug use, all have a role in addiction. And each of these provides numerous potential targets for pharmacotherapies for the future.

In other words, when an addiction has been active for a sustained period, the first-line treatment of the future is likely to come in the form of a pill. New addiction treatments will come—and in many cases already do come—in the form of drugs to treat drug addiction. Every day, addicts are quitting drugs and alcohol by availing themselves of pharmaceutical treatments that did not exist twenty years ago.

But things have changed. “This scientific stall may have seemed to come out of the blue,” writes Dr. Steven E. Hyman, Professor of Stem Cell and Regenerative Biology at Harvard University, in the Dana Foundation publication, Cerebrum. Hyman sketches a dismal picture:

The molecular and cellular underpinnings of psychiatric disorders remain unknown; there is broad disillusionment with the animal models used for decades to predict therapeutic efficacy; psychiatric diagnoses seem arbitrary and lack objective tests; and there are no validated biomarkers with which to judge the success of clinical trials. As a result, pharmaceutical companies do not see a feasible path to the discovery and development of novel and effective treatments…. progress for the many patients who respond only partially or not at all to current treatments requires the discovery of medications that act differently in the brain than the limited drugs that we now possess…. and regulatory agencies have given up their willingness to accept even more expensive new drugs.

Genes aren’t simple, and the kinds of studies that would lead to new anti-craving drugs are not cheap. Moreover, the medications themselves do not represent cures. Even if drugs that block dopamine receptors treat psychotic symptoms, Hyman writes, “it does not follow that the fundamental problem is excess dopamine any more than pain relief in response to morphine suggests that the original problem is a deficiency of endogenous opiates.”

What can change this picture for the better? “One exciting recent development is the emerging recognition that genes involved in schizophrenia, bipolar disorder, and autism do not represent a random sample of the genome,” Hyman writes. “Rather, the genes are beginning to coalesce into identifiable biochemical pathways and components of familiar neural structures…. Many researchers hope that such efforts will help attract the pharmaceutical industry back to psychiatry by demonstrating new paths to treatment development. The emerging genetic results may be the best clues we have ever had to the etiology of psychiatric disorders.”

Detractors worry, naturally enough, about the shrinking pie of funds available for this sort of endeavor. According to Steven Paul, president of Lilly Research Laboratories, “I am worried that obtaining the kind of molecular probes required for even in vivo testing may prove to be too time-consuming and expensive, and may divert precious NIH funds away from basic or clinical biomedical research.”

But Hyman remains optimistic, “based partly on the extraordinary vitality of neuroscience and perhaps, even more important, on the emergence of remarkable new tools and technologies to identify the genetic risk factors for psychiatric disorders, to investigate the circuitry of the human brain, and to replace current animal models that have failed to predict efficacious new drugs that act by novel mechanisms in the brain.”

Photo Credit: http://www.insidecounsel.com/

Interview with Dr. Bankole Johnson of the University of Virginia

Tailoring addiction medicine to fit the disease.

(The “Five-Question Interview” series.)

25 years ago, when Dr. Bankole Johnson first began giving lectures about addiction and neurotransmitters in the brain, he had a hard time getting a hearing. That’s because 25 years ago, everybody knew what addiction was: a lack of “moral willpower.” Or, at best, some sort of psychological “impulse control” disorder.  

As a neuropharmacologist by training, and currently professor and chairman of the University of Virginia’s Department of Psychiatry and Neurobehavioral Sciences, Dr. Johnson thought otherwise, and went on make a name for himself by discovering that topiramate, a seizure drug that boosts levels of the neurotransmitter GABA, could be used in the treatment of alcoholism. “I just wasn’t a hospital-type doctor,” he once said. “I was for more intersted in research than clinical practice.” Johnson’s work was featured in the 2007 HBO series, "Addiction."

Born in Nigeria, Dr. Johnson attended the University of Oxford and received his medical degree in Glasgow, Scotland in 1982. At the time, medical understanding of addiction was poor to nonexistent. “Everything we knew—really knew—probably could be written on the back of a postage stamp,” he recalled.

Since then, Dr. Johnson has published numerous articles on psychopharmacology and addiction, and has served on several National Institutes of Health committees and panels. (See my earlier POST on Johnson’s study of drugs for addiction in the American Journal of Psychiatry.)


1. You’re a native of Nigeria. How did you first become interested in medicine?

Bankole Johnson: My father was a doctor and encouraged me. Back then, I had little interest in medicine and was more interested in the arts and perhaps going to law School, for which I had been promised a scholarship.

2. Addiction is called a “disease of the brain,” in Alan Leshner’s famous phrase, but it is still a hugely controversial subject. Are innate biological differences the cause of addiction?

Johnson: Addiction is a brain disease. The roots of the disease lie in brain abnormalities, and these are exacerbated when a vulnerable person uses alcohol excessively or takes illicit drugs.

3. How did you discover that topiramate helped some alcoholics drink less?

Johnson: It was an idea that developed from a hypothesis I came up with based on brain neurochemistry. The central idea was to alter the signals of dopamine, a critical path for the expression of rewarding behavior, through two different and opposite systems—glutamate and GABA.

4. That work led to Topamax for alcoholism, and your more recent work with ondansetron, another GABA antagonist. But what role do environmental and sociocultural factors play in the development of addiction?

