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Adrafinil (Olmifon, CRL-40028) is also known as (RS)-2-benzhydrylsulfinylethanehydroxamic acid. It is classified as a eugeroic drug promoting wakefulness and mental arousal.
It is a mild central nervous system stimulant drug but lacks amphetamine-like stimulatory side effects and has a low abuse liability.
Adrafinil is indicated for research into nootropic mechanisms of action, hypersomnia (excessive sleepiness), inattention and ADHD, depression, anxiety and weight loss.
Adrafinil (Olmifon, CRL-40028) is a precursor drug to Modafinil (Provigil, Modalert, Alertec, Modavigil, Modiodal).
This means that when the body breaks it down inside the liver, it is converted into Modafinil. It has similar pharmacological effects to Modafinil, including:
- Increases diurnal and noctural activity (locomotion)
- Increases motivation and speed of performance
- Inhibits dopamine transporter and increases dopamine levels in brain
- Lacks typical side effect profile of stimulants
Product Name: Adrafinil (Olmifon, CRL-40028)
Chemical Name: (RS)-2-benzhydrylsulfinylethanehydroxamic acid
Formula: C15H15NO3S
Molecular Weight: 289.351 g/mol
CAS Number: 63547-13-7
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Wakeful- ness
Thinking- Converted into Modafinil by the liver
- Increases energy, wakefulness & motivation
- Boosts mental performance & focus
Adrafinil Nootropic Research
Related Topics
Adrafinil was developed in France during the late 1970’s by a research team at Lafon pharmaceutical company, now known as Cephalon.
Adrafinil was initially researched as an experimental therapy for narcolepsy but was eventually discontinued following the isolation of its chief metabolite, Modafinil (Provigil). [1]
Adrafinil is a prodrug or precursor and is metabolized in vivo into active Modafinil (CRL 40476) and inactive Modafinilic Acid (CRL 40467) following ingestion. [1]
Pharmacological effects are almost identical to its active metabolite, however, it takes 30-60 minutes longer for active levels to accumulate in the bloodstream. [7]
In one human study on elderly individuals, Adrafinil concentrations peaked in the blood approximately one hour following oral ingestion.
Neurological effects did not become apparent until one hour after Modafinil, which suggests that conversion to Modafinil happens first. Peak behavioral and EEG response to Adrafinil was observed at 2 hours post oral ingestion. [7]
In one rat study, a 20mg/kg dose of oral Adrafinil had a Tmax four hours following ingestion with a maximum serum concentration of 60µg/mL. The half-life was noted at 4.95 hours and Adrafinil could be detected in the blood for 7 hours. [6]
Structure Compared to Modafinil
The chemical structure of Adrafinil is similar to Modafinil, except for the addition of a terminal amide hydroxyl group.
The chemical structure of Adrafinil is ((diphenylmethyl)sul?nyl-2 acetohydroxamic acid)) while the structure of Modafinil is (diphenylmethyl)sul?nyl-2 acetamide). [1]
Pharmacology Compared to Modafinil
Adrafinil exhibits a lower potency than Modafinil with typical therapeutic dosages of 300 mg versus 200 mg for Modafinil. It also exhibits a greater risk of side effects including skin irritation. [1]
The processing of Adrafinil into Modafinil in the liver tissue may result in elevated liver enzymes which could be associated with a risk of hepatoxicity following long-term use.
This increase in liver enzymes is seen in less than 1% of patients who orally ingest of Modafinil. [18] Liver toxicity is further covered later on in this article. [Link]
- Increases energy, wakefulness and motivation
- Boosts mental performance and focus
- Supports memory and cognition
Adrafinil Adrenergic Activity
The primary behavioral effect of Adrafinil is an increase in activity, especially nocturnal activity.
Administration of Adrafinil results in behavioral responses consisting of increased locomotion and decreased immobility during a forced swimming test. [2]
It is theorized that the mechanism of action for Adrafinil comes from an increase in postsynaptic alpha-adrenergic activity.
