The Losing Battle For Perpetual Reward

Or why you can't stay high forever.

The amphetamine high, like the cocaine high, is a marvel of biochemical efficiency. Stimulants work primarily by blocking the reuptake of dopamine molecules in the synaptic gap between nerve cells. Dopamine remains stalled in the gap, stimulating the receptors, resulting in higher dopamine concentrations and greater sensitivity to dopamine in general. Since dopamine is involved in moods and activities such as pleasure, alertness and movement, the primary results of using cocaine or speed—euphoria, a sense of well being, physical alertness, and increased energy—are easily understood. Even a layperson can tell when lab rats have been on a meth binge. The rapid movements, sniffing, and sudden rearing at minor stimuli are not that much different in principle from the outward signs of meth intoxication among higher primates.

Chemically, cocaine and amphetamine are very different compounds. Psychoactively, however, they are very much alike. Of all the addictive drugs, smoked cocaine and speed have the most direct and most devastatingly euphoric effect on the dopamine systems of the brain. Cocaine and amphetamine produce rapid classical conditioning in addicts, demonstrated by the intense cravings touched off by such stimuli as the sight of a building where the user used to buy or sell. Environmental impacts of this nature can produce marked blood flow increases to key limbic structures in abstinent addicts.

In clinical settings, cocaine users have a hard time distinguishing between equal doses of cocaine and Dexedrine, administered intravenously. As we know, it is the shape of the molecule that counts. The amphetamines are shaped like dopamine and norepinephrine, two of the three reward chemicals. Speed, then, is well suited to the task of artificially stimulating the limbic reward pathway. Molecules of amphetamine displace dopamine and norepinephrine in the storage vesicles, squeezing those two neurotransmitters into the synaptic gap and keeping them there. By mechanisms less well identified, cocaine accomplishes the same feat. Both drugs also interfere with the return of dopamine, norepinephrine, and serotonin molecules to their storage sacs, a procedure known as reuptake blocking. Cocaine works its effects primarily by blocking the reuptake of dopamine.

Amphetamine was once one of the most widely prescribed drugs in the pharmacological cornucopia. It exists in large part now as a recreational drug of choice, abuse, and addiction. The same is true of cocaine. It was replaced as a dental anesthetic long ago, in favor of non-addictive variants like Novocain. The same tragic list of statistical side effects that apply to abusers of alcohol, heroin and nicotine also apply to stimulant abusers: Increased risk of car accidents, homicides, heart attack, and strokes.

In the late 1990s, scientists at Johns Hopkins and NIDA showed that opiate receptors play a role in cocaine addiction as well. PET scans demonstrated that cocaine addicts showed increased binding activity at mu opiate receptors sites in the brain during active cocaine addiction. Take away the cocaine, and the brain must cope with too many empty dopamine and endorphin receptors. It is also easy to understand the typical symptoms of cocaine and amphetamine withdrawal: lethargy, depression, anger, and a heightened perception of pain. Both the cocaine high and the amphetamine high are easily augmented with cigarettes or heroin. These combinations result in “nucleus accumbens dopamine overflow,” a state of neurochemical super saturation similar to the results obtained with the notorious “speedball”—heroin plus cocaine.

With the arrival of smokable forms of cocaine and amphetamine, the race to pin down the biology of stimulation became even more urgent. Stimulants in smokable form—crack and ice—are even more rapidly addictive for addiction-prone users. “The reason has to do with the hydraulics of the blood supply,” a researcher at the University of Minnesota explained to me. “High concentrations are achieved with each inhalation, and sent right upstairs to the brain—but not all of the brain simultaneously. The target of the flow of blood is the limbic system, whereas the remainder of the brain is exposed to much milder concentrations.”

This extraordinarily concentrated jolt to the reward center is the reason why smokable cocaine and speed are able to pack such a wallop. The entire range of stimulative effects hits the ventral tegmental area and associated reward regions of the brain in seconds, and the focused nature of the impact yields an astonishingly pleasurable high.

