Big Tobacco Hasn't Given Up On Smoking. Have You?

World No Smoking Day.

Women, Cigarettes, and Meth

More bad news for young female addicts.

A blizzard of research findings this year continues to demonstrate that women have gender-specific issues to deal with when it comes to cigarettes and speed. None of the findings have anything to do with the old canard that women cannot “hold their liquor,” or do drugs like men do. Women hold their liquor fine, on a pound for pound basis. And women are well represented, presently, among the ranks of alcoholics. That is unfortunate, since a great deal of research has shown that alcohol causes neurological damage in women more quickly than in men. And now comes more evidence that women don’t respond metabolically to cigarettes and speed the same as men, either.

Start with cigarettes: Women who begin smoking have a great risk of heart attack than men who take up the addiction—but scientists don’t know exactly why. Cardiovascular diseases remain the leading cause of female deaths in the developed world. One theory is that smoking lowers levels of “good” cholesterol more markedly in women than in men. This is not news, but preliminary research in the Journal of Clinical Endocrinology and Metabolism now appears to show that teenaged girls in Australia were more sensitive to the effects of second-hand smoke than teenaged boys. If true, it could mean that “childhood passive smoke exposure may be a more significant cardiovascular risk factor for women than men,” lead author Chi Le-Ha said in a press release. 

And there’s more bad news: Research published in Diabetologia, the journal of the European Association for the Study of Diabetes, suggests that women who continue to smoke during pregnancy increase the risk for obesity and diabetes in their unborn daughters. Kristin Mattsson of Lund University in Sweden, along with Matthew Longnecker and members of the National Institute on Environmental Health Sciences in North Carolina, reported that data from the Medical Birth Register of Sweden showed that the risk (odds ratio) of gestational diabetes increased 52-62 per cent for women exposed to moderate or heavy smoking while in the womb. After adjusting the data for a host of outside factors, the researchers also concluded that women exposed to moderate amounts of smoking while in the womb were 36 per cent more likely to become obese, while the daughters of heavy smokers during pregnancy were 58 per cent more likely to be obese compared to non-smokers in the study.

Again, researchers are not quite sure what accounts for this effect. The researchers suggest a variety of possible answers: Alterations in appetite regulation, death of insulin-producing cells in the pancreas, gene transcription changes causing the formation of fat cells, and epigenetic changes. But it may be that other factors—undetected differences in nutrition, extent of prenatal care, neglect, abuse, and many other variables—make it difficult to determine the major difference in outcomes between smoking and non-smoking families. Nailing down these risk factors becomes all the more important as young women in countries all around the world take up daily smoking in greater numbers than ever. The authors emphasize the importance of recognizing such long-term detrimental effects on offspring.

As for methamphetamine: A study in the Journal of Adolescent Health, conducted by the UCLA Center for Behavioral and Addiction Medicine, followed a group of adolescents in treatment for methamphetamine addiction. They found that girls were more likely to continue using meth during treatment than boys. Overall, boys returned twice as many meth-free urine samples as the girls in the program. Lead author Keith Heinzerling said in a prepared statement that the findings may have significant implications for treatment: “The greater severity of methamphetamine problems in adolescent girls compared to boys, combined with results of studies in adults that also found women to be more susceptible to methamphetamine than men, suggests that the gender differences in methamphetamine addiction observed in adults may actually begin in adolescence.” The small NIDA-funded study, involving only 19 teenagers, also found that the antidepressant Wellbutrin, used effectively in many smoking cessation programs, was not effective in curbing use among the teen meth addicts.

Marijuana and Diabetes: Does Pot Make You Thin?

Teasing out the insulin effect.

On the face of it, the study seems to come out of left field: A group of researchers claimed that marijuana smokers showed 16 per cent lower fasting insulin levels than non-smokers. The study, called “The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults,”  is in press for The American Journal of Medicine. The authors are a diverse group of medical researchers from Harvard, Beth Israel Deaconess Medical Center, and the University of Nebraska College of Medicine. The study concluded: “We found that marijuana use was associated with lower levels of fasting insulin and HOMA-IR [a measure of insulin resistance], and smaller waist circumference.”

