Where Are All the New Anti-Craving Drugs?

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/

Short Subjects

Brief news on drugs and addiction.

The editorial staff at Addiction Inbox (see photo), occasionally finds itself overwhelmed with news and opinion worth broadcasting. Hence, this bullet list of drug/alcohol related news from recent weeks:

•    Children with heavy alcohol exposure show decreased brain plasticity, according to recent research on fetal alcohol spectrum disorders (FAS) using magnetic resonance imaging (MRI) scans. The research, supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), included 70 children heavily exposed to alcohol in utero. According to NIAAA, the children showed “lost cortical volume,” described in the study as a pattern of static growth “most evident in the rear portions of the brain—particularly the parietal cortex, which is thought to be involved in selective attention and producing planned movement.”

•    Combining medications for a better outcome is a staple of medical practice. So it’s not surprising to see the same thing being investigated in addiction treatment. Scientists evaluating medications for alcoholism have found that in some cases, mixing the medicine gives better outcomes. In two separate trials, naltrexone proved to be a more effective treatment for alcoholism when combined with either acamprosate (reported in Addiction), or baclofen (as detailed by Dr Mark Gold at the recent meeting of the Society for Neuroscience). In the Addiction study, the authors concluded that “acamprosate has been found to be slightly more efficacious in promoting abstinence and naltrexone slightly more efficacious in reducing heavy drinking and craving,” which suggests the possibility of using different drugs at different stages of recovery for maximum benefit. In preliminary work on baclofen, some researchers now claim that combining it with naltrexone often leads to better outcomes.

•    Every year at about this time, the rumors start flying: Did you hear that Amsterdam is closing its marijuana coffee shops? This breathless annual announcement is never true, and this year, despite all the fuss over “weed passes” and border skirmishes over drug traffic in the south of the Netherlands, Amsterdam’s mayor recently announced that he has no attention of closing the roughly 200 cannabis shops in his city by year’s end, as originally mandated by the now-defunct conservative government. In addition, rumors are flying that the incoming cabinet of Prime Minister Mark Rutte is already backing away from the previous government’s position on banning foreigners from the shops, according to a New York Times report. “Changes to the new policy have not been finalized,” according to a spokesperson for the Dutch Justice Ministry, quoted in the Times. Rutte himself has hinted that the ban may remain intact, but that local councils may be allowed to override that decision—an outcome not untypical of Dutch politics. “I’m guessing that behind the curtains, it’s already been arranged,” said Michael Veling of the Dutch Cannabis Retailers Association.

•    Here’s a finding you can easily test for yourself. Conduct a conversation with a heavily intoxicated chronic drinker. Introduce ironic, “wink-wink” comments into the exchange. Really lay on the irony. And then sit back and watch most of it sail right by your drunk and maddeningly literal companion. And now science is attempting to confirm it: A modest recent study in Alcoholism: Clinical and Experimental Research says that “drinking too much alcohol can interfere with men’s feelings of empathy and understanding of irony.” 22 men in an alcoholic treatment program read a series of stories ending with either an ironic comment or a straightforward one. Chronic heavy drinkers identified ironic sentences 63 % of the time, compared to a group of non-alcoholics, who identified 90 % of the ironic comments. Lead researcher Simona Amenta said in a press release that the results may mean that alcoholics “tend to underestimate negative emotions; it also suggests that the same situation might be read in a totally different way by an alcoholic individual and another person.” Ya think?

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

Gateway to Absurdity

State law criminalizes “gateway sexual activity.”

It’s the gateway to hell and perdition, that’s what it is. It doesn’t necessarily lead to drugs but it will drag you in the direction of Ess Eee Exx. And while sex is probably not addictive in the traditional sense, it is always and inevitably very bad when unaccompanied by marriage and the procreative urge.

Like anthropology’s search for the “missing link,” or the physicist’s search for a “unified field theory,” psychologists and social workers have spent decades hunting for the mythical gateway drug. This is the drug that, when used regularly, will head you reliably down the path of full-blown addiction. The findings of addiction medicine now make the identification of any kind of universal gateway drug an antique pursuit. Every addict finds his or her own gateway, and pushes through. If any drugs qualify as gateway drugs in a broad sense, it would have to be alcohol and tobacco, simply on the basis of ready availability.

