During the 80's, Gamma-hydroxybutyrate (GHB), which was readily available over-the-counter in nutrition stores, enjoyed widespread popularity among bodybuilders for its ability to stimulate growth hormone release (as well as its euphoric properties). It was subsequently pulled from the marke due to a few isolated instances of abuse (all of which also involved other drugs) and, it is thought by some, to protect prescription pharmaceutical sleep-aids from safer, more effective (and less expensive) competition and to pave the way for the wave of SSRI's that started with Prozac.

Not coincidentally, since it sale became illegal in 1990, its popularity has spread considerably.

Introduction

GHB is a four carbon, fatty acid derivative originally synthesized in the early 1960's by Dr. Henry Laborit , who was looking for an analogue of GABA (the brain's primary inhibitory neurotransmitter) that would readily cross the blood brain barrier -- a property GABA lacked (1). Indeed, GHB did prove to easily cross the blood brain barrier -- However, it was found to exert of number of effects not shared by GABA (2). It is now known that it does not bind to either GABA receptor under readily achievable concentrations (3). And though it is formed from GABA in brain tissues, that is not its only or perhaps even primary source (3).

A decade after its synthesis, GHB was shown to occur naturally in the human brain (4). Twenty-five years later, specific receptors for GHB were discovered (5), and it is now thought by many to be a neurotransmitter, or at least a neuromodulator (6, 7).

GHB is also found in various peripheral tissues such as kidney, heart, skeletal muscles, and brown fat (8) -- at higher concentrations that in the brain -- but as of yet, no peripheral receptors have been discovered, thus is function in these tissues not known at this time (9, 10).

Biochemistry

As mentioned, GHB is a naturally occurring component of mammalian brain metabolism. Highest brain levels occur in the substantia nigra, thalamus, and hypothalamus, lowest levels are found in the cerebellum and frontal cortex (11). It can be formed from GABA in the brain as well as being metabolized from it -- both via the intermediate succinic semialdehyde (12), which can also enter the Krebs cycle as succinate. The recently banned supplement ingredients, gammabutyrolactone and 1,4 butanediol, are also naturally occurring precursors (13).

Pharmocokinetics

GHB is readily bioavailable with oral administration, however, oral clearance rate and % absorption decrease and half-life increases with escalating doses, indicating that these processes are capacity limited (14, 15). This does not appear to be true for GBL (15), which explains the differing subjective effects between the two.

Pharmacology

Following oral, intravenous, or intraperitoneal administration, GHB produces CNS depressant effects similar to alcohol -- and, in fact, it has been shown to substitute for alcohol in physically dependent rats (16). At doses as low as .1 mg/kg in humans, it produces a state of sedation indistinguishable from human sleep (17). The mechanism behind its subjective effects are not completely understood, and involve multiple neurotransmitter systems:

Dopamine

The central neurotransmitter dopamine has been consistently shown to be altered by GHB, and is considered as the primary mediator of its subjective effects. At low doses, it causes a reduction in dopaminergic activity, due to inhibition of dopamine releasing neurons -- which possess GHB receptors (11). This combined with GHB stimulation of tyrosine hydroxylase (18) -- the enzyme which converts the amino acid tyrosine to dopamine -- causes a buildup of dopamine, which, when finally released when the drug has worn off, is quite likely responsible for the refreshed, hyper-alert state one experiences upon waking from a GHB induced sleep.

There is animal data showing an INCREASED release of dopamine at high doses (19, 20). These are intravenous doses in the 400-700mg/kg range, which would around 50 grams for a 200 lb man. Rats metabolize GHB much faster than humans (21), but a conservative estimate would still put an equivalent dose at 15g or so (though I don't know if equivalent blood levels are even possible orally due to the afore mentioned transport saturation).