Research ArticleRegular Article

Psychiatric Side Effects of Mefloquine: Applications to Forensic Psychiatry

Elspeth Cameron Ritchie, Jerald Block and Remington Lee Nevin
Journal of the American Academy of Psychiatry and the Law Online June 2013, 41 (2) 224-235;

Abstract

Mefloquine (previously marketed in the United States as Lariam®) is an antimalarial medication with potent psychotropic potential. Severe psychiatric side effects due to mefloquine intoxication are well documented, including anxiety, panic attacks, paranoia, persecutory delusions, dissociative psychosis, and anterograde amnesia. Exposure to the drug has been associated with acts of violence and suicide. In this article, we discuss the history of mefloquine use and describe plausible mechanisms of its psychotropic action. Mefloquine intoxication has not yet been successfully advanced in legal proceedings as a defense or as a mitigating factor, but it appears likely that it eventually will be. Considerations for the application of claims of mefloquine intoxication in forensic settings are discussed.

Mefloquine is a 4-quinolinemethanol antimalarial first synthesized in the early 1970s1 by researchers affiliated with the United States military's Walter Reed Army Institute of Research (WRAIR).2 The drug's development was the culmination of a 10-year drug discovery effort, during which time more than 300,000 compounds were screened for their antimalarial properties.2 Of a handful of compounds active against chloroquine-resistant strains of Plasmodium falciparum malaria that demonstrated seemingly favorable toxicity profiles,2 mefloquine (initially known as WR 142490) was selected for further development and testing in humans.3

To secure the drug's commercial manufacture and its continued availability, intellectual property rights and research related to mefloquine were transferred at no cost to F. Hoffman-La Roche Ltd. (Roche).4 The company pursued regulatory approval and marketed the drug to civilian travelers in the United States under the trade name Lariam® after its initial Food and Drug Administration (FDA) licensure in 1989.5 Owing to its efficacy, presumed safety, and convenient dose schedule that facilitated prophylactic use, mefloquine was soon identified as the drug of choice6,7 for use by U.S. travelers to areas of chloroquine-resistant malaria at a dose of one 250-mg tablet weekly.8,9

Early prelicensure studies on mefloquine were conducted predominantly among male prisoners,2,10 military personnel,5,11,12 and subjects in third-world countries.11,13,14 Although vertigo and nausea were commonly reported in these early trials, in the absence of sensitive and unbiased prospective reporting15 the drug was considered to be largely free of the severe psychiatric side effects that had characterized the related antimalarial compounds chloroquine16,17 and quinacrine.18,19

The purported safety of mefloquine was so well established that when reports of severe psychiatric side effects, including amnesia, confusion and psychosis, first emerged in the literature following the drug's early European licensure,20,–,23 these symptoms were frequently dismissed as coincidental24 or were later attributed by influential authors to the stresses of overseas travel, recreational drug use, or pre-existing or latent mental illness.25,–,27 Despite continued reports in the literature of severe psychiatric side effects following the drug's U.S. licensure, it was only in 2001, after the drug had been in widespread use for over 15 years and the first formal blinded and controlled prospective studies were conducted in a representative civilian population,28,29 that mefloquine's potent psychotropic capability became more widely appreciated. Results of these and subsequent trials have since demonstrated that the incidence of specific neuropsychiatric symptoms including nightmares, anxiety, and psychosis during prophylactic use are each at least 100 times more common28,30,31 than has been previously reported.32,–,35

More recent reports of suicide31,36,37 and suicidal ideation,38,–,47 and studies linking the drug to acts of violence48 have raised additional safety concerns.49,50 As public awareness of the potential dangers of mefloquine have grown,51,–,54 and civil litigation related to the drug has increased,55,56 mefloquine has lost significant market share in the United States57 in favor of safer and better tolerated antimalarial medications.28 Today, mefloquine is no longer considered the drug of choice, either in therapy or in chemoprophylaxis of malaria.58 Roche recently withdrew Lariam® from the U.S. market, although generic forms remain widely available.59

Use of mefloquine had previously been encouraged among United States overseas diplomatic staff60 and Peace Corps volunteers.8,25 Mandatory use of the drug was also broadly directed among deployed U.S. military service members.61,62 Recently, growing awareness of the drug's inappropriate prescribing33,34,63 to service members with mental health contraindications,39,62,64 including those with a history of posttraumatic stress disorder and traumatic brain injury,34,63 and poor documentation of its prescribing64 has significantly diminished the utility of mefloquine in deployed settings.65 As a result, today, mefloquine is considered the drug of last resort by U.S. military policy,66,67 to be used only when doxycycline and the combination drug atovaquone/proguanil (Malarone) cannot be used.58,65,68,69

Because the drug is associated with an increased risk of violence48 and psychiatric symptoms, users of mefloquine may be likely to be encountered in the civil or criminal legal systems. Current or past users of the drug may claim that exposure has caused physical or mental injury. The psychiatric effects of the drug may be featured in future forensic evaluations, and thus forensic psychiatrists may be called to comment on the drug's effects. In this review, the psychiatric side effects of mefloquine and the putative pathophysiology of these effects are discussed, and specific forensic concerns are considered. This information is anticipated to be useful when forensic psychiatrists are asked to consult on cases involving military personnel and veterans, civilian travelers, and employees on overseas assignment who claim legal implications from their exposure to the drug.

Psychiatric Side Effects

According to the current U.S. mefloquine package insert,70 psychiatric symptoms associated with prophylactic mefloquine use include abnormal dreams, anxiety, paranoia, agitation, confusion, memory impairment, and hallucinations. Despite over 20 years of licensed use, the underlying pathophysiology of these side effects has been poorly understood.71 Recent insights37,40,72 suggest that these side effects result directly from the accumulation of the drug within and acting on specific targets in the brain. In this section, the putative pathophysiology of mefloquine intoxication is described in further detail following a discussion of its typical clinical presentation.

Clinical Presentation

Case reports suggest that mefloquine intoxication may begin with a variable prodrome which may present with personality change,40 unease,40 anxiety,73,–,75 phobias,76,77 and a sense of impending doom and restlessness.76 These prodromal symptoms may progress to outright paranoia,38,46,73,74,78,–,81 delusions,46,47,78,81 magical thinking,79 persecutory mania,73,78,81,–,83 restlessness,84 aggression,22 and panic attacks.44,85,86 Confusion38,39,87,–,91 and symptoms of depression38,39,44,47,92 have also been reported. Such symptoms have been reported after only a single 250-mg tablet40,93,–,96 and may progress in severity with subsequent doses.40,96

Since the drug's initial licensing in 1989,97 the U.S. mefloquine package insert has warned that “if signs of unexplained anxiety, depression, restlessness, or confusion are noticed, these may be considered prodromal to a more serious event.” The package insert further cautions that should these prodromal symptoms occur, “[i]n these cases, the drug must be discontinued.”

Many, but not all,96 users of mefloquine will correctly discontinue use of the drug at the onset of the unsettling prodromal symptoms of intoxication.28 However, those with a history of mental illness may erroneously attribute such symptoms to their preexisting condition,39 or have them obscured or confounded by psychotropic drug use.39 Since 2002, mefloquine has therefore been contraindicated among those with a current or recent history of psychiatric illness,61,62,97 as these users may be at greater risk of failing to discontinue mefloquine as directed. The current package insert cautions that mefloquine “should not be prescribed for prophylaxis in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders.”70

It is tempting to speculate that the “more serious event” referenced in the package insert is a euphemism for psychosis. Mefloquine psychosis was characterized as early as 1983,89 and its early descriptions were consistent with the psychosis caused by related antimalarial compounds.98,–,100 Mefloquine psychosis frequently includes auditory40,73,80 or true visual hallucinations,22,38,39,80,101 frequently involving religious or morbid themes.102 Auditory hallucinations typically feature voices that may be incoherent or mumbling.40,102 Some individuals report a sense of the presence of a nearby nondescript figure.40 Olfactory hallucinations103 have also been reported. The often vivid and terrifying nature of the hallucinations produced by mefloquine are illustrated by an early unindexed case report, similar to at least one other published report,41 describing a man who jumped from his hotel room in the false belief that his room was on fire. Of note, vivid dreams or horrific, terrifying nightmares,39,104 also frequently reported by users of mefloquine, are characterized as having “Technicolor clarity” and being “vividly remembered days later,”5 suggesting that these may also be prodromal to or inform later symptoms of psychosis. Hypnopompic hallucinations and sleep paralysis have also been reported.39

Mefloquine psychosis may be distinguished from schizophrenia and certain other forms of psychiatric illness in that it may feature prominent characteristics of dissociation.105 Symptoms of derealization40,103 and depersonalization,40,93,101 compulsions toward dangerous objects,106 and morbid curiosity about death43 may accordingly underlie reports of seemingly spectacular and impulsive36 suicide, suicide attempt,41 and parasuicidal behavior40 associated with the use of mefloquine.