Of course, it was that last tidbit about waist circumference that was picked up by the media. “Why Pot Smokers Are Skinnier,” headlined the Atlantic. However, the important implications are not so much for weight control, or the discovery of some built-in offsetting mechanism for the marijuana munchies, but rather for insulin control and the treatment of diabetes.

But in a clinical study, remarkable observations require remarkable documentation. What does the research actually say?

There are problems with the study worth noting. While researchers took blood samples after a 9-hour fast to determine insulin and glucose levels, they relied on self-reporting for marijuana use data. And self-reporting for alcohol and drug use has its limitations as an investigative tool. Namely, lack of honesty. But let’s get beyond that for a moment: From a database of 4,657 men and women who participated in the National Health and Nutrition Examination Survey, the researchers determined that 579 were current marijuana users, while 1,975 were pot smokers in the past.

The marijuana-smoking cohort tended to be young males who also smoked cigarettes. After running everything through a series of complicated multivariable-adjusted models, marijuana came out associated with lower insulin levels, and “lower waist circumference” than those who reported never using marijuana. And the results didn’t change much after adjusting for BMI numbers and excluding participants who actually had diabetes. Furthermore, the association was strongest in current smokers, “suggesting that the impact of marijuana use on insulin and insulin resistance exists during periods of recent use.” (It should also be noted that other health habits can affect glucose and insulin activity, including cigarettes, alcohol, and lack of physical activity.)

The investigators don’t offer a solution to the increased appetite/decreased waistline conundrum they claim to have identified. “We did not find any significant associations between marijuana use, and triglyceride levels, systolic blood pressure, or diastolic blood pressure,” they concluded.

We know marijuana has a complicated relationship with appetite mechanisms, as evidenced by its use with chemotherapy patients who need to eat. The theory is that the metabolic effects are mediated by a complex mix of cannabinoid type 1 and type 2 receptor interactions, since type 1 receptor antagonists like rimonabant improve insulin resistance in humans, and type 1 knockout mice also show resistance to diet-induced obesity.

Does marijuana smoking protect against diabetes? Wisely, the researchers don’t go that far, on the basis of this one uncontrolled study.  The researchers’ conclusions neatly hedge the bets, suggesting that with recent trends in the direction of marijuana legalization, “physicians will increasingly encounter patients who use marijuana and should therefore be aware of the effects it can have on common disease processes, such as diabetes mellitus.”

As it happens, the findings aren’t entirely new. Anecdotal reports abound. Back in 2010, on the Diabetes Daily support board, there was a long discussion of marijuana’s effect on blood glucose levels in diabetics. And there are several mouse models showing the same effects. In a prepared statement, lead investigator Murray A. Mittleman of Beth Israel Deaconess Medical Center in Boston conceded that previous epidemiological studies have found “lower prevalence rates of obesity and diabetes mellitus in marijuana users compared to people who have never used marijuana, suggesting a relationship between cannabinoids and peripheral metabolic processes.” However, he believes that “ours is the first study to investigate the relationship between marijuana use and fasting insulin, glucose, and insulin resistance.”

Perhaps so. A 2011 study in the American Journal of Epidemiology concluded that “the prevalence of obesity is lower in cannabis users than in nonusers.” And the British Medical Journal featured a finding in 2012 by Los Angeles researchers that marijuana use was “independently associated with a lower prevalence of diabetes mellitus.” But the online patient guide for marijuana offered by Mayo Clinic  says without equivocation that “cannabis may lower blood sugar. Caution is advised in patients with diabetes or hypoglycemia, and in those taking drugs, herbs, or supplements that affect blood sugar.” In fact, Mayo Clinic advises that patients may want to monitor their blood glucose levels if they smoke medical marijuana.

Regarding the current study, the editor-in-chief of the American Journal of Medicine said in a statement that there is a need for “a great deal more basic and clinical research into the short- and long-term effects of marijuana in a variety of clinical settings such as cancer, diabetes, and frailty of the elderly.” Editor Joseph S. Alpert also called on the National Institutes of Health (NIH) and the Drug Enforcement Administration (DEA) to collaborate in “developing policies to implement solid scientific investigations that would lead to information assisting physicians in the proper use and prescription of THC in its synthetic or herbal form.”

Penner E.A., Buettner H. & Mittleman M.A. (2013). The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults, The American Journal of Medicine,    DOI: 10.1016/j.amjmed.2013.03.002

Photo Credit: http://www.herbalmission.org/

From the Archives: Have Americans Become Afraid of Their Doctors?

