Addiction Inbox

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

2013-05-19T16:20:00.000-05:00

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

2013-05-14T11:34:00.000-05:00

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

2013-05-11T15:10:00.000-05:00

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

2013-05-07T19:59:00.001-05:00

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.

Clock Ticking On Colorado’s Marijuana Repeal Bill

2013-05-06T11:10:00.000-05:00

Proposal to revote on pot legalization is losing steam.

While the rest of the nation argues over Colorado’s recent decision to legalize limited amounts of marijuana, a small but determined group of legislators in that state have been promoting a bill that would allow a “conditional repeal” of the pot amendment.

The proposal to resubmit the question of retail marijuana sales to Colorado voters is supported by Senate President John Morse (D-Colorado Springs) and Senate Minority Leader Bill Cadman (R-Colorado Springs).* The proposed ballot measure would first ask voters to approve previously promised higher tax rates on marijuana. On April 29, the Colorado House passed a bill placing a 15% excise tax and a 10% sales tax on marijuana, and came up with the idea of submitting the plan to the voters as a ballot proposal. If the higher tax doesn’t pass, citizens would then be asked whether retail sales should be repealed. “People voted for marijuana and tax,” said State Senator Morse, “and what they got was marijuana and we’ll see if they get the tax."

Republican Senator Larry Crowder (R-Alamosa) and others point to the fact that Amendment 64 called for $40 million in new excise taxes for state school funds, in addition to the legal cultivation of 6 plants and possession of a ounce or less. “So if there’s no money,” Crowder told a Denver TV station, “we shouldn’t have marijuana.”

“The marijuana legalization repeal — or suspension — proposal would also have to be approved by voters,” according to the Denver Post. “But, before it could reach the ballot, it would need two-thirds support in the Capitol because it would change a provision of Colorado's constitution.”

Today is the last day that House Bill 1380 can move forward in the final hours of Colorado’s legislative session, a disheartening prospect for marijuana supporters, faced with the notion of fighting the fight all over again. The Boulder Weekly called it “a sneak attack on Amendment 64.” But it appears that most of the steam has leaked out of the repeal drive. Rep. Dan Pabon (D-Denver) told the Post that “there was a pretty strong grassroots response that I think every member received that said, 'Don't threaten us.'"

Here’s how SMART Colorado, a group opposing legalization, puts the argument: “Amendment 64 raised the possibility of new taxes on marijuana but didn’t enact them. If voters don’t now approve new taxes on marijuana, Colorado’s budget will take a major hit and Amendment 64 will have exactly the opposite effect from what was promised voters.”

Supporters of state legalization claim the legislators are trying to change the rules in midstream, by asking voters to approve a sales tax that is higher than necessary. Mason Tvert of the Marijuana Policy Project claims the move amounts to “extortion of the voters. They’re being told they must approve a higher tax level proposed by legislators or otherwise the constitutional amendment they adopted in November will be repealed.”

The measure’s chances are slim in the Colorado legislature—a group altogether mindful of the 55% margin by which voters passed the original amendment.

Meanwhile, in the state of Washington, legalization plans ran up against a major hurdle when it was discovered that the current law defines marijuana, the drug, as anything with more than 0.3 % THC content. Unfortunately for the state’s crime lab, that bar is so low that law enforcement actions against large grower operations and possession of large quantities would founder over the fact that most of what cops seized would be defined, in effect, as hemp. Yes, the state of Washington managed to criminalize the large-scale possession of hemp, so the House and Senate quietly scrambled to re-criminalize large-scale marijuana possession, not hemp possession, by defining THC content more scientifically.

This is only a snapshot of the regulatory issues that await attention in Washington and Colorado, as they attempt to become the first states to navigate new waters and divorce themselves from federal drug policy imperatives. There is still a very long way to go. In a speech in Mexico City last Friday, President Obama firmly closed the door on the idea that the feds might be persuaded to support state marijuana legalization efforts.

