Curses, Madness, and Mefloquine
OLADIPO KUKOYI, M.D.
CAROLINE P. CARNEY, M.D., M.SC.
M efloquine is a quinoline-methanol compound struc-
turally similar to quinine. Because of its efficacy and
once-weekly dosing, mefloquine is a good choice for ma-
laria prophylaxis for travelers to areas with chloroquine-
resistant Plasmodium falciparum malaria. It is recom-
mended as the drug of choice by most authorities.1 It has
a wide volume of distribution, can cross the blood-brain
barrier, is extensively metabolized by the liver, and has a
half-life of 13–30 days.2 Mild neuropsychiatric symptoms,
such as vivid dreams, nightmares, and light-headedness
(described as an inability to concentrate), are common side
effects. Mefloquine has rarely been linked to more severe
mental status changes such as psychosis.3–5 This report
presents the case of a young woman who developed severe
psychosis after re-exposure to mefloquine and whose treat-
ment was complicated by sociocultural issues.
Case Report
Ms. A, a 25-year-old American woman of Korean descent
who is married to a Nigerian, had plans to travel to Nigeria
with her husband to visit his family. She had been to Ni-
geria once before for an extended period of time and had
taken mefloquine prophylaxis without problem. Ms. A had
no pertinent medical or psychiatric history and had no
known drug allergies. Her family history was not known,
as she had been adopted as an infant. She used no alcohol
or other substances. Her only other prescribed medication
was an oral contraceptive.
She started her once-weekly 250-mg mefloquine pro-
phylaxis the week before leaving for Nigeria. Four weeks
later, while in Nigeria, she developed bizarre paranoid de-
lusions accompanied by auditory and visual hallucinations.
She reported hearing conversations between Heaven and
Hell. She had delusions of reference related to television
and radio broadcasts. She claimed that a light bulb had
been stolen in the middle of the night. She became con-
Psychosomatics 44:4, July-August 2003
vinced that her husband was the Devil. She started to eat
from garbage cans, as she believed her food was being
poisoned.
Her husband’s emigration to the United States was
considered a sign of success in his home community. It
was proposed by her in-laws that people jealous of his suc-
cess had cast a spell on his wife to drive her insane. The
local culture included popular beliefs in the presence of
supernatural forces and in the ability of people to call on
powerful healing spirits. Ms. A’s in-laws, believing that she
had been cursed, took her to their church, where continuous
prayer and fasting commenced. After several days without
improvement in his wife’s symptoms, Ms. A’s husband sur-
reptitiously took her and their 3-year-old daughter and
boarded a flight back to the United States. The alleged
culprit who had cast the spell had been identified, and he
wanted to get as far away from her as possible. On the
transatlantic flight Ms. A became more agitated, hiding in
the bathroom with her daughter and muttering unintelligi-
bly. She was very fearful of her husband, still believing
that he was the Devil. The flight attendants gave Ms. A a
benzodiazepine, which sedated her, and the airport author-
ities were alerted. Her husband was initially held on sus-
picion of having abused his wife, but he was soon released
to join her in the Midwestern city where she was hospital-
ized. Specialists from the hospital’s infectious diseases,
neurology, dermatology, and psychiatry departments eval-
uated Ms. A, and the results of her workup were unre-
markable, except for slightly elevated liver transaminase
concentrations (40 U/liter for aspartate aminotransferase
and 44 U/liter for alanine aminotransferase). After infec-
tious, neurologic, and metabolic diseases were ruled out,
Received Nov. 13, 2002; accepted Dec. 13, 2002. From the Departments
of Psychiatry, Family Medicine, and Internal Medicine, University of
Iowa Carver College of Medicine; and the Department of Epidemi-
ology, University of Iowa College of Public Health, Iowa City. Address
reprint requests to Dr. Carney, 2-126 MEB/Psychiatry Research, Uni-
versity of Iowa Carver College of Medicine, Iowa City, IA 52242;
caroline-carney@uiowa.edu (e-mail).
Copyright 䉷 2003 The Academy of Psychosomatic Medicine.