This is demonstrated by Duteil et al. who reported that Alpha-adrenergic antagonists phenoxybenzamine, prazosin, and yohimbine are all able to block the activity-increasing effects of Adrafinil. [8]
The effects were repeated by Chermat et al. (13) when studying the effects of Adrafinil on quaking mice.
Quaking mice are neurological mutants of the C57 BL/6J strain that are useful in models for studying neurotransmission at adrenergic receptors.
Adrafinil blocks convulsions in quaking mice and this effect is antagonized by the selective alpha-1 receptor antagonist prazosin. [9]
These effects may be isolated to the central nervous system. Alpha-1 agonism in the peripheral nervous system is associated with an increase in salivary viscous secretions.
However, Adrafinil does not increase salivary secretions which suggests it does not activate peripheral alpha-1 receptors. [8]
Dopaminergic Activity
Adrafinil, by way of conversion into Modafinil, inhibits the reuptake of dopamine. It blocks the effects of dopamine transporters and increases dopamine levels in the human brain.
It is noted to increase dopamine in the nucleus accumbens which is involved in pleasure, the reward circuit, reinforcement leaing and addiction. [19]
This mechanism of action was found by Young and Geyer to explain the motivation-enhancing effects of Modafinil.
In a 2010 study on mice, they found that Modafinil increased motivation as measured by increased breakpoints on a given task in wildtype (WD) and heterozygous (HT) mice.
This increase in motivation was reduced in dopamine D1R HT mice and D1R knockout (KO) mice did not respond to the task at all.
This data shows that Modafinil (and thereby Adrafinil’s) positive effects on motivation are mediated by an increase in dopaminergic activity in the brain. [20]
Therapeutic Effects
Several studies have shown an increase in activity (locomotion) following administration of Adrafinil.
Duteil et al showed an increase following dosages of 64 and 128 mg/kg in mice. Rambert et al had similar findings of activity increasing at doses between 64 and 256 mg/kg. [2]
Milhaud and Klein studied how Adrafinil affects the nocturnal activity of monkeys. They found that a 60 mg/kg dose doubled activity, only after the second treatment. Doses of 90 and 120 mg/kg quadrupled activity. [3]
Siwak et al used two separate studies to look at the effect of Adrafinil on the behavior of dogs. In one study looking at elderly dogs, doses of between 20 and 40 mg/kg increased locomotion in most dogs.
There was a subpopulation that showed no effect of decreased locomotion. In their other study, Adrafinil showed a sustained increase in activity for the entire duration of the 33 day study. [4]
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Adrafinil Toxicology
In mice and rats, the LD50 of Adrafinil has been established at 1,250 mg/kg. The oral LD50 is 3,400 mg/kg for rats.
While lethal doses vary greatly between species, this is many hundred times greater than the typical human dose on a mg/kg basis.
Rats given a 100, 200, or 400 mg/kg daily dose for one month did not develop any signs of toxicity. Nor did signs of toxicity develop in rats given 50, 100 or 200 mg/kg for three months. [7]
Hepatoxicity
There are numerous sources online stating that Adrafinil is hepatoxic, however no trials are available which demonstrate this.
There are no studies available on Adrafinil that analyze aminotransferase and alkaline phosphatase elevations in the liver. One study did find an increase of aminotransferase activity in less than 1% of Modafinil users. [18]
Because Adrafinil is a prodrug, it is possible that it may lead to increased liver enzymes following long-term use. Manufacturer warnings did indicate that enzyme levels should be monitored when using Olmifon Adrafinil tablets.
One report suggests that limiting Adrafinil use to three times a week for less than 5 months will negate the risk.
Orofacial Dyskinesia
In one instance, a 900 mg daily Adrafinil dose over a ten month period resulted in the development of orofacial dyskinesia (involuntary repetitive movements of the mouth and face).
This condition was improved following treatment with dopamine depleting agent tetrabenazine. This side effect has also occurred with long-term Modafinil use. [16]
Regulatory Status
Adrafinil is unregulated in the United States and has not been approved by the FDA for clinical uses. It is not considered a controlled substance in the United States, Canada or the United Kingdom.