*Late Monday night, the bill's sponsors backed off, and the marijuana repeal proposal died for lack of support.

Graphics Credit: http://blog.sfgate.com http:/

Where Are All the New Anti-Craving Drugs?

2013-04-30T16:33:00.000-05:00

The dilemma of dwindling drug development.

Drugs for the treatment of addiction are now a fact of life. For alcoholism alone, the medications legally available by prescription include disulfiram (Antabuse), naltrexone (Revia and Vivitrol)—and acamprosate (Campral), the most recent FDA-approved entry. A fourth entry, topiramate (Topamax), is currently only approved by the Food and Drug Administration (FDA) for other uses. But none of these are miracle medications, and more to the point, no bright new stars have come through the FDA pipeline for a long time.

New approvals for drugs in this category, like psychiatric drugs in general, have lately been confined to repurposed, “me-too” medications—which, insurance companies complain, are far too expensive. As health insurance giant Cigna explains on its website: “If anticraving medications are not covered by your insurance plan, keep in mind that the price of anticraving medications is usually small compared to the cost of alcohol and/or other drugs.” Perhaps so, but evidently not small enough for the expense to be routinely covered by the prescription portion of insurance policies.

Federal health officials have the same complaints. In a 2004 report entitled “Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products,” the U.S. Food and Drug Administration called for increased public-private collaboration and a “critical development path that leads from scientific discovery to the patient.”

As detailed by Professor Mary Jeanne Kreek, a senior attending physician at the Laboratory of the Biology of Addictive Diseases at Rockefeller University and one of the primary developers of methadone therapy:

Toxicity, destruction of previously formed synapses, formation of new synapses, enhancement or reduction of cognition and the development of specific memories of the drug of abuse, which are coupled with the conditioned cues for enhancing relapse to drug use, all have a role in addiction. And each of these provides numerous potential targets for pharmacotherapies for the future.

In other words, when an addiction has been active for a sustained period, the first-line treatment of the future is likely to come in the form of a pill. New addiction treatments will come—and in many cases already do come—in the form of drugs to treat drug addiction. Every day, addicts are quitting drugs and alcohol by availing themselves of pharmaceutical treatments that did not exist twenty years ago.

But things have changed. “This scientific stall may have seemed to come out of the blue,” writes Dr. Steven E. Hyman, Professor of Stem Cell and Regenerative Biology at Harvard University, in the Dana Foundation publication, Cerebrum. Hyman sketches a dismal picture:

The molecular and cellular underpinnings of psychiatric disorders remain unknown; there is broad disillusionment with the animal models used for decades to predict therapeutic efficacy; psychiatric diagnoses seem arbitrary and lack objective tests; and there are no validated biomarkers with which to judge the success of clinical trials. As a result, pharmaceutical companies do not see a feasible path to the discovery and development of novel and effective treatments…. progress for the many patients who respond only partially or not at all to current treatments requires the discovery of medications that act differently in the brain than the limited drugs that we now possess…. and regulatory agencies have given up their willingness to accept even more expensive new drugs.

Genes aren’t simple, and the kinds of studies that would lead to new anti-craving drugs are not cheap. Moreover, the medications themselves do not represent cures. Even if drugs that block dopamine receptors treat psychotic symptoms, Hyman writes, “it does not follow that the fundamental problem is excess dopamine any more than pain relief in response to morphine suggests that the original problem is a deficiency of endogenous opiates.”

What can change this picture for the better? “One exciting recent development is the emerging recognition that genes involved in schizophrenia, bipolar disorder, and autism do not represent a random sample of the genome,” Hyman writes. “Rather, the genes are beginning to coalesce into identifiable biochemical pathways and components of familiar neural structures…. Many researchers hope that such efforts will help attract the pharmaceutical industry back to psychiatry by demonstrating new paths to treatment development. The emerging genetic results may be the best clues we have ever had to the etiology of psychiatric disorders.”

