Mefloquine and Tafenoquine Care Pack 3 of 3 - Medical research fact and fiction and what needs to be done NOW dated some time in February this year before the first Health Forum of its kind was held in Townsville.

1. AUSTRALIAN MEFLOQUINE & TAFENOQUINE
VETERANS
Current Situation
Needs of Affected Veterans and Families
Major Stuart McCarthy
Correct as at 7 February 2016
Tafenoquine
Mefloquine
“We owe it this generation of veterans to recognize the
neurological and psychiatric effects of mefloquine
neurotoxicity alongside PTSD and TBI for what they are:
the third signature injury of modern war.”
Dr Remington Nevin, 2013

2. Scope
• Background on mefloquine & tafenoquine toxicity in
Australian veterans
• Mefloquine neurotoxicity and health impacts
• Mefloquine as a cause of suicide
• Problems Experienced by Veterans with
Mefloquine/Tafenoquine Toxicity (M/TfT)
• Misinformation from Department of Defence
• Needs of mefloquine & tafenoquine veterans
• Support from Repatriation Medical Authority
• Support from Department of Veterans’ Affairs

3. Background on Mefloquine & Tafenoquine
Toxicity in Australian Veterans
• Synthetic quinoline anti-malarials known for their neurotoxic
properties since 1940s.
• Mefloquine:
• Developed by WRAIR in the 1970s, early testing on prisoners, soldiers
and subjects third world countries.
• Licensed by regulators in late 1980s - early 1990s in absence of
Phase III clinical trials.
• Introduced into ADF in the early 1990s but has never been first-line
anti-malarial:
• Prior to 2001 – several thousand prescriptions?
• Timor Leste trials 2000-2002 – approx 1,300 prescriptions.
• Since 2001 – additional approx 500 prescriptions.
• Concerns about long term neuropsychiatric health impacts raised by
US Dept of Veterans Affairs et al since 2004.
• Found to be neurotoxic in mid 2000s, able to cause lasting or
permanent brain injury, at dosages equivalent to prophylaxis.

4. Background on Mefloquine & Tafenoquine
Toxicity in Australian Veterans (cont)
• Tafenoquine:
• Similar drug to mefloquine, from same family, similar elimination half
life also allows for weekly dose.
• Has never been licensed by regulators including Australian TGA.
• Prescribed to approx 1,500 ADF personnel during trials in Bougainville
and Timor Leste 1998-2001.
• Found to be “more neurotoxic than mefloquine” in 2009.
• Scope of the problem:
• Since early 1990s, approx 5,000 Australian veterans administered
mefloquine or tafenoquine.
• Say 10-25% = 500-1,250 veterans with neurotoxic brain injury.
• Commonly misdiagnosed with PTSD, personality disorders,
“psychosomatic” neurological disorders.
• Confounding factor in PTSD, TBI, etc, with implications for research.
• Defence and DVA refuse to undertake follow-up studies, research etc.
• No acknowledgement, rehab or support for veterans and families.
• Denials, fraud, corruption and cover-ups, adding to distress.

5. Mefloquine (Lariam®)
Background:
• Member of the quinoline family of antimalarial compounds (quinine,
chloroquine)
• Highly effective prophylaxis / therapeutic for malarial infection
Mode of action:
• In the malarial parasite:
• Not well understood – possible effects on malaria parasite include:
• Alteration of heme ion transport
• Binding / inhibition of cellular processes in the parasite gut / nervous system
• Inhibition of cellular hemozoin formation
• Inhibits viral replication (ssDNA binding)
• In the nervous system:
• Binds to intra- and intercellular ion channels
• Disrupts mitochondrial function
• Alters neurotransmitter release
• Causes neuronal cell death

