In 1974, 2 chemists at Lafon Ltd., a pharmaceutical company in France, discovered a new molecule which would change the nootropics industry four decades later. While working on discovering new analgesics in their laboratory in Maisons-Alfort, a commune in the southeastern suburbs of Paris, Assous and Gombert discovered benzhydrl sulfinyl-2 acetohydroxamic acid – aka adrafinil. When they passed on this new molecule to Duteil and Rambert, 2 pharmacologists at Lafon, initial studies revealed that this molecule induced hyperactivity in mice. Further investigations by another scientist, Jouvet, revealed that the molecule increased wakefulness in cats, while Milhaud and Klein found that the molecule increased nocturnal activity in monkeys. In 1976, the active metabolite in adrafinil was correctly identified as modafinil.
By 1977-1978, Jouvet first prescribed adrafinil to narcoleptic patients, the results of which were highly inconsistent. A natural question arose. Could modafinil being the active metabolite lead to a better outcome? Modafinil went through the same level of scrutiny that adrafinil encountered. The results were positive. Laboratory studies revealed that modafinil led to a dose-dependent increase in locomotor activity in mice, increased wakefulness and decreased sleep in the cat, and increased nighttime activity in monkeys. By 1983, Jouvet was once again ready for experimentation with narcoleptic patients. The results were wildly successful. By 1984, Lafon Ltd. sanctioned the start of clinical trials on both healthy volunteers and narcoleptic and idiopathic hypersomnia patients. Thus, 10 years after the serendipitous discovery of adrafinil, modafinil entered the era of serious clinical investigation.
The first official non-clinical use of modafinil is tied to the arrival of the Gulf War in 1991. The French Ministry of Defense provided the French Army with modafinil, which was then tested in normal military subjects for potential use in military operations. The results were positive, with 200mg of modafinil administered every 8hrs for 3 days leading to no noticeable decline in cognition and no major side effects. Finally, between Feb 24 – Feb 28, 1991, modafinil was officially used by French operatives during Operation Desert Storm. Unfortunately, no scientific experiments could be carried out due to the nature of the operation.
Soon after, the first large-scale, randomized, placebo-controlled trial of modafinil in hypersomnia patients was carried out. An overall clinical benefit was noted, as well as a significant improvement in the results of MWT (Maintenance of Wakefulness Test) for patients on modafinil compared to placebo. Thus, in June 1992, modafinil was officially registered for narcolepsy in France, and by 1994 was commercially available.
It wasn’t until 1993, almost two decades after the discovery of adrafinil, that clinical research on modafinil began in the United States. An east coast pharmaceutical company, Cephalon, acquired the rights to modafinil from Lafon Ltd, and began a series of studies to investigate the molecule further. The robust effects of modafinil on wakefulness, along with its positive adverse effects profile, finally led to an approval by the Food and Drug Administration (FDA) in 1998.
In 2004, the use of modafinil was expanded to include obstructive sleep apnea/hypopnea syndrome (OSAHS), and shift work sleep disorder (SWSD). With its expanded usage, modafinil was more readily available than ever before, and word about its off-label reputation as a cognitive enhancer began to reverberate in many underground “smart pill” communities. In addition to the prescription crowd, modafinil spread to finance executives on Wall Street, techies in Silicon Valley, and truckers all across the country. Today, four decades since the initial discovery, modafinil is considered one of the top nootropics in the world.