An additional distinguishing feature reported with mefloquine psychosis is impairment of short-term memory. Consistent with prodromal symptoms of confusion, this deficit may be marked by initial attentional disturbances, with later insufficiencies in short-term working and spatial memory,40 verbal memory,38 and temporospatial disorientation.39,40,101,106,–,108 With preserved implicit memory, those affected by mefloquine intoxication may take part in highly complex and directed actions74 and may even demonstrate improved psychomotor performance109 during learned tasks, but may later experience profound anterograde amnesia to actions and events.20,106,107

Pathophysiology

These diverse psychiatric side effects may now be understood as manifestations of a single underlying pathophysiological process best characterized as a toxic limbic encephalopathy. The limbic system, which includes the hippocampus and amygdala, is one of the oldest portions of the brain phylogenetically and is considered the system responsible for preservation of the self and the species via the generation of emotions, reward mechanisms, sexual drive, and the formation of long-term memories, including fear memory.110

The current U.S. package insert for mefloquine warns of a risk of “encephalopathy of unknown etiology.” However, unlike the more generalized toxic encephalopathies, including hepatic encephalopathy,111,112 the acute effects of mefloquine appear to affect limbic and related structures predominantly, while relatively sparing much of the cortex.58 As a result, clinically, the symptoms of limbic encephalopathy resulting from mefloquine intoxication appear very similar to those observed with the various forms of limbic encephalitis113 and limbic epilepsy.114 Although the underlying molecular targets are distinct and while the etiology of limbic encephalitis and epilepsy are variable, a pathophysiological mechanism shared in common among these conditions appears to be a dysfunction of limbic inhibitory interneurons, which contributes, among other effects, to dysregulated limbic dopaminergic neurotransmission.58,115

Mefloquine is highly lipophilic116 and may accumulate in the limbic system117 relative to other areas of the brain,118,119 where it acts to disrupt a form of direct intercellular electrical communication120 that is essential for coordinated inhibitory control. Gap junction channels, composed of proteins called connexins, are involved in coordinated synchronization of neuronal activity, particularly of inhibitory interneurons121 found throughout the limbic system.122 At concentrations consistent with limbic accumulation, mefloquine has been demonstrated to inhibit electrical coupling of neurons with effects on limbic inhibition123,124 and resultant mesolimbic dopaminergic tone.125,126 In dysregulating limbic inhibition, this mechanism may mimic to some degree what is also seen with intoxication by phencyclidine (PCP),127 ketamine,128 and other dissociative amnestics and hallucinogens,129,–,131 whose effects share many schizomimetic properties in common with those of mefloquine intoxication and limbic encephalitis.

In addition to a dose-dependent progression, symptoms of mefloquine intoxication may exhibit a waxing and waning presentation. It is tempting to speculate that in some cases, this presentation may reflect the clinical course of an underlying limbic status epilepticus114 or limbic seizure132,–,134 kindled by the drug.135 In this regard, it is reasonable to speculate further that simultaneous use of alcohol or certain other drugs together with mefloquine could lower limbic seizure threshold or cause a further dysregulation of limbic inhibitory interneurons,125 contributing to a risk of sudden potentiation. Reports describing seizures and psychotic reactions immediately following alcohol ingestion are well represented in the literature,42,136,137 and alcohol use is frequently raised as a potential confounding factor in cases of severe reactions to the drug.27,138

Careful neuropsychological testing reveals that mefloquine intoxication may induce very specific deficits, including in word finding, processing speed, verbal learning, and auditory and visual memory38,39,40 broadly suggestive of dysfunction of the hippocampus, as is observed to be caused by mefloquine in experimental studies.139,–,141

While characteristically affecting limbic centers, the effects of mefloquine intoxication may extend beyond the limbic system. As is frequently reported with limbic encephalitis,142,143 limbic brain injury,144 and intoxication from PCP and ketamine,127,128 mefloquine intoxication may also result in complex behavioral changes, including social and behavioral disinhibition,78,101 irritability,39 heightened or altered sexual libido,81,144 and impaired judgment,40 suggestive of involvement of the frontal lobe or the prefrontal cortex. Similarly, reports of very complex visual illusions distinct from hallucinations40,80,85 suggest extralimbic involvement encompassing the visual pathways. Reports of multifocal myoclonus145,146 and deficits in motor speed38,39,40 and motor learning147 are suggestive of further involvement of the basal ganglia and inferior olive.

As with certain forms of limbic encephalitis,142,148,149 limbic encephalopathy resulting from mefloquine intoxication may also progress to involve the brainstem,40 and consequently users of mefloquine may experience numerous physical symptoms, including nausea and emesis, which are broadly referable to interconnected limbic and brainstem centers.150 Additional probable brainstem symptoms reported with mefloquine use include vertigo, disequilibrium, nystagmus, photophobia, and accommodative dysfunction suggestive of involvement of the vestibuloocular nuclei40,70,151; paresthesias of the extremities and face,43,45,70,152 suggestive of posterior column153 or trigeminal nerve nuclei involvement; autonomic dysfunction including temperature sensitivity,39 bradycardia, bradypnea, and postural orthostatic tachycardia syndrome45,154,155; and gastrointestinal complaints including abdominal pain,156 esophageal dysmotility, anorexia,45 and diarrhea, signaling possible involvement of the vagus nerve dorsal motor nuclei. Rare reports of anticholinergic syndrome157 may indicate further brainstem involvement.

As is observed in cases of limbic encephalitis,158 PCP toxicity,159 and limbic seizure,160 limbic and associated brainstem encephalopathy may also cause chronic symptoms arising from permanent neurotoxicity40,158 and neurodegeneration of limbic and brainstem centers.160 While long-term follow up of mefloquine intoxication is only rarely documented in the literature,45 vertigo lasting as long as 18 months has been reported.94 Supporting experimental findings of mefloquine neurotoxicity153,161,–,163 are observations that related antimalarial compounds99,164,–,168 cause a multifocal pattern of microscopic lesions, visible on careful histopathologic study, that affect numerous brain and brainstem regions, but are typically too small to be visualized with conventional magnetic resonance imaging (MRI).40 Mefloquine has itself recently been demonstrated to induce similar microscopic lesions in the brainstem of animal models.153

Forensic Applications

Mefloquine has been implicated in many cases of aggressive violence169,–,172 and in cases of behavior change linked to nonviolent criminal conduct,173,174 but we know of no case in which exposure to the drug has been successfully used as a defense or raised to mitigate criminal responsibility at trial. Similarly, mefloquine has been frequently linked to suicide and self-harm,30,169,175,–,177 but to the authors' knowledge this association has never been a factor in any successful and publicly documented legal action. In addition, both military and civilian users of mefloquine have advanced claims of harm and damages in civil courts,55,56,178 but the outcomes of many of these cases have not been made publicly available.

Historically, the forensic application of a claim of mefloquine intoxication has been made challenging by missed diagnosis and the attribution of psychiatric effects to other causes.178 These problems may now be ameliorated by an improved understanding of the unique clinical presentation of mefloquine intoxication and by insight into the pathophysiology of related neurotoxic effects.40 Successful forensic application of a claim of mefloquine intoxication today rests on establishing that plausible exposure to the drug has occurred and in demonstrating the onset of characteristic or pathognomonic signs or symptoms of intoxication and subsequent neurotoxicity, in temporal association to exposure and to the reasonable exclusion of other plausible etiologies, by record review, careful clinical history, or neuropsychiatric evaluation and in consultation with other medical specialists.

Exposure

The forensic application of a claim of mefloquine intoxication begins with establishing plausible evidence of exposure. In cases where clear documentation of individual prescribing exists in the medical record or if an individual has retained individually labeled medication, exposure may be readily proven or conceded. However, as mefloquine is commonly mass prescribed as a public health measure,65 often without individualized documentation or labeling, unequivocal evidence of exposure may frequently be unavailable. In U.S. military settings, where individualized documentation may be poor64 and widespread experimental use before licensure is known to have occurred,2,5,12 presumptive evidence of exposure may rest on the individual's reporting a reliable history of taking the drug and of being assigned to a military unit to which the drug was issued by policy or procedure,62 evidence of which may on occasion be publicly available or may be found in individual service records.

In cases of individual travelers for whom records have been misplaced or are not available, presumptive evidence of exposure may be established by a process of ruling out the prescribing of alternative drugs as plausible options. For example, mefloquine exposure should be considered highly probable among U.S. travelers who report a reliable history of taking a single tablet weekly9 for malaria prophylaxis during travel to malaria-endemic areas with documented chloroquine resistance,3,35 where use of weekly chloroquine would have been inappropriate according to prevailing recommendations65 and published standards of care.179,–,181

In cases of more recent use where exposure remains in contention, demonstration of the drug or its metabolite in body fluids may be required. Owing to the drug's exceptionally long excretion half-life of approximately one month,182,183 sensitive testing may provide direct evidence of exposure, even many months after final use. Because of its lipophilicity116 and its recycling within the enterohepatic circulation, mefloquine may be excreted unchanged in the feces12 and also may be found in the gastric juices and bile. As a result of the drug's accumulation in tissue,12 it also may remain readily detectable at low concentrations in serum.183 The various hydrophilic metabolites of mefloquine182 may also be found at low concentrations in urine, bile, feces, and serum.12 Testing for such compounds is readily available at analytic reference laboratories using established techniques.12,184

Mefloquine may also be occasionally detected in the cerebrospinal fluid,21,185 although cerebrospinal fluid concentrations correlate poorly with concentrations in other compartments,21,24,186 and cerebrospinal fluid186 and serum concentrations themselves correlate poorly with brain accumulation119,187 and with propensity to psychiatric effects.24,188,189 Owing to the marked heterogeneity of mefloquine neuropharmacokinetics,190 which remain poorly understood but are most likely subject to multifactorial genetic191,192 and pharmacologic influences,193,194 any demonstration of mefloquine or its metabolite in any compartment of body fluid should be considered sufficient evidence of exposure and hence of potential brain accumulation and plausible intoxication.

