Not enough research exists to link persistent neurological and psychiatric conditions, like post-traumatic stress disorder, to anti-malaria drugs taken by U.S. troops, an influential scientific panel announced Tuesday.
A year-long National Academies of Sciences, Engineering and Medicine investigation has found “insufficient or inadequate evidence” of any association between chronic health problems and malaria preventives, including mefloquine, a medication that can cause neurological or psychiatric side effects for months or years after taking it, according to the Food and Drug Administration.
The panel members noted, however, that the findings do not show “evidence of lack of adverse effects,” and they recommended further research, especially on mefloquine and tafenoquine.
For its review, the 10-member National Academies panel reviewed thousands of abstracts and papers on six medications commonly used to prevent malaria: mefloquine (also known by the brand Lariam), tafenoquine, atovaquone/proguanil (also known as Malarone), doxycycline, primaquine and chloroquine.
The goal was to determine what, if any, permanent side effects may be caused by taking the drugs.
But the panel, led by Dr. David Savitz, associate dean for research at Brown University, was able to identify just 21 studies that met their criteria for documenting lasting harmful symptoms, and only 10 studies they felt were of rigorous scientific quality.
With such a dearth of information, members could only conclude there wasn’t enough evidence to demonstrate associations between most of the drugs, including the two most controversial drugs — mefloquine and tafenoquine — and permanent side effects.
Savitz, however, said the bottom line is that more research is needed to draw any conclusions about the safety of anti-malarial drugs.
“This is important to emphasize, because it’s one thing to say there’s a substantial body of high quality research that has looked and not found anything. But this is a small set of studies with methodological limitations and it really leaves us to determine that the evidence is simply inadequate or insufficient to draw conclusions,” Savitz said during an interview with Military Times.
The Department of Veterans Affairs commissioned the Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis to determine what, if any, long-term health conditions may be caused by medicines taken regularly by U.S. troops to prevent and treat malaria.
VA requested the research following persistent reports and case studies of active duty and former service members developing neurological damage and psychiatric symptoms after taking antimalarials, namely mefloquine.
Worldwide, former service members have filed a number of lawsuits alleging they have permanent brain damage as the result of taking mefloquine.
In their review of existing scientific literature on the medications, panel members received briefings from government officials responsible for malaria prevention policy as well as veterans, Peace Corps volunteers and travelers who described how their lives were upended by mefloquine, leaving them with debilitating, chronic health issues.
Those affected pleaded with panel members to review their medical histories and records before issuing their findings, aware that not much research exists on the long-term health consequences of these medications, mainly mefloquine and tafenoquine.
Savitz said the panel members listened to those affected and while their assignment was not to weigh individual cases or anecdotal information, they found the testimony useful to emphasize that more research is needed.
“We heard them and we took them very seriously,” Savitz said. “I think we were very clear in saying that this issue deserves to be taken seriously, that this is a credible or plausible scenario by which these drugs could produce longer term consequences."
The panel recommended that research be conducted in several major areas, including the relationships between: mefloquine and eye conditions as well as neurologic and psychiatric conditions like PTSD; tafenoquine and eye conditions, as well as psychiatric issues; Malarone and eye conditions; and doxycycline and long-term gastrointestinal problems.
The panel did find there was sufficient evidence to link tafenoquine with development of an corneal condition known as vortex keratopathy that may cause hazy vision.
The report’s conclusions are sure to disappoint veterans of the U.S. military, the State Department and the Peace Corps as well as travelers who attribute debilitating mental and physical health symptoms to mefloquine, the once-a-week malaria pill issued to thousands who have served overseas.
U.S. service members routinely take malaria prophylaxis medications when deploying to countries where malaria is endemic, such as Afghanistan, Djibouti and throughout Africa.
Until 2009, mefloquine, which is taken once a week, was the malaria preventive of choice in many overseas locations. But that year, following growing concerns over the medication’s short-term side effects, which can include hallucinations, anxiety and sleep problems, the Defense Department issued a policy listing it as a last-choice malaria preventive.
In January 2012, the assistant secretary of defense for health ordered a full-scale review of mefloquine prescription policies, and in 2013, the FDA placed its strongest warning on mefloquine, saying the drug can cause ongoing or permanent neurological and psychiatric conditions, including dizziness, loss of balance, tinnitus, anxiety, depression, paranoia and hallucinations, even after discontinuing use.
If the National Academies panel had determined a causal relationship between taking malaria medications and disabling health effects, it would have helped veterans who are seeking health care and disability benefits from VA for resulting conditions.
VA researchers had previously found no “significant associations” between mefloquine and mental disorders when variables such as combat exposure and deployment were considered.
The National Academies panel also noted that combat exposure, psychological stressors, the deployment environment and exposure to chemical and biological pollutants or agents adds to the complexity of determining any relationship between prophylactic antimalarials and permanent psychological damage.
“Because of the many other factors and stresses associated with deployed environments like combat, specific effects attributable to the use of an antimalarial drug may be difficult to tease out,” they wrote.
Savitz said that in positive news, the panel members did conclude that no further research was needed for more than 20 alleged associations, and they also found that the medications did not cause latent effects – as in, symptoms beginning years later after the medications were stopped.
The panel recommended additional research be undertaken to include observational studies and randomized trials.
Dr. Remington Nevin, a former Army preventive medicine officer, researcher and executive director of The Quinism Foundation, a group dedicated to supporting research on the effects of antimalarial drugs, said he warned that the National Academies investigation was premature, given the weaknesses of the available evidence, and was disappointed the committee did not look at individual medical records or case studies.
“The reason we are here today is because of the concerns raised about mefloquine in a small number of individual case reports which led the FDA and international drug regulators to put boxed warnings on international mefloquine labels, stating quite confidently that mefloquine is associated with permanent neuropsychiatric adverse effects,” Nevin told members of the panel during a briefing Tuesday in Washington.
“The European Medicines Agency ... determined there is sufficient causal evidence to conclude an association with mefloquine use and permanent adverse effects,” he said.
Patricia Kime is a senior writer covering military and veterans health care, medicine and personnel issues.