But a gateway for full-blown recreational teenage sex—did you ever think about that? One might have thought the legislators would answer, yes, it’s called puberty, and move on. But no. The Tennessee legislature, led by Rep. Jim Gotto (R), managed to push through a bill  “allowing parents to sue teachers and other outside parties for ‘promoting or condoning gateway sexual activity’ by students.”

Interestingly, the bill apparently fails to define such activity in concrete terms. Evidently, Rep. Gotto has attempted to outlaw “first base.” Or, as TPMMuckraker put it, “other things.” Gateway sexual activity is defined, according to what I shall dub the bill’s "money" sentence, “sexual conduct encouraging an individual to engage in a non-abstinent behavior.” Okay, then. Earnest glances, hair tossing, hand holding—all potentially actionable, should any sex ed teachers be caught “promoting” such activities.

And not without reason: According to data released last month by the National Center for Health Statistics, the states with the highest teen birth rate in 2010 include Tennessee, which ranked 10th worst with 43.2 births per 1,000 teenage girls. And according to a 2009 risk behavior study in Memphis City, 61 percent of high school students have had sex, along with 27 percent of middle school students, putting Memphis City, and by extension Tennessee, considerably above the national average.

Apparently, the real target here is Planned Parenthood, which has been known to provide sex education information in Tennessee schools, and which would be facing fines and penalties under the new law. The bill calls for abstinence-only instruction.

Photo Credit: http://cbcpforlife.com/?p=4277

Interview with Dr. Bankole Johnson of the University of Virginia

Tailoring addiction medicine to fit the disease.

(The “Five-Question Interview” series.)

25 years ago, when Dr. Bankole Johnson first began giving lectures about addiction and neurotransmitters in the brain, he had a hard time getting a hearing. That’s because 25 years ago, everybody knew what addiction was: a lack of “moral willpower.” Or, at best, some sort of psychological “impulse control” disorder.  

As a neuropharmacologist by training, and currently professor and chairman of the University of Virginia’s Department of Psychiatry and Neurobehavioral Sciences, Dr. Johnson thought otherwise, and went on make a name for himself by discovering that topiramate, a seizure drug that boosts levels of the neurotransmitter GABA, could be used in the treatment of alcoholism. “I just wasn’t a hospital-type doctor,” he once said. “I was for more intersted in research than clinical practice.” Johnson’s work was featured in the 2007 HBO series, "Addiction."

Born in Nigeria, Dr. Johnson attended the University of Oxford and received his medical degree in Glasgow, Scotland in 1982. At the time, medical understanding of addiction was poor to nonexistent. “Everything we knew—really knew—probably could be written on the back of a postage stamp,” he recalled.

Since then, Dr. Johnson has published numerous articles on psychopharmacology and addiction, and has served on several National Institutes of Health committees and panels. (See my earlier POST on Johnson’s study of drugs for addiction in the American Journal of Psychiatry.)


1. You’re a native of Nigeria. How did you first become interested in medicine?

Bankole Johnson: My father was a doctor and encouraged me. Back then, I had little interest in medicine and was more interested in the arts and perhaps going to law School, for which I had been promised a scholarship.

2. Addiction is called a “disease of the brain,” in Alan Leshner’s famous phrase, but it is still a hugely controversial subject. Are innate biological differences the cause of addiction?

Johnson: Addiction is a brain disease. The roots of the disease lie in brain abnormalities, and these are exacerbated when a vulnerable person uses alcohol excessively or takes illicit drugs.

3. How did you discover that topiramate helped some alcoholics drink less?

Johnson: It was an idea that developed from a hypothesis I came up with based on brain neurochemistry. The central idea was to alter the signals of dopamine, a critical path for the expression of rewarding behavior, through two different and opposite systems—glutamate and GABA.

4. That work led to Topamax for alcoholism, and your more recent work with ondansetron, another GABA antagonist. But what role do environmental and sociocultural factors play in the development of addiction?

Johnson: The environment interacts with genes and brain chemistry to govern behavior. But in the end, it is the changes in the brain that ultimately direct alcohol and drug taking behavior.  The environment therefore provides the context and tuning of the neurochemical signals in the brain.

