May 21 (UPI) -- Mounting evidence suggests the anti-malaria drug
Lariam -- prescribed to Peace Corps volunteers, travelers and U.S.
soldiers -- has triggered mental problems so severe that in a small
percentage of users it has led to the ultimate side effect: suicide.
-- also known as mefloquine -- is a product of Hoffmann-La Roche,
a giant Swiss pharmaceutical company with U.S. headquarters in Nutley,
N.J. Lariam has been prescribed to more than 22 million people worldwide
since 1985. It was cleared for use in the United States in 1989.
experts charge that neither patients nor doctors in the United States
are being adequately warned about the risk of suicide from taking
Lariam, which is prescribed by U.S. doctors 1,000 times every day.
In a two-month
investigation, United Press International reporters found:
* In thousands
of pages of internal Roche documents obtained by UPI spanning a
decade, the company tracks increasing reports of suicides, suicidal
behavior and other mental problems among Lariam users.
* A 1994
Roche safety report notes that because Lariam can cause depression
and depression can lead to suicide, "a causal link to Lariam can
in theory not be ruled out."
of soldiers, Peace Corps volunteers, other government workers and
private travelers, in interviews with UPI, court filings, case studies
and reports from medical personnel, said they had no history of
mental illness before taking Lariam, but then attempted or considered
suicide. Families gave similar accounts of several who succeeded
in killing themselves.
* An activist
group said it has heard from 120 Somalia veterans who had problems
they attributed to Lariam, including suicide attempts. Military
medical officers in charge of giving Lariam to more than 20,000
U.S. troops there in 1992 and 1993 said they saw no evidence of
a problem. Troops in Afghanistan are taking Lariam as the weather
warms, but some officers on the ground in Afghanistan said they
themselves were not taking it because they feared liver damage.
U.S. Food and Drug Administration's files contain reports over the
past four years alone of 11 suicides, 12 suicide attempts, 41 cases
of thinking about suicide and 144 cases of depression among Lariam
* A statistical
analysis of FDA data, commissioned by UPI, indicates that Lariam
users are five times more likely to report having mental problems
that could lead to suicide than those taking a different drug --
the antibiotic doxycycline -- also used to prevent malaria.
than a dozen lawsuits over the alleged effects of Lariam have been
filed in the United States -- at least seven against Roche, and
the others against doctors or pharmacists. Some have been dismissed
or settled out of court.
have been a number of cases of suicide, both in the United States
and abroad, that are clearly associated with the use of Lariam,"
said Susan Rose, an adjunct assistant professor at George Washington
University's public health school and an attorney who has represented
plaintiffs suing Roche.
has won a case against Roche alleging Lariam caused a suicide, but
Rose, speaking as an advocate for plaintiffs with a background in
public health, said: "Suicidal thoughts and impulses are far more
commonly experienced than the current product information sheet
would lead physicians or consumers to believe. This is critical,
life-saving information that must be conveyed now to travelers and
the medical community."
consistently has denied there is evidence showing taking Lariam
can cause the kinds of mental problems that could lead to suicide.
The company said Lariam is an important drug for combating malaria.
me, as a company we support this drug and stand behind it," said
Roche spokesman Charles Alfaro. "Roche works with all regulatory
authorities both before and after product approval to ensure recommendations
for product use that take into account current medical evidence."
remains a drug of choice for the prevention and treatment of malaria
by such leading health authorities as the CDC (Centers for Disease
Control and Prevention), the WHO (World Health Organization) as
well as many travel organizations, clinics, and individual physicians,"
whether Lariam could cause suicide, Alfaro said he could not answer
because it was an issue in pending litigation.
side effects of drugs are voluntarily reported by physicians and
others to the FDA and drug companies. The FDA said in general, drug
side effects are reported in only 1 percent to 10 percent of cases.
