Vote of No Confidence For Prometa

Addiction drug loses major funding.

It is composed of three common and inexpensive drugs used for other purposes. It has never been subjected to clinical double blind testing. It costs thousands of dollars for the full treatment package, and the company that markets it says it cures about 80 percent of the drug addicts who use it.

If that description sounds familiar—if it seems to give off a faint whiff of blue-green algae and multi-level marketing—such concerns have not stunted the promotion and acceptance of the anti-addiction drug Prometa. But MSNBC reported last week that Prometa, the drug “cocktail” designed to combat addiction to cocaine and methamphetamine, was dealt a severe blow when accountants in Pierce County, Washington froze the funding for an $800,000 pilot program, citing irregularities in testing.

The treatment involves intravenous infusions of Flumazinil, a reversal agent for benzodiazepines like Valium and Klonopin. The second drug, hydroxyzine, is an antihistamine, and the third, sold as Neurontin, as an anti-seizure medication frequently used “off prescription” as a treatment for a number of ailments, including alcoholism and hearing loss.

The treatment does not require approval by the Food and Drug Administration (FDA) because all three ingredients are already in common use in clinics and hospitals. The Prometa Regimen marketed by Hythium involves formulating the protocol and contracting with doctors to deliver the medications.

To date, there is no published clinical data to support treatment for addiction with these three drugs in proprietary combination.

Marketed heavily by anecdote and personal testimonials, the Prometa marketing campaign included ads in 2006 featuring the late comedian Chris Farley, who died of a drug overdose.

Hythiam, the company that markets Prometa, has touted the treatment with claims of success rates as high as 98 per cent, but Pierce County Councilman Shawn Bunney found the results of the county audit “alarming,” according to MSNBC. “It’s clear to me that we are much more involved in a marketing scheme…”

Hythiam Executive Vice President Richard Anderson disagreed. “The people who are using it,” he said, “the doctors, patients, administrators, and drug court judges—are seeing an impact with it, so I think the treatment will carry it at the end of the day.”

The dispute centers on the manner in which dropouts were counted in surveys done by Hythiam’s non-profit arm, the Pierce County Alliance. The Alliance had been responsible for administering the Prometa program in Pierce County drug courts. According to county auditors, dropouts and no-shows (patients who fail to show up for drug testing) were not included in the Alliance’s final report on 35 patients over a 14-month period. In Pierce and neighboring counties of Washington, drug courts record no-shows as equivalent to positive drug tests. This was not how the alliance scored it, although alliance spokespeople have insisted that county officials have misunderstood the mechanics of the study.

An investigation by the Tacoma News Tribune threw more cold water on the Prometa numbers. “According to the multiple public statements by the alliance,” wrote Sean Robinson, 86 percent of the Prometa clients ‘remained drug-free’ at the end of the 14-month program. According to county auditors, the number was 50 percent.”

Furthermore, the alliance “defined success in the Prometa program as 60 or more days of clean drug tests…. In Pierce County, drug-court clients must show 90 days of clean drug tests… In Snohomish and Thurston counties, drug-court clients must show six months.”

Investors in Hythiam, which is publicly traded, were counting on the Pierce program after similar programs in Fulton County, Georgia, and in Idaho failed to get off the ground. Things only got worse when the Tacoma News Tribune revealed that several county officials who had gotten behind the program also owned Hythiam stock.

Small rural communities that have felt the impact of meth sales and production in their communities are looking for help, and represent a significant market for an anti-addiction medication. However, in the case of Prometa, “The marketing is way ahead of the science,” claimed Lori Karan of the Drug Dependence Research Laboratory at the University of California-San Francisco.

Double-blind studies of Prometa are underway at the University of California-Los Angeles and at the University of South Carolina.

Cocaine Prices Climb, U.S. Drug Czar Declares A Win

NPR Investigation Suggests Otherwise.

It’s hard to win a war on drugs. Success stories are few, so it is not surprising that a temporary hike in recent cocaine prices in selected American cities was seized upon by U.S. Drug Czar John Walters as the lynchpin of a promotional campaign touting a victory in the war on drugs. After the U.S Coast Guard’s seized a record 160 metric tons of cocaine in early December, Walters declared: “These seizures are having a profound effect on availability of drugs in the U.S.”

But are they? In late December, National Public Radio (NPR) undertook an investigation of this claim by contacting the police departments in the 37 cities—including Los Angeles, San Francisco, Minneapolis, and Milwaukee--in which Drug Czar Walters claimed that interdictions had seriously disrupted cocaine supplies. Police officials in ten of the cities, including New York and Atlanta, confirmed that a cocaine scarcity existed. Some cities declined to respond. Five cities reported no signs of shortage, and police officials in 18 other cities gave “qualified responses,” according to NPR.

For example, officials in Boston, Chicago and Washington, D.C., acknowledged some scarcity, but said that the price and availability of rock cocaine on the street had remained essentially unchanged. Police in Detroit and Pittsburgh scoffed at the notion that cocaine was in short supply in their cities. “I spoke to my detectives out there in the streets making buys,” said Police Commander Sheryl Doubt, “and we all kind of agreed that if there’s a shortage here in Pittsburgh, we are not aware of it and don’t find that necessarily to be true.”

Police in Dallas and San Diego said they were unaware of any cocaine shortages in their cities. In San Antonio and Jacksonville, prices had gone up, but retail cocaine was readily available. In Philadelphia, Denver, and Houston, prices increased last summer, but have largely returned to normal, city officials told NPR.

Overall, said NPR, “The results suggest how difficult it is for law enforcement to create any long-term disruption in retail sales in America, which is the largest cocaine market in the world.”

Nonetheless, a stubborn Michael Braun, Chief of Operations for the Drug Enforcement Administration (DEA), said: “I don’t believe that we’ve ever seen this price/purity phenomenon over a 10-month period. This could all change next month. I hope that it doesn’t. I don’t think it will.”

But it did. In a statement not for attribution, an official at the National Drug Intelligence Center told NPR: “Cocaine availability appears to have returned to previous levels in some, but not all, drug markets, as traffickers re-establish stable sources of supply and distribution networks.” In Philadelphia, showcased as a major federal success story in choking off cocaine supplies, Police Captain Christopher Werner reported a recent bust involving 16 pounds of cocaine and more than $100,000 in cash “So,” Werner said, “is there a cocaine shortage right now? I don’t believe so.”

Even when drug wars seem to be working, and demand goes down, lowered usage of a particular drug often disguises the fact that a new drug has replaced it. There is an essential flaw in the logic behind the drug war. Demand for drugs is like a balloon--squeeze it in one place, and it bulges out somewhere else. Police officials contacted by NPR reported that wherever spot shortages of cocaine existed, “regular users turn to meth, heroin, prescription, drugs, and high-potency marijuana. In other words, enforcement had not appeared to curtail demand—one of the chief aims of the war on drugs.”

John Carnevale, a former budget director under four different drug czars, told NPR that there have been “occasional moments where we’ve seen spikes in cocaine prices… but eventually the trend continues to decline.” Such fleeting price changes, Carnevale contends, do not meaningfully affect overall demand and usage.

If it all sounds familiar, it should. By the early 1990s, after having spent more than $100 billion dollars over the preceding ten years, the Reagan-Bush drug war had almost no lasting successes to report. Interdiction at the border was a joke, cocaine and heroin were cheaper than ever, and people addicted to alcohol, cocaine, and other drugs were still committing the majority of violent crimes. Treatment for drug and alcohol addiction in prison was still an afterthought. After the “just say no” years of the Reagan administration, and the “lock ‘em up,” policy thrust of the senior Bush years, many policy reform advocates were buoyed by Bill Clinton’s election and his ardent backing of treatment on demand (which never came to fruition).