Detractors worry, naturally enough, about the shrinking pie of funds available for this sort of endeavor. According to Steven Paul, president of Lilly Research Laboratories, “I am worried that obtaining the kind of molecular probes required for even in vivo testing may prove to be too time-consuming and expensive, and may divert precious NIH funds away from basic or clinical biomedical research.”

But Hyman remains optimistic, “based partly on the extraordinary vitality of neuroscience and perhaps, even more important, on the emergence of remarkable new tools and technologies to identify the genetic risk factors for psychiatric disorders, to investigate the circuitry of the human brain, and to replace current animal models that have failed to predict efficacious new drugs that act by novel mechanisms in the brain.”

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

Addiction Inbox (D)Evolves Into Paperback

2013-04-28T18:10:00.000-05:00

A curated collection of blog posts in print.

Online is where journalism is happening now, but it is a truism that most of the world’s repository of knowledge is still found in books. It is also true that Addiction Inbox now comes in paperback, from Amazon. For cheap. Also available in Kindle, for unbelievably cheap.

I have selected and arranged a “best of the blog” collection, meant to serve as a handy off-the-shelf compendium of science-based information on drugs and addiction. Is shoplifting the opiate of the masses? Does menthol really matter? Can ketamine and other party drugs cause permanent bladder damage? The posts are arranged in four sections: Research, The New Synthetics, Treatment, and Interviews/Book Reviews. This 330-page anthology of articles is designed to bring multiple perspectives to bear on questions of drugs, addiction, and treatment. For just ridiculously cheap.

Cassie Rodenberg at Scientific American’s White Noise blog was kind enough to review Addiction Inbox, the book: “The author relates the real life to the scientific, noting his own struggles with addiction, yet doesn’t get bogged down in personal tales. Rather, the writings use life tidbits as jumping off points for scientific explanation and an overarching discussion of addiction’s media landscape.”

Which was pretty much what I was hoping to do when I started this blog….

Nature, Nurture, and Me

2013-04-25T12:45:00.000-05:00

Which came first, the addiction or the trauma?

About a year ago, Jonathan Taylor, a professor at California State University in Fullerton, assigned his students some reading from my book, The Chemical Carousel, for his “Drugs, Politics, and Cultural Change” course. At the same time, the class watched an interview with Dr. Gabor Maté, author of In the Realm of Hungry Ghosts: Close Encounters with Addiction. In a letter written for his readers, Dr. Mate´ insists that addiction “is very close to the core of the human experience. That is why almost anything can become addictive, from seemingly healthy activities such as eating or exercising to abusing drugs intended for healing. The issue is not the external target but our internal relationship to it. Addictions, for the most part, develop in a compulsive attempt to ease one’s pain or distress in the world…. The more we suffer, and the earlier in life we suffer, the more we are prone to become addicted."

I find this perspective interesting, because I agree with so little of it. I do not believe that almost anybody can become involved in an addictive relationship with almost anything—not unless they have the genes for it. I do not believe that the genuine heart of addiction, its true root cause, is childhood abuse—although that is frequently and tragically a component of addiction, for many reasons. Overall, I see addiction as a biochemical disorder with strong behavioral attributes, mostly genetic in origin, influenced by—but not hostage to—environmental impacts, making it not so different from, say, diabetes or depression.

No doubt about it, there is a fair amount of distance between the doctor and your humble science journalist, from the nature/nurture point of view. And, students being students, they picked up on this, and wanted an explanation that would make some sense of these two seemingly opposite positions. Professor Taylor threw the question back to me:

My class was wondering how one would reconcile your and Mate’s views. Both of you discuss the addicted brain and clearly view addiction as a brain disorder. The fundamental difference is that Mate disputes the genetic component of addiction, or at least he says there is some genetic component but that the majority of the brain dysfunction and low levels of neurotransmitters found in addicted individuals relates to environmental influences during early childhood (or in the womb), rather than a genetic component…. In the book he discusses studies that indicate that insufficient maternal care, exposure to conflict etc. all lead to improper brain development which leads to increase susceptibility to addiction. So while you write about “inherited susceptibility,” he seems to favor an “environmental induced susceptibility…. Any elucidation I can share with my students would be helpful.

