in response to an earlier successful trial, a larger trial was conducted, known as fatigue intervention by nurses evaluation. in the fine trial, patients fulfilling oxford 1991 cfs criteria who were allocated to pragmatic rehabilitation reported a statistically significant but "clinically modest" improvement in fatigue when compared to patients allocated to either "supportive listening" or "treatment as usual", but after 12 months follow-up there were no statistically significant differences. there was no significant improvement to physical functioning at any time. about 10% of the trial participants were non-ambulatory and about 30% met london me criteria, but separate results for these groups were not published. in an accompanying editorial, possible reasons are given for why the earlier success was not replicated in this trial, and further research is encouraged; the patients in this trial had higher comorbidity and disability than patients in the earlier trial or most other trials, and received less sessions than most successful trials of cbt and get. the question was also raised whether generalists are as successful as specialists in offering behavioural interventions. placebo response a meta-analysis conducted in 2005 examined the incidence of study-defined improvement within various control groups used in cfs intervention studies. the study reported a pooled improvement rate of 19.6%. however, this figure included a number of studies where the control conditions were passive or unblinded, and therefore participants would not have any expectation of improvement. therefore, it is by no means a direct measure of the "placebo response". recovery a 2014 systematic review reported that estimates of recovery from cfs ranged between 0 and 66% in intervention studies and from 2.6 to 62% in naturalistic studies. there was a lack of consensus in the literature on how recovery should be defined, with almost all of the 22 included studies measuring recovery differently. recovery was operationally defined by reference to, either alone or in combination: fatigue or related symptoms; function; premorbid function; and/or brief global assessment (which was the most common outcome measure, but does not provide information on symptoms and function, and does not "provide assurance that patients have substantially recovered rather than simply improved"). focusing on only fatigue or function may overestimate recovery rates, because patients may show selective rather than overall change. a patient with reduced self-reported fatigue may still experience functional disruptions, pain, sleep disturbances, or malaise. "recovery" in the reviewed studies was often based on limited assessments, less than a full restoration of health, and self-reports with a general lack of more objective measures. in the absence of definitive measures, recovery criteria should set high but reasonable standards for behavioural recovery which approach restoration of pre-morbid health. when objective measures are used, such as the relatively objective behavioural measure of actigraphy, the results have been contrary to the cognitive behavioural model of cfs which predicts increased physical functioning as a result of intervention, as otherwise 'successful' trials did not find significant changes in physical activity. the authors state "a more modest interpretation of 'recovery' might characterize such outcomes as successful adaptation of illness-related behaviour and attitudes to ongoing but perhaps diminished illness", "improved or recovered patients may have continued to avoid activity levels that provoked debilitating postexertional symptom flare-ups", which "would seem to be more consistent with a hypothesis of successful adaptation rather than recovery". it was concluded that more precise and accurate labels other than "recovery" (e.g. clinically significant improvement) may be more appropriate and informative for the improvements reported in previous research, and in keeping with commonly understood conceptions of recovery from illness, recommended a consistent definition of recovery that "captures a broad-based return to health with assessments of both fatigue and function as well as the patient's perceptions of his/her recovery status" and "the recovery time following physical and mental exertion". a 2012 systematic review on exercise therapy for cfs reported that exercise therapy is not a cure for cfs. the authors stated that "despite the consistent positive outcomes of exercise therapy studies for cfs, full recovery from cfs is rare. in addition, exercise therapy is not a sole treatment for people with cfs. a comprehensive treatment for cfs comprises of education of the aetiology and pathophysiology of the illness, stress management, cognitive restructuring, sleep hygiene and get together with graded activity. but even such a comprehensive rehabilitation programme only rarely results in full recovery." research pharmaceuticals no pharmacological treatments have been established as a cure for cfs, but various drugs are used to manage the symptoms of cfs. in subsets of patients, various viruses and bacteria have been reported as the causative agents of cfs, although consistent and compelling supportive evidence is still lacking. a number of antiviral and antibacterial treatment studies have been conducted with inconsistent results. more research and treatment studies of subtypes of cfs are needed to reduce the inconsistencies. rintatolimod nucleic acid (double-stranded rna) compounds represent a potential new class of pharmaceutical products that are designed to act at the molecular level, it is an inducer of interferon and is considered to be antiviral and immunomodulatory. one rct evaluated rintatolimod and found an overall beneficial effect. in december 2009 the u.s. food and drug administration (fda) refused to approve a new drug application (nda) by the developer of the drug (hemispherx biopharma) to market and sell ampligen for treatment of cfs. the fda concluded that the two rcts submitted "did not provide credible evidence of efficacy." hemispherx biopharma performed additional analyses on their data and submitted a new nda to the fda in 2012. after reviewing the data, the fda did not approve the application citing "insufficient safety and efficacy data". rintatolimod has achieved statistically significant improvements in primary endpoints in phase ii and phase iii double-blind, randomized, placebo-controlled clinical trials with a generally well tolerated safety profile and supported by open-label trials in the united states and europe. rintatolimod has been approved for marketing and treatment for persons with cfs in argentina, and in 2019 the u.s. fda regulatory requirements were met for exportation of rintatolimod from the united states to argentina. valacyclovir nucleosidic class drugs such