Woosley, dean of the University of Arizona Medical School and an
expert on drug side effects, said he would be "very comfortable"
with an estimate of actual suicides 100 times greater than the 11
reported to the FDA in the past four years.
said the FDA lacks the resources to follow up on side effect reports
even for drugs recently approved.
be very surprised if there's very much surveillance of this drug
(Lariam) at all," said Woosley. "It's 12 years old. The FDA probably
wouldn't have the people power. They're understaffed, they have
inadequate resources and they're putting out fires and looking at
said in a written statement to UPI it would have taken action if
it had confirmation Lariam caused suicide. But the FDA said confirmation
required either biological or statistical evidence.
the FDA database included reports of 11 suicides among Lariam users,
all but one of them outside the United States, the agency said "to
'blame' Lariam for all these cases is not scientifically justified."
we believe the risk of such rare and poorly substantiated events
is more than offset by the benefit in preventing malaria deaths,"
the FDA statement said.
the "less frequently reported adverse events" section on Lariam's
label, Roche added in 1999: "Suicidal ideation (thinking) has also
rarely been reported, but no relationship to drug administration
has been established." These labels in the United States come as
fine-print package inserts that patients do not automatically receive.
nations have acted to ensure consumers receive warnings of possible
adverse reactions to Lariam --which is chemically related to the
quinolone group of antibiotics, long documented as capable of causing
the British Malaria Advisory Committee, for instance, stopped recommending
Lariam for trips of two weeks or less. Patients who do take it receive
a written warning that includes: "Effects on nervous system: psychiatric
reactions which may be disabling and last for more than several
weeks. These include unusual changes in mood or behavior, feelings
of worry or anxiety, depression, feelings of persecution, crying,
aggression, restlessness, forgetfulness, agitation, confusion, panic
and hallucinations. If you experience any of these effects you should
immediately stop taking Lariam and consult a doctor."
"Information for the Consumer" from Roche states: "It is best to
avoid alcoholic drinks during treatment with Lariam." No such warning
appears on the U.S. label despite increasing concerns alcohol can
be a problem when mixed with Lariam.
alcohol, in particular, can be a confounder with Lariam," said Dr.
Alan Magill, a Walter Reed Army Medical Center official who was
in charge of the health of U.S. soldiers deployed to Somalia in
the early 1990s.
said he saw no major side effects among troops taking Lariam. By
contrast, Jeanne Lese, information manager of the activist group
Lariam Action, said "more than 120 Somalia vets have contacted us
about Lariam and 11 said they have considered or tried suicide --
one tried it 10 times and shot herself twice" but survived.
half a dozen of the Somalia veterans who had contacted the group.
They spoke of marked personality changes in themselves and others,
suicidal thoughts and suicide attempts, flashbacks, nightmares and
paranoia. One said that most soldiers drank alcohol daily, aggravating
the side effects. Another said his doctor in the United States did
not seem aware of Lariam side effects.
declared Lariam its "drug of choice" in March 1990 and that fall
recommended doses of Lariam be doubled from once every two weeks
to once a week, after the first four weeks of weekly doses. Because
the CDC is the guidepost for malaria prevention in the United States,
other government agencies, private travel clinics and doctors quickly
adopted the regimen.
followed a survey of 562 Peace Corps volunteers, led by the CDC's
chief malaria expert, Dr. Hans Lobel. The study results eventually
appeared in the Journal of the American Medical Association in January
adverse reactions were observed," Lobel wrote of the volunteers
who took Lariam. Because some of those volunteers contracted malaria,
a sometimes-deadly disease, Lobel said weekly doses of Lariam "should
said the U.S. government never should have used the Peace Corps
study as a basis for increasing doses of Lariam.
increase was "an astonishing piece of non-evidence-based science,"
said Dr. Ashley Croft, a British army lieutenant colonel who has
done extensive research on Lariam and who said he believes it can
cause serious mental problems that increase as doses rise.
really quite amazing that this doubling-the-dose policy - which
of course doubled the company's profits at a stroke - was immediately
adopted everywhere, and on the basis of such a flawed study," Croft
he believes that in the Peace Corps study, some of the volunteers
may have quit taking the drug because it bothered them, and got
malaria as a result.
