Good afternoon, Chairman and members of the committee. It is a real pleasure to be here today.
I would like to share the perspective of a military psychiatrist, which is what I was for many years. I have been around mefloquine, and consistently been uninformed as to the toxic effects of mefloquine.
Normally, when I give a presentation, I start with World War I and roll up through World War II, Korea and Vietnam. In the interest of time I will truncate that today and I will start with Somalia, but all wars produce both physical and psychological reactions to a war, and we often don't know which it is. You remember shell shock from World War I, or the Gulf War syndrome more recently, with which we've gone round and round.
The short version of the presentation is that many things we have seen over the last 30 years that we thought were psychological we can now attribute, partially or completely, to the effects of mefloquine. With regard to Somalia, I deployed there early in Operation Restore Hope, as an army psychiatrist, a young major. I deployed with the 528th combat stress control team out of Fort Bragg. Our purpose was to diagnose, treat and evaluate combat stress control reactions.
We knew very little about mefloquine then. The day I got into the country a young solider was evacuated, acutely psychotic, we believe secondary to the effects of mefloquine.
I worked mainly with the American forces, although I was asked to evaluate Corporal Matchee after his suicide attempt. He was in a coma so I could not evaluate him.
During our time there we spent a lot of time discussing the dangers of malaria, and the neuropsychiatric short-term effects of mefloquine became apparent to us, but we did not think about the long-term effects at that time.
Fast-forward, we returned home. We were using less mefloquine. The murders, murder-suicides at Fort Bragg happened in 2002, shortly after we had gone into Afghanistan. I was part of a team asked to look at mefloquine; could this be related? At that time, again we didn't know very much about mefloquine. Various studies said one in 4,000, one in 10,000, one in 18,000 people may have neuropsychiatric effects from mefloquine. We were just told or knew about the short-term effects. We studied the indexed cases—you may or may not remember—Staff Sergeant Nieves, who killed his wife and then himself; Master Sergeant Wright, who killed his wife, hanged himself in a jail cell six months later, apparently hallucinating; and Staff Sergeant Brandon Floyd, who had been off mefloquine for six months when he killed his wife and then himself.
We looked at a lot of factors, but again, back then we didn't think about long-term effects of mefloquine. When you stop most medications, the effects go away. We found a combination of things responsible for the murder-suicides, which included marital fidelity and rapid operations tempo, but I got interested in mefloquine as a result of both those experiences. Back in 2004 I presented a paper on the neuropsychiatric effects of mefloquine.
Moving quickly through time, I retired from the army in 2010. Staff Sergeant Bales committed the atrocities in early 2012, and I immediately thought of mefloquine. During that intervening period the U.S. Army's use of mefloquine had declined precipitously, although it was still being used. Another factor was that headquarters repeatedly said we had to screen and document the screening of soldiers to make sure they didn't have mental illness or traumatic brain injury. Over and over again our systems found problems with the way we screened and documented soldiers for mental illness, traumatic brain injury, anxiety or suicide. Of course, during that time period from about 2004 to 2010, our suicide rate in the army doubled.
After my retirement, my most recent work has been with the VA as a psychiatrist. I cannot speak for the VA here, but I will say that we started to look through the risks at the War Related Illness and Injury Study Center. We looked at soldiers and other veterans in the U.S. who we thought may have suffered long-term effects from mefloquine. We found a variety of diagnoses. We found very seldom a clear picture, but certainly a lot of veterans who ascribed their symptoms to mefloquine.
Although I've been retired from the army since 2010, I've been very active in veterans' and military issues. I have followed the mefloquine controversy closely. Just last week one of my newest books came out, entitled Veteran Psychiatry in the US. We cover a whole range of issues for veterans, including toxic exposures. My colleague Dr. Nevin has a chapter on the effects of mefloquine.
I would like to leave you with a couple of thoughts. One is that, again, every war has produced physical and psychological reactions that we don't understand at the time. I think the last 20...or going back to Somalia or longer. After a period of time, there are both physical and psychological reactions. At the conference we just had on mefloquine, my colleague Dr. Kudler, who is a world-renowned expert in post-traumatic stress disorder, talked about how 40 or 45 years ago, nobody believed in PTSD, post-traumatic stress disorder. Later on, we had people who thought traumatic brain injury wasn't a factor. Over and over again, you hear case reports or discussions that gradually lead to recognition.
