An Insite-ful Decision

Canadian Supreme Court clears the way for Vancouver’s safe-injection facility.

Insite, the controversial supervised injection site for addicts in Vancouver, has won its case before the Supreme Court of Canada for a permanent exemption from the nation's drug laws. CBC News reports that, in a unanimous decision, “The court ordered the federal minister of health to grant an immediate exemption to allow Insite to operate.”

Written by chief justice Beverley McLachlin, the ruling said in part: "Insite saves lives. Its benefits have been proven. There has been no discernable negative impact on the public safety and health objectives of Canada during its eight years of operation." A member of Parliament told the CBD: "The Conservative government has been relentless in their opposition so today's decision by the court just feels like an incredible victory. It feels like a great day."

The Supreme Court of Canada was forced to determine the fate of Insite, where addicts use clean needles with a nurse on the premises, after numerous governmental attempts to shutter the facility led to lawsuits. Numerous studies have demonstrated the benefits of such programs, but Insite remains the only long-term injection facility in North America. The eight-year old clinic has increasingly won both professional and popular support as a workable method of harm reduction in high-risk drug areas. As the Vancouver Sun sensibly notes: “It is increasingly mainstream thinking in Canadian health care as reflected by other interveners in the Supreme Court case--Canadian Nurses Association, Association of Registered Nurses of British Columbia, Registered Nurses Association of Ontario, Canadian Medical Association, and Canadian Public Health Association.” You can’t get much more mainstream than that. 

As The Fix recently reported, Insite has reduced drug overdose deaths by 35% in its notorious Downtown Eastside headquarters in a neighborhood housing the highest population of needle addicts in Canada. A recent study found  that drug overdoses do occur at Insite—but among its recorded 2,000 ODs, there has not been a single fatality (doctors are on hand with a ready supply of the anti-OD drug Naloxone). Injection centers offer other public health benefits, including steering addicts into treatment and reducing hepatitis C and HIV infections. Opposition in the U.S. has centered on the notion that safe injection facilities will encourage the use of injectable narcotics by somehow sanctioning the activity.

The Globe and Mail editorialized that when the Supreme Court of Canada convened in May to take evidence on Vancouver’s supervised injection site, it heard “detailed arguments that hinge on the fine print of the Canadian Constitution. But besides being a landmark showdown between federal and provincial powers, the hearing also sets the stage for a ruling expected to affect not only the daily lives of injection drug users on Vancouver’s Downtown Eastside but drug policy across the country and potentially farther afield.”

This was a big one, a verdict much awaited, because it will be widely seen as playing a crucial role in determining whether facilities like Insite will be allowed to operate in North America. Technically, a court ruling against Insite would not have automatically put the operation out of business, but would have left it in the twilight zone of operating under a federal government exemption that could be pulled at any time—and the current Canadian government has broadly hinted that it would do so.

The Supreme Court victory means that Insite can operate without benefit of any kind of federal government legal exemption from drug laws, a situation that has always put Insite at the mercy of political posturing.

Photo Credit:
http://www.canada.com/story_print.html?id=af132f6b-2099-407d-af87-13c12016af5a&sponsor=

The Biology of Stimulants, or Why You Can’t Stay High Forever

An essay on the losing battle for perpetual reward.

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.

Photo Credit: http://etinkata.blogspot.com

An Interview with Pharmacologist David Kroll

On synthetic marijuana, organic medicines, and drugs of the future.

(Second post in the “Five-Question Interview” series.)

Back in July, Addiction Inbox ran a fascinating 5-question interview with clinical and research psychologist Vaughan Bell. The post touched on abnormal brain function, drugs, hallucinations, and addiction. It was a blast.

The huge and multi-talented staff here at Addiction Inbox has hopes of making this a semi-regular feature, since there is no shortage of interesting and accomplished people out there who can sometimes be successfully pestered into answering broad-ranging questions about drugs and addiction for an obscure science blog.

Herewith, a 5-question interview with pharmacologist David Kroll, Ph.D., Professor and Chair of Pharmaceutical Science at North Carolina Central University in Durham, and a well-known blogger in the online science community.

