In this cross-sectional, case-control study of CFS in Georgia we found that virtually all participants had used a drug or a supplement during the preceding two weeks (95.6% of CFS, 88.6% of ISF, and 90.3% of Well controls). This is higher than the average estimate of 82% for the US population in 2004 and 2006 . Among the three study groups, the highest prevalence of drug use occurred in the CFS group (~93% used at least one drug), while the highest prevalence of supplement use occurred in the Well group (~52.4%).
Our findings confirm those from a previous study of medication use in persons with CFS from Wichita, Kansas . Both studies found significantly higher usage of pain relievers, gastrointestinal drugs, antidepressants and benzodiazepines by persons with CFS compared to Well controls. Unlike the Wichita study, though, persons with CFS in Georgia were not significantly more likely than controls to use hormones and supplements but were significantly more likely than controls to use muscle relaxants and anti-allergy and cold/sinus medications. Overall, compared to persons with CFS from the Wichita study , a smaller proportion of persons with CFS in Georgia used pain-relievers (65.5% in Georgia vs. 87.8% in Wichita), supplements/vitamins (44.3% vs. 62.2%), antidepressants (36.3% vs. 41.1%), antibiotics (7.1% vs. 16.7%), hormones (43.4% vs. 52.5%. among women only, 11.8% among all CFS), antihypertensive drugs (17.7% vs. 21.1%), muscle relaxants (8.9% vs. 12.2%), anti-asthma medications (7.1% vs. 12.2%), glucose-lowering drugs (0.9% vs. 4.4%.). Use of other prescription drug categories such as lipid-lowering drugs (11.5% vs.12.2%) and benzodiazepines (12.4%, vs. 11.1% respectively) was similar in Georgia and Wichita (Kansas). The relatively lower usage of most prescription drug medications by persons with CFS in Georgia compared to Wichita may reflect lower seeking of, or lower access to, health care.
The more common use of pain-relievers by persons with CFS compared to those in the ISF and the Well groups is not surprising because joint and muscle aches belong to the symptom complex of CFS and because most pain-relievers of the NSAID group are accessible over the counter. Persons with CFS used a variety of pain relieving/anti-inflammatory drugs to treat arthritis and bodily pain, which predominated as reasons for NSAID use (in the CFS group). The significantly more common use of narcotic pain relievers by the CFS group, as compared to either the Well or the ISF groups, may be due to more severe pain and/or insufficient relief from conventional pain-relievers among persons with CFS. The 27% frequency of use of NSAIDs (aspirin excluded) among controls in our study appears comparable to the 32% estimated prevalence of joint pain in the general population of Georgia, or 33% for the USA , as not all persons with joint/muscle pain take medications all the time. The different profile of NSAIDs use by the CFS and Well groups (i.e., ibuprofen was most commonly used by the CFS group and aspirin was most commonly used by the Well group), seems to reflect different reasons for use. Overall, almost 22% of the Well controls used aspirin versus only 13% in the CFS and the ISF groups. Since the major reason for use of aspirin was "heart health"/prevention, it appears that more preventive use of aspirin occurred in the Well group. Use of acetaminophen-containing drugs in the CFS group (~24%) was higher than the estimated national average of 19%, while both the Well controls and the ISF group had lower usage than the national average .
The higher frequency of antihistamine drugs most likely reflects higher prevalence of allergies and/or cold symptoms in the CFS population. It is notable also that the antihistamine use in our control group (21.8%) was higher than the 15% antihistamine use in a control group of another U.S. study  and may reflect local practices and prescription patterns. In our study, about 20% of antihistamine users in the CFS and ISF groups used antihistamines as sleep aids, which was twice as much as that in the Well controls (11%). Use of antihistamines, which have sleepiness and drowsiness as side effects, may also be an iatrogenic contribution to the CFS symptom complex.
