Addiction

New Medicine For Addiction: Fighting Fire With Fire.

ALCOHOL

There are four medications now legally available by prescription for alcoholism: disulfiram (Antabuse), SSRI antidepressants (informally and off-prescription), naltrexone (Revia)--and acamprosate, the newest entry. Acamprosate binds to both GABA and glutamate receptors. Acamprosate, marketed in the U.S. as Campral, has been widely used in Europe on problem drinkers.

American researchers came late to this one. Acamprosate attacks the craving and relapse dilemma by stimulating GABA, the inhibitory transmitter that is the target of benzodiazepines like Valium, Xanax and Klonopin. However, Campral, or calcium acetyl-homotaurinate, is not sedating. It doesn’t do anything for anxiety, like benzodiazepines, barbiturates, and alcohol. It is not a hypnotic, or a sedative, or an antidepressant, or a muscle relaxant. Scientists aren’t entirely sure what it is. But there is no buzz, no psychoactive effect, and no evidence of abuse potential whatsoever. Major side effects are at this point limited to gastrointestinal cramps and diarrhea.

While acamprosate enhances the GABA mechanism, it inhibits the glutaminergic system by occupying sites on the glutamate (NMDA) receptors. Acamprosate, then, can find binding sites on receptors for both GABA and NMDA receptors.

In a dozen clinical trials conducted in Europe, involving thousands of alcohol abusers, 50 percent of acamprosate users maintained sobriety for three months without relapse, compared to 39 percent of the placebo group. (The distressingly low numbers are testimony to the fierce mechanism of relapse.)

The long-standing, often bitter debate about the ethics of treating addiction with prescription medications came to a head when German drug maker Merck KgaA (no relation to Merck, the American company.) decided to market Campral in the U.S., as it had been doing with some success in Europe. In the U.S., fierce advocates for drug-free addiction therapy came out in force to oppose its adoption here.

Determined to prevail, Lipha S.A., a French subsidiary of Merck KgaA, found a U.S. partner, Forest Laboratories, and awarded that firm the U.S. marketing rights to Campral—even though Forest Labs could not then legally exercise those rights. Due in no small part to differences in methodology between American and European drug studies (acamprosate was already in use in 28 other countries), the FDA, in a rare action that went against the recommendations of its own advisory committee, turned down the first attempt at certification in 2001.

At this writing, Forest Labs and Merck KgaA have submitted additional data, and the FDA is expected to approve the drug for use in the treatment of alcoholism. Campral does not appear to have any direct effect on opiate receptors. This opens the possibility of combining it with naltrexone, and clinical trials of that combination are underway. Studies submitted to the FDA showed lower relapse rates over a 12-week period, compared to naltrexone (23 percent, compared with 19 percent.).

Dozens of high-quality European studies of the drug’s usefulness in alcoholism treatment were already available in France. Several double-blind studies documented an increase in abstinence days in alcoholic subjects. Patients reported reductions in anxiety, irritability, and insomnia. “Once patients give up alcohol and go on with their lives, they see it, smell it, dream about it,” Dr. Karl Mann of the University of Tubingen in Germany told the New York Times. “Acamprosate helps them get through all that.”

Acamprosate superbly fulfills several of the criteria for a successful anti-craving drug. To start with, about 90 per cent of acamprosate is excreted in the urine without being metabolized by the liver. This eliminates both potential liver toxicity, and potentially lethal drug interactions. Low liver toxicity is essential, if a new drug is to be widely adopted. Campral appears to have no abuse potential, and it is reasonably cheap (at least the European version). It works directly on the desire to drink by reducing alcohol cravings and the initial distress of sobriety.

Acamprosate is intended to be used during abstinence, not during an active drinking phase. MORE...

NICOTINE

The first medication to genuinely realize the promise of a widely effective anti-craving drug was not a serotonin uptake blocker, or a tricyclic, but rather a mid-range, broad-spectrum antidepressant known as bupropion. Marketed as Wellbutrin, bupropion did not fall into any of the existing chemical classes of antidepressants. Glaxo’s repackaging of the antidepressant drug Wellbutrin as the anti-smoking medication Zyban in 1998 was the beginning of true pharmacological treatment for nicotine addiction.

