An interview with the man who blew the whistle on the neurotoxic malaria drug in the U.S. Army’s kit bag.
Monday, February 6, 2012
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reality, and is finally being withdrawn as the first-line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.