What is Drug Craving?

Exploring the engine of drug relapse.


“In terms of treatment, you can’t just attack the rewarding features of the drug. In the case of alcohol, we already have a perfect drug to make alcohol aversive--and that’s Antabuse. But people don’t take it. Why don’t they take it? Because they still crave. And so they stop taking it. You have to attack the other side, and hit the craving.”
--Dr. Ting-Kai Li, 1990 interview

It causes relapses and treatment failure. It leads good people to break good promises and do harm to themselves and others. What is this thing called craving? Isn’t it just another word for lack of will power?

Scientists have gained a much deeper understanding of how and why addicts crave. For years, craving was represented by the tortured tremors and sweaty nightmares of extreme heroin and alcohol withdrawal. Significantly, however, the symptom common to all forms of withdrawal and craving is anxiety. This prominent manifestation of craving plays out along a common set of axes: depression/dysphoria, anger/irritability, and anxiety/panic. These biochemical states are the result of the “spiraling distress” (George Koob’s term) and “incomprehensible demoralization” (AA’s term) produced by the addictive cycle. The mechanism driving this distress and demoralization is the progressive dysregulation of brain reward systems, leading to biologically based craving. The chemistry of excess drives the engine of addiction, which in turn drives the body and the brain to seek more of the drug.

Whatever the neuroscientists wanted to call it, addicts knew it as “jonesing,” from the verb “to jones,” meaning to go without, to crave, to suffer the rigors of withdrawal. Most doctors don’t get it, and neither did many of the therapists, and least of all the public policy makers. Drug craving is ineffable to the outsider.

Drug craving itself is mediated by glutamate receptor activity in the hippocampus—the seat of learning and memory. A fundamental branch of what we might dub the “relapse pathway” runs through the glutamate-rich areas of the hippocampus. The puzzling matter of craving and relapse began to come into focus only when certain researchers began to rethink the matter of memory and learning as it applies to the addictive process. This led back to the role of glutamate, and it gradually became clear that the drug high and the drug craving were, in a manner of speaking, stored in separate places in the brain. Research at the National Institute for Drug Abuse (NIDA) strongly supports the hypothesis that drug memories induced by environmental triggers originate primarily in the hippocampus. And glutamate may be the substance out of which the brain fashions “trigger” memories that lead certain addicts down the road to relapse.

Glutamate is the most common neurotransmitter in the brain. (In sodium salt form, as monosodium glutamate, it is a potent food additive.) About half of the brain’s neurons are glutamate-generating neurons. Glutamate receptors are dense in the prefrontal cortex, indicating an involvement with higher thought processes like reasoning and risk assessment. The receptor for glutamate is called the N-methyl-D-aspartate (NMDA) receptor. And unfortunately, as the gifted science writer Constance Holden related in Science 292, NMDA antagonists, which might have proven to be potent anti-craving drugs, cannot be used because they induce psychosis. Dissociative drugs like PCP and ketamine are glutamate antagonists.

However, drugs that play off receptors for glutamate are already available, and more are in the pipeline. As a precursor for the synthesis of GABA, glutamate has lately become a tempting new target for drug research. Ely Lilly and others have been looking into glutamate-modulating antianxiety drugs, which might also serve as effective anti-craving medications for abstinent drug and alcohol addicts.

Photo credit: Changing Lives Foundation

“Drug Foods” and Addiction

Amino acid restoration therapy

Addicts frequently resort to sugar foods and other high-carbohydrates snacks as a substitute drug addiction, therapists frequently report. Since diet has a direct effect on neurotransmission in the brain, food of this type may play a role in keeping drug cravings alive.

Dr. Candace Pert, one of the founders of modern neuroscience, believes that the pain of drug withdrawal and the stress of associated cravings could be drastically lessened through attention to nutritional needs. “Recovery programs,” she writes in her book Molecules of Emotion: Why You Feel the Way You Feel, “need to take into account this multi-system reality by emphasizing nutritional support and exercise. Eating fresh, unprocessed foods, preferably organic vegetables, and engaging in mild exercise like walking to increase blood flow through the liver can speed the process up.”

Other alternative researchers speak of the body’s “natural stimulant capacity,” and suggest that proteins and raw vegetables replace drugs and “drug foods” like coffee, chocolate, and sugar.

Since the 1990s, various researchers have been experimenting with amino acid combinations, developing therapeutic “cocktails” composed of precursors for dopamine, serotonin, endorphin, norepinephrine, and other brain chemicals. Kenneth Blum, the co-author of numerous controversial dopamine-alcohol studies at the University of Texas, worked with a neurotransmitter restoration cocktail called SAAVE, composed of phenylalanine, glutamine, tryptophan, pyridoxal-5-phosphate, and various enzymes.

However, tryptophan has been difficult to obtain in the U.S. for years now, ever since the FDA told consumers to stop taking tryptophan after the supplement was linked to an outbreak of a rare blood disorder called eosinophilia-myalgia syndrome (EMS). The Centers for Disease Control eventually reported 24 deaths. A specific bacillus the Japanese had cultivated to use as a “factory” for the production of tryptophan had gone haywire, and, through a process akin to fermentation, produced a pathogen responsible for the outbreak.

If we are what we eat, then it behooves us all to eat a little more carefully—especially since some of the things we eat are either drugs, or else natural substances that exert a similar effect. For example, cigarette smoking puts additional demands on the body’s store of vitamin C. This is another good reason why pregnant women should not smoke, and need to eat foods rich in vitamin C. Otherwise, they may be depriving the fetus of ascorbic acid.

By elevating key neurotransmitter levels through amino acid “loading,” and by inhibiting the enzyme-induced degradation of these amino acids, amino acid restoration therapy may be “a useful adjunct to psychotherapy in achieving sobriety, not only in an inpatient setting but as a crucial element for continued recovery,” Blum believes. Blum eventually sold his patent rights to NeuroGenesis, Inc., which continues to market variations of his product.

Other researchers say that the ratio of the precursor amino acid to other amino acids present in the body is too complicated, and too little understood, to allow amino acid replacement therapy to be effective at present. Tryptophan, for example, must compete with other amino acids for entry into the brain. The serotonin uptake blockers, on the other hand, apparently produce a decrease in blood concentrations of neutral amino acids, which lessens the competition across the blood-brain barrier. Nonetheless, amino acid replacement therapy is being tried experimentally at clinics around the country.

The CYP2D6 Factor

Enzymes And Drug Abuse

Different drugs effect different people differently.

Drugs are broken down into their constituent waste products by specific sets of enzymes. A subset of the human population, variously estimated at 3% to 7%, are categorized as “poor metabolizers.” For them, a drug’s recommended dosage is often far too high. The culprit is a gene variant that codes for a liver enzyme called cytochrome P450 isoenzyme 2D6, known in shorthand as CYP2D6. Poor metabolizers produce less of this crucial enzyme, which means that drugs are broken down and excreted at a much slower pace. In these people, the recommended dose results in higher drug concentrations. This obviously can make a crucial difference in how a person reacts to the drugs.

About one out of 20 people has a mutation in the 2D6 gene that causes a lack of the enzyme, according to UC-San Francisco biochemist Ira Herskowitz. “Those people are really getting a whopping dose”(New York Times, registration required). In addition, if a person with normal CYP2D6 levels is taking several drugs that are broken down by CYP2D6, then the enzyme’s ability to degrade one drug can greatly inhibit its ability to degrade the others. This increases the possibility of adverse drug interactions, particularly among the elderly, who may already be suffering from liver disease or impaired renal function.

Drugs of abuse severely complicate these enzymatic issues, since addicts and alcoholics are not known for volunteering information about their condition to medical or hospital personnel. Poor metabolizers often have little or no reaction to codeine-based medications. Screening tests for CYP2D6 variations are becoming cheaper and more widely available.

