Mefloquine toxicosis, or “mef tox”, is a serious health problem that probably afflicts many tens of thousands of military veterans globally. The anti-malarial drug mefloquine (or Lariam™), like several other drugs from the same family of synthetic quinolines, is known to be neurotoxic. The neurotoxicity of these drugs can cause a lasting or permanent brain injury in a sizeable minority of people who have used them to prevent or treat malaria. This acquired brain injury (ABI) in turn results in a distinct and debilitating set of chronic neurological and psychiatric symptoms that can have a severe impact on an affected veteran’s quality of life, career and relationships.
Despite extensive media coverage of mefloquine toxicosis over many years, little if any real effort has been made to provide appropriate medical care and support to affected veterans and their families. There are several understandable reasons for this, which will be discussed in these posts. Regardless, the consequences have often been tragic, including homelessness, interpersonal violence and/or suicide. This situation is unacceptable and requires urgent attention from health professionals, policy makers, veterans organisations and related community groups.
The aim of this series of posts is to provide a clear understanding of mefloquine toxicosis in order to properly diagnose, manage and support affected veterans and their families. Although military veterans are not the only people affected by this illness, there are specific reasons for focusing on this group which will also be discussed. The series will cover:
- Part 1 – What is Mefloquine Toxicosis?
- Part 2 – The Impact of Mefloquine Toxicosis on Military Veterans
- Part 3 – Diagnosis of Mefloquine Toxicosis in Military Veterans
- Part 4 – Management of Mefloquine Toxicosis in Military Veterans
- Part 5 – Other Quinoline Anti-malarial Drugs of Concern
A great deal of research remains to be done to address the problems affecting mefloquine veterans, which again will be discussed in each post, but enough has already been published to recognise mefloquine toxicosis as an illness and take urgent action. The veterans themselves are taking the lead. All that remains to be done is for the health professions and the research community to follow that lead and get proactively involved. The veterans’ community needs and deserves this help.
The evidence for this first post is covered in my recently published review paper and other relevant, peer-reviewed research. Key references are listed at the end of the post and a more comprehensive list of published papers can be found here.
Part 1 – What is Mefloquine Toxicosis?
Bottom Line Up Front
Mefloquine is an anti-malarial drug that has been widely used in military forces since the late 1980s. The drug is known to be neurotoxic, and in a sizeable minority of users can cause a lasting or permanent brain injury. This acquired brain injury (ABI) results in a distinct and debilitating toxicosis – a chronic illness with a variety of neurological and psychiatric symptoms. Mefloquine toxicosis is not a “mental health” problem – it is the result of a physical injury to the brain caused by a toxic substance, marked by physical as well as psychiatric symptoms.
Dr Remington Nevin, Presentation to the U.S. Food and Drug Administration on Mefloquine Neurotoxicity, 11 January 2013
What is Mefloquine?
Mefloquine (Lariam™) is a prescription-only drug that has been widely used since the late 1980s for prevention and treatment of malaria. When used for malaria prevention, the drug is taken as a once weekly 250mg oral tablet, sometimes with a “loading dose” of three 250mg tablets during the week prior to arrival in a malarious area. Mefloquine usually comes in distinctive packaging (see below) and by law should be provided with a manufacturer’s product information leaflet which includes warnings about possible side effects, although this has not always occurred in military operational settings.
Mefloquine has two chemical characteristics that are key to understanding it’s ability to cause toxicosis. Firstly, mefloquine is a small, lipophilic molecule, which allows it to cross the blood-brain barrier and interact directly with neurons and related structures in the brain. Secondly, the drug has a relatively long elimination half-life of around two to four weeks. This is what allows it to be used as a weekly tablet rather than a daily one like most other preventative anti-malarial drugs. However this characteristic also allows it to concentrate in the brain and in some individuals (explained below) accumulate in particular regions such as the brainstem and limbic system before it is eliminated. These areas of the brain are involved in motivation, emotion, learning, memory and balance, and are linked to the behavioural and physical symptoms that characterise mefloquine toxicosis.