This question about the long-term effects is something that has puzzled me. Back when I was in Somalia or at Fort Bragg, and we were trying to figure out why Sergeant Floyd would have murdered his wife and then himself, being apparently very paranoid and psychotic at the time, we didn't have a mechanism to understand that. Now we have more ideas about how the drug may affect the brain stem and other parts of the brain to cause both neurologic and psychological problems.
I would like to close with an example that's very relevant to me in my current sitting. I'm chair of psychiatry at a hospital in Washington, D.C. I'm not speaking on their behalf, so I won't go into that in detail. As a psychiatrist, however, I work with a lot of patients who have been on antipsychotics in the past or who are on antipsychotics now. You're familiar with these medications—thorazine, haloperidol or haldol, risperdal, quetiapine and olanzapine; there's a range of them. We know they cause such short-term effects as dystonia, which is a rapid clamping of the muscle, or extrapyramidal symptoms, or akathisia, a lot of muscle movements. We also now know that they cause long-term problems such as tardive dyskinesia. You've perhaps all heard of that. That's TD, the oral buccal movements of the mouth or the tongue. If you go to a nursing home, you will often see the repeat movement. We know that these symptoms wax and wane over time, but when the medication is stopped, they may not go away. They may get worse. I'm not saying that the long-term effects of mefloquine toxicity are the same as tardive dyskinesia. Rather, that's a model that can be used. There are short-term effects that may stop when the drug goes away, but then there can be long-term effects.
As we move into the question and answer period, I know that you'll ask me many questions I don't know the answer to, because in many cases we don't have the science. We haven't done the studies. You might ask me how mefloquine affects women differently, to which I might say, “Well, I think it does; we have some studies...”, or you might ask why mefloquine toxicity is so prominent in veterans from Somalia and maybe less so in other conflicts. I have some hypotheses, but I don't have all the answers.
There are, however, a couple of things I'm very sure of. One is that in both the U.S. and Canada, we need to do a better job of screening veterans for exposure to mefloquine. That would be fairly simple.
Have you ever taken the once-a-week anti-malaria pill? As a follow-up to that, have you ever experienced a variety of symptoms that include dizziness and nystagmus?
The other question that I'm very clear on is that you have some percentage of your veterans who will have significant and permanent problems because of mefloquine. I cannot tell you the exact percentage and I cannot tell you who they are. Based on all of the work that Dr. Nevin and I, and others, have done, you have veterans who have suffered permanent injury. I think it is critically important for you all to identify those veterans.
As a psychiatrist I see a lot of people who are suicidal; that's my bread and butter. One of the things I've seen over and over with people suffering from mefloquine toxicity is they don't know where the suicidal feelings are coming from. They want to jump in front of a bus, they want to stab themselves or sometimes they want to kill their family. It can be just so helpful to them to know that this isn't just them; it's that they've been poisoned by a drug and that's why they're feeling this way. Just knowing about that exposure can be very helpful in having them say, “Okay, it's not just me. It's the medication.” The relief that veterans get is enormous.
With that, let me conclude my remarks.
I'll be happy to take your questions. Some of your questions I won't be able to answer because they're either outside my scope or we don't know, and some I may defer to Dr. Nevin to answer.
Thank you very much for your attention.
Thank you, Mr. Chair, and thank you, members of the committee, for inviting me here today.
I'm Dr. Remington Nevin, and I'm the executive director of the Quinism Foundation, which is a Vermont-based non-profit organization. Our mission is to support and promote education and research on the medical condition known as chronic quinoline encephalopathy, otherwise known as neuropsychiatric quinism. This is the medical condition caused by poisoning of the central nervous system by mefloquine and related quinoline anti-malarials.
I last provided evidence to this committee in December 2016 in the form of a written brief on the topic of mefloquine, and in that brief I commented in part on what were then the recent changes to the Canadian mefloquine product monograph updated in August of that year. The monograph was subsequently updated again in, I believe, September 2017, following the publication of both the Canadian Forces surgeon general report on mefloquine and the Health Canada report on mefloquine. It is the language from this most recent update that I will refer to in my testimony today.
