The history of modafinil dates back to 1974 in France. As they were screening molecules in search of analgesics, two chemists from Lafon Ltd., a pharmaceutical company based in Maisons-Alfort, near Paris, Assous and Gombert, identified a new molecule, adrafinil [benzhydryl sulfinyl-2 acetohydroxamic acid], later passed on to two pharmacologists, Duteil and Rambert, also from Lafon Ltd. These pharmacologists observed that mice treated with this molecule were hyperactive [1] and foresaw a potential interest for it. Following further tests in mice and rats, and more refined pharmacology in dogs, the molecule was given to Jouvet for evaluation in the cat and to Milhaud and Klein for evaluation in the monkey. Interestingly, a decrease of sleep and an increase of wakefulness were found by the first group and an increase of nocturnal activity by the second group. Eventually, in 1977–1978, Jouvet prescribed adrafinil to narcoleptic patients subjects with inconsistent results.

Meanwhile, in 1976, the kinetic of adrafinil led to the identification of an active metabolite, modafinil (2-[diphenylmethyl) sulfinyl] acetamide). Modafinil went through the same steps of development leading to the demonstration of a dose-dependent increase of locomotor activity in mice [2], an increase of wakefulness and a decrease of sleep in the cat [3], and an increase in nocturnal activity and in behavioural arousal without stereotyped behaviour in rhesus monkeys [4]. As soon as early 1983, Jouvet prescribed modafinil to narcoleptic patients and the results outdid the expectations. From then on, Jouvet continued to use modafinil with success in both narcoleptic and idiopathic hypersomnia patients subjects. In 1984, Lafon Ltd. decided to start clinical trials in both healthy volunteers [5, 6] and narcoleptic and idiopathic hypersomnia patients [7] under the leadership of Lubin and Weil, medical and clinical directors at Lafon Ltd.

As the Gulf War (August 1990–February 1991) was breaking out and French troops were to be sent to Iraq, the French Ministry of Defense demanded that Lafon Ltd. provide the French Army with modafinil, in view of testing the drug in normal military subjects before a possible use in military operations. The drug was tested in eight normal military subjects undergoing sleep deprivation for 60 h. Modafinil 200 mg or a placebo was given every 8 h for 3 days [8]. Results on cognitive tests were positive and no consistent adverse effect was recorded. In January 1991, the military doctors accompanying the “Daguet” operation (the name given to the French participation in the international coalition) were allowed to prescribe modafinil and the drug was used on 24–28 February 1991, during the Operation Desert Storm, mainly by military pilots and mechanics. Unfortunately, the prescriptions were not scientifically conducted, neither in terms of dosage nor in terms of timing, an aerial and ground combat zone not being the best environment to test a novel compound.

Following further open label studies conducted in different French sleep centres, the first multicenter, randomized, placebo-controlled trial of modafinil in hypersomnia patients subjects (33 men and 17 women) was performed [9]. Modafinil was administered in a double-blind cross-over design, at a dosage of 300 mg versus placebo and results judged through questionnaire on therapeutic effects, sleep log, polysomnography and MWT. An overall clinical benefit was noted by physicians as well as by subjects. Above all there was a significant improvement in the results of the MWT for patients on modafinil in comparison with placebo ( p< 0.05).

Modafinil was officially registered for narcolepsy in France in June 1992 and became commercially available, also in France in September 1994.

After oral administration the maximal concentration of the product was reached within 2–4 h. The elimination half-life was 10–13 h. The adverse effects were relatively limited and not significant. These included headaches, irritability and insomnia, particularly at the onset of treatment. The compound was judged effective in 60–70 % of narcoleptic patients. It was prescribed at a dose of 100 mg in the morning and 100 mg at noon up to 400 mg/day.