Noncompliance and the paranoid style.

[Originally published June 27, 2007]

Note: In the everlasting battle between consumers and Big Pharma, amid a string of recent exposes concerning whose doctor took what payment under which table, I am republishing an essay I wrote several years ago, in which I attempt to view the doctor/Pharma/patient interaction from a different angle.


Once upon a time, Americans went to their doctors to get pills. Doctors complained that patients believed competent medical care consisted of being handed a prescription. In the absence of that piece of paper with the unintelligible signature, a patient was apt to claim that the doctor’s visit had been a waste of time. What was the point of seeing a doctor if the doctor didn’t give you anything that would cure what ailed you?

That was then. Patients now demand that doctors and pill makers come clean about the safety of the products they offer (long overdue), and that the pills themselves be absolutely benign in their effects (utterly impossible). In ever-greater numbers, Americans are coming to fear prescription drugs. This condition, in extremis, is a phobia with a recognized set of diagnostic criteria: pharmacophobia—an abnormal fear of medicine.

Today, Americans go to their doctors to be healthy and “drug-free.” If they are taking prescription medications, their goal is to get off them. Yesterday, patients demanded pills for conditions they didn’t have, or for which pills were ineffective. Today, patients are routinely filing lawsuits, demanding to know why their doctor gave them pills. Ironically, one of the major hindrances to health care, from a doctor’s point of view, is “patient non-compliance”—sick people often don’t take their pills properly. (This may be a good place to note that I do not work for, or with, or against Big Pharma, as the drug companies are now called. I don’t work for anybody.)

The drug industry, one of the most tightly regulated industries in America, is the kind of corporate villain Americans understand. What particularly rankles many critics is that the drug companies advertise. They market.

“Presumably,” Joseph Davis concedes in his jeremiad against drug advertising in the journal Hedgehog Review, “some percentage of those who identify their face and their feelings with those signified in the ads actually suffer from a debilitating condition. So much to the good.”

But of little significance, it seems. The central issue for Davis is: What if people who don’t need those pills are exposed to those ads? Normal people might think they need those pills—and they don’t! And very soon, as you can easily see, you’ve got trouble in River City. In the same issue of Hedgehog Review, biomedical ethics professor Leigh Turner professes similar shock, recounting with indignation “a world where a host of marketing strategies are used to package tidy, authoritative, and often profoundly misleading claims” about the safety and effectiveness of products. You can imagine how I felt when I learned that commercial advertisers were capable of doing that.

For lack of a better term, we will have to settle for calling it the real world, where soap, life insurance, housing, cars, psychiatric care, and legal advice are all marketed in misleading ways, to people who don’t always need them. And so it is with pills. However, where once patients desired this, they now resent the offer. Writing in the May 2007 issue of Harper’s, Gary Greenberg declares that “Under the agreement we’ve made—that they are doctors, that I am sick, that I must turn myself over to them so they can cure me—the medicine must be treated with the reverence due a communion wafer.”

Previously, patients wanted their communion wafers, and doctors were often accused of withholding them. Now, as Greenberg makes clear, patients fear doctors will drag them to the altar and force the holy wafers down their throats. One cannot help wondering what manner of pact Greenberg would like to arrive at with his treating physicians. His approach does not seem like a particularly promising step forward in doctor-patient relations.

Interestingly, Americans have shown little interest in a thorough examination of the adverse side effects of non-pharmaceutical approaches to health. Talk therapists and holistic practitioners of every stripe operate in a virtually regulation-free environment. Where, for example, can one find a list of common side effects associated with the practice of various forms of psychotherapy, from post-Freudian talk therapy to, say, the increasingly popular varieties of cognitive therapy? Where, I would like to know, is the list of unwanted side effects that can occur as the result of an on-air encounter with that manipulative bruiser, Dr. Phil?

Science writer Sharon Begley, in a June 18 Time column entitled “Get Shrunk at Your Own Risk,” declares: “What few patients seeking psychotherapy know is that talking can be dangerous, too—and therapists have not exactly rushed to tell them so.”

