Adrafinil

Modafinil prodrug from the 1980s, withdrawn from French market 2011 for an unfavorable risk-benefit ratio (hepatotoxicity, including ALT/AST elevation and case reports of clinical hepatitis). With modafinil itself now cheap and globally accessible via Indian generics ($0.50-1.50/pill), there is no rational use case for taking the hepatotoxic prodrug instead of the active metabolite. SKIP-PERMANENT for nearly every archetype.

Adrafinil is a hepatic prodrug of modafinil. Oral adrafinil itself has minimal direct CNS activity — its effects come from liver-mediated conversion to:

1. Modafinil (the active eugeroic) — produced via deamidation/sulfoxide reduction in hepatocytes
2. Modafinil-acid (CRL-40467) — inactive metabolite, ~60% of dose ends up here
3. Modafinil-sulfone (CRL-41056) — inactive

Because the conversion happens after absorption, plasma modafinil rises only after first-pass hepatic metabolism. The downstream pharmacology — once modafinil is in circulation — is identical to taking modafinil directly:

• Weak DAT inhibition (~50% striatal occupancy at therapeutic plasma modafinil)
• Orexin → histamine → cortical wakefulness cascade
• Glutamate up, GABA down in hypothalamus, thalamus, hippocampus
• Mild NE/5-HT/D1 effects in PFC

The mechanistic problem is not the destination — it's the toll booth. Adrafinil forces the liver to do conversion work that modafinil itself doesn't require. At chronic high doses (600-1200 mg/day) this manifests as elevated serum aminotransferases (ALT, AST) and, in case reports, clinical hepatitis. Modafinil, which bypasses this conversion step entirely, has a LiverTox likelihood score of E (unlikely cause of clinically apparent liver injury). Adrafinil does not.