5. Some people find the notion of addiction as a progressive and incurable condition a hard pill to swallow, so to speak. Why has effective medical treatment for addiction been so slow to develop, and why hasn’t talk therapy been more effective?

Johnson: Talk therapy has some effectiveness, but alone it is not a comprehensive or robust treatment. Progress in the last two decades has been quite rapid. With growing and clear acceptance of the neurobiological underpinnings of addiction, the next decade should herald even more exciting discoveries.  For example, our work on pharmacogenetics promises to provide effective medications—such as ondansetron—that we can deliver to an individual likely to be a high responder, based on his or her genetic make up.

Photo Credit: Luca DiCecco

Army Doctor Sees Victory, and a Dangerous Drug Bites the Dust—Almost.

An interview with the man who blew the whistle on the neurotoxic malaria drug in the U.S. Army’s kit bag.

A dangerous malaria drug invented by the Army and commonly used by soldiers and civilians alike causes everything from episodes of psychotic violence to nightmares more real than reality, and is finally being withdrawn as the first-line treatment for troops in malarial zones.

Lariam, known medically as mefloquine, has also been a licensed treatment for civilians abroad for more than 25 years. Yet it has only been in the recent past that common knowledge of Lariam’s dangers has surfaced publically.

The development of Lariam was a prime example of military-industrial cooperation. Discovered at the Walter Reed Army Institute of Research during the Vietnam war, initially tested on prisoners at the Joliet Correctional Center in Illinois, and marketed worldwide by Hoffmann-La Roche, mefloquine was an urgent response to high malaria rates in U.S. combat troops overseas. Unfortunately, such close cooperation also led to a lack of adequate clinical testing—the practice that underpins the notion of drug safety. Ashley M. Croft of the Royal Army Medical Corps in Britain has written that in the case of Lariam, “the first randomized controlled trial of the drug in a mixed population of general travellers was not reported until 2001.” Croft believes the FDA was influenced by “the powerful military-industrial-governmental lobby into over-hasty decisions.”

In addition, “travel medicine experts in most countries were slow to recognize the danger signals associated with Lariam…. As late as 2005 a reviewer in the New England Journal of Medicine, also an employee of the US military for over 20 years, continued to maintain… that Lariam was a ‘well tolerated’ drug,” according to Croft. The victims of all this pharmacological hoodoo, Croft maintains, “have been those many business travellers, embassy staff, tourists, aid workers, missionaries, soldiers and others who were well at the start of their journeys into malaria-endemic areas…”

Largely due to the efforts of Dr. Remington Nevin, a medical epidemiologist and a physician in the U.S. Army, who went public about Lariam’s potential for causing psychological illness, military officials announced in December that the Army was done with Lariam as a first-line malaria preventative except for “special circumstances.” In the past, such special circumstances have allegedly included its use as an interrogation drug at Guantanemo.

As far back as 2004, an alarming number of suicides among troops in Iraq prompted calls for an investigation of Lariam. “The military is ignoring this drug’s known side effects,” Steve Robinson of the National Gulf War Resource Center told UPI. In October of 2004, Sen. Dianne Feinstein (D-Calif) urged then-Secretary of Defense Donald Rumsfeld to investigate the drug: “Given the mounting concerns about Lariam as expressed by civilians, service members and medical experts about its known serious side effects, I strongly urge you to reassess,” she wrote to Rumsfeld. Meanwhile, Mark Benjamin and Dan Olmsted of UPI were reporting that “mounting evidence suggests Lariam has triggered mental problems so severe that in a small percentage of users it has led to suicide. UPI also reported that soldiers involved in a string of murder-suicides at Fort Bragg, N.C., in the summer of 2002 after returning from Afghanistan had taken the drug.”

Almost ten years later, Sen. Feinstein wrote another letter, this one to Secretary of Defense Leon Panetta, complaining that a 2009 policy limiting the use of mefloquine among U.S. troops was not being followed. Although parent company Roche discontinued Lariam in the U.S., generic versions remain available, and the company continues to sell Lariam in other countries. “My office has been contacted recently by servicemembers who were prescribed mefloquine when one of the other medications would have been appropriate and were not given the FDA information card. These servicemembers are now suffering from preventable neurological side effects,” including  balance problems, vertigo, and psychotic behavior,” she wrote.

