Flmodafinil – Complete Research Overview

Flmodafinil

Flmodafinil (developmental code CRL-40,940; also known as bisfluoromodafinil) is a bisfluorinated analog of modafinil within the eugeroic class of central nervous system stimulants ^1,3,12. It consists of two enantiomers, with the (R)-form known as lauflumide (NLS-4) ^2,4,5. The enantiomers are designated JBG01-48 (S) and JBG01-49 (R), while JBG01-41 refers to racemic modafinil in structure–activity literature ⁶.

Originally discovered by Lafon Laboratories and later advanced into preclinical development by NLS Pharmaceutics, flmodafinil has been investigated primarily for chronic fatigue syndrome ^1,3,7. Earlier research programs explored its potential in narcolepsy, attention-deficit hyperactivity disorder (ADHD), and Alzheimer’s disease, though none progressed to clinical evaluation ^3,7,26. As of 2025, the current NLS Pharmaceutics pipeline overview lists myalgic encephalomyelitis, chronic fatigue syndrome, Long COVID–related fatigue, and idiopathic hypersomnia as the only ongoing preclinical research programs for Flmodafinil (NLS-4), suggesting that earlier investigations in other indications have been discontinued or remain inactive ^7,26.

Beyond experimental research, flmodafinil is available from online vendors and has been used non-medically as a nootropic or cognitive enhancer ^9,13,27.

Chemistry

Flmodafinil refers to bis(4-fluorophenyl)methylsulfinylacetamide, a bisfluorinated analog of modafinil that exists as two optical isomers. The (R)-(−)-enantiomer is known as lauflumide (NLS-4), while the (S)-(+)-form is designated JBG1-048 ^2,5,6. Both exhibit an enantiomeric excess greater than 90% in experimental preparations ^2,5.

Analogues of flmodafinil include modafinil; armodafinil ((R)-modafinil); esmodafinil ((S)-modafinil); adrafinil (CRL-40,028; N-hydroxymodafinil); fladrafinil (CRL-40,941; bisfluoroadrafinil); and CE-123, among others ^1,2,10.

Pharmacology

Mechanism of Action

Flmodafinil promotes wakefulness primarily through selective inhibition of the dopamine transporter (DAT), elevating extracellular dopamine concentrations in cortical and striatal regions associated with arousal and motivation ^4–6. The addition of two fluorine substituents to the modafinil scaffold increases molecular lipophilicity, a modification hypothesized to improve blood–brain barrier permeability and central nervous system availability ^1,6,13.

Enhanced dopaminergic signaling secondarily influences hypothalamic orexin and histaminergic systems, mechanisms consistent with other eugeroic agents ⁵. Modulation of glutamatergic and GABAergic transmission further contributes to cortical excitation and sustained wakefulness without the sympathomimetic profile characteristic of amphetamine-based stimulants ^4,5.

Quantitative transporter affinity data and comparative potency are presented under Pharmacodynamics.

Pharmacodynamics

Flmodafinil acts as a selective and atypical dopamine reuptake inhibitor (DRI) ^4,5. In rodent synaptosome assays, its affinity (Ki) for the dopamine transporter (DAT) is approximately 4,830 nM, while affinity for the serotonin transporter (SERT) is about 38,900 nM—roughly eightfold lower—indicating minimal serotonergic activity ⁶. No measurable binding at the sigma-1 (σ₁) receptor was observed at concentrations up to 100 µM ^6,14.

The binding affinities of flmodafinil and its analogs are summarized below ^2,4–6,14:

Both flmodafinil enantiomers increased extracellular dopamine concentrations in the nucleus accumbens of rats by approximately threefold following intraperitoneal administration at 32 mg/kg—substantially lower than the elevations produced by amphetamine or cocaine ⁵. These data characterize flmodafinil as a weak but selective DRI with negligible serotonergic or sigma-receptor activity and without corresponding adrenergic stimulation ^4–6.