A cancer pharmacologist whose field is natural products—he’s currently involved in a project to explore the potential anticancer action of chemicals found in milk thistle and various sorts of fungi—Dr. Kroll received his Ph.D. from the University of Florida, and completed his postdoctoral fellowship in Medical Oncology and Molecular Endocrinology at the University of Colorado School of Medicine. He went on to spend the first nine years of his independent research and teaching career at the University of Colorado School of Pharmacy, where he taught all aspects of pharmacology, from central nervous system-active drugs, to anticancer and antiviral medications. He has also worked as a research pharmacologist for the Research Triangle Institute, and for SmithKline and French Laboratories. He’s responsible for Terra Sigillata—a natural products pharmacology and chemistry blog—and Take As Directed, his personal blog. He is also co-author of Breast Cancer Recurrence and Advanced Disease: Comprehensive Expert Guidance.


1. You’ve been writing about the new synthetic marijuana products on your blog, Terra Sigillata, since they first leaked into the drug underground. Can you briefly explain the origin of these “fake” cannabis chemicals, and the work done by the Huffman lab?

Every area of CNS pharmacology has chemists who try to figure out the smallest possible chemical structure that can have a biological effect. In fact, this is a longstanding practice of any area of pharmacology. Huffman was an excellent chemist who in the 1990s was trying to figure out the most important part of the active component of marijuana that might have psychotropic effects. These compounds made by him and his students, surprisingly simple ones, I prefer to call cannabimimetics since they mimic the effect of the more complex cannabinoids in marijuana. These basic chemistry and pharmacology studies are what ultimately lead to new drugs in every field - a facet of chemistry called "structure-activity relationships" or SAR.

But since they are simple, they are relatively easy to make - some of Huffman's work at Clemson was actually done by undergraduate chemistry majors. So, it was no surprise that they would be picked up by clandestine drug marketers, even though cannabis (UK) and marijuana (US) are freely available. The attraction to users was, until recently, that Huffman compounds (prefixed with "JWH-" for his initials) could not be detected in urine by routine drug testing. Hence, incense products containing these compounds have been called “probationer's weed.”

2. In a recent guest blog post for Scientific American titled “Drugs from the Crucible of Nature,” you remind us that several hundred common drugs are modified natural products. What stands in the way of discovering, isolating, and testing more of these plant drugs?

Fully 25% of all pharmaceuticals can trace their roots to natural products: chemicals made by plants, bacteria, fungi, and marine creatures that possess biological effects in mammals. The first ones we recognized as humans were those which altered our perception of reality or our ability to adapt to the strenuous, pre-modern life: hallucinogens for religious purposes and stimulants to support physical activity and suppress hunger. Over time, we found other drugs that treated pain (opiates), heart failure or "dropsy" (digitalis), or cancerous lesions (podophyllin from the Penobscot Native Americans).

We know today that natural products have much greater chemical diversity than drugs made by man and are useful additions to the study of new drug targets. However, naturally-occurring drugs sometimes have major drawbacks: they are difficult to make in the laboratory or require large amounts of their natural source to be commercially viable, they can have undesired effects that may not be apparent from traditional uses, or they require chemical modifications to be safer, more resistant to metabolism, and to become patentable intellectual property.

Over the last 10-15 years, the short-term, investor- and market-driven view of pharmaceutical companies has led the big firms to eliminate their natural product research programs. Today, much of the discovery of naturally occurring drugs has been left to academic researchers and small companies where many former pharma researchers reside. Once we get compounds that may be viewed as "druggable" by the pharmaceutical industry or the National Cancer Institute (in the US), they can then move to clinical trials.

3. Psychoactive plant drugs like the poppy played a major role in the development of modern pharmacology and neurology. One school of thought says that psychoactive drugs are overprescribed, addictive, and ineffective panaceas. The other side views such drugs as targeted, effective, and increasingly sophisticated treatments for diseases once thought to be untreatable. Have we become a nation of crazed pill heads, or is this simply pharmaceutical medicine on the march?