6. Adverse Effects - Disorders & Incidence Reported by
the Manufacturer (despite systematic under-reporting)
Frequency categories are defined using the following convention: very common (>1/10), common (≥
1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare
(<1/10,000).
Psychiatric disorders
Very common Abnormal dreams, insomnia.
Common Anxiety, depression.
Uncommon Agitation, restlessness, mood swings, panic attacks, confusional state,
hallucinations, aggression, bipolar disorder, psychotic disorder including delusional
disorder, depersonalisation and mania, paranoia, suicidal ideation.
Nervous system disorders
Common Dizziness, headache.
Uncommon Balance disorder, somnolence, syncope, convulsions, memory impairment,
peripheral sensory neuropathy and peripheral motor neuropathy (including
paraesthesia, tremor and ataxia), encephalopathy.
Ear and labyrinth disorders
Common Vertigo.
Uncommon Vestibular disorders (long term) including tinnitus and hearing impaired.

7. Symptoms of mefloquine toxicity - a toxic ‘limbic
encephalopathy’ (R. Nevin, 2015)
Psychiatric Physical
Vivid nightmares, hyper-realistic dreams, insomnia Vertigo
Anxiety, irritability, restlessness, anger, extreme violence towards self
and others, extraordinary self-harming behaviors, loss of social /
behavioral inhibition, suicidal ideation, suicide, depression
Accommodative
dysfunction (convergence
insufficiency)
Paranoia / persecutory delusions, psychosis Photophobia
Seizures (grand and petit mal) Disequilibrium
Visual / auditory / olfactory hallucinations Visual / hearing loss
Confusion, memory loss, impaired cognitive processing, loss of
concentration, amnesia, dissociation, de-reaslisation
Tinnitus
Problems with executive, spatial and verbal memory
‘COMMON’ – prodromal, lasting or permanent

8. SN
VTA
NAc
Str
Cb
Nigrostriatal / peduncluopontine (GABA, 5HT)
Hip
Am
Reward / Mesolimbic (DA)
Mesocortical (GABA, ACh)
PPTg
Sc
Rn
Dysregulation
Increased excitation
Loss of inhibition
Striato-cortical (Glut)
Ctx
Cortex / hippocampus:
Memory
Spatial coordination
Dreaming
Seizures
Psychosis
mTBI
PTSD
Subcortical:
Anger
Paranoia
Anxiety
Depression
PTSD
Brain stem:
Balance
Hearing
Vision
How / where
mefloquine affects
the brain?
‘Complex’ PTSD with additional defining features
J. C. Quinn, “Complex Membrane Channel Blockade: A
Unifying Hypothesis for the Prodromal and Acute
Neuropsychiatric Sequelae Resulting from Exposure to the
Antimalarial Drug Mefloquine”, Journal of Parasitology
Research, vol. 2015 , Article ID 368064, 2015.

9. Dose / Tissue Loading
Risk/severityofadverse
neuropsychiatricevents
0
100
Px Tx
Mild
Moderate
Severe
‘normal’
population
‘normal’
population
Co-morbidity
(other MH
issues)
Genetic
variants
Co-morbidity
‘Other’
interactions
Genetic
variants
(CYP450,
PgP, G6PD)
Genetic
variants
‘Other’
interactions
Co-morbidity
‘Other’
interaction
(drugs /
alcohol)
MaleFemale
Up to 100%
Why Are Some Affected and Not Others?
J. C. Quinn, “Complex Membrane Channel Blockade: A Unifying Hypothesis for the Prodromal and Acute Neuropsychiatric Sequelae Resulting from Exposure to the Antimalarial Drug Mefloquine”,
Journal of Parasitology Research, vol. 2015 , Article ID 368064, 2015.