Enzyme interactions can work the other way, too. St. John’s Wort, for example, is suspected of activating another drug breakdown enzyme, CPY3A, thereby accelerating, rather than retarding, the destruction of other drugs. The herb can alter the metabolization of Phenobarbital, tamoxifen, oral contraceptives, and antiviral medications (Science, subscription required). Drugs must be combined with caution, and people need to monitor dosages, because of the tremendous degree of metabolic variation that exists.

“Start low and go slow” is still the best advice. A 2002 report from Georgetown University’s Center for Drug Development Science found that the dosage recommendations of 21 per cent of the drugs coming to market from 1980 to 1999 were later revised. Fully 80 per cent of those revisions involved a reduction in the original recommended dose. A related survey undertaken in Europe by the World Health Organization obtained similar results. “It’s long been known that for individual subjects the dosage listed on a drug label is not necessarily the right one,” said one of the authors of the Georgetown study. Typically, the recommended dosage is set early in the testing process, after analyzing results from a limited number of volunteer subjects (New York Times, registration required.) A more rigorous analysis of initial data would help get the dosage right the first time. Metabolic profiles that screen for CYP2D6 mutations will greatly assist this process.

Nicotine Vaccine Doubles Quit Rate in Human Trials

NicVax still showing promise against cigarette addiction

Nabi Biopharmaceutical announced this week that an experimental vaccine it has been testing against nicotine addiction had shown itself to be effective in human trials. Volunteers were more than twice as likely to quit, compared to a control group whose members were injected with a placebo.

The company-funded study gave volunteers five injections of NicVax, Nabi’s proprietary drug, or else a placebo. In regulatory filings, the company claims that the vaccine triggers an antibody response, which prevents nicotine molecules from reaching the brain. The antibodies bind with the nicotine molecules, making nicotine too large to cross the exceedingly fine blood-brain barrier of the brain. Roughly 15 per cent of smokers who received injections of NicVax were nicotine-free after one year. For comparison, early studies of Chantix as an anti-smoking medication show a quit response rate in the range of 20 per cent for heavy smokers. Studies of NicVax undertaken last year were also positive. It is one of several nicotine vaccines currently under development, and while it is farthest along in the FDA pipeline, it is still a year or two away from any possible commercial introduction.

Vaccines for specific addictive drugs represent one of two different approaches to developing pharmaceuticals for addiction treatment. The other approach, represented by Chantix and Zyban, decreases drug craving by altering the neuroregulation of dopamine and other substances in the brain. In this respect, these two drugs, which are non-addictive, are related to nicotine gums and patches, which also attempt to diminish cravings for cigarettes.

A vaccine like NicVax, however, does not attack the craving for nicotine. It contains no nicotine and is non-addictive. Rather, the vaccine makes the attempt to assuage nicotine cravings an impossible task. And in this respect, NicVax resembles Antabuse for alcoholism--except that the vaccine does not cause the smoker to become seriously ill when he or she takes a puff. . (The company reported that side effects were “well tolerated.”) It simply (or not so simply) cancels out the nicotine high altogether, or at least that is the idea. It is unclear to what extent the antibody reaction prevents nicotine binding in other areas of the body where nicotine-type receptors are found, such as acetylcholine receptors in muscle tissue.

In addition, NicVax must be injected, while Chantix and Zyban or taken orally. “Some people prefer a shot and some people will do anything to avoid one,” Rennard said. “It’s important to have options.”

Stephen Rennard of the University of Nebraska Medical Center, one of the authors of the company’s study, which is funded by a grant from the National Institute on Drug Abuse (NIDA) and is now in midstage, said that when smokers “don’t get the hit they would normally get, it makes it easier for them to quit because smoking doesn’t really do it for them any more.”

The results were presented at the American Heart Association Scientific Sessions in Orlando, Florida. “This double-blind, placebo-controlled trial has demonstrated [that] there is a correlation between antibody level and the ability of patients to quit smoking and remain abstinent over long periods of time,” Rennard told the group. Leslie Hudson, CEO and Interim President of the company, said he was “excited and encouraged.” Nabi Biopharmaceutical, headquartered in Boca Raton, Florida, is traded on the NASDAQ stock market [NABI].

Overdose Kits for Heroin Addicts

Massachusetts to offer Narcan nasal spray

Noting that heroin overdoses kill more people in Massachusetts each year than firearms, Dr. Peter Moyer, medical director of Boston’s fire, police and emergency services, applauded the state’s decision to offer addicts an overdose reversal kit. The package contains two nasal doses of naloxone, known as Narcan, a drug that reverses heroin overdose and saves uncounted lives (many victims of heroin overdose never see a hospital) when administered quickly enough. “It’s a remarkably safe drug,” said Dr. Moyer. “I’ve used gallons of it in my life to treat patients.”

Predictably, other health authorities aren’t so sure. “You give them the Narcan, where is their motivation to change?” said Michael Gimbel, director of substance abuse for Baltimore County, Maryland. “Giving Narcan might give them that false sense that ‘I can live forever,’ which is not what we want,” he told the Associated Press. Although similar programs have met with success in Chicago and New York City, the Massachusetts program is not supported by the Office of National Drug Control Policy in the White House. Drug Policy officials do not like the idea of addicts medically treating other addicts. Other officials argue against distribution of the kits, as they have frequently argued against needle distribution programs—in the belief that distributing the Narcan antidote will encourage heroin use and delay treatment for addicts.

Almost no one disputes the fact that heroin is currently popular throughout New England due to low prices and a surge in demand. “It’s the perfect storm in all the wrong directions. We talk about availability, price and potency,” said Kevin Norton of CAB Health & Recovery Services, one of the state-designated Narcan overdose kit providers.

The state-sponsored overdose kits were first tried in a pilot program in Boston, where Public Health Commissioner John Auerbach decided to go statewide after the kits were used to save 66 overdoses in the Boston area. “Narcan’s been around for a long time,” according to Cindy Champagne, director of nurses at the Greater New Bedford Community Health Center. Nonetheless, Champagne expressed some reservations about the drug “being out there for addicts to use,” noting its powerful effects and the rapid reversal of overdose, which leaves some addicts “combative.”

But Joanne Newton of the Seven Hills Behavioral Health Center of New Beford, another of the administrators of the program chosen by the Massachusetts Department of Public Health (DPH) cautioned that the program is carefully regulated, and will not increase the likelihood of addict overdoses. “There will be protocols and policies,” she said. “We’ll have to see what DPH’s plan is.”

Food Addiction: Snacking on Serotonin

The neurology of carbohydrate craving.

Eighteen years ago, Richard and Judith Wurtman, a husband and wife research team at the Massachusetts Institute of Technology (MIT) reported in Scientific American:

"We wondered whether the consumption of excessive amounts of snack carbohydrates leading to severe obesity might not represent a kind of substance abuse, in which the decision to consume carbohydrates for their calming and anti-depressant effects is carried to an extreme--at substantial cost to the abuser’s health and appearance."

In the case of certain carbohydrate cravers, the Wurtmans discovered, dietary tryptophan was being converted into serotonin, like always—but this concentrated serotonin surge acted like a powerful mood-booster. It acted like medicine.

The Wurtmans had hit on something important. People who tended to binge late in the day on carbohydrate foods, particularly simple sugars, got a drug-like “buzz” that was highly reinforcing. In the experiments, these people quite specifically, if unconsciously, selected the kinds of foods richest in serotonin-building compounds.

The serotonin-boosting effects of carbohydrates may explain why addicts in recovery, as well as carbohydrate cravers and PMS sufferers, show a tendency to binge on sugar foods. Abstaining addicts apparently turned to the overconsumption of carbohydrates as a means of attempting to redress the neurotransmitter imbalances at the heart of their disorder. Perhaps some addicts discover early in life that carbohydrate-rich foods are their drug of choice.