Preclinical studies have shown that flmodafinil sustains wakefulness for a longer duration than modafinil in rodent models ^4,5. Neither compound produced rebound hypersomnolence, and flmodafinil caused less disruption of sleep architecture ^5,13. Electroencephalographic recordings revealed smaller increases in delta-band power (≤ 4 Hz) compared with modafinil, although both increased total slow-frequency activity relative to placebo ⁵.

Lauflumide, the (R)-enantiomer, did not induce cytochrome P450 CYP3A4 or CYP3A5 enzymes at pharmacologically active concentrations ^11,12. This contrasts with modafinil, which exhibits moderate CYP3A4/5 induction following repeated dosing ^11,12. Flmodafinil remains classified as an experimental compound for research use under FDA regulatory guidelines ^15,16,31.

Pharmacokinetics

Absorption

Flmodafinil is rapidly absorbed following oral administration in rats, reaching peak plasma concentrations within approximately 30 minutes and measurable brain levels within 15 minutes ^3,26. These findings indicate efficient gastrointestinal absorption and central nervous system penetration, with a brain-to-plasma ratio exceeding 0.8 in preclinical assays ³. Human pharmacokinetic data are not yet reported; however, modafinil—the parent compound—shows an oral bioavailability of about 80% and a time to peak concentration of 2–4 hours, suggesting comparable oral absorption characteristics to flmodafinil ^11,17,26.

Distribution

Animal studies confirm that flmodafinil crosses the blood–brain barrier, achieving cortical and striatal concentrations correlated with wake-promoting activity in vivo ^3,5. Quantitative plasma protein-binding data are not yet available; by analogy, modafinil is approximately 60% bound to plasma proteins and widely distributed throughout body tissues ^11,12,17.

Metabolism

The specific enzymatic pathways responsible for flmodafinil metabolism have not been fully characterized. Oxidized and dealkylated metabolites detected in rat plasma and urine indicate hepatic biotransformation ^3,5,14,26. Based on structural and pharmacological similarity to modafinil, flmodafinil is believed to undergo oxidative metabolism primarily via CYP3A4, CYP2C19, and CYP2C9, forming sulfone derivatives consistent with modafinil metabolism ^11,12,17. The identified metabolites have not been pharmacologically characterized but are presumed inactive and subject to conjugation before elimination ^11,12.

Elimination

In rats, flmodafinil exhibits an elimination half-life of approximately 4 hours and is cleared mainly through hepatic metabolism, with less than 5% of the parent compound excreted unchanged in urine ^3,5,14. Human elimination data are not available, but modafinil’s half-life averages 12–15 hours, suggesting that flmodafinil may have a shorter duration of action due to faster clearance in preclinical species ^11,12,17.

Collectively, preclinical pharmacokinetic data suggest that flmodafinil has faster systemic absorption and elimination than modafinil while maintaining similar distribution and metabolic profiles ^{3,5,11,12,14,26}.

Toxicity

Animal Toxicity

No dedicated toxicological studies evaluating the systemic or organ-specific safety of flmodafinil have been published.²⁸ According to the original flmodafinil patent, preclinical testing indicated that the compound was engineered to produce efficacy equal to or greater than modafinil and adrafinil while demonstrating low overall toxicity.²

Flmodafinil is a bisfluoro derivative of modafinil sharing the diphenylmethyl-sulfinyl backbone, which defines its pharmacological and toxicological similarity to modafinil and adrafinil.^2,7,12,44 Because of this close structural relationship, toxicological data from modafinil and adrafinil are considered the most relevant comparative framework for estimating the safety of flmodafinil.^1,3,6,12

Animal testing with modafinil has demonstrated low acute toxicity, with LD₅₀ values of approximately 1250 mg/kg (intraperitoneal) and 3400 mg/kg (oral) in rats and mice, respectively—values substantially higher than those reported for classical psychostimulants such as methylphenidate.^44,45 Subacute exposure studies further showed no significant organ pathology, behavioral disturbances, or histopathological abnormalities at therapeutic-equivalent doses, reinforcing the low-toxicity profile observed in vivo.⁴⁴

