GHB

Two Sites, Three Orders of Magnitude Apart

GHB is pharmacologically strange: it is an endogenous molecule — synthesised in neurons from GABA and present in brain at low micromolar concentrations — that acts on two distinct classes of site with affinities separated by roughly a thousand-fold. At the physiological, nanomolar–micromolar concentrations reached by endogenous GHB, it engages a high-affinity "GHB binding site" (K_i ≈ 4 µM by [³H]NCS-382 displacement). At the millimolar concentrations reached only by an exogenous recreational or therapeutic dose, it becomes a weak agonist of the metabotropic GABA_B receptor (EC₅₀ ≈ 5 mM). The GABA_B action is what sedates, anaesthetises, and — at a slightly higher dose — stops your breathing. The affinity gap is the danger: because the sedating target is only recruited across a narrow, steep band of the concentration curve, small changes in dose produce enormous changes in effect.

The clinically decisive fact sits in the numbers above. A GABA_B agonist with an EC₅₀ in the millimolar range only produces meaningful receptor occupancy when brain concentration climbs into that same range — and because GHB's own metabolism and absorption saturate (see §02), the brain concentration does not rise smoothly with dose. A gram that lands you pleasantly disinhibited and a gram-and-a-half that lands you unconscious sit on the near-vertical portion of the same mass-action curve.

Saturable Everything — Why the Curve Is Vertical

GHB's pharmacokinetics are nonlinear (capacity-limited / Michaelis–Menten) at every step, and this — more than any receptor property — is why the drug is so unforgiving. Oral absorption is saturable, first-pass metabolism is saturable, and renal reabsorption is saturable. The practical consequence is that exposure rises faster than dose: as each capacity fills, a proportionally larger fraction of the next increment reaches the brain. The apparent half-life lengthens with dose (from ~20 min at low dose toward ~50–60 min at intoxicating dose) because clearance enzymes are running flat-out. There is no linear "twice the dose, twice the level" intuition to fall back on.

Metabolic fate: GHB is not excreted; it is burned. It is oxidised to succinic semialdehyde (chiefly by cytosolic GHB dehydrogenase and mitochondrial SSA reductase running in reverse), then by SSADH to succinate, which enters the TCA (Krebs) cycle and is oxidised to CO₂ and water. Because clearance is metabolic and enzyme-limited, alcohol — which competes for the same NAD⁺-dependent dehydrogenase capacity — both slows GHB elimination and adds its own depression.

Prodrugs make it worse. GBL (γ-butyrolactone, an industrial solvent) is rapidly hydrolysed to GHB by serum lactonases and is more bioavailable and faster-onset than GHB itself; 1,4-butanediol (1,4-BD) is oxidised to GHB by alcohol dehydrogenase and aldehyde dehydrogenase — the very enzymes ethanol competes for, so co-ingested alcohol delays and then unpredictably prolongs the conversion. Gram-for-gram these prodrugs are more potent than GHB, so a dose calibrated for one is an overdose of another. In SSADH deficiency (a rare inborn error), GHB accumulates endogenously — the human proof that this molecule is a native metabolite whose disposal is a bottleneck.

Licensed Medicine, Steep Recreational Curve, Brutal Withdrawal

The same GABA_B-driven inhibition that makes GHB dangerous makes it a genuinely effective medicine at controlled, divided doses — and a fast, physically dependence-forming drug when taken around the clock. GHB compresses the full arc of a sedative-hypnotic into a narrow dose window and a short time course, which is exactly what turns a pleasant effect into an emergency.

The through-line of GHB is narrowness: a narrow dose window, a narrow time course, a narrow affinity band that separates pleasant from lethal. It is a real endogenous signalling molecule and a real medicine — and, taken recreationally without precise measurement, one of the least forgiving drugs a person can put in their body.