My name is Dr. Jane Quinn. I'm an associate professor and associate dean for research in the faculty of science at Charles Sturt University. I'm also a co-founder of the Australian Quinoline Veterans and Families Association.
My background relevant to this inquiry is 30 years of experience in comparative biomedical research. I'm a Ph.D.-qualified neuroscientist and undertake research on the impact of toxins in whole animal systems and tissues, specifically the brain. Of relevance to this inquiry, I have personal lived experience of the adverse effects of mefloquine, also known as Lariam, as my late husband committed suicide after taking mefloquine for overseas exercises with the British military.
There is no doubt that there are many thousands of veterans globally whose lives have been significantly impacted by taking mefloquine for military service. These are genuine people who have suffered for many years without necessarily understanding their symptoms, why they did not go away with treatment or continued to get worse over time, some to the point of severe cognitive impairment; radical sleep disorders; severe anxiety and mood disturbances, such as bipolar disorder; or in some cases, they succumbed to suicidal ideation and suicidal completion.
Mefloquine causes permanent neurological and neuropsychiatric changes in a significant minority of those who take it. Many of these veterans have been told they have treatment-resistant post-traumatic stress disorder, without it being acknowledged that their symptoms were actually caused by an ongoing neurological brain injury. Some have been subjected to treatment regimes with multiple drugs, including antipsychotics, and in some cases their brain is further exposed to injury through ECT without ever having received a true or complete diagnosis.
As you have heard from other witnesses to this inquiry, the neurological and neuropsychiatric side effects of mefloquine and other quinoline antimalarials have been well-known for many decades. It is a key question as to why it has taken so long for the impact of this drug to be acknowledged in military veterans. Recognition that mefloquine causes long-term brain injury and other systemic medical conditions is a first and necessary step to getting effective and appropriate treatment, and ongoing medical support for those impacted.
You've heard from a number of experts who have suggested this is not the case, that their brain injury does not exist, but their arguments are not supported by a veteran's experience nor that of the emerging literature, when mefloquine exposure is taken into account.
One of the witnesses to this committee commented that the medical condition caused by exposure to mefloquine cannot be diagnosed. This is not the case. The spectrum of symptoms commonly observed in individuals who have suffered a severe or lasting reaction to this family of drugs is quite discrete. It includes insomnia, sleep disturbances, vivid dreams, depression, anxiety, paranoia, cognitive impairment and memory loss, tinnitus, vestibular dysfunction, peripheral neuropathies, gastrointestinal frequency or chronic diarrhea, and can include seizures, suicidal ideation and attempted and completed suicide.
The disease cannot be identified by name in a diagnostic manual under a discrete code in either DSM-5 or ICD-10, but this is not the same as the condition not existing.
There is a syndrome that has a consistent pattern of comorbid symptoms that can be identified in response to mefloquine exposure, very similar to the diagnostic process used to identify lupus or, indeed, post-traumatic stress disorder. Therefore, is this a condition that exists? Absolutely, yes.
Chronic or acute mefloquine toxicity syndrome, which has been shortened by some to the term “quinism”, is the condition we are talking about today.
Can the particular set of symptoms associated with mefloquine toxicity be confirmed by a discrete diagnostic process, creating a differential to other specific neurological or neuropsychiatric conditions? The answer to that is yes.
The science behind the syndrome is complex. Mefloquine is a pan-neuronal drug with broad activity within the brain. It's highly lipophilic and able to cross the blood brain barrier. It can, therefore, have broad reaching impacts across the central nervous system.
Others have questioned the role of a brain stem lesion in mefloquine toxicity syndrome. We must be mindful in making sweeping statements about the area of the brain impacted by mefloquine that both deep brain areas, such as the brainstem, Raphe nuclei and ascending reticular activation system, or subcortical areas impacting emotion and those controlling learning and memory, such as the hippocampus, all are impacted by exposure to mefloquine. Definitive biological studies in humans to confirm this would be simply unethical.
The broad mode of action is reflected in the variety, but consistency, of symptoms that mefloquine toxicity can show, impacting both superficial and deep brain regions. It does not just cause seizures and psychosis, which are indicative of higher cortical to subcortical effects, but also emotional and behavioural changes controlled by the amygdala and other subcortical regions.
Tinnitus and vestibular disorders can be both central and peripheral, and this is where the brain stem can be involved. As such, a description of mefloquine as a brain stem injury and, therefore, simply looking for cellular impacts in the brain stem would be conferring a simplicity to this syndrome that is not reflected in its symptomatology.
