Modafinil - an Overview

For decades scientists and pharmacologists have experimented with various drug formulations to enhance brain activity and break the limits of imagination and power of the human mind. Generally classified as stimulant drugs these drugs enhance memory, cognition, creativity and to some extent motivation. They earned the name of 'smart drugs' or 'cognitive enhancers'.

In the 1970s while searching for compounds with analgesic properties, French neurophysiologist Michel Jouvet in collaboration with Lafon laboratories came across benzhydril sulfonyl compounds which instead of promoting sleep had the opposite effect. Upon further research and controlled experiments the first of these drugs Adrafinil was discovered in 1974. It had psychostimulant properties and promoted wakefulness and hyperactivity. By 1976 its active metabolite or break down product Modafinil was discovered which was more potent and efficacious than the latter.

By 1980s both these drugs after controlled trials were sought out for the treatment of narcolepsy. As the years passed more research was done and although Adrafinil was eventually discontinued, Modafinil continued to be used for various diseases including narcolepsy, shift work sleep disorder and sleepiness associated with obstructive sleep apnea. Off label because of its psychostimulant properties Modafinil use increased in students, heavy workers, night time laborers and even the military. Today it continues to flourish despite its exact mechanism of action still unclear.

Having a broad biochemical action profile a lot of research has been carried to find its various uses. It has shown to improve performance in kids suffering from Attention Deficit Hyperactivity Disorder (ADHD). It is also beneficial in patients with seasonal affective disorder and depersonalization disorder, pspecially with negative psychosomatic symptoms. Other diseases where it has shown a positive impact include:

  • Cognitive enhancement;
  • Cognitive impairment (post chemotherapy);
  • Motion Sickness (in combination with scopolamine);
  • Concussion patients;
  • Addiction treatment (cocaine and opioids);
  • Delayed sleep phase syndrome;
  • Weight loss;
  • Parkinson disease;
  • Bipolar disorder;
  • Schizophrenia;
  • Depression;
  • Sleep apnea and other fatigue syndromes;
  • Used by various armies to enhance strength and morale, fight tiredness.

Pharmacologically it is categorized under indirect acting sympathomimetic; an alpha1-adrenergic agonist. Generally these drugs can have one of the two different mechanisms; first they may enter the sympathetic nerve ending and displace stored catecholamine transmitter; they are called 'displacers'. Second they may inhibit the reuptake of released transmitter by interfering with the action of norepinephrine transporter, NET. Modafinil being unique in structure, neurochemical profile and behavioral effects inhibits both norepinephrine and dopamine transporters thus increasing their concentration. It also increases serotonin and glutamate in the brain, whereas it decreases the GABA levels. It achieves this by elevating the histamine levels in the hypothalamus. It effects dopamine ( by blocking uptake at the dopamine transporter) in striatum and nucleus accumbens, norepinephrine in the hypothalamus and venterolateral preoptic nucleus and serotonin in the amygdala and prefrontal cortex. It is mainly metabolized in the liver and both the liver and the kidney play a role in its excretion. It peaks plasma levels in abt 2-3 hours and has a half life of around 10-12 hrs.

The best part of Modafinil discovery was that it didn't share the addiction potential of other stimulants like amphetamines, cocaine, ephedrine and methamphetamines. Although not addictive, its potential for abuse is high, among students, workers and athletes alike. Thus Modafinil availability is legally restricted and prescription only. However the black market has sold a large number of the medicine and to control it further Modafinil is also included in the doping tests for athletes and some government agencies; also it is not ideally prescribed under the age of 17. Its reported side effects include anorexia, headache, dry mouth, palpitations, itchiness, buccofacial dyskinesia, nausea, nervousness, diarrhea, insomnia (generally after discontinuation) and anxiety; but these were reported in a minority of cases only. As with all medication some serious side effects have been reported although only in a minority of cases, these include Steven Johnson Syndrome, Erythema Multiforme, Toxic Epidermal Necrolysis and DRESS syndrome.

Caution is advised while using Modafinil in hepatic and renal impairment ( where the dosage must be halved). Care should also be taken in hypertensive patients as well. It is completely contraindicated in conditions like pregnancy, breast feeding, myocardial infarction ( specially non ST- segment elevation), hypertension with underlying angina and hypertension of pregnancy. Furthermore it should not be taken with alcohol and opioids such as hydrocodone, oxycodone and fentanyl. Caffeine and chocolate consumption should also be reduced while taking Modafinil. It is important to mention that women using hormonal control methods of birth control such as birth control pills, shots, implants, patches, vaginal rings and intrauterine devices have a higher chance of pregnancy while using Modafinil and one month thereafter.

The medicine is available in tablets of 100 and 200mg, whereas new formulations are being developed. Very few cases of overdose have actually been reported and an acute overdose does not pose any life threatening effects however the following were reported on overdose:

  • Insomnia and sleep issues;
  • Disoriented;
  • Chest pain;
  • Nausea;
  • Diarrhea;
  • Irritability;
  • Hallucinations;
  • Change in Blood Pressure.

Studies are still underway to determine the side effects after prolonged use and generally include anxiety and insomnia but can be managed under professional supervision. Mostly cold turkey is to be avoided and tapering the dosage before discontinuation is advised.

Despite these minor side effects the safety profile of Modafinil is high and controlled use under doctor supervision has yielded excellent results for the masses. Further research continues to be done to understand the exact mechanism of action by which it exerts its various beneficial effects on the human brain. It is a breakthrough drug and efforts to increase its efficacy under safe limits are ongoing. For the layman any person hoping to exceed and excel in their work or life otherwise can benefit from the use of Modafinil.