I have a middle-of-the-road view on this topic. As you know (and my blog readers will know) my father suffered from alcoholism that was comorbid with clinical depression. Real, biochemically-based depression has been undertreated in Western societies, in part due to the stigma that admitting mental disorders is somehow viewed as compromising one's intellect. Nothing could be farther from the truth, of course. Some of the most brilliant and creative minds in all fields have suffered from depression, mania, and, sadly, ended their lives early by suicide.

So, drugs certainly have their place for those unfairly dealt a hand of bad brain biochemistry. We should not view this as any worse than getting the bad genes for hypertension or diabetes. The problem seems to be those with mild-to-moderate psychiatric disorders, many of which can be managed without drugs but that require personal effort in the form of psychotherapy, cognitive behavioral therapy, or other flavors of hard, personal work. As Americans, what do we want? The hard work or the pill? If we want to lose weight, do we want exercise, caloric restriction, or a pill? Hence, we are the ones who are complicit with pharmaceutical companies. We want the pill rather than the hard work and the companies supply that demand. Anyone who doesn't realize that we as a society facilitate what we demonize in pharmaceutical companies is just simply in denial.

4. It’s increasingly obvious that our legal and cultural approaches to addictive drugs have not been successful. What’s your take on the drug war, and on the problematic distinction between “legal” and “illegal” drugs of abuse?

My primary research field is cancer drugs, but my teaching brings me into the realm of drugs of abuse, simply because so many of those drugs are naturally-occurring. So, my views must be taken in that perspective. In the US, I think that it is morally difficult to justify the legality of addictive drugs like alcohol and tobacco while restricting other psychoactive compounds. I do not advocate for other drugs to be used recreationally. I just feel that US laws need to be consistent. Our experiment with criminalizing alcohol was an abysmal failure that fostered organized crime. Our continued experiment with criminalizing other drugs has been equally a failure. However, I am very much against a libertarian argument that society should be free to determine what they want because, frankly, many drugs impair one's decision-making ability.

But I like your question: many drugs declared illegal for recreational use are among the most useful therapeutics for pain, especially the pain associated with surgery and cancer. My greater humanistic concern is that our society's zero tolerance approach to drugs that "could" be illegal is that people who need them for their desired effect often go without. Undermanagement of pain is the major casualty of the war on drugs. No, let me fix that. People who suffer unnecessarily from pain when useful drugs could be used are the major casualties of the war on drugs.

5. What’s going on in pharmaceutical research these days that has you excited?

When I was graduating with my toxicology degree in 1985 from the Philadelphia College of Pharmacy and Science, I asked my chairman Dr. Gary Lage where I should expect new drugs to come from. His words of wisdom were that I should pay close attention—not to drug companies, but rather to major advances in physiology. Learning that the kidney played a role in red blood cell count led to the use of erythropoeitin for anemia caused by renal failure and chemotherapy.

Today, I see major drug targets in the epigenome—the part of genetics that is affected by environmental influences. We are all stuck with the static part of our inherited DNA—the exact base sequences and their polymorphisms and mutations. However, we're learning that those things can be modified by diet, environmental exposures, and, yes, drugs. The epigenome is a broad target for a multitude of diseases, never more complicated but never more promising.

The Saga of Phen-Fen

How a blockbuster diet pill died.

It took many years to bring depression and its treatment into the rational light of day. Addiction in the mid-1990s was in the process of undergoing a similar medical transformation. Even so, scientists were wary of pronouncing that overeating was in some cases a treatable chemical disorder.

Obesity, in any form other than pituitary cases, was not typically considered a medical disorder at all. In a 1998 interview with MIT’s student newspaper, The Tech, neurology professor Richard Wurtman recalled that ten years earlier, the major drug companies had shown little interest in a drug treatment for obesity: “They thought that if you were obese, it was your fault.” It was the same view that had prevailed concerning depression, alcoholism, and other drug addictions. Bulimia and carbohydrate craving were no different: a simple failure of will was once thought to explain them all. But everything changed when the serotonin-boosting diet pill called Redux (dexfenfluramine) won full FDA approval in 1996. Redux was the first drug ever approved in the U.S. for the long-term treatment of obesity.