None of this should be taken to mean that large doses of supplemental tryptophan constitutes some sort of easy remedy for serotonin-mediated disorders. It isn’t that simple. However, many drug treatment experts are convinced that dietary alterations, vitamin therapy, and nutritional supplements--as well as strenuous exercise, which also has a marked effect on neurotransmission—play vital roles in addiction treatment programs.

Dopamine is involved with eating behaviors, too. A Princeton University animal study compared dopamine levels while rats were experiencing stimulant drugs, and while they were eating preferred foods. The researchers found that “amphetamine and cocaine increase dopamine in a behavior reinforcement system which is normally activated by eating. Conversely, the release of dopamine by eating could be a factor in addiction to food.”

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.

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.

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.

Profiles in Addiction Science

Henri Begleiter and the P3 wave


At the State University of New York’s Health Science Center in Brooklyn, the late Dr. Henri Begleiter, a professor of psychiatry, began investigating the brain wave activity of alcoholics in the early 1980s. According to Dr. Ting-Kai Li, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA):

“Starting with the ground-breaking finding, published in Science, that some neurophysiological anomalies in alcoholics were already present in their young offspring before any exposure to alcohol and drugs, he proposed a model that changed the thinking in the field: namely, rather than a consequence of alcoholism, this neural hyperexcitability was a predisposing factor leading to the development of alcoholism and related disorders. This innovative study was replicated throughout the world and launched him on a systematic search to elucidate the genes underlying this predisposition.”

People have heard of alpha waves and theta waves, but there are many other brain waves, evoked by various kinds of stimulation. Scientists can now measure electrical phenomena called evoked potentials (EPs), and event-related potentials (ERPs). For example, certain characteristic waveforms occur when the brain reacts to visual and auditory stimuli--when a person sees flashes of light, for example, or hears a clicking noise. As the signal of the flashing light makes its way from the retina of the eye to the cortex of the brain, electrodes placed on the scalp record the nerve impulses.

Begleiter and his coworkers recorded various event-related potentials, using scalp electrodes. The result was a series of sine wave-like printouts measuring amplitude and elapsed time for any given brain wave. The so-called P3 voltage, a measure of reaction time invoked by such stimuli as flashing lights or clicking noises, especially interested the researchers. Prior testing had shown that people suffering from schizophrenia or attention deficit disorder exhibited low P3 amplitudes. When Begleiter’s team tried recording P3 waves, something odd turned up. Diminished P3 waves were characteristic of an overwhelming majority of practicing alcoholics. As it turned out, the same event-related P3 wave abnormalities could be found in recovering alcoholics--even when they had been abstinent for years.

It was left for Begleiter’s team to round up a group of children ranging in age from six to eighteen, all of whom had an alcoholic parent, and all of whom, as Begleiter’s team documented, showed the same diminished amplitude in P3 waves. None of the children had ever been exposed to alcohol before. Nonetheless, there it was: The P3 waves of these children exhibited exactly the same waveform abnormalities as their actively alcoholic parents.

When Begleiter limited the pool of brain scan volunteers to the sons of fathers who had been diagnosed as Type 2 alcoholics, and compared their P3 waves with the P3 waves of a control group, he was able to correctly identify the children of Type 2 fathers almost 90 per cent of the time. Begleiter had discovered an organic impairment in the brains of non-drinking siblings of alcoholics.

Begleiter’s work caught most genetic researchers by surprise. Numerous laboratories raced to replicate Begleiter’s findings--and consistently succeeded. The P3 deficit was verifiable, and repeatable. Addiction researchers sat up and took notice: Here was compelling evidence of a marker for alcoholism; a specific abnormality in the brain which was apparently passed on genetically in alcoholic families.

“Actually, it’s more than just the P3,” Begleiter told me at the time. A colleague of Begleiter’s, neuroscientist Bernice Porjesz, found that an additional neurological oscillation, the N400 waveform, was markedly different in the children and families of alcoholics. The children with abnormal P3 or N400 waves were more likely to abuse drugs and tobacco in later years. The P3 findings have been thoroughly verified in other laboratories all over the country. There have been no retractions, and little difficulty in duplicating the findings. Begleiter’s markers are solid.

This Is Your Brain on Drugs

High-tech imaging reveals the chemistry of addiction

Drug intoxication produces characteristic waveform signatures in the mammalian brain. The search for specific biological markers in the brain was made possible by positron emission tomography, better known as the PET scan. The idea is simple: Doctors inject test subjects with radioactively tagged glucose, which passes the blood-brain barrier with ease. The more electrochemically active portions of the brain burn extra glucose for energy. By noting precisely where the tagged glucose has gone, and converting that information into a digital two-dimensional array, a PET scan serves as a neurobiological map of brain activity in response to specific stimuli. Functionally, PET scans are pictures of the brain, showing specific areas that “light up” during the performance of a task, or in response to a drug.

Neuroimaging techniques like nuclear magnetic resonance imaging, or MRI, provide another level of detail. With MRIs, scientists could study the brain as a living work in progress. They could create a three-dimensional picture of the brain, with the sagittal, transaxial and coronal planes all visible at once—almost a brain hologram. For the first time, addiction scientists could watch areas of the brain light up with activity under the influence of specific mood-altering chemicals.

Two areas were of particular interest. One was the nucleus accumbens, which was involved in the regulation of dopamine and serotonin synthesis. The other was the locus ceruleus—a tiny area of the brain saturated with cells involved in the production and release of the neurotransmitter norepinephrine. Norepinephrine is another important neurotransmitter in the story. It is also known as noradrenaline, and is essentially identical to adrenaline (the latter also called, confusingly, epinephrine). For practical purposes, the four terms are essentially synonymous.

Alcohol, cocaine, the opiates, and other drugs made these two areas of the brain bloom with activity on the MRI and PET scans. These snapshots of your brain on drugs specifically showed that psychoactive drugs of abuse, the ones that altered mood and emotion, did so at the very sites in the brain known to be involved in regulating emotional states. As a general rule, the same areas of the brain tended to light up no matter what addictive drug was under study. Whether it was a molecule of rapture, or a molecule of sorrow, sooner or later it went surging through the brain’s limbic system--a diffuse aggregation of mid-brain structures involved with emotion, memory, mood, sleep, and a host of specific behaviors ranging from appetite to risk-taking.

That the subjects also showed characteristic brain activity when they quit doing drugs was of equal interest. Dr. Kenneth Blum and his coworkers at the University of Texas Health Science Center demonstrated that certain waveforms occur in the locus ceruleus when abstinent addicts experience cravings. The locus ceruleus helps control levels of the original “fight or flight” chemical, norepinephrine, and when an addict in withdrawal panics, the locus ceruleus lights up like the Fourth of July.

Other studies of the nucleus accumbens showed abnormal firing rates in scanned addicts who were deep into an episode of craving. Drug hunger in abstinent addicts, it appeared, was not all in the head, or strictly psychological. Cravings have a biological basis.

OxyContin Back in Court

Kentucky goes after makers of “hillbilly heroin”

The attorney general for the state of Kentucky filed a lawsuit last week against Purdue Pharma L.P., makers of OxyContin, seeking to recover damages related to widespread addiction to the painkiller commonly known as “hillbilly heroin.”

Brought to widespread attention by Rush Limbaugh’s well-publicized addiction, OxyContin is a prescription narcotic for which a thriving black market has been established. It did not take drug users long to discover that OxyContin could also be ground up and either snorted or injected for a heroin-style high. Hundreds of deaths have been attributed to the street use of this Schedule II narcotic. Kentucky state officials say the social costs associated with fighting addiction have increased dramatically since the drug’s introduction. Others states are prepared to make the same argument.

