Fladrafinil (CRL-40,941): Exploring the Fluorinated Adrafinil Analog

Fladrafinil, also known by its laboratory code CRL-40,941 or the chemical name 2-(bis(4-fluorophenyl)methylsulfinyl)-N-hydroxyacetamide, is a synthetic wakefulness-promoting agent (eugeroic) closely related to Adrafinil and Modafinil. It is essentially Adrafinil with two fluorine atoms added to the diphenylmethyl group. Developed by the same French company (Lafon Laboratories, later acquired by Cephalon) that created Adrafinil and Modafinil, Fladrafinil was investigated for its potential effects on vigilance and wakefulness. While it never reached widespread clinical use or regulatory approval as a medication, it has gained attention within the gray market nootropic and research chemical communities as a potentially more potent or longer-lasting alternative to its parent compounds.

Chemical Structure and Relationship to Adrafinil/Modafinil

Understanding Fladrafinil requires understanding its predecessors:

Adrafinil: A prodrug, meaning it is metabolized in the body into the active compound. Its primary active metabolite is Modafinil. Adrafinil was developed first and used primarily in Europe to promote alertness and vigilance in the elderly. It has a slower onset and potentially higher liver strain due to the metabolism required. Adrafinil's profile is detailed here.
Modafinil: The main active metabolite of Adrafinil. It is a potent wakefulness-promoting agent approved for narcolepsy, SWSD, and OSA. Modafinil itself is widely used off-label as a cognitive enhancer.
Fladrafinil (CRL-40,941): A structural analog of Adrafinil. It features the same core structure but with a fluorine atom substituted onto each of the two phenyl rings. Fluorine substitutions are common in medicinal chemistry to alter a molecule's properties, such as potency, metabolic stability, lipophilicity, and binding affinity.

Like Adrafinil, Fladrafinil is also thought to be a prodrug, likely metabolized in the body to the corresponding active sulfide metabolite, CRL-40,940 (Flmodafinil).

Proposed Mechanisms of Action

Given its structural similarity and its likely metabolism to Flmodafinil (CRL-40,940), Fladrafinil's mechanisms are presumed to be similar to those of Modafinil and its fluorinated counterpart, Flmodafinil, although potentially modified in potency or duration by the fluorine atoms. These likely include:

Dopamine Reuptake Inhibition (DRI): Weak inhibition of the dopamine transporter (DAT), increasing extracellular dopamine levels, particularly in the nucleus accumbens and prefrontal cortex. This is considered key for wakefulness and potential cognitive effects.
Histamine System Activation: Potential increase in hypothalamic histamine release, promoting arousal.
Orexin System Modulation: Possible activation of orexin pathways involved in regulating the sleep-wake cycle.
Effects on Norepinephrine, Serotonin, GABA, Glutamate: Potential modulation of these systems, contributing to overall effects on alertness and vigilance.

The fluorine atoms in Fladrafinil (and its active metabolite Flmodafinil) might alter the binding affinity to DAT or other targets, potentially increasing potency or changing the pharmacokinetic profile (e.g., half-life, brain penetration) compared to Modafinil. Some sources claim Fladrafinil/Flmodafinil are significantly more potent or bioavailable than Modafinil, but rigorous comparative data in humans is lacking.

Reported Effects and Potential Benefits

Fladrafinil is primarily sought for its wakefulness-promoting and potential cognitive-enhancing effects, similar to Modafinil but often claimed to be stronger or longer-lasting by users. Reported effects include:

Increased Wakefulness and Alertness: Combating fatigue and promoting vigilance.
Enhanced Focus and Concentration: Improved ability to sustain attention on tasks.
Increased Productivity and Motivation: Reduced procrastination, enhanced drive.
Potential Mood Elevation: Possible mild mood boost, likely related to dopamine.
Cognitive Enhancement: Potential improvements in working memory or executive function (largely extrapolated from Modafinil research).

Aggression Concerns: One notable difference reported in limited studies or anecdotal accounts concerning Fladrafinil (or potentially its active metabolite Flmodafinil) is a potential increase in aggression or irritability compared to Modafinil. A study by Lazaroids Pharmaceuticals (related to Cephalon) reportedly found CRL-40,941 produced "antiaggressive" effects in animals, but user reports sometimes mention increased irritability or aggression as a side effect. This requires careful consideration and further investigation.

