"like caffeine...in terms of safety, and yet as effective as the amphetamines." 
 - USAF Aerospace Medical Association
Science News 62, pp. 423-435

 

 What are Modafinil and Adrafinil?
Modafinil and Adrafinil are the first of an entirely new class of pharmaceutical - the Eugeroics ("good arousal") - designed to promote vigilance and alertness. This unique class contains only Modafinil and Adrafinil, both of which have been developed by Lafon Laboratories as wake-promoting agents that improve wakefulness. The basis of their uniqueness lies in their ability to stimulate only when stimulation is required. As a result, the "highs and lows" associated with other stimulants such as amphetamine are absent with Eugeroics. Modafinil and Adrafinil won't prevent a person from sleeping if they want to, but if they wish to remain awake they will do so with a far greater alertness. Numerous clinical trials and studies since the mid 1980's have confirmed the ability of Modafinil and Adrafinil to increase awakeness and alertness without serious side effects or dependency. One of those involved volunteers who were subjected to 60 hours of sleep deprivation.  During their continued wakefulness, their vigilance was assessed using questionnaires, visual scales and sleep latency tests. The subjects received either 200 mg Modafinil or a placebo every 8 hours. The Modafinil group sustained a satisfactory level of vigilance with an absence of sleep episodes, unlike the placebo group who gradually declined and slipped into "micro-sleep" episodes, (as one might expect when awake for longer than 24 hours).  Another study conducted over 3 years discovered that Modafinil reduced drowsiness in 83% of hypersomniac patients and 71% of narcoleptics. Modafinil did not produce side effects, disturb night sleep, or promote drug dependence.

NAME:Modafinil
CHEMICAL NAME:Benzhydrylsulphinylacetamide
TRADE NAME:Provigil®, Modiodal®, Vigil®, Alertec®, Modasomil®
CHEMICAL FORMULA:C15H15NO2S
MOLECULAR WEIGHT:273.351
PATENT #:U.S. - 4,177,290
CLASSIFICATION:Stimulant
MECHANISM OF ACTIONAlpha 1 adrenoceptor, Agonist effect
LEGAL STATUS (US):Schedule IV, Controlled Substance - Requires Prescription
Moleculer Structure:Modafinil

NAME:Adrafinil
CHEMICAL NAME:Benzhydrylsulphinyl-acetohydroxamic Acid
TRADE NAME:Olmifon®
CHEMICAL FORMULA:C15H15NO3S
MOLECULAR WEIGHT:289.351
PATENT #:U.S. - 4,066,686
CLASSIFICATION:Stimulant
MECHANISM OF ACTIONAlpha 1 adrenoceptor, Agonist effect
LEGAL STATUS (EU):Available over the counter (OTC)
LEGAL STATUS (US):Unscheduled, Uncontrolled
Moleculer Structure:Adrafinil
 

 What are some publications available to download on Modafinil and Adrafinil?
 Modafinil still effective for sleep apnea after 17 weeks of therapy.(Neuropsychiatric Medicine):Clinical Psychiatry News
Modafinil shows limits in non-sleep deprived.(Neuropsychiatric Medicine): Clinical Psychiatry News

 How does Modafinil / Adrafinil work?
The effects of Modafinil (Provigil) and Adrafinil are based on their ability to selectively stimulate adrenergic neuron receptors in the brain (hypothalamus and brain stem) thought to be involved in regulating normal wakefulness and general alertness towards the external environment. These sites are receptive to Norepinephrine (Noradrenaline), a neurotransmitter linked to alertness, learning, and memory. They work by directly stimulating the neurological postsynaptic receptor sites called, alpha-1 adrenergic. The central function of Norepinephrine is a fairly recent discovery, it appears to regulate alertness and the waking-sleep cycle and has a role in the maintenance of attention, memory, learning, cerebral plasticity and even has neuro-protection qualities. Since Modafinil (Provigil) and Adrafinil works directly on those sites which control alertness and does not interfere with any other brain function, it has been a very successful treatment. (It should be noted that this direct action means that mental stimulation is achieved without raising blood pressure or affecting heart rate). The more focused activity profile may account for the relative lack of adverse side effects of  Modafinil (Provigil) and Adrafinil.  In addition using Modafinil (Provigil) and Adrafinil does not require "catching up sleep" or "rebound sleep". Theoretically it is possible to stay awake on Modafinil (Provigil) and Adrafinil for hundreds of hours without sleeping. This is in direct contrast to conventional stimulants, which stimulate a broader spectrum of brain receptors, including those involving dopamine. 