In truth, Ely Lilly and Company did move forward with earlier efforts to win approval of high-dose Prozac for weight loss. That petition had been languishing in the FDA pipeline for years under the trade name Lovan. Back in the late 1980s, when Eli Lilly scientists were investigating rats that consumed fewer calories on fluoxetine, the company called upon Dr. Richard Wurtman, the MIT brain scientist who specialized in the connection between serotonin levels and carbohydrate intake. Scientists at Lilly had become increasingly concerned that the weight loss from Prozac was short-lived, and the mechanism of action remained maddeningly imprecise. For more than a decade, Eli Lilly had pursued Prozac along three separate but related lines of development: depression, weight control, and alcoholism. If you took it for depression, and it worked, you might also lose a few pounds, and drink less. If you took it for bulimia or weight loss, you might also feel better emotionally, and drink less. When the FDA made encouraging noises about Prozac as a new front-line treatment for bulimia in 1994, Eli Lilly followed that indication to market, and again chose not to follow up on weight loss or alcoholism.

Eli Lilly was no longer interested, but Richard and Judith Wurtman were undeterred. As it happened, the couple had already patented a serotonin-active drug of their own—dexfenfluramine—which French laboratories had been testing as a weight loss pill. The Wurtmans went public with a new company, Interneuron Pharmaceuticals, and filed with the FDA to market their weight-loss remedy. The Wurtmans became instant millionaires on paper.

“Diet pills” had always had a somewhat unsavory reputation. Typically, they were amphetamines, or the near-beer equivalent, ephedrine—and neither compound was anything like a healthy long-term answer to chronic overeating. The serotonin-active drugs were a new class of medications altogether. Dexfenfluramine wasn’t addictive, any more than Prozac was addictive. Moreover, fenfluramine was specifically intended for use by people suffering from carbohydrate-craving obesity. But would doctors be able to resist the demands of other patients who just wanted to trim off a few pounds?

Initially, the Wurtmans licensed the serotonin-active weight loss drug to several marketers in Europe, where it met with initial success. After a few small-scale studies, Rochester University in New York published a report showing that the weight loss effect was enhanced when fenfluramine was combined with a drug called phentermine. The resulting combination was widely known as “phen-fen.” As with Prozac, dexfenfluramine was tested as an anti-obesity medication at dosages several times higher than the amount typically prescribed for depression.

Early red flags were raised when Johns Hopkins researchers reported some cases of neurological toxicity in monkeys on dexfenfluramine, but MIT, which shared patent rights with the Wurtmans, was understandably enthusiastic when Redux, as dexfenfluramine became known, won full FDA approval in 1996.

And for many people, Redux worked. In the first six months after its approval, physicians wrote at least two million prescriptions for Redux. The phen-fen combination swept the weight loss industry. Estimates of total users of phen-fen ran as high as six million in the U.S. alone. Doctors and weight loss clinics sometimes prescribed Redux, sometimes the phen-fen combination. Initial earnings estimates were running as high as $600 million a year for the Redux portion of phen-fen, netting MIT between one and five per cent of the royalties.

The euphoria didn’t last long. By the time Redux made the cover of Time, researchers were already rumbling about continued reports of high toxicity and hypertension in rat studies. In addition, the serotonin surge associated with the use of dexfenfluramine caused concerns about pulmonary hypertension. In August of 1997, doctors at the Mayo Clinic in Minnesota reported serious heart valve abnormalities in 24 women taking the phen-fen combination.

A month later, at the FDA’s request, phen-fen and Redux were permanently pulled off the market.  In 2002, American Home Products settled a class action suit on behalf of almost 300,000 phen-fen users for $3.75 billion. As class action suits go, this put it right between the $2.4 billion Dalkon Shield settlement and the $4.5 billion breast implant accords.

