Modafinil

        "...modafinil ('Provigil', 'Alertec', 'Vigicer', 'Modalert', etc) is a memory-improving and mood-brightening psychostimulant. It enhances wakefulness, attention capacity and vigilance, but its pharmacological profile is notably different from the amphetamines, methylphenidate (Ritalin) or cocaine. Modafinil is less likely to cause jitteriness, anxiety, or excess locomotor activity - or lead to a hypersomnolent 'rebound effect' - than traditional stimulants. Subjectively, modafinil feels smoother and cleaner than the amphetamines too. It may even be anxiolytic, though reports vary. The normal elimination half-life of modafinil in humans is between 12 - 15 hours. So it's worth fine-tuning one's dosage schedule accordingly. Executive function may be enhanced by its use; but not divergent "creative" thinking or empathy.

        Current research suggests modafinil, like its older and better-tested analogue adrafinil, is a safe, effective and well-tolerated agent. It is long-acting and doesn't tend to cause peripheral sympathetic stimulation. Yet its CNS action isn't fully understood. Modafinil induces wakefulness in part by its action in the anterior hypothalamus. Its dopamine-releasing action in the nucleus accumbens is weak and dose-dependent; the likelihood of a euphoric response ("abuse potential"), dose-escalation and tolerance is thus apparently small. However, antagonism of the dopamine D1 and D2 receptors completely prevents modafinil-induced arousal. Modafinil's mood-brightening ("antidepressant") effect is apparently mediated via the dopamine D2 rather than D1 receptors.

        Modafinil-induced alertness is partially antagonised by the endogenous cannabinoid neurotransmitter anandamide. Modafinil has central alpha 1-adrenergic agonist effects i.e. it directly stimulates the receptors. Modafinil inhibits the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons of ventrolateral preoptic nucleus (VLPO). More significant, perhaps, is its ability to increase excitatory glutamatergic transmission. This reduces local GABAergic transmission, thereby diminishing GABA(A) receptor signalling on the mesolimbic dopamine terminals.

        Modafinil is proving clinically useful in the treatment of narcolepsy, a neurological disorder marked by uncontrollable attacks of daytime sleepiness. Narcolepsy is caused by dysfunction of a family of wakefulness-promoting and sleep-suppressing peptides, the orexins. Orexin neurons are activated by modafinil. Orexinergic neurons are found exclusively in the lateral hypothalamic area. Their activation is associated with enhanced pleasure-seeking and motivation as well as arousal. Orexinergic fibers project to the entire central nervous system. Genetically modified orexin-knockout animals offer a model of human narcolepsy. Narcoleptics suffer profound disturbances in normal sleeping patterns and variable degrees of depression. These symptoms can be reversed with modafinil. Selective orexin receptor agonists of the future may prove useful both to narcoleptics and the population at large.

         Experimentally, modafinil is also used in the treatment of Alzheimer's disease; depression; attention-deficit disorder (ADHD); myotonic dystrophy; multiple sclerosis-induced fatigue; post-anaesthesia grogginess; cognitive impairment in schizophrenia; spasticity associated with cerebral palsy, age-related memory decline; idiopathic hypersomnia; methamphetamine ('Ice') abuse; apathy in the elderly; jet-lag; cancer-associated fatigue and opioid-induced sedation; fatigue in Charcot-Marie-Tooth Disease (CMT); Kleine Levin syndrome ('Rip van Winkle' disease); and everyday cat-napping. Sceptics cite the broadly comparable therapeutic equivalance of a cup of coffee.

        There is tentative evidence that modafinil may be neuroprotective against the "dopamine-deficiency disorder" Parkinson's disease. Depressives who feel sleepy and fatigued on SSRIs can augment their regimen with modafinil. In September 2003, an advisory panel to the FDA endorsed its use for treating shift work sleep disorder and obstructive sleep apnea.

        The US military are interested in modafinil too. Modafinil was reportedly used by Allied combat soldiers in both Gulf Wars, though this seems unlikely to feature prominently in its future promotional literature.

        Modafinil is marketed as 'Alertec' in Canada - and over the Net. 'Alertec' is less expensive than 'Provigil'. Cheap generic modafinil has been available since 2006. But Cephalon has vigorously litigated to defend its patents.

        In October 2011, Cephalon were acquired by the even more litigious generic drug company Teva. Consumer advocates and the FTC are worried that Teva's purchase of Cephalon is anti-competitive and will inflate prices.

        In August 2006 Cephalon unexpectedly received a 'non-approvable' letter from the FDA for modafinil tablets branded as Sparlon. Taken in this guise, modafinil was intended for the treatment of so-called attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. The FDA's rejection of modafinil/Sparlon for ADHD was based on a single adverse incident during clinical trials. One child developed a rash suggestive of Stevens-Johnson syndrome - a serious hypersensitivity complex affecting the skin and mucous membranes. There is no evidence that Stevens-Johnson syndrome is more common in adult modafinil users. The physician who diagnosed SJS in the affected 10 year old later recanted the diagnosis. Meanwhile, millions of lively American school students controversially diagnosed with ADHD continue to be prescribed toxic amphetamine-based products instead.

        Modafinil is used experimentally in the treatment of "atypical" depression. Atypical depression is marked by hypersomnia, hyperphagia [over-eating], low energy, and rejection-sensitivity. The syndrome is actually quite common. The results of preliminary studies have been encouraging, but large-scale trials are needed.

        In March 2005, Cephalon filed a New Drug Application (NDA) with the FDA for 'Nuvigil' (r-modafinil, armodafinil) - a single isomer formulation of modafinil. Nuvigil has been marketed aggressively to offset the anticipated loss of revenue from Provigil. Nuvigil received FDA approval in June 2007. R-modafinil / Nuvigil is licensed for the treatment of narcolepsy and shift work sleep disorder, and as an adjunctive treatment for obstructive sleep apnea.

        In March 2010, the FDA declined to approve use of r-modafinil / Nuvigil as the first medicinally-specific drug to treat jet-lag.

        More generally, modafinil is increasingly used as a 'lifestyle drug' - a lucrative 'off-label' market its makers have not been unduly keen to discourage. Some prescribing physicians have reportedly been surprised at a previously hidden epidemic of narcolepsy among hard-working young professionals attending their surgeries.

        Increasing numbers of students use modafinil. Task-related pleasure and motivation may be enhanced. Even so, the benefits of modafinil as a "smart drug" or neuroenhancer are modest at best. Prolonged sleep deprivation can enhance synaptic strength while impairing memory. Modafinil may even be used therapeutically to disrupt long-term memory consolidation in "animal models" of PTSD. But the consumption of modafinil at several leading British universities is quite common among students seeking a competitive edge in exams, where drug-testing is not yet routine. Reports of modafinil-popping dons suggest smart-drug use is creeping up the academic foodchain too.

        Prudence, however, should be exercised in drastically curtailing one's sleep. Prolonged sleeplessness weakens immune function. A surprising study published in the January 2009 edition of Archives of Internal Medicine suggested that people who sleep less than seven hours a night are almost three times as likely to catch a cold as sounder sleepers who sleep eight hours or more. And non-human animals tortured in sleep-deprivation experiments eventually die from massive bacterial infections of the blood..."

Refs
further reading

Structure
Product Info
BLTC Research
Cephalon Provigil
The Good Drug Guide
Modafinil (Wikipedia)
Modafinil (review, 2015, PDF)
Modafinil (review, 2016, PDF)
Narcolepsy & Sleep Disorders
Modafinil (Provigil): prescribing information (PDF)

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