Oxycontin racked up sales of $2 billion for the year ended August 2005. At least two companies, Pain Therapeutics (PTIE) and Alpharma, (ALO) are aiming at the market for more abuse-proof versions of OxyContin. “The big issue,” writes The Motley Fool’s Brian Lawler, “is whether insurers and government health programs will be willing to pay the premium price for an abuse-resistant drug.”

Oxycodone, as the drug is known medically, is a semi-synthetic derivative of thebaine, an alkaloid found in opium. It was developed in Germany in the early years of the 20th Century as a morphine substitute. Today, oxycodone is used extensively and very effectively for pain relief in terminal cancer patients. The Food and Drug Administration (FDA) approved the used of OxyContin in a time-release version in 2004.

Purdue Pharma said it will contest the lawsuit, which charges fraud, conspiracy and negligence--but the company recently settled other litigation with West Virginia and the U.S. Department of Justice for $685 million in cases alleging illegal marketing and promotion of the drug. U.S Attorney John Brownlee of the Western District of Virginia said that company sales reps falsely implied that OxyContin had less potential for addiction and abuse than similar prescription narcotics. Several other states were parties to those complaints, in which Purdue Pharma officials pled guilty last year to charges of misleading the public. Several states have taken a similar approach toward Merck, the manufacturers of Vioxx.

The Kentucky attorney general’s office said OxyContin addiction was so widespread that officials in Pike County were forced to build a $5.6 addition to the county jail to cope with increased convictions for oxycodone addiction. “It’s ironic that those who manufacture a drug that is meant to ease the pain of those suffering from debilitating diseases… have in fact inflicted so much pain by being deceptive and greedy,” said Country Judge-Executive Wayne Rutherford.

With the plethora of state lawsuits brought on behalf of Medicaid programs and law-enforcement agencies against OxyContin, “I think we have the answer as to whether government health programs will cover the costs of these abuse-resistant drugs,” Lawler concludes. “Count this as one less hurdle for Pain Therapeutics, Alpharma, and the other developers of these abuse-resistant compounds."

Defining Alcoholism

How much is too much?

Alcohol consumption lies on a spectrum, from nondrinkers on one end to patients dying of alcohol-related liver disease on the other. Novelist Jim Harrison once claimed that his ambition was to be a “problem drinker,” rather than an alcoholic.

How do we make the distinction?

Professor George Vaillant of Harvard felt obliged to study that question, an inclination that resulted in his 1983 landmark work, The Natural History of Alcoholism, revised in 1995.

Dr. Vaillant was the motive force behind the Harvard Medical School’s Study of Adult Development, which began in 1940. The study was divided into three groups: the middle-class College sample, the so-called “Core City Longitudinal Study”, and a later group, the Clinic sample, comprised solely of people who had been admitted to a clinic for detoxification, and the only one of the three groups that included women.

So what did George Vaillant discover in the longest formal study of drinking behavior ever undertaken in the United States? One of the first observations Vaillant drove home was that the amount of alcohol consumed is NOT a reliable indicator of alcoholism. Not only is “amount of alcohol ingested” an unreliable predictor of alcoholic drinking—so is “frequency of intoxication.” Both attributes, Vaillant found, proved to be very poor “discriminators” when it came to distinguishing alcoholics from “problem” drinkers.

So, if how much you drink, and how often you drink, are not reliably predictive of alcoholism, what, IS a reasonable predictor? The key item on Vaillant’s questionnaires turned out to be: “Admits problem controlling alcohol use.”

Vaillant showed that “multiple alcohol-related problems result not from ingesting large amounts of alcohol but from being unable consistently to control when, where, and how much alcohol is consumed.” Alcoholism, Vaillant concluded, is “defined by the number, not by the specificity, of alcohol-related problems.”

This insight dovetailed neatly with the definition of alcoholism the National Council on Alcoholism had adopted way back in 1976: “The person with alcoholism cannot consistently predict on any drinking occasion the duration of the episode or the quantity that will be consumed.”

For George Vaillant and other pioneers of the disease model, the conceptual view had shifted long ago: “As with coronary heart disease, we must learn to regard alcoholism as both disease and behavior disorder.” Genetic loading, says Vaillant, “is an important predictor of whether an individual develops alcoholism,” while a difficult childhood environment “is an important predictor of when an individual loses control of alcohol.”

Based on his lifelong study, Vaillant discloses that chronic alcoholics are involved in at least half of all vehicle accident deaths, which comes as no surprise. Half of all emergency room patients with severe multiple fractures are alcoholics, and alcoholics are six times as costly to keep when hospitalized, says Vaillant. Alcoholics—22 million of them in the U.S. alone, by a recent federal estimate—commit suicide far more often than non-alcoholics do. 10 to 30 per cent of all suicides may be alcoholics, according to statistics cited by Vaillant. And this does not include suicides by people addicted to drugs other than alcohol.

“Progressive” alcoholics—those who never abstain or go through periods of stable social drinking—were twice as likely to smoke two packs of cigarettes a day, compared to other drinkers. Indeed, alcoholics almost never stop smoking. Vaillant believes that heavy drinking acidifies the urine in a way that increases the urinary excretion of nicotine. Hence, there is a need to smoke more while you are drinking more, lest blood nicotine levels fall below the comfort range.

And along with cigarettes, says Vaillant, comes depression: “Like smoking and alcohol abuse, depression is associated with premature mortality; and if alcoholics were three times as likely to be dead, they were also three times as likely to be depressed.” Depressed men and women, then, drink more, smoke more, and take more drugs than non-depressed people. It is never hard to anticipate the chorus of complaint that such reasoning elicits. Everybody has emotional vicissitudes, but not everybody resorts to abusing drugs. Everybody gets the blues, but not everybody drowns them in drink. With courage and discipline, people can resist the easy notion of a whiskey, neat, for every problem.

To combat that notion, Vaillant also documents the dismal stats concerning “treated” alcoholism: “For short periods, middle-class individuals respond well to treatment in the medical model, but that response may be short-lived and reflect premorbid variables rather than the efficacy of specific treatment.” It turns out that if you simply control for two “premorbid” variables—marriage and employment—you can account for most of the difference. Alcoholics who are solidly married and have jobs fare better in treatment. But even they don’t always do very good for very long.

(Image courtesy of Medline Plus-National Library of Medicine)

Shining New Light on Addiction

SAD phototherapy may help with alcoholism

It’s that time of the year again.

For many people, autumn is a bracing and enjoyable time of the year. But for an unlucky minority of people, the advent of seasonal affective disorder, or SAD, is only, and literally, a matter of time. Since the autumnal equinox at 9.51 a.m. GMT on September 23, when daytime lost its annual circadian struggle with nighttime, the amount of daily sunlight slowly but surely diminishes by as much as several minutes a day. And for a few months, it will only get worse. For dwellers in the northern latitudes, the long dark has begun.

To be precise, seasonal affective disorder is not typically considered to be a separate or unique disorder, but rather a symptom of unipolar or general depression, the “garden-variety” form of depression. Both general depression and its seasonal variant involve symptoms such as lethargy, weight gain, carbohydrate craving, oversleeping and joylessness.

The addition of strong light in certain frequencies—a form of phototherapy—helps some people combat this seasonal form of depression. The so-called SAD lights have become a fixture in homes, offices, and mail-order catalogs. The evidence for effectiveness is somewhat controversial, but generally accepted.

