Monday, February 6, 2012
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alike causes everything from episodes of psychotic violence to nightmares more real than reality, and is finally being withdrawn as the first-line treatment for troops in malarial zones.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.
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.