PAGE 3 — THE DRUGS: SCIENTIFIC BACKGROUND

The Drugs: 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 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:

The Australian mefloquine product data sheet lists the following adverse reactions:

Very common reactions (affecting more than 1 in 10 users): abnormal dreams, insomnia.

Common reactions (affecting 1 in 10 to 1 in 100 users): anxiety, depression, visual impairment, vertigo.

Uncommon reactions (affecting 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:

"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 now classified by the ADF as a drug of last resort.

Evidential register: Established — FDA black box warning (2013), Australian product data sheet, TGA and EMA regulatory documentation, peer-reviewed literature.

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 — a finding of considerable significance given that mefloquine was by that point already a drug of last resort for the ADF. 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 report draws, tafenoquine was not registered in Australia. That position has since changed: in September 2018 the TGA registered tafenoquine for clinical use (as Kozenis and Kodatef), and the US FDA granted parallel approvals in July and August 2018 (Krintafel and Arakoda). 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: Established (WRAIR research, TGA registration records, DAEN) / Absence of longitudinal follow-up: documented (QVFA Senate submission, Royal Commission).

3.3 The ADF Trial Dosing Conditions

The dosing context of the AMI trials is material to any assessment of neurotoxicity risk.

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. One study (1 RAR, East Timor) used a 600 mg loading dose followed by 200 mg weekly.

The peer-reviewed and advocacy literature reviewed in the underlying research report notes that at these dosages, both drugs can concentrate at toxic levels in brain regions including the brainstem, vestibular system, and limbic system. Animal model studies have established that mefloquine at prophylactic-equivalent doses can cause lasting or permanent neuronal injury.

Evidential register: Dosing figures sourced from QVFA Senate submission — primary AMI trial records are recommended for verification where these figures are to be relied upon for legal or formal purposes. 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.

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: CYP2D6 mechanism: established in pharmacological literature / Application to quinoline toxicity susceptibility: plausible mechanism, consistent with available data / Voluntary testing results: documented (QVFA submission) — 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 advocate. His submission is detailed, sourced, and consistent with the international peer-reviewed literature. Readers should be aware of his standing as an advocate as well as a witness.

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. The advocacy submissions and the peer-reviewed Australian papers are not wholly independent sources, and this site notes that relationship wherever it is relevant.