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Adrafinil is a precursor drug to modafinil, which means adrafinil is metabolized in the body to produce modafinil. Both are stimulants with no amphetamine-like effects.

Our evidence-based analysis on adrafinil features 21 unique references to scientific papers.

Research analysis led by and reviewed by the Examine team.
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Research Breakdown on Adrafinil

1Sources and Structure


Adrafinil ({diphenylmethyl}sulfinyl-2 acetohydroxamic acid), sold until recently under the brand name of Olmifon, is a prodrug of the stimulant Modafinil and synthetic substance not found in any dietary source. Due to a lack of purported amphetamine-like stimulatory effects, adrafinil is classified as a eugregoric agent (an agent who promotes wakefulness and alertfulness).[2]

Adrafinil is sometimes used as a stimulatory agent in athletes[3] despite being considered a banned substance for competitive sports. The World Anti-Doping Agency (WADA) currently has adrafinil on its banned substances list, classifying it as a “non-specified stimulant”. [4]

Adrafinil is a synthetic prodrug for modafinil, formerly sold under the brand name of Olmifon. It is banned in competitive sports usage under WADA due to its stimulatory properties.


Adrafinil is very structurally similar to its close chemical cousin and bioactive metabolite, modafinil. The only structural difference is the that terminal amide hydroxyl group of adrafinil ((diphenylmethyl)sulfinyl-2 acetohydroxamic acid)) is lacking in modafinil (diphenylmethyl)sulfinyl-2 acetamide).[5]



In rats, 20mg/kg oral ingestion of adrafinil was noted to have a Tmax at four hours post-ingestion, reaching a Cmax of 60µg/mL.[6] The half life of adrafinil at this dose was 4.95 hours and was still detectable in serum 7 hours after oral ingestion.[6] In elderly humans, a single dose of 900mg adrafinil peaked in the blood within one hour, although the neurological effects of adrafinil were only present an hour after that following conversion to modafinil was noted.[7]

Adrafinil peaks in the blood of elderly humans approximately one hour after oral ingestion, although neurological effects occur mostly after this peak due to the time it takes to convert it to modafinil, its active metabolite. Adrafinil has a half-life of around five hours based on rat data.


Orally ingested adrafinil may undergo one of two metabolic fates. The main metabolite is the active modafinil, which is itself metabolized to the inactive modafinilic acid. Adrafinil can also be metabolized to inactive modafinilic acid without conversion to modafinil.[5] The resulting modafinil can also be metabolized to a second inactive product, modafinil sulfone,[5] but only after modafinil is produced from adrafinil.[8]

Adrafinil can be metabolized into modafinil, which is then metabolized to the inert modafinilic acid or modafinil sulfone. Adrafinil may also be metabolized directly to modafinilic acid without producing modafinil.


Similar to modafinil, the urinary metabolite of adrafinil is modafinilic acid, although elimination of adrafinil from the plasma appears to occur faster than either of its metabolites.[5] The only possible way to differentiate the two compounds in the urine is via detecting the parent compound in plasma or urine.[3] Modafinil itself can be detected in urine via GC-MS[9] whereas LC-MS can be used for parent adrafinil.[10] Whereas GC/MSD detects a single artifact for modafinil, adrafinil, and modafinilic acid, the LC-MS/MS method was able to identify and distinguish between all three compounds.[10]

A dose-response study in canines showed that after 10 hours, serum adrafinil levels associated with a high dose (50mg/kg) was lower than that of a low dose treatment (10mg/kg) (although not significantly so) with moderate dose therapy (30mg/kg) having the highest levels[2]. After two hours, adrafinil showed dose-dependent increases in serum levels. The authors suggested that high doses could induce elimination or metabolism of adrafinil more than lower doses.[2]

Elimination of adrafinil from the body parallels that of modafinil, via urinary excretion.


3.1Adrenergic Neurotransmission

The mechanism of adrafinil appears to rely on postsynaptic α-adrenergic activity, since an increase in locomotion caused by adrafinil is blocked by prazosin (α1 antagonist), yohimbine (α2 antagonist), or phenoxybenzamine (mixed α-antagonist).[11] This was confirmed in another study using quaking mice (a model for assessing adrenergic neurotransmission) which noted that benefit with adrafinil was blocked by prazosin.[12] Adrafinil is thought to act in part centrally, givn the lack of promotion of salivary viscous secretion, which should occur with peripheral α1 activation.[11] Its action in reducing the secretion of pancreatic fluids can be attributed to decreasing vagal stimulation of the pancreas.[13][14]

Adrafinil or its bioactive metabolite (modafinil) seems to act on α-adrenergic receptors, based on animal data.

It has been noted that blocking synthesis of catecholamines (with α-methyltyrosine) does not prevent the actions of adrafinil,[12] providing further evidence differentiating the actions of adrafinil as distinct from that of amphetamine-like stimulants.


