Adrafinil, ≥98%

Chemical Information:

Technical Information:

Background:

Adrafinil ({diphenylmethyl}sulfinyl-2 acetohydroxamic acid; Olmifin) is a prodrug of the stimulant Modafinil and was developed as a powerful stimulant and wakefulness and alertness-promoting (eugregoric) substance. [1]

It is the first discovered eugeroic (eugregoric) agent, and was the ‘grandfather’ of a family of eugeroic compounds, with the end result of Modafinil. [2] Adrafinil is of relevance to researchers involved in studies pertaining to stimulant effects, novel stimulant development, and research into the biochemical pathways of eugeroic substances.

Adrafinil is sometimes considered as functional in athletes for use as a stimulant. As a result, it is a banned substance in competitive sports – banned by the World Anti-Doping Agency (WADA) for its stimulant-like effects. [3]

Modes of action:

Adrafinil is primarily metabolized into pharmacologically active Modafinil. A certain percentage of Adrafinil is metabolized into an inactive secondary metabolite – modafinilic acid. [2]

Animal models show a T_max of four hours for a 20mg/kg dose, p.o. administration with a Cmax of 60µg/mL. At this dosage, Adrafinil’s half-life was found to be just under 5 hours and was detectable in serum up to 7 hours after administration. [4]

In humans, a single 900mg Adrafinil dosage peaked in blood serum after one hour. Neurological effects of Adrafinil were observable an hour following the noted conversion to Modafinil. [5]

Modifinil is eliminated through urine as the metabolite modafinilinc acid. Modafinil can be detected in the urine through GC-MS testing, while LC-MS can be used for Adrafinil. The LC-MS/MS method is capable of distinguishing between Modafinil, Adrafinil, and Modafinilic acid.[6]

The mechanism of action for Adrafinil relies on postsynaptic α-adrenergic activity. This has been confirmed through studies using prazosin (a α1 antagonist), yohimbine (α2 antagonist), and phenoxybenzamine (unselective α-antagonist), which block some of the behavioral effects of Adrafinil in animal models.[7]

Furthermore, Adrafinil has been shown to reduce secretion of pancreatic fluids – attributed to decreasing vagal stimulation of the pancreas due to effects on α-adrenergic activity.[8]

One key distinction of the mechanism of action for Adrafinil, when compared to that of other stimulants, is that blocking catecholamine synthesis (using α-methyltyrosine) does not decrease the actions of Adrafinil. Most amphetamine-like stimulant effects are blocked by α-methyltyrosine and similar compounds.[9]

Further Scientific research:

Please note that this is not a comprehensive account of the published literature on Adrafinil to date, and it is simply meant to give the reader an overview of the types of research conducted on this product. For more information, please search on PubMed journal articles.

Clinical Reviews:

A 2008 review looked into the effects of Modafinil. It is important to note that Adranfinil is metabolized to Modafinil after ingestion, and so mechanisms of action that relate to Modafinil may also be applicable to Adrafinil.

According to the review, pre-clinical studies suggest a complex and dynamic mechanism of action, distinct from those of amphetamine and amphetamine-like stimulants. Modafinil is a schedule IV controlled substance in the US. In certain circumstances and in some countries, it is used to treat disorders like narcolepsy, and hypersomnia. It is also used in psychiatry for a number of indications including ADHD and schizophrenia. 

The review found that Modafinil produces pronounced effects on catecholamines and other neurotransmitter systems including serotonin, glutamate, GABA, orexin, and histamine systems. There may be some selectivity for corticol over subcortical sites of action. Additionally, well-tolerated dosages of Modafinil improve cognitive functions in several domains, including memory and processes that are dependent on prefrontal cortex and cognitive control.

The authors of the review suggest that Modafinil “is an excellent candidate agent for remediation of cognitive dysfunction in neuropsychiatric disorders.”[10]

Human studies:

The effects of Adrafinil’s primary metabolite, Modafinil, has been studied in human subjects with narcolepsy and hypersomnia. The study found that sleep attacks and drowsiness were reduced significantly in 83% of hypersomnic subjects, and in 71% of narcoleptics. Some patients had been using Modafinil for up to 3 years with no side effects or tolerance, and with undisturbed sleep at night. [11]

There is room for more research and clinical studies into the effects of Adrafinil on human subjects.

