Fladrafinil

Fladrafinil (developmental code name CRL-40,941), also known as fluorafinil or as bisfluoroadrafinil , is a synthetic compound, structurally related to modafinil.^1,2 It is an unscheduled compound, available online as a research chemical and has been discussed in nootropic communities for its potential cognitive effects, despite never being marketed, or approved for medical use.^3,4 It has also not been approved or evaluated by the FDA.^1,5

Modafinil is known to act as a weak dopamine reuptake inhibitor and this is thought to be involved in its wakefulness-promoting effects.^1,6 A similar mechanism is hypothesized for its analogues like fladrafinil, though this has not been experimentally confirmed.¹ Chemically, fladrafinil is a derivative of adrafinil (N-hydroxymodafinil) and is also known as bisfluoroadrafinil (it is the bis(4-fluoro) phenyl ring-substituted derivative of adrafinil).¹ It is closely related to flmodafinil (CRL-40,940; bisfluoromodafinil) ^1,3,4

Pharmacology

Central Nervous System Activity

Fladrafinil (developmental code CRL-40,941) is a halogenated derivative of adrafinil within the benzhydrylsulfinylacetohydroxamic acid family developed by Laboratoire L. Lafon S.A. ⁸.

According to patent CA1192222A, these halogenated analogues act on the central nervous system (CNS) as psychotonic agents, a classification used by the inventors to describe compounds that promote wakefulness and increase motor activity ⁸.

Behavioral and Physiological Effects

The patent reports that fladrafinil produces brief sedation followed by sustained excitation, increased spontaneous motility, recovery of motor activity after inactivity or hypoxia, mild hypothermia, hypermotility, mydriasis, and transient respiratory depression in rodents ⁸.

These behavioral and physiological responses are consistent with stimulant-type CNS activation observed in related benzhydrylsulfinyl compounds ⁸.

Toxicity

Animal Toxicity

According to the original Lafon patent, acute oral toxicity testing in rodents established approximate LD₅₀ values of 1000 mg/kg in mice and 800 mg/kg in rats, indicating relatively low acute toxicity compared with reference psychotonic agents.^8,9 No chronic, reproductive, or genotoxicity studies were reported, and no modern toxicological data have since been published.^8,9

Patent data further indicate that fladrafinil exhibits a low toxicity profile and an improved safety margin relative to its parent compound adrafinil.^8,9 The compound demonstrated greater tolerance in mice and rats following both oral and intraperitoneal administration, with no notable behavioral or physiological abnormalities observed at behaviorally active doses.^8,9 It produced psychostimulant effects comparable to adrafinil but with a more favorable therapeutic index and higher LD₅₀, confirming reduced acute toxicity.^8,9

A sub-acute toxicology study of adrafinil in rats administered daily doses of 100, 200, and 400 mg/kg for one month found no clinical or histopathological signs of toxicity.³⁶ Because fladrafinil demonstrated a higher LD₅₀ than adrafinil in patent testing, these findings collectively suggest that fladrafinil possesses an equal or lower toxicity profile under comparable experimental conditions.^8,9,36

In summary, available animal data from both the original patent and subsequent comparative toxicology studies support the conclusion that fladrafinil exhibits low acute and sub-acute toxicity in animal models, with no adverse behavioral or physiological effects observed at therapeutic or behaviorally active doses.^8,9,36

Human Toxicity and Overdose

Human toxicity data on fladrafinil remain extremely limited due to the absence of formal clinical trials ^5,15,23–26. No known published cases of toxicity in humans existed prior to 2022.³⁷ In 2022, a single case presented at the North American Congress of Clinical Toxicology (NACCT) described an individual who ingested fladrafinil in combination with 4-fluorophenibut (4-FP, “BaFLofen”).³⁷ The patient exhibited alternating agitation and stupor, but investigators concluded that the clinical features were consistent with GABA-B receptor intoxication caused by 4-fluorophenibut rather than by fladrafinil itself.³⁷

Comparative Findings

In comparative testing, fladrafinil induced lower levels of inter-group aggressiveness and tremor in mice than adrafinil under identical conditions, leading the inventors to describe a difference in relative behavioral response ⁸.

However, the data do not show suppression of aggression or tremor below baseline levels. Some secondary references have cited the patent as evidence of intrinsic ‘anti-aggressive’ properties without acknowledging that the comparison was made specifically against mice administered adrafinil, rather than untreated controls ⁸.

Unverified Mechanisms

No receptor-binding, transporter-affinity, or neurochemical data were disclosed, and no peer-reviewed studies have independently confirmed the pharmacological profile of fladrafinil beyond these patent-reported animal observations ⁸. The corresponding Japanese patent (JPS6136829B2) confirms the same pharmacological profile and extends the disclosure to pharmaceutical preparations intended for oral use, citing proposed applications in psychasthenia and hypersomnia ^8,9.