In addition, as a military medical instructor told Addiction Inbox: “Some service members might ‘double up’ on their weekly dose, or increase the frequency of dosing, intentionally for recreational purposes. There is no evidence that the military educates service members to avoid this temptation or that it is unsafe. Users might even justify it by believing it could enhance the drug's anti-malarial activity. In the military, it is frequently a tenet of our culture that ‘if one is good, two is better.’"

In November,  military officials overseas stopped almost all use of mefloquine in malaria-prone areas in Africa and the Middle East. Army Col. Carol Labadie, the service’s pharmacy program manager, commented on the long overdue change: “If that means changing from one drug to another because now this original drug has shown to be potentially harmful… it is in our interests to make that change.”

As Croft wrote, it was not a case of inconvenient research being deliberately witheld. Rather, “the necessary pre-licensing research was simply never carried out.”

Questions still remain about the use of mefloquine at Guantanamo as an “enhanced interrogation technique.” Last year, Stars and Stripes ran an investigation of the matter and concluded: “Medical experts say the Defense Department policy of giving detainees large doses of mefloquine is poor medical practice at best and torture at worst.”

INTERVIEW WITH DR. REMINGTON NEVIN

—Is there any good science behind the notion that mefloquine might be addictive?

Dr. Remington Nevin: I am speaking to you in an individual capacity, and my opinions are my own and in no way reflect those of the U.S. Army or the Defense Department. There is no evidence that mefloquine is addictive per se, but the drug is well-known to produce vivid, technicolor dreams, and as a result it is frequently viewed as an incidental and convenient form of recreation among people, including Peace Corps volunteers and military service members, who find themselves already required to take the drug, and otherwise typically without access to alternative drugs of abuse, such as alcohol. The vivid "rock star" fantasies frequently reported are often perceived as consolation for the isolation and loneliness that typical accompany travel to remote areas where mefloquine is prescribed.

Ann Patchett, a prize-winning author, recently wrote a book called State of Wonder in which mefloquine features prominently, and her writing was likely based to a good degree on her and her acquaintances' experiences with the drug. Patchett herself actually refers to the drug's "recreational" properties and alludes in a recent interview to her having wanted to "take the drug out for a spin" (see http://thedianerehmshow.org/)

REHM: Did you take Lariam when you went to the Amazon?
PATCHETT: I did, I did. And actually, if I hadn't gone to the Amazon, I probably would've just taken it recreationally at home because I really wanted to take it out...
REHM: Experience it.
PATCHETT:...for a spin, right.
REHM: Yeah.
PATCHETT: And the side effects of Lariam listed on the package, psychotic dreams, terrible nightmares, paranoia, suicide is a possible side effect and I've known a lot of people who have had true psychosis on Lariam.

—Can you lay out what you know about mefloquine causing hallucinatory and dissociative effects in travelers who take it for malaria?

Dr. Nevin: [The symptoms] closely mimic those of a condition known as anti-NMDA receptor encephalitis, which an expert in the field, Dr. Dalmau, describes as including "anxiety, fear, bizarre or stereotypical behaviour, insomnia, and memory deficits". It is thought that rising levels of antibody to the NMDA receptor induces… widespread downstream dysregulation of  limbic dopaminergic and noradrenergic tone, which ultimately are responsible for producing the syndrome's psychotic effects… This limbic dysregulation may also be similar to what is seen with the chemical NMDA receptor antagonists, including ketamine and phencyclidine, which share with mefloquine a particular propensity towards impulsivity and dissociation. For these reasons I conclude that mefloquine should be characterized as a dissociative hallucinogen.

—What is a dissociative hallucinogen?

Dr. Nevin: It is this property that also likely explains the drug's association with suicidality and acts of violence. Mefloquine is the only non-psychotropic drug listed among the top ten associated with acts of violence, and there is a growing literature linking it causally to suicide.  It may be that the combination of mefloquine-induced amnesia, dissociation, and hallucinations (many with vivid religious or persecutory themes) creates a perfect storm that can trigger impulsive acts of violence. It is not uncommon for those recovering from (and surviving) mefloquine psychosis to report engaging in suicidal gestures that in retrospect were devoid of any fear of consequences…. Just within the past year, in a paper in the journal Science, Bissiere and colleagues demonstrated mefloquine interfering with context fear response in the hippocampus.