But the long-term result is exactly the opposite. It may sound dour and religious, but the scientific fact of the matter is that continuous chemical pleasure extracts its fee in the end: The body’s natural stock of these neurotransmitters starts to fall as the brain, striving to compensate for the artificial flooding of the reward center, orders a general cutback in production. At the same time, the receptors for these neurotransmitters become excessively sensitive due to the frequent, often unremitting nature of the stimulation.

“It’s clear that cocaine causes depletion of dopamine, norepinephrine, serotonin—it is a general neurotransmitter depleter,” said my research source. “That may account for many of the effects we see after someone has stopped using cocaine. They’re tired, they’re lethargic, they sleep; they may be depressed, moody, and so on.” Continued abuse of stimulant drugs only makes the problem worse. One reason why cocaine and amphetamine addicts will continue to use, even in the face of rapidly diminishing returns, is simply to avoid the crushing onset of withdrawal. Even though the drugs may no longer be working as well as they once did, the alternative—the psychological cost of withdrawal—is even worse. In the jargon used by Alcoholics Anonymous, addicts generally have to get worse before they can get better.

When addicts talk about “chasing a high,” the metaphor can be extended to the losing battle of neurotransmitter levels.

[First published September 28, 2011]

Graphics Credit: http://www.keepcalm-o-matic.co.uk

Crack Babies Are Turning Out Okay

Major study concludes that crack panic was overblown.

In an excellent story for the Philadelphia Inquirer, Susan FitzGerald traces the fortunes of Philadelphia children enrolled in a study that began in 1989, at the height of the crack “epidemic” in the U.S. Headed up by Hallam Hurt, then the chair of neonatology at Albert Einstein Medical Center, a group began the in-vitro study of babies exposed to maternal crack cocaine use. One of the longest-running studies of its kind, the NIDA-funded research on 224 babies born between 1989 and 1992, half of them cocaine-exposed, the other half normal controls, was now coming to a close. And the results were not what most people were expecting.

In the Inquirer article, Hurt notes that cocaine can in fact trigger premature labor, raise blood pressure, and risk a condition in which the placenta breaks loose from the uterine wall. So it was natural to go looking for long-term effects in all of those twitching, underweight newborn crack babies viewers  saw on television. Physicians warned that damage to developing dopamine systems would result in long-term or permanent impairments in attention, language, and memory. So Hurt and colleagues went looking—and couldn’t find them. Neither could researchers at other institutions.  Said Hurt: “We began to ask, ‘Was there something else going on?’”

As FitzGerald writes: “The years of tracking kids have led Hurt to a conclusion she didn’t see coming. ‘Poverty is a more powerful influence on the outcome of inner-city children than gestational exposure to cocaine,'" Hurt said.  For example, babies born to mothers on heroin or methadone will have certain characteristic withdrawal symptoms, which can be managed by informed hospital staff. The same is true with newborns whose mothers have been using crack. In most cases, these withdrawals can be managed without permanent harm to the infant.

In a paper authored by Hurt, Laura M Betancourt, and others, the investigators write: “It is now well established that gestational cocaine exposure has not produced the profound deficits anticipated in the 1980s and 1990s, with children described variably as joyless, microcephalic, or unmanageable.” The authors do not rule out “subtle deficits,” but do not find evidence for them in functional outcomes like school or transition to adulthood.

How did this urban legend get started? In the 1980s, during the Reagan-Bush years, Americans were confronted with yet another drug “epidemic.” The resulting media fixation on crack provided a fascinating look at what has been called “drug education abuse.” This new drug war took off in earnest after Congress and the media discovered that an inexpensive, smokable form of cocaine was appearing in prodigious quantities in some of America’s larger cities. Crack was a refinement to freebasing, and a drug dealer’s dream. The “rush” from smoking crack was more potent, but even more transient, than the short-lived high from nasal ingestion.