 What is the difference between Modafinil / Adrafinil and conventional stimulants?
Many stimulant chemicals, such as caffeine, methylphenidate (Ritalin®), Adderall® (amphetamine salts) dexedrine, and methamphetamine, are known to produce similar alerting/energizing effects, yet are highly addictive. Modafinil (Provigil) and Adrafinil have been described as gentler stimulants with much less anxiety, agitation, jitteriness, excess locomotor activity and insomnia associated with conventional stimulants. Central nervous stimulants (CNS) such as amphetamine or pemoline are the most widely used drugs to treat narcolepsy, hypersomnia and catoplexy, but these have a number of well documented problems, such as cardiovascular side effects, interference with sleep, psychiatric disturbances and addiction. The use of these "classic" stimulants such as amphetamines threaten to reduce total sleep time and REM sleep, this will ultimately mean higher and higher doses are required and thus creates cycle of dependency. In contrast to stimulants like amphetamine and caffeine, Modafinil (Provigil) and Adrafinil do not disturb sleep patterns or cause withdrawal symptoms. The effects of Modafinil (Provigil) and Adrafinil are totally different from the other psychostimulants such as amphetamine, caffeine, or ephedrine. These substances only lead to fleeting stimulation and cause problems of tolerance when they are used for long periods. Modafinil (Provigil) and Adrafinil do not stimulate dopaminergic neurons in the nigrostriatal region of the brain [De Sereville et al. ,1994]. As a result, the stimulatory effect of Modafinil (Provigil) and Adrafinil on vigilance and locomotor activity (movement) is not associated with anxiety side effects [Simon et al,1994). Furthermore, in a double-blind cross-over study of 16 "healthy volunteers" (half men and half women, all moderate caffeine users), Warot and colleagues [1993] found that the subjective effects of Modafinil (Provigil) "differed markedly" from amphetamine and were "close" to those of an equal amount of caffeine. They concluded that modafinil "does not possess amphetamine-like subjective effects in a healthy population," and speculated that it probably has low abuse potential.

Modafinil

Amphetamine

CA = caudate   H = Hypothalamus
Data adapted from Lin, Hou, Jouvet, 1996

 What are the properties of Modafinil / Adrafinil?

  • Promotes daytime wakefulness without affecting ability to sleep when sleep is desired

  • Works selectively through the brain' s sleep-wake centers to activate only the cortex, not the entire brain

  • Efficacy established objectively and subjectively in numerous clinical trials

  • Among the safest stimulants available

  • Promotes wakefulness without generalized CNS stimulation in preclinical models

  • Has none of the side effects associated with stimulants such as amphetamine, caffiene, ephedrine, etc

  • Can safely be used without danger of addiction

  • Does not affect normal sleep patterns

  • Acts selectively through the sleep/wake centers of the brain believed to regulate normal wakefulness

  • Does not mediate wakefulness by a dopaminergic mechanism

  • Increases alertness without elevating motor activity

  • Improves patients ability to stay awake and participate in daily activities

  • Does not interfere with nighttime sleep architecture or with patients ability to fall asleep when needed

  • Improves attention and concentration

  • Enhances clarity of thought, cognitive function, mental focus, and memory

  • Normalizes sleep patterns

  • Reduces mental fatigue

  • Improves wakefulness in patients with excessive daytime sleepiness (EDS) associated with narcolepsy

 

 What has Modafinil / Adrafinil been used for?