How Mefloquine Can Cause an Acquired Brain Injury (ABI)
ABI is defined as damage to the brain that occurs after birth. That damage can be caused by an accident or trauma, by a stroke, a brain infection, by alcohol or other drugs, or by diseases of the brain. Recognising mefloquine toxicosis as an ABI, rather than a “mental health” disorder, is crucial for the affected veteran to be correctly diagnosed and managed. Although further research needs to be done to improve our understanding of mefloquine toxicosis, there is already a good understanding of two of the ways that the drug is able to damage the brain and cause the symptoms that distinguish this illness.
Mefloquine is able to interfere with the electrical and chemical signals that pass between neurons (nerve cells), in a variety of complex ways. The impaired functioning caused by this interference in these areas of the brain is linked to the behavioural and physical symptoms of mefloquine toxicosis. This can occur “acutely”, ie while the drug is still being taken, and/or “subacutely”, ie shortly after the drug has been discontinued. In severe cases, mefloquine toxicosis can result in psychotic reactions, hallucinations or seizures, but much more commonly it can cause relatively mild symptoms such as headaches, insomnia, nightmares or anxiety.
In addition to these acute effects, the drug can also cause lasting or permanent injury to neurons in these same regions of the brain. This physical injury to neurons, including cell deaths, is what distinguishes mefloquine toxicosis from a psychological or “mental health” disorder. Mefloquine toxicosis is an ABI which results in psychiatric symptoms as well as physical or neurological symptoms. The lasting or permanent nature of the injury is what makes the toxicosis “chronic”, ie the symptoms can persist for months or years after the drug is no longer being taken, or can even be permanent.
Mefloquine toxicosis has been described by one researcher as as an idiosyncratic central nervous system (CNS) toxicity syndrome, which is common to several historically used synthetic quinoline anti-malarial drugs. The term “idiosyncratic” simply means that the drug can effect different people in different ways, which is discussed in the next section, while the term “syndrome” means a group of symptoms that occur together to characterise a particular illness. The toxicosis has also been described as “neurotoxic vestibulopathy” or “limbic encephalopathy” and “vestibulopathy”, which are medical terms referring to a brain disorder affecting particular parts of the brain. The illness is now well documented in decades of case reports and related research, including a review written to assist psychiatrists in correctly diagnosing those affected.
Why Mefloquine Toxicosis Doesn’t Affect Everyone Who Takes Mefloquine
One of the reasons that mefloquine toxicosis is so contentious is that not everyone who takes the drug is adversely affected. Mefloquine veterans are often told by colleagues or superiors “Well, I took it and it didn’t affect me.” There have been cases of mefloquine veterans being accused of malingering or cowardice. Others have been told by doctors that mefloquine merely exacerbated a pre-existing mental health disorder, regardless whether they had any history of psychiatric problems. However there are good scientific reasons why these individuals could be affected by the toxicosis while the majority are not.
A key factor in the toxicity of drugs like mefloquine is the role of enzymes in drug metabolism. Enzymes throughout the body interact chemically with the drug in numerous ways from the time it is taken orally until the time the last traces of the drug are eliminated. Two of these relevant interactions in the case of quinolines are, firstly, activating the drug so that it can work against the malaria parasite in the bloodstream and, secondly, eliminating the drug and related toxic biproducts from the CNS.
Individuals with relatively “normal” levels of the enzymes involved in this second metabolic process would be able to eliminate the drug from the CNS before it built up to toxic levels and caused an ABI. However there is wide variation from person to person in some of the enzymes involved in drug metabolism. One well-known example of this is the G6PD enzyme, which plays a key role in metabolising another synthetic quinoline anti-malarial drug – primaquine. For individuals with G6PD deficiency, primaquine can cause a serious blood disorder called haemolytic anemia. This is the reason that individuals are tested for their G6PD status as a precautionary measure before being given primaquine.
More recent research into the role of enzymes in primaquine metabolism provides another clue as to the idiosyncratic nature of quinoline toxicosis. A series of laboratory studies have found that the CYP2D6 enzyme is involved in metabolising the drug in several ways that effect the drug’s toxicity as well as its effectiveness as an anti-malarial. CYP2D6 levels are highly variable from person to person, so it is logical that if certain levels of this enzyme are required to eliminate similar drugs such as mefloquine from the CNS then this could be one of the answers for the varied susceptibility to mefloquine toxicosis. This line of research is not yet conclusive but it is very significant for this family of drugs.