In a 1994
internal Roche document, the company said an evaluation by Lobel,
director of the CDC's malaria prevention program at the time, indicated
the Lariam package insert was adequate.
to a consultant expert in the field of malaria, Dr. H. Lobel, CDC,
Atlanta, the current package insert adequately addresses suicidal
ideation under 'depression', in view of the isolated reports received,"
the 1994 Roche safety report read. "No change in the package insert
is required at present."
declined to discuss Lobel's recommendation with UPI or his status
in the 1994 report, which called him a consultant expert. CDC rules
prohibit compensated or uncompensated consulting without express
Tom Skinner said the agency does not have records indicating Lobel
received such permission, if it was needed.
never been a consultant for Roche," Lobel told UPI. He did say he
often worked as a consultant for other organizations, such as the
World Health Organization, but not for Roche.
said the CDC had opened an ethics inquiry in the issue. "There is
a formal process the CDC must go through to determine if any action
needs to be taken," Skinner said.
thousands of pages of Roche's internal safety reports for the decade
after the drug dose was increased. "Eight patients attempted suicide,
three by leaping out a window," reads one Roche safety report of
side effects documented through 1993, in a section titled "Depression
with Suicidal Tendency."
safety report said because Lariam can cause depression and depression
can lead to suicide, "therefore a causal link to Lariam can in theory
not be ruled out." It went on to say reports of suicide attempts
were rare and fell within the incidence of suicides among the general
also noted "the first report of suicide with the use of Lariam"
and went on to say "Roche has received eight reports of attempted
suicide, four of them associated with depression (previous (medical)
additional patients reported suicidal thoughts. All were associated
with psychiatric disturbances" including depression, the 1994 report
report of suicide in 1994 was of Canadian Army Cpl. Scott Smith,
who was stationed with the United Nations in Rwanda. Smith reported
having hallucinations he attributed to Lariam months before his
October 1994 interview with a journalist on a flight from Somalia
to Rwanda, Smith said the difficulties began when he was stationed
in Somalia. The writer, a correspondent for Canadian Transportation
Logistics, reported the conversation in the December 1994 edition
of the magazine. It appeared shortly before Smith's death.
Scott Smith ... is one of the unfortunate ones to react to the malaria
medicine everyone has to take. He experiences hallucinations," the
safety report on Smith made no mention of the reported hallucinations
and said use of Lariam was "more likely coincidental" to the suicide,
especially since Smith had been drinking.
safety report for 1998 -- the last year examined by UPI -- said
of Smith: "There is insufficient information for assessment of this
case. The Canadian military has not confirmed this information nor
have they provided any clarification. All information has been compiled
from the media," it said.
Member of Parliament John Cummins studied reports of Lariam side
effects among Canadian soldiers. Cummins said Roche should have
known and stated in its report that Smith had hallucinations he
attributed to Lariam.
that is gross negligence on their part," Cummins told UPI.
David Carpenter, head of the Canadian military's communicable disease
control section, said Lariam remains the drug of choice "where indicated"
by the kind of malaria and whether the disease is resistant to other
drugs. Asked about the Smith case, Carpenter told UPI, "I vaguely
have heard of it," but he said a government review found "there
was nothing to substantiate it was mefloquine-related."
Lariam's rare psychiatric side effects are well-known and troops
are carefully monitored for bad reactions, in which case they are
generally given doxycycline. But he said, "When you're doing travel
medicine for the military as I do, you have to weigh the real and
often very common risk of getting malaria against the risk of psychiatric
problems. Usually the balance is toward preventing malaria."
Roche safety report also attributed suicidal tendencies chiefly
to factors such as "the progressive break down of traditional values"
and family structure, substance abuse and unemployment, not to Lariam
Roche reported that four suicides during the year might be connected
to Lariam, but said, "No causal relationship could be established."