Potency and Duration

Potency: Often claimed to be significantly more potent than Adrafinil and potentially 2-4 times more potent than Modafinil by weight, meaning smaller doses are required. However, these claims largely stem from anecdotal reports and require scientific validation.
Duration: The duration of effects is also debated, with some users reporting a longer duration than Modafinil, potentially due to altered metabolism conferred by the fluorine atoms.

Research Evidence (or Lack Thereof)

Crucially, Fladrafinil has very limited published scientific research, especially in humans.

It was patented by Lafon Laboratories in the 1980s alongside related compounds.
Some internal or limited preclinical studies likely exist but are not widely available in peer-reviewed literature.
There are no formal clinical trials published establishing its efficacy, safety, pharmacokinetics, or optimal dosage in humans for any indication.

Its use and purported effects are almost entirely based on its structural relationship to Adrafinil/Modafinil, theoretical pharmacology, and anecdotal reports from users purchasing it as a research chemical. This lack of data makes it significantly riskier than its approved relatives. It stands in contrast to substances like Piracetam, the original nootropic with decades of study.

Safety and Side Effects

Due to the lack of human clinical data, the safety profile of Fladrafinil is largely unknown and inferred from related compounds, with added uncertainty due to the structural modification.

Potential Side Effects (Based on Modafinil/Analogs): Likely includes headache, nausea, anxiety, insomnia, dry mouth, dizziness.
Liver Strain: As a prodrug potentially requiring liver metabolism (similar to Adrafinil), concerns about liver enzyme elevation might exist, although possibly less than Adrafinil if it's more efficiently converted. This is speculative.
Cardiovascular Effects: Potential for increased heart rate or blood pressure, similar to Modafinil.
Psychiatric Effects: Risk of anxiety, mania, or other psychiatric symptoms, especially in susceptible individuals.
Severe Skin Reactions: The risk of rare but serious rashes (SJS/TEN/DRESS) seen with Modafinil cannot be ruled out and might potentially be altered by the fluorination.
Aggression: As mentioned, potential for increased irritability or aggression requires specific caution.
Drug Interactions: Likely interacts with liver enzymes (CYP450 system) similarly to Modafinil, potentially affecting other medications, including reducing the effectiveness of hormonal contraceptives.
Long-Term Effects: Completely unknown.

Using Fladrafinil involves taking on significant unknown risks due to the lack of safety data.

Legal Status and Availability

Not Approved: Fladrafinil is not approved as a medication anywhere in the world.
Unscheduled/Gray Market: In most countries, including the US, it is not explicitly scheduled as a controlled substance. However, it cannot be legally sold as a dietary supplement.
Research Chemical: It is primarily sold online by vendors specializing in research chemicals or nootropics, often labeled "not for human consumption." Purchasing and possessing these substances can carry legal risks depending on jurisdiction and intended use. Product purity and quality from these sources are not guaranteed.

Conclusion: An Under-Researched Eugeroic Analog with Unknown Risks

Fladrafinil (CRL-40,941) is a fluorinated analog of Adrafinil, likely acting as a prodrug for the Modafinil analog Flmodafinil (CRL-40,940). Based on its structure and relationship to approved eugeroics, it is presumed to promote wakefulness and potentially enhance cognition via mechanisms involving dopamine reuptake inhibition and modulation of other neurotransmitter systems like histamine and orexin. Anecdotal reports suggest it may be more potent and longer-lasting than Modafinil, but also potentially associated with increased aggression or irritability.

The critical issue is the profound lack of published scientific research, particularly human clinical trials. Its efficacy, safety profile, pharmacokinetics, optimal dosage, and long-term effects are largely unknown. Relying on anecdotal reports and extrapolations from related compounds is inherently risky. Potential side effects, including serious ones like severe skin reactions or psychiatric symptoms, cannot be ruled out, and the specific impact of the fluorine substitution is not well characterized. Sold as an unregulated research chemical, Fladrafinil represents a high-risk option within the eugeroic class, and its use outside formal research settings involves significant unknowns and potential dangers. Safer, better-studied alternatives for wakefulness and cognitive enhancement should be prioritized.