What went wrong? Researchers now believe that the two drugs, which were never offered for sale as a single pill, should never have been combined in the first place. Somehow the fact that the phen part of the combination allegedly acted as an MAO inhibitor, and hence should not have been combined with yet another serotonin-enhancing medication, escaped notice. The combination of the two drugs apparently raised blood plasma levels of serotonin to abnormal levels. Too much serotonin in the bloodstream can damage blood vessels in the heart and lungs. Other suspected MAO inhibitors, like St. John’s Wort, or the Chinese herbal remedy ma huang, would not have combined well with Redux or phen-fen, either. Referring to the casual use of Ecstasy, Dr. Rick Doblin drew a parallel with phen-fen in the autumn 1995 issue of the Multidisciplinary Association for Psychedelic Studies (MAPS):

This use of MDMA, though not conducted in the context of a scientifically controlled experiment, does provide an opportunity for a very large epidemiological study. Similarly, over fifty million people have tried a prescription drug called fenfluramine, a diet aid prescribed for daily use for months or years at a time that causes the same kind of neurotoxicity in animals as does MDMA.

The phen-fen disaster highlighted the need to investigate drug synergies thoroughly before combining them as a pharmacotherapy. The phen-fen heart and lung damage may have been related to a potentially toxic condition known as “serotonin syndrome.”

And the Wurtmans? Ironically, Richard and Judith Wurtman had patented the use of Prozac for severe PMS years earlier, and ultimately sublicensed the rights back to Eli Lilly for several million dollars. Eli Lilly disguised the fact that their PMS drug was a case of old wine in new bottles. As Wellbutrin had become Zyban, so Prozac metamorphosed into Serafem, when prescribed for premenstrual syndrome.

Photo credit:  http://youoffendmeyouoffendmyfamily.com/

What Do We Mean When We Talk About Craving?

An essay on drug addiction and need.

For years, craving was represented by the tortured tremors and sweaty nightmares of extreme heroin and alcohol withdrawal. Significantly, however, the one 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 know it as “jonesing,” from the verb “to jones,” meaning to go without, to crave, to suffer the rigors of withdrawal. Spiraling distress, to say the least—a spiraling rollercoaster to hell, sometimes. Most doctors don’t get it, and neither do a lot of the therapists, and least of all the public policy makers. Drug craving is ineffable to the outsider.

As most people know, behavior can be conditioned. From maze-running rats to the “brain-washed” prisoners of the Korean War, from hypnotism to trance states and beyond, psychologists have produced a large body of evidence about behavior change—how it is accomplished, how it can be reinforced, and how it is linked to the matter of reward.

It is pointless to maintain that drug craving is “all in the mind,” as if it were some novel form of hypochondria. Hard-core addicts display all the earmarks of the classical behavioral conditioning first highlighted almost a century ago by Ivan Pavlov, the Russian physiologist. Pavlov demonstrated that animals respond in measurable and repeatable ways to the anticipation of stimuli, once they have been conditioned by the stimuli. In his famous experiment, Pavlov rang a bell before feeding a group of dogs. After sufficient conditioning, the dogs would salivate in anticipation of the food whenever Pavlov rang the bell. This conditioned response extended to drugs, as Pavlov showed. When Pavlov sounded a tone before injecting the dogs with morphine, for example, the animals began to exhibit strong physiological signs associated with morphine use at the sound of the tone alone. Over time, if the bell continued to sound, but no food was presented, or no drugs were injected, the conditioned response gradually lost its force. This process is called extinction.

Physical cravings are easy to demonstrate. Abstinent heroin addicts, exposed to pictures of syringes, needles, or spoons, sometimes exhibit withdrawal symptoms such as runny noses, tears, and body aches. Cravings can suddenly assail a person months—or even years—after discontinuing abusive drug use. Drug-seeking behavior is a sobering lesson in the degree to which the human mind can be manipulated by itself. The remarkable tenacity of behavioral conditioning has been demonstrated in recent animal studies as well. When monkeys are injected with morphine while recorded music is played, the music alone will bring on withdrawal symptoms months after the discontinuation of the injections.  When alcoholics get the shakes, when benzodiazepine addicts go into convulsions, when heroin addicts start to sweat and twitch, the body is craving the drug, and there is not much doubt about it. But that is not the end of the matter.

“Craving is a very misunderstood word,” said Dr. Ed Sellers, now with the Centre for Addiction and Mental Health in Toronto. “It’s a shorthand for describing a behavior, but the behavior is more complicated and interesting than that. It’s thought to be some intrinsic property of the individual that drives them in an almost compulsive, mad way. But in fact when you try to pin it down—when you ask people in a general context when they’re exposed to drugs about their desire to use drugs, they generally give rather low assessments of how important it really is.”