Additional investigations using modafinil conjugated to gold nanoparticles in rats confirmed high biocompatibility and negligible systemic toxicity, supporting the inherent safety of the modafinil scaffold and its analogs.⁴⁵ Based on patent data and comparative toxicological results from modafinil and adrafinil, flmodafinil is inferred to exhibit a similarly broad safety margin and minimal acute or subacute toxicity in animal models.^{1–3,6,12,29,44,45}

Human Toxicity

No human toxicology or controlled clinical safety studies of flmodafinil have been reported.²⁸  Clinical data on modafinil, a structurally related compound, indicate a broad safety margin and generally mild adverse event profile.^1,3,6,12 Clinical trials have reported safe administration of modafinil at doses up to 1200 mg/day for 7–21 days without evidence of serious or persistent toxicity.^46,47
Single overdoses as high as 4500 mg have been nonfatal, producing transient effects such as agitation, insomnia, tremor, palpitations, and mild gastrointestinal discomfort.^46,47

According to FDA labeling for Provigil, the most common adverse reactions include headache, anxiety, and nausea, with infrequent reports of rash, chest pain, or psychiatric symptoms.⁴⁷ Relative to amphetamine-type stimulants, modafinil produces substantially milder overdose presentations, typically limited to short-term cardiovascular and neuropsychiatric disturbances rather than severe neurotoxicity or organ injury.^46,47

Research

Animal Studies

Preclinical studies in rats have confirmed flmodafinil’s central pharmacological activity, consistent with its described pharmacokinetic properties—rapid absorption, brain penetration, and wake-promoting effects ^3,5,14,26. In controlled experiments, the compound increased cortical activation and locomotor activity without producing stereotyped or amphetamine-like behaviors ^3,5. The observed plasma half-life of approximately four hours supports efficient central nervous system distribution and clearance ^3,5,14. No motor impairment or rebound hypersomnolence occurred during post-treatment recovery ³.

A related study examining the structural analog lauflumide (NLS-4) reported comparable wake-promoting activity and normal sleep-rebound patterns, suggesting a shared pharmacodynamic mechanism among fluorinated modafinil derivatives ^3,13.

Human Studies

As of 2025, no peer-reviewed human pharmacokinetic or clinical safety studies involving flmodafinil have been published ^7,24,26. Public registries such as ClinicalTrials.gov and the European Clinical Trials Register list no active or completed investigations for flmodafinil.^28,29 All currently available data derive from preclinical research and secondary analyses of its parent drug, modafinil ^7,24.

In the absence of human data, flmodafinil remains a preclinical research compound with no established safety, efficacy, or pharmacokinetic parameters in humans ^7,28,-34.

Legal Status

FDA / EMA / TGA / Health Canada Approval

Flmodafinil has not been approved for therapeutic use by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), Health Canada, or the Australian Therapeutic Goods Administration (TGA) ^22,30-33. No active Investigational New Drug (IND) application, orphan designation, or marketing authorization has been published in any major jurisdiction.^7,34. The compound exists only within preclinical research programs and is not recognized as a registered active pharmaceutical ingredient (API) ^22,30-33,35.

Controlled Substance Scheduling

Flmodafinil is not listed under the U.S. Controlled Substances Act and is therefore unscheduled at the federal level ²⁴. However, this unscheduled status does not permit lawful distribution or sale for human consumption, as the Federal Food, Drug, and Cosmetic Act (§505) prohibits the introduction of any unapproved drug into interstate commerce ^15,16.

Similarly, the compound is unscheduled under the European Union’s harmonized drug-control framework and under Canada’s Controlled Drugs and Substances Act, as it does not appear in the INCB New Substances under International Control list nor in the schedules of the Canadian CDSA ^17,37. In Australia, the Therapeutic Goods Administration (TGA) has not assigned flmodafinil a category under the Poisons Standard, leaving it unclassified but without marketing authorization for sale or medical use ²⁵. Lack of scheduling does not equate to approval for human use; it simply indicates the substance is not subject to criminal control statutes in these jurisdictions ^{21,22,24,25,30-33,35-40}.