Animal studies:

Two studies from the early 1980s using animal models indicated that Adrafinil increases locomotive activity. Dosage ranges used were between 64mg/kg to 256mg/kg in mice.[12]

A similar study was conducted using dogs. The study, published in 2000, confirmed the results of previous studies which found that Adrafinil increased locomotive activity with long-lasting effects from a single dose and persistent effects of chronic treatment. Furthermore, the authors found that Adrafinil caused a long-lasting increase in high-frequency electroencephalographic activity recorded from cortical electrodes. [13]

At a dosage of 60mg/kg, Adrafinil was able to effectively double locomotive activity in monkeys. A second dose of 90-120mg/kg was able to quadruple locomotive activity, further testifying to the compound’s eugeroic effects.² It was contrasted to amphetamine-like stimulants due to the lack of anxiety-related side effects.[14]

Toxicology cases:

In 2004, a case was reported of orofacial abnormal movements (dyskinesias) induced by Adrafinil, which did not spontaneously recover even after 4 months without use. After a 4-month period without Adrafinil use, tetrabenazine was administered and the patient recovered fully. [15]

A suicide attempt by a human subject using Modafinil (the primary metabolite of Adrafinil) at a dose of 4,500mg caused insomnia and hyperexcitation, which was reversed after 24 hours in hospital. [10]

Animal models have explored the toxicological effects of month-long chronic treatment with up to 400mg/kg, and three months treatment with 200mg/kg Adrafinil. At both of these doses, Adrafinil failed to produce signs of toxicity. [2]

In mice, the LD₅₀ is around 1,250mg/kg, while in rats it is closer to 3,400mg/kg.

References:

• [1] Siwak CT, Callahan H, Milgram NW. (2000) Adrafinil: effects on behavior and cognition in aged canines. Prog Neuropsychopharmacol Biol Psychiatry. Jul;24(5):709-26.
• [2] Milgram NW, Callahan H, Siwak C. Adrafinil: A Novel Vigilance Promoting Agent. CNS Drug Rev. (2006)
• [3] PROHIBITED LIST (2016), World Anti-Doping Agency, [online] available at: https://www.wada-ama.org/sites/default/files/resources/files/wada-2016-prohibited-list-en.pdf (retrieved on August 10, 2017)edong-lasting increase in high-f Medicine [online], available at: e functions in several domains, including memory and processes
• [4] Rao RN, et al. LC-ESI-MS determination and pharmacokinetics of adrafinil in rats. J Chromatogr B Analyt Technol Biomed Life Sci. (2008)
• [5] 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. (January 1970)
• [6] 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. doi: 10.4103/0253-7613.59928.
• [7] Duteil J, et al. A possibe alpha-adrenergic mechanism for drug (CRL 40028)-induced hyperactivity. Eur J Pharmacol. (1979)
• [8] Rozé C, Chariot J, Vaille C. Drug CRL 40 028-induced inhibition of pancreatic secretion in rats. Arch Int Pharmacodyn Ther. (1983)
• [9]Chermat R, et al. Effects of drugs affecting the noradrenergic system on convulsions in the quaking mouse. Naunyn Schmiedebergs Arch Pharmacol. (1981)
• [10] Minzenberg, M.J., Carter, C.S., Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology. 2008 Jun;33(7):1477-502. Epub 2007 Aug 22.
• [11] Bastuji H, Jouvet M. Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuropsychopharmacol Biol Psychiatry. (1988)
• [12] Rambert FA, et al. A unique psychopharmacologic profile of adrafinil in mice. J Pharmacol. (1986)
• [13] Siwak, C.T., Callahan, H., Milgram, N.W., Adrafinil: effects on behavior and cognition in aged canines. Prog Neuropsychopharmacol Biol Psychiatry. 2000 Jul;24(5):709-26.
• [14] Hascoët M, Bourin M. A new approach to the light/dark test procedure in mice. Pharmacol Biochem Behav. (1998)
• [15] Thobois, S., et al., Adrafinil-induced orofacial dyskinesia., Mov Disord. 2004 Aug;19(8):965-6.