The current Canadian mefloquine product monograph now warns physicians and other prescribers, in bold typeface, that:
Patients should be advised to consult a healthcare professional if any neurological and/or psychiatric symptoms occur during the prophylactic use of mefloquine
—for the prevention of malaria—
as healthcare professionals may have to discontinue mefloquine and prescribe an alternative medicine for the prevention of malaria.
The monograph further clarifies, in a boxed warning, that not only may mefloquine have to be discontinued, but that “mefloquine should be discontinued” and an alternative medication substituted if psychiatric or neurologic symptoms occur during prophylactic use.
The updated monograph then also makes clear that:
Psychiatric symptoms ranging from anxiety, paranoia...and depression to hallucinations and psychotic behavior...can occur with mefloquine use. Symptoms may occur early in the course of mefloquine use and on occasion...these symptoms have been reported to continue long after mefloquine has been stopped.
The monograph then also makes clear that:
In a small number of patients it has been reported that dizziness or vertigo and loss of balance may continue for months or years after discontinuation of mefloquine, and in some cases vestibular damage may be permanent.
There are several important points being made in this approved labelling, which has been approved by Health Canada and, therefore, presumably are being agreed to by Health Canada.
The first point being made is that there is an acknowledgement by Health Canada and the product's manufacturer that in some cases there are long-term psychiatric and neurologic symptoms that result from mefloquine use. The assumption in the labelling is that there is a likelihood of these symptoms being causal, meaning caused by the drug, and not merely associated with its use. To be clear, this causality is really not disputed by experts. There is broad consensus among international drug regulators on this fact. There's good evidence from the medical and scientific literature and from the accumulated pharmacovigilance data—meaning the adverse-event reports—that symptoms such as insomnia, abnormal dreams, nightmares, anxiety, depression and cognitive dysfunction, among other psychiatric symptoms, for example, can continue for years after use of the drug. That's the first point.
The second point being made by this updated language is that there's also tacit acknowledgement by Health Canada and the drug's manufacturer that to reduce the risk of these long-term symptoms, mefloquine should be discontinued at the onset of any psychiatric or neurologic symptom. This is made clear by the additional language in the monograph, that:
During prophylactic use, if signs of acute anxiety, depression, restlessness or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative medication should be substituted.
It should be clear, given the other language in the monograph, as well as international drug labelling, that these specific symptoms—the acute anxiety, depression, restlessness or confusion—should be considered illustrative and not exclusive. For example, the European drug labelling makes clear that abnormal dreams, nightmares and insomnia should also require the drug's discontinuation. I believe this is clear from the Canadian product monograph language as well.
For the purposes of this committee’s mandate, these two points have profound implications for the care of Canadian veterans, tens of thousands of whom since the 1990s have been exposed to mefloquine, in most cases without the benefit of these enhanced warnings.
One obvious and profound implication is that for those Canadian veterans who were ordered to take mefloquine prior to these warnings appearing in the product monograph, and who were therefore not told to discontinue the drug at the onset of any psychiatric symptoms, there is an increased risk that they experienced the “more serious event” that these psychiatric symptoms are considered prodromal to. To be clear, this more serious event is in fact the development of the long-term psychiatric and neurologic symptoms that in some cases can contribute to disability.
This then raises the question: what is being done systematically by Veterans Affairs Canada and others to identify those veterans who did in fact develop these long-term psychiatric and neurologic symptoms as a result of their use of mefloquine? The answer appears to be nothing. As a result, in a recent letter to the former Minister of Veterans Affairs, we called upon VAC to implement a program to screen veterans for a history of symptomatic mefloquine exposure, meaning those veterans who not only recall having taken mefloquine but who recall having experienced those symptoms that are specifically listed as being prodromal to the more serious event, which we understand is a euphemism for the development of disability from the drug’s use.
Unfortunately, what we received in reply from the current was a very unsatisfying response, which suggests to us that VAC is not taking this issue seriously. I'd be happy to share this response for the record on request.
As we noted in our original letter to the veterans affairs minister, we believe that screening veterans “for symptomatic mefloquine exposure is a necessary first step to raising clinicians’ awareness of the prevalence of mefloquine poisoning among the recent Canadian veteran population”. We also believe that screening will permit VAC to more accurately and validly “estimate the total number of veterans exposed to mefloquine” and “how incomplete prescribing documentation may be”. We also believe that this will permit VAC to estimate “how many veterans may be suffering disability who may become eligible for disability compensation” as a result. As we noted in our original letter, our organization would be pleased to work with VAC to help implement such screening in this population.