339
Case Reports
the differential diagnosis was narrowed to drug-induced
psychosis versus new-onset bipolar illness. Ms. A was
treated with divalproex sodium, haloperidol, and benztro-
pine, but she had minimal change in her symptoms. Six
days later, she was transferred to a tertiary care hospital
closer to her home in another Midwestern city for contin-
ued care. On admission, she had psychomotor restlessness,
akathisia, and emotional lability. She was distressed by the
persistent delusions and hallucinations, and she indicated
that she wanted them to stop. Her mood was not elevated.
Her sleep and appetite were severely disturbed. The results
of a physical examination were remarkable for tachycardia,
old mosquito bites, and mild right upper quadrant tender-
ness. Haloperidol, divalproex sodium, and benztropine
were discontinued, and risperidone and lorazepam were in-
stituted in their place. A medical workup was further pur-
sued. The results of a magnetic resonance imaging scan of
the brain and magnetic resonance angiography were un-
remarkable. An EEG showed diffuse cerebral dysfunction.
Although her liver transaminase concentrations remained
elevated, she had negative serological tests for hepatitis A,
B, and C, and her blood count and thyroid functioning tests
were normal. Her potassium level of 2.9 was low, and this
deficit was corrected by intravenous infusion of potassium
chloride. An ultrasound of the right upper quadrant showed
mild fatty infiltration of the liver with small gallbladder
stones but no other abnormalities. Spinal fluid analysis was
unremarkable. A malaria smear was negative. A urine test
for pregnancy was negative.
An infectious diseases consultant concurred that Ms.
A’s symptoms were most likely secondary to mefloquine
and suggested finishing her prophylactic course with doxy-
cycline. She was hospitalized for 6 days, and by discharge
she had only mild referential and paranoid thinking, with
no other psychotic symptoms. She was discharged home
with a prescription for 1 mg of risperidone twice daily. At
follow-up 4 weeks later, she had no residual symptoms,
and the antipsychotic was stopped. She was symptom free
at 2-year follow-up.
Discussion
Ms. A’s symptoms were initially attributed to witchcraft,
consistent with prevailing local beliefs. Spiritual healing is
a parallel health care system in Nigeria, and many patients
are first taken to spiritual healers before an attempt is made
340
to access the biomedical health care system.6 This pattern
is particularly true in cases of psychiatric disorders, which
are believed by many to be caused by curses and therefore
to require a spiritual cure. In Ms. A’s case, this course of
action led to a delay in the initiation of appropriate medical
care, which likely did not affect her outcome but may have
affected the outcome if her condition had had an infectious
or vasculitis etiology. On arrival in the United States, her
husband was briefly held by the police, on the basis of the
prevailing belief that an agitated woman who was afraid of
her husband was likely to have been harmed by him. The
patient and her family had not been informed about the po-
tential side effects of mefloquine. At the 2-year follow-up,
her husband was still clinging to the belief that her symp-
toms were caused by witchcraft, while the patient only fog-
gily remembered the events that had happened 2 years ago.
Risk factors for psychosis associated with the use of
mefloquine that have been reported in the published case
reports include dosage, a family or personal past history of
neuropsychiatric disease, previous exposure to mefloquine,
use of psychotropic drugs within the last 2 months, con-
comitant use of alcohol and other medications, and female
gender;7 Ms. A had some of these risk factors.
Mefloquine appears to be a noncompetitive inhibitor
of both acetylcholinesterase and butyrylcholinesterase, and
this process is thought to explain some of its CNS effects.8
The general incidence of severe neuropsychiatric events
has been estimated to be 1 in 8,000 mefloquine users,
equivalent to 1 in 215 therapeutic users or 1 in 10,000–
15,000 prophylactic users.4 This rate is similar to the rate
of similar side effects described with chloroquine use.5
Psychotic symptoms generally resolve promptly with dis-
continuation of the drug, although reports of symptoms
persisting for as long as a year or more have been pub-
lished.9–11
Until the past decade, most CNS side effects were be-
lieved to be minor and few in number. The accumulating
data suggest that earlier estimates were conservative. In a
recent randomized, controlled trial in a heterogeneous
group of nonimmune Western travelers, the incidence rate
of neuropsychiatric side effects was 33%, with 6% of pa-
tients seeking medical advice.12 A recent review of 516
reports in the literature published between 1976 and 2000
suggested that a transient hepatocellular injury was possi-
bly the mechanism for the mefloquine-induced symptoms.