So. I was well and truly on the hook. I kept my response short, for the obvious reasons, but there is no getting around the fact that it’s a damn good question. Here’s what I ended up telling the class:

-------------------------------------------------------------------------------------------------------------------------
Jon:

"Your students ask, quite rightly, how to reconcile the views expressed in The Chemical Carousel and In the Realm of Hungry Ghosts. Or, nature vs. nurture. Dr. Maté looks to environmental impacts during early childhood as the addiction trigger, while I advocate a view of addiction as a genetic disorder, expressed because of changes in DNA, not bad mothering. (It wasn’t very long ago that schizophrenia was firmly believed to be a result of bad mothering, too!) More to the point, Maté believes, for example, that ALL female heroin addicts were sexually abused as children. That is certainly not an assertion widely agreed upon or well supported by the scientific literature. In the most recent population study of addicts and non-addicted siblings, published in Science (Feb. 3 2012), when the researchers looked at the early lives of sibling pairs, they found all the same risk factors: both the addicts and their siblings had seen roughly equal amounts of trauma in childhood. 'We really looked at their childhoods,' says Karen Ersche, lead author of the study and group leader for human addiction research at the University of Cambridge in England, quoted at Time Healthland. 'There was a lot of domestic violence, there was sexual abuse — but both [groups] had that.'

"So, which came first, the trauma, or the trauma-prone personality? Where Dr. Maté sees childhood trauma, I tend to see behavioral dysregulation. Children born with an addictive propensity also carry with them the potential for various kinds of behavioral problems, impulsivity being a common one. And it is entirely likely that most addicts have had rocky childhoods, since, quite often, they have had alcoholics in the nuclear family, with all the attendant problems, including sexual violence. Or, their own behavioral template leads to problems—angst, worry, fights, trauma. In a sense, we can say that sooner or later, something, or someone, or a series of environmental impacts, will traumatize a child with addictive propensities, in the same way that latent schizophrenia is “switched on” by a traumatic or highly emotional event. Addicts feel like outsiders from an early age, and many of them sense that something is not quite right with them, long before they ever take a drink or a drug.

"Sorting out this chicken-egg problem is a major headache. And we haven’t even discussed the possibility of trauma in the womb. But I am willing to say that none of this is as settled or as straightforward as Dr. Maté would have it. On the matter of nature/nurture, I’m willing to put the odds of that mix at 60/40, which is a good deal less genetically loaded than my estimates used to be. The growing research field of epigenetics has brought the two views closer together by demonstrating that a person’s DNA can in some cases be modified, and genes turned off and on, by environmental impacts.

"Overall, it’s safe to say that Dr. Maté and I do agree on this: One of the best defenses against the scourge of addictive disease is a stable, loving, empathetic family."

Best,
Dirk

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

Let the Light Shine In: Addiction and Optogenetics

2013-04-22T16:23:00.000-05:00

Study says laser light can turn cocaine addiction on and off in rats.

Francis Collins, the director of the National Institutes of Health (NIH), had one word for it: “Wow.”

Writing in the director’s blog at the online NIH site, Collins said that a team of researchers from NIH and UC San Francisco had succeeded in delivering “harmless pulses of laser light to the brains of cocaine-addicted rats, blocking their desire for the narcotic.”

Wow, indeed. It didn’t take long for the science fiction technology of optogenetics to make itself felt in addiction studies. The idea of using targeted laser light to strengthen or weaken signals along neural pathways has proven surprisingly robust. The study by the NIH and the University of California at San Francisco, published in Nature, showed that lab rats engineered to carry light-activated neurons in the prefrontal cortex could be deterred from seeking cocaine. Conversely, laser light used in a way that reduced signaling in this part of the brain led previously sober rats to develop a taste for the drug. As Collins described the work:

The researchers studied rats that were chronically addicted to cocaine. Their need for the drug was so strong that they would ignore electric shocks in order to get a hit. But when those same rats received the laser light pulses, the light activated the prelimbic cortex, causing electrical activity in that brain region to surge. Remarkably, the rat’s fear of the foot shock reappeared, and assisted in deterring cocaine seeking.