10. Mefloquine as a Cause of Suicide
1. Demographic factors – males aged 30-34, indigenous, rural and remote populations.
2. Psychopathology & psychiatric hospitalisation – diagnosis of a mental disorder, particularly
affective disorders, substance abuse, anxiety disorders, personality disorders and
psychiatric comorbidity.
3. Previous non-fatal suicidal behaviour and suicidal ideation.
4. Family history of psychopathology and suicidal behaviour.
5. Physical illness, chronic physical pain.
6. Negative life events and low coping potential.
7. Marital status of divorced, widowed or separated.
8. Low socioeconomic status, unemployment.
9. Neurobiological activity – hypo-activity of the serotonergic system.
10. Psychological factors – hopelessness; high aggression and impulsivity, lack of reasons for
living, cognitive rigidity, low ability to solve problems, perfectionism, psychological pain.
11. Social isolation and lack of social support.
“Level A” Risk Factors for Suicide (Dunt, 2009)

11. Problems Experienced by Veterans with
Mefloquine/Tafenoquine Toxicity (M/TfT)
• No formal recognition of the chronic toxicity syndrome.
• Incomplete or wrong diagnosis – malingering, failure to perform in the
workplace, wrongful discharge, effects on career profile, family
breakdown – currently NO veteran support organisation for M/TfT
sufferers
• Underlying effects on brain chemistry cause paradoxical drug
reactions where treatments are applied – poor prognosis.
• Mis- or confounding diagnosis of PTSD, further precluding
appropriate treatment.
• ‘Complex’ syndrome when PTSD and / or mTBI also identified –very
poor long-term prognosis without correct diagnosis and treatment:
long-term hospitalisation, incapacitation or suicide.

12. Misinformation from Defence – Mefloquine*
“Approval” by the Therapeutic Goods Administration
• Claim: “Mefloquine … is … approved by the Therapeutic Goods
Administration (TGA) for malaria prevention.”
• Claim: “The ADF uses a loading dose prior to deployment to achieve
protective levels more quickly. This involves taking one dose on
each of three days in the week before deployment.”
• Fact: The TGA has approved mefloquine chemoprophylaxis as a
once weekly dose of 250mg.
• Fact: A once weekly dose of 250mg can cause permanent brain
injury.
• Fact: The ADF loading dose is three times the weekly dose
approved by the TGA for malaria chemoprophylaxis.
*http://www.defence.gov.au/Health/HealthPortal/Malaria/Anti-malarial_medications/Mefloquine/default.asp

13. Misinformation from Defence – Mefloquine*
Numbers of Personnel Affected by Mefloquine Neurotoxicity
• Deceit: 137 ADF members prescribed mefloquine 2010-2015.
• Fact: In 2000-2002 alone, 1,312 ADF members prescribed mefloquine
in AMI clinical trials in East Timor.
• Fact: In 2006 U.S. Army researchers found that Mefloquine is able to
cause permanent brain injury.
Permanent Brain Injury is “Rare”
• Claim: “In rare cases some neurological side-effects may be long
lasting or permanent.”
• Fact: There are at least several hundred serving and former ADF
members whose neurological and psychiatric symptoms are
consistent with mefloquine neurotoxicity.
• Fact: Defence refuses to undertake medical follow-up studies.
*http://www.defence.gov.au/Health/HealthPortal/Malaria/Anti-malarial_medications/Mefloquine/default.asp

14. Misinformation from Defence – Tafenoquine*
Tafenoquine is “Not Related to Mefloquine”
• Claim: “Tafenoquine is not related to mefloquine and acts quite
differently in the body.”
• Fact: Tafenoquine and mefloquine are both synthetic quinoline
drugs.
• Fact: Tafenoquine and mefloquine are both known to be neurotoxic.
Tafenoquine is not Neurotoxic
• Deceit: “Tafenoquine has not been shown to have any neurotoxic or
neuropsychiatric side effects.”
• Fact: In 2009 U.S. Army researchers found that “tafenoquine is more
neurotoxic than mefloquine.”
• Fact: The report of the 2000-01 AMI trial states “There was no
significant difference between [mefloquine and tafenoquine] in the
number or type of adverse events.”
*http://www.defence.gov.au/Health/HealthPortal/Malaria/AMI_research/tafenoquine-mefloquine/default.asp