You have heard from a number of other witnesses that mefloquine can cause both short-term and long-term neuropsychiatric and neurological side effects, but these are not the only health impacts associated with mefloquine. They can include severe gastrointestinal disease, joint pain and peripheral neuropathies, so there is a spectrum of ill health associated with a reaction to mefloquine, all of which can have a significant life-changing impact on the sufferer and last for many decades post-exposure.
Perhaps some of the most compelling arguments to support this statement that exposure to mefloquine causes long-term health deficits are findings in a recent study commissioned by the Australian Department of Defence and Department of Veterans' Affairs. This study reviewed health surveys undertaken by Australian soldiers who had been given mefloquine or another anti-malarial treatment during active service in Bougainville or East Timor. This was, therefore, a study comparing like with like, apart from their drug exposure, and included exposure to battle conditions. Although it was based an opportunistic retrospective dataset, this analysis identified that the personnel who had been given mefloquine were more likely to have poorer health scores in the long term than those who had received doxycycline or another anti-malarial.
As an analysis, commissioned by Defence, of scientists who were trusted Defence research partners, this evidence could not be overlooked. Perhaps on the basis of this finding, the Australian government accepted in principle all of the recommendations of the recent Senate inquiry into the use of mefloquine and tafenoquine in the Australian Defence Force, and committed $2.1 million Australian dollars to a treatment and rehabilitation program currently being implemented by the Department of Veterans' Affairs in conjunction with its counselling service, Open Arms.
I'm proud to say that I sit on the steering committee for this program, and I hope it will provide significant assistance to the group of veterans who have, to date, been left without assistance by the organizations meant to help and treat them.
Acceptance that mefloquine causes long-term harm is critical to resolving the health issues for those affected, and I believe that this evidence is not in doubt. The question is what the next steps are for those individuals and what strategies can be implemented to help them.
Comprehensive neurocognitive screening should be applied to all veterans to determine their neurocognitive, as well as psychological, health status. A 360-degree health review should be implemented to look holistically at the health and well-being of these veterans and their families, and appropriate support strategies should be applied, including access to occupational therapists, psychologists, psychiatrists or other health care professionals as appropriate.
Pharmacogenomics screening, particularly for metabolic enzymes of the cytochrome oxidase P450 family and for pharmacogenetics markers that have been shown to be required for mefloquine metabolism, should become mandatory for all military personnel prior to their being prescribed any anti-malarial drugs to ensure both efficacy and safety, as well as the efficacy and safety of other treatments that they may be given during their military service or after.
This screening should also be applied to all veterans, particularly those affected by mefloquine, to ensure that any drugs now being prescribed are not going to cause further complications.
I would urge this committee to look to the future to ask the question “What is the best assistance that can be given to the veterans suffering from long-term health impacts from mefloquine for military service?” and to look to programs currently being designed in Australia to go at some of their outcomes.
I very much appreciate being invited to speak to this committee, and I am happy to answer any questions.
I'll make a few brief comments.
I'm a professor emeritus of pharmacology and toxicology, psychiatry and medicine at the University of Toronto. I've been involved in research, teaching, and clinical care, involving psycho-pharmacology—that is drugs that act on the brain—for over 40 years.
I must say, Mr. Chairman, I was somewhat surprised to be invited to meet with the committee because it wasn't entirely evident to me what you expected. I suspect it may have something to do with my very broad background in basic and clinical neuroscience and my involvement in pharmacal kinetics and risk factors for drugs. One area that I have worked in that might of particular use to the committee is the causality assessment of drug-related events. That is the determination of whether a drug has actually caused a particular adverse event.
One of my papers, for which I was the senior and supervising author, is probably particularly relevant to the work of the committee. This paper was called “A method for estimating the probability of adverse drug reactions”. It is a systematic algorithm for looking at all the factors and rating the likelihood that a drug actually caused a reaction and to take into account the relative contribution that the drug might have had in the face of other factors that may bear on a joint risk between the drug and the particular adverse event.
I agree with Professor Quinn's characterization of the evidence that there are acute and chronic, often serious, adverse events of administering mefloquine. I've used this particular algorithm in many settings, from single patients and groups of patients to literature reviews and so forth. Several years ago, I used this particular way of assessing causality to apply to a non-military individual who in error dispensed mefloquine instead of Malarone and had a profound, acute, and chronic, neurotoxic reaction.
Professor Quinn has outlined some of the issues around diagnosis. Of course, it's very tempting to try and fit what happens after a drug is given into a very tight box. You give penicillin; you get a rash, and it seems fairly straightforward.