Forensic Evaluation

While the unique presentation of mefloquine intoxication has been clinically well characterized in the present review, where exposure to mefloquine has been established, it is appropriate for the forensic psychiatrist to consider the diagnosis only when other psychiatric, medical, and substance-induced etiologies can be reasonably excluded as more probable causes. Advancing a defensible claim of mefloquine intoxication may therefore require the collaborative involvement of other medical specialists in addition to conventional neuropsychiatric evaluation, so as to rule out confidently other plausible etiologies, including those caused by other intoxicants and disease states. Careful record review, clinical history, and appropriate consultation, are essential for improving the specificity and sensitivity of the diagnosis.

As the characteristic limbic symptoms of mefloquine intoxication may closely mimic those caused by PCP, ketamine, and other dissociative amnestics and hallucinogens, the forensic psychiatrist considering a claim of mefloquine intoxication should address the possibility of voluntary or involuntary intoxication by these substances. Similarly, consultation with neurology should be considered to rule out closely related conditions such as limbic encephalitis or prior clinical history of limbic seizure, which in certain cases may also confound the diagnosis of mefloquine intoxication. While EEG is typically normal after both asymptomatic administration of mefloquine195 and after some cases of mefloquine intoxication,41,101 the presence of deep epileptiform or other abnormal activity,20,84,107,137,186,196,197 in the absence of a clinical history of limbic seizure disorder, strongly supports the diagnosis of mefloquine intoxication or neurotoxicity.

In the absence of a clinical history of central injury or neurologic disorder, certain brain or brainstem findings, including persistent vertigo or disequilibrium,40 or certain visual disorders85 that develop subsequent to mefloquine exposure should be considered pathognomonic of mefloquine neurotoxicity. With appropriate history, these symptoms strongly support a claim of preceding intoxication. Specialty consultation with neuro-optometry, neuro-otology, or ear, nose, and throat specialists, with a particular focus on identifying central nervous system injury, should therefore be considered an invaluable component of the forensic evaluation, particularly in individuals previously considered for a diagnosis of somatoform, conversion, malingering, or personality disorder, which the complex signs and symptoms of mefloquine neurotoxicity may mimic or be mistaken for on casual evaluation.40

Routine brain imaging, including MRI, would be expected to be normal in most cases of mefloquine intoxication and neurotoxicity40 and should not be considered essential for diagnosis, although such studies are useful, in that they may help to rule out potential confounding etiologies such as mass effect and stroke. Similarly, limited reports of positron emission tomography (PET) studies in cases of mefloquine intoxication have shown normal results,137 but both PET and other functional imaging modalities may hold promise as additional experience is gained. Similarly, as the resolution of MRI improves to encompass the visualization of submillimeter lesions, conventional imaging may also hold promise. In this manner, histopathological findings at autopsy of characteristic multifocal brain or brainstem lesions, in the absence of other plausible etiologies, would also be pathognomonic of mefloquine neurotoxicity.

Among the challenges faced by the forensic psychiatrist in advancing a claim of mefloquine intoxication, even when other plausible conditions have been confidently excluded, is that many of its characteristic or pathognomonic signs and symptoms may remit with time.40 Delays inherent to the legal system may therefore rob the traditional neuropsychiatric examination of much of its utility and sensitivity when conducting a forensic evaluation on an individual with mefloquine exposure. Detailed record review or the taking of a very careful clinical history may overcome some of these limitations by helping to identify the characteristic or pathognomonic signs and symptoms of intoxication or of subsequent neurotoxicity, in temporal association with exposure. As short-term memory loss and anterograde amnesia may limit the sensitivity of self-reported history,101 obtaining collateral information from friends and family members40,46,101 and from fellow travelers24,46 or service members39 may be very helpful in this regard.

The presence of comorbid conditions may create a challenge for the forensic psychiatrist in evaluating a claim of mefloquine intoxication. For example, it is now well established that symptoms of mefloquine intoxication may confound the diagnosis of posttraumatic stress disorder and traumatic brain injury.65 In certain cases, particularly those involving U.S. service members or veterans in whom these conditions may be common or may not be ruled out, the combination of certain symptoms on careful history, including auditory, visual, or olfactory hallucinations; confusion; and anterograde amnesia, developing in proper temporal relation to exposure, may aid in establishing the diagnosis of mefloquine intoxication to a reasonable degree of certainty, even in the presence of these comorbid conditions.

For illustrative purposes, we refer readers to a representative case of mefloquine intoxication published by United Press International.173,174

Conclusions

After 40 years of experimental and licensed use where the intoxicating properties of mefloquine were poorly appreciated, the drug now appears to have significant forensic importance. As public and professional awareness and understanding grows of the drug's significant psychotropic and neurotoxic potential, the prior use of mefloquine is nearly certain to get increasing attention within criminal, civil, and military courts. In cases involving suicide, homicide, and other acts of violence or criminal conduct associated with mefloquine exposure, or in cases where a litigant alleges that exposure to mefloquine caused harm, the forensic psychiatrist may be called on to provide expert testimony at trial. In all cases, the relationship between the drug's administration and the symptoms in question must be carefully evaluated and the temporal relationship adequately established,198 to assign causation confidently. The pathophysiological insights presented in this review will aid the forensic psychiatrist in conducting an evaluation and in securing appropriate consultation in support of this goal.

As evidence is increasingly clear that use of mefloquine is associated with a risk of long-term injury and harm, as well as death of self or others, so long as the drug remains licensed for use, physicians who continue to prescribe it must exercise caution to minimize potential liability. Such care includes implementing careful screening for contraindications and ensuring consideration of alternative medications. The insights of the present review also emphasize the critical importance of thoroughly documenting patient education should mefloquine be prescribed, including informing patients of those prodromal symptoms that should compel them to discontinue the medication immediately and seek medical assistance.96 However, as mefloquine intoxication that adversely affects decision-making may occur after only a single 250-mg tablet,40 and as the onset of psychosis may take place suddenly and even without prodromal symptoms, such education may minimize, but will clearly not eliminate,96 the risk of acute harm and subsequent neurotoxicity associated with the drug.

Our evolving experience with mefloquine raises questions about the potential for lasting behavioral effects from other antimalarial medications, including those presently under development,199 as well as from those long assumed to be benign. Our experience with mefloquine reemphasizes that many decades may pass before the dangers of a drug are widely appreciated.10,186 In the particular case of mefloquine, the reasons for this delay, including those related to the unusual circumstances of its development and initial testing200 and its frequent use among individuals with limited personal autonomy and within highly regimented organizations, would clearly benefit from further exploration.

Acknowledgments

The authors thank Ms. Danielle Feldman, MSPH, of the Henry M. Jackson Foundation, for her assistance in directing the authors to many of the manuscripts referenced in this report, and Sergeant First Class Georg-Andreas Pogány, U.S. Army (Retired), for his helpful review of the vignette and for his efforts in helping to raise awareness of the concerns referenced in this report.

Footnotes

  • Disclosures of financial or other potential conflicts of interest: Dr. Nevin has served as paid and pro bono consultant to attorneys representing litigants advancing claims of harm from exposure to mefloquine.