While cravings can sometimes drive addicts in an almost autonomic way, drug-seeking urges are often closely related to context, setting, and the expectancy effect. It has become commonplace to hear recovering addicts report that they were sailing through abstinence without major problems, until one day, confronted with a beer commercial on television, or a photograph of a crack pipe, or a pack of rolling papers—or, in one memorable case of cocaine addiction, a small mound of baking powder left on a shelf—they were suddenly overpowered by an onrush of cravings which they could not successfully combat. “If you put them in a setting where the drug is not available, but the cues are,” said Sellers, “it will evoke a conditioned response, and you can show that the desire to use goes up.” Most people have experienced a mild approximation of this phenomenon with regard to appetite. When people are hungry, a picture of a cherry pie, or even the internal picture of food in the mind’s eye, is enough to cause salivation and stomach rumblings. Given the chemical grip which addiction can exert, imagine the inner turmoil that the sight of a beer commercial on television can sometimes elicit in a newly abstinent alcoholic.

When addicts start to use drugs again after a period of going without, they are able to regain their former level of abuse within a matter of days, or even hours. Some sort of metabolic template in the body, once activated, seems to remain dormant during abstinence, and springs back to life during relapse, allowing addicts to escalate to their former levels of abuse with astonishing speed. This fact, and no other, is behind the 12-Step notion of referring to oneself as a “recovering,” rather than recovered, addict—a semantic twist that infuriates some people, since it seems to imply that an addict is never well, never cured, for a lifetime.

Relapse sometimes seems to happen even before addicts have had a chance to consciously consider the ramifications of what they are about to do. In A.A., this is often referred to as forgetting why you can’t drink. It sounds absurd, but it is a relatively accurate way of viewing relapse. Addiction, as one addict explained, “is the only disease that tells you you ain’t got it.”

Graphics Credit: http://www.aapsj.org/

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The Strange and Secret Keeley Cure for Addiction

“Drunkenness is a disease and I can cure it.”

In America in the late 1800s, curing alcoholism was a serious business—and for Dr. Leslie Keeley, a very lucrative one. Dozens of clinics and cures already existed, and some treatment centers had even experimented with franchising. For the late 19th Century alcoholic in search of treatment, what most of them had on offer was either outright patent medicine fraud, or else well intentioned if ultimately misguided “opium” cures. None of them, writes William L. White in Slaying the Dragon, “was more famous, more geographically dispersed, more widely utilized, and more controversial than Leslie Keeley’s Double Chloride of Gold Cure for the treatment of alcoholism, drug addiction, and the tobacco habit.”

The Irish-born Dr. Keeley served as a surgeon in the Civil War, and, as family lore would have it, started a treatment program for alcoholism in a Union hospital during the war. We do know that in 1879, he opened the first Keeley Institute in Dwight, Illinois, south of Chicago. His sales pitches were colorful and varied, but boiled down to this pledge: “Drunkenness is a disease and I can cure it.” He could cure it with a secret, specific formula, injected four times daily, about which all he would hint publically was that it contained, as one of its ingredients, gold. This was not so outlandish as it may seem. Gold, silver, strychnine, and other potentially poisonous ingredients were already employed in dozens of standard medicines—and, in many cases, still are. But everything else about Dr. Keeley’s magic elixir was as secret as the ingredients in Coke.

Nonetheless, something seemed to be working. He claimed an outlandish 95% success rate, bolstered by legions of enthusiastic followers who formed proto-AA groups with the catchy title of Bi-Chloride of Gold Clubs, better known as the Keeley Leagues. And Keeley himself employed the largest collection of formerly addicted doctors in the known world. There were no counselors at Keeley clinics. There were enough doctors on staff to go around, even though an estimated total of half a million alcoholics and other addicts eventually took the Keeley Cure.

Treatment consisted of the infamous injections, a liquid cordial every two hours, and, according to White, the following modalities: “daily rest, nutrition, mutual sharing, and alternative diversions worked to improve the patient’s physical and psychological health.” We can assume, from this regimen, that some alcoholics and addicts probably improved, regardless of what was in the medicine. And there was the frequent suggestion that, really, it was probably best not to ask too many questions about what was in the medicine, anyway.

