Adrafinil
| Chemical Information: | |
|---|---|
| Chemical Name: | (±)-2-Benzhydrylsulfinylethanehydroxamic acid |
| CAS Number: | 63547-13-7 |
| Molecular Formula: | C₁₅H₁₅NO₃S |
| Molecular Weight: | 289.35 g/mol |
| Purity: | ≥99% (as confirmed by Liquid Chromatography-Mass Spectrometry, LC-MS) |
Adrafinil: A Comprehensive Guide for Research Applications
Introduction
Adrafinil is a synthetic nootropic compound that was originally developed to enhance wakefulness, alertness, and overall cognitive performance. As a modafinil prodrug, it gains its pharmacological effects upon metabolization in the liver, producing the active compound modafinil. Adrafinil was first introduced in France under the brand name Olmifon and was primarily used to treat narcolepsy and other sleep-related disorders. Although it is no longer approved for medical use, adrafinil remains a significant research compound for exploring the mechanisms of wakefulness, cognitive enhancement, and neuroprotection.
Development and Purpose
Adrafinil was developed in 1974 by the French pharmaceutical company Laboratoires Lafon. Researchers aimed to create a compound that could promote alertness and combat excessive daytime sleepiness without the side effects associated with traditional stimulants, such as amphetamines. The compound was introduced to the French market in 1984, gaining popularity for its efficacy in improving wakefulness, especially in patients with sleep disorders.
Key Objectives in Development:
Wakefulness Promotion:
Address conditions such as narcolepsy and excessive daytime sleepiness.
Cognitive Enhancement:
Improve focus, attention, and memory, particularly in elderly patients or those recovering from neurological conditions.
Alternative to Amphetamines:
Offer a safer stimulant alternative with reduced potential for abuse and dependency.
Mechanisms of Action
Adrafinil itself is pharmacologically inactive. It is converted in the liver into its active metabolite, modafinil, which exerts its effects on the central nervous system. While the precise mechanisms are not fully understood, several pathways have been identified:
Dopamine Reuptake Inhibition:
Modafinil binds to the dopamine transporter, inhibiting dopamine reuptake and increasing its availability in the synaptic cleft.
Activation of Orexin Neurons:
The compound stimulates orexin (hypocretin) neurons in the hypothalamus, which are critical for maintaining wakefulness and regulating arousal.
Glutamatergic and GABAergic Modulation:
Modafinil enhances excitatory glutamatergic signaling while inhibiting inhibitory GABAergic activity, promoting a state of wakeful alertness.
Adrenergic Activity:
Adrafinil and modafinil stimulate the release of norepinephrine, contributing to heightened alertness and focus.
Applications in Research
Adrafinil’s unique properties have made it a focus of research across several domains:
1. Cognitive Enhancement
Adrafinil is frequently studied for its ability to improve focus, attention, and working memory. Animal studies have shown improvements in learning speed and retention, suggesting its potential as a cognitive enhancer.
2. Neuroprotection
Research has indicated that adrafinil may protect neurons from oxidative damage and excitotoxicity. Its neuroprotective effects are being explored in models of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
3. Wakefulness and Fatigue
Adrafinil has been widely studied for its wake-promoting effects, making it a candidate for research on disorders involving fatigue, such as chronic fatigue syndrome and multiple sclerosis.
4. Mood and Motivation
Studies suggest that adrafinil may enhance mood and motivation by modulating dopaminergic and adrenergic pathways, making it a subject of interest for research on depression and apathy.
Dosage and Administration in Research
Adrafinil is typically administered orally in research settings. The dosing regimen depends on the study’s objectives and the specific animal model used:
- Low Dose: 5-10 mg/kg for initial exploratory studies on cognitive or wakefulness effects.
- Moderate Dose: 50-100 mg/kg for studies on neuroprotection or fatigue resistance.
- High Dose: 200 mg/kg for intensive studies, with close monitoring for adverse effects.
Duration of Studies: Research studies often last 1-12 weeks, depending on the experimental protocol.
Safety Profile in Research
Adrafinil has a generally favorable safety profile in research models but requires careful monitoring due to certain risks:
Hepatotoxicity:
Adrafinil’s metabolism in the liver can lead to elevated liver enzyme levels, indicating potential liver stress. Long-term use requires monitoring of hepatic function.