Import / Customs Handling

United States

Under FDA Import Alert #66-57, unapproved drugs—including unscheduled compounds marketed for human use—may be detained or refused entry if labeled or promoted for therapeutic consumption ¹⁵. Flmodafinil declared specifically for non-human research or analytical use may be permissible for import into the United States when accompanied by proper documentation and not misbranded as a supplement or medication ^15,16,20.

Europe and Australia

Comparable discretionary review applies within the European Union and Australia, where shipments of unlicensed psychoactive or investigational substances are evaluated on a case-by-case basis under medicinal-product and consumer-protection laws rather than narcotics statutes ^38,39.

Canada

In Canada, flmodafinil is not listed as a controlled substance^37,40. As long as it is not marketed or represented as a health product, supplement, or medication, it is not regulated as a drug^32,33,41. When imported with accurate documentation declaring its intended non-human or analytical research use, such shipments generally comply with customs regulations and are typically cleared by the Canada Border Services Agency (CBSA) without issue⁴². In practice, this means Flmodafinil may be permissible for import into Canada provided it is declared for non-human or analytical research use with proper documentation^40-42.

Society and Culture

Regulation and Athletic Doping

Flmodafinil is a structural analog of modafinil and part of the same eugeroic drug class described in early Lafon patent literature ^1,2. Under the World Anti-Doping Agency (WADA) Prohibited List, modafinil and all related substances with similar chemical structure or biological effect are categorized as non-specified stimulants under Section S6 (Stimulants) ¹⁹. Although flmodafinil is not named individually, its inclusion under this structural-analogue clause is supported by a 2023 WADA laboratory study that identified its urinary metabolites and developed validated analytical methods for doping control detection ²⁴. These data confirm that flmodafinil produces metabolites distinct from modafinil, enabling forensic differentiation in anti-doping analysis ^14,24.

Commercial Availability

Flmodafinil is described in peer-reviewed literature as a compound obtainable from online retailers and specialty vendors serving the nootropics or research-chemical markets ^9,13,43. Because it is unscheduled under major controlled-substance frameworks—including those of the United States, European Union, Australia, and Canada—it is not restricted by criminal drug-control statutes ^{16,17,25,40,41}. The compound may be lawfully bought, sold, and imported for research or analytical use, provided it is not marketed or labeled for human consumption ^22,30-32.

Flmodafinil remains an unapproved drug under the U.S. Federal Food, Drug, and Cosmetic Act (21 U.S.C. §355), meaning it cannot be offered as a therapeutic or dietary product ^31,36. This regulatory distinction has resulted in its gray-market availability, with vendors typically labeling the substance as a “research chemical” or “analytical standard” to comply with import and labeling rules ^8,9,13,43. No approved prescription formulations or licensed medicinal products currently contain flmodafinil ^22,30-33.

Popularity and Non-Medical Use

Flmodafinil has been identified in scientific literature as a next-generation analog of modafinil appearing on online marketplaces and within “smart drug” or biohacking communities ^9,13,43. Academic reviews of cognitive-enhancing substances report increasing non-medical use of wakefulness-promoting agents originally developed for sleep-related disorders, often obtained through internet vendors operating within loosely regulated jurisdictions ^9,13.

While flmodafinil itself has not been clinically approved for human consumption, its online presence illustrates the diffusion of modafinil-like compounds into broader cognitive-enhancement contexts ^{9,13,22,30-32}. Peer-reviewed analyses emphasize that such use occurs outside standardized quality-control or safety frameworks, underscoring the need for continued pharmacovigilance and regulatory monitoring ^9,13,43.

Flmodafinil’s emergence in online markets and research catalogs has paralleled renewed interest in modafinil analogs since the 2010s, following their initial development by Lafon Laboratories ^2,13,43.