That concludes my prepared testimony. I would be very pleased to answer any questions the committee members may have. Thank you.
You maybe asking the same question, but as a clinician and as a psychiatrist, let me say how I put it together.
There are lots of drugs, either illegal or legal, that cause things like hallucinations—things like LSD. There are things like PCP that cause hallucinations. PCP can also cause long-term problems. One thing that confused me initially when I was looking at it..... We knew about the insomnia, the bad dreams, the anxiety and the hallucinations. That was pretty obvious back then. More recently, we've learned that people will actually pop two or three of these drugs because they want the hallucinations. We knew about the technicolour dreams.
In the medical and psychiatric literature there is a lot of information about the neuropsychiatric side effects of all these things I'm talking about. What we are just beginning to put together in the literature are the neurological side effects and chronic psychiatric side effects specifically of mefloquine. Although, again, we know that with other things like PCP, you can have flashbacks and insomnia for a long period afterwards.
One thing that confuses many of us, perhaps, is that we got PTSD after the end of the Vietnam War. To remind you, we all know that the symptoms of that are flashbacks, the feelings of being numb and distant, and intrusive thoughts. What we haven't totally sorted out is that in Vietnam, many of our veterans were also on variations of the quinolones. We don't know if that actually confused the picture and we didn't recognize it back then. We labelled it all PTSD.
As I've gone along on this journey and learned more about the neurological side effects, the distinction between psychological and physical becomes blurry. It's all in the brain, whether or not it's the damage to the neurons, which we're seeing more and more of. Is it the psychological trauma? We're going down the road that this is really a toxin to the brain.
Did I answer your question?
It wasn't quite how you asked it.
So we know that mefloquine and the related quinolines are neurotoxic and we know that this neurotoxicity is demonstrated in animal models. It affects very specific areas of the brain stem and limbic system. As Dr. Ritchie was alluding to, on animal model studies, these drugs cause microscopic lesions in particular areas of the brain and brain stem, and based on our knowledge of neuroanatomy and neurophysiology, we would expect that lesions in those areas manifest as certain signs and symptoms.
For example, if there were tiny microscopic lesions in the vestibular nuclei in the brain stem that control the balance sense and that contribute to our orientation in space, such lesions would manifest as chronic disequilibrium, dizziness, a sense of vertigo and an abnormal gait. This is precisely what we see in veterans who complain both of psychiatric symptoms from mefloquine and of these symptoms.
These veterans who return home complaining of persistent nightmares, anxiety, depression and cognitive dysfunction, on careful examination by clinicians such as neuro-optometrists or neuro-otologists, are found to have evidence of central—meaning brain stem—visual or vestibular dysfunction.
We have a mechanism to explain this. It's not just PTSD. It's not just traumatic brain injury. The most parsimonious explanation for this is that they were exposed to a neurotoxicant that resulted in permanent dysfunction in their brain stem, and this explains the chronic disability.
Thank you. The product monographs for any drug are routinely updated on the basis of new safety signals and the need to warn the public of drug safety risks.
I am more familiar with the history of the U.S. label, but I believe the Canadian label language closely mirrors that of the United States. I can say that in general, beginning with the first availability of mefloquine in the late eighties, early nineties, the product insert should have said that if during prophylactic use of the drug—meaning for prevention of malaria—anxiety, depression, restlessness or confusion are noted, these either may or must be considered prodromal to a more serious event, and the drug must be discontinued.
In fact, in pretty much every jurisdiction where mefloquine, then marketed as Lariam, was available, this language existed in the product insert. We have known all along that mefloquine can produce a toxic encephalopathy that manifests with these symptoms and that the early manifestation of these symptoms predicts the development of more serious encephalopathy that can over time contribute to this risk of permanent neurotoxicity and disability. I think this is what permitted Roche—the original manufacturer of Lariam—to minimize their legal exposure such that they could with confidence market an inherently dangerous product. I think if you ask lawyers they will say that Roche has some very limited exposure, because they have warned all along that you are to stop taking this drug if you develop anxiety.