Zyban had no detectable effect on serotonin uptake, and did not inhibit MAO. Rather, it exhibited a weak affinity for dopamine and norepinephrine receptors. After more than twenty years of study, scientists still don’t understand exactly how it works. But it arrived at a propitious time. As nicotine researcher Ovide Pomerleau of the University if Michigan said: “We are seeing more and more heavily dependent smokers, over the years. The easy ones quit first, and increasingly we’re left with the ones who are more nicotine-dependent.”

It is ironic that the addiction affording neuroscientists their first big splash of publicity was generally considered, in a sort of loose tie with heroin, to be the toughest of them all: nicotine addiction. Few scientists had expected cigarettes to be among the early success stories.
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Wellbutrin was actually approved for release before Prozac, and would have beaten Prozac to the market if not for a major study demonstrating that Wellbutrin was two to four times more likely to cause seizures than Prozac. Dr. Sheldon H. Preskorn, a member of the FDA’s neuropsychopharmacology advisory committee that reviewed and recommended bupropion for approval, remembers that the finding “caused Burroughs-Wellcome to literally recall the trucks that were delivering the drug to pharmacy shelves.” The seizures caused by Wellbutrin were dose-related. At the level of 300 milligrams per day, the recommended dosage for smoking cessation, the frequency of seizures fell to within normal ranges associated with other antidepressants--about two per 1,000. A revised low-dose, slow-release version of Wellbutrin was subsequently approved for use. But the widely publicized association with seizures remained, and Wellbutrin was never a hit with prescribing physicians and their patients.
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Zyban works amazingly well for many intransigent smokers. Zyban was tried at a variety of clinics, and with a cross-section of patients, and the percentage of users who remained smoke-free for 3 to 12 months or more averaged 25 to 60 percent. The numbers were best when Zyban was combined with nicotine patches over a period of ten weeks or more. In fact, they were the best numbers anybody had ever seen in trials of an anti-craving medication. Every struggling smoker who was tested did better on the Zyban-patch combination than on any other mix of therapies--better at six months, at 12, at 18. The combination approach was pioneered by Dr. Linda Ferry at the VA Medical Center in Loma Linda, California, along with Dr. Neal Benowitz of UC-San Francisco, and Dr. Alex Glassman of Columbia University.

No one can say with certainty that Zyban’s action on dopamine and norepinephrine receptors is the whole answer. Even though SSRI antidepressants do not inhibit craving for cigarettes, it is still conceivable that Zyban works in some cases by addressing the underlying clinical depression suffered by a disproportionately large number of smokers (a sort of sneaky end-run around any recalcitrance the smoker might have felt about taking an antidepressant drug.)

Whatever the precise mechanisms involved, there was no doubt about Zyban’s ability to help quell cravings in a large number of nicotine users trying to quit. Before Zyban, no medication that claimed to block cravings for tobacco had ever been approved by the FDA. Within three years, Zyban had become the most striking success story in the short history of anti-craving drugs. MORE...

MARIJUANA

Perhaps it is marijuana’s more diffuse manner of playing on the brain’s reward pathways that has made America's most popular illegal drug into a difficult target for drug therapies. The U.S. government’s essentially unchanged opposition to marijuana research has meant that, until quite recently, precious few dollars were available for pot research. This official recalcitrance is one of the primary reasons for the belated recognition and characterization of marijuana’s distinct withdrawal syndrome.

To pluck one statistic out of many, representing estimates in one decade out of many, more than 11 million Americans smoked marijuana in the month under study in 1997’s NIDA-sponsored “National Household Survey on Drug Abuse.” What NIDA learned about cannabis addiction, according to the principal investigator of a recent NIDA study, was that “we had no difficulty recruiting dozens of people between the ages of 30 and 55 who have smoked marijuana at least 5,000 times. A simple ad in the paper generated hundreds of phone calls from such people” (This would be roughly equivalent to 14 years of daily pot smoking).