  • Update 2004 FDA Approved: General physical and mental fatigue including shift work sleep disorder

  • Update 2004 FDA Approved: Improve wakefulness in patients with excessive sleepiness

  • Narcolepsy (excessive daytime sleepiness) - FDA Approved

  • Hypersomnia (excessive sleep)

  • Catoplexy (a condition of sudden muscular weakness or fatigue)

  • Alzheimer's disease

  • Senility and age-related memory decline

  • Depression

  • Myotonic dystrophy

  • Attention-deficit disorder (ADD)

  • Athletics and athletic training regimes

  • US Army, USAF, Special Forces, (as recently as Afghanistan and Iraq) French Foreign Legion, Dutch and Belgian military

 What are the differences between Modafinil and Adrafinil?
Modafinil (Provigil)  is a recently developed analogue of Adrafinil; it is more potent, more expensive, and has fewer side-effects.  Average doses of Adrafinil are in the region of 600 mg to 1200 mg daily, compared to Modafinil's 200 mg to 400 mg daily.  Adrafinil is attributed to some possible side effects that have not been associated with Modafinil (Provigil), including skin irritation in long term use (over 3 months), and an increase in liver enzyme levels, (which is reversible by reduction or withdrawal). Adrafinil may require regular blood testing to monitor liver enzyme levels if used on a regular basis.  

  What are some information resources and articles on Modafinil and Adrafinil?
ABCNews
NY Times
Utne Magazine
Slate.com Magazine
Esquire Magazine
Webmd.com
FindArticles.com
 Modafinil.com
 Provigil.com
Nevapress.com
American Sleep Disorders Association
American Sleep Apnea Association
Narcolepsy Network
National Sleep Foundation

 Are there any side effects or interactions with Modafinil and Adrafinil?
Modafinil (Provigil) has been evaluated for safety in over 2000 subjects, and the long-term safety of Modafinil (Provigil) has been established for up to 136 weeks. No clinically significant changes in body weight in patients treated with Modafinil in clinical trials. Most frequently reported adverse events were headache, nausea, nervousness and anxiety. Most adverse events were mild to moderate. Modafinil (Provigil) may interact with drugs that inhibit, induce or are metabolized by cytochrome P450 isoenzymes. No clinically significant change in hemodynamic parameters such as heart rate and blood pressure in clinical trials. Although Adrafinil is generally regarded as quite safe, a few adverse effects have been reported with long-term use, including occasional instances of elevated liver enzymes, specifically SGOT, SGPT, GGPT, and hepatic alkaline phosphatase.  It is suggested that liver function be tested to establish a baseline before using Adrafinil, and then after 3 months and again every 6 months thereafter. If abnormalities appear, reducing the dose or stopping the drug should permit a return to normal. Adrafinil has a good safety record, however there a number of important precautions; those with epilepsy, liver or kidney impairment should not use Adrafinil . Adrafinil should not be used along with major tranquillizers, e.g. pimozide, haloperidol, chlorpromazine etc. or drugs that enhance norepinephrine activity (such as yohimbine). Adrafinil is noted as contraindicated with epilepsy and has been shown to enhance the potency of anti-epileptic drugs such as phenytoin (Dilantin/ Epanutin).

 What are some of the medical and scientific studies and trials of Modafinil / Adrafinil and where are they published?
National Library
of Medicine

5th Euro Cong sleep research, Copenhagen 586. Laffont F, Cathala HP, Kohler F "Effect of modafinil on narcoleptic and idiopathic hypersomnia"   .

5th Int Cong Sleep Research (149). Goldenberg F, Weil JS, Van Frenkeel R, "Effects of modafinil on diurnal variation of objective sleepiness in normal subjects"

9th Euro Cong sleep research, Israel. Laffont F,Cathala HP, Waisbord P, Kohler F "Effect of modafinil on narcoleptic patients" 

Act. Med. Inter. Psychiatrie (6): No.90. Dewailly Ph

Am J Psychiatry, Vol 158 (No 6) June 2001; 970-971. Modafinil for narcolepsy, Teitelman E

Am J Respir Crit Care Med, Vol 163 (No 4) Mar 2001; 918-923. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome, Kingshott RN, Vennelle M, Coleman EL, Engleman HM, Mackay TW, Douglas NJ

Ann Neurol. 1998;43:88-97. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy.

