The mystery of gamma-hydoxybutyrate efficacy in narcolepsy type 1


Kilduff, Thomas S. “The Mystery of GHB Efficacy in Narcolepsy Type 1.” Sleep (2023): zsad156.


Over 40 years have elapsed since the original description of the effects of sodium gamma-hydroxybutyrate (GHB) on sleep [1] and the subsequent description of GHB as an effective treatment for narcolepsy [2, 3], yet the neurobiological basis for its efficacy in narcolepsy remains a mystery. Since that time, the pathophysiology of human narcolepsy has been generally accepted to be due to the loss of hypocretin/orexin (HCRT) neurons [4, 5], although perhaps not in all cases [6]. In 2018, a compelling article from the Siegel lab at University of California at Los Angeles described a 54% increase in the number of HCRT neurons in the brains of heroin addicts and a 22% shrinkage in the size of these neurons compared to human controls [7]. In wild-type mice, morphine administration for 2 or more weeks (50 mg/kg, s.c.) similarly produced a 38% increase in the number of Hcrt neurons and shrinkage in the size of Hcrt cells, indicating greater plasticity of the hypocretin system than previously recognized. Moreover, in transgenic “orexin-DTA” mice [8] in which the Hcrt neurons had degenerated to 40% of normal levels, daily morphine administration (50 mg/kg, s.c.) for 2 weeks restored the number of Hcrt neurons detected to normal levels and prevented cataplexy [7]. A subsequent study found that opiates suppressed narcoleptic symptomatology in patients [9], which led the authors of the paper by Wu et al. [10] in SLEEP to evaluate whether GHB might reduce cataplexy through similar effects on the Hcrt neurons or its downstream connections, specifically, the locus coeruleus (LC).

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