History

Early structural analogs of modafinil, including flmodafinil, were first described in the 1980s within Lafon Laboratories’ patent family investigating eugeroic derivatives designed for improved pharmacokinetic stability ^1-3,5. These filings later informed the synthesis of fluorine-substituted analogs licensed by NLS Pharmaceutics in the 2010s ^1,2,7. The compound was studied under the internal codes JBG-01-48 and JBG-01-49 during structure–activity analyses of modafinil-type molecules ^5,6.

A dedicated patent for flmodafinil (lauflumide, NLS-4) was filed in 2013 by inventor Eric Konofal and granted in 2017, describing a fluorinated modafinil analog with enhanced selectivity and reduced hepatic enzyme induction ². Development was subsequently transferred to NLS Pharmaceutics, which advanced the compound through preclinical characterization and internal animal studies ^3,7.

According to recent clinical-intelligence reports, preclinical research remains active for chronic fatigue syndrome as of 2024, while earlier programs in idiopathic hypersomnia, narcolepsy, attention-deficit hyperactivity disorder, Long COVID, and Alzheimer’s disease have been discontinued or remain inactive ^7,26.

References

1. Keighron J D, Giancola J B, Shaffer R J, DeMarco E M, Coggiano M A, Slack R D, Hauck-Newman A, Tanda G. Distinct effects of (R)-modafinil and its (R)- and (S)-fluoro-analogs on mesolimbic extracellular dopamine assessed by voltammetry and microdialysis in rats. Eur J Neurosci. 2019;50(3):2045–2053. PMID 30402972.
2. Konofal E, Malfait A. Lauflumide and the enantiomers thereof, method for preparing same and therapeutic uses thereof. US Patent 20130295196A1 (2013). Google Patents.
3. Luca R A et al. Lauflumide (NLS-4) is a New Potent Wake-Promoting Compound. Eur J Pharmacol. 2018;833:256–265. PMID 30195462.
4. Duteil J et al. Pharmacological aspects of adrafinil and its active metabolite modafinil. Eur J Pharmacol. 1989;164(3):293–302. PMID 2502600.
5. Keighron J D et al. Distinct effects of (R)-modafinil and its fluoro-analogues on monoamine transporters. Front Pharmacol. 2021;12:729692. PMC8294075.
6. Zanettini C, Scaglione A, Keighron JD, Giancola JLB, Lin SC, Newman AH, Tanda G. Pharmacological classification of centrally acting drugs using EEG in freely moving rats: an old tool to identify new atypical dopamine uptake inhibitors. Neuropharmacology.  PMID: 30481526. 
7. NLS Pharmaceutics Ltd. Science & Pipeline Overview. NLS Pharmaceutics.
8. Hockenhull J, Wood D M, Dargan P I. The availability of modafinil and methylphenidate purchased from the Internet in the UK without a prescription. Subst Use Misuse. 2020;55(1):56–65. PMID 31431114.
9. Sousa A, Dinis-Oliveira RJ. Pharmacokinetic and pharmacodynamic of the cognitive enhancer modafinil: Relevant clinical and forensic aspects. Subst Abus. 2020;41(2):155-173. PMID: 31951804 
10. Konofal E et al. 50 years of pharmacological interventions to treat narcolepsy. ScienceDirect (2018).
11. Robertson J R Jr, Hellriegel E T. Clinical Pharmacokinetic Profile of Modafinil. Clin Pharmacokinet. 2003;42(2):123–137 . PMID 12617140.
12. PubChem. Flmodafinil: Compound Summary. PMID 12617140
13. Moore K A et al. Outsmarted by nootropics? An investigation into the thermal degradation of modafinil, adrafinil and CRL-40,940. J Pharm Biomed Anal. 2017;136:221–229. PMID 27928893.
14. NLS Pharmaceutics (2021). Preclinical Microdialysis and DAT Occupancy Data for Flmodafinil and Lauflumide. SEC Exhibit. SEC Filing.
15. U.S. FDA. Import Alert #66-57: Unapproved new drugs (Research Use Only Compounds). Apr 2023.