But the question remains. How is one supposed to use a drug in a military setting, a drug designed for military use, that has to be discontinued at the onset of anxiety? Isn't anxiety a ubiquitous emotion in deployed settings? How is one realistically to distinguish between anxiety from a toxic encephalopathy from mefloquine and anxiety from being deployed? It suggests the drug is inherently defective for the indications for which it was developed.
Now, that being said, that language was never emphasized. It was never understood by rank-and-file troops. It was never understood by military psychiatrists in the field, and certainly soldiers taking the drug were never told to discontinue the drug at the onset of those symptoms.
It's an excellent question.
The fact is there are individuals who, for whatever reason, and we don't understand why—are fortunate to have escaped the horrific adverse effects that other veterans and service members have experienced from this drug. Good for them. Thank goodness they haven't gone through what some service members have gone through. There are intelligent individuals, doctors and senior officers, who I think we can all agree have made a fully informed decision to take mefloquine. As I mentioned, the drug is licensed. It is approved by Health Canada for prevention of malaria, so there would have to be some sort of policy, and some very good reason, for that drug to be denied to service members.
I think a very strong case can be made that even if an individual states a preference for the use of mefloquine on deployment, and they have previously tolerated the drug—again, fortunately, for whatever reason—the residual risks to the military, and to that individual, from their subsequent use of mefloquine are simply too high to permit them to make that choice. A reasonable argument can be made for policy to restrict the use of that drug in operational settings.
I don't believe Canada has such a policy. At times, military organizations have implemented such a policy. For example, soon after the boxed warning in the United States in 2013, U.S. Army special forces, presumably on the basis of their long experience with bad things having happened from the drug, banned its use outright. I don't oppose those policies. I think those policies are quite wise. The drug simply isn't worth the risk in operational settings.
Dr. Ritchie and Dr. Nevin, you're both aware of the circumstances around Somalia, where tens of thousands of mefloquine tablets were given to our Canadian Airborne Regiment. In 2017, in the Canadian Armed Forces surgeon general's report, he said, “The CAF members deploying to Somalia did not participate in the SMS study, since the guidelines of the study were not compatible with the operational requirement to deploy to Somalia,” and yet they still gave it to them. Not only did they give it to them, they were forced to use this drug. This has resurfaced since 2016.
Dr. Nevin, you know one of the Canadian airborne heard you speaking and the realization came to his mind that this is what impacted him. Since then, this committee has heard tons of anecdotal evidence, plus more than that coming to my office, of these individuals, but they continue to be ignored. We talk about anecdotal evidence. If you don't have it, you don't have a reason to do a study.
In my mind, why is it, then, that this was shut down in that inquiry? Why have VAC, DND and Health Canada refused to do what you are saying they fully need to do to deal with this issue, with the screening. No one has talked to our veterans since these changes came about with that report and with Health Canada's views on this. It's very frustrating to me, and I am not a veteran who was in those circumstances.
Again, with the benefit of the doubt for these individuals who have come forward, and with all the research taking place now, should they not be receiving proper screening, proper diagnosis, all these things that you're discussing?
The use of mefloquine in 1992 among deploying members of the Canadian Airborne Regiment to Somalia is extremely problematic. I don't understand the legal basis for the Canadian military's use of mefloquine in that population. Drugs cannot be prescribed or distributed without a legal basis.
The drug became available to the Canadian Forces under the guise of an existing small-scale clinical research protocol that, up until that point, had resulted in the distribution of the drug to dozens of Canadian Forces personnel after they had completed informed consent and after they had reviewed information that included the warning to discontinue the drug at the onset of symptoms such as anxiety.
Clayton Matchee and about 1,000 other deploying members of the Canadian Airborne Regiment received industrial quantities of mefloquine that were ordered under that protocol. The Canadian Forces readily admits they had no intention of abiding by the terms of that clinical research study. They were not victims of a botched clinical study. The clinical study was not being performed. The clinical study was the mechanism by which the Canadian Forces obtained industrial quantities of the drug that they otherwise could not have obtained.
The legal basis for the use of that drug has never, I think, been properly explored, but the consequences of not abiding by the clinical protocol have been profound to your country.
