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Abstract Introduction The chronic fatigue syndrome (CFS) is a heterogeneous disorder characterized by easy fatigability, feverishness, diffuse pains, and depression. Many COVID-19 patients expressed a long-term effect of coronavirus (long-COVID), with some characteristics typically found in CFS. To examine the efficacy of NLS-4 (Lauflumide), in comparison with a positive control, modafinil, which has been shown to improve recovery from CFS in human, to improve recovery from severe fatigue in rats. Methods Male 7-8 weeks old Sprague-Dawley rats were subjected to a fatigue procedure for seven consecutive days. Their locomotor activity in home cage was then recorded for 3 days following the end of the fatigue procedure. A Sham group was subjected to the same measurement of circadian activity but without the fatigue procedure. Rats were divided into different groups which received, before the start of the dark period, three daily administrations of NLS-4, modafinil or vehicle (Control and Sham groups). Results The fatigue procedure induced an impairment in the circadian activity, that is a decrease in motor activity during the dark period and an increase in motor activity during the period of light. Accordingly, the difference of distance travelled between the dark period and the light period was lower in the Control group than in the Sham group. This impairment was still present 3 days after the end of the fatigue procedure. modafinil and NLS-4 dose-dependently increased locomotor activity during the dark phase and, to a lesser extent, during the light phase. The increase in activity during the dark phase was significant at doses of 16, 32 and 64 mg/kg with NLS-4 and at doses 64 and 128 mg/kg with modafinil but the effect of NLS-4 was more sustainable than that of modafinil. Conclusion This study suggests that the impairment of circadian rhythm induced by a fatigue procedure was reduced to a similar magnitude by modafinil (64 mg/kg) and NLS-4 (16 mg/kg). Since modafinil has been shown to improve recovery from chronic fatigue in human, these results show that NLS-4 could improve recovery from CFS in human at doses four times lower than that used for modafinil. Support (if any) NLS Pharmaceutics