Chemistry

Identity

Fladrafinil is 2-[[bis(4-fluorophenyl)methyl]sulfinyl]-N-hydroxy-acetamide (IUPAC), with molecular formula C15H13F2NO3S, CAS 90212-80-9, and developmental code CRL-40,941; common synonyms include fluorafinil and bisfluoroadrafinil ^2,10,11,12.

Structural Lineage

Fladrafinil is the bis(4-fluorophenyl) ring-substituted derivative of adrafinil, placed within the halogenobenzhydrylsulfinylacetohydroxamic acids disclosed by Laboratoire L. Lafon S.A. (e.g., CA1192222A; JP S61-36829), which define this chemical series and its substitution patterns ^8,9.

Analogue Context

Analogues of fladrafinil include modafinil, armodafinil ((R)-modafinil), esmodafinil ((S)-modafinil), adrafinil (CRL-40,028; N-hydroxymodafinil), flmodafinil (CRL-40,940; bisfluoromodafinil), and CE-123, among others; these appear together across FDA analytical method materials, the Provigil dossier context for the class, PubChem identifiers, and peer-reviewed CE-123 reports. ^1,2,10,11.

Analytical Considerations

Fladrafinil is included in analytical/degradation and method-development work alongside modafinil-series analogues, supporting its recognition as a distinct analyte in forensic and regulatory workflows; these sources characterize detection and thermal behavior rather than primary pharmacology ^1,4.

History

Fladrafinil (CRL-40,941) was disclosed by Laboratoire L. Lafon within a series of halogenated benzhydrylsulfinyl-acetohydroxamic acid derivatives related to adrafinil, as documented in the Lafon patent family covering this chemical class ^2,13. The Canadian family record fixes the disclosure window with a priority date of 1982-06-04, a filing date of 1983-05-27, and publication on 1985-08-20 for the series that includes CRL-40,941 ¹³.

The only publicly documented preclinical work on fladrafinil (CRL-40,941) consists of comparative animal assays reported in the original Lafon patent family, rather than independent peer-reviewed pharmacology studies ^8,9,13.

As of 2025 there is no record in FDA’s substance registries or drug approval materials of any subsequent clinical development for fladrafinil in humans, and the UNII listing explicitly does not imply regulatory review or approval ¹².

Research

Animal Research

Preclinical pharmacological data on fladrafinil (CRL-40,941) originate solely from animal assays disclosed in patent CA1192222A by Laboratoire L. Lafon S.A. ⁸. In these studies, male mice and rats were administered intraperitoneal doses ranging from 16 mg/kg to 1024 mg/kg, suspended in an aqueous gum arabic solution. Observations were conducted at intervals of 15 minutes to 24 hours following administration.

At doses of 64–256 mg/kg in mice, fladrafinil produced brief sedation (≈15 minutes) followed by approximately three hours of excitation, mild hypothermia (−1.9 °C), and increased spontaneous motility ⁸. Rats receiving 128 mg/kg exhibited excitation, heightened tactile reactivity, transient respiratory depression (~30 minutes), and mydriasis persisting for several hours ⁸. The compound’s maximum non-lethal dose (LD₀) exceeded 512 mg/kg i.p. in mice, with mortality observed only at 1024 mg/kg ⁸.

In behavioral tests, fladrafinil reduced inter-group aggression relative to both control and adrafinil-treated groups, with decreases of 58–61 % at 64–128 mg/kg and 20 % at 256 mg/kg ⁸. The inventors described this as a relative inhibition of aggressive encounters, not a baseline anti-aggressive effect. Additional assays demonstrated reduced tremor intensity, enhanced recovery of motility following habituation or hypoxia, shortened barbital-induced sleep duration, and potentiation of amphetamine- and apomorphine-induced stereotypies ⁸.

These data collectively indicate central nervous system stimulant and psychotonic effects comparable to adrafinil but with distinct behavioral modulation in rodents. No formal preclinical replication studies or receptor-binding assays have been published outside the original patent record ⁸.

Human Research

No formal clinical trials evaluating fladrafinil in humans have been conducted or registered as of 2025 ^12,15. The only publicly reported human-related research involves a pharmacokinetic study initiated by the World Anti-Doping Agency (WADA) investigating urinary metabolites of fladrafinil to support its inclusion in doping-control procedures. The project, approved in 2023, remains ongoing as of October 2025 ¹⁴.

