Editorial [Drugs Promoting Wakefulness and Performance Executive Editor: J.G. Ramaekers]

In modern society the market for drugs to enhance human performance is large. Health-food stores and Internet sites already offer a large variety of ‘smart drugs’ or ‘nootropics’ that are claimed to improve intelligence in humans of all age categories. Such products usually include multivitamins or herbal extracts from ginseng, ginko biloba or other substances derived from non-Western cultures. Most of these claims are largely unsubstantiated but there is growing evidence that some of these substances can actually mildly improve overall cognitive functioning in healthy subjects as indicated by composite neuropsychological measures of cognitive performance [1]. Similarly, drugs are being used that sustain or increase arousal to help stimulate human performance, particularly during periods of fatigue or sleepiness. The classical examples being amphetamine use in long-haul truck drivers, students, athletes and the military at times of war. Though amphetamines when given in low doses have been repeatedly shown to improve performance and cognitive function the drugs are also associated with a range of psychological en physical side effects, particularly after repeated use. When the drugs wear off, a long period of sleep ensues, often followed by hunger and depression, which can lead to further use of amphetamines. Amphetamine addiction has been common among those who have used the drugs for increased energy, alertness, or endurance. Side effects that are associated with amphetamine use are believed to be absent or relative minor with modafinil as reviewed in the paper by Wesensten [2]. Modafinil is a schedule IV drug promoting wakefulness that has been approved for the treatment of narcolepsy, sleep apnea syndrome, and shift work sleep disorder. Modafinil's performance enhancing effects were quickly discovered by the military as a means to keep military personnel at work for 40 hours straight, without feeling "wired" and without crashing afterward [3]. Also, elite athletes were quick to discover modafinil. In November 2004, the U.S. Olympic gold medal for the 1600 meter relay was revoked and given to France because US athlete Calvin Harrison tested positive for modafinil. Discovering molecules that enhance cognition and performance comprises one of the most exciting areas in drug development. At present the psychopharmacology of wakefulness has focused primarily on 2 parallel pathways that activate the cortex. The first pathway includes monominergic projections from the brainstem to the cortex via the ascending reticular formation. Stimulation of this pathway may be mediated by dopamine, serotonine, noradrenaline and acetylcholine and result in increased levels of ‘external’ vigilance or hypervigilance. Stimulants such as amphetamines and caffeine are supposed to activate this system. Stimulation of the second pathway is believed to increase levels of another form of arousal: i.e. ‘internal‘ vigilance. Internal vigilance may be mediated by the ascending histaminergic neurons and stimulation of this pathway should lead to enhanced problem solving and cognitive function without producing any of the side effects associated with ‘external’ vigilance as in the case of amphetamines. The papers by Smitt and coworkers [4], Mehta and Riedel [5] and Theunissen and coworkers [6] provide a detailed review of the association between serotonin, dopamine, histamine and human performance enhancement. Interestingly, the search for a ‘viagra for the brain’ also comprises studies on the association between cognition enhancement and PDE5 inhibitors, a drug class of which viagra is a distinguished member. PDE5 inhibitors have been repeatedly shown to improve recognition memory in animals. The mechanism underlying the nootropic effect of PDE5 inhibitors however is largely unknown. PDE5 has been implicated to play a role in memory formation in animals through long-term potentiation. It is hypothesized that presynaptic cGMP stimulates the release of glutamate that in turn will bind to postsynaptic NMDA receptors. Human studies demonstrating memory enhancing effects of PDE5 inhibitors are presently lacking but will offer an interesting challenge for researchers in the near future. The article by Blokland and coworkers [7] nicely analyzes and reviews the present data on cognition enhancements and PDE5 inhibitors. This special issue on "Drugs promoting wakefulness and performance" encompasses psychopharmacological research related to the issues outline above. Key concepts include 1) the pharmacological pathways and substrates