Arzneimittelforschung Oct 39 (10) 1268-73. Saletu B, Frey R, Krupka M, Anderer P, Grunberger J, Barbanoj MJ "Differential effects of a new central adrenergic agonist- modafinil and d-amphetamine on sleep and early morning behaviour in elderly" 

Brain Res Bull 1993 (32) 2 87-90. Nicoladis S, DeSaint, Hilarre Z "Nonamphetamine awakening agent modafinil induces feeding changes in the rat" 

Brain Res. 1992;591:319-326. Lin J, Roussel B, Akaoka H, Fort P, Debilly G, Jouvet M. Role of catecholamines in modafinil- and amphetamine-induced wakefulness,  a comparative pharmacological study in the cat.

Clin Neuropharmacol, Fed 16 (1) 46-53. Boivon DB, Montplisir J, Petit D, Lambert C, Labin S "Effects of modafinil on symptomatology of human narcolepsy" 

Dept of Phar & Tox, Med Coll VA, USA. Gold LH, Balster RL, "Evaluation of the cocaine like discriminative stimulus effects and reinforcing effects of modafinil" 

Encephale May 1991 17 (3) 187-195.  Jouvet M, Albarede JL, Lubin S, Meyrignac C "Noradrenaline and cerebral aging" 

Esquire Magazine. Feb. 2003, pp116-117 Hylton W, "The war on drugs"

Eur. J. Pharmacol. 59(1-2):121-123. Duteil J

Fund Clin Pharmacol 1995 (9) 3- 271-9. Lagarde D, Batejat D, Van Beers P, Sarafian D, Pradella S "Interest of modafinil, a new psycostimulant during a sixty hour sleep deprivation experiment"

Int J Clinical Pharm Res (3) 183-185. Saletu B, Frey R, Krupka M, Anderer P, Grunberger J, Barbanoj MJ "Differential effects of a new central adrenergic agonist- modafinil and d-amphetamine on sleep and early morning behaviour in young healthy volunteers" 

JAMA Sep. 96, 11 276 (10) 765-766.  Lamberg L "Narcolepsy researchers barking up the right tree" 

J Neurol, Vol 248 (No 7) Jul 2001; 632-634. Successful treatment of excessive daytime sleepiness in Parkinson's disease with modafinil, Happe S, Pirker W, Sauter C, Klosch G, Zeitlhofer J

Journal of Neuropathology and Experimental Neurology 38(5):490-497.  Vijayashankar N

J Neurosci, Vol 21 (No 5) Mar 1, 2001; 1787-1794. Dopaminergic role in stimulant-induced wakefulness, Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM

J Pharmacol Exp Ther. 1997;283:757-769. Edgar DM, Seidel WF. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat. 

J Pharmacol, Vol 17 (No 1) Jan-Mar; 37-52. Unique psychopharmacologic profile of adrafinil in mice,
Rambert FA, Pessonnier J, de Sereville JE, Pointeau AM, Duteil J

J Pharmacol, Vol 16 (No 4) Oct-Dec; 372-380. The effect of adrafinil on the nocturnal activity of the rhesus monkey ,
Milhaud CL, Klein MJ

J Child Adolesc Psychopharmacol, Vol 10 (No 4) Winter 2000; 311-320. Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults,
Taylor FB, Russo J

Journal of Sleep Research, 1998 Jun; 7(2): 105-14. Brun J; Chamba G; Khalfallah Y; Girard P; Boissy I; Bastuji H; Sassolas G; Claustrat B, "Effect of modafinil on plasma melatonin, cortisol and growth hormone rhythms, rectal temperature and performance in healthy subjects during a 36 h sleep deprivation" 

Journees d'etude sur le vieillissement, organisees par L'ORPHEM, Marseille, 25-26 mars. Jouvet M

La Revue de Geriatrie 13(4) Avril Schneider H   

La Press Medicale 15 (28) 1330. Bastuji H, Jouvet M "Traitement des hypersomnies per la modafinil" 