“The atmosphere was informal and friendly at the clinics,” White writes, “with a marked absence of the bars and restraints that were typical in most inebriate asylums of the period.” There were, of course, some very vocal detractors. Dr. T. D. Crothers, a leader in the inebriate asylum movement, said: “There is no gold cure for inebriety. There are no facts to show that gold has any value in this disease. All the assertions and statements concerning gold as a remedy are delusions, and will not bear the test of critical examination.”  Perhaps not. But success was success, and soon, the marketplace saw the introduction of Dr. Haines Golden Remedy, the Geneva Gold Cure, the Boston Bichloride of Gold Company, and many other knockoffs. (Keeley proclaimed that his Double Chloride of Gold cured all forms of inebriety by “speeding up the restoration of poisoned cells to their pre-poisoned condition.”)

From 1892 through 1900, the Keeley Company pulled in almost $3 million, including mail-order business. There was a Keeley Day at the 1893 World’s Fair in Chicago. Here is an excerpt from the pamphlet, “To the Keeley Graduate,” given to every patient who completed treatment:

You are now numbered among thousands of men and women who have broken the shackles of alcohol and drug addictions by the Keeley method of treatment. Your cure will be as permanent as your life, you will never have any craving for alcohol or other sedative drugs as long as you live, unless you create it by returning to their use, thus re-poisoning your nerve cells.

But by 1900, the bloom was off the Keeley miracle, as insiders fought for financial control, and congressional investigators looked into the affairs of Keeley League president Andrew J. Smith.

Of course, if Keeley had really possessed a specific, replicable formula that took away the craving for alcohol, it would have been monstrously unethical to hold it a secret. And he was constantly accused of using harmful ingredients, such as codeine, strychnine, and cocaine in his magic injections.

Keeley wouldn’t say. And neither did any of his heirs or business partners. The only thing most court records agree on is that the injection didn’t contain any gold—too many possible side effects. According to the testimony of Keeley’s original business partner, “The only patient who ever received Keeley medicine that actually had gold in it almost died.”

The secret ingredient was probably atropine—a powerful compound belonging to a very weird family of plant drugs known collectively as “anticholinergenic deliriants.”  Atropine is the active ingredient in Belladonna, aka Deadly Nightshade. Along with mandrake, henbane, and jimsonweed, the so-called Belladonna alkaloids are among the primary hallucinatory ingredients found in many a witch’s and sorcerer’s brew throughout the ages. Belladonna can cause terrifying hallucinations, feelings of flight or paralysis, blurred vision, impaired motor control, and other side effects usually experienced as highly unpleasant. It was likely Belladonna, not LSD, that served as the basic rocket fuel for the Manson’s family’s horrific activities, according to some accounts. More mundanely, atropine is familiar to armed forces personnel in the form of a self-injection device for serious wounds. Atropine has the ability to speed up a slowing or overworked heart. In ancient times, it was used as an anesthetic for surgery. Atropine is also a poison. (Scopolamine, used medically for motion sickness, is another.)

But one person’s unpleasant side effect is another’s chemical cure. Did the Keeley concoction just terrify the bejesus out of addicts, as some sort of ad hoc version of aversive therapy, or did it sedate his patients into a semi-catatonic, immobile haze, in which they could pass 3 weeks of detox in relative comfort, or at least immobility and minimal disruption? Probably both, depending on drug dosage, drug combination, and patient metabolism. There were widespread reports of Keeley patients who allegedly died or went insane.

“The pulp image of Dr. Leslie Keeley—that of the country physician who had stumbled onto a revolutionary cure for the inebriety problem that had stumped the best medical scientists,” was key to his success, White believes. “Keeley introduced an approach that carried an aura of scientific truth and all the emotional support and intensity of a revival meeting.”

“The likely ingredients of the Double Chloride of Gold remedy and tonics—alcohol, atropine, strychnia, apomorphine —did aid detoxification,” White concludes. And the graduation pamphlet went on to emphasize the importance of “sustaining the new Keeley habits: regular patterns of sleep, regular and balanced meals, regular consumption of water, abstinence from tobacco and caffeinated drinks, healthy recreation, and care in the selection of personal associates.”

