The Origins and Development of Adrafinil
Adrafinil was first developed in 1974 by chemists at the French pharmaceutical company Laboratoires Lafon who were initially searching for new analgesics [1.9.2]. However, pharmacological studies revealed that the compound had psychostimulant-like effects, such as increased hyperactivity and wakefulness in animal subjects [1.9.2]. This led to its investigation for human use, specifically for treating narcolepsy, with the first human tests conducted between 1977 and 1978 [1.9.2].
Adrafinil was introduced to the market in France in 1984 under the brand name Olmifon, where it was used to relieve excessive sleepiness and inattention, particularly in elderly patients [1.2.1, 1.8.5]. Two years after adrafinil's discovery, in 1976, its active metabolite, modafinil, was identified [1.9.2]. Modafinil proved to be more potent in animal studies and was selected for further development, eventually also reaching the market [1.9.2]. The company that developed both, Lafon, was acquired by Cephalon in 2001, and by September 2011, Cephalon had discontinued the production of Olmifon (adrafinil) [1.9.2].
How Adrafinil Works: Mechanism of Action
Adrafinil is a prodrug, which means it is inactive until it is metabolized in the body [1.2.2]. The liver converts adrafinil into modafinil, which is the active compound responsible for its effects [1.3.1]. This conversion process means that the onset of adrafinil's effects is delayed, typically taking 45-60 minutes when consumed on an empty stomach [1.2.1].
The precise mechanism of action for modafinil (and therefore adrafinil) is not completely understood [1.3.2]. It is believed to act as a mild central nervous system stimulant [1.2.1]. Unlike traditional stimulants such as amphetamines, it does not appear to work by increasing the release of monoamines [1.3.2]. Instead, proposed mechanisms include:
- Dopamine Reuptake Inhibition: It may act on the dopamine transporter (DAT) to reduce the reuptake of dopamine, increasing its availability in the brain [1.3.2].
- Neurotransmitter Modulation: It is thought to boost levels of other neurotransmitters like norepinephrine and histamine, which play roles in alertness and cognitive function [1.3.1, 1.8.3].
- Orexin System Activation: Some evidence suggests it activates orexin neurotransmission, a key system involved in regulating wakefulness and arousal [1.3.2, 1.8.3].
- Glutamate and GABA Influence: It may modulate glutamate (an excitatory neurotransmitter) and GABA (an inhibitory neurotransmitter) transmission [1.3.2].
Primary and Off-Label Uses
Historically, adrafinil was prescribed in France to combat excessive sleepiness (hypersomnia) and disorders of attention and vigilance in the elderly [1.2.1, 1.9.5]. Today, with the drug discontinued commercially and unregulated in the United States, its use is primarily off-label, sourced from online vendors [1.2.1, 1.2.4].
The most common motivations for its use include:
- Promoting Wakefulness: Users take adrafinil to prevent fatigue and stay alert for extended periods, similar to its original intended use for narcolepsy and for night-shift workers [1.2.2, 1.2.4].
- Cognitive Enhancement (Nootropic): A significant portion of users take adrafinil to increase focus, productivity, and motivation [1.2.4]. It is often marketed and sold online as a nootropic supplement [1.2.4, 1.8.4].
- Replacement for Prescription Stimulants: Some individuals use adrafinil as a substitute for prescription drugs like methylphenidate or modafinil, either due to difficulty in obtaining a prescription, cost, or perceived side effects of the other drugs [1.2.4].
Comparison: Adrafinil vs. Modafinil
Since adrafinil is a prodrug for modafinil, they share nearly identical pharmacological effects [1.4.1]. However, there are key differences in their pharmacokinetics, legal status, and risk profile.
| Feature | Adrafinil | Modafinil |
|---|---|---|
| Mechanism | A prodrug that converts to modafinil in the liver [1.2.1]. | The active metabolite of adrafinil [1.4.1]. |
| Onset of Action | Slower; requires time for the liver to metabolize it (approx. 45-60 min) [1.4.1]. | Faster; it is already in its active form [1.4.3]. |
| Legal Status (USA) | Unregulated and not approved by the FDA. Sold as a 'research chemical' or nootropic supplement online [1.2.1, 1.4.2]. | A Schedule IV controlled substance, available only by prescription [1.4.2]. |
| Metabolic Load | Puts a greater strain on the liver due to the conversion process [1.7.4]. | Bypasses the initial liver metabolism required by adrafinil [1.3.5]. |
| Potency | Less potent than an equivalent dose of modafinil because not all of it is converted. | More potent and has a more direct dose-response relationship [1.9.2]. |
Risks, Side Effects, and Safety Concerns
The use of adrafinil is not without risks. Because it is metabolized by the liver, there is a significant concern for liver health with long-term or high-dose use. Regular monitoring of liver enzymes is recommended for anyone taking it for an extended period [1.7.1, 1.7.4].
Common side effects are similar to those of modafinil and can include [1.5.3, 1.7.1]:
- Headache
- Nausea
- Anxiety and nervousness
- Insomnia
- Dizziness
- Dry mouth
- Stomach pain
More serious but rare side effects associated with its active metabolite, modafinil, include severe skin reactions like Stevens-Johnson Syndrome (SJS), psychiatric symptoms (anxiety, mania, hallucinations, suicidal ideation), and cardiovascular events [1.5.4]. Adrafinil might also increase blood pressure and should be used with caution [1.2.3]. Furthermore, it is banned by the World Anti-Doping Agency (WADA) for use in competitive sports [1.6.1, 1.6.3].
Legal Status and Regulation
In the United States, adrafinil has not been approved by the Food and Drug Administration (FDA) and is therefore unregulated [1.2.1]. It exists in a legal gray area where it cannot be sold as a dietary supplement but is not classified as a controlled substance, making it available for purchase online, often labeled for 'research use only' [1.4.2, 1.2.5]. Its marketing authorization in France was withdrawn in September 2011 [1.2.1].
Conclusion
Adrafinil is primarily used for its wakefulness-promoting and cognitive-enhancing effects, which stem from its conversion into modafinil in the body [1.2.2]. While it was originally developed to treat narcolepsy and relieve inattention in the elderly, it is now almost exclusively used off-label as a nootropic, sourced through online channels [1.2.4, 1.8.4]. Users should be aware of its legal status, the lack of long-term safety data, and the potential for side effects, most notably the strain it places on the liver [1.7.4]. Its active metabolite, modafinil, is a prescription-only controlled substance in the U.S., highlighting the pharmacological significance of the compound [1.4.2].
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Consult with a healthcare professional before taking any new supplement or medication.
