No one will dispute that malaria is a killer. Millions have died from the raging and uncontrollable fevers that accompany the parasitic infection. Millions more are left with life-long and life altering symptoms. There are regions of the world where the disease is so resistant to drugs to be nearly impervious to all antibiotics and medical interventions. The need for an effective prophylactic is critical, particularly for troops attempting to achieve military objectives in places where the disease is endemic.
In the 1970’s, a very interesting precedence was set. Scientists and a pharmaceutical company partnered with the Federal government on the development of the next-generation anti-malaria drug. This was the first time such a partnership, termed a Public-Private Venture was undertaken. The results of what some have termed this unholy alliance have been chilling.
The developed drug was mefloquine. Of all the anti-malarial drugs, it showed the lowest potential for liver or kidney side-effects. More importantly, it was designed to be effective with weekly dosing. Because it is based on that old standby quinine, it would not contribute to the development of drug resistant strains of malaria; it is a prophylactic that prevents the symptoms, not an antibiotic that treated the disease.
There are levels of testing that drugs must go through to ensure both their efficacy and safety. In short, once a drug has been developed and has passed preclinical (animal) trials, it is moved to Phase I testing. At this stage, healthy volunteers are dosed to determine the most common side-effects, how a drug is metabolized and how it is excreted.
If toxicity is determined to be at acceptable levels, the drug is moved on to Phase ll where effectiveness is determined by a controlled trial. Some people are given the drug, others are given a placebo and the results prove the drug’s efficacy.
The next step is Phase lll. Now the drug is given to a larger population to further study safety and effectiveness. Again, once those studies prove the efficacy and safety of the drug, it can then be prescribed to the general public. It is important to note that even once a drug is released, doctors and clinicians still report any adverse events, information which is continuously collected and determines if additional warnings will be required by the FDA to be added to the label.
In the case of mefloquine, this step was never taken. Phase lll clinical testing did not occur. The significance of skipping this crucial step cannot be overstated. Instead, all of the data collected during preclinical, Phase l and Phase ll was turned over to the manufacturer, and with FDA approval Mefloquine was rolled out to our troops.
It is very important to note the sample sizes typically used in Phase l and Phase ll will generally total less than 500 individuals. Yet, even with that small sampling, a significant percentage of side effects were reported. Because of the speed at which the drug was moved along the testing pipeline, only the immediate and shortest of the short term effects could be noted, but they included reports of adverse reactions rates of 70% or more of the participants. But, those reactions were deemed both brief and insignificant and the drug itself held such promise, so those adverse events were ignored, dismissed or considered inconsequential.
Anyone who has taken mefloquine will recognize those immediate reactions, as they are still experienced; changes in mood, depression, anxiety, sleeplessness, irritability and ringing in the ears. Bear in mind that none of these reactions can be medically or scientifically quantified – they are all subjective. A doctor cannot look in your ear canal and see the ringing you hear any more than they can run a blood test for irritability.
What became apparent was that many of these symptoms persisted beyond the 4-6 hour expected window after dosing. With each subsequent dose, the side-effects were more pronounced but because they were expected by the patient, were often better self-managed. The most important factor to bear in mind is that in the 1980’s and 1990’s, very few of our troops dosed with mefloquine encountered combat. There were no large scale wars involving hundreds of thousands of personnel.
This bears repeating. Mefloquine was developed as a Public-Private Venture between a pharmaceutical company and the Department of Defense. Without Phase lll testing, it was approved by the FDA for use, though it was not made available to the general public as a prophylactic until 1989. The first randomized, controlled study was not conducted until 2001 at which point more than two-thirds of study participants reported adverse events. Had this data been available previously, the FDA would not have approved the drug.
Yet, for all practical purposes the data was available because testing had been done on thousands of members of the U.S. military, though not according to any clinical protocols. Phase lll testing requires the drug be given to a large and diverse, healthy population, an apt description of our troops. But contraindications were not studied and adverse reactions were dismissed and/or ignored. Because the drug worked as intended – it prevented most cases of malaria with minimal concurrent renal and hepatic side-effects with a single weekly dose.