as acyclovir, valacyclovir and ganciclovir are inhibitors of viral replication during dna (for dna- and retroviruses) or rna (for rna viruses) multiplication. a small 1988 rct compared acyclovir against placebo and found that an equal proportion of patients improved from placebo and with active treatment. the authors concluded that the improvement reflected either spontaneous remission or the placebo effect. three people withdrew from acyclovir treatment due to reversible renal failure. antidepressants antidepressants are often prescribed to cfs patients. their purpose can be to treat secondary depression or mood swings, but low dosage tricyclic antidepressants are sometimes prescribed to improve sleep quality and reduce pain. the evidence for antidepressants is mixed and their use remains controversial. in a review of pharmacological treatments for cfs, five trials of antidepressants were included but only one of these reported a statistically significant improvement in symptoms and this effect was only observed in patients who received 12 weeks of cbt before starting treatment with mirtazapine. stimulants psychostimulants such as amphetamine, methylphenidate, and modafinil have been studied in the treatment of cfs. hormones treatment with steroids and thyroid hormones, such as hydrocortisone, fludrocortisone, and nasal flunisolide, has been studied. the evidence for corticosteroids is limited. a 2006 systematic review examined rcts of steroids, primarily hydrocortisone, which found one with a significant difference between groups for fatigue, but two other rcts found no benefit for steroid treatment. the study which showed statistical significance was noted as scoring poorly for validity. during a randomized, double-blind trial conducted between 1992 and 1996, hydrocortisone treatment (at a higher dose of 20–30 mg) was associated with some statistical improvement in symptoms of cfs. however, the authors concluded that the degree of adrenal suppression precludes its practical use for cfs. additionally, long-term use of these medications carry risks of steroid-induced osteoporosis and muscle atrophy. fludrocortisone is commonly used for patients with postural orthostatic tachycardia syndrome (pots) to treat orthostatic intolerance. given the high comorbidity rate between cfs and pots, it's possible that fludrocortisone could reduce symptoms in these patients. however, there is no research available which examines its effect on comorbid cfs and pots. nadh there is no good evidence that nadh is of benefit for cfs patients. rituximab a potential use for rituximab was identified by two norwegian doctors who were treating people who had cancer with rituximab; two people also had chronic fatigue syndrome and the cfs improved. as of 2017 this use had been explored in some small clinical trials and was undergoing some larger ones; it was unclear as of 2017 whether there is enough benefit in light of the known adverse effects, for rituximab to be a viable treatment for cfs. results from the 2-year randomized, placebo-controlled, double-blind, multicenter rituxme trial comparing multiple brands of rituximab infusions with placebo in 151 me/cfs patients published online april 1, 2019, in annals of internal medicine concluded that "b-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with me/cfs," and thirty-four patients had serious events. " staphylococcal toxoid vaccine there have been two rcts with staphylococcal toxoid vaccine. a small rct showed considerable benefit and a large follow up rct showed overall benefit. however the quality of the follow-up rct was low and there were relatively high levels of adverse effects, although the increase in adverse effects in the treated patients compared to controls did not reach statistical significance. a 2006 review concluded that there is still insufficient evidence for immunological therapies of this type. interferon a systematic review found two small rcts that evaluated interferon. one rct found an overall beneficial effect and the other showed some positive effects in relation to immunological outcomes only. the quality of both of these studies was considered poor. a 2007 review of research needs for cfs concluded that trials for interferon beta are an important priority. igg a systematic review found five rcts to have assessed the effects of immunoglobulin treatment for cfs; of these, two rcts showed an overall beneficial effect and two rcts showed some positive results, although in one of the studies this was for physiological effects only. the largest of the rcts found no effect for the treatment. another review concluded that "given the weak evidence of benefit for immunotherapy, the potential harms indicate that it should not be offered as a treatment for cfs." alternative medicine people with cfs may use more alternative medicine treatments than people without cfs. in a twin study, 91% of twins with cfs and 71% without cfs used at least one alternative treatment. a large proportion of the study participants said alternative treatments were helpful. dietary supplements a 2006 updated systematic review concluded that the supplements essential fatty acids and magnesium have shown beneficial effects but only in one or two trials and further rigorous trials of these interventions would be helpful. a 2008 review found insufficient evidence to recommend dietary supplements as a treatment in chronic fatigue syndrome. one rct compared a polynutrient supplement (containing several vitamins, minerals, and coenzymes, taken twice daily) with a placebo for 10 weeks, but found no difference in fatigue scores. carnitine l-carnitine is an amino acid which includes alc, a group of natural compounds that have an important role in cellular function. it is required for the transport of fatty acids into the mitochondria during the breakdown of lipids(or fats) for the generation of metabolic energy including in muscles and in the brain. two rcts found benefit from dietary supplementation with l-carnitine or its esters. a 2006 systematic review reported one rct with overall benefit, although there was no placebo control. in 2008 a randomised double-blind placebo-controlled six-month trial on 96 aged subjects with cfs symptoms administering acetyl l-carnitine was reported. by the end of the treatment, significant differences between the two groups were found for both physical and mental fatigue and improvements in both the cognitive status and physical functions. a 2002 double‐blind randomized controlled trial with 53 patients found no difference in fatigue severity between groups when given a supplement containing 1200 mg carnitine. essential fatty acids a randomized controlled trial on patients diagnosed with post viral fatigue syndrome (pvfs) and deficient rbc levels, using essential fatty acids consisting of evening primrose oil containing