Legal Status

FDA / EMA / TGA / Health Canada Approval

Fladrafinil has never been granted therapeutic approval by any major drug authority, including the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), Health Canada, or Australia’s Therapeutic Goods Administration (TGA) ^5,22–26. There are no active Investigational New Drug (IND) submissions, orphan designations, or marketing authorizations listed in public regulatory databases ²⁷. The compound does not appear in official registries of approved active ingredients or authorized medicinal products maintained by these agencies ^{5,18,22,33,34}.

Controlled Substance Scheduling

Fladrafinil is not included in the U.S. Controlled Substances Act schedules and therefore holds no federal scheduling designation ⁷. Despite that absence, it remains unlawful to market or sell for human use under the Federal Food, Drug, and Cosmetic Act (21 U.S.C. §355), which prohibits unapproved drugs from being introduced into interstate commerce for human consumption or human research ²⁹.

Comparable treatment applies internationally. The International Narcotics Control Board (INCB) has not placed fladrafinil under global control, and Canada’s Controlled Drugs and Substances Act likewise omits it from the national schedules ^18,33. In Australia, the TGA has never assigned the compound a classification under the Poisons Standard, leaving it unlisted and without marketing authorization ²². Across these regions, the lack of scheduling should not be interpreted as approval—it merely indicates the substance is not subject to criminal narcotics control ^{18,23–26,33–35}.

Import / Customs Handling

United States

The FDA’s Import Alert #66-57 authorizes detention of unapproved drugs, including any unscheduled compounds labeled or promoted for therapeutic use ¹⁶. Fladrafinil may be imported solely for laboratory or analytical research when shipment documentation clearly identifies it as non-human-use material and the labeling complies with FDA research-use requirements ^16–17.

Europe and Australia

Within the European Union and Australia, customs and health authorities evaluate imports of unlicensed psychoactive or investigational compounds individually, applying consumer-protection and medicinal-product laws rather than narcotics regulations ^31–32.

Canada

Fladrafinil is not scheduled under the Canadian CDSA and is generally admissible when declared for analytical or non-human research use ³³. Provided it is not marketed as a therapeutic or dietary product, it falls outside the scope of Canada’s drug-licensing framework ^{25–26,33–35}. Shipments accompanied by transparent documentation normally clear Canada Border Services Agency review without issue ³⁵.

Society and Culture

Regulation and Athletic Doping

Fladrafinil—chemically related to adrafinil and modafinil—is part of the eugeroic stimulant class first described in Lafon patent filings ^8–9. Under the World Anti-Doping Agency’s (WADA) Prohibited List, modafinil and all substances with similar chemical structures or biological effects are listed under Section S6 (Stimulants) as non-specified stimulants ^14,19. While fladrafinil is not named directly, analytical studies supported by WADA have documented its metabolism and urinary biomarkers, confirming it is detectable through standard anti-doping testing protocols ^14,19.

Commercial Availability

Fladrafinil is distributed online through research-chemical and nootropics vendors ^3–4. It is unscheduled under the major controlled-substance laws of the U.S., EU, Australia, and Canada, allowing possession or sale when marketed strictly for laboratory use ^{7,18,23–26,33–35}. Because it remains unapproved under the U.S. Food, Drug, and Cosmetic Act, any sale for therapeutic or dietary use would violate federal law ²⁹. Most suppliers therefore describe the material as a “research chemical” to comply with import labeling policies ^3–4. No authorized prescription medicines or over-the-counter products currently contain fladrafinil as an active ingredient ^5,22–26,28.

Popularity and Non-Medical Use

Academic and online reports describe fladrafinil as a second-generation derivative of adrafinil appearing in biohacking and “smart-drug” communities ^3–4. Reviews of cognitive-enhancement practices note persistent off-label use of wake-promoting compounds originally intended for sleep-disorder therapy, often obtained from research suppliers operating in jurisdictions with limited oversight ^1,3,4. Such usage occurs outside established safety frameworks and underscores the need for further toxicological evaluation and regulatory surveillance ^3,29.