It was previously marketed in France under the name Olmifon, but was discontinued in 2011. Both Modafinil and Adrafinil are banned by the World Anti-Doping Agency (WADA) as nonspecific stimulant compounds.
Study Summaries
Milhuad CL, Klein MJ. The effect of adrafinil on the nocturnal activity of the rhesus monkey (Macaca mulatta). J Pharmacol. 1985 Oct-Dec;16(4):372-80.
Adrafinil was found to increase nocturnal activity in ten rhesus monkeys. The monkeys were placed in a controlled environment and monitored to determine activity level.
They were given 60, 90 and 120 mg/kg doses of Adrafinil with the 60 mg/kg dose resulting in a doubling of nocturnal activity and the 90 and 120 mg/kg doses resulting in a quadrupling of activity, similar to daytime activity levels.
Stimulating effects were observable 36 hours following administration. There was no recovery period noted following the wearing off of Adrafinil effects. [3]
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- Rambert FA, et al. A unique psychopharmacologic profile of adrafinil in mice. J Pharmacol. 1986 Jan-Mar; 17(1):37-52.
- Milhuad CL, Klein MJ. The effect of adrafinil on the noctu al activity of the rhesus monkey (Macaca mulatta). J Pharmacol. 1985 Oct-Dec;16(4):372-80.
- Siwak CT, Callahan H, Milgram NW. Adrafinil: effects on behavior and cognition in aged canines. Prog Neuropsychopharmacol Biol Psychiatry. 2000 Jul;24(5):709-26.
- Siwak CT, et al. Behavioral activating effects of adrafinil in aged canines. Pharmacol Biochem Behav. 2000 Jun;66(2):293-300.
- Rao RN, et al. LC-ESI-MS determination and pharmacokinetics of adrafinil in rats. J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Sep 15;873(1):119-23.
- 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.
- Duteil J, et al. A possibe alpha-adrenergic mechanism for drug (CRL 40028)-induced hyperactivity. Eur J Pharmacol. 1979 Oct 26;59(1-2):121-3.
- Chermat R, et al. Effects of drugs affecting the noradrenergic system on convulsions in the quaking mouse. Naunyn Schmiedebergs Arch Pharmacol. 1981 Dec;318(2):94-9.
- Rozé C, Chariot J, Vaille C. Drug CRL 40 028-induced inhibition of pancreatic secretion in rats. Arch Int Pharmacodyn Ther. 1983 Sep;265(1):119-27.
- Chariot J, et al. Effect of modafinil on pancreatic exocrine secretion in rats. A comparison with adrafinil and related drugs. Fundam Clin Pharmacol. 1987;1(4):243-52.
- Hascoët M, Bourin M. A new approach to the light/dark test procedure in mice. Pharmacol Biochem Behav. 1998 Jul;60(3):645-53.
- Edgar DM, Seidel WF. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat. J Pharmacol Exp Ther. 1997 Nov;283(2):757-69.
- Bastuji H, Jouvet M. Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuropsychopharmacol Biol Psychiatry. 1988;12(5):695-700.
- Thobois S, et al. Adrafinil-induced orofacial dyskinesia. Mov Disord. 2004 Aug;19(8):965-6.
- Maser RV, Liao B, Pandya R. Modafinil-induced orofacial dyskinesia in an elderly patient with refractory bipolar depression. J Neuropsychiatry Clin Neurosci. http://www.ncbi.nlm.nih.gov/pubmed/21037146
- 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 Dec;41(6):278-83.
- Roth T, Schwartz JR, Hirshkowitz M, Erman MK, Dayno JM, Arora S. Evaluation of the safety of modafinil for treatment of excessive sleepiness. J Clin Sleep Med 2007; 3: 595-602.
- Volkow ND, et al. Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. JAMA. 2009 Mar 18;301(11):1148-54.
- Young JW1, Geyer MA. Action of modafinil--increased motivation via the dopamine transporter inhibition and D1 receptors? Biol Psychiatry. 2010 Apr 15;67(8):784-7.
Article last updated on: July 24th, 2018 by Nootriment