Among many other examples, Begley reminds us of the “recovered memory” therapies that tore families apart and sent innocent people to prison for the alleged sexual abuse of children. And “stress debriefing,” a method of re-experiencing traumatic events in an effort to eliminate Post Traumatic Stress Disorder, sometimes leads to increased stress and higher levels of anxiety, compared to PTSD victims who do not undergo such therapy. I’ll privilege an upset stomach and occasional loose stools from pills over that kind of deep-seated trauma any day.

Begley also cites a 2000 study of professional grief counseling which concluded that four out of ten people grieving for the death of a loved one through formal therapy would have been better off with no therapy at all. Compared to a control group, 40 per cent of mourners in professional therapy experienced increased depression and grief. (In some cases, the most benign contraindication is when the treatment doesn’t do anything at all.)

The side effects associated with talk therapies remain shrouded in mystery. “The number of people undergoing potentially risky therapies reaches into the tens of thousands,” Begley concludes. “Vioxx was yanked from the market for less.”

Six Arguments For the Elimination of Cigarettes

Prohibition and the “tobacco control endgame.”

Despite all our efforts in recent years to reduce the percentage of Americans who smoke cigarettes—currently about one in five—the idea of full-blown cigarette prohibition has not gained much traction. That may be changing, as prominent nicotine researchers and public police officials start thinking about what is widely referred to as the “tobacco control endgame.”

Considering the new regulatory powers given the FDA under the terms of the Tobacco Control Act of 2009, as a commentary in Tobacco Control framed it, “will the government be a facilitator or barrier to the effective implementation of strategies designed to achieve this public health goal?”
Two newer approaches have gained some traction in the research community: Reduce the level of nicotine in cigarette products (the FDA is prohibited by law from reducing nicotine content to zero), and continuing to emphasize the non-combustible forms. Plus, everybody pretty much agrees on higher prices.

Here are the six arguments for going all the way:

1) Death. Six million of them a year, worldwide, a number that will grow before it starts shrinking. A billion deaths this century, compared to 100 million in the 20th Century. Robert Proctor, author of The Golden Holocaust and a professor of history at Stanford, whose six arguments these are, calls the cigarette “the deadliest object in the history of human civilization.” So there’s that.

2) Other product defects. The cigarette is defective, Proctor writes in defense of his six arguments in Tobacco Control, because it is “not just dangerous but unreasonably dangerous, killing half its long-term users.” Indeed, it is hard to imagine the FDA green-lighting a drug product like that today. In addition, Proctor claims cigarettes are defective because the tobacco has been altered by flue curing to make it far more inhalable than would otherwise be the case. “The world’s present epidemic of lung cancer is almost entirely due to the use of low pH flue-cured tobacco in cigarettes, an industry-wide practice that could be reversed at any time.”

3) Financial burdens. These can be reckoned principally in terms of the costs of treating smoking-related illnesses. This, in turn, leads to diminished labor productivity, especially in the developing world, a process that “in many parts of the world makes the poor even poorer,” Proctor observes.

4) Big Tobacco’s impact on science. By sponsoring shoddy and distracting research, by publishing “decoy” findings and by otherwise confusing and corrupting scientific discourse on the cigarette question in the advertising-dependent popular media. The tobacco industry has proved to everyone’s satisfaction that it can put politicians and regulators under intense pressure to see things its way. Not to mention other institutions that have been “bullied, corrupted or exploited,” according to Proctor: The AMA, The American Law Institute, sports organizations, Hollywood, the military, and the U.S. Congress, for starters. (Until 2011, American submarines were not smoke-free.)

5) Environmental harms. More than you might think falls into this category: Deforestation, pesticide use, loss of savannah woodlands for charcoal used in flue curing, fossil fuels for curing and transport, fires caused by burning cigarettes, etc.

6) Smokers want to quit. Smoking is not a recreational drug, as Proctor takes pains to point out. Most smokers hate it and wish they could quit. This makes cigarettes different from alcohol or marijuana, Proctor insists. He quotes a Canadian tobacco executive, who said that smoking isn’t like drinking; it’s more like being an alcoholic. This rings true to for the majority of addicted smokers I know, and was certainly true of me when I was a smoker.