—Could you expand on the notion of "vivid rock star fantasies" experienced by some users?

Dr. Nevin: Extremely vivid dreams are among the most widely reported "adverse effect" of the drug. Users can frequently describe their dreams in great detail even well into the next day and, in some cases, the dreams seem to take on an almost lucid quality. Many experience gratifying and deeply pleasurable dreams that they almost don't wish to awaken from; conversely, for some others, the effect seems to be quite the opposite, with the reported nightmares being particularly haunting the next day.

—You have referred to Lariam as a "zombie" drug. Could you expand on that?

Dr. Nevin: If you must know, the reporter for AP caught me on Halloween, but I believe the term is quite apropos. The drug is the pharmaceutical equivalent of the living dead; it is somehow able to survive controversies that would have quickly killed other drugs. Interestingly, Lariam has been quietly delisted although generics remain widely available. To further stretch the metaphor, the drug is also decidedly neurotoxic and kills brain cells; one can say it "eats brains", and lastly, I would argue that a "zombie-like" state is not an unreasonable description of the most extreme adverse effects of the drug.

—I'm shocked to discover mefloquine on the list of top 10 drugs associated with acts of violence. Could you comment on a non-psychoactive drug making that list?

Dr. Nevin: It is quite shocking. Mefloquine isn't typically considered a psychotropic drug, but it probably should be recharacterized as a psychotropic medication with incidental anti-malarial properties. Of the drug contained in a 250mg tablet, only about 1-2mg, less than 1%, is ultimately found at the site of its intended anti-malarial activity, in the circulation. And although the neuropharmacokinetics are still somewhat unclear, arguably a far greater percentage of the drug is ultimately found in brain tissue than in the circulation. Incredibly, when the drug was undergoing FDA licensing, this brain penetration wasn't even well-characterized. Transcripts from the licensing meetings clearly show committee members skipping over this fact without much consideration. Certainly there seems to have been no requirement to submit the drug to neurotoxicity testing, despite many related quinoline compounds having demonstrated well-characterized, permanent neurotoxicity at least 40 years earlier.


—How common is the use of mefloquine in the U.S. as a whole?

Dr. Nevin: There has been a fairly rapid decline in the use the drug, correlating with rising appreciation of mefloquine's dangers and awareness of contraindications to its safe use. Malarone is now the predominant anti-malarial prescribed within a large network of U.S. travel clinics. The U.S. military, which developed the drug just over 40 years ago, recently prohibited the use of mefloquine as first-line agent, and has dramatically curtailed its use after research revealed the drug had been widely prescribed to service members with mental health contraindications. Recently, the U.S. Centers for Disease Control further clarified guidance against routine use of mefloquine in service members, conceding that use of mefloquine may "confound the diagnosis and management of posttraumatic stress disorder and traumatic brain injury".

—What are the consequences of mixing Lariam with alcohol?

Dr. Nevin: There is fairly good evidence from case reports that alcohol may potentiate the deleterious effects of mefloquine, but the mechanism remains controversial. It had been suspected that alcohol simply exerted an inhibitory effect on mefloquine metabolism, but now… it seems likely that alcohol exerts a direct pharmacodynamic effect.


—Lariam is still sometimes prescribed for children traveling in malaria zones. Are there special dangers for kids?

Dr. Nevin: As the popularity of the drug is declining among adults, some experts with ties to industry have been peddling the drug for niche pediatric use, ostensibly because it is well tolerated. Unfortunately, such claims are based on studies which in many cases are deeply flawed and…. even verbally fluent but younger children may not have the experience or perspective to properly describe these symptoms. Apart from these considerations, I would argue that I don't think enough is understood about the neurophysiological effects of the drug to justify its use even in older children and adolescents.  Mefloquine is a psychotropic drug. Given what we are learning of mefloquine's effects on the limbic system, even at relatively low doses, it seems at least plausible that the developing brain might in some way be adversely affected by the drug, particularly during long-term dosing.

