Adrafinil

Medical uses

Adrafinil is a wakefulness-promoting agent and was used to promote alertness, attention, wakefulness, and mood. It was particularly used in the elderly.

Available forms

Adrafinil was available in the form of 300mg oral tablets.

Side effects

There is a case report of two patients that adrafinil may increase interest in sex.

A case report of adrafinil-induced orofacial dyskinesia exists. Reports of this side effect also exist for modafinil.

Pharmacology

Pharmacodynamics

Because α1-adrenergic receptor antagonists were found to block effects of adrafinil and modafinil in animals, "most investigators assume[d] that adrafinil and modafinil both serve as α1-adrenergic receptor agonists." However, adrafinil and modafinil have not been found to bind to the α1-adrenergic receptor and they lack peripheral sympathomimetic side effects associated with activation of this receptor; hence, the evidence in support of this hypothesis is weak, and other mechanisms are probable. Modafinil was subsequently screened at a variety of targets in 2009 and was found to act as a weak, atypical blocker of the dopamine transporter (and hence as a dopamine reuptake inhibitor), and this action may explain some or all of its pharmacological effects. Relative to adrafinil, modafinil possesses greater specificity in its action, lacking or having a reduced incidence of many of the common side effects of the former (including stomach pain, skin irritation, anxiety, and elevated liver enzymes with prolonged use).

Pharmacokinetics

In addition to modafinil, adrafinil also produces modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056) as metabolites, which form from metabolic modification of modafinil.

Chemistry

Adrafinil is the N-hydroxylated analogue of modafinil and is also known as N-hydroxymodafinil.

Analogues of adrafinil include modafinil, armodafinil, CRL-40,940, CRL-40,941, and fluorenol, among others.

History

Adrafinil was discovered in 1974 by two chemists working for the French pharmaceutical company Laboratoires Lafon who were screening compounds in search of analgesics. Pharmacological studies of adrafinil instead revealed psychostimulant-like effects such as hyperactivity and wakefulness in animals. The substance was first tested in humans, specifically for the treatment of narcolepsy, in 1977–1978. Introduced by Lafon (now Cephalon), it reached the market in France in 1984, and for the treatment of narcolepsy in 1985.

In 1976, two years after the discovery of adrafinil, its active metabolite modafinil was discovered. Modafinil appeared to be more potent than adrafinil in animal studies, and was selected for further clinical development, with both adrafinil and modafinil eventually reaching the market. Modafinil was first approved in France in 1994, and then in the United States in 1998. Lafon was acquired by Cephalon in 2001. As of September 2011, Cephalon has discontinued Olmifon, its adrafinil product, while modafinil continues to be marketed.

Society and culture

Names

Adrafinil is the generic name of the drug and its and . It is also known by its brand name Olmifon and its developmental code name CRL-40028.

Regulation

Athletic doping

Adrafinil and its active metabolite modafinil were added to the list of substances prohibited for athletic competition according to World Anti-Doping Agency in 2004.

Additive in United States dietary supplements

Adrafinil is sometimes included as an ingredient in misbranded or adulterated dietary supplements. One company had attempted to get a New Dietary Ingredient pre-market notification approved for adrafinil in 2017, but the Food and Drug Administration rejected it:

A position that adrafinil is an unapproved drug was indicated in a warning letter by the FDA in 2019:

A position that adrafinil is an unapproved drug was also indicated by FDA in a press release regarding a criminal action undertaken in 2019:

FDA indicated a position that adrafinil is an unapproved drug in later criminal action undertaken during 2022: “[The defendants in a 2022 enforcement action] also illegally sold multiple other unapproved and misbranded drugs, including adrafinil crystalline powder...” Most recently in 2023, the FDA fined an Arizona company 2.4 million U.S. dollars for introducing misbranded drugs into interstate commerce:

FDA has not approved drugs containing tianeptine, adrafinil, phenibut, and racetams for use in the United States. Racetam drugs include piracetam, aniracetam, and coluracetam, and phenylpiracetam."}}

Certain products, formulated with adrafinil in them, have been listed as subject to a May 2023 import alert by Food and Drug Administration because they are considered as containing an active pharmaceutical ingredient.

Adrafinil containing products, purporting to be dietary supplements, are not allowed for use by military service members. This is because the Department of Defense considers adrafinil an unapproved drug.

New Zealand

In 2005 a Medical Classification Committee in New Zealand recommended to MEDSAFE NZ that adrafinil be classified as a prescription medicine due to risks of it being used as a party drug. At that time adrafinil was not scheduled in New Zealand.

Research

In a clinical trial with the tricyclic antidepressant clomipramine and placebo as comparators, adrafinil showed efficacy in the treatment of depression. In contrast to clomipramine however, adrafinil was well-tolerated, and showed greater improvement in psychomotor retardation in comparison. The authors concluded that further investigation of the potential antidepressant effects of adrafinil were warranted.

References

References

1. (2019-12-20). "Peak Nootropics LLC aka Advanced Nootropics - 557887 - 02/05/2019". U.S. Food and Drug Administration.
2. Office of Regulatory Affairs. (2019-12-20). "Hermitage Man Sentenced for Importing and Selling Drugs Not Approved by FDA". U.S. Department of Justice.
3. (June 10, 2022). "Fort Collins Couple Sentenced to Federal Prison for Illegally Selling Unapproved Drugs". FDA Office of Criminal Investigations.
4. (October 30, 2023). "Arizona Company and CEO Plead Guilty to the Distribution of Drugs Not Approved by the FDA and Will Pay $2.4 Million". FDA Office of Criminal Investigations.
5. (2003). "Clinical pharmacokinetic profile of modafinil". Clin Pharmacokinet.
6. (1999). "Adrafinil: A Novel Vigilance Promoting Agent". CNS Drug Reviews.
7. AFSSAPS. (2011). "Point d'information sur les dossiers discutés en commission d'AMM Séance du jeudi 1er décembre 2011 - Communiqué".
8. (January 2000). "Index Nominum 2000: International Drug Directory". Taylor & Francis.
9. (2009). "Pharmaceutical Substances". Georg Thieme Verlag.
10. (31 December 2012). "Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions". Newnes.
11. (2004). "Adrafinil-induced orofacial dyskinesia". Mov. Disord..
12. (1983). "Pharmacological evidence of the stimulation of central alpha-adrenergic receptors". Prog. Neuropsychopharmacol. Biol. Psychiatry.
13. (May 2009). "Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil". The Journal of Pharmacology and Experimental Therapeutics.
14. (Feb 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence.
15. (Dec 2015). "Dopaminergic mediation of the discriminative stimulus functions of modafinil in rats". Psychopharmacology.
16. (July 2002). "Modafinil: past, present and future". Expert Review of Neurotherapeutics.
17. (2009). "The American Psychiatric Publishing Textbook of Psychopharmacology". American Psychiatric Pub.
18. (28 November 2014). "Drug Treatment of Sleep Disorders". Springer.
19. (27 March 2013). "Modern Drug Synthesis". John Wiley & Sons.
20. (2023-05-24). "Stocks".
21. (2007). "Prohibited List". World Anti-Doping Agency.
22. "Regulations.gov".
23. "Import Alert 54-16".
24. "DOD PROHIBITED DIETARY SUPPLEMENT INGREDIENTS".
25. (23 May 2013). "MCC Minutes Out of Session Meeting". Medsafe.govt.nz.