Johnson: The environment interacts with genes and brain chemistry to govern behavior. But in the end, it is the changes in the brain that ultimately direct alcohol and drug taking behavior.  The environment therefore provides the context and tuning of the neurochemical signals in the brain.

5. Some people find the notion of addiction as a progressive and incurable condition a hard pill to swallow, so to speak. Why has effective medical treatment for addiction been so slow to develop, and why hasn’t talk therapy been more effective?

Johnson: Talk therapy has some effectiveness, but alone it is not a comprehensive or robust treatment. Progress in the last two decades has been quite rapid. With growing and clear acceptance of the neurobiological underpinnings of addiction, the next decade should herald even more exciting discoveries.  For example, our work on pharmacogenetics promises to provide effective medications—such as ondansetron—that we can deliver to an individual likely to be a high responder, based on his or her genetic make up.

Photo Credit: Luca DiCecco

The Future of Addiction Treatment

Is there some way out of here?

Addictions are chronic diseases. They may require a lifetime of treatment. After a number of severe episodes of alcohol or drug abuse, the brain may be organically primed for more of the same. Long-term treatment is sometimes, if not always, the most effective way out of this dilemma. (The same is true of unipolar depression.)

We will need to learn a lot more about chemicals—the ones we ingest, and the ones that are produced and stored naturally in our bodies—if we plan to make any serious moves toward more effective treatment. What we have learned about the nature of pleasure and reward is a strong start. The guiding insight behind most of the work is that addiction to different drugs involves reward and pleasure mechanisms common to them all. The effects of the drug—whether it makes you sleepy, stimulated, happy, talkative, or delusional—constitute a secondary phenomenon. A good deal of earlier research was directed at teasing out the customized peculiarities of one drug of abuse compared to another. Now most addiction scientists agree that receptor alterations in response to the artificial stimulation produced by the drugs are the biochemical key, and that recovery occurs when the brain’s remarkable “plastic” abilities go to work at the molecular level, re-regulating and adjusting to the new, drug-free or drug-reduced status quo. An addict beats addiction by ceasing the constant and artificial manipulation of neuronal receptors, to be entirely unromantic for a moment about the nature of recovery.

But in order for that to happen most effectively, you have to stop taking the drugs.

Comparing our reservoir of pleasure chemicals to money in the bank, Dr. George Koob, Chairman of the Committee On The Neurobiology Of Addictive Disorders at the Scripps Institute in La Jolla, California, draws the following analogy:

We can expend that money over the course of a single weekend’s binge on cocaine or we can expend it over a two-week period in the normal pleasures of everyday life. If you spend these pleasure neurochemicals in one lump sum such as a crack binge, you use up your supply of pleasure for a certain period, and so you pay for it later.

Addicts vividly demonstrate a compulsive need to use alcohol and other drugs despite the worst kinds of consequences—arrest, illness, injury, overdose. What kind of euphoria could be worth such psychic pain? Even stranger, why continue when the drug no longers works as well as it once did due to tolerance? What makes these people eat their words, shred their best intentions, break their promises, and starting using or drinking again and again?

There really is no cheating in this game. The system has to self-regulate. Craving and drug-seeking behavior, once set in motion, disrupt an individual’s normal “motivational hierarchy.” How does this motivational express train come about? It happens at the point where casual experimentation is replaced by the pharmacological dictates of active addiction. It happens when the impulse to try it with your friends transforms itself into the drug-hungry monkey on your back.

 Formal medical treatment and intervention can work, but the results are inconsistent and often little better than no formal treatment at all. Most alcoholics and smokers and other drug addicts, it is frequently asserted, become abstinent on their own, going through detoxification, withdrawal, and subsequent cravings without benefit of any formal programs. Our health policy should not only encourage addicts to heal themselves, but must also help equip them with the medical tools they need in treatment. After all, behavioral habits as relatively harmless as nail biting can be all but impossible to break.

 As detailed by Dr. Mary Jeanne Kreek, a professor and senior attending physician at the Laboratory of the Biology of Addictive Diseases at Rockefeller University:

Toxicity, destruction of previously formed synapses, formation of new synapses, enhancement or reduction of cognition and the development of specific memories of the drug of abuse, which are coupled with the conditioned cues for enhancing relapse to drug use, all have a role in addiction. And each of these provides numerous potential targets for pharmacotherapies for the future.

In other words, when an addiction has been active for a sustained period, the first-line treatment of the future is likely to come in the form of a pill. New addiction treatments will come—and in many cases already do come—in the form of drugs to treat drug addiction. Every day, addicts are quitting drugs and alcohol by availing themselves of pharmaceutical treatments that did not exist twenty years ago. Sometimes medications work, and we all need to reacquaint ourselves with that notion. As more of the biological substrate is teased out, the search for effective medications narrows along more fruitful avenues. This is the most promising, and, without doubt, the most controversial development in the history of addiction treatment.

Fighting fire with fire is not without risk, of course. None of this is meant to deny the usefulness of talk therapy as an adjunct to treatment.  However, consider the risks involved in not finding more effective medical treatments. Better addiction treatment is, by almost any measure, a cost-effective proposition.

Photo: http://www.manorhouserehab.com/