—Why was the Army so slow to move on mefloquine?

Dr. Nevin: To put things in perspective, understand that mefloquine is the sole product of an aggressive 20-year, multi-million dollar effort by the U.S. Army. Mefloquine was identified only in the early 1970s after tens of thousands of other quinoline compounds had failed toxicity and efficacy tests. By the time of mefloquine's U.S. licensure in 1989, it was essentially DoD's last and only hope. So, if I could rephrase your question, if mefloquine is as safe as the Army once claimed, then why is it no longer the drug of choice? If we assume that this quiet policy change was made in tacit acknowledge of safety concerns, then the question is, precisely what new information has informed this decision, why has this change taken so long to occur, and most importantly, what harm might this policy change now be seeking to avoid, which may already have accrued among those in whom the drug had been previously used?  

The reasons for the Army's silence on these questions are likely quite banal. Admitting mefloquine is a dangerous drug would be a bitter pill for any Army medical leader to swallow. Many of today's senior medical leaders were intimately involved in the studies that saw the drug rise to prominence, and many are on record over the previous decades publicly defending the drug against the increasingly validated claims of its earlier critics. Absent external pressure to do so, it is likely of little benefit for these senior medical leaders to suffer the humiliation that would come from admitting what they might now otherwise privately concede. Saying nothing is the path of least resistance on their journey to a comfortable retirement.

—Could you comment on allegations of Lariam use as an interrogation drug at Guantanamo?

Dr. Nevin: The use of mefloquine at Guantanamo represents either medical malpractice with culpability at some of the highest levels of military medical leadership, or it suggests something far more intentional and sinister. I typically believe that one should never ascribe to malice what can be attributed to simple incompetence, but in this case, I am not so certain. There are too many inconsistencies and unanswered questions. The issue will ultimately require the release of medical records, open hearings, and testimony to resolve. I am confident this will happen.

Drug Addiction in 10 Slides or Less

Dr. David Friedman explains it all.

Dr. David Friedman, a professor of physiology and pharmacology at Wake Forest University School of Medicine, is also the co-founder and director of the Addiction Studies Program, a workshop for science journalists in Washington, D. C., funded by the National Institute on Drug Abuse (NIDA).

Sometimes it helps to step back and attempt to make the scientific case for addictive disorders as simply as we are able. Herewith, some highlights from Dr. Friedman’s useful presentation at the recent Addiction Studies Program workshop. Slides reproduced with Dr. Friedman’s kind permission. The comments adjacent to the slides are my own, as are any errors of fact or interpretation.

 There are important distinctions to be made between drug abuse and drug addiction, as Dr. Friedman makes clear in the slide to the right and the slide below. Unfortunately, government agencies have tended to take the position that any drug use is ipso facto drug abuse; a political position not well supported by the relevant science

  As a chronic medical condition, or “brain disorder,” addiction has a fair amount in common with other diseases, like hypertension, asthmas and diabetes, Friedman said. Relapses and setbacks are frequent, but not found in every case. 

  The key questions, indeed: What is different about the brains or the genes or the nerve cells of those who become dangerously addicted, compared to those who can take it or leave it? Scientists have discovered various so-called “markers” over the years in the brains of the children of adult alcoholics, but none of these have been broad enough in scope to point toward anything like an effective near-term treatment. However, the recent shift from chasing genes to studying neurobiological brain processes is a hopeful turn of events.

Again, a crucial distinction must be made between a state of physical dependence (at right) and a state of withdrawal (below). Non-addicts can become physical dependent on a variety of prescription medications. Such physical dependence precedes a full-blown state of addiction, but is not to be confused with addiction itself.

 The symptoms and intensity of drug withdrawal can vary from horrifying to essentially non-existent. It depends upon the drug, the drug taker’s metabolism, the social setting, environment and expectations of the users, etc. Craving and withdrawal represent the basic mechanism responsible for relapse.

 Most people are familiar with the “rebound effect” sometimes produced by over-the-counter nose sprays. Whey you inhale these medications regularly enough, the result of going turkey is… a profoundly stuffed-up nose.

In an effort to expand on the “chronic disease of the brain” label affixed by former NIDA director Alan Leshner, Dr.Friedman directs our attention toward specific brain mechanisms: reward, motivation, and memory.