So there it is, the case for tobacco prohibition. But hasn’t all this prohibition business been tried and found wanting? We know the results of drug and alcohol prohibition, whatever their rationales: Smuggling, organized crime, increased law enforcement, more money. This argument, says Proctor, has been central to the cigarette industry since forever: “Bans are ridiculed as impractical or tyrannical. (First they come for your cigarettes…)”

Proctor’s response is that smuggling is already common, and people should be free to grow tobacco for their personal use. He advocates a ban on sales, not possession.

There are at least two major obstacles to cigarette prohibition. First, an enormous amount of tax revenue is generated by the production and sale of cigarettes. And the troubling question of a steep rise in black marketeering goes largely ignored or unaddressed. In the same special issue of Tobacco Control, Peter Reuter has sobering thoughts on that front: “Cigarette black markets are commonplace in high tax jurisdictions. For example, estimates are that contraband cigarettes now account for 20-30% of the Canadian market, which has restrained government enthusiasm for raising taxes further. All the proposed ‘endgame’ proposals for shrinking cigarette prevalence toward zero run the risk of creating black markets.”

In the end, Proctor argues that the cigarette industry itself has repeatedly promised to quit the business if its products where ever found to be profoundly harmful to consumers. As recently as 1997, Philip Morris CEO Geoffrey Bible swore under oath that if cigarettes were found to cause cancer “I’d probably… shut it down instantly to get a better hold on things.” Incredible statements like this by company executives go back to the 1950s. Perhaps it’s time to let them stop lying. “The cigarette, as presently constituted,” writes Proctor, “is simply too dangerous—and destructive and unloved—to be sold.”

Proctor R.N. (2013). Why ban the sale of cigarettes? The case for abolition, Tobacco Control, 22 (Supplement 1) i27-i30. DOI: 10.1136/tobaccocontrol-2012-050811

Photo: AAP/April Fonti

The Pot President

Hendrik Hertzberg on the hypocrisy of the hip.

In a blog post at the New Yorker last week, Hendrik Hertzberg spotlighted a recent joke made by the President of the United States at the White House Correspondents dinner. In reference to the rapidly changing media landscape, Obama said: “You can’t keep up with it. I mean, I remember when BuzzFeed was just something I did in college around two A.M. (Laughter.) It’s true! (Laughter.)”

The days of expressing a cringing contrition for your “youthful experimentation,” or claiming that you didn’t inhale, or clearly over.

But of course, the president’s joke wasn’t really that funny. Hertzberg cites statistics from Ethan Nadelmann of the Drug Policy Alliance, suggesting that “from fifty to a hundred thousand Americans are behind bars for pot, and only pot, on any given night.” The Office of National Drug Control Policy (ONDCP) disputes those figures, but the point is not so much whose numbers are closer to the truth, but rather the simple fact that while the president made his joke, too many people are locked up in federal and state prisons for an offense that a growing number of states are backing away from enforcing.

As Hertzberg put it, the subtext of the president’s pot joke was that it “allowed the tuxedoed, evening-gowned, middle-aged audience at the Washington Hilton to feel, for a precious moment, hip. The subtext was that smoking pot, whether a lot or a little, is just a normal part of growing up…. Nor has it done much to blight the lives of the other people in the Hilton ballroom, most of whom, like the rest of the media, political, and Hollywood elites, have smoked pot, too.”

Obama, they say, was a champ stoner in school. He was, writes David Maraniss in his biography of Obama, skilled at “interceptions”—sneaking an extra hit off the joint when it hadn’t gotten all the way around yet.  Obama, writes Hertzberg, really ought to feel “a smidgen of shame that the government he heads treats people who do exactly what he used to do, and now casually jokes about, as criminals.”

We haven’t heard much lately about the Boomer hypocrisy inherent in such roomfuls of high achievers who used to get high. (Some of them still do.) Jobs and reputations and bank loans are not endangered by these sly references and knowing winks. What hurts jobs and reputations is a stretch in federal prison—the unwilling route taken by many less fortunate Americans.

Hertzberg is wrong when he says that “marijuana-associated suffering enters the picture only when prohibition does.” Like most pro-legalization commentators, he does not mention addiction liability, or lasting cognitive effects on younger smokers.  But it is true that a disproportionate amount of suffering is caused by marijuana prohibition laws. The farthest corners of the debate are staked out, but decriminalization—the missing middle ground—still offers society a more balanced starting point than full-tilt legalization. Merriam-Webster says that to decriminalize is “to repeal a strict ban on, while keeping under some form of regulation.” State policy makers, although they don’t use the term very often, are pursuing what amounts to decriminalization. Nobody other than world-peace-through-weed zealots is arguing for a repeat of the track record with cigarettes (a drug in the process of being re-criminalized). And the regulation of alcohol does not offer a compelling model for marijuana’s future as a semi-legal drug. Happily, marijuana is not nearly as dangerous as alcohol or nicotine, so that helps.

