We’re back with another installment of Spotlight on Science. Dr. Beatrice A. Golomb (University of California, San Diego) talks about her research into how the chemical compound Coenzyme Q10 could benefit Gulf War veterans suffering from Gulf War Illness (GWI). Her article is among the most popular from the journal Neural Computation over the last year, according to Altmetric Explorer. Read the article for free on our SOS page.
How did you first become familiar with Gulf War Illness (GWI)? Has there been a significant increase recently in awareness of this condition?
I first heard about the condition in the mid-1990s, around the time reports came out on the condition from the Presidential Advisory Committee (PAC) and Institute of Medicine (IOM). I was immediately concerned that the demands for evidence differed radically for postulated physiological vs. psychological causes. Where postulated “organic” (physiological) causes were considered, the bar was high: absence of evidence for a causal role was construed as evidence of absence of a role. Moreover, they hadn’t looked hard for evidence—e.g. omitting consideration of animal studies, the primary setting in which controlled exposure to toxins is allowed. In contrast, for hypothesized stress and psychological causes, mere suggestion of a role was deemed sufficient proof. No evidence was required that those with more stress were more likely to become ill. No demands were made for evidence that people in other historical settings with similar psychological stress, without the chemical stress, had become similarly ill, etc.*
I was a Robert Wood Johnson Clinical Scholar at RAND/UCLA from 1994-6. The head of the Health program at RAND (Dr. Robert Brook, who was also the head of the Clinical Scholar program) asked if I wanted to get involved on DoD funded work by RAND on Gulf War illness, and I jumped at the chance— not because I had a prespecified idea about the cause of illness, but because I wanted to be sure there was an honest, evenhanded look at the evidence. Ultimately, through my work there, I traveled to the Middle East as the sole civilian/scientist on a high level DoD mission (I learned that everyone else in the group got hazardous duty pay!); and authored or coauthored four book-length RAND reports on this topic (one of which was never released; but that is a story for another time.) I was also lampooned on Jon Stewart’s “The Daily Show” when I gave a press briefing from the Pentagon on the topic, as the lead Headline News segment, entitled “Pills Bury Doughboys”.
*In fact, studies now show that combat stress—while showing a dose-response relationship to PTSD—has no independent relation to Gulf War illness. Meanwhile exposure to acetylcholinesterase inhibiting agents (e.g. Pyridostigmine bromide (PB) pills) has shown a dose response relationship to Gulf War illness in many studies. This is corroborated by gene environment interaction data (people with genetically impaired detoxification of PB were markedly more likely to become ill—but only if they were exposed to PB). And triangulating evidence shows persons exposed to this chemical class in other settings, have similar chronic multisymptom illness. Finally, mechanisms of toxicity linked to these agents—such as mitochondrial dysfunction—are now documented to be present in affected Gulf War veterans.
What led you to consider CoQ10 as a treatment option, when the only other treatments currently considered and used are exercise and cognitive-behavioral therapy?
Of course, exercise can help almost everyone, and doesn’t necessarily help veterans more so (and it worsens some), and isn’t highly specific. CBT also helps people with many conditions, to a (small) point: many veterans say that cognitive-behavioral therapy helps them live with their symptoms better, but does not affect the symptoms themselves. Both treatment modalities are time and labor intensive from the standpoint of the veteran and the system, and neither goes very directly to mechanisms likely to be causing the symptoms. Actually, exercise does a bit, because it may enhance blood delivery, antioxidation, and cell energy production, and stress reduction may also modestly benefit cell energy by reducing the adverse contribution by catecholamines to energy supply-demand balance.
The goal is something that more directly targets critical mechanisms.
First, both the symptom profile and exposure relations converged to make me think that mitochondrial dysfunction was likely a critical factor in Gulf War illness. All major aspects of the profile of symptoms fit a picture of mitochondrial dysfunction – protean symptoms spanning many organs, with symptoms varying from person to person, but emphasizing brain and muscle, “post-mitotic” energy demanding organs especially vulnerable in settings of mitochondrial impairment (e.g. cognitive dysfunction, muscle pain and weakness). Symptoms also showed variable latency to onset, consistent with mitochondrial phenomena termed “heteroplasmy” (by which organs vary within a person in their vulnerability) and “threshold effects” (symptoms arise when a threshold of mitochondrial injury or resulting cell loss has been reached).
Of note, many have tried to assert that a toxic cause can’t account for symptoms if symptoms persist after the toxin is gone—and even newly arise—but with mitochondrial injury, symptoms can persist or arise anew. This is because when mitochondria are damaged, free radicals are produced in excess within the mitochondria, and lead to further mitochondrial damage. This contributes to how toxins produce conditions like ALS and Parkinson’s disease.