References

  1. 1.↵
    1. Ohnmacht CJ,
    2. Patel AR,
    3. Lutz RE
    : Antimalarials. 7. Bis(trifluoromethyl)-(2-piperidyl)-4-quinolinemethanols. J Med Chem 14:926–8, 1971
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Maugh TH
    : Malaria drugs: new ones are available, but little used. Science 196:415, 1977
    OpenUrlFREE Full Text
  3. 3.↵
    1. Fernex M
    : Urgent need to develop new antimalarials (in German). Schweiz Rundsch Med Prax 70:1025–32, 1981
    OpenUrlPubMed
  4. 4.↵
    1. Enserink M
    : Malaria researchers wait for industry to join fight. Science 287:1956–8, 2000
    OpenUrlFREE Full Text
  5. 5.↵
    1. Boudreau E,
    2. Schuster B,
    3. Sanchez J,
    4. et al
    : Tolerability of prophylactic Lariam regimens. Trop Med Parasitol 44:257–65, 1993
    OpenUrlPubMed
  6. 6.↵
    1. White NJ
    : Mefloquine. BMJ 308:286–7, 1994
    OpenUrlFREE Full Text
  7. 7.↵
    1. Macarthur JR,
    2. Parise ME,
    3. Steketee RW
    : Letter to the Editor. Am J Trop Med Hyg 66:445, 2002
    OpenUrlFREE Full Text
  8. 8.↵
    1. Lobel HO,
    2. Bernard KW,
    3. Williams SL,
    4. et al
    : Effectiveness and tolerance of long-term malaria prophylaxis with mefloquine: need for a better dosing regimen. JAMA 265:361–4, 1991
    OpenUrlCrossRefPubMed
  9. 9.↵
    Centers for Disease Control and Prevention (CDC): Change of dosing regimen for malaria prophylaxis with mefloquine. MMWR 40:72–3, 1991
    OpenUrlPubMed
  10. 10.↵
    1. Burke BM
    : Tragic time-lag. New Sci150:51, 1996
    OpenUrl
  11. 11.↵
    1. Dixon KE,
    2. Williams RG,
    3. Pongsupat T,
    4. et al
    : A comparative trial of mefloquine and fansidar in the treatment of falciparum malaria: failure of fansidar. Trans R Soc Trop Med Hyg 76:664–7, 1982
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Sweeney TR
    : The present status of malaria chemotherapy: mefloquine, a novel antimalarial. Med Res Rev 1:281–301, 1981
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Hall AP
    : The treatment of malaria. BMJ 1:323–8, 1976
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Heimgartner E
    : Practical experience with mefloquine as an antimalarial (in German). Schweiz Rundsch Med Prax 75:459–62, 1986
    OpenUrlPubMed
  15. 15.↵
    1. Rønn AM,
    2. Rønne-Rasmussen J,
    3. Gøtzsche PC,
    4. et al
    : Neuropsychiatric manifestations after mefloquine therapy for Plasmodium falciparum malaria: comparing a retrospective and a prospective study. Trop Med Int Health 3:83–8, 1998
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Rab SM
    : Two cases of chloroquine psychosis. BMJ 1:1275, 1963
    OpenUrlFREE Full Text
  17. 17.↵
    1. Rockwell DA
    : Psychiatric complications with chloroquine and quinacrine. Am J Psychiatry 124:1257–60, 1968
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Kingsbury AN
    : Psychoses in cases of malaria following exhibition of Atebrin. Lancet 2:979–87, 1934
    OpenUrl
  19. 19.↵
    1. Mergener JC
    : Psychosis following administration of quinacrine hydrochloride for malaria; neuropsychiatric study of a case. War Med (Chic 1941) 8:250–52, 1945
    OpenUrl
  20. 20.↵
    1. Lapras J,
    2. Vighetto A,
    3. Trillet M,
    4. et al
    : Transient disorders of memory after a malaria attack: caused by mefloquine (in French)? Presse Med 18:776, 1989
    OpenUrlPubMed
  21. 21.↵
    1. Rouveix B,
    2. Bricaire F,
    3. Michon C,
    4. et al
    : Mefloquine and an acute brain syndrome. Ann Intern Med 110:577–8, 1989
    OpenUrlPubMed
  22. 22.↵
    1. Stuiver PC,
    2. Ligthelm RJ,
    3. Goud TJ
    : Acute psychosis after mefloquine. Lancet 2:282, 1989
    OpenUrlPubMed
  23. 23.↵
    1. Björkman A
    : Acute psychosis following mefloquine prophylaxis. Lancet 2:865, 1989
    OpenUrlPubMed
  24. 24.↵
    1. Bem JL,
    2. Kerr L,
    3. Stuerchler D
    : Mefloquine prophylaxis: an overview of spontaneous reports of severe psychiatric reactions and convulsions. J Trop Med Hyg 95:167–79, 1992
    OpenUrlPubMed
  25. 25.↵
    1. Lobel HO
    : Adverse health events and malaria prophylaxis. Healthwise: A Newsletter for Peace Corps Medical Officers Worldwide 5:3–4, 1996
    OpenUrl
  26. 26.↵
    1. Schlagenhauf P
    : Mefloquine for malaria chemoprophylaxis 1992-1998: a review. J Trav Med 6:122–33, 1999
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Schlagenhauf P,
    2. Steffen R
    : Neuropsychiatric events and travel: do antimalarials play a role? J Trav Med 7:225–6, 2000
    OpenUrlPubMed
  28. 28.↵
    1. Overbosch D,
    2. Schilthuis H,
    3. Bienzle U,
    4. et al
    : Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. Clin Infect Dis 33:1015–21, 2001
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    1. van Riemsdijk MM,
    2. Sturkenboom MCJM,
    3. Ditters JM,
    4. et al
    : Atovaquone plus chloroguanide versus mefloquine for malaria prophylaxis: a focus on neuropsychiatric adverse events. J Clin Pharm Ther 72:294–301, 2002
    OpenUrl
  30. 30.↵
    1. Jacquerioz FA,
    2. Croft AM
    : Drugs for preventing malaria in travelers. Cochrane Database Syst Rev Cd006491, 2009
  31. 31.↵
    1. Meier CR,
    2. Wilcock K,
    3. Jick SS
    : The risk of severe depression, psychosis or panic attacks with prophylactic antimalarials. Drug Saf 27:203–13, 2004
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Weinke T,
    2. Trautmann M,
    3. Held T,
    4. et al
    : Neuropsychiatric side effects after the use of mefloquine. Am J Trop Med Hyg 45:86–91, 1991
    OpenUrlAbstract/FREE Full Text
  33. 33.↵
    Department of the Army Office of the Surgeon General: Memorandum. Subject: Updated health care provider information on use of mefloquine hydrochloride (Lariam®) for malaria prophylaxis. October 3, 2002. Available at http://www.pdhealth.mil/downloads/Mefloquine_Hyrochloride_Use.pdf. Accessed June 13, 2012
  34. 34.↵
    Department of the Army Office of the Surgeon General: Memorandum. Subject: Updated guidance on use of mefloquine (Lariam®) for malaria prophylaxis. February 2, 2009. Available at https://www.pdhealth.mil/downloads/DASG_Memorandum.pdf. Accessed June 13, 2012
  35. 35.↵
    1. Freedman DO
    : Malaria prevention in short-term travelers. N Engl J Med 359:603–12, 2008
    OpenUrlCrossRefPubMed
  36. 36.↵
    1. Jousset N,
    2. Rougé-Maillart C,
    3. Turcant A,
    4. et al
    : Suicide by skull stab wounds: a case of drug-induced psychosis. Am J Forensic Med Pathol 31:378–81, 2010
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Nevin RL
    : Hallucinations and persecutory delusions in mefloquine-associated suicide. Am J Forensic Med Pathol 33:e8, 2012
    OpenUrlPubMed
  38. 38.↵
    1. Javorsky DJ,
    2. Tremont G,
    3. Keitner GI,
    4. et al
    : Cognitive and neuropsychiatric side effects of mefloquine. J Neuropsychiatry Clin Neurosci 13:302, 2001
    OpenUrlCrossRefPubMed
  39. 39.↵
    1. Peterson AL,
    2. Seegmiller RA,
    3. Schindler LS
    : Severe neuropsychiatric reaction in a deployed military member after prophylactic mefloquine. Case Reports in Psychiatry, 2011. Available at http://www.hindawi.com/crim/psychiatry/2011/350417. Accessed June 13, 2012
  40. 40.↵
    1. Nevin RL
    : Limbic encephalopathy and central vestibulopathy caused by mefloquine: a case report. Travel Med Infect Dis 10:144–51, 2012
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Lebain P,
    2. Juliard C,
    3. Davy JP,
    4. et al
    : Neuropsychiatric symptoms in preventive antimalarial treatment with mefloquine: apropos of 2 cases (in French). L'Encéphale 26:67–70, 2000
    OpenUrlPubMed
  42. 42.↵
    1. Wittes RC,
    2. Saginur R
    : Adverse reaction to mefloquine associated with ethanol ingestion. CMAJ 152:515–17, 1995
    OpenUrlAbstract
  43. 43.↵
    1. Burke BM
    : Mefloquine. Lancet 341:1605–6, 1993
    OpenUrlPubMed
  44. 44.↵
    1. Caillon E,
    2. Schmitt L,