Recently, Science magazine has spotlighted work being done on other conditions that may respond to SAD phototherapy. Citing the work of Alfred Lewy and Thomas Wehr at the National Institute of Mental Health (NIMH), who showed that phototherapy worked by decreasing the production of melatonin through a complicated set of reactions leading to an increase in blood levels of serotonin, the article summarizes the evidence showing that many people suffering from either seasonal depression or general depression benefited from spending 30 minutes each morning sitting three feet away from bright white fluorescent lighting--light banks very much like the indoor “grow lights” people often purchase for their house plants.

However unorthodox it may sound, recent studies strongly suggest that phototherapy might also aid people suffering from bipolar disorder, commonly called “manic-depression.” This is a striking possibility, since bipolar depression is distinct from general depression, and rarely responds to the same therapies and medications used for that condition.

This development has led researchers to wonder whether other mental or behavioral disorders partially mediated by fluctuations in serotonin might also respond to light therapy. Last year, writing in the American Family Physician, Stephen J. Lurie and coworkers pointed out that “SAD is associated with serotonergic dysregulation and… may overlap with other diagnoses that share similar mechanisms.”

One diagnosis that shares similar mechanisms is alcoholism. The neurological connection between alcoholism and major depression is well documented by now, and involves serotonin, among other neurotransmitters and neurotransporters that ferry molecules around the brain and the rest of the central nervous system. Brain imaging studies of alcoholics do indeed show a marked reduction in serotonin transporter availability in cases of accompanying depression.

According to Lurie, a summary of recent research findings reveals that “some patients with alcoholism may be self-medicating an underlying depression with alcohol or manifesting a seasonal pattern to alcohol-induced depression.” Such patterns also show genetic underpinnings—SAD often runs in families with a strong history of alcoholism and general depression. All of this, the paper states, “may be related to serotonergic functioning.”

Dr. Leo Sher of the Department of Psychiatry at Columbia University believes that “Family and molecular genetic studies suggest that there may be a genetic link between seasonality and alcoholism.” In an article for the January 2004 issue of Comprehensive Psychiatry, Sher writes:

“The fact that SAD and alcoholism may be comorbid [occur together] shows the importance of a thorough diagnostic interview. Both mental health and drug and alcohol professionals should be provided with education to assist with appropriate identification, management and referral of patients presenting with comorbid alcoholism and SAD.”

For alcoholics who also suffer from seasonal affective disorder, a therapy regimen that includes exposure to bright lights in the morning could do more than boost their moods. It might also help them drink less. Much more research is needed, but the possibility that SAD phototherapy might help curb alcohol cravings or prevent relapse is a hypothesis worthy of further investigation.

Sources:

Bhattacharjee, Yudhijit, “Is Internal Timing Key to Mental Health?” Science, 317 14 September 2007. (Subscription).

“Alcohol and Seasonal Affective Disorder.” Comprehensive Psychiatry.

“Serotonergic dysfunction, negative mood states, and response to alcohol.” Alcoholism, Clinical and Experimental Research.

"Circadian Phase Variation in Bipolar I Disorder." Chronobiology International

"Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of total sleep deprivation in bipolar depression." Journal of Clinical Psychiatry.

“Seasonal Affective Disorder.” American Family Physician

“Shedding Some Light on Bipolar Disorder.” Living the Scientific Life (Scientist, Interrupted).

The Morphine Scandal

Patients in Pain Due to "Opium Phobia"

“Opium has been recently made from white poppies, cultivated for the purpose, in Vermont, New Hampshire, and Connecticut.... comparatively large quantities are regularly sent East from California and Arizona, where its cultivation is becoming an important branch of industry, ten acres of poppies being said to yield, in Arizona, twelve hundred pounds of opium.”

--Massachusetts Government Health Report, 1871

By the mid-1800s, as many people know, opium could be legally purchased in the United States as laudanum, patent medicines, and various elixirs. Less well known is the fact that opium was a godsend during the bloody years of the Civil War. Maimed and disabled soldiers found relief in morphine, the potent alkaloid of opium named after Morpheus, the Greek god of dreams. Used against constant, intractable pain, opium and its derivatives were among the most humane medical drugs ever discovered. How could a physician withhold them?

Today, after countless drug wars have merged into a single, inflexible federal stance on “drugs,” morphine and its derivatives remain so stigmatized, so entangled in drug wars and global narco-politics, that the danger of losing sight of their humanitarian applications looms larger than ever.

At least half of all cancer patients seen in routine practice report inadequate pain relief, according to the American College of Physicians. For cancer patients in pain, adequate relief is quite literally a flip of the coin.

A September 10 New York Times report by Donald G. McNeil Jr. highlights studies by the World Health Organization which amply document the ongoing scandal in pain management. At least 6 million cancer and AIDS patients currently receive no appropriate pain treatment of any kind. In addition, WHO estimates that four out of five patients dying of cancer are also suffering severe pain. The numbers of untreated patients suffering intractable, unrelieved pain from nerve damage, burns, gunshots, sickle cell anemia, and a host of other medical conditions can only be guessed at.

Figures gathered by a different U.N. agency, the International Narcotics Control Board, make clear that “citizens of rich nations suffer less.” To put it starkly, the use of morphine per person in the United States is 17,000 times higher than per person usage in Sierra Leone. Doctors in Africa paint a grim picture of patients hanging themselves or throwing themselves in front of trucks as an alternative to life without pain relief. The U.S., Canada, Britain, France, Germany, and Australia together account for roughly 80 per cent of the world’s medicinal morphine use. Other countries, particularly the poor and undeveloped nations, scramble for what’s left.

The ironies fly thick and fast: In many cases, pain relief is the one thing doctors can offer their patients, and the one thing they withhold. Studies show that 70 per cent of patients present with painful conditions. Typically, non-addicted patients take morphine therapeutically for pain at doses in the 5 to 10 mg. range. But experienced morphine addicts regularly take several hundred milligrams a day—a huge difference.

As for concerns about addiction, recent evidence for the heritability of opiate addiction looks strong. “Harvard did some really superb studies using a huge cohort of military recruits in the U.S. Army,” according to Mary Jeanne Kreek, a specialist in opiate addiction at Rockefeller University in New York. “Heroin addiction has even a larger heritable component than any of the other addictions, so that up to 54% of heroin addictions seem to be on a genetic basis or a heritable basis.”

Opium, the main ingredient, is in abundant supply worldwide, and is relatively cheap to grow. The problem, as David E. Joranson of the University of Wisconsin’s Pain and Policy Studies Group told the Times, is the “intense fear of addiction, which is often misunderstood. Pain relief hasn’t been given as much attention as the war on drugs has.”

Moreover, generations of doctors have been taught in medical school that morphine must be used sparingly, with great caution, even if this “opium phobia” results in agony for patients, including infants. (Morphine is safe and effective for use in premature babies.)

The problem is not a new one. Ten years ago, a report by the American Academy of Pain Medicine laid the blame squarely on doctors, who were routinely underutilizing opiate derivatives for pain relief. Not much has changed. It is no secret that the move to HMOs has compounded the problem, as effective pain relief often gives way to the need to move patients out of beds as quickly as possible.

In 2001, the American College of Physicians called for more extensive pain-management education in the nation’s medical schools, noting that doctors are not learning enough about how to treat pain, or about how to talk to patients ABOUT pain, despite what Scott Fishman of the Division of Pain Medicine at the University of California, Davis, calls a “revolution” in the development of new pain medications.

We also need to recognize the problem of under prescribing morphine and other
addictive painkillers for children in hospital settings. If we continue to stringently prohibit the use and sale of opiates, then we had better remember to make one important exception: Pain abatement in medical applications “There’s a certain amount of hysteria about narcotics among doctors,” maintains one researcher. Patients suffering from serious pain cannot get adequate and sustained relief in many cases, because doctors and nurses remain reluctant to provide it.

This, rather than flashy cocaine seizures at the border, represents the lasting outcome of drug wars.