Also, the exposure profile fits. Acetylcholinesterase inhibitors show the strongest evidence for a connection to Gulf War illness, and are known to produce toxicity mediated through mitochondrial dysfunction (though historically, more attention has gone to their effects on acetylcholine).
Coenzyme Q10 has benefited people with mitochondrial problems (not all fully or equally), and has statistically helped many symptoms and conditions reported in Gulf War veterans.
It is true that mitochondrial problems often do better with a cocktail of agents targeting cell energy and antioxidation, than with a single treatment agent. But it seemed prudent to start by testing coenzyme Q10, to help proof of concept that targeting mitochondria may help. It is generally easier to get studies accepted with one treatment item than a cocktail of things unproven for the condition—though now that the mitochondrial story is stronger, cocktail studies are underway.
One of the limitations of the study was complete and reliable participant cooperation—for example, some participants suffered from cognitive and mood problems which sometimes predict medication noncompliance, and another participant admitted that he didn’t follow the instructions given to him for taking his pills. If you had a do-over, or looking towards the future, how would you account for or combat this limitation?
The main problem these considerations impose is bias to the null. This basically means that the “true” effect may be greater than the observed effect. (One still has the double blinding and placebo control, so that when a significant finding is observed, it is likely to be real.) The smaller effect size and larger variance that result from these factors can be offset, at least in terms of generating adequate statistical power to show significance, by a (sufficiently) larger sample size.
The profile of GWI differs between men and women, and in the study, female veterans had a different experience with the treatment than the male veterans. Were you able to notice any significant trends in the female results, and do you see this as a subject for further investigation?
A few people, like researcher Nancy Klimas, have underscored the need to separately study male and female Gulf War veterans. One factor in our veterans was that the 100mg dose led to lower achieved blood levels of coenzyme Q10 in the female veterans, and coenzyme Q10 blood levels correlated with improvement. There weren’t many female veterans in the study, so this difference could have been due to chance. But a study designed to test the effect of achieving target blood levels of coQ10 might be worth considering. It may be worth assessing what factors lead to differences in achieved Q10 blood levels (or, uptake and elimination).
The paper provides an excellent explanation of the pretreatment adjunct for nerve agents AChEi (acetylcholinesterase inhibitors). These inhibitors, as you write in the paper, cause oxidative stress and mitochondrial dysfunction and are strongly linked to GWI. The US government, in its textbook of military medicine Medical Aspects of Chemical and Biological Warfare, state that while there are adverse effects of these inhibitors, they are the best method at present of protecting soldiers from nerve agents. Do you foresee veterans of more recent wars eventually developing similar symptoms to GWI, and if so, do you believe that would prompt a larger-scale study of treatment options?
In my 399-page 1999 RAND report on Pyridostigmine bromide and Gulf War illness, A Review of the Scientific Literature As It Pertains To Gulf War Illnesses Volume 2: Pyridostigmine Bromide, I presented evidence that pyridostigmine bromide would likely worsen both lethality and mission completion, for all nerve agents except soman (the sole nerve agent that no intelligence had suggested Iraq had). I had been led to understand that military policy in both the US and Israel had, in response to this, changed so that the order to take PB would occur only if there were evidence of soman per se on the battlefield. (I gather that in some subsequent deployments, PB was passed out but the order to take was not given.).
However (and arguably contrary to the common refrain of no weapons of mass destruction J ), I have read news accounts that some later personnel were exposed to “abandoned” caches of nerve gas, which like PB is an acetylcholinesterase inhibitor, and evidence also links it to Gulf War illness. Moreover, I have personally spoken to a number of people who developed Gulf War illness-like conditions following civilian organophosphate (OP) exposure, through agricultural or home use, and via “aerotoxic syndrome” – jet fuel contains OP chemicals, and air intake is through the engine; under some circumstances of leaks, OP can come into the cabin affecting pilots and aircrew – and presumably passengers, though I gather they are not necessarily notified when an event is known or suspected to have occurred. So the lessons we learn from affected Gulf War veterans are important for civilians, as well as for current and future military who may be exposed to carbamate and OP classes of pesticides (i.e. acetylcholinesterase inhibitors) used by the military to control insect vectors of disease; and who may be exposed to nerve agent, as well as, potentially, PB in battle. (Findings may also have relevance following exposure to other mitochondrial toxins.)
In the introduction, you write that antioxidants administered just before or after exposure to the AChE inhibitor significantly lessens AChEi lethality and morbidity in animals. Do you believe that the use of antioxidants could render the nerve agent pretreatment safe?
I think the right antioxidants would probably reduce health effects arising from with nerve gas, and very possibly the nerve agent pretreatment. But, I would be surprised if the protection were complete.