Addiction is a pediatric disorder, Friedman emphasizes. This is particularly true with marijuana abuse and addiction.  Lke sugar in your blood, you can choose to control the amount of drugs you take, but you cannot choose your reaction to them.

We know for certain these days that adolescent brains are not yet fully formed, and that adolescent brains react to drugs differently than adult brains. For example, recent studies show that the actual composition of adult nicotine receptors in the brain is affected by exposure to nicotine in adolescence.

The net result of all this? Things happen at the biochemical level that change how things play out at the behavioral level.







Photo Credit: http://www.wakehealth.edu/

An Interview with Pharmacologist David Kroll

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

An Assortment of Drug-Related Articles

Misc. Stuff Etc.

In this post, I offer up an assortment of links to articles, mostly by me, and other related material, so that I can put checkmarks after a few items on the official Addiction Inbox to-do list, here on the official Addiction Inbox plexiglass clipboard. So let’s see….

* Here’s an article I wrote awhile ago for Brain Blogger, called "Why Do Schizophrenics Smoke Cigarettes?" The comments alone are worth a look. Spoiler: Schizophrenics smoke cigarettes because nicotine helps quell both audio and visual hallucinations.

* One of the very early posts here at Addiction Inbox, called "Marijuana Withdrawal," transformed itself into a self-help support board over time, with lengthy and enlightening comments appended to a short original post about the symptoms of marijuana dependency. The post has accumulated more than 1,000 comments at this writing, and is still going strong. Have a look here.

* The title of the Dutch study, published in the journal Alcohol and Alcoholism, is unambiguous: “Alcohol Portrayal on Television Affects Actual Drinking Behaviour.” But the dirt, as always, is in the details. My article at Adi Jaffe’s All About Addiction site.

* This feature of mine about synthetic marijuana products like “Spice” ran last month at The Fix, where I am now serving as senior contributing editor. 

* I contributed a comment or two to this follow-up piece on synthetic cannabis that ran in the New York Daily News.

* Also at The Fix, that irritating fraud James Frey gets his ass totally kicked by Time Healthland’s Maia Szalavitz, who demands that he apologize to addicts for all the harm he has done their cause in this article. Great stuff. 

* Here’s a hard-hitting excerpt from James Brown’s phenomenal addiction memoir, This River, which redeems the entire genre from the likes of James Frey. Read the harrowing “Instructions on the Use of Heroin.”

* Science of Blogging is a great site that regularly features interviews with, you guessed it, science bloggers. Travis Saunders was kind enough to do a Question and Answer session with me recently.

And here are a dozen recent blog posts by yours truly over at the The Fix:

Deaths Linked to Botched Batch of Designer Mescaline

2C-E, a research hallucinogenic best left to the professionals, may have killed two people in Oklahoma.

GOP Goes Gaga for Drug Testing

Almost 30 states now intend to test welfare recipients for drug use.

Top 10 (or 20) Recovery Songs

From the Hold Steady to the Rolling Stones to Nine Inch Nails: best all-time recovery songs.

Saving OD Victims May be Illegal in Your State

Lawmakers argue over how to do the right thing for people who do the wrong thing.

Mexico's Massacred Kids

As bodies pile up in Mexico's drug war, murdered children account for over 1,000 deaths.

Google Faces Fines for Pill Mill Ads

The internet giant may pony up some serious dough for promoting prescription-pill abuse.

Former Assistant Drug Czar Slams the Medical Establishment

Provocative Penn psychologist wonders what would happen if our health care system treated diabetics like it treats most addicts. Nothing good.

Drug Criminals See Cigarettes as the New Black Market

Cigarette trafficking is now so lucrative that organized drug and gun smuggling operations want in on the action.

Do Alcoholic Students Score Better on Tests if They Stay Drunk?

How does alcohol affect memory? New research suggests that students perform much better on tests when their "memory states" match.

A Toast to the Black Monk of Thamkrabok

For over 30 years, a charismatic Vietnam vet and mercenary named Gordon Baltimore helped hardcore addicts recover with a controversial regimen at a Thai monastery. A former heroin addict, he died last week at the age of 60

Charity Pays Thousands of Addicts to Get Sterilized

An American "charity" is paying thousands of U.S. drug addicts not to have children. Buoyed by its success, the group has moved on to Britain. Now Denmark may be taking up the trend.