In the case of chronic neuropsychiatric toxicity, it's not really that simple because a drug that has such reaction interacts with the individual's past history, their concurrent history, if they have mental disorders or are subject to other stresses. It's not surprising that the manifestations are quite diverse. I have heard people sort of argue, “How could a drug cause such a broad kind of effects?” Anyone who's involved in behavioural science and neuroscience doesn't find it surprising, really, because very many different parts of the brain can be affected by drugs that can bind to different receptors in different parts of the brain. The way the adverse event shows up—it's phenotype, as we call it—is determined by antecedent and concurrent factors.
A problem that frequently comes up is that often the information that's available is incomplete. Many of the studies alleging that the neuropsychiatric consequences of mefloquine are very rare are really done from data sets that are very weak. In those that have been designed properly, prospectively or with matched controls—mefloquine has even been given to healthy, normal volunteers—indicate that it has a very narrow margin of safety. You can raise the dose two-fold or three-fold, and you'll have 40% or 50% of the healthy, normal volunteers having acute effects from the drug.
The acute effects sometimes get passed off as if they're not important, but we're talking about a drug that's used for prophylaxis in people who don't have the disease. When you give the drug to normal volunteers and you see vivid dreams, disassociation, and effects on cognition, this is a warning sign that this drug has potentially serious toxicity.
One issue that comes up with mefloquine is that the toxicity doesn't seem to be entirely predictable. Now, it is true that higher dosages give rise to greater frequency of adverse events, and some of them are very unpleasant. However, it's not so clear with the onset of chronic neurotoxicity. Often, an acute event after taking the drug is a warning that the individual has some risk factor, that the drug is interacting and is going to cause a problem.
What we find is that there are other things that must be afoot. For example, we know that mefloquine gets out of the brain by a particular transport protein. There are individuals who lack this transport protein, so mefloquine can reach very high concentrations in their brains, and that puts them at particular risk. It's really the mefloquine in the brain—amount or concentration—that's important.
The final comment I would make is to endorse the systematic approach that Professor Quinn has urged. It is extremely important that individuals who are to receive any drug that has risk be explicitly warned and that there be careful documentation, and that individuals who have the risk factors don't receive certain drugs.
I know that there's been interest in this particular field in drug labelling, but drug labelling is not a good way to inform patients or even physicians about what the problems are. The surgeon general's review identified a lack of proper documentation among military individuals with respect to having even received this drug, and identified individuals who received the drug who had contraindications.
There's something clearly not right, and I think Professor Quinn outlines a very reasonable, systematic and probably long overdue approach.
Having said that, I think that the current practice of not prescribing this drug is entirely appropriate. I noticed in some of the material I looked at before today that somehow patients are given an option that they can indicate they would be prepared to take the drug. I think we're past that. I don't think this is a drug—except in situations where there is extremely careful monitoring and very knowledgeable individuals are prescribing the drug—that somebody can say, “Well, yes, I'd like to take mefloquine”. There's an implication here that is outside of the normal medical world that I work in.
My recommendation is that you take this assessment of causality, this strategy, and apply it systematically to cases that are either emergent ones or retrospectively.... This involves two steps: applying the algorithm to assess causality, and then assessing what information is missing that makes it difficult to make the assessment of causality. Just because it looks like it's not likely the drug doesn't mean there isn't a reaction caused by the drug. It's usually because the information is not available to make the assessment. This is the problem in most of the literature that people point to when they're trying to support that this is a very rare kind of thing, or that it doesn't happen at all and so forth. That's not the real situation.
Yes, to some extent. We have an interesting situation and it's somewhat comparable to Canada's in that there were a number of veterans who received mefloquine during clinical trials carried out by defence during the late 1990s and early 2000s.
Interestingly, because they were exposed to the drugs during a clinical trial regime, that exposure wasn't documented in their main military records. It was held separately. What became apparent when we were first investigating the situation here in Australia was that those individuals were not aware that they had been exposed to mefloquine or another experimental drug, tafenoquine, because that was not documented in their general medical records. Those medical records had been held separately. So accessing those medical records became extremely important.
What is unique, slightly, about the Australian situation is that those individuals are therefore extremely well documented, and the retrospective study that I talked about in my opening statement actually was cross-referencing between some of those data sets, because there were individuals who could be discretely identified. We know quite precisely the number who were exposed during clinical trials—it's around 4,500—to the two experimental drugs, one of which was mefloquine, and then there has been some detailed documentation kept since about 2010 that allows us to know that there were at least another 500 individuals exposed after that.