We don’t really need animal models to study many aspects of cannabis, but there now exists a nice body of clinical trials showing that mice and dogs also show evidence of cannabis withdrawal. (For THC-addicted dogs, it is the abnormal number of wet-dog shakes that give them away.) Today, scientists have a much better picture of what anandamide, the brain's own THC, does in the body than they did a few years ago. This knowledge helps explain a wide range of THC withdrawal symptoms. Among the endogenous tasks performed by anandamide are pain control, memory blocking, appetite enhancement, the suckling reflex, lowering of blood pressure during shock, and the regulation of certain immune responses.

These functions shed light on common hallmarks of cannabis withdrawal, such as anxiety, chills, sweats, flu-like physical symptoms, and decreased appetite. At Columbia University’s Substance Abuse Division, where a great deal of NIDA-funded research takes place, researchers have found that abrupt marijuana withdrawal leads to symptoms similar to depression and nicotine withdrawal.

In a 2003 research report entitled “Nefazodone Decreases Anxiety During Marijuana Withdrawal in Humans,” published in Psychopharmacology, researchers at the New York State Psychiatric Institute used Serzone (nefazodone) to decrease some symptoms of marijuana withdrawal in human subjects who had been regularly smoking six joints of pot per day. Anxiety and muscular discomfort were reduced, but Serzone had no effect on other symptoms, like irritability and sleep problems. The drug did not alter the perceived effects of marijuana intoxication (the SSRIs didn’t, either). Serzone is another antidepressant, a modest inhibitor of serotonin and norepinephrine, but its mechanism of action is ill defined. It is not in the SSRI or tricyclic families.

Serzone has also been looked at for use in the treatment of pathological gambling, and a few small, controlled trials have shown promise there, too, as reported in the Journal of Clinical Psychiatry. More studies would be needed to determine if the gambling reductions were a function of antidepressant effects.

But no such studies will ever take place, on gamblers or marijuana addicts. At this writing, Serzone has been recalled in Canada due to the discovery of liver failures associated with its use. This action will be followed by its recall in the U.S. as well. The experience with nefazodone does point to the possibility of future serotonin-active drugs that might be of use in withdrawing from protracted marijuana smoking. MORE...

HEROIN

A quiet revolution is taking place in the treatment of heroin addiction. Buprenorphine, a partial opiate agonist sometimes used in hospitals as a pain medication, offers addicts a different approach to abstinence. Approved for heroin treatment by the FDA in 2002, “bupe” targets opiate receptors and is itself addictive, like methadone. But it has several advantages over methadone.

As of this writing, there are three government-approved drug therapies available for heroin addiction: methadone, LAAM (a methadone analogue), and buprenorphine, sometimes combined with naltrexone. NIDA-sponsored research at Johns Hopkins University, under the direction of Dr. Rolley Johnson, compared the results of four treatment groups.... According to Dr. Johnson, there are several advantages to buprenorphine: “Less-than-daily dosing reduces the need for take-home medication, requires fewer clinic visits, and allows a more normal lifestyle.” Equally significant is the unprecedented circumstances for the dispensing of bupe: It can be prescribed by an M.D., and obtained at a local pharmacy. Methadone is dispensed daily at special government clinics. NIDA has estimated that at least half of the heroin addicts offered methadone treatment turn it down, often due to the atmosphere of bureaucratic overregulation at methadone clinics.

Buprenorphine became the first medical treatment for heroin addiction that could be obtained at a local doctor’s office. Some European countries have been using the drug for several years. Buprenorphine is marketed as Subutex, or, in combination with naltrexone, as Suboxone. Buprenorphine has proven relatively easy to withdraw from, compared to methadone, and it frees people from the daily methadone regimen. It also presents less danger of overdose than methadone—always an important consideration. Buprenorphine is less sedating, with less of a traditional opiate buzz than methadone.