References

1. 1. Food, Drug Administration. Modafinil Methods Poster
  2. Fladrafinil Compound Summary. PubChem Summary.
  3. Schifano F, Catalani V, Sharif S, Napoletano F, Corkery JM, Arillotta D, Fergus S, Vento A, Guirguis A. Benefits and Harms of ‘Smart Drugs’ (Nootropics) in Healthy Individuals. Drugs. 2022;82(6):633–647. DOI: 10.1007/s40265-022-01701-7. PMID: 35366192.
  4. Dowling G, Kavanagh PV, Talbot B, O’Brien J, Hessman G, McLaughlin G, Twamley B, Brandt SD. LJMU Research Online.
  5. U.S. Food and Drug Administration. Drug Approvals and Databases.
  6. Karl Greenblatt; Ninos Adams. Modafinil.
  7. U.S. DEA. Controlled Substances Act Schedules Database. DEA 2024.
  8. CA1192222A. Halogenobenzhydrylsulfinylacetohydroxamic acids. Laboratoire L. Lafon S.A., filed May 27 1983, published Aug 20 1985. Google Patents.
  9. JPS6136829B2. Halogenobenzhydrylsulfinylacetohydroxamic acids and therapeutic compositions thereof. Laboratoire L. Lafon S.A., filed June 4 1983, granted Aug 20 1986. Google Patents.
  10. Kristofova M, Aher YD, Ilic M, et al. A daily single dose of a novel modafinil analogue CE-123 improves memory acquisition and retrieval. Behav Brain Res. 2018;343:83–94. DOI: 10.1016/j.bbr.2018.01.032. PMID: 29410048.
  11. U.S. Food and Drug Administration. PROVIGIL (modafinil) Tablets: NDA 20-717 Approved Labeling, August 17, 2007. FDA.
  12. U.S. Food and Drug Administration. Fladrafinil (UNII 5RT6X0M01F) — GINAS Substance Record. Precision FDA.
  13. Lafon L. Halogenobenzhydrylsulfinylacetohydroxamic Acids. Canadian Patent CA1192222A, filed May 27 1983; granted Aug 20 1985. Google Patents.
  14. World Anti-Doping Agency (WADA). Investigations into the metabolism and elimination of flmodafinil and fladrafinil as well as their prevalence in elite sports. WADA.
  15. U.S. National Library of Medicine. ClinicalTrials.gov – Search “Fladrafinil”. ClinicalTrials.gov.
  16. U.S. FDA. Import Alert #66-57: Unapproved new drugs (Research Use Only Compounds). Apr 2023.
  17. U.S. FDA. 21 CFR §312.160: Drugs for tests in vitro and in laboratory research animals. Code of Federal Regulations, 2025.
  18. International Narcotics Control Board (INCB). New Substances under International Control. INCB Database.
  19. World Anti-Doping Agency (WADA). Prohibited List 2024: Section S6 (Stimulants). WADA 2024.
  20. AdisInsight (2024). Modafinil analog pipeline summary. Springer Database.
  21. U.S. FDA. Guidance for Industry: Bioavailability and Bioequivalence Studies. CDER Guidance.
  22. Therapeutic Goods Administration (TGA). Poisons Standard and Scheduling of Medicines and Chemicals. TGA.
  23. European Medicines Agency (EMA). Guideline on the Investigation of Bioequivalence. EMA 2025.
  24. Therapeutic Goods Administration (TGA). Australian Register of Therapeutic Goods (ARTG). TGA ARTG.
  25. Government of Canada. Drug Product Database. Health Canada.
  26. Government of Canada. Drug and Health Product Portal. Health Canada DHPP.
  27. U.S. FDA. Investigational New Drug (IND) and Related Databases. FDA.
  28. U.S. FDA. List of Drug Master Files (DMFs). FDA DMFs.
  29. Federal Food, Drug, and Cosmetic Act (FD&C Act). 21 U.S.C. §355. Cornell Law.
  30. National Association of Pharmacy Regulatory Authorities. Controlled Drugs and Substances Act (CDSA), S.C. 1996, c.19. NAPRA.
  31. Therapeutic Goods Administration (TGA). Importing therapeutic goods — legal requirements for importing unapproved therapeutic goods and controlled substances. Australian Government.
  32. European Commission. Importation of active substances — listing of third countries under the Falsified Medicines Directive. European Commission.
  33. Government of Canada. Controlled Drugs and Substances Act (CDSA). Justice Laws Canada.
  34. Government of Canada. Food and Drugs Act. Justice Laws Canada.
  35. Government of Canada. Customs Act. Justice Laws Canada.
  36. Milgram, N.W., Callahan, H. and Siwak, C. (1999), Adrafinil: A Novel Vigilance Promoting Agent. CNS Drug Reviews, 5: 193-212. doi: 10.1111/j.1527-3458.1999.tb00100.x
  37. Adkins, A.; Gramm, E.; Shulman, J.; Pizon, A. BaFLofen: a case of nootropics gone awry leading to 4-fluorophenibut toxicity. In: North American Congress of Clinical Toxicology (NACCT) 2022 Abstracts, Clinical Toxicology, 2022, 60(S2): 1–162. University of Pittsburgh Medical Center, Pittsburgh, PA, USA; University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. doi:10.1080/15563650.2022.2107776. Full text accessed November 11 2025 via https://www.clintox.org. Also indexed as: *Fladrafinil/f-phenibut overdose.* Reactions Weekly 1940, 194 (2023). doi:10.1007/s40278-023-32052-2.

Fladrafinil – Complete Research Overview