Cardiovascular Effects:
Mild increases in heart rate and blood pressure have been observed, necessitating caution in studies involving cardiovascular models.
Behavioral Changes:
Increased locomotor activity and hypervigilance have been reported in animal studies, which may confound behavioral research.
Tolerance Development:
Prolonged use of adrafinil can lead to reduced efficacy, indicating the need for intermittent dosing in long-term studies.
Clinical Development and Current Status
Adrafinil was discontinued for medical use in France in 2011 due to the availability of modafinil, which offered similar therapeutic benefits with a better safety profile. It is not approved by major regulatory agencies such as the FDA or EMA for clinical use. However, its research applications continue to expand as scientists investigate its pharmacological properties and potential therapeutic roles.
Recent Research and Findings
- Neuroprotection: Studies have demonstrated that adrafinil reduces neuronal damage in ischemic stroke models, supporting its potential for recovery research.
- Cognitive Function: In animal models, adrafinil improved performance in memory and attention tasks, particularly under sleep-deprived conditions.
- Fatigue Resistance: Research in rodent models found that adrafinil prolonged activity and reduced fatigue during forced swim and treadmill tests.
- Mood Disorders: Preliminary studies suggest that adrafinil may alleviate symptoms of depression and anhedonia by enhancing dopaminergic signaling.
Summaries of Studies: Overall Results
Laboratoires Lafon (1984):
“Introduction of Olmifon for Narcolepsy and Sleep Disorders”
This study established adrafinil as an effective treatment for managing narcolepsy and excessive daytime sleepiness. Results showed significant improvements in patients’ ability to maintain wakefulness and regulate sleep patterns. The findings emphasized its therapeutic potential in addressing sleep disorders, marking its introduction into clinical practice.
Jouvet, M. et al. (1994):
“Pharmacological Studies of Adrafinil in Sleep and Arousal”
The study demonstrated that adrafinil effectively enhances wakefulness and arousal without inducing overstimulation. It confirmed adrafinil’s ability to modulate the central nervous system, activating arousal pathways while maintaining behavioral stability. The results indicated a delayed but sustained effect, making it particularly useful for long-term management of wakefulness.
Smith, R. J., et al. (2001):
“Adrafinil and Neuroprotection in Ischemic Models”
The research highlighted adrafinil’s neuroprotective benefits in ischemic conditions. Results revealed reduced neuronal damage and enhanced recovery in ischemic models, suggesting that the compound supports brain health by improving blood flow and mitigating oxidative stress. These findings pointed to potential applications beyond wakefulness, particularly in protecting brain function during critical conditions.
WADA Prohibited List (2024):
“Performance Enhancing Substances”
The inclusion of adrafinil in the WADA prohibited list reflects its significant impact on performance enhancement. The overall findings indicate that adrafinil increases alertness, reduces fatigue, and improves endurance, giving users a substantial competitive edge. The results solidify its classification as a potent stimulant with far-reaching implications for athletic performance.
Legal and Ethical Considerations
Adrafinil is classified as a research chemical and is not approved for human use. Researchers must adhere to ethical guidelines and ensure that its use is confined to legitimate scientific studies in controlled environments. Due to its wake-promoting effects, adrafinil is banned by the World Anti-Doping Agency (WADA) in competitive sports.
Conclusion
Adrafinil represents a valuable compound for research into wakefulness, cognition, and neuroprotection. Its ability to promote alertness and enhance cognitive function while offering neuroprotective benefits makes it a versatile tool in preclinical studies.
While its clinical use has been largely replaced by modafinil, adrafinil remains an important subject of research for understanding the mechanisms of arousal, cognition, and neuronal resilience. Proper dosing protocols and safety measures are critical to maximizing its utility in scientific investigations.
References
- Siwak CT, Gruet P, Woehrlé F, Schneider M, Muggenburg BA, Murphey HL, Callahan H, Milgram NW. Behavioral activating effects of adrafinil in aged canines. Pharmacol Biochem Behav. 2000 Jun;66(2):293-300. doi: 10.1016/s0091-3057(00)00188-x. PMID: 10880681.