Finally, and perhaps most significantly of all, buprenorphine has a definite “ceiling effect.” Beyond a certain dosage, taking more of the drug will not increase the intensity of its effect. A user cannot get higher on bupe simply by taking more and more. The buprenorphine molecules fit the opiate receptors tightly enough that opiate molecules cannot knock them off, so taking a shot of heroin while on bupe won’t work, either. In fact, it won’t work for three full days, as buprenorphine remains tenaciously locked to the heroin receptors. All of this combines to make withdrawal from buprenorphine less rigorous than going off methadone or heroin itself.

“I’m more clear-headed than I’ve been in years,” one recovering addict, who previously had been on methadone for five years before switching to buprenorphine, told the New York Times. “I feel better physically. For the first time in a long time, I can see myself getting off everything…”
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Drug experts are hoping to double or triple the number of heroin addicts currently in treatment. “Buprenorphine is the most important advance certainly in heroin and opiate treatment if not all addiction treatments in the last 30 years,” declared NIDA’s former director, Dr. Alan Leshner. Dr. Rolley Johnson believes that “expanding the numbers and types of potential treatment medications should help bring the treatment of opiate addiction into mainstream medical practice.” In 2003, radio host Rush Limbaugh’s addiction to OxyContin served as a reminder of the nation’s problem with addictions to various forms of prescription opiates, including hydrocodone and codeine. Buprenorphine should be of use in these cases as well.

In time, buprenorphine will quite likely replace methadone as the drug treatment of choice for opiate addiction. It is a more targeted, receptor-active drug that fulfills many of the criteria for a successful anti-craving medication. Bupe stands a very good chance of being much more effective for addicts than methadone. Indeed, we may be seeing the last days of methadone as a front line treatment for heroin addiction. MORE...

AMPHETAMINE

The grimmest treatment story of all. Amphetamine, whether in the form of prescription Dexedrine or street meth, is perhaps the “stickiest” addiction of all, from the standpoint of receptor science. Speed’s impact on the reward system is direct, profound, and long lasting. Addiction science simply has not caught up with this one, and there is very little in the pipeline--which makes meth a very scary proposition.

The leading candidate at present does not act directly on dopamine transmission. Interestingly, it is a serotonin booster, but of a different kind. Unlike SSRI drugs, which have not been very successful with amphetamine addiction, ondansetron is an antagonist at serotonin 5-HT3 receptors. Rats on amphetamine reduce their amphetamine-induced hyperactivity under the influence of ondansetron, so there was already evidence that this serotonin-active drug had a secondary effect on dopamine. Currently in the FDA approval pipeline, ondansetron may become the first anti-craving drug approved for use against amphetamine addiction. Ondansetron is already in use as a medication for nausea and vomiting in chemotherapy patients.

COCAINE

Anna Rose Childress and Charles O’Brien, in a 2000 article for Trends in Pharmacological Sciences, spelled out the bleak facts: “Despite an intensive search for specific drug therapies since the mid 1980s, there is still no uniformly effective medication for human cocaine craving and there are no medications that are able to prevent cocaine relapse.”

We simply do not have any anti-craving drugs that work reliably for cocaine and speed—but new drug trials are continuing. The problematic nature of dopamine-receptor antagonists complicates the picture. Drugs that block the dopamine D2 receptor—antipsychotics like haloperidol—do not always block the stimulant rush. Their side effects, such as lethargy, emotional blunting, and tardive dyskinesia, make them unsuitable for ongoing addiction therapy. Conversely, some drugs that act as dopamine agonists turn out to be addictive in their own right. Many designer drugs are like that. Other avenues of attack will have to be exploited, such as partial agonists. But here again, drugs that fill the bill tend to have unacceptable side effects.