Neurology. 2000;54:1166-1175. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a treatment for the excessive daytime somnolence in narcolepsy

Neurophysiol Clin 1996 26 (1) 60-66. Basset A, Chetrit M, Carlander B, Billard M "Use of modafinil in the treatment of narcolepsy, a long term follow up study"

Neurology 1997 Aug (49) 2 P444-451. Broughton RJ, Fleming JA, George CF, Hill JD, Kruger MH, Moldofsky H, Montplasir JY, Morehouse RL, Moscovitch A, Murphy WF "Randomised double blind placebo controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy" 

Neuroreport, Vol 12 (No 2) Feb 12, 2001; 375-378. Effects of modafinil in children with attention-deficit/hyperactivity disorder: an open-label study, Beracochea D, Cagnard B, Celerier A, le Merrer J, Peres M, Pierard C

Neuro Sci Lett 1996 Dec 6 220 (1). Ferraro L, Tanganelli S, O’Connor WT, Antonelli T, Rambert F, Fuxe K "The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rate; possible involvement of the serotonergic 5-HT3 receptor"

Prog Neuropsychopharmacol Biol Psychiatry, 14(2):195-214 1990.Saletu B; Saletu M; Grunberger J; Frey R; Zatschek I; Mader R, "On the treatment of the alcoholic organic brain syndrome with an alpha-adrenergic agonist modafinil: Double-blind, placebo-controlled clinical, psychometric and neurophysiological studies.

Psychiatr. 2(3):318-321 (1987)

Proc Natl Acad Sci USA. 1996;93:14128-14133.  Lin JS, Hou Y, Jouvet M. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. 

Prog Neuropsychopharmacol Biol Psychiatry, Vol 24 (No 5) Jul 2000; 709-726. Adrafinil: effects on behavior and cognition in aged canines, Siwak CT, Callahan H, Milgram NW

Pharmacol Biochem Behav, Vol 66 (No 2) June 2000; 293-300. Behavioral activating effects of adrafinil in aged canines,
Siwak CT, Gruet P, Woehrle F, Schneider M, Muggenburg BA, Murphey HL, Callahan H, Milgram NW

Pharmacol Ther. 1994;61:227- 236. Pascoe P. Drugs and the sleep-wakefulness continuum.

Pharmacol Biochem Behav, Vol 66 (No 2) June 2000; 301-305. Oral administration of adrafinil improves discrimination learning in aged beagle dogs, Milgram NW, Siwak CT, Gruet P, Atkinson P, Woehrle F, Callahan H

Prog. Neuropsychopharmacol. Biol. Psychiatry 7)(2-3):183-186.  Simon P  

Prog Neuro Psy Pharm 12 (5) 695-700.  Bastuji H, Jouvet M "Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil" 

Psychopharmacology (Berl) 2000 Jun; 150(3):272-82 Caldwell JA Jr, Caldwell JL, Smythe NK 3rd, Hall KK

Psychologie Medicale 19(10):1901-1910  Guyotat J

Psychologie Medicale 21(8):1235-1255. Israel L

Respiration 1997 64 (2) 159-161. Arnuff I, Homeyer P, Garma L, Whitelaw WA, Derenne JP "Modafinil in obstructive sleep apnea hypopnea syndrome, a pilot study in 6 patients" 

Sem. Hop. Paris 62(34):2772-2775.  Kurtz D

Sleep 1994 Dec 17 (8) 5113-115.  Maffont F, Mayer G, Minz M, "Modafinil in diurnal sleepiness, a study of 123 patients" 

Sleep 1994 Dec 17 (8) 5107-112. Billiard M, Besset A, Montplasir J, Laffont F, Goldenberg F, Weill JS, Lubin S "Modafinil, a double blind multicentric study"

Science News Note, 62 432-5. Lyons TJ, French J "Modafinil the unique properties of a new stimulant" USAF School of Aerospace, Brooks TX  

Smart Drug News. 1994;3:1-5. Fowkes S. Adrafinil and modafinil. 

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