    3. Moron P
    : Acute depressive symptoms after mefloquine treatment. Am J Psychiatry 149:712, 1992
    OpenUrlPubMed
  45. 45.↵
    1. Lysack JT,
    2. Lysack CL,
    3. Kvern BL
    : A severe adverse reaction to mefloquine and chloroquine prophylaxis. Aust Fam Physician 27:1119–20, 1998
    OpenUrlPubMed
  46. 46.↵
    1. Tran TM,
    2. Browning J,
    3. Dell ML
    : Psychosis with paranoid delusions after a therapeutic dose of mefloquine: a case report. Maleria J 5:74, 2006
    OpenUrl
  47. 47.↵
    1. Even C,
    2. Friedman S,
    3. Lanouar K
    : Bipolar disorder after mefloquine treatment. J Psychiatry Neurosci 26:252–3, 2001
    OpenUrlPubMed
  48. 48.↵
    1. Moore TJ,
    2. Glenmullen J,
    3. Furberg CD
    : Prescription drugs associated with reports of violence towards others. PloS One 5:e15337, 2010
    OpenUrlPubMed
  49. 49.↵
    1. Croft AM,
    2. Whitehouse DP,
    3. Cook GC,
    4. et al
    : Safety evaluation of the drugs available to prevent malaria. Expert Opin Drug Saf 1:19–27, 2002
    OpenUrlCrossRefPubMed
  50. 50.↵
    1. Croft AM,
    2. Herxheimer A
    : Tolerability of antimalaria drugs. Clin Infect Dis 34:1278, 2002
    OpenUrlFREE Full Text
  51. 51.↵
    1. Choo V
    : Uncertainty about mefloquine will take time to resolve. Lancet 347:891, 1996
    OpenUrlPubMed
  52. 52.↵
    1. Thompson C
    : Malaria pill stands accused. New Sci 150:14–15, 1996
    OpenUrlPubMed
  53. 53.↵
    1. Clift S,
    2. Grabowski P
    : Malaria prophylaxis and the media. Lancet 348:344, 1996
    OpenUrlPubMed
  54. 54.↵
    Consumer Reports: Lariam's Legacy. Consumer Reports. March, 2002, pp 60–1
  55. 55.↵
    1. Burton B
    : Australian army faces legal action over mefloquine. BMJ 329:1062, 2004
    OpenUrlFREE Full Text
  56. 56.↵
    1. Bateman C
    : MCC “tardy” as couple suffer Mefliam “nightmare.” S Afr Med J 99:429–31, 2009
    OpenUrlPubMed
  57. 57.↵
    1. Larocque RC,
    2. Rao SR,
    3. Lee J,
    4. et al
    : Global TravEpiNet: a national consortium of clinics providing care to international travelers—analysis of demographic characteristics, travel destinations, and pretravel healthcare of high-risk US international travelers, 2009-2011. Clin Infect Dis 54:455–62, 2012
    OpenUrlAbstract/FREE Full Text
  58. 58.↵
    1. Nevin RL
    : Mefloquine neurotoxicity and gap junction blockade: critical insights in drug repositioning. Neurotoxicology 32:986–7, 2011
    OpenUrlCrossRefPubMed
  59. 59.↵
    1. Strauch S,
    2. Jantratid E,
    3. Dressman JB,
    4. et al
    : Biowaiver monographs for immediate release solid oral dosage forms: mefloquine hydrochloride. J Pharmaceut Sci 100:11–21, 2011
    OpenUrlCrossRefPubMed
  60. 60.↵
    1. Rathnam PJ,
    2. Bryan JP,
    3. Wolfe M
    : Epidemiology of malaria among United States government personnel assigned to diplomatic posts. Am J Trop Med Hyg 76:260–6, 2007
    OpenUrlAbstract/FREE Full Text
  61. 61.↵
    1. Nevin RL,
    2. Pietrusiak PP,
    3. Caci JB
    : Prevalence of contraindications to mefloquine use among USA military personnel deployed to Afghanistan. Malar J 7:30, 2008
    OpenUrlCrossRefPubMed
  62. 62.↵
    1. Nevin RL
    : Mefloquine prescriptions in the presence of contraindications: prevalence among US military personnel deployed to Afghanistan, 2007. Pharmacoepidemiol Drug Saf 19:206–10, 2010
    OpenUrlCrossRefPubMed
  63. 63.↵
    Office of the Assistant Secretary of Defense for Health Affairs: Memorandum. Subject: Policy memorandum on the use of mefloquine (Lariam®) in malaria prophylaxis. Washington, DC: Department of Defense, September 4, 2009. Available at http://www.health.mil/libraries/HA_Policies_and_Guidelines/09-017.pdf. Accessed June 13, 2012
  64. 64.↵
    Office of the Assistant Secretary of Defense for Health Affairs: Memorandum. Subject: Service review of mefloquine prescribing practices. January 17, 2012. Available at http://truth-out.org/files/Mefloquine-QA-Memo-JAN-2012-(Signed).pdf. Accessed June 13, 2012.
  65. 65.↵
    1. Magill AJ,
    2. Cersovsky SB,
    3. DeFraites RF
    : Advising travelers with specific needs: special considerations for US military deployments. CDC Health Information for International Travel, Chap 8:2012, July 26, 2011. Available at http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-8-advising-travelers-with-specific-needs/special-considerations-for-us-military-deployments.htm. Accessed June 13, 2012
  66. 66.↵
    United States Central Command (USCENTCOM): Modification 11 to USCENTCOM Individual Protection and Individual/Unit Deployment Policy. December 2, 2011
  67. 67.↵
    United States Africa Command: Change 2 to ACM 4200.03. Force health protection procedures for deployment and travel. Notice 4200.02, September 20, 2011
  68. 68.↵
    1. Kime P
    : New concerns rising over antimalaria drug. Army Times, April 11, 2012. Available at http://www.armytimes.com/news/2012/04/military-new-concerns-antimalaria-doxycycline-mefloquine-041112w. Accessed June 13, 2012
  69. 69.↵
    1. Milatovic D,
    2. Aschner M
    : Response to Nevin RL: Mefloquine neurotoxicity and gap junction blockade: critical insights in drug repositioning. Neurotoxicology 32:988, 2011
    OpenUrlPubMed
  70. 70.↵
    Roche: Lariam® (Mefloquine Hydrochloroquine) Medication Guide. Nutley, NJ: F. Hoffman-La Roche, September 2008
  71. 71.↵
    1. Schlagenhauf P,
    2. Adamcova M,
    3. Regep L,
    4. et al
    : The position of mefloquine as a 21st century malaria chemoprophylaxis. Malar J 9:357, 2010
    OpenUrlCrossRefPubMed
  72. 72.↵
    1. Nevin RL
    : Mefloquine blockade of connexin 36 and connexin 43 gap junctions and risk of suicide. Biol Psychiatry 71:e1–2, 2012
    OpenUrlPubMed
  73. 73.↵
    1. Gascón J,
    2. Almeda J,
    3. Corominas N,
    4. et al
    : Severe neuropsychiatric reaction following mefloquine use (in Spanish). Med Clin (Barc) 101:515–16, 1993
    OpenUrlPubMed
  74. 74.↵
    1. Fuller SJ,
    2. Naraqi S,
    3. Gilessi G
    : Paranoid psychosis related to mefloquine antimalarial prophylaxis. P N G Med J 45:219–21, 2002
    OpenUrlPubMed
  75. 75.↵
    1. Potasman I,
    2. Seligmann H
    : A unique case of mefloquine-induced psoriasis. J Trav Med 5:156, 1998
    OpenUrlPubMed
  76. 76.↵
    1. Clattenburg RN,
    2. Donnelly CL
    : Case study: neuropsychiatric symptoms associated with the antimalarial agent mefloquine. J Am Acad Child Adolesc Psychiatry 36:1606–8, 1997
    OpenUrlPubMed
  77. 77.↵
    1. Colebunders R
    : Cured of fear of flying. Travel Med Infect Dis 9:82, 2011
    OpenUrlPubMed
  78. 78.↵
    1. Tor PC,
    2. Lee HY,
    3. Tan CH
    : Mefloquine-induced mania in a 22-year-old Chinese man. Singapore Med J 47:549–50, 2006
    OpenUrlPubMed
  79. 79.↵
    1. Meszaros K,
    2. Kasper S
    : Psychopathological phenomena in long-term follow-up of acute psychosis after preventive mefloquinine (Lariam) administration (in German). Nervenarzt 67:404–6, 1996
    OpenUrlPubMed
  80. 80.↵
    1. Folkerts H,
    2. Kuhs H
    : Psychotic episode caused by prevention of malaria with mefloquine: a case report. Nervenarzt 63:300–2, 1992
    OpenUrlPubMed
  81. 81.↵
    1. Piening RB,
    2. Young SA
    : Mefloquine-induced psychosis. Ann Emerg Med 27:792–793, 1996
    OpenUrlPubMed
  82. 82.↵
    1. Eaton L
    : Adverse reactions. Nurs Times 92:16–17, 1996
    OpenUrlPubMed
  83. 83.↵
    1. Thapa R,
    2. Biswas B
    : Childhood mefloquine-induced mania and psychosis: a case report. J Child Neurol 24:1008–9, 2009
    OpenUrlAbstract/FREE Full Text
  84. 84.↵
    1. Kukoyi O,
    2. Carney CP
    : Curses, madness, and mefloquine Psychosomatics 44:339–41, 2003
    OpenUrlCrossRefPubMed
  85. 85.↵
    1. Borruat FX,
    2. Nater B,
    3. Robyn L,
    4. et al
    : Prolonged visual illusions induced by mefloquine (Lariam): a case report. J Trav Med 8:148–9, 2001
    OpenUrlPubMed
  86. 86.↵