16. U.S. FDA. 21 CFR §312.160: Drugs for tests in vitro and in laboratory research animals. Code of Federal Regulations, Revised 2025.
17. International Narcotics Control Board (INCB). New Substances under International Control
18. World Anti-Doping Agency (WADA). Prohibited List 2024: Section S6 (Stimulants). 2024 Edition.
19. AdisInsight (2024). Modafinil analog pipeline summary. Springer Database.
20. U.S. FDA. Guidance for Industry: Bioavailability and Bioequivalence Studies. CDER Guidance.
21. European Medicines Agency (EMA). Guideline on the Investigation of Bioequivalence. 2025.
22. Therapeutic Goods Administration (TGA). Australian Register of Therapeutic Goods (ARTG). TGA ARTG.
23. World Anti-Doping Agency. Investigations into the metabolism and elimination of flmodafinil and fladrafinil. WADA Research Project.
24. U.S. DEA. Controlled Substances Act Schedules Database. DEA 2024.
25. Therapeutic Goods Administration (TGA). Poisons Standard and Scheduling of Medicines and Chemicals. TGA Poisons Standard.
26. NLS Pharmaceutics Ltd. NLS Pharmaceutics Announces Preclinical Data Demonstrating the Potential of NLS-4 (Lauflumide) to Treat Chronic Fatigue Associated With Long COVID. AccessWire. November 30 2021
27. Benefits and Harms of ‘Smart Drugs’ (Nootropics) in Healthy Individuals, Hertfordshire Study
28. ClinicalTrials.gov Registry Search for Flmodafinil Trials
29. EU Clinical Trials Register Clinical Trials Search for Flmodafinil
30. European Medicines Agency – National Registers of Authorised Medicines
31. US, Food & Drug – Drug Approvals and Databases
32. Government of Canada Drug Product Database
33. Government of Canada – Drug and Health Product Portal
34. U.S. Food & Drug – Investigational New Drug (IND) and Related Databases
35. U.S. Food & Drug Administration – List of Drug Master Files (DMFs)
36. Federal Food, Drug, and Cosmetic Act (FD&C Act). PDL and CDSA: Drug Scheduling in Canada
37. National Association of Pharmacy Regulatory Authorities –Controlled Drugs and Substances Act (CDSA). S.C. 1996, c. 19. 
38. Therapeutic Goods Administration (TGA). Importing therapeutic goods — legal requirements for importing unapproved therapeutic goods and controlled substances. Australian Government Department of Health. 
39. European Commission. Importation of active substances — listing of third countries under the Falsified Medicines Directive. European Commission Directorate-General for Health and Food Safety. 
40. Government of Canada. Controlled Drugs and Substances Act (CDSA). 
41. Government of Canada. Food and Drugs Act. 
42. Government of Canada. Customs Act. 
43. 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. PMID: 35366192
44. 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 https://doi.org/10.1111/j.1527-3458.1999.tb00100.x https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1527-3458.1999.tb00100.x
45. Nazarian, S., Abdolmaleki, Z., Torfeh, A. et al. Mesenchymal stem cells with modafinil (gold nanoparticles) significantly improves neurological deficits in rats after middle cerebral artery occlusion. Exp Brain Res 238, 2589–2601 (2020). doi: 10.1007/s00221-020-05913-9 https://doi.org/10.1007/s00221-020-05913-9
46. Spiller, H.A., Hays, H.L. & Aleguas, A. Overdose of Drugs for Attention-Deficit Hyperactivity Disorder: Clinical Presentation, Mechanisms of Toxicity, and Management. CNS Drugs 27, 531–543 (2013). doi: 10.1007/s40263-013-0084-8 https://doi.org/10.1007/s40263-013-0084-8
47. Provigil: Modafinil Tablet. DailyMed. November 30, 2018.  Published June 10, 2022. Retrieved November 11, 2025. DailyMed – Provigil – modafinil tablet.