In this section, published evidence of the efficacy of some biological, non-psychological, non-psychiatric interventions for CFS/ME/SEID are described. (One physician, himself bedridden with ME, has even argued that graded exercise therapy and cognitive behavioural therapy may be harmful to patients [84].)

From the description of the NO/ONOO− cycle earlier in this paper, it follows that downregulation of this cycle might be expected to be of therapeutic value in CFS/ME/SEID. One candidate to achieve such downregulation is vitamin B 12 , which is available over the counter in different forms, including as hydroxocobalamin, cyanocobalamin and methylcobalamin. In 1995, using porcine endothelial cells from the aorta, Rochelle and colleagues published evidence favouring the existence of a redox reaction between reduced cobalamin and NO, with binding of NO occurring in a reversible manner to oxidised cobalamin [85]. Since then, several studies, both in vitro and in vivo, have established the NO scavenger role of cobalamin [15, 86]. This may help explain the results of an early double-blind cross-over trial in patients complaining of tiredness (the study was from the 1970s, well before the publication of more recent operational criteria for the diagnosis of CFS/ME/SEID), in which twice-weekly injections of hydroxocobalamin, for a fortnight, were associated with improved well-being which persisted for at least a month [87]. At the time of writing, there have been no publications of any similar trials in operationally defined CFS/ME/SEID, although anecdotal reports suggest that there may be a benefit of this vitamin in such patients, with this benefit not necessarily being associated with a pre-existing vitamin B 12 deficiency [15, 88,89,90].

The lipophilic coenzyme known as coenzyme Q 10 (CoQ 10 ) has important roles in ATP generation, inflammatory cascade inhibition and apoptosis prevention [91]. CoQ 10 can act as an antioxidant which can inhibit the oxidation of DNA, lipids and proteins [92]. It can also prevent the initiation and propagation of lipid peroxidation, including by means of the recycling action of NAD(P)H:(quinone acceptor) oxidoreductase 1 activity [92,93,94]. These actions occur in vivo in mammals; murine experiments have shown that dietary supplementation is associated with reduced lipid peroxidation [95, 96]. This occurs also in membranes of mitochondria located both peripherally and in the CNS and is associated with improved mitochondrial function, again both peripherally and centrally [97, 98]. Therefore, it would seem reasonable to propose that supplementation with CoQ 10 and NADH could be beneficial in CFS/ME/SEID. In a recent double-blind 8-week study by Castro-Marrero and colleagues of 80 CFS patients who were randomised to receive either this supplement combination or a matching placebo, the active group showed a reduced maximum cardiac rate during a cycle ergometer test at the end of the study (compared with baseline) and indeed also a reduced perception of fatigue [99]. It is of interest to note that another mitoprotective dietary intervention which has been proposed for CFS/ME/SEID patients is caloric restriction, but this has not yet been the subject of a published trial in this disease [100].

The mainly pineal neurohormone melatonin (N-acetyl-5-methoxytryptamine) has important antioxidant, neuroprotective and immunomodulatory properties and may help prevent or treat bacterial and viral infections [101]. Furthermore, the normal circadian rhythms of fatigue and of urinary melatonin levels covary [102], while administration of this indole to healthy volunteers has been found to be associated with a reduction in self-rated fatigue or tiredness [103]. It seems reasonable, therefore, to suggest that melatonin supplementation may be of therapeutic value in CFS/ME/SEID patients. While some earlier pilot studies in CFS/ME/SEID gave essentially negative results, or, in one case, there was evidence of high nocturnal melatonin levels therefore suggesting that it would be inappropriate to administer melatonin, a few more recent studies have given positive findings [104,105,106,107]. On balance, the evidence suggests that it would be appropriate to conduct larger, randomised, double-blind trials of melatonin supplementation in CFS/ME/SEID patients [108]. Meanwhile, it would appear sensible to advise CFS/ME/SEID patients, and indeed most people whether ill or not, to avoid the prolonged evening use of electronic gadgets that employ light-emitting diode screens giving off relatively high levels of blue light (with a wavelength of approximately 470 nm), as exposure of healthy volunteers to such light for just half an hour, starting at 8 p.m., is associated with a strong suppression of nocturnal melatonin production (of over 90%) [109].

The association of CFS/ME/SEID with EBV or HHV-4 infection has been mentioned above. The use of antiviral treatment for infectious mononucleosis is controversial and is not currently routinely recommended [110]. However, in the mid-1990s a small, double-blind, placebo-controlled, phase III cross-over study of antiviral treatment in CFS patients showed promising results, with continued improvement in symptomology with up to 18 months’ treatment [111]. It could therefore be argued that a larger trial in CFS/ME/SEID would be in order. Meanwhile, it may be prudent to consider the role of the intestinal microbiota and virome, with the use of suitable supplementation (although again evidence from clinical trials is currently lacking) [112].

Twenty nine CFS/ME patients took part in an open-label study of the monoclonal anti-CD20 antibody rituximab, administered as a couple of infusions a fortnight apart followed by maintenance treatments [113]. Use of this monoclonal antibody is associated with depletion of B lymphocytes; in this study, clinical improvements were observed in almost two-thirds of the participants, with remission being maintained at the time of 3-year follow-up in a majority of the responders [113]. At the time of writing, it is not yet known how to differentiate responders from non-responders, although it has been noted that responders have lower levels of baseline serum IgG [114]. Furthermore, in late 2017, it was reported that preliminary results from a phase III trial of rituximab in CFS/ME may have been associated with negative findings; the authors feel that it would be prudent to await formal publication of the full results before commenting further.

Unsurprisingly, in light of the above findings, it has recently been suggested that rehabilitation for CFS/ME/SEID patients should be extended from a narrow psychologically based domain and become multidisciplinary, including for example exercise physiologists and physiotherapists [115].