Oral administration of adrafinil in research animals is known to increase activity (measured by locomotion) at doses ranging from 64mg/kg to 256mg/kg in mice.[15][11] The effects of adrafinil have been noted to be both time and dose dependent in dogs.[2] When testing nocturnal activity in monkeys, it has been noted that 60mg/kg was able to effectively double activity after the second dose whereas 90-120mg/kg quadrupled activity after the first dose (original text in French, cited via review[5]). The increase in locomotion seen in animals is deemed to be eugregoric (increases wakefulness) rather than amphetamine-like, due to a lack of induced anxiety,[16] and in dogs has been noted to persist in magnitude of efficacy over the course of 33 days of continuous supplementation (20-40mg/kg).[17] It is hypothesized that the adrafinil-induced increase in locomotion is secondary to increased wakefulness, as it has been noted to have a larger increase in locomotion when tested in the nocturnal period of monkeys[5]. Moreover, at least when testing the bioactive metabolite modafinil, a failure to increase locomotion has been noted when testing the waking period alone despite increases over a time frame spanning into the nocturnal period.[18]

Adrafinil appears to dose-dependently increase locomotion in rats, which is indicative of a stimulatory effect. Since adrafinil lacks anxiogenic (anxiety producing) effects and has greater efficacy during periods when research animals would typically be asleep, the effect of adrafinil on locomotion is thought to be secondary to promoting wakefulness.

4Safety and Toxicology


In rats, one month of oral treatment up to 400mg/kg or three months treatment up to 200mg/kg has failed to cause any signs of toxicity.[5] LD50 values vary amongst species but have been measured at 1,250mg/kg (mice) and 3,400mg/kg (rats). An apparent suicide attempt in a human subject through modafinil overdosing (4,500mg acutely) produced insomnia and hyperexcitation which reversed after 24 hours of hospitalization.[19]

4.2Case Studies

One case study with adrafinil dosed at 900mg daily for ten months has noted the development of orofacial dyskinesia without tremor or other symptoms of Parkinson's which, despite not improving over a four month absence from adrafinil therapy, improved with the dopamine depleting agent tetrabenazine.[20] Such a side-effect is also reported with modafinil therapy,[21] suggesting that adrafinil-induced orofacial dyskinesia may be associated with conversion to modafinil after ingestion. Notably, the patient in the modafinil case study had multiple medical problems that may have led to reduced clearance of modafinil[21], possibly causing the orofacial dyskinesia.

Case studies indicate that adrafinil and modafinil are capable of inducing orofacial dyskinesia that may persist after cessation of therapy. This phenomenon is thought to be caused by abnormal metabolism of modafinil in these individuals, leading to reduced clearance.


  1. ^ 2014 List of Prohibited Substances. S6. Stimulants.
  2. ^ a b c d Siwak CT, Callahan H, Milgram NW. Adrafinil: effects on behavior and cognition in aged canines. Prog Neuropsychopharmacol Biol Psychiatry. (2000)
  3. ^ a b Deventer K, et al. Prevalence of legal and illegal stimulating agents in sports. Anal Bioanal Chem. (2011)
  4. ^ 2014 List of Prohibited Substances. S6. Stimulants.
  5. ^ a b c d e f g Milgram NW, Callahan H, Siwak C. Adrafinil: A Novel Vigilance Promoting Agent. CNS Drug Rev. (2006)
  6. ^ a b Rao RN, et al. LC-ESI-MS determination and pharmacokinetics of adrafinil in rats. J Chromatogr B Analyt Technol Biomed Life Sci. (2008)
  7. ^ Saletu B, et al. Pharmaco-EEG, psychometric and plasma level studies with two novel alpha-adrenergic stimulants CRL 40476 and 40028 (adrafinil) in elderlies. New Trends Exp Clin Psychiatr.
  8. ^ Burnat P, Robles F, Do B. High-performance liquid chromatographic determination of modafinil and its two metabolites in human plasma using solid-phase extraction. J Chromatogr B Biomed Sci Appl. (1998)
  9. ^ Tseng YL, et al. Detection of modafinil in human urine by gas chromatography-mass spectrometry. J Pharm Biomed Anal. (2005)
  10. ^ a b Dubey S, et al. A novel study of screening and confirmation of modafinil, adrafinil and their metabolite modafinilic acid under EI-GC-MS and ESI-LC-MS-MS ionization. Indian J Pharmacol. (2009)
  11. ^ a b c Duteil J, et al. A possibe alpha-adrenergic mechanism for drug (CRL 40028)-induced hyperactivity. Eur J Pharmacol. (1979)
  12. ^ a b Chermat R, et al. Effects of drugs affecting the noradrenergic system on convulsions in the quaking mouse. Naunyn Schmiedebergs Arch Pharmacol. (1981)
  13. ^ Rozé C, Chariot J, Vaille C. Drug CRL 40 028-induced inhibition of pancreatic secretion in rats. Arch Int Pharmacodyn Ther. (1983)
  14. ^ Chariot J, et al. Effect of modafinil on pancreatic exocrine secretion in rats. A comparison with adrafinil and related drugs. Fundam Clin Pharmacol. (1987)
  15. ^ Rambert FA, et al. A unique psychopharmacologic profile of adrafinil in mice. J Pharmacol. (1986)
  16. ^ Hascoët M, Bourin M. A new approach to the light/dark test procedure in mice. Pharmacol Biochem Behav. (1998)
  17. ^ Siwak CT, et al. Behavioral activating effects of adrafinil in aged canines. Pharmacol Biochem Behav. (2000)
  18. ^ Edgar DM, Seidel WF. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat. J Pharmacol Exp Ther. (1997)
  19. ^ Bastuji H, Jouvet M. Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuropsychopharmacol Biol Psychiatry. (1988)
  20. ^ Thobois S, et al. Adrafinil-induced orofacial dyskinesia. Mov Disord. (2004)
  21. ^ a b Maser RV, Liao B, Pandya R. Modafinil-induced orofacial dyskinesia in an elderly patient with refractory bipolar depression. J Neuropsychiatry Clin Neurosci. (2010)