That year, it added a new appendix to the annual safety report entitled,
"Special Review: Lariam and Suicide, Suicide Attempt and Suicidal
Ideation" (thinking about suicide). The report said the company
was tracking seven suicides, 13 suicide attempts, 46 cases of thinking
about suicide and 3,419 "psychiatric events."
men and women troubled by Lariam, those dry statistics were very
real and sometimes deadly experiences.
a raving, crazy lunatic," Martin Giannini said in an April telephone
interview with UPI from Dublin, where he is trying to rebuild a
life he says was shattered by Lariam. He took Lariam from June 1995
through September 1996 as a Peace Corps volunteer while in Togo
in West Africa.
his mental problems started with nightmares, headaches and dizziness.
He said his condition the next two months quickly deteriorated into
an enveloping psychosis that required him to be evacuated.
went to pieces," Giannini said. "I'd been telling (Peace Corps medical
personnel) since Day One that I had been having problems with this
the United States, Giannini suffered from hallucinations. He heard
voices. His mental problems climaxed in a three-day high-speed car
trip that led him from Oklahoma to Illinois and into Wisconsin,
where after a car crash he was found wandering in the woods. He
has been hospitalized several times. He said he considered suicide.
were times ... It was amazing I survived."
Corps medical officials said reports of mental problems among volunteers
are due to the onset of schizophrenia that can show itself in the
early 20s, when most volunteers join up, but not because of Lariam.
get people who develop schizophrenia in the Peace Corps, but it
is not associated with mefloquine," said Russell Gerber, chief of
the epidemiology unit at the Peace Corps.
sought back wages from the U.S. government, because the Peace Corps
is a federal agency. In March 1998, the U.S. Department of Labor
wrote Giannini a letter saying the department agreed to pay his
medical expenses and compensate him for lost wages, "for a single,
sustained, but acute psychotic reaction to mefloquine use" that
lasted a full year.
to 32 doctors, scientists and other experts, and 27 people who said
they suffered adverse side effects from Lariam use. UPI reporters
also reviewed dozens of e-mails from around the world -- from soldiers,
travelers and medical experts in the field -- about problems with
Lariam, as well as published reports.
Macleod Matthews, a 37-year-old lawyer who had taken Lariam a year
earlier but continued to be troubled by bad dreams, threw himself
off the roof of an apartment building in London. The coroner, Paul
Knapman, ruled the death a suicide and said, "It is more likely
than not that Lariam played some part," according to the Times of
tourist Malcolm Edge, 27, was found hanging in a hotel room in Ho
Chi Minh City, Vietnam, in 2000; he was taking Lariam. Edge had
undergone a startling personality change on the trip, according
to a traveling companion. The Dublin coroner notified the Irish
Medicines Board that "concerns were expressed at the inquest in
relation to possible psychotic reactions to Lariam," but the coroner
made no conclusion whether Lariam was a contributing factor in the
Australia, John O'Callaghan, 29, committed suicide after being treated
with Lariam for malaria he contracted on a surfing trip to Indonesia.
"Almost immediately," his mother Jan wrote in an e-mail to the group
Lariam Action, "he suffered severe neuropsychological and physical
side effects. We did not know he was suffering from mefloquine toxicity.
He had no history of these (physical and mental) illnesses. For
a couple of years he tried to return to his previous healthy lifestyle.
Finally, in September 2000, he took his own life." He left a note:
God will forgive me. No one could live with how I am feeling now.
I know I will never forgive the bastards that gave me Larium. I
am now the same as when I first had it -- fully spinning can't even
walk properly - the walls are moving. My head feels like someone
let a box of ants in it, extreme pain in my head. I am fully losing
it. What does the future hold -- 'psyciatric wards' no way. I know
I've always been a little bit different even before I had Larium
but since it first blew my brains apart and then settled down I
have never been the same, always dazed and confused, always physically
sick. I never thought this could happen to me. Sorry Mum, Dad"
account of symptoms mirrors those of several others: Charles Perry,
who committed suicide in Ohio in 1999, spoke of a relentless pain
at the base of his cranium, said his wife, Linda: He would put his
head on the table and hold his hand over the base of his skull,
saying, "This is where it hurts." (Linda Perry sued Roche for alleged
failure to warn about side effects, including suicide. The lawsuit
recently was settled out of court. The terms were not disclosed).
