Showing posts with label chemical imbalance addiction drugs addictive drugs neurotransmitters serotonin. Show all posts
Showing posts with label chemical imbalance addiction drugs addictive drugs neurotransmitters serotonin. Show all posts

Wednesday, September 28, 2011

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

Tuesday, September 20, 2011

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/

Tuesday, September 6, 2011

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
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