They have been profound because Clayton Matchee, for example, was never told that when he began to experience restlessness, anxiety and hallucinations he was to stop taking the drug. In fact, when he told others that he was experiencing those symptoms—when he returned home on leave, for example—and family members expressed concern, he said that he couldn't stop taking the drug. We all know what happened in subsequent weeks, don't we?
We know that led to the disbandment of the Canadian Airborne Regiment, which is something that could have been prevented had the Canadian Forces not taken what I think were extreme liberties with the law.
We mentioned that we just had a symposium, and we had veterans from both Canada and the U.S. there. I don't want to name any names, but what several people told me quietly was that as a result of this, they had extreme homicidal thoughts about killing their most intimate family members. That they were scared to sleep with their wives because of fears that they would choke their wives, dreaming of bayoneting their babies, massacring their whole families.
This was very discongruent to them. How could they be thinking of this? The people who were there had not committed suicide but they talked of others who they believed had committed suicide rather than murder their families and those whom they loved.
That is just profoundly, deeply, morally troubling. So what could we do about it? Again, I'm from a different country. I can make only a few suggestions, but a public education campaign, using your media, reaching out, not being ashamed and trying to cover it up but rather saying, “Okay, we didn't know enough; in whatever happened, whether it was legal or not, we didn't do the right thing and now we want to make it right. So come in and talk to us.”
Again, it's also a provider education piece. Make sure that the psychologists, psychiatrists, primary care.... I'm a psychiatrist in my office. Somebody comes in to me with complaints of bad dreams from the war. My first instinct is to say, “Oh, it must be post-traumatic stress disorder”. Maybe I've read up and I know a little bit about people who get their vehicle blown up and they hit their head. So I'll do some screening for TBI. But what can you do to make sure?
This is medical school curriculum, as well as for advanced practice nurses, medics and physician's assistants, just so they all have the knowledge to at least ask the question, “Did you take anti-malarial agents?” Then if the answer is yes, either weekly dose or refer them to the next level of care. You can model it depending where they are. But a mass level of education, I think, would go a very long way.
Canadian mefloquine veterans have been fairly consistent in recent years in calling for three things that they need from the Canadian government: acknowledgement, outreach and research, in that order.
As I mentioned initially, acknowledgement is the single most important thing that can occur. So much will come from an acknowledgement, a mea culpa, or a statement from someone in a position of authority simply stating the obvious that follows naturally from what is in the product monograph and simply acknowledging what is very clearly true.
Individuals within the halls of government who know mefloquine is dangerous, who have patients that they would like to write case reports on, and who would like to fund and conduct research with existing funds will feel empowered to do this. Clinicians will feel empowered to diagnose on paper and for the record what they already know to be true, when previously they had perhaps been hesitant.
Acknowledgement must come first. Someone must say that this drug has caused disability among our troops. It's as obvious as day.
Then there is outreach. With that acknowledgement, which individuals are not reached by the media and which individuals are not reached by social media and word of mouth? We can identify these individuals. We should know who has deployed in the last 25 to 30 years to areas where mefloquine may have been used. Hopefully there's a postal mailing address or some other way to get in touch with them. It could be as simple as saying, “Did you take mefloquine? Did you have problems on the drug? Then call this number and we'll get you the support that you need.”
Then there is research. Research comes in many flavours and varieties. The type of research that you will hear about from government scientists and others who manufacture doubt about the dangers of this drug is not good, quality research. It's retrospective research. It's based on existing data. If we don't ask the right questions about symptoms experienced by individuals who have taken mefloquine and if we don't ask specifically about their mefloquine experiences, the existing data on which many of these studies are based is not going to capture what actually happened. New prospective research at patient level that is conducted with the involvement of clinicians is going to be essential.
It really begins with case finding and empowering individual physicians to identify those veterans who are suffering the long-term adverse affects of this drug. Then it is getting them the type of sophisticated testing that I believe one of your earlier witnesses had discussed, fully describing the extent of their symptoms, and then beginning to count them and figure out what they have in common with each other to identify these risk factors that we're alluding to.
The first step is not to ask Veterans Affairs to look at the existing data again or look at the existing research again and come to the very same conclusions. To solve this problem, we need acknowledgement, outreach and research. A component of that is the screening process that we described.