Around the time that researchers found conclusively in 2006 that mefloquine is neurotoxic, the U.S. Army called for private industry to undertake research into the “idiosyncratic” aspect of the drug’s toxicity, suggesting the possibility of a genetic mechanism:
Unfortunately, as many as 25% of indviduals taking mefloquine at prophylactic doses (250 mg per week) and 70% of those taking it at treatment doses (1250 mg over 24 hours) experience neurological or psychiatric adverse effects. While most of these are minor (dizziness, anxiety, nightmares, reduced sleep), serious adverse effects such as psychosis also occur. The fact that only certain individuals appear to be adversely affected points to a genetic mechanism, possibly a single polynucleotide polymorphism (SNP) that is yet to be identified.
If any such research was completed in the ten years since then, unfortunately it has not been published. One of the reasons that I have called for a public inquiry into the use of mefloquine is to seek access to any research that has been done by the manufacturer or other research institutions, which will help medical professionals to correctly diagnose and treat patients with mefloquine toxicosis.
Mefloquine toxicosis is much more common than is reflected in the published research. This is due to a number of factors that will be discussed in parts 2 and 3, including what has been described as a systemic under-reporting of mefloquine side effects in clinical trials and post-market reporting. I have previously estimated that around 10-25% of military veterans who have taken weekly 250mg mefloquine for malaria prevention (typically for periods of around six months, often with an initial weekly “loading dose” of 3 x 250mg) will now suffer from mefloquine toxicosis. I will explain my rationale for this estimate in Part 2. The only way to establish the true figure, which may in fact be even higher, will be to undertake proper follow up medical studies which have not yet been conducted.
Military vs Civilian Use of Mefloquine
Since its introduction into market in the late 1980s mefloquine has reportedly been used by well over 30 million people. Despite repeated safety concerns being raised throughout this history and now extensive published research on mefloquine neurotoxicity, the manufacturer, government officials and the medical profession have generally maintained that mefloquine is a safe drug. The reasons for this disparity will be discussed in more detail in subsequent posts, but for the purpose of this post it is important note that military veterans who have used mefloquine are more likely to have been affected by toxicosis than a typical civilian tourist or business traveller who has taken the drug for several weeks.
Military personnel have typically taken mefloquine for many months at a time, often for multiple operational deployments amounting to years. A significant proportion have continued taking the drug despite experiencing what the manufacturer calls “prodromal” symptoms, ie symptoms that indicate the user should immediately cease taking the drug to avoid experiencing “a more serious event”. These symptoms may have seemed benign and non-specific – for example anxiety, depression, confusion, mood swings or unusual behaviour – yet are consistent with the onset of toxic encephalopathies (brain disorders caused by toxic agents) and neurotoxicity syndromes. These non-specific symptoms are difficult to distinguish from the normal stresses associated with a military operational deployment, including lack of sleep, physical fatigue, the risk of violence and exposure to trauma. Unfortunately, large numbers of veterans who continued to take mefloquine despite these symptoms now face the real possibility that they have a chronic toxicosis resulting from an ABI.
One of the reasons for focusing on veterans is that military personnel are a significant proportion of the subjects who have been involved in clinical trials of mefloquine. These include thousands of personnel from Canada, the Netherlands, the United States and Australia. The incidence of adverse side effects reported during these trials is something that will be discussed in Part 2. Regardless, this is an important group of people who can readily be involved in follow up medical research given that their involvement in these trials and their subsequent medical histories are well documented. This research would help to determine the long term health impacts of mefloquine use and develop clinical guidelines for the diagnosis and management of mefloquine toxicosis.
Symptoms of Mefloquine Toxicosis
Much of the media reporting of mefloquine toxicity has focused on relatively rare but severe, psychotic reactions, which have sometimes resulted in extreme acts of violence or suicide. These have typically occurred while the drug was still being taken or shortly afterwards. This series of posts instead focuses on the chronic toxicosis or “syndrome” of symptoms which can continue for many years after the ABI has occurred.
Some of the more common symptoms of mefloquine toxicosis include:
- Insomnia (sleeplessness).
- Tinnitus (ringing in the ears).
- Treatment resistant depression and anxiety.
- Impaired cognition, including memory and concentration (including specific deficits that can be detected in neuropsychological testing).
- Agitation, restlessness, mood swings, panic attacks, anger, confusion.
- Abnormal, vivid dreams or nightmares (this common symptom frequently contributes to misdiagnosis of PTSD, which will be discussed in Part 3).