    1. De Gennes C,
    2. Colas C,
    3. Nollet D,
    4. et al
    : Panic attack after therapeutic administration of mefloquine (in French). Ann Med Interne (Paris) 142:631, 1991
    OpenUrlPubMed
  87. 87.↵
    1. Nosten F,
    2. Imvithaya S,
    3. Vincenti M,
    4. et al
    : Malaria on the Thai-Burmese border: treatment of 5192 patients with mefloquine-sulfadoxine-pyrimethamine. Bull World Health Organ 65:891–896, 1987
    OpenUrlPubMed
  88. 88.↵
    1. Briand V,
    2. Bottero J,
    3. Noël H,
    4. et al
    : Intermittent treatment for the prevention of malaria during pregnancy in Benin: a randomized, open-label equivalence trial comparing sulfadoxine-pyrimethamine with mefloquine. J Infect Dis 200:991–1001, 2009
    OpenUrlAbstract/FREE Full Text
  89. 89.↵
    1. Harinasuta T,
    2. Bunnag D,
    3. Wernsdorfer WH
    : A phase II clinical trial of mefloquine in patients with chloroquine-resistant falciparum malaria in Thailand. Bull World Health Organ 61:299–305, 1983
    OpenUrlPubMed
  90. 90.↵
    1. Fiaccadori E,
    2. Maggiore U,
    3. Rotelli C,
    4. et al
    : Thrombotic-thrombocytopenic purpura following malaria prophylaxis with mefloquine. J Antimicrob Chemother 57:160–1, 2006
    OpenUrlFREE Full Text
  91. 91.↵
    1. Loefler I
    : Mefloquine and anticoagulant interaction. J Trav Med 10:194–5, 2003
    OpenUrlPubMed
  92. 92.↵
    1. Oueriagli Nabih F,
    2. Touhami M,
    3. Laffinti A,
    4. et al
    : Mood disorder after malaria prophylaxis with mefloquine (two case reports) (in French). L'Encéphale 37:393–6, 2011
    OpenUrlPubMed
  93. 93.↵
    World Health Organization (WHO): Review of central nervous system Adverse events related to the antimalarial drug, mefloquine (1985-1990). WHO/MAL/91.1063, 1991
  94. 94.↵
    1. Grupp D,
    2. Rauber A,
    3. Froscher W
    : Neuropsychiatric disturbances after malaria prophylaxis with mefloquine (in German). Akt Neurol 21:134–6, 1994
    OpenUrl
  95. 95.↵
    1. Gascón J,
    2. Pujol A,
    3. Codina C,
    4. et al
    : Side-effects of the antimalarial mefloquine: presentation of 20 cases (in Spanish). Med Clin (Barc) 95:277, 1990
    OpenUrlPubMed
  96. 96.↵
    1. Stürchler D,
    2. Handschin J,
    3. Kaiser D,
    4. et al
    : Neuropsychiatric side effects of mefloquine. N Engl J Med 322:1752–3, 1990
    OpenUrlPubMed
  97. 97.↵
    Roche: Lariam® (Mefloquine Hydrochloroquine) Medication Guide. Nutley, NJ: F. Hoffman LaRoche, November, 1989
  98. 98.↵
    1. Ocko FH
    : A case of atabrine psychosis in a civilian. Am J Psychiatry 103:833, 1947
    OpenUrlCrossRefPubMed
  99. 99.↵
    1. Loken AC,
    2. Haymaker W
    : Pamaquine poisoning in man, with a clinicopathologic study of one case. Am J Trop Med Hyg 29:341–52, 1949
    OpenUrlPubMed
  100. 100.↵
    1. Quintanilla J
    : Psychosis due to quinidine intoxication. Am J Psychiatry 113:1031–2, 1957
    OpenUrlCrossRefPubMed
  101. 101.↵
    1. Recasens C,
    2. Zittoun C,
    3. Féline A
    : A psychotic episode in a patient coming home from Africa: the possible role of mefloquine (in French). Ann Psychiatr 8:100–3, 1993
    OpenUrl
  102. 102.↵
    1. Croft AM,
    2. World MJ
    : Neuropsychiatric reactions with mefloquine chemoprophylaxis. Lancet 347:326, 1996
    OpenUrlCrossRefPubMed
  103. 103.↵
    1. Hollweg M,
    2. Soyka M,
    3. Greil W
    : Mefloquine-induced psychoses–problems in etiologic classification based on 2 case reports (in German). Psychiatr Prax 22:33–6, 1995
    OpenUrlPubMed
  104. 104.↵
    1. Wallace MR,
    2. Sharp TW,
    3. Smoak B,
    4. et al
    : Malaria among United States troops in Somalia. Am J Med 100:49–55, 1996
    OpenUrlCrossRefPubMed
  105. 105.↵
    1. Barrett PJ,
    2. Emmins PD,
    3. Clarke PD,
    4. et al
    : Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: postal and telephone survey of travellers. BMJ 313:525–8, 1996
    OpenUrlAbstract/FREE Full Text
  106. 106.↵
    1. Hennequin C,
    2. Bourée P,
    3. Bazin N,
    4. et al
    : Severe psychiatric side effects observed during prophylaxis and treatment with mefloquine. Arch Int Med 154:2360–2, 1994
    OpenUrlCrossRefPubMed
  107. 107.↵
    1. Marsepoil T,
    2. Petithory J,
    3. Faucher JM,
    4. et al
    : Encephalopathy and memory disorders during treatments with mefloquine (in French). Rev Med Intern 14:788–91, 1993
    OpenUrl
  108. 108.↵
    1. Carme B,
    2. Nevez G,
    3. Peguet C,
    4. et al
    : Neuropsychiatric intolerance during mefloquine prophylaxis.:5 case reports (in French). Med Mal Infect 26:728–9, 1996
    OpenUrl
  109. 109.↵
    1. Vuurman EF,
    2. Muntjewerff ND,
    3. Uiterwijk MM,
    4. et al
    : Effects of mefloquine alone and with alcohol on psychomotor and driving performance. Eur J Clin Pharmacol 50:475–482, 1996
    OpenUrlCrossRefPubMed
  110. 110.↵
    1. Roxo MR,
    2. Franceschini PR,
    3. Zubaran C,
    4. et al
    : The limbic system conception and its historical evolution. Sci World J 11:2428–41, 2011
    OpenUrl
  111. 111.↵
    1. Mas A
    : Hepatic encephalopathy: from pathophysiology to treatment. Digestion 73(Suppl 1):86–93, 2006
    OpenUrlCrossRefPubMed
  112. 112.↵
    1. Córdoba J
    : New assessment of hepatic encephalopathy. J Hepatol 54:1030–40, 2011
    OpenUrlCrossRefPubMed
  113. 113.↵
    1. Anderson NE,
    2. Barber PA
    : Limbic encephalitis: a review. J Clin Neurosci 15:961–71, 2008
    OpenUrlCrossRefPubMed
  114. 114.↵
    1. Kaplan PW,
    2. Rossetti AO,
    3. Kaplan EH,
    4. et al
    : Proposition: limbic encephalitis may represent limbic status epilepticus—a review of clinical and EEG characteristics. Epilepsy Behav 24:1–6, 2012
    OpenUrlPubMed
  115. 115.↵
    1. Alisky JM,
    2. Chertkova EL,
    3. Iczkowski KA
    : Drug interactions and pharmacogenetic reactions are the basis for chloroquine and mefloquine-induced psychosis. Med Hypotheses 67:1090–4, 2006
    OpenUrlCrossRefPubMed
  116. 116.↵
    1. Chevli R,
    2. Fitch CD
    : The antimalarial drug mefloquine binds to membrane phospholipids. Antimicrob Agents Chemother 21:581–586, 1982
    OpenUrlAbstract/FREE Full Text
  117. 117.↵
    1. Baudry S,
    2. Pham YT,
    3. Baune B,
    4. et al
    : Stereoselective passage of mefloquine through the blood-brain barrier in the rat. J Pharm Pharmacol 49:1086–90, 1997
    OpenUrlPubMed
  118. 118.↵
    1. Dow GS,
    2. Milner E,
    3. Bathurst I,
    4. et al
    : Central nervous system exposure of next generation quinoline methanols is reduced relative to mefloquine after intravenous dosing in mice. Malar J 10:150, 2011
    OpenUrlPubMed
  119. 119.↵
    1. Jones R,
    2. Kunsman G,
    3. Levine B,
    4. et al
    : Mefloquine distribution in postmortem cases. Forensic Sci Int 68:29–32, 1994
    OpenUrlCrossRefPubMed
  120. 120.↵
    1. Cruikshank SJ,
    2. Hopperstad M,
    3. Younger M,
    4. et al
    : Potent block of Cx36 and Cx50 gap junction channels by mefloquine. Proc Natl Acad Sci USA 101:12364–9, 2004
    OpenUrlAbstract/FREE Full Text
  121. 121.↵
    1. Connors BW,
    2. Long MA
    : Electrical synapses in the mammalian brain. Annu Rev Neurosci 27:393–418, 2004
    OpenUrlCrossRefPubMed
  122. 122.↵
    1. Dere E,
    2. Zlomuzica A
    : The role of gap junctions in the brain in health and disease. Neurosci Biobehav Rev 36:206–17, 2012
    OpenUrlCrossRefPubMed
  123. 123.↵
    1. Allison DW,
    2. Ohran AJ,
    3. Stobbs SH,
    4. et al
    : Connexin-36 gap junctions mediate electrical coupling between ventral tegmental area GABA neurons. Synapse 60:20–31, 2006
    OpenUrlCrossRefPubMed
  124. 124.↵
    1. Lassen MB,
    2. Brown JE,
    3. Stobbs SH,
    4. et al
    : Brain stimulation reward is integrated by a network of electrically coupled GABA neurons. Brain Res 1156:46–58, 2007
    OpenUrlCrossRefPubMed
  125. 125.↵
    1. Steffensen SC,
    2. Bradley KD,
    3. Hansen DM,
    4. et al