Use of antidepressants by Well controls was ~9%, mirroring the 9.2% national prevalence of depression over a 12-month period . The more frequent use of psychotropic medications (antidepressants and sedatives) in the CFS group suggests that perhaps more depressed mood, anxiety and sleep disturbance are manifested by individuals fully meeting criteria for CFS. Indeed, in our study depression and anxiety were the most common psychiatric co-morbid conditions in persons with CFS . Nevertheless, regardless of the more frequent use of antidepressants at higher mean dosages, persons with CFS and ISF had higher (worse) mean scores on the Zung self-rating depression scale than did Well controls. These results suggest that the clinical presentation of CFS, especially in subjects on antidepressants, may be related in part to untreated or treatment resistant symptoms of depression. Indeed, symptoms of fatigue in depressed patients have been found to be particularly resistant to conventional antidepressant therapy [21, 22]. Moreover, depressed patients with early life stress – overrepresented in our CFS population , have also been shown to be less responsive to antidepressant medication . Taken together, these results suggest that in some persons with CFS and depression, particularly those on antidepressants, unresolved depressive symptoms may significantly confound the diagnosis of CFS.
We were unable to find representative data for the use of acid-reducing drugs in the USA but the 12.9% use among the Well group was similar to the 10% overall use of anti-acids (again within last two weeks) in other parts of the developed world . Half of the of users of acid-reducing drugs in the CFS group also concurrently used NSAIDs, whose major side effects are heartburn/acid reflux, gastritis, and even ulcers. At least one person from the CFS group specified that the reason for using anti-acid drugs was to counter side effects of an NSAID. Therefore, it is possible that anti-acids may have been used to treat side effects of NSAID drugs.
The 9% use of muscle relaxants in the CFS group was significantly greater not only when compared to the ISF (3%) or the Well group (0%) but also when compared to the national average of 1% . In the national survey, half of the users of muscle relaxants took them for more than a year . Because joint/muscle pain in CFS is chronic, persons in our study may also be taking muscle relaxants for extended periods of time and may experience their side effects (e.g., drowsiness, confusion, reduced alertness), which overlap with some of the CFS symptoms and may perpetuate them (i.e., iatrogenic effects of these drugs).
The approximately two-fold more common use of thyroid hormones in the CFS group compared to the ISF group deserves further study. Hypothyroidism presents a similar clinical picture to CFS; in fact, previously unrecognized hypothyroidism was the most common exclusionary condition detected during this study . Autoimmune diseases are considered exclusionary for CFS as well, but were not particularly common in the study population . Subjects who were successfully treated with thyroid replacement (as evidenced by TSH and T4 levels within the normal laboratory limits) were not excluded from our study. It is possible that some subjects treated with thyroid hormones may have chemically controlled hypothyroidism and CFS or, alternatively, they may be chemically euthyroid but functionally hypothyroid resulting in their presentation with CFS. Additional testing to address this possibility may be needed in future studies. Co-morbid depression and other psychiatric conditions were common in persons with CFS . Thyroid hormones are sometimes prescribed to augment the effects of antidepressants  but there was no evidence for such indications in our study despite the combined use of thyroid hormone and an antidepressant by a few subjects in the CFS and the ISF group. Therefore, such use could not explain the higher frequency of thyroid hormone use by the CFS group in comparison to the ISF group.
Persons with CFS were taking, on average, approximately 6 preparations (ranging from 1 to 29 drugs and/or supplements). Polypharmacy (the use of multiple medications) raises the question of drug interactions, side effects and also the potential to use more drugs to treat symptoms that are side effects of drugs started earlier. The problem of iatrogenic symptoms is not trivial, particularly for chronic patients, as use of multiple drugs is an increasing problem . The risks and consequences of polypharmacy should be a serious concern in the setting of CFS, where symptoms are chronic, treatment is largely only symptomatic, patients have about 22 doctors' visits per year  and may see multiple providers who independently prescribe different medications. Side effects of certain drugs may resemble symptoms of fatiguing illness. Therefore careful evaluation with respect to potential drug side effects and also drug-drug interactions is warranted for persons with CFS.
The findings from our study should be interpreted in view of its strengths and limitations. Major strengths of our study are its population-based design and the accuracy of the collected information: all drugs and supplements were brought to clinic where a research nurse viewed them and recorded the name and the dose. A limitation to consider is that reporting the reasons for drug/supplement use may not have been perfect, as subjects were not provided with a standardized list of reasons to choose from, and health literacy may have affected the accuracy of these data. Our study was cross-sectional in nature and does not allow for proper evaluation of treatment efficacy. Also, data on drug and supplement use limited to only two weeks may not be fully representative when studying a chronic, fluctuating condition such as CFS.