Weight Loss Redux

Why diet pills are problematic.

"Physicians who treat obesity hailed the Food and Drug Administration's recent approval of two new diet drugs—the first in 13 years—as a new era in weight-loss management."
--Wall Street Journal, July 30, 2012

 (The following post was originally published on September 20, 2011)

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://www.drugnet.net/

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/

Why are Treatment Centers Afraid of Anti-Craving Medications?

Using What Works

Why do so many drug treatment centers continue to shun science by ignoring medications that ease the burden of withdrawal for many addicts? That’s the question posed in an article by Alison Knopf in the May-June issue of Addiction Professional, titled “The Medication Holdouts.”

“Nowhere else in medicine,” Knopf writes, “are the people who treat a condition so suspicious of the very medications designed to help the condition in which they specialize.”

Acamprosate, a drug used to treat alcoholism, is a good case in point. A dozen European studies examining thousands of alcohol test subjects found that the drug increased the number of days that most subjects were able to remain abstinent. But when a German drug maker decided to market the drug in the U.S., fierce advocates for drug-free addiction therapy came out in force, even though the drug was ultimately approved for use.

Disulfiram, naltrexone, acamprosate, methadone, buprenorphine—the evidence for all of them is solid. Knopf cites the case of buprenorphine:

“‘There are scores of peer-reviewed journal articles that evaluate the success of buprenorphine,’ says Nicholas Reuter, MPH, senior public health adviser in the Division of Pharmacologic Therapies at the federal Center for Substance Abuse Treatment (CSAT). ‘It's well established that the data and the evidence are there. Not treating patients with a medication consigns most of them to relapse, adds Reuter. While some opioid-addicted patients, as many as 20 percent, do respond to abstinence-based therapy, ‘That still leaves us with the 80 percent who don't,’ he says.”

Dr. Charles O'Brien, one the nation’s most respected addiction professionals and a Professor of Psychiatry at the University of Pennsylvania, is incensed that anti-craving medications are not more widely used. “It's unethical not to use medications,” he says. “This is a subject that I feel very strongly about.” O’Brien told Addiction Professional he no longer cares who he offends on the subject. “If you're discouraging people from taking medications, you are behaving in an unethical way; you are depriving your patients of a way to turn themselves around. Just because you don't like it doesn't mean you have to keep your patients away from it.”

And at the Association for Addiction Professionals, “the prevailing philosophy is pro-medication,” Knopf writes. Misti Storie, education and training consultant for the group, told Knopf that the “disconnect” at treatment centers is due to a “lack of education about the connection between biology and addiction.” Counselors working in centers that do not allow anti-craving medications are in a tough spot, Storie acknowledged.

It is continually astonishing that treatment centers--where the primary goal is supposed to be the prevention of relapse, even though the success rate remains abysmal--would spurn medications that often help to accomplish precisely that goal. Relapse rates hover around 80%, by an amalgam of estimates, so it’s not like rehabs are wildly successful at what they do. What’s really behind the resistance?

What stands between many addicts and the new forms of treatment is “pharmacological Calvinism.” I would love to claim this term as my own, but it was coined by Cornell University researcher Gerald Klerman. Pharmacological Calvinism may be defined as the belief that treating any psychological symptoms with a pill is tantamount to ethical surrender, or, at the very least, a serious failure of will. As Peter Kramer quoted Klerman in Listening to Prozac: If a drug makes you feel better, then by definition “somehow it is morally wrong and the user is likely to suffer retribution with either dependence, liver damage, or chromosomal change, or some other form of medical-theological damnation.”

Photo credit: www.life123.com

The History of Prozac

How a pill for alcoholism became a blockbuster antidepressant.

Back in the 1970s, while doing research on antidepressants at Eli Lilly and Co., several organic chemists had been working on identifying new compounds that showed activity at serotonin receptor sites. The Lilly researchers came across Compound 82816, which very cleanly and very selectively blocked the reuptake of serotonin, and it did so without effecting any other neurotransmitter system at all. Clinical trials of compound 82816, chemically known as fluoxetine, continued into the early 1980s. At the same time, compounds with profiles similar to fluoxetine were being tested at various universities and drug firms.

The new drugs—with names like citalopram, zimelidine, fluoxetine, and fluvoxamine—were extensively investigated in animal models, and along the way, investigators made some unexpected discoveries. European investigators had shown that one serotonin uptake blocker in particular—zimelidine—seemed to reduce the self-administration of morphine and alcohol in addicted rats. A good part of the research began to center on three serotonin-enhancing compounds—zimelidine, citalopram, and fluoxetine.

Since rats decreased their administration of both alcohol and morphine when given zimelidine, and since low serotonin is a strong potential marker for human alcoholics and other addicts, Dr. Claudio Naranjo and Dr. Ed Sellers, along with their colleagues at Toronto’s Addiction Research Foundation, began testing zimelidine on heavy drinkers. Characterized as “early stage problem drinkers,” the test subjects showed a slight but noticeable decrease in the number of drinks consumed per day when they took zimelidine. There was also a consistent increase in the number of days the drinkers were completely abstinent. (Zimelidine was later withdrawn from use worldwide because of immune system side effects.)

As research continued, it became consistently evident that drugs capable of increasing concentrations of brain serotonin tended to cause large numbers of animals and human test subjects to drink less alcohol. But it wasn’t simply an aversive reaction at work, as in the case of Antabuse. People in the clinical trials still drank, but in many cases, the urge to drink seemed to diminish, and while the decrease was modest, it was measurable.

Moreover, rats given serotonin-enhancing drugs selectively cut back on carbohydrates, and lost weight. Ultimately, Lilly’s investment centered on flouxetine. In late 1987, Fortune magazine’s article on fluoxetine reported that “the prospect of making people both happy and thin has helped Lilly stock rise 28 per cent this year.”

The prospect of making alcoholics drink less, or stop drinking altogether, was a less publicized but equally attractive notion. Lilly already had a trade name picked out for fluoxetine. They were calling it Prozac.

A year after its introduction as an antidepressant, Prozac was a runaway success. Prozac quickly proved the existence of a huge potential market for serotonin reuptake inhibitors. Research continued on the diminished craving response that the serotonin uptake blockers seemed to produce in certain drinkers. The drug’s allure as an anti-craving medication for alcoholism and other possible addictions remained an open secret among researchers. Lilly wasn’t saying much in public about it, and with sales booming for fluoxetine as an antidepressant, the company could afford to concentrate on that indication. In the end, Lilly chose not to pursue further investigation of Prozac’s ability to reduce drinking and initiate weight loss.

Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008

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