All this light zapping took place in a brain region known as the prelimbic cortex. In their paper, Billy T. Chen and coworkers said that they “targeted deep-layer pyramidal prelimbic cortex neurons because they project to brain structures implicated in drug-seeking behavior, including the nucleus accumbens, dorsal striatum and amygdala.” These three subcortical regions are rich in dopamine receptors. In rats that had been challenged with foot shocks before being offered cocaine, “optogenetic prelimbic cortex stimulation significantly prevented compulsive cocaine seeking, whereas optogenetic prelimbic cortex inhibition significantly increased compulsive cocaine seeking.”

What this demonstrates is that similar regions in the human prefrontal cortex, known to regulate such actions as decision-making and inhibitory response control, may be “compromised” in addicted people. This abnormally diminished excitability in turn “impairs inhibitory control over compulsive drug seeking…. We speculate that crossing a critical threshold of prelimbic cortex hypoactivity promotes compulsive behaviors”

This all sounds vaguely unsettling; sort of a cross between phrenology and lobotomy. But it is no such thing, and the study authors believe that stimulation of the prelimbic cortex “might be clinically efficacious against compulsive seeking, with few side effects on non-compulsive reward-related behaviors in addicts.” For now, the researchers confess that they don’t know whether the reduction in cocaine seeking is caused by altered emotional conditioning, or pure cognitive processing.

Actually, nobody expects optogenetics to be used in this way with humans. The thinking is that transcranial magnetic stimulation, the controversial technique that employs noninvasive electromagnetic stimulation at various points on the scalp to alter brain behavior, would be used in place of invasive zaps with lasers. Expect to hear about clinical trials to test this theory in the near future. David Shurtleff, acting deputy director at the National Institute on Drug Abuse (NIDA), said in a prepared statement that the research “advances our understanding of how the recruitment, activation and the interaction among brain circuits can either restrain or increase motivation to take drugs.”

Chen B.T., Yau H.J., Hatch C., Kusumoto-Yoshida I., Cho S.L., Hopf F.W. & Bonci A. (2013). Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking, Nature, 496 (7445) 359-362. DOI: 10.1038/nature12024

Photo credit: Billy Chen and Antonello Bonci

On Dead Salmon, Drugs, and “Lighting Up” the Brain

2013-04-18T17:04:00.000-05:00

Are fMRIs truly useful in addiction medicine?

What would it take to make neuroimaging a truly valuable tool for addiction medicine? Pictures of brain regions “lighting up” have always been exciting, as the early phase of neuroimaging predictably inspired rapture. Phase 2 arrived when a group of U.S. postdocs created the infamous dead salmon fMRI scan, showing that an exciting and colorful picture of false positives was entirely possible. As Neuroskeptic put it to the Globe and Mail, “Scientific journals prefer to publish results that are positive and ‘sexy,’ just like other media.”

That is nice to hear, since it takes the full blast of the heat lamp off journalists and directs it at those scientists with a habit of overamping MRI studies, even when the sample in the studies is exceedingly small. Plenty of blame to go around. Moreover, both scientists and journalists must contend with the fact that the bulk of the scientific world’s research resides behind steep pay walls—steep enough that even prestigious universities have been wailing lately about the cost of just getting one’s hands on the research reports, let along doing the research. “Media literacy in science journalism is really stunted by the fact that we don’t have access to primary sources,” said a spokesperson for the Electronic Frontier Foundation.