Dopamine reuptake inhibitors, operating on the same principle as the SSRIs, are another avenue of approach. Methylphenidate, trade name Ritalin, stalls dopamine in the synaptic gap, but it is still a highly reinforcing chemical—the user feels a muted stimulus, like methadone. However, just as methadone is considered to produce a qualitative life improvement compared to continued heroin use, the longer duration of action and the lower level of reinforcement of Ritalin, or some other drug like it, may constitute a reasonable tradeoff for crack or speed addiction.

No antidepressants have shown themselves to be reliably useful in clinical trials on cocaine or amphetamine addiction. Serotonin-boosting drugs do not seem to help, any more than they help with nicotine addiction. The direct ride to the pleasure pathway provided by stimulants makes it difficult to tamper selectively with their effects.
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Another GABA receptor agonist under study for cocaine addiction is baclofen, trade name Lioresal. Baclofen is an antispastic muscle relaxant commonly used in the treatment of multiple sclerosis. After looking into the use of baclofen for opium and alcohol withdrawal, research has centered on its ability to reduce cocaine administration in rats. In late 2003, researchers at UCLA showed that baclofen can reduce cocaine use in human addicts as well, and more NIDA-funded tests are in progress. The evidence thus far suggests that baclofen reduces “withdrawal symptom intensity,” but we do not yet know the extent to which the drug attenuates craving itself. Associated preclinical studies on rats support the idea of trying baclofen for methamphetamine and nicotine as well. The interaction between GABA receptors and dopamine release in the nucleus accumbens seems to be the common factor. Baclofen appears to show promise for use with many drugs of abuse, and has a chance of becoming the first drug to be approved for the treatment of cocaine addiction.

Research on baclofen at the University of Minnesota again pointed up the perennial problem of gender differences in drug studies. In animal trials, baclofen suppressed cocaine more robustly in female rats than in males. “These studies highlight the importance of paying attention to sex differences in the development of pharmacotherapies and in other drug abuse research,” said Dr. Cora Lee Wetherington, NIDA’s women and gender research coordinator.

There is also some research in the making--the sexiest drug in this class is called BP897. BP897 is a partial agonist at D3 receptors, which are yet another dopamine receptor subtype. The drug has been shown to curtail drug-seeking behavior in cocaine-addicted rats. BP897 works around what Anna Rose Childress and Charles O’Brien call the “medications quandary”—finding a drug that is neither wholly an antagonist, nor wholly an agonist. BP897 is a little bit of both. Even pure antagonist drugs that bind snugly to dopamine receptors do not always confer complete protection against a cocaine binge.
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Propranolol, originally developed to treat hypertension and cardiac arrhythmia, blocks a form of norepinephrine receptor. Early reports suggest that it lessens cocaine withdrawal symptoms. Another drug under investigation is the GABA-active drug gabapentine, sold as Neurontin and currently available as a prescription drug for nerve pain. MORE...

CAFFEINE

Even thought it is consumed casually by millions of people every day, caffeine is a legitimate drug of addiction, and more troublesome to kick than many people think. Headaches, inability to concentrate, constipation, low-level body aches, depression, drowsiness—the same set of symptoms frequently listed by people withdrawing from any kind of addictive drug are present in caffeine withdrawal. Doctors tend to advise caffeine addicts not to attempt cold turkey detoxification—not because it is life-threatening, but because the severe headaches, persistent depression, and rebound drowsiness that mark rapid caffeine detox can often cause the coffee drinker to abandon his plan of moderation altogether.

Why are we usually able to escape a 50-cup a day habit with this classic reinforcer, a drug that shares some of the same kick as cocaine and amphetamine? While the stimulant effect of caffeine can rev up brain structures, boost energy levels, produce anxiety, and interfere with sleep-wake cycles, caffeine does not hammer the nucleus accumbens with enough extra pleasure chemicals to trigger the same kinds of responses as other stimulants. As with nicotine, older people who drink coffee have a lower rate of Parkinson’s disease than their caffeine-free counterparts do. Caffeine appears to prevent the loss of dopamine in key brain areas through its ability to block adenosine receptors, but nobody is entirely sure of the mechanisms involved. Perhaps the day is coming when seniors will be encouraged to brew a strong pot of Joe to go along with that nicotine patch.