    : The role of connexin-36 gap junctions in alcohol intoxication and consumption. Synapse 65:695–707, 2011
    OpenUrlCrossRefPubMed
  126. 126.↵
    1. Allison DW,
    2. Wilcox RS,
    3. Ellefsen KL,
    4. et al
    : Mefloquine effects on ventral tegmental area dopamine and GABA neuron inhibition: a physiologic role for connexin-36 gap junctions. Synapse 65:804–13, 2011
    OpenUrlPubMed
  127. 127.↵
    1. Collins GB,
    2. McAllister MS
    : Chloroquine psychosis masquerading as PCP: a case report. J Psychoactive Drugs 40:211–14, 2008
    OpenUrlCrossRefPubMed
  128. 128.↵
    1. Domino EF
    : Taming the ketamine tiger. 1965. Anesthesiology 113:678–84, 2010
    OpenUrlPubMed
  129. 129.↵
    1. Ellison G
    : The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. Brain Res Brain Res Rev 20:250–67, 1995
    OpenUrlCrossRefPubMed
  130. 130.↵
    1. Hoaken PN,
    2. Stewart SH
    : Drugs of abuse and the elicitation of human aggressive behavior. Addict Behav 28:1533–54, 2003
    OpenUrlCrossRefPubMed
  131. 131.↵
    1. Dinis-Oliveira RJ,
    2. Carvalho F,
    3. Duarte JA,
    4. et al
    : Suicide by hanging under the influence of ketamine and ethanol. Forensic Sci Int 202:e23–7, 2010
    OpenUrlPubMed
  132. 132.↵
    1. Landtblom AM
    : The “sensed presence”: an epileptic aura with religious overtones. Epilepsy Behav 9:186–8, 2006
    OpenUrlPubMed
  133. 133.↵
    1. Dolgoff-Kaspar R,
    2. Ettinger AB,
    3. Golub SA,
    4. et al
    : Numinous-like auras and spirituality in persons with partial seizures. Epilepsia 52:640–4, 2011
    OpenUrlPubMed
  134. 134.↵
    1. Kasper BS,
    2. Kasper EM,
    3. Pauli E,
    4. et al
    : Phenomenology of hallucinations, illusions, and delusions as part of seizure semiology. Epilepsy Behav 18:13–23, 2010
    OpenUrlCrossRefPubMed
  135. 135.↵
    1. Amabeoku GJ,
    2. Farmer CC
    : Gamma-aminobutyric acid and mefloquine-induced seizures in mice. Prog Neuropsychopharmacol Biol Psychiatry 29:917–21, 2005
    OpenUrlCrossRefPubMed
  136. 136.↵
    1. Singh K,
    2. Shanks GD,
    3. Wilde H
    : Seizures after mefloquine. Ann Intern Med 114:994, 1991
    OpenUrlPubMed
  137. 137.↵
    1. Ries S
    : Cerebral spasm during malaria prophylaxis with mefloquine (in German). Dtsch Med Wochenschr 118:1911–12, 1993
    OpenUrlPubMed
  138. 138.↵
    1. Potasman I,
    2. Beny A,
    3. Seligmann H
    : Neuropsychiatric problems in 2,500 long-term young travelers to the tropics. J Trav Med 7:5–9, 2000
    OpenUrlPubMed
  139. 139.↵
    1. Gee CE,
    2. Benquet P,
    3. Demont-Guignard S,
    4. et al
    : Energy deprivation transiently enhances rhythmic inhibitory events in the CA3 hippocampal network in vitro. Neuroscience 168:605–12, 2010
    OpenUrlPubMed
  140. 140.↵
    1. Behrens CJ,
    2. Ul Haq R,
    3. Liotta A,
    4. et al
    : Nonspecific effects of the gap junction blocker mefloquine on fast hippocampal network oscillations in the adult rat in vitro. Neuroscience 192:11–19, 2011
    OpenUrlCrossRefPubMed
  141. 141.↵
    1. Bissiere S,
    2. Zelikowsky M,
    3. Ponnusamy R,
    4. et al
    : Electrical synapses control hippocampal contributions to fear learning and memory. Science 331:87–91, 2011
    OpenUrlAbstract/FREE Full Text
  142. 142.↵
    1. Dalmau J,
    2. Gleichman AJ,
    3. Hughes EG,
    4. et al
    : Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7:1091–8, 2008
    OpenUrlCrossRefPubMed
  143. 143.↵
    1. Kleyensteuber B,
    2. Ruterbusch V,
    3. Bennett J,
    4. et al
    : Limbic encephalitis presenting with seizures, anterograde amnesia, and psychosis in a patient seven weeks status post immature ovarian teratoma removal. Mil Med 175:616–18, 2010
    OpenUrlPubMed
  144. 144.↵
    1. Miller BL,
    2. Cummings JL,
    3. McIntyre H,
    4. et al
    : Hypersexuality or altered sexual preference following brain injury. J Neurol Neurosurg Psychiatry 49:867–73, 1986
    OpenUrlAbstract/FREE Full Text
  145. 145.↵
    1. Jiménez-Huete A,
    2. Gil-Nagel A,
    3. Franch O
    : Multifocal myoclonus associated with mefloquine chemoprophylaxis. Clin Neuropharmacol 25:243, 2002
    OpenUrlPubMed
  146. 146.↵
    1. Besser R,
    2. Krämer G
    : Suspected convulsive side-effect of mefloquine (Lariam) (in German). Nervenarzt 62:760–1, 1991
    OpenUrlPubMed
  147. 147.↵
    1. van Essen TA,
    2. Van der giessen RS,
    3. Koekkoek S,
    4. et al
    : Anti-malaria drug mefloquine induces motor learning deficits in humans. Front Neurosci 4:191, 2010
    OpenUrlPubMed
  148. 148.↵
    1. Dalmau J,
    2. Graus F,
    3. Rosenblum MK,
    4. et al
    : Anti-Hu–associated paraneoplastic encephalomyelitis/sensory neuronopathy: a clinical study of 71 patients. Medicine (Baltimore) 71:59–72, 1992
    OpenUrlPubMed
  149. 149.↵
    1. Sakuma H,
    2. Sugai K,
    3. Sasaki M
    : Acute nonparaneoplastic limbic encephalitis in childhood: a case series in Japan. Pediatr Neurol 43:167–72, 2010
    OpenUrlPubMed
  150. 150.↵
    1. Napadow V,
    2. Sheehan JD,
    3. Kim J,
    4. et al
    : The brain circuitry underlying the temporal evolution of nausea in humans. Cereb Cortex 23:806–13, 2013
    OpenUrlAbstract/FREE Full Text
  151. 151.↵
    1. Hessén-Söderman AC,
    2. Bergenius J,
    3. Palme IB,
    4. et al
    : Mefloquine prophylaxis and hearing, postural control, and vestibular functions. J Trav Med 2:66–9, 1995
    OpenUrlCrossRefPubMed
  152. 152.↵
    1. Chester AC,
    2. Sandroni P
    : Peripheral polyneuropathy and mefloquine prophylaxis. Am J Trop Med Hyg 85:1008–9, 2011
    OpenUrlAbstract/FREE Full Text
  153. 153.↵
    1. Dow G,
    2. Bauman R,
    3. Caridha D,
    4. et al
    : Mefloquine induces dose-related neurological effects in a rat model. Antimicrob Agents Chemother 50:1045–53, 2006
    OpenUrlAbstract/FREE Full Text
  154. 154.↵
    1. Kofi Ekue JM,
    2. Phiri DE,
    3. Mukunyandela M,
    4. et al
    : Severe orthostatic hypotension during treatment of falciparum malaria. BMJ 296:396, 1988
    OpenUrl
  155. 155.↵
    1. Bhanji A,
    2. Atkins C,
    3. Karim M
    : Postural orthostatic tachycardia syndrome: a case report of palpitations and dizziness following prophylactic mefloquine use. Int J Clin Pharmacol Ther 48:577–581, 2010
    OpenUrlPubMed
  156. 156.↵
    1. Hall AP,
    2. Doberstyn EB,
    3. Karnchanachetanee C,
    4. et al
    : Sequential treatment with quinine and mefloquine or quinine and pyrimethamine-sulfadoxine for falciparum malaria. BMJ 1:1626–8, 1977
    OpenUrlAbstract/FREE Full Text
  157. 157.↵
    1. Speich R,
    2. Haller A
    : Central anticholinergic syndrome with the antimalarial drug mefloquine. N Engl J Med 331:57–8, 1994
    OpenUrlCrossRefPubMed
  158. 158.↵
    1. Bien CG,
    2. Elger CE
    : Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life. Epilepsy Behav 10:529e38, 2007
    OpenUrl
  159. 159.↵
    1. Nabeshima T,
    2. Mouri A,
    3. Murai R,
    4. et al
    : Animal model of schizophrenia: dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine. Ann N Y Acad Sci 1086:160–8, 2006
    OpenUrlCrossRefPubMed
  160. 160.↵
    1. Ebert U,
    2. Brandt C,
    3. Löscher W
    : Delayed sclerosis, neuroprotection, and limbic epileptogenesis after status epilepticus in the rat. Epilepsia 43(Suppl 5):86–95, 2002
    OpenUrlPubMed
  161. 161.↵
    1. Dow GS,
    2. Hudson TH,
    3. Vahey M,
    4. et al
    : The acute neurotoxicity of mefloquine may be mediated through a disruption of calcium homeostasis and ER function in vitro. Malar J 2:14, 2003
    OpenUrlCrossRefPubMed
  162. 162.↵
    1. Dow GS,
    2. Koenig ML,
    3. Wolf L,
    4. et al
    : The antimalarial potential of 4-quinolinecarbinolamines may be limited due to neurotoxicity and cross-resistance in mefloquine-resistant Plasmodium falciparum strains. Antimicrob Agents Chemother 48:2624–32, 2004
    OpenUrlAbstract/FREE Full Text
  163. 163.↵
