Why Isn't There A Medical Cure for Addiction?

By David Linden 08/04/11

Antabuse, Revia, Wellbutrin, Chantix: Many prescription drugs have been hailed as magic bullets against various addictions. But few have lived up to the hype. In an excerpt from his acclaimed new book, a leading scientist explains why.

Shooting Blanks? Science

Most of the drugs that are presently available to help addicts recover and stay clean are pretty crude. The most commonly used treatments simply substitute one form of addictive substance for another: Nicotine patches can replace or reduce tobacco smoking. This approach does reduce some smoking-related health problems, but it does not by itself treat the underlying addiction: The subject is still a nicotine addict. Likewise, treatment of heroin addicts with the semi-synthetic opiates methadone and buprenorphine is only a stopgap measure. These drugs act more slowly than heroin and produce less euphoria. They also are delivered orally, thereby eliminating risks associated with injection (like transmission of blood-borne infections). Nonetheless, as with the nicotine patch, the underlying addiction remains untreated, and so they are not a viable long-term solution. One proposal, fraught with ethical issues, is to offer these vaccines early in life to those with a strong genetic predisposition for addiction.

Another strategy has been to design drugs that promote abstinence by creating an aversive response. Disulfiram (marketed as Antabuse), which has been approved as a treatment for alcoholism by the FDA since 1954, works by inhibiting a key enzyme in the multistep breakdown of ethanol called acetaldehyde dehydrogenase. When this enzyme is blocked, consuming ethanol will produce an increase in levels of acetaldehyde in the bloodstream, which makes the drinker feel very ill. Of course, disulfiram is only useful in carefully monitored settings. Anyone who really wants to drink alcohol will simply discontinue taking the disulfiram pill. And of course, this drug does nothing to blunt the craving for alcohol, but only makes relapse extra painful.

A third strategy has been to develop therapies that prevent a drug of abuse from getting into the brain and thereby exerting its psychoactive effects. One of the most interesting approaches along these lines involves making a vaccine directed against a drug that will engage the patient’s own immune system to bind and destroy the drug in the bloodstream, before it enters the brain. Vaccines using nicotine, methamphetamine, or cocaine bound to immune-response-triggering proteins are currently undergoing testing in animal studies. 

Only in the last few years have there emerged drugs that actually help blunt the cravings of recovering addicts. One of these is naltrexone (a generic drug, also marketed as Revia), which seems to significantly blunt cravings in abstaining alcoholics. When combined with cognitive behavioral therapy, it produces a significant additional decrease in the rate of relapse. Naltrexone is an antagonist of a particular type of endorphin/opiate receptor. The tendency of patients to discontinue taking naltrexone pills can be reduced by use of a newer long-lasting form of naltrexone (sold as Vivitrol), which can be administered as an injection once per month. Naltrexone has also seen some success in reducing relapse in heroin addicts.

Two different drugs have been approved for treating nicotine addiction. Bupropion (sold as Wellbutrin or Zyban) is a dopamine transporter blocker, while varenicline (sold as Chantix) reduces activation of a particular type of nicotine receptor in the brain. Both of these substances are reported to reduce nicotine cravings in abstaining smokers, and both significantly reduce the rate of smoking relapse (although varenicline seems to be a bit more effective). Unfortunately, both drugs also carry risky side effects, most notably an increase in suicidal thoughts, and so should only be used under close supervision of a psychiatrist.  Verenicline has also been linked to an increase in serious cardiovascular events (which is not entirely surprising as these nicotine receptors are not limited to the brain but are also found in muscle tissue, including heart muscle).

While we are now starting to see the first useful drugs for reducing cravings for nicotine and sedative drugs like alcohol and heroin, almost nothing is available to help those who are trying to abstain from stimulants like cocaine and amphetamines. It’s encouraging, therefore, that a large number of new anti-addiction drugs are in various stages of development. While some of these drugs are targeting slightly different aspects of the core biochemical systems of pleasure, like dopamine, opioids, and endocannabinoids, others are branching off into exciting new directions. For example, because we know that stress is a common trigger for relapse in most addictions, including substance addictions like alcohol and behavioral addictions like gambling, one obvious solution is to try to reduce stress through behavioral methods such as exercise or meditation. Another is to try to interfere with stress hormone action in the brain by using drugs to block receptors for stress hormones such as CRF and neurokinin-1 in the hope that cravings will be reduced. 

The hypothesis that the development of addiction involves slow, persistent changes in the strength and microstructure of glutamate—using synapses within the brain’s pleasure circuit—suggests that drugs directed against glutamate receptors or the proteins that modulate their function might be more useful targets in developing anti-addiction therapies. The problem here is that glutamate is the most widely distributed neurotransmitter in the brain, and so drugs that impact glutamate neurotransmission have an unusually large potential for side effects. Fortunately, because there are a wide variety of glutamate receptors, drugs targeting one particular subtype of them have a chance of being useful. This is particularly true of a subset of slow-acting glutamate receptors called metabotropic receptors, which have a more limited distribution in the nervous system and which are only engaged by particular patterns of neural activity. One receptor, called the metabotropic glutamate receptor type 5 (mGluR5), has received particular attention, as it is strongly expressed in key portions of the brain’s pleasure circuit.

When François Conquet and his colleagues at GlaxoSmithKline Laboratories in Lausanne, Switzerland used genetic tricks to create a mouse that lacked mGluR5, they made an astonishing discovery: These mice were utterly indifferent to cocaine. They would not press a lever to self-administer the drug and they had no special interest in the experimental chamber where cocaine was administered. It’s not as if the cocaine had failed to act: Dopamine levels in the pleasure circuit of mGluR5 null mice were still elevated. Rather, it appeared as if the mice simply failed to develop a cocaine addiction. Of course, this result and other like it have helped to spur an enormous interest among drug companies in developing compounds that specifically block or modulate mGluR5. At present, most of these substances are in the preclinical stage: Experiments with rats and mice have suggested that mGluR5 antagonists may hold promise for treating addiction to cocaine, amphetamines, nicotine, and alcohol. As these compounds move into human clinical trails it will become possible to test their effectiveness on behavioral addictions, like gambling, for which there are no viable animal models. It may be that some years hence optimal anti-addiction treatment will involve a combination of drugs to reduce craving (e.g., naltrexone plus an mGluR5 antagonist) together with behavioral therapy.

David J. Linden, Ph.D., is a Professor in the Department of Neuroscience at the Johns Hopkins University School of Medicine. What appears above is an excerpt from his recently released book, The Compass of Pleasure: How Our Brains Make Fatty Foods, Orgasm, Exercise, Marijuana, Generosity, Vodka, Learning, and Gambling Feel So Good. Click here to read more on his book.

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