Coupled with this development were the cocaine-related deaths of two well-known athletes, college basketball star Len Bias and defensive back Don Rogers of the Cleveland Browns. Bias played for Maryland, a home team in Washington, D.C. Six months earlier, Reagan had brought the military into the drug wars in a major way. The initial test of the directive was Operation Blast Furnace, a no-holds-barred attack on cocaine laboratories in the jungles of Bolivia.

As I wrote in 2008 in The Chemical Carousel:

The death of Len Bias elevated cocaine paranoia to the realm of the mythic. Cocaine became America’s first living-room drug, courtesy of the nightly news. The summer of 1986 will be remembered as the season of the “crack plague,” as viewers were bombarded with long news stories and specials. NBC Nightly News offered a special report on crack, during which a correspondent told viewers:  “Crack has become America’s drug of choice... it’s flooding America....”

The hyperkinetic level of television coverage ultimately led TV Guide Magazine to commission a report from the News Study Group, headed by Edwin Diamond at New York University. The investigators quickly demolished the notion that cocaine had become America’s “drug of choice,” and were at a loss to account for where the networks had come up with it:  “Statistically, alcohol and tobacco are the legal ‘drugs of choice’:  53 million people smoke cigarettes; 17.6 million are dependent on alcohol or abuse it. Marijuana still ranks as the No. 1 illegal drug. According to NIDA, 61.9 million people in the United States have experimented with marijuana.” The study group went on to note that the often-deadly “Black Tar” heroin had hit the streets of American cities the same summer. “Why was crack a big story [that summer] while Black Tar was not? One reason [is that] crack is depicted as moving into ‘our’—that is, the comfortable TV viewers’—neighborhood.”  

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).

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

Vaccinating Against Vices

Developing a pill or a vaccine for a specific drug addiction has long been one of the tantalizing potential rewards of addiction research. Now a company in Florida has garnered national attention, a spate of clinical trails, and a positive response from the National Institute on Drug Abuse (NIDA) with a compound called NicVAX, aimed at nicotine addiction. In addition, Celtic Pharma in Bermuda is working on a similar product for cocaine addiction.

The idea of vaccinating for addictions is not new. If you want the body to recognize a heroin molecule as a foe rather than a friend, one strategy is to attach heroin molecules to a foreign body--commonly a protein which the body ordinarily rejects--in order to switch on the body’s immune responses against the invader. The idea of a vaccine for cocaine, for example, is that the body’s immune system will crank out antibodies to the cocaine vaccination, preventing the user from getting high. A strong advantage to this approach, say NIDA researchers, is that the vaccinated compound does not enter the brain and therefore is free of neurological side effects.

Preliminary research at the University of Minnesota showed that a dose of vaccine plus booster shots markedly reduce the amount of nicotine that reaches the brain. Animal studies have shown the same effect. NicVAX, from Nabi Biopharmaceuticals, consists of nicotine molecules attached to a protein found in a species of infectious bacteria. When smokers light up, antibodies attack the protein-laden nicotine molecules, which, further encumbered by these antibodies, can no longer fit through the blood-brain barrier and allow the user to enjoy his smoke.

That, at least, is the idea. It is a difficult and expensive proposition, the closest thing to a miracle drug for addiction, but it does not specifically attack drug craving in addicted users. The idea of vaccination is that, once a drug user cannot get high on his or her drug of choice, the user will lose interest in the drug.

This assertion is somewhat speculative, in that users of the classic negative reinforcer, Antabuse, have found ways to circumvent its effects--primarily by not taking it. There remain a wealth of questions related to the effects of long-lasting antibodies. And it is sometimes possible to “swamp” the vaccine by ingesting four or five times as much cocaine or nicotine as usual.

Drugs that substantially reduce the addict’s craving may yet prove to be a more fruitful avenue of investigation. While several anti-craving medications have been approved for use by the Food and Drug Administraton (FDA), no vaccines have made it onto the approved least yet.

For more on pharmaceutical approaches to fighting drug addiction, see my website at http://www.dirkhanson.org