Due to a combination of randomized trials conducted as late as the early 2000’s, alarming reports from doctors and medical practitioners who prescribed the drug to the traveling public, and some U.S. Army researchers, mefloquine was finally acknowledged as a neurotoxin with significant incidents of neuropsychiatric side effects. But it wasn't until the end of the decade that action was finally taken by the Army.
In 2009, the Army Surgeon General Lt.General Eric Schoomaker issued a directive stating in part that mefloquine should not be given to soldiers who have experienced a Traumatic Brain Injury, or TBI or who exhibited symptoms of a TBI. Later that year, doxycycline, an antibiotic, was made the antimalarial prophylactic of choice for our military. Still, it wasn’t until September of 2013 that Special Forces Operations in Ft. Bragg issued a ban on mefloquine for those, our most elite troops. Perhaps it was finally understood that if those who have proven themselves the most physically and mentally tough are being diagnosed with severe PTSD and succumbing to suicide, there is something other than combat as a causative factor.
Mefloquine was not prescribed only to US military personnel. Troops in other countries were also dosed, but those neuropsychiatric adverse events were acknowledged and taken seriously. In Ireland, for example, the manufacturer of mefloquine under the name brand Lariam has added warnings that the drug can cause suicide. Since the drug was released to the general public in 1989, the U.S. product label has carried the warning that the drug can cause anxiety, depression, hallucinations and other psychotic reactions, but the addition of suicide, suicidal ideation and self-harm is significant.
The single most upsetting fact to note is that prior to dosing our troops, there were no studies done on drug interactions. But, there were clinically noted contraindications for mefloquine long before the drug was released to the general public in 1989. By the early 1990's, it was clear that adverse reactions were so common and significant in concurrent dosing of mefloquine and opiates, anti-anxieties, anti-depressants, anti-psychotics and sleep-aids, warnings were attached to the label. Each of those drugs cause symptoms that are identical to PTSD. Mefloquine causes symptoms that are identical to PTSD. Now, we are sending our troops into combat with compromised nervous systems from mefloquine toxicity, exposing them to the stressors assumed to be the prime cause of PTSD, then treating those symptoms with more drugs that also cause symptoms of PTSD. And the Deparment of Defense and the Army in particular are surprised and baffled at the skyrocketing rates of PTSD and suicide among our military and veterans.
The U.S. military has been strongly encouraged to study the causal relationship between mefloquine and suicide, yet those studies have yet to be done. Instead, statements by the Department of Defense, including statements made to Congress, are still blaming suicide among our troops and veterans on pre-existing mental health issues and personal relationship failings as the prime causative factors.
Worst of all is how our military institutions still refer to PTSD as a mental illness when it has been known for all these years that PTSD can be caused by the neurotoxin mefloquine. At the very least, every member of the military and every veteran who presents with PTSD symptoms should have their history checked for mefloquine dosing. If they took the little pill even once, their diagnosis should read “Mefloquine Toxicity”, not “PTSD”. There is no cure for mefloquine toxicity. That said, we do know how to make it worse - by adding other drugs to the already compromised nervous system, specifically drugs intended to treat symptoms of PTSD. Considering this, proper diagnosing is critical; this intentional misdiagnosis is criminal.
This is one of those things that just baffle the mind. There is a drug that was prescribed to our troops, that everyone was ordered to take, that has known and admitted significant psychological adverse reactions. Concurrent or subsequent administration of anti-psychotics, anti-depressants, anti-anxiety and sleep aids is contraindicated. Those with a TBI or symptoms of a TBI are also contraindicated for this drug. The U.S. military has violated, by standard operating procedure, all of these contraindications, but doesn’t believe this drug is a factor and therefore refuses to even conduct studies based on the mountains of data already collected. Instead, their stance is the suicide epidemic is a mystery but most probably related to individual, personal or pre-existing issues.
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