15. Misinformation from Defence – Tafenoquine
Drug Trial in East Timor, 2000-2001*
Claims:
“Participation in the study was offered to a battalion group deploying to
Timor-Leste for a six month period. It was optional and voluntary. Efforts
were made to ensure deploying personnel were fully informed of the risks
and benefits of participation before they made their decision. They were
given a written information sheet, a verbal briefing and were asked to sign
a consent form. Those who chose to participate were also advised of the
option to opt out or withdraw from the trials at any time with no detriment to
their career or future health care.”
“Participation in the trials was not a pre-requisite for deployment. To
provide deploying personnel with appropriate protection against malaria,
those who chose to not participate in the trials were prescribed anti-
malarial medication in accordance with extant health policy, which included
doxycycline and mefloquine.”
*http://www.defence.gov.au/Health/HealthPortal/Malaria/AMI_research/tafenoquine-mefloquine/default.asp

16. Misinformation from Defence – Tafenoquine
Drug Trial in East Timor, 2000-2001*
Facts:
“… evidence before a Senate inquiry in Australia has called into question the ethics of
clinical trials conducted by the Australian Army Malaria Institute in 2000-2002. These
trials … failed to meet applicable ethical standards which describe military personnel
as vulnerable subjects. The subjects did not provide properly informed consent.
Hundreds were coerced into participating under threat of being excluded from the
deployment and investigators provided misleading or deceptive information regarding
the drug’s side effects. Foreseeable risks of lasting or permanent CNS injury were
disregarded and there was no appreciable benefit given the availability of safer
alternative drugs. The safety and wellbeing of the subjects were compromised by
administering personnel deployed on military operations with a drug known to cause
neuropsychiatric side effects, without first conducting appropriate laboratory testing.
Proper medical care has not been provided for subjects afflicted by chronic CNS
toxicity as a result of the trials. When the trial reports were eventually published, relevant
scientific findings regarding mefloquine CNS toxicity were omitted. According to the
applicable contemporary standards, the trials were unethical.”
*Major Stuart McCarthy, Were the Australian Army Malaria Institute’s 2000-2002 Mefloquine Clinical Trials in Timor
Leste Ethical?, 6 February 2016

17. Needs of Mefloquine & Tafenoquine Veterans
• Recognition/acceptance/information for affected veterans.
• Repatriation Medical Authority to determine mefloquine & tafenoquine
CNS toxicity as a distinct disease requiring dedicated rehabilitation.
• Support for outreach program/advocacy.
• Treatments/interventions:
• Harm minimisation – proper diagnosis to prevent mistreatment.
• Targeted wellness programs.
• Research:
• Follow-up health studies for affected veterans and families.
• Therapeutics, impact of M/TfT + mTBI + PTSD.
• Effective wellness/support programs – quality of life, return to work.

18. Need for a Dedicated RMA SOP
The Repatriation Medical Authority (RMA) has determined mefloquine and other
synthetic quinolines (tafenoquine is a synthetic quinoline) to be a causal and/or
aggravating factors in a variety of psychiatric, neurological, vestibular, and cardiac
diseases, however there is a need for correct diagnosis & management to
prevent mistreatment (including suicide risk) and ensure effective rehabilitation.
“Screening for mefloquine neurotoxicity … would assist investigation, correct diagnosis,
and differential diagnosis, not only improving the management of other prevalent
illnesses but also reducing the risk of misdiagnosis and subsequent mistreatment.
For example, pharmacotherapy presents an array of possible adverse effects. Despite
misconceptions to the contrary, trauma-focused psychotherapies can cause adverse
effects such as depression, panic attacks, suicide ideation, and substance abuse relapse,
even when found to be efficacious in correctly diagnosed patients. Minimizing extraneous
exposure to these therapies reinforces the case for proactively identifying and screening
mefloquine recipients to aid correct diagnosis, rather than relying on self-reporting of
psychiatric symptoms. A further measure would then be developing guidelines to assist
clinical care providers in identifying personnel affected by mefloquine neurotoxicity,
conducting differential diagnosis with other prevalent conditions, and providing ongoing
care and management.”
S. McCarthy, “Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness and Risk-Benefit
Analysis in the Australian Defence Force”, Journal of Parasitology Research, vol. 2015, Article
ID 368064, 2015.