It is known that elevated transaminase concentrations are
commonly found in mefloquine users.7 Other agents that
are metabolized by the liver, including oral contraceptives
and alcohol, were found to be present in half of the patients
Psychosomatics 44:4, July-August 2003

with psychiatric side effects. One of the earliest reports of
suicidal ideation described a healthy Canadian who became
psychotic and suicidal when he drank half a bottle of
whisky with his dose of mefloquine and whose symptoms
resolved after he stopped drinking the alcohol.13 It is in-
teresting to note that his colleague, who drank the remain-
ing half-bottle of whisky but who was not taking an anti-
malarial, never developed psychiatric symptoms. Ms. A
was taking an oral contraceptive and had a persistent rise
in her transaminase concentrations that is consistent with
the aforementioned hepatocellular injury hypothesis.
Given that the symptoms of hepatocellular injury are non-
specific, a prospective trial testing this hypothesis would
be needed before this hypothesis can be widely accepted.
Mefloquine has recently received media attention be-
cause of a postulated link to suicide and homicide, includ-
ing the murders and suicides committed in the summer of
2002 by soldiers at Fort Bragg, N.C., who had taken me-
floquine.14,15 There are several antimefloquine web sites
References
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Psychosomatics 44:4, July-August 2003
Case Reports
and reports in the press of “mefloquine survivors.”16 The
manufacturer Roche has recently strengthened its label
warning to include a statement that suicides have been re-
ported among users of mefloquine, although the company
emphasizes that no relationship to drug administration has
been confirmed.2 The warning label recommends that pa-
tients with active depression or a history of major psychi-
atric disorders, such as anxiety disorders, psychotic disor-
ders, or depressive disorders, not take the drug for
prophylaxis. The company also warns that if symptoms of
acute anxiety, depression, restlessness, or confusion occur,
the medicine should be stopped, as such symptoms could
constitute a prodrome to a more serious event.2 As yet, it
cannot be reliably predicted which patients may develop
serious psychiatric symptoms while taking mefloquine,
thus limiting the effectiveness of these recommendations.
The authors thank Aminat B. Kukoyi, Pharm.D., for
her contributions to this report.
9. Potasman I, Berry A, Seligmann H: Neuropsychiatric problems in
2,500 long-term young travelers to the tropics. J Travel Med 2000,
7:5–9
10. Borruat FX, Nater B, Robyn L, Genton B: Prolonged visual illu-
sions induced by mefloquine (Lariam): a case report. J Travel Med
2001; 8:148–149
11. Miller V: Bradley overcame side effects of anti-malaria drug. Iowa
City Press-Citizen, Sept 25, 2002, p 1
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Clarke PD, Toovey S, Knobloch J, Nothdurft HD, Shaw D,
Roskell NS, Chulay JD (Malarone International Study Team):
Atovaquone-proguanil versus mefloquine for malaria prophylaxis
in nonimmune travelers: results from a randomized, double-blind
study. Clin Infect Dis 2001; 33:1015–1021
13. Whittes RC, Sanginur R: Adverse reaction to mefloquine associ-
ated with ethanol ingestion. Can Med Assoc J 1993; 152:515–517
14. Benjamin M, Olmsted D: UPI Investigates: Lariam and Suicide.
http://www.upi.com/print.cfm?StoryID⳱20052002-054200-9601r
15. Burns R: Army sending health experts to Fort Bragg to look for
links to spousal killings. Detroit News, Aug 24, 2002. http://www.
detnews.com/2002/nation/0208/25/nation-569998.htm
16. Mefloquine References. Bloomington, Indiana University. http://
www.indiana.edu/˜primate/lariam.html
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