There is a paucity of information from the late 1980s through to about 2000, when more detailed electronic medical records were kept, so it's an open book as to who exactly was taking mefloquine and who wasn't. That's a very similar situation to that in the U.K., the U.S. and Canada, where there's been a period of time prior to electronic medical record-keeping when it is actually very difficult to know exactly who took the drug and who didn't. What we do know is who was deployed to regions where it was the drug of first choice, so individuals deployed to those locations could almost be guaranteed to have taken that drug.
However, as Dr. Sellers says, one of the key things that need to be done is to actually interrogate those personnel to find out if that was the case, because recollections of whether a drug was taken daily or weekly can certainly give a very strong indication for those who were exposed during that period of time as to whether they were likely to be taking—
I was asked to submit evidence to the Repatriation Medical Authority in order to assist them in the process of defining whether or not they would accept a statement of principles for acquired brain injury in relation to mefloquine, tafenoquine and primaquine specifically.
It was an interesting process in that I thought the remit of the investigation was flawed. It had looked across three drugs, one of which has a very discrete neuropsychiatric profile that's well documented; one that was at that time an experimental drug that had very limited evidence available about it outside of the development process for the pharmaceutical industry; and another that had not been systematically reviewed for some time in terms of its safety in terms of neuropsychiatric side effects.
It was an investigation that was very difficult to provide evidence to; therefore, the outcome, which was that the causality link was not determined, was probably quite predictable. However, what should be noted is that the Repatriation Medical Authority currently accepts 15 separate conditions associated with quinolines, or mefloquine specifically, in terms of poor health outcomes that can be claimed through the system in Australia.
If you put those 15 statements of principles together, you essentially get the syndrome we have described as mefloquine toxicity syndrome.
We were looking to confirm that the neurocognitive component could be identified as a separate condition, and unfortunately that was not upheld. I think the evidence for that is emerging and will need to be confirmed through specific, targeted case series. One of the issues around this area is that the desire to undertake those specific review case series has been extremely poor. The more recent evidence coming out of Australia in that sense will, I think, strongly assist us in the process of defining that statement of principles in the future.
Thank you to the witnesses for being here today to give your perspectives on this.
I want to put things in context for you. You may or may not know this, but I think it's worth getting on the record that we had the top medical people of the Canadian military here—this would be our Department of National Defence, or DND—and Brigadier Downes, the surgeon general of our DND. He said that he had done extensive research and had read just about everything there was about mefloquine and its effects on military people—this is the top medical officer in our national defence department—but could not agree with anything you would have said today.
In other words, his view was there is not enough evidence and not enough study, just as my colleague across the table, from a medical background, was trying to draw the connection between a study and the fact that it did not show any evidence of the correlation that both of you clearly outlined to us today. Not surprisingly, either, the other witnesses we have had at this committee have all drawn the same connection that you have—except for our military brass, the people making the decisions within our military circles. This was the drug of first choice right up to Afghanistan, in particular the one that stands out in Canadian history in terms of some of the effects and psychological and mental health issues that happened in Somalia and the atrocities that happened through military hands.
One of our more respected generals, I believe, who's now a senator, is Roméo Dallaire. He has said unequivocally that we should not be giving this to people in the military. He forcefully said it, publicly, and yet we are here at committee asking questions of our military leaders who don't find any credibility in what you're saying. They obviously haven't read Professor Quinn's references to what's happened in Australia.
Obviously, you have had study. Interestingly enough, there was never a reference to the fact that Australia had taken action on this and had developed policy within government to compensate and help these individuals who are struggling so much.
I put that in context because it's simply a matter of screening, of asking those who served whether they took this drug. That would be up to and including Afghanistan and including the ones who are still taking it in our military.
So I'm outraged; you might be able to see that across the video screens. I'm outraged by the fact that this government has not taken action on it—or other governments previously, if we had this information. It seems to me that the database is there. That was another question brought up: How do we know who took it? Well, we know who served. We have all their records. We ask them, “Did you take it?” That's all. Then we acknowledge the fact that there is a correlation. Australia has dealt with it, the United States is dealing with it and banning it, and yet we somehow stubbornly within our military want to continue to allow our military people to take it. If we did nothing more than just stop it from being offered, we'd be doing a service to our military people and to future veterans. We're here talking about veterans, the ones who took it and the ones who have claimed the correlation of these symptoms and these problems with their health issues, and we have a defence and a government trying to say that it doesn't exist.
When I give you that context, my question is, what do you think the next steps for Canada should be on this issue of those veterans who consumed this toxic drug and those who are continuing to consume it? Could I have your general thoughts, each of you?
Why don't you go first, Professor Quinn? Then perhaps Dr. Sellers could weigh in as well.