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Food Addiction

Carbohydrates on the Brain, Food Rehab in the Future

Earlier this month, Yale University hosted the first-ever conference on Food and Addiction. Dr. Nora Volkow of the National Institute on Drug Abuse told the collection of experts on nutrition, obesity and drug addiction that “commonalities in the brain’s reward mechanisms” linked compulsive eating with addictive drug use. “Impaired function of the brain dopamine system could make some people more vulnerable to compulsive eating,” Volkow said.

Moreover, animal studies and brain imaging research in humans strongly support the notion of food addiction. In particular, research has pointed toward a form of food addiction known as “carbohydrate-craving obesity.” Dr. Mark Gold, chief of addiction studies at the McKnight Institute at the University of Florida, and a well-known authority on cocaine abuse, argued that “failed diets and attempts to control overeating, preoccupation with food and eating, shame, anger, and guilt look like traditional addictions.”

Conference organizer Kelly Brownell, director of the Rudd Center for Food Policy and Obesity at Yale, conceded that “it wasn’t obesity experts who got interested in addiction, it was the addiction scientists who got interested in food.” Brownell suggested that psychologists have been slower to grasp the import of food addiction “in part because of a bias that obesity is all about failure and personal responsibility, so why look at biology?”

As Dr. Gold summed it up, “It turns out that food and drugs compete for the same reward system in the brain.”

SOURCES:

--“Yale Hosts Historic Conference on Food and Addiction.” Yale University Office of Public Affairs. July 9, 2007. http://www.yale.edu/opa/newsr/07-07-09-01.all.html

--Hellmich, Nancy. “Does food ‘addiction’ explain explosion of obesity?” USA Today, July 9, 2007.

--“Yale Hosts Historic Conference on Food Addiction.” Medical News Today. 11 July 2007. www.medicalnewstoday.com

--Hathaway, William. “Experts Chew Over Eating as Addiction.” The Hartford Courant. July 11, 2007. http://www.courant.com/news/health

What's Wrong With This Picture?

A bit of cognitive dissonance, perhaps?

The situation could easily be reversed, but cigarette manufacturers mostly advertise in magazines, not newspapers. Otherwise, we might be reading about the dangers of consuming too much alcohol in casinos, while looking at an ad for a new brand of cigarettes.

European Tree Yields New Alcoholism Treatment in Early Tests

Anti-Smoking Drug Also Curbs Alcohol Craving

A drug approved last year for smoking cessation has also shown promise for use against alcoholism, researchers at the University of California, San Francisco (UCSF), announced yesterday.

Varenicline, currently marketed by Pfizer for smoking cessation under the trade name Chantix, dramatically curbed drinking in alcohol-preferring rats, according to the study, which will be published online this week by “The Proceedings of the National Academy of Sciences.”

The synthetic drug was modeled after a cytosine compound from the European Labumum tree, combined with an alkaloid from the poppy plant.

Since an estimated 85 per cent of alcoholics are also cigarette smokers, varenicline could have an immediate effect on this common dual addiction. The drug has already been approved by the Food and Drug Administration (FDA) for human use, so Pfizer is likely to be granted a speedy approval for the new indication, sources say. The drug is likely to join Antabuse (disulfiram), Revia (naltrexone), and Campral (acamprosate) as FDA-approved treatments for alcoholism.

Selena Bartlett of the UCSF-affiliated Gallo Clinic and Research Center, a co-author of the study, said that the drug works by disrupting the neuronal “reward pathway” of the brain. Specifically, the drug binds to acetylcholine receptors, a neurotransmitter involved in arousal and attention. Through a cascade effect, stimulating these receptors causes a release of dopamine, one of the primary pleasure chemicals in the brain. Varenicline prevents alcohol and nicotine from causing a release of dopamine at those sites.

“Treatments for alcoholism today are like those for schizophrenia in the ‘60s,” Bartlett said. “People don’t talk about it. There are very few treatments, and most drug companies are not interested in it.”

Bartlett said she hoped the research would spur additional studies of drugs for alcoholism. “It’s a disease. If you’ve inherited a gene variant, of if some other cause leads you to alcohol dependence, it should be treated--like any disease.”

Sources:

“Drug to curb smoking also cuts alcohol dependence.” University of California, San Francisco, News Office. 09 July 2007. http://pub.ucsf.edu/newsservices/releases/200707063/

“Need a Cigarette and a Cocktail? Just Pop a Pill Instead.” ScientificAmerican.com July 09, 2007

New World Nicotine: A Brief History

“Drinking the Smoke”

The prototypically North American contribution to the world drug trade has always been tobacco. Tobacco pipes have been found among the earliest known Aztec and Mayan ruins. Early North Americans apparently picked up the habit from their South American counterparts. Native American pipes subjected to gas chromatography show nicotine residue going back as far as 1715 B.C. “Drinking” the smoke of tobacco leaves was an established New World practice long before European contact. An early technique was to place tobacco on hot coals and inhale the smoke with a hollow bone inserted in the nose.

The addicting nature of tobacco alarmed the early missionary priests from Europe, who quickly became addicted themselves. Indeed, so enslaved to tobacco were the early priests that laws were passed to prevent smoking and the taking of snuff during Mass.

New World tobacco quickly came to the attention of Dutch and Spanish merchants, who passed the drug along to European royalty in the 17th Century. In England, American tobacco was worth its weight in silver, and American colonists fiercely resisted British efforts to interfere with its cultivation and use. Sir Francis Bacon noted that “The use of tobacco is growing greatly and conquers men with a certain secret pleasure, so that those who have once become accustomed thereto can later hardly be restrained therefrom.” (As a former smoker, I am hard pressed to imagine a better way of putting it.)

Early sea routes and trading posts were determined in part by a desired proximity to overseas tobacco plantations. The expedition routes of the great 17th and 18th Century European explorers were marked by the strewing of tobacco seeds along the way. Historians estimate that the Dutch port of Amsterdam had processed more than 12 million pounds of tobacco by the end of the 17th Century, with brisk exports to Scandinavia, Russia, Prussia, and Turkey. (Historian Simon Schama has speculated that a few enterprising merchants in the Dutch tobacco industry might have “sauced” their product with cannabis sativa from India and the Orient.)

Troubled by the rising tide of nicotine dependence among the common folk, Bavaria, Saxony, Zurich, and other European states outlawed tobacco at various times during the 17th Century. The Sultan Murad IV decreed the death penalty for smoking tobacco in Constantinople, and the first of the Romanoff czars decreed that the punishment for smoking was the slitting of the offender’s nostrils. Still, there is no evidence to suggest that any culture that has ever taken up the smoking of tobacco has ever wholly relinquished the practice voluntarily.

A century later, the demand for American tobacco was growing steadily, and the market was worldwide. Prices soared, with no discernible effect on demand. “This demand for tobacco formed the economic basis for the establishment of the first colonies in Virginia and Maryland,” according to drug researcher Ronald Siegel. Furthermore, writes Siegel, in his book “Intoxication”:

"The colonists continued to resist controls on tobacco. The tobacco industry became as American as Yankee Doodle and the Spirit of Independence…. British armies, trampling across the South, went out of their way to destroy large inventories of cured tobacco leaf, including those stored on Thomas Jefferson’s plantation. But tobacco survived to pay for the war and sustain morale."

In many ways, tobacco was the perfect American drug, distinctly suited to the robust American lifestyle of the 18th and 19th Centuries. Tobacco did not lead to debilitating visions or rapturous hallucinations—no nodding out, no sitting around wrestling with the angels. Unlike alcohol, it did not render them stuporous or generally unfit for labor. Tobacco acted, most of the time, as a mild stimulant. People could work and smoke at the same time. It picked people up; it lent itself well to the hard work of the day and the relaxation of the evening. It did not act like a psychoactive drug at all.