If you skip the atropine injections, that series of admonitions remains the bedrock of drug and alcohol treatment programs everywhere.

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

On Chemical Imbalances in the Brain

Maybe it’s not such a bad theory after all.

The brain, as always, bats last. It compensates, reregulates, and adjusts. One of the major ways it accomplishes this is through the neuroadaptive phenomenon called downregulation. When we take drugs continuously, the brain compensates for the artificial flood of, or sensitivity to, serotonin, dopamine, and other neurotransmitters by cutting back on its own production, and the receptors on the cell surfaces ultimately degrade. This is, in fact, what can happen in a case of active addiction, or with the habitual use of any receptor-active drug. The phrase “chemical imbalance,” as a means of describing this process, fell out of favor as soon as Pfizer started using the analogy in its television advertising for zoloft.

Call it a receptor imbalance, then. Call it neuronal dysregulation, if that helps. The concern with downregulation is that, over time, chronic use of serotonin reuptake blockers or dopamine-active drugs of abuse can lead to both a decrease in the number of receptors and a desensitization of existing receptors. The brain does not stay idle during these artificial rains of neurotransmitters. As explained by Peter Kramer in Listening to Prozac: “The chronic, constant, reliable presence of high levels of neurotransmitter causes the cell to downregulate—reducing the number of receptors, by drawing them back into the cell membrane, where they become inactive, or by otherwise uncoupling them from further events.”

The brain adjusts to the constant bombardment of addictive drugs. Downregulation and upregulation are not well understood. If significant downregulation takes place, then conceivably, there could be a rebound effect. Even withdrawal from non-addictive drugs can be difficult and stressful, as the brain upregulates to account for the new biochemical dispensation. Drugs of abuse, and the drugs used against them, share one important trait—they both illustrate the adage that too much of a good thing is a bad thing.

The entire field of addiction medicine has its detractors, of course. In particular, the SSRI medications have been a prominent target since their inception. Dr. Peter Breggen, Dr. Joseph Glenmullen, and other critics have been particularly vocal in their objections to the use of serotonin-active drugs. They argue that psychoactive drugs cause assorted brain dysfunctions, and that such medications do far more harm than good. But these jeremiads aside, there are legitimate issues surrounding the use of many of the receptor-active drugs that addicts and alcoholics may encounter, or may request—whether treatment consists of a formal in-patient clinic or an informal arrangement with a family practitioner. Since addiction and mental illness overlap, a percentage of addicts are likely to encounter antidepressant and other psychoactive drugs during treatment. Drawing on work by Robins, Kessler, and Regier, Dr. Lance Longo, Medical Director of Addiction Psychiatry at Sinai Samaritan Medical Center, wrote as far back as 2001: “Approximately half of individuals with bipolar disorder or schizophrenia and approximately one third of those with panic disorder or major depression have a lifetime substance use disorder. In general, among patients with alcoholism, nearly half have a lifetime history of coexisting mood, anxiety, and/or personality disorders.”

The optimistic view of anti-addiction drugs says that depressive and addictive episodes feed on themselves. The more you get that way, the more you get that way, so if you can somehow give the brain a giant holiday from being serotonin- and dopamine-impaired, it will naturally adjust, compensate, rewire. It will teach itself. It will learn how not to be addicted and depressed all the time. In this view, what the addict/depressive needs is normalcy, a period of feeling better, a chance to sort things out, adjust behavior, become productive, and build confidence. While all of this is happening, under the influence of an antidepressant or an anti-craving drug, the patient learns to experience a different kind of world on a daily, even minute-to-minute basis. Like training wheels, the medications give the brain its first chance in a long time, possibly ever, to operate within the normal parameters of serotonin, dopamine, norepinephrine, and GABA metabolism.

Okay, “chemical imbalance” is a very imprecise description of all this. But branding it as a “myth” has the potential of doing far more damage, by discouraging active addicts from seeking medical treatment.

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson.

Graphics Credit: http://bentobjects.blogspot.com/2007/11/slight-chemical-imbalance.html