    1. Hood JE,
    2. Jenkins JW,
    3. Milatovic D,
    4. et al
    : Mefloquine induces oxidative stress and neurodegeneration in primary rat cortical neurons. Neurotoxicology 31:518–23, 2010
    OpenUrlPubMed
  164. 164.↵
    1. Richter R
    : The effect of certain quinoline compounds upon the nervous system of monkeys. J Neuropathol Exp Neurol 8:155–70, 1949
    OpenUrlCrossRefPubMed
  165. 165.↵
    1. Schmidt IG
    : Effects of pamaquine on the central nervous system. Anat Rec 97:367, 1947
    OpenUrlPubMed
  166. 166.↵
    1. Schmidt IG,
    2. Schmidt LH
    : Neurotoxicity of the 8-aminoquinolines; reactions of various experimental animals to plasmocid. J Comp Neurol 91:337–67, 1949
    OpenUrlCrossRefPubMed
  167. 167.↵
    1. Lyle DJ,
    2. Schmidt IG
    : The selective effect of drugs upon nuclei of the oculogyric system. Am J Ophthalmol 54:706–16, 1962
    OpenUrlPubMed
  168. 168.↵
    1. Sipe JC,
    2. Vick NA,
    3. Schulman S,
    4. et al
    : Plasmocid encephalopathy in the rhesus monkey: a study of selective vulnerability. J Neuropathol Exp Neurol 32:446–57, 1973
    OpenUrlPubMed
  169. 169.↵
    Canadian Department of National Defense (DND): Report of the somalia commission of inquiry: the mefloquine issue. Ottawa, Ontario, Canada: Minister of Public Works and Government Services, 1997. Available at http://www.dnd.ca/somalia/vol5/v5c41e.htm. Accessed June 13, 2012
  170. 170.↵
    1. Benjamin M,
    2. Olmsted D
    : Army eyes malaria drug in Bragg killings. UPI.com, August 9, 2002. Available at http://www.upi.com/Top_News/2002/08/09/Army-eyes-malaria-drug-in-Bragg-killings/UPI-40391028935596. Accessed June 13, 2012
  171. 171.↵
    1. Benjamin M,
    2. Olmsted D
    : Ft. Bragg suspect said to be delusional. UPI.com, August 31, 2002. Available at http://www.upi.com/Top_News/2002/08/31/Ft-Bragg-suspect-said-to-be-delusional/UPI-97421030839085. Accessed June 13, 2012
  172. 172.↵
    1. Orth M
    : Fort Bragg's deadly summer. Vanity Fair, December 2002. Available at http://www.vanityfair.com/politics/features/2002/12/fortbragg200212. Accessed June 13, 2012
  173. 173.↵
    1. Benjamin M,
    2. Olmsted D
    : Malaria-drug diagnosis for ‘coward’ GI. UPI.com, June 4, 2004. Available at http://www.upi.com/Business_News/Security-Industry/2004/06/04/Malaria-drug-diagnosis-for-coward-GI/UPI-40941086385037. Accessed June 13, 2012
  174. 174.↵
    1. Benjamin M,
    2. Olmsted D
    : Exclusive: Army surrenders to ‘coward’ GI. UPI.com, July 16, 2004. Available at http://www.upi.com/Business_News/Security-Industry/2004/07/16/Exclusive-Army-surrenders-to-coward-GI/UPI-51631089996907. Accessed June 13, 2012
  175. 175.↵
    1. Hall KM
    : U.S. army base tries to stop soldier suicides. USA Today, April 25, 2010. Available at http://www.usatoday.com/news/military/2010-04-24-army-suicides_N.htm. Accessed June 13, 2012
  176. 176.↵
    1. Lydersen K
    : Lost to Lariam? Reader, September 24, 2009. Available at http://www.chicagoreader.com/chicago/lost-to-lariam/Content?oid=1201006. Accessed June 13, 2012
  177. 177.↵
    1. Notte J
    : Toxic cocktail: army struggles with mental-health care. The Street, September 16, 2010. Available at http://www.thestreet.com/story/10856361/1/toxic-cocktail-army-struggles-with-mental-health-care.html. Accessed June 13, 2012
  178. 178.↵
    1. McCarthy JS
    : Malaria chemoprophylaxis: in war and peace. Med J Aust 182:148–9, 2005
    OpenUrlPubMed
  179. 179.↵
    1. Chen LH,
    2. Wilson ME,
    3. Schlagenhauf P
    : Prevention of malaria in long-term travelers. JAMA 296:2234–44, 2006
    OpenUrlCrossRefPubMed
  180. 180.↵
    1. Schlagenhauf P,
    2. Tschopp A,
    3. Johnson R,
    4. et al
    : Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study. BMJ 327:1078, 2003
    OpenUrlAbstract/FREE Full Text
  181. 181.↵
    1. Schlagenhauf P,
    2. Petersen E
    : Malaria chemoprophylaxis: strategies for risk groups. Clin Microbiol Rev 21:466–72, 2008
    OpenUrlAbstract/FREE Full Text
  182. 182.↵
    1. Franssen G,
    2. Rouveix B,
    3. Lebras J,
    4. et al
    : Divided-dose kinetics of mefloquine in man. Br J Clin Pharmacol 28:179–84, 1989
    OpenUrlCrossRefPubMed
  183. 183.↵
    1. Schwartz DE,
    2. Weber W,
    3. Richard-Lenoble D,
    4. et al
    : Kinetic studies of mefloquine and of one of its metabolites, Ro 21-5104, in the dog and in man. Acta Trop 37:238–42, 1980
    OpenUrlPubMed
  184. 184.↵
    1. Rozman RS,
    2. Canfield CJ
    : New experimental antimalarial drugs. Adv Pharmacol Chemother 16:1–43, 1979
    OpenUrlPubMed
  185. 185.↵
    1. Ajana F,
    2. Fortier B,
    3. Martinot A,
    4. et al
    : Mefloquine prophylaxis and neurotoxicity: report of a case (in French). Sem Hop Paris 66:918–19, 1990
    OpenUrl
  186. 186.↵
    1. Rønn AM,
    2. Bygbjerg IC
    : Acute brain syndrome after mefloquine treatment (in German). Ugeskr Laeger 156:6044–5, 1994
    OpenUrlPubMed
  187. 187.↵
    1. Pham YT,
    2. Nosten F,
    3. Farinotti R,
    4. et al
    : Cerebral uptake of mefloquine enantiomers in fatal cerebral malaria. Int J Clin Pharmacol Ther 37:58–61, 1999
    OpenUrlPubMed
  188. 188.↵
    1. Schwartz E,
    2. Potasman I,
    3. Rotenberg M,
    4. et al
    : Serious adverse events of mefloquine in relation to blood level and gender. Am J Trop Med Hyg 65:189–92, 2001
    OpenUrlAbstract
  189. 189.↵
    1. Schlagenhauf P,
    2. Steffen R,
    3. Lobel H,
    4. et al
    : Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance. Trop Med Int Health 1:485–94, 1996
    OpenUrlCrossRefPubMed
  190. 190.↵
    1. Nevin RL
    : Pharmacokinetic considerations in the repositioning of mefloquine for treatment of progressive multifocal leukoencephalopathy. Clin Neurol Neurosurg 114:1204–5, 2012
    OpenUrlPubMed
  191. 191.↵
    1. Zaigraykina N,
    2. Potasman I
    : Polymorphism at the MDR1 locus as a cause of mefloquine-induced psychosis (in Hebrew). Harefuah 149:583–4, 2010
    OpenUrlPubMed
  192. 192.↵
    1. Aarnoudse AL,
    2. van Schaik RH,
    3. Dieleman J,
    4. et al
    : MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine. Clin Pharmacol Ther 80:367–74, 2006
    OpenUrlCrossRefPubMed
  193. 193.↵
    1. Barraud de Lagerie S,
    2. Comets E,
    3. Gautrand C,
    4. et al
    : Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice. Br J Pharmacol 141:1214–22, 2004
    OpenUrlCrossRefPubMed
  194. 194.↵
    1. Riffkin CD,
    2. Chung R,
    3. Wall DM,
    4. et al
    : Modulation of the function of human MDR1 P-glycoprotein by the antimalarial drug mefloquine. Biochem Pharmacol 52:1545–52, 1996
    OpenUrlCrossRefPubMed
  195. 195.↵
    1. Potasman I,
    2. Juven Y,
    3. Weller B,
    4. et al
    : Does mefloquine prophylaxis affect electroencephalographic patterns? Am J Med 112:147–9, 2002
    OpenUrlCrossRefPubMed
  196. 196.↵
    1. Bernard J,
    2. Le Camus J,
    3. Sarrouy J,
    4. et al
    : Toxic encephalopathy caused by mefloquine (in French)? Presse Med 16:1654–65, 1987
    OpenUrlPubMed
  197. 197.↵
    1. Burgmann H,
    2. Winkler S,
    3. Uhl F,
    4. et al
    : Mefloquine and sulfadoxine/pyrimethamine overdose in malaria tropica (in German). Wien Klin Wochenschr 105:61–3, 1993
    OpenUrlPubMed
  198. 198.↵
    1. Leong GB,
    2. Leisenring SE,
    3. Dean MD
    : Commentary: Intoxication and settled insanity—unsettled matters. J Am Acad Psychiatry Law 35:183–7, 2007
    OpenUrlAbstract/FREE Full Text
  199. 199.↵
    1. Brueckner RP,
    2. Lasseter KC,
    3. Lin ET,
    4. et al
    : First-time-in-humans safety and pharmacokinetics of WR 238605, a new antimalarial. Am J Trop Med Hyg 58:645–9, 1998
    OpenUrlAbstract
  200. 200.↵
    1. Croft AM
    : A lesson learnt: the rise and fall of Lariam and Halfan. J R Soc Med 100:170–4, 2007
    OpenUrlFREE Full Text
View Abstract
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools

Jump to section