- Dizziness or vertigo.
Some of the less commonly reported but often more serious symptoms of mefloquine toxicosis include:
- Severe tinnitus and hearing loss.
- Hallucinations and visual disturbances (this sometimes contributes to misdiagnosis of PTSD, which will be discussed in Part 3).
- Seizures or convulsions (which in some cases have been diagnosed as conversion disorder).
- Psychoses including delusions, paranoia, mania and depersonalisation.
- Personality disorders including bipolar disorder.
- Cardiac disorders.
- Suicidal thoughts and behaviours.
Many of the problems experienced by these veterans result from a lack of awareness of mefloquine toxicosis in the health professions, coupled with the fact that the symptoms are often mistaken for PTSD, mild traumatic brain injury (mTBI) or other prevalent disorders. Misdiagnosis with PTSD has been very common, as has diagnosis with depressive, anxiety and personality disorders that are symptomatic of mefloquine toxicosis, however treatments for these have typically been unsuccessful in the absence of a correct diagnosis of the ABI and can be dangerous. Less severe but still debilitating neurological symptoms such as tinnitus, vertigo and dizziness have typically been untreated, while more serious symptoms such as seizures have been misdiagnosed as conversion disorder. This in turn has compounded the stresses on these veterans and their families.
Part 2 of this series will describe the impact of mefloquine toxicosis on military veterans, including the difficulty in recognising mefloquine toxicosis amid other health and environmental threats experienced by military personnel, the incidence and severity of the illness, its impact on the quality of life and relationships of those affected, and how it contributes to veteran homelessness and suicide.
A. M. Croft, A lesson learnt: the rise and fall of lariam and halfan, Journal of the Royal Society of Medicine, vol. 100, no. 4, pp. 170-174, 2007.
A. M. Croft, Mefloquine, madness and the Ministry of Defence, The Pharmaceutical Journal, 12 November 2015.
F. A. Jacquerioz and A. M. Croft, Drugs for preventing malaria in travellers, Cochrane Database of Systematic Reviews, no. 4, Article ID CD006491, 2009.
D. E. Hartman, Neuropsychological toxicology: identification and assessment of neurotoxic syndromes, Archives of Clinical Neuropsychology, vol. 2, no. 1, pp. 45–65, 1987. http://dx.doi.org/10.1016/0887-6177(87)90033-3
Y. Kim and J. W. Kim, Toxic encephalopathy, Safety and Health at Work, vol. 3, no. 4, pp. 243–256, 2012.
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.
R. L. Nevin, Rational Risk-Benefit Decision-Making in the Setting of Military Mefloquine Policy, Journal of Parasitology Research, vol. 2015 , Article ID 260106, 2015.
R. L. Nevin, Limbic encephalopathy and central vestibulopathy caused by mefloquine: A case report, Travel Medicine and Infectious Disease, vol. 10, no. 3, pp. 144-151, 2012.
R. L. Nevin, Mefloquine and post-traumatic stress disorder, in Elspeth C. Ritchie (ed.), Forensic and Ethical Issues in Military Behavioural Health, Borden Institute, Surgeon General U.S. Army, Falls Church, 2014.
R. L. Nevin, Idiosyncratic quinoline central nervous system toxicity: historical insights into the chronic neurological sequelae of mefloquine, International Journal for Parasitology: Drugs and Drug Resistance, vol. 4, no. 2, pp. 118-125, 2014.
R. L. Nevin, Unexpected pharmacological and toxicological effects of tafenoquine, Occupational Medicine, vol. 65, no. 417, 2015.
R. L. Nevin, Organic depersonalization as a chronic sequela of mefloquine intoxication, Psychosomatics, vol. 56, no. 1, 2015.
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.
E. C. Ritchie, J. Block and R. L. Nevin, Psychiatric side effects of mefloquine: applications to forensic psychiatry, Journal of the American Academy of Psychiatry and the Law, vol. 41, no. 2, pp. 224-235, 2013.
Roche Products, Lariam (Mefloquine Hydrochloride) Product Information 141107, Dee Why, Australia, 2014.
S. Toovey, Mefloquine neurotoxicity: A literature review, Travel Medicine and Infectious Disease, vol. 7, no. 1, pp. 2-6, 2009.