It might surprise some readers to know that a majority of the Dutch aren’t interested in legalizing marijuana. They are concerned about keeping it out of the hands of minors. They’re not very happy with the trend towards higher and higher levels of THC. This is expressed in the fact that marijuana is, and likely will remain, illegal in The Netherlands. The narrow coffee shop exception is misleading in this regard. It was not designed to make marijuana more acceptable, but to deal creatively with the problem of street sales. You almost never see a drug deal going down on the streets of Amsterdam. That’s because a) It’s stupid, you can just waltz into a coffee shop if you’re over 21. b) Dealers have a hard time beating coffee shop prices. c) Dutch police come down heavily on street dealers.  Why? See a) above. The Dutch are no freer to wander their canal-lined streets with a joint in hand than Americans are free to wander Capitol Mall Boulevard with an open bottle of Jack.

Now that’s decriminalization. And an unfair comparison, of course, since the Dutch nation is so much smaller and more homogenous than the U.S. But lately, the talk has been about states, not the country at large. And at the state level, some of the Dutch lessons may apply.

What should our president do about all of this? Hertzberg has three proposals:

—Tell the Justice Department to “end the absurd classification of marijuana as a supremely dangerous Schedule I drug, like heroin.” Alcohol, let us recall, does not have a drug classification because it is not a scheduled substance at all. This American ambivalence is reflected by the names of the country’s premier drug research groups, the National Institute on Drug Abuse (NIDA), and the Monty Pythonesque National Institute on Alcohol Abuse and Alcoholism (NIAAA).

—Promise to “avoid making life unnecessarily difficult” for the states that have made provisions for medical marijuana or legalization.

—Change the name of the Drug Czar’s Office of National Drug Control Policy to something like the “Office of National Harm Reduction Drug Policy.”

Adopting any or all of these changes would be a useful step toward a decriminalized future for marijuana. Here’s the essential point: We have to make a space for marijuana use in American culture. I mean above the ground, and unassociated with jail time. While still murky from a medical point of view, there is just no doubting that millions of Americans prefer pot to alcohol as a recreational drug. Given alcohol’s role in the American death toll, and the lack of any such grim trail of the dead in marijuana’s case, there’s no shame in that decision, from my point of view.

Graphics Credit: http://www.anonymousartofrevolution.com/

Orexin and Insomnia

If Valium makes you groggy, and Ambien makes you sleepwalk…

A compound that blocks a brain receptor you probably have never heard of may hold the key to the next generation of sleeping pills—and there is always a next generation of sleeping pills.

A new class of hypnotic compounds that serve as antagonists for the neurotransmitter orexin may combat insomnia without the “confusional arousals” that have come to plague some users of zolpidem, otherwise known as Ambien. Sleepwalking, sleep driving, and sleep sex are common among the reports. Orexin is involved in central nervous system arousal. So-called DORAs, or dual orexin receptor antagonists, discovered in 1998, are being seen as potential therapies for insomnia, without the daytime drowsiness and rebound insomnia typical of existing treatments. The sleep disorder narcolepsy, which is in many ways the exact opposite of insomnia, is caused by “an autoimmune attack against neurons that express orexin,” according to Emmanuel Mignot of Stanford’s Center for Sleep Sciences, in an article for Science magazine.

 If these drugs are already being thought of as potential insomnia therapies, their addiction potential will have to be much lower than that of earlier generations of sleep medications. But that just might be the case, since DORA-style drugs don’t appear to promote sleep by inhibiting brain activity through neurotransmitter systems for GABA, as most existing treatments do. A study last month in Science Translational Medicine by J.M. Uslaner and coworkers asserted that DORA-type drugs caused less cognition and memory impairment in rats than Valium or Ambien, and are effective at lower doses.  With drugs that modulate the orexin system, the hope is that there would be less rebound insomnia, less memory loss, less addiction, and less weird wandering around like a zombie in the middle of the night.