Waller of Cincinnati kept a diary of symptoms that developed after
she took Lariam in the summer of 1997. Her entry for May 3, 1999,
reads: "Scalp burning, gripping intensified into worst-ever headache."
On June 8 she noted "almost continuous scalp sensations of burning,
crawling, gripping, hole-boring through in one of several spots
von Joeden-Forgey, who went to Africa in 1995 as part of her doctoral
work at the University of Pennsylvania, described "this horrible
burning sensation in the back of my head, in my lower cranium, this
burning, constant burning."
a March e-mail from Nairobi, Kenya, psychiatrist Dr. Lorin Mimless
wrote of treating seven patients with what he said were clear Lariam
the cases he describes is a 32-year-old man he saw a year ago who
he said had no history of psychiatric problems and was on no other
medicine. He said the man became paranoid and over a two-day period
his problems "developed into a full-blown psychosis requiring hospitalization
in Britain. The patient on arrival tried to kill himself by hanging."
said he saw the man recently and "he still had significant psychiatric
symptoms -- depression, occasional paranoid thoughts when anxious,
and suicidal thoughts that would come and go not connected to the
depression. He could not explain them but they would come once or
twice a month, sometimes for a day, sometimes for a few hours. He
would attribute them to Lariam, although he always had the fear
they would not go away."
who formerly reviewed Lariam side-effect reports at Roche said he
now believes the company has been too hesitant to alert physicians
and consumers to side effects that emerged after a drug had been
has developed an attitude of not adjusting the information it supplies
to physicians and patients about the performance and safety characteristics
of their drugs," said Dr. Donald H. Marks, former associate director
of clinical research at Roche. Marks said he left Roche in 1991
to take a promotion to director at another company.
said there is "ample reason" to believe Lariam causes suicide. Marks
said Lariam can cause "spontaneous neurological activity" and "irritation
of certain sensitive areas inside the brain" that could lead to
suicidal behavior long after someone stops taking it.
did not respond to UPI's written questions about Marks' comments.
Alfaro, the Roche spokesman, said: "Roche takes the issue of safety
very seriously and is diligent in monitoring the safety of all its
studies of FDA data commissioned by UPI showed a far higher incidence
of problems that could lead to suicide in people taking Lariam than
in those taking doxycycline, an antibiotic recommended by the CDC
as another drug to prevent malaria.
authors said that because both drugs are recommended by the CDC
for prevention of malaria, a comparison of reported mental problems
among users of both drugs is valid.
said in a statement to UPI that suicide rates of patients taking
doxycycline and Lariam cannot be validly compared because most people
treated with doxycycline receive it for acute bacterial infection
-- a much shorter therapeutic regime -- and not for prevention of
also said doxycycline has its own drawbacks: it cannot be used in
children, sensitizes people to the sun, has to be taken daily while
Lariam is taken weekly, and causes anorexia, nausea and vomiting.
is the malaria preventive President Clinton was prescribed when
he traveled to India and Pakistan in early 2000.
of Bethesda, Md., and Fibonacci Group, a Philadelphia-based consulting
group, conducted two separate studies of FDA raw data. Both firms
do work with attorneys suing drug companies.
study for UPI, PharmaGenesis determined people taking Lariam were
five times more likely to have reported mental problems that could
lead to suicide than people taking doxycycline. In the other, Fibonacci
examined the FDA data and calculated the rate of side effects per
prescription. It found a 150 times greater rate of depression and
a 40 times greater rate of suicide attempts among Lariam users compared
with doxycycline users.
