Unacknowledged Casualties · Page 3
The Drugs: Scientific Background
Mefloquine, Tafenoquine, and What They Do to the Brain
3.1 Mefloquine (Lariam)
Mefloquine is a synthetic quinoline antimalarial developed by the United States Army's Walter Reed Army Institute of Research (WRAIR) in the late 1960s, as part of a military drug discovery programme responding to chloroquine resistance in South-East Asian conflict theatres. It was commercialised by F. Hoffmann-La Roche and reached the market in the 1980s following limited clinical testing.
It became the first-line malaria prophylactic for US and UK military personnel deployed to malaria-endemic regions, and the ADF's second-line prophylactic drug. Since the first published case report of mefloquine-related encephalopathy in the late 1980s, three decades of research have established that mefloquine is neurotoxic in a subset of users, capable of causing lasting or permanent brain damage, with chronic symptoms that are typically misdiagnosed as PTSD or other psychiatric disorders.
What the Australian product data sheet records:
| Frequency | Documented adverse reactions |
|---|---|
| Very common more than 1 in 10 users |
Abnormal dreams, insomnia. |
| Common 1 in 10 to 1 in 100 users |
Anxiety, depression, visual impairment, vertigo. |
| Uncommon 1 in 100 to 1 in 1,000 users |
Agitation, restlessness, mood swings, panic attacks, confusional state, hallucinations, aggression, bipolar disorder, psychotic disorder including delusional disorder, depersonalisation, mania, paranoia, suicidal ideation, memory impairment, and long-term vestibular disorders. |
The 2013 FDA black box warning:
The FDA's black box warning — its most serious safety designation, reserved for drugs with demonstrated risk of severe or life-threatening adverse effects — states:
US FDA Black Box Warning — Mefloquine (2013)
"Mefloquine may cause neuropsychiatric adverse reactions that can persist after mefloquine has been discontinued."
On psychiatric effects: "Psychiatric symptoms ranging from anxiety, paranoia, and depression to hallucinations and psychotic behavior can occur with mefloquine use... In some cases, these symptoms have been reported to continue for months or years after mefloquine has been stopped. Cases of suicidal ideation and suicide have been reported."
On neurological effects: "Dizziness, vertigo, tinnitus, and loss of balance can go on for months or years after mefloquine is stopped or may become permanent."
The Australian TGA and the European Medicines Agency have issued parallel strengthened warnings. Mefloquine is currently classified by the ADF as a drug of last resort (ADF Malaria Policy, as cited in QVFA Submission 94).
Evidential register
3.2 Tafenoquine
Tafenoquine is a newer quinoline antimalarial, also developed by WRAIR and trialled by the ADF's Army Malaria Institute across Bougainville from late 1998 and East Timor until mid-2001, involving more than 1,540 trial subjects.
In 2009, WRAIR laboratory studies found tafenoquine to be more neurotoxic than mefloquine. This finding was of considerable significance. Mefloquine was by that point already classified by the ADF as a drug of last resort. Despite this finding, no longitudinal follow-up health studies have ever been conducted on the original AMI tafenoquine trial subjects.
At the time of the original Senate submissions on which much of this site draws, tafenoquine was not registered in Australia. That position has since changed: in September 2018 the TGA registered tafenoquine for clinical use, and the US FDA granted parallel approvals in July and August 2018. Adverse event reports held by the TGA can therefore no longer be assumed to derive solely from the ADF trial cohort. The ADF-trial-subject reports in the TGA's Database of Adverse Event Notifications (DAEN) nonetheless include completed suicide, suicidal ideation, brain injury, and various chronic psychiatric disorders.
Evidential register
3.3 The ADF Trial Dosing Conditions
The doses administered during the AMI trials matter. They were not standard doses.
The standard TGA-approved prophylactic dosing regimen for mefloquine is 250 mg per week. During AMI clinical trials and in general ADF use, personnel were administered loading doses of 750 mg per week. The QVFA Senate submission documents cases of trial subjects receiving loading doses of up to 1,500 mg per week — six times the approved prophylactic dose. During the tafenoquine Bougainville and East Timor post-exposure prophylaxis study, subjects received up to 1,200 mg over three days.
(mefloquine)
loading dose
maximum dose
Animal model studies have established that mefloquine at prophylactic-equivalent doses — not just the elevated trial doses — can cause lasting or permanent neuronal injury. At the dosages documented in the AMI trials, the peer-reviewed and advocacy literature notes that both drugs can concentrate at toxic levels in brain regions including the brainstem, vestibular system, and limbic system. At the trial dosages, the neurotoxic risk was compounded.
Evidential register
Animal model findings: Established — Dow et al. (2006), Antimicrobial Agents and Chemotherapy.
3.4 Individual Metabolic Vulnerability: The CYP2D6 Pathway
Not everyone who took these drugs experienced severe neuropsychiatric effects. A plausible biological mechanism for differential susceptibility has been identified in the CYP2D6 enzyme pathway.
CYP2D6 plays a critical role in clearing toxins from the central nervous system in the relevant brain regions. Individuals who are poor metabolisers or intermediate metabolisers of the CYP2D6 pathway — estimated to comprise 12 to 23 percent of Caucasian populations — may be unable to clear quinoline compounds from the brain before toxic concentrations accumulate, potentially causing lasting or permanent brain injury.
The Senate submission from the Quinoline Veterans and Families Association (QVFA) reports that over the years preceding its submission, dozens of AMI tafenoquine trial subjects who experienced chronic neuropsychiatric illness voluntarily underwent CYP2D6 testing. Every single result returned a poor metaboliser or intermediate metaboliser phenotype. These results are reported in the QVFA submission and have not been independently verified by this site, but they are consistent with the known prevalence of CYP2D6 poor metaboliser phenotypes in Caucasian populations.
WRAIR scientists have themselves stated in the published literature that there is a need for antimalarial agents that do not require CYP2D6 metabolism for activity — an implicit acknowledgement of the pathway's significance for toxicity risk. Despite this, the ADF Surgeon General has rejected requests for CYP2D6 screening of personnel prior to tafenoquine administration.
Evidential register
Application to quinoline toxicity susceptibility: Plausible mechanism, consistent with available data.
Voluntary testing results: Documented (QVFA Submission 94). Figures have not been independently verified by this site.
A Note on Source Transparency
Two figures are central to the Australian evidence base drawn on throughout this site.
Major Stuart McCarthy, through the Quinoline Veterans and Families Association (QVFA), prepared Senate Submission 94, which is the primary source for much of the Australian-specific factual and institutional detail cited here. Major McCarthy is himself an affected ADF veteran and an advocate. His submission is detailed, sourced, and consistent with the international peer-reviewed literature. Readers should be aware of his standing as both witness and advocate.
Professor Jane Quinn of Charles Sturt University prepared Senate Submission 73. She is a neurotoxicologist who has published peer-reviewed work on quinoline toxicity. She is also the widow of a British Army officer who died by suicide in 2006 following a severe adverse reaction to mefloquine. Her scientific expertise and her personal history are both relevant to her evidence. Both are disclosed here so that readers can weigh her contributions with that context in view.
The underlying neurotoxicology that both draw upon is independently established in the international peer-reviewed literature. Readers should note that in some cases the same individuals have contributed to both peer-reviewed literature and Senate submissions. This site identifies that overlap wherever it is relevant to assessing the independence of sources.