Vancouver’s Supervised Shooting Up Site: 2,000 ODs, 0 Deaths

An officially-sanctioned injection site for heroin and cocaine addicts in Vancouver prompts a dramatic fall in death rates. So why is the Canadian government so dead-set against it?

Thank you and good night.

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

Personalizing Addiction Medicine

Gene variants make anti-craving drugs a hit-or-miss affair.

Rather than taking on another broad hunt for the genes controlling the expression of alcoholism, noted addiction researcher Dr. Bankole Johnson and co-workers at the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia took a different tack. The researchers focused, instead, on investigating whether genetic variations among alcoholics might affect their responses to a specific anti-craving medication.

The result, according to Kenneth Warren, acting director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), is a study that represents “an important milestone in the search for personalized treatments for alcohol dependence.”

For any addiction, once it has been active for a sustained period, the first-line treatment of the future is likely to be biological. 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 drug treatments that did not exist fifteen years ago. As more of the biological substrate is teased out, the search for effective approaches narrows along avenues that are more fruitful. This is the most promising, and, without doubt, the most controversial development in the history of addiction treatment.

The researchers were interested in variations in the gene controlling the expression of a serotonin transporter protein. Dr. Johnson’s earlier work had centered on teasing out the influence the serotonin 5-HTT transporter exerts on the development of alcoholism. Previous research had focused attention on the so-called LL and TT variants of this transporter gene. After performing genetic analyses to determine which test subjects were carrying which versions of the gene in question, Dr. Johnson and his colleagues conducted a controlled trial of ondansetron on a randomized group of 283 alcoholics.
The findings were published in the American Journal of Psychiatry.

Ondansetron is an anti-emetic medication that has shown promise in treating addictions, particularly alcoholism. Ondansetron (trade name Zofran), helps block the nausea of chemotherapy by altering serotonin activity in the GI tract. (Vomiting is a serotonin-mediated reflex.) The scientists found that “individuals with the LL geno-type who received ondansetron had a lower mean number of drinks per day (-1.62) and a higher percentage of days abstinent (11.27%) than those who received placebo.”  This put the ondansetron drinkers under five drinks a day. All of the placebo drinkers continued to exceed the five drinks per day mark.

But the strongest difference was found in the group of alcoholics who possessed both the LL and TT genetic variants. The LL/TT alcoholics taking ondansetron “had a lower number of drinks per drinking day (-2.63) and a higher percentage of days abstinent (16.99%) than all other geno-type and treatment groups combined.” 

The goal here is straightforward. In an email exchange, Dr. Johnson told me: “I agree that it would be great if we could use a pharmacogenetic approach to study other anti-craving drugs. The idea of providing the right drug to the right person is definitely important for optimizing therapeutic effects and minimizing side-effects.” Here is a video of Dr. Johnson discussing the research, courtesy of the University of Virginia:

It won’t be easy. Such genetic testing is still in its infancy, and complications abound. For example, in an earlier study in the Journal of the American Medical Association, Dr. Johnson found that diagnosed patients who received ondansetron over an 11-week period increased their days of abstinence compared to alcoholics on placebo. However, in that study, “The researchers found no differences between ondansetron patients with late-onset alcoholism and those who received placebo.” This suggests that, along with genetic variations, ondansetron’s effectiveness with alcoholics may also depend on the type of alcoholism under consideration: early onset or late onset.

We have a long way to go, but individualized pharmaceutical assistance in the early stages of addiction recovery remains the Holy Grail for many addiction researchers. And hopes are running high.

Johnson, B., Ait-Daoud, N., Seneviratne, C., Roache, J., Javors, M., Wang, X., Liu, L., Penberthy, J., DiClemente, C., & Li, M. (2011). Pharmacogenetic Approach at the Serotonin Transporter Gene as a Method of Reducing the Severity of Alcohol Drinking American Journal of Psychiatry DOI: 10.1176/appi.ajp.2010.10050755

Graphics credit: Sergey Ivanov at http://pn.psychiatryonline.org/content/