did not find a single successful suicide associated with doxycycline
in the past four years, even though doxycycline, an antibiotic,
is prescribed 25 times more often than Lariam, which is used only
for treatment and prevention of malaria. Lariam is prescribed some
350,000 times a year, doxycycline is prescribed 9 million times
a year for a variety of medical reasons, according to data from
IMS Health, a healthcare information company.
on drug side effects warned the FDA's data cannot solely be used
to draw conclusions about drug safety, but they agreed analyses
from 1997 forward are best because at that point the agency began
analysis found three reports involving suicide prior to 1997 were
"high probability," based on a review of the psychiatric side effects
reported in those patients.
documents said seven suicides were reported by the end of 1998 as
associated with Lariam use, including one in 1994, two in 1997 and
four in 1998.
and Lobel have said mental problems in those taking Lariam might
be related to increased stress during travel. Keith Altman of Fibonacci
Group said he thinks the 1997-2001 data debunk that assertion --
particularly considering the different prescription totals for the
looking at rates-per-prescription, you're talking about a 40 times
greater rate of suicide attempts in Lariam than in doxycycline,"
Altman said. "Look at depression: the rate of depression is 150
times greater in Lariam. I just can't see a 150-times-greater rate
of depression when you consider that a lot of these people are happy
they're going on a trip."
study in October 2001 in the peer-reviewed Clinical Infectious Diseases
journal showed 29 percent of travelers taking Lariam complained
of neuropsychiatric side effects and that 5 percent were so bothered
they quit taking the drug altogether. The "randomized controlled
trial" was done among 976 travelers in the field.
drug company, Glaxo-Wellcome, funded the study and used Lariam as
a control pill to gauge the safety of its own anti-malaria drug,
Malarone, approved by the FDA in July 2000. FDA data shows two suicides
reported among Malarone users.
the British army lieutenant colonel, said the Glaxo-Wellcome study
shows the U.S. government warnings for Lariam "need to be revised
urgently now that there is good evidence for the potential harms
also makes Accutane, the popular acne drug that has also been associated
with reports of suicide mainly among young people. In one high-profile
case in Florida, the mother of Charles Bishop filed suit against
Roche April 16, alleging Accutane made Bishop, 15, fly a Cessna
plane into a Tampa high-rise and kill himself in January.
and some drug experts have both said there is no concrete scientific
evidence to link Accutane to suicide. Unlike its approach with Lariam,
however, Roche in May 2000 put new language on the Accutane label
warning of suicide risks, almost 20 years after the FDA approved
the drug in 1982.
failure by Roche to provide adequate warning of Lariam side effects,
including suicide, was at the heart of the lawsuit filed by Linda
Perry in federal court in Ohio. The suit recently was settled. Charles
Perry, 54 and a father of seven with no history of mental illness,
took Lariam in 1998 during an African safari to celebrate his 30th
wedding anniversary with his wife, Linda, a nurse.
alleged the information provided by the pharmacy that filled their
Lariam prescription warned only of possible "nausea, diarrhea, stomach
upset, vomiting, dizziness or vision problems" and to "report difficulty
Perry contended that before her husband took the fourth pill, he
was hallucinating. She said after returning to Ohio, they followed
directions and took another four pills over the next four weeks.
But Charles Perry spiraled into psychosis. He was hospitalized in
the weeks before he killed himself with a shotgun in January 1999.
His psychiatrist filed a report with the FDA blaming the suicide
contended in court that there was nothing to prove Lariam can cause
suicide. "The proposition advanced by plaintiff here -- that Lariam
causes such profound psychotic episodes that suicide is a known
or knowable consequence of Lariam use -- is simply not supported
by competent medical and scientific literature," Roche lawyers wrote
in a court filing in January.
clinical study supports such a causal relationship. As such, it
is not generally accepted in the medical community that Lariam use
leads to suicide."
widow contends there is a connection. She said they would have stopped
taking Lariam if they had been clearly warned of the risks. In an
interview in the months after her husband's death, she said: "There
was absolutely nothing on the bottle, from the pharmacy or from
the health department that would have indicated that we should stop
© 2002 United Press