So much blame going around, in fact, that enthusiasm for President Obama’s recently announced brain initiative seems particularly muted among one group universally expected to rally around the project—neuroscientists themselves. Having helped to create the hype, some brain scientists are now suggesting that the only appropriate attitude is healthy skepticism about where the money will be used, and whose pockets will be picked to come up with the $100 million in kickoff funds. Rather than jumping in unison when Obama said the program would allow us to “better understand how we think and how we learn and how we remember,” skeptical neuroscientists note that “Manhattan Project”-style programs are out of fashioned in today’s distributed, system-wide landscape of experiment. “Without specific goals, hypotheses, or endpoints,” said an Emory University neuroscientist in the Globe and Mail article, “the research effort becomes a fishing expedition.”

Myself, I like to fish. But not if the pond’s too small. In a recent post at National Geographic’s blog, “Not Exactly Rocket Science,” Ed Yong quoted a neuroscientist at the University of Bristol: “If you have lots of people running studies that are too small to get a clear answer, that’s more wasteful in the long-term.”

Exactly so, and one might think that a large, coordinated, possibly international initiative at studying the architecture and function of the human brain might serve as a powerful antidote to a micro-universe of tiny studies and insignificant findings.

But forget the big and little pictures for a moment. Let’s focus on what’s in it for addiction studies. What would have to happen—how would fMRIs, PETs and EEGs have to be used in order to advance our understanding of drug and alcohol abuse?

In a recent editorial —“What neuroimaging has and has not yet added to our understanding of addiction”—Martina Reske of the Institute of Neuroscience and Medicine in Julich, Germany, argues that we must take “three critical steps to implement neuroimaging as a new basis for diagnostics and treatment of substance use disorders: first, we need to merge diverse imaging findings into one comprehensive brain imaging perspective of addiction. Next, we need to identify prediction algorithms for individual substance users.” And finally, Reske writes in Addiction, “The ultimate goal has to be the development of treatment regimens based on neuroimaging results.” The interested lay public may be forgiven for assuming that all three of these conditions were already being met.

Specifically, Reske argues for “multi-modal approaches to overcome technological shortcomings. Simultaneous EEG-fMRI, for instance, combines high temporal and spatial resolution of exactly the same mental process, and hybrid MR-PET imaging allows for functional/structural and molecular characterizations.” What might stand in the way of such solutions, you ask? Reske answers that it is likely to be “the existing researchers’ hesitation, unwillingness or inability to consolidate findings from different imaging modalities.” In this case, she suggests, it is the scientists themselves, perhaps overly protective of individual turfs and research fiefdoms, who are hemming and hawing about large-scale collaborative efforts.

To reach a level of clinical relevance for addiction, neuroimaging must be used to delineate and identify “occasional versus habitual versus compulsive use or intoxication versus abstinence versus relapse.” These are not things that existing neuroimagery can do for us, but Reske believes one promising avenue will be the identification of subjects with an abnormally high risk for relapse, something neither patients nor therapists are very good at predicting. (This immediately brings neuroimaging up against a ripe field of ethical questions having to do with the identification and disclosure of high-risk subjects.)

What other payoffs might there be? Reske can think of a few: “First, linkage of neuroimaging and pharmacological studies will prove useful for predicting response to medication. Secondly, knowledge of the biological differences between responders and non-responders to available treatments might facilitate identification of the best-suited therapy for that particular individual. Thirdly, understanding which brain regions show alterations in functioning should spur the development of specific medications, cognitive-behavioral or neuroimaging-based trainings that target optimal activation levels in these regions.”

Neuroimaging is not yet specific or sensitive enough, and its practitioners not yet practiced enough, to accomplish these tasks except in a tantalizingly patchwork fashion. Neuroimaging-based predictions of addiction liability and damage and relapse make up an infant science, ripe for both growth and abuse. Obviously, it will take the gold standard of longitudinal studies involving enormous samples of participants, who would ideally be followed and scanned for decades. But such studies are, as Reske reminds us, “methodologically challenging, expensive and not promising in terms of short-term publication of results.” It sounds like the kind of Big Project that might fit under the umbrella of, say, a major, well-funded, multi-year brain research initiative endorsed by the President of the United States….

Photo Credit: https://docs.uabgrid.uab.edu/