What can we say with reasonable certainty about the long-term health effects of coffee? Despite reports of linkages to everything from cardiac arrhythmia to breast cancer, it appears that moderate coffee drinkers are not greatly endangering their health. Coffee is associated with higher cholesterol levels, though it is difficult to rule out the effects of dietary fats in such studies.

It will come as no surprise that people who are clinically depressed drink more coffe than non-depressed people. But the true drugs of choice for those plagued by chronic, debilitating depression are the high-octane stimulants—cocaine and amphetamine. MORE...

CARBOHYDRATES

The carbohydrate connection also turns up in studies of the mood disorder known as Premenstrual Syndrome, or PMS. Common symptoms of PMS begin several days before a woman’s menstrual period and include depression, anger, anxiety, irritability--plus cravings for carbohydrates. Women who suffer from severe PMS and its accompanying depression tend to markedly increase their intake of carbohydrates during these monthly bouts, and they may be doing it for the same reason that drug addicts in withdrawal do so: because serotonin synthesis increases after carbohydrate intake, causing increased feelings of reward and well being.

The thinking about gateway drugs may need to be rerigged yet again, according to the alternative view shared by Janice Keller Phelps and other nutrition-oriented practitioners. In their view, the gateway drug is, and always has been, refined sugar. The idea of a link between addiction and appetite control is not new, and the controversy over the addictive properties of sugar foods is an old one. Heroin addicts, alcoholics, and cigarette smokers, when deprived of their drug of choice, will sometimes binge on sugar foods in a pattern highly suggestive of cross-addiction or substitute addiction. Old-time alcoholics tell stories of pouring bottles of pancake syrup down the gullets of colleagues in dire need of sobering up. (Fructose does indeed speed the elimination of alcohol.) The practice of referring to drug cravings as “drug hunger” may be closer to the mark than we realize. Intense physical hunger may be as close as any non-addict ever comes to experiencing the mind/body sensations of drug craving.
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This considerably widens the field when it comes to cross-addiction and pan-addiction. Take away an alcoholic’s liquor, and he or she is likely to become addicted to some other drug. Take the heroin away from a heroin addict, and he or she is at high risk for becoming an alcoholic. Many addicts with alcoholic relatives report that they have experienced substitute addictions and multiple addictions repeatedly—and sometimes, these substitutions and additions center on food.

The case of nicotine is also instructive. Under the dictates of earlier, predominately psychological models of addiction, food binges by abstaining smokers were commonly considered to be a case of substituting one classic oral fixation for another. As we have seen, though, one of the reasons smoking induces a sense of well being in smokers is because it raises serotonin and dopamine levels. The concentrations of serotonin, dopamine, insulin, and other neurotransmitters involved in both drug addiction and appetite control begin to change, as the brain readjusts during withdrawal from nicotine. And the result, for many people, is a raging sweet tooth. Carbohydrates also increase the secretion of insulin, which in turn increases the rate at which most amino acids are taken up from the bloodstream. Tryptophan, the serotonin precursor found in foods, is unaffected by this insulin-aided uptake, and thus the proportion of tryptophan in the blood stream increases when carbohydrates are eaten. Under these conditions, tryptophan has less competition from other amino acids for transport from the blood to the brain. The result is an increase in circulating brain serotonin.

As usual, some of the best hard evidence comes from rats. In a study by Dr. Neil Grunberg at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, rats were regularly injected with nicotine over long periods. When the injections were suddenly withdrawn, the rats chose sweetened food over regular food--a complete reversal of the food preference they had previously shown.

Not all overeaters are abstaining drug addicts, of course. Obesity, like drug addiction, comes in a variety of forms, and is influenced both genetically and environmentally. But the spotlight is now on a subset of obese people in which obesity does not seem to be a behavior learned from obese parents, any more than alcoholism is inevitably a learned behavior picked up from alcoholic parents. MORE...