19. Evidence for RMA Determination & SOP
“The RMA are yet to publish a determination relating to mefloquine as a
cause of toxic encephalopathy, although … they have previously
recognized chronic solvent encephalopathy as a diagnosable
disease. This may provide a useful guide on any future
determinations regarding mefloquine CNS toxicity. Notwithstanding any
remaining disputes or uncertainties regarding mefloquine toxicity, use
of synthetic quinolines has been independently determined by the
RMA to be a causal factor in a variety of psychiatric, neurological,
vestibular, and cardiac diseases. These are strikingly similar to a list
of conditions that the US Department of Veterans’ Affairs had identified
from case reports in a document advising of possible long-term health
effects of mefloquine as early as 2004.”
S. McCarthy, “Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness and
Risk-Benefit Analysis in the Australian Defence Force”, Journal of Parasitology Research,
vol. 2015, Article ID 368064, 2015.

20. Evidence for RMA Determination & SOP (cont)
“Reporting of psychiatric disorders linked to mefloquine use includes
cases of depression, anxiety, bipolar disorder, and suicide or suicidal
ideation. Reporting of neurological disorders linked to mefloquine use
includes cases of neuropathies, vertigo, and hearing loss or tinnitus.
Case reporting has also causally linked mefloquine to tachycardia. One
interesting observation about this list of disorders is that, although
mefloquine is a known ototoxicant, there is as yet no direct evidence
that it can injure the peripheral nervous system; therefore a number of
the recognized peripheral disorders may be more plausibly attributed to
the CNS toxicity syndrome previously described.”
S. McCarthy, “Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness and
Risk-Benefit Analysis in the Australian Defence Force”, Journal of Parasitology Research,
vol. 2015, Article ID 368064, 2015.

21. Evidence for RMA Determination & SOP (cont)
“… there is now compelling evidence for the previously described chronic CNS toxicity
syndrome, linked to mefloquine prophylaxis, consistent with the literature on
epidemiology and neurotoxicology. There is direct evidence that mefloquine is able to
accumulate in the human brain and interact with neuronal targets in the CNS, consistent
with both clinical observations and plausible pathophysiological mechanisms. There is
direct evidence that mefloquine … [is] able to cause lasting or permanent [neuronal]
injury ... Multiple neurological syndromes occur in response to this single neurotoxic
agent, including a variety of chronic, clinical disorders which have been determined as
causally linked to mefloquine use by [the RMA], in accordance with epidemiological
principles, against an appropriate standard of medical-scientific evidence. The syndrome
has varying presentations involving a host of nonspecific symptoms. The symptoms are
often mimicked by other prevalent neuropsychiatric disorders, with competent medical
authorities having determined that mefloquine use is able to confound the diagnosis and
management of those disorders.”
S. McCarthy, “Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness and Risk-Benefit Analysis in the Australian
Defence Force”, Journal of Parasitology Research, vol. 2015, Article ID 368064, 2015.
This evidence exceeds the standard required by the RMA.

22. Department of Veterans’Affairs
• Public recognition of mefloquine and tafenoquine CNS toxicity – no
more denials.
• Awareness for affected veterans, families, medical practitioners,
counsellors and case managers.
• Funding for research, including toxicology, diagnostics, veterans’
health and social studies.
• Dedicated rehabilitation programs.
• Dedicated family and social support programs.

23. Conclusion
Mefloquine and tafenoquine have almost certainly killed
and seriously wounded more Australian veterans than the
Taliban.
For these veterans and their families there has been no
acknowledgement or support. Indeed they have been
subjected to more than a decade of systematic neglect,
denial, fraud, corruption and abuse, by the medical system
that is supposed to support them.
This needs to be addressed urgently, including support
from DVA and other veterans’ organisations.