The search for safer sleep drugs was recently given a shot in the arm by a disturbing report from the U.S. Substance Abuse & Mental Health Services Administration (SAMHSA). Emergency room visits caused by Ambien more than doubled from 2005 to 2010, and patients 45 years and up accounted for 74% of adverse zolpidem reactions. Overall, male ER visits went up by 144%, whereas female ER visits went up almost twice as much. Overall, women made up two-thirds of all Ambien-related emergency visits—a bald fact that led the Food & Drug Administration (FDA) in January 2013 to cut the recommended dose for females in half. Lower doses were also recommended for men as well.

But a closer look at the report shows the typical confusion of polydrug use: 50% of emergency department visits for Ambien involved its use in combination with other drugs. And in 37% of cases, Ambien was used specifically in combination with other central nervous system depressants. “Although short-term medications can help patients,” SAMSHA Administrator Pamela Hyde said in a prepared statement, “it is exceedingly important that they be carefully used and monitored.”

A new class of medications based on orexin-active drugs would follow three earlier generations of sleeping pills. And each new generation of sleeping pills seems to bring its own history of unintended consequences.

In the beginning, there was meprobamate, the postwar tranquilizer known as Miltown. In additional, powerful barbiturates like phenobarbital were marketed as miracle drugs for the anxious insomniac. By the 1950s, it had become clear that these drugs were seriously addictive, and dangerous in overdose. Emmanuel Mignot noted that in high doses, barbiturates “lead to pulmonary arrest and death, outcomes that gained further notoriety with the deaths of celebrities Marilyn Monroe and Jimi Hendrix.” Barbiturates do their work by activating chloride channel receptors for the inhibitory neurotransmitter GABA. In addition, strong sedatives were increasingly being used on psychotic patients in the 1950s, and found their way into the treatment of insomnia.

The continued promise of a safe and effective hypnotic for insomnia drove research that led to the development of the first benzodiazepines, and eventually to Valium. The benzodiazepines like Valium were safer in overdose, came in a bewildering variety of flavors, and found widespread use for sleep induction—but also as anticonvulsants, anti-anxiety agents, and muscle relaxers. The benzos bound to GABA receptor sites just like the barbiturates, but the effects were less extensive. Still, it was not long before Valium, another “perfect” drug, showed it’s adverse side, in the form of sedation, memory problems, and addiction.

Then, in 2007 came the 3rd generation, in the form of the now wildly popular “Z-drugs”—zolpidem, (Ambien) zopiclone (used overseas), and zaleplon (Sonata). And again, the side effect profiles looked better in testing, the effective dose was lower, and the binding site—GABA again—looked like the right place to bring on slower brain activity and more inclination toward sleep without the “knockout effect” of earlier barbiturates and benzos. These drugs are now the default treatment for insomnia. But over time, predictably, problems revealed themselves: “Occasional problems with dependence, tolerance, and ‘confusional arousals’ are still reported with Z-drugs…. And viewed with some suspicion by doctors and patients,” writes Mignot.

Put simply, any sleep treatment that relies on the broad-brush inhibition of GABA will likely produce a range of unwelcome side effects. There are only about 70,000 orexin-producing neurons in the hypothalamus, researchers have found. But this small band of neurons has projections to histamine systems, as well as “the adrenergic locus coeruleus, and various cholinergic and aminergic cell groups,” as Mignot sums up the research. “Blocking orexin may thus be closer to treating the underlying issue of excess alertness in insomnia compared to promoting sleep by inhibiting brain activity.”

That’s the idea, at least. And it may represent a change in thinking. Researchers are no longer looking for a better knockout drug by bludgeoning the brain into inactivity. Instead, they are looking for ways to combat hyper-alertness as a key component of insomnia.

Uslaner J.M., Tye S.J., Eddins D.M., Wang X., Fox S.V., Savitz A.T., Binns J., Cannon C.E., Garson S.L. & Yao L. &  (2013). Orexin Receptor Antagonists Differ from Standard Sleep Drugs by Promoting Sleep at Doses That Do Not Disrupt Cognition, Science Translational Medicine, 5 (179) 179ra44-179ra44. DOI: 10.1126/scitranslmed.3005213

Photo Credit: F Delventhal under license from Creative Commons.