As with plant drugs in other times and cultures, women generally weren’t allowed to use it. Smoking tobacco was a man’s habit, a robust form of relaxation deemed inappropriate for the weaker sex. (Women in history did take snuff, and cocaine, and laudanum, and alcohol, but mostly they learned to be discreet about it, or to pass it off as doctor-prescribed medication for a host of vague ailments, which, in most cases, it was.)

Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.
By Dirk Hanson

Drug Rehab in China

After two years of a nationwide “people’s war” against drug addiction in China, government authorities are claiming major accomplishments—but treatment, which is mostly compulsory, remains limited and largely ineffective, Chinese doctors say.

The Chinese surge against drugs was credited with numerous successes almost before it had begun. Zhou Yongkang, Minister of Public Security, told the official news agency Xinhua that officials had seized more than two tons of methamphetamine, and three million “head-shaking pills”--otherwise known as Ecstasy tablets.

Two years later, in June of 2007, Minister Yongang, claimed that the number of drug abusers in China had been cut from 1.16 million to 720,400 due to compulsory rehabilitation measures. “The effort has yielded remarkable results,” Yongang told the China Daily. (Other drug experts estimate the number of Chinese drug addicts to be 3 million or more.)

However, a recent paper co-authored by several Chinese physicians, published in the Journal of Substance Abuse Treatment, suggests that things are not so rosy. The report, titled, “Attitudes, Knowledge, and Perceptions of Chinese Doctors Towards Drug Abuse,” paints a dismal picture: Less than half the Chinese doctors working in drug abuse had any formal training in the treatment of drug addicts, the report found. Moreover, less than half of the treatment physicians believed that addiction was a disorder of the brain. (One cannot help wondering whether the percentage for American doctors would be any higher.)

The study could find no coherent doctrine or set of principles for drug rehabilitation being employed in China, beyond mandatory detox facilities. In the Chinese government’s White Paper on “Narcotics Control in China,” the practice of “reeducation-through-labor” is considered to be the most effective form of treatment. Another name for this form of treatment would be: prison.

There are perhaps as many as 200 voluntary drug treatment centers as well. These centers emphasize treating withdrawal symptoms, and feature more American-style group interaction and education, but observers say such centers are often used by people evading police or running from their parents.

In addition, the lack of formal support from the Chinese government has led to the closing of several such facilities after only a few months. The American origins of such treatment modalities have not helped sell such programs to government officials. Pharmaceutical treatments for craving remain unavailable in China.

SOURCES:

--Fan, Maureen. “U.S.-Style Rehabs Take Root in China as Addiction Grows.” Washington Post Foreign Service, A14, January 19, 2007.

--Yi-Lang Tang, et. al. “Attitudes, Knowledge, and Perceptions of Chinese Doctors Towards Drug Abuse.” Journal of Substance Abuse Treatment. vol. 29 no. 3. 215-220.

--“Anti-Drug Campaign Yields Result.” China Daily. June 16, 2007. http://www.china.org.cn.

--“With Prohibition Failing, China Calls for ‘People’s War’ on Drugs.” Drug War Chronicle. vol. 381. 4/8/05 http://stopthedrugwar.org

Is Marijuana Addictive?

The argument continues.

For more, see Marijuana Withdrawal.
See also Marijuana Withdrawal Revisited

Marijuana may not be a life-threatening drug, but is it an addictive one?

There is little evidence in animal models for tolerance and withdrawal, the classic determinants of addiction. For at least four decades, million of Americans have used marijuana without clear evidence of a withdrawal syndrome. Most recreational marijuana users find that too much pot in one day makes them lethargic and uncomfortable. Self-proclaimed marijuana addicts, on the other hand, report that pot energizes them, calms them down when they are nervous, or otherwise allows them to function normally. They feel lethargic and uncomfortable without it. Heavy marijuana users claim that tolerance does build. And when they withdraw from use, they report strong cravings.

Marijuana is the odd drug out. To the early researchers, it did not look like it should be addictive. Nevertheless, for some people, it is. Recently, a group of Italian researchers succeeded in demonstrating that THC releases dopamine along the reward pathway, like all other drugs of abuse. Some of the mystery of cannabis had been resolved by the end of the 1990s, after researchers had demonstrated that marijuana definitely increased dopamine activity in the ventral tegmental area. Some of the effects of pot are produced the old-fashioned way after all--through alterations along the limbic reward pathway.

By the year 2000, more than 100,000 Americans a year were seeking treatment for marijuana dependency, by some estimates.

A report prepared for Australia’s National Task Force on Cannabis put the matter straightforwardly:

There is good experimental evidence that chronic heavy cannabis users can develop tolerance to its subjective and cardiovascular effects, and there is suggestive evidence that some users may experience a withdrawal syndrome on the abrupt cessation of cannabis use. There is clinical and epidemiological evidence that some heavy cannabis users experience problems in controlling their cannabis use, and continue to use the drug despite experiencing adverse personal consequences of use. There is limited evidence in favour of a cannabis dependence syndrome analogous to the alcohol dependence syndrome. If the estimates of the community prevalence of drug dependence provided by the Epidemiologic Catchment Area Study are correct, then cannabis dependence is the most common form of dependence on illicit drugs.

While everyone was busy arguing over whether marijuana produced a classic withdrawal profile, a minority of users, commonly estimated at 10 per cent, found themselves unable to control their use of pot. Addiction to marijuana had been submerged in the welter of polyaddictions common to active addicts. The withdrawal rigors of, say, alcohol or heroin would drown out the subtler, more psychological manifestations of marijuana withdrawal.

What has emerged is a profile of marijuana withdrawal, where none existed before. The syndrome is marked by irritability, restlessness, generalized anxiety, hostility, depression, difficulty sleeping, excessive sweating, loose stools, loss of appetite, and a general “blah” feeling. Many patients complain of feeling like they have a low-grade flu, and they describe a psychological state of existential uncertainty—“inner unrest,” as one researcher calls it.

The most common marijuana withdrawal symptom is low-grade anxiety. Anxiety of this sort has a firm biochemical substrate, produced by withdrawal, craving, and detoxification from almost all drugs of abuse. It is not the kind of anxiety that can be deflected by forcibly thinking “happy thoughts,” or staying busy all the time. A peptide known as corticotrophin-releasing factor (CRF) is linked to this kind of anxiety.

Neurologists at the Scripps Research Institute in La Jolla, California, noting that anxiety is the universal keynote symptom of drug and alcohol withdrawal, started looking at the release of CRF in the amygdala. After documenting elevated CRF levels in rat brains during alcohol, heroin, and cocaine withdrawal, the researchers injected synthetic THC into 50 rats once a day for two weeks. (For better or worse, this is how many of the animal models simulate heavy, long-term pot use in humans). Then they gave the rats a THC agonist that bound to the THC receptors without activating them. The result: The rats exhibited withdrawal symptoms such as compulsive grooming and teeth chattering—the kinds of stress behaviors rats engage in when they are kicking the habit. In the end, when the scientists measured CRF levels in the amygdalas of the animals, they found three times as much CRF, compared to animal control groups.

While subtler and more drawn out, the process of kicking marijuana can now be demonstrated as a neurochemical fact. It appears that marijuana increases dopamine and serotonin levels through the intermediary activation of opiate and GABA receptors. Drugs like naloxone, which block heroin, might have a role to play in marijuana detoxification.

In the end, what surprised many observers was simply that the idea of treatment for marijuana dependence seemed to appeal to such a large number of people. The Addiction Research Foundation in Toronto has reported that even brief interventions, in the form of support group sessions, can be useful for addicted pot smokers.

--Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.

addiction drugsmedical marijuana