GHB effect on brain.

GHB, Gamma OH effects on the brain

The action of GHB has yet to be fully elucidated. GHB clearly has at least two sites of action, stimulating the newly characterized and aptly named “GHB receptor” as well as the GABAB. GHB, if it is indeed a neurotransmitter, will normally only reach concentrations high enough to act at the GHB receptor, as it has relatively weak affinity for the GABAB. However, during recreational usage, GHB can reach very high concentrations in the brain, relative to basal levels, and can act at the GABAB receptor as well.[7] GHB’s action at the GABAB is probably responsible for its sedative effects. GHB-mediated GABAB receptor stimulation inhibits dopamine release as well as causes the release of natural sedative neurosteroids (like other GABAB agonists e.g. Baclofen). In animals GHB’s sedative effects can be stopped by GABAB antagonists (blockers).

The relevance of the GHB receptor in the behavioural effects induced by GHB is more controversial. It seems hard to believe that the GHB receptor is not important when it is densely expressed in many areas of the brain, including the cortex, as well as it being the high affinity site of GHB action. There has only been limited research into the GHB receptor. However, evidence shows that it causes the release of glutamate, which is a stimulatory neurotransmitter. Drugs which selectively activate the GHB receptor but not the GABAB receptor, such as trans-4-hydroxycrotonic acid and 4-(p-chlorobenzyl)-GHB, cause convulsions in animals and do not produce GHB appropriate responding.

It does not seem that activation of the GHB receptor alone explains GHB’s addictive properties; research using selective GABAB agonists and analogues of GHB which are selective agonists for the GHB receptor but do not activate GABAB, suggest that both the GHB receptor and the GABAB receptor are important for dopamine release and consequently abuse liability. Compounds which activate only one of the receptors but not both, do not seem to induce acute dopamine release or produce the abuse potential typical of GHB itself.

One can propose a scheme where high doses of GHB are sedative through its action at the GABAB receptor, while a lower dose is stimulatory via activation of GHB receptors. This may explain the otherwise paradoxical mix of sedative and stimulatory properties typical of GHB intoxication, as well as the so-called “rebound” effect, experienced by individuals using GHB as a sleeping agent, where they awake suddenly after several hours of GHB-induced deep sleep. That is to say, that over time, the concentration of GHB in the system decreases (because of metabolism) below a threshold for stimulating GABAB receptor function, and simply stimulates the GHB receptor, leading to wakefulness.

Recently, similar molecules to GHB, such as 4-hydroxy-4-methylpentanoic acid have been synthesised and tested on animals, in order to gain a better understanding of GHB’s mode of action[4]. Analogues of GHB such as 3-methyl-GHB, 4-methyl-GHB and 4-phenyl-GHB have been shown to produce similar effects to GHB in some animal studies, but these compounds are even less well researched than GHB itself. Of these analogues, only 4-methyl-GHB (gamma-hydroxyvaleric acid, GHV) and its prodrug form gamma-valerolactone (GVL) have been reported as drugs of abuse in humans, and on the available evidence seem to be less potent but more toxic than GHB, with a particular tendency to cause nausea and vomiting.

Other prodrug ester forms of GHB have also rarely been encountered by law enforcement, including 1,4-diacetoxybutane, methyl-4-acetoxybutanoate and ethyl-4-acetoxybutanoate, but these are generally covered by analogue laws in jurisdictions where GHB is illegal and little is known about them beyond their presumably delayed onset and longer duration of action. The intermediate compound 4-hydroxybutaldehyde is also a prodrug for GHB, however as with all aldehydes this compound is caustic and is strong-smelling and foul tasting; actual use of this compound as an intoxicant is likely to be unpleasant and result in severe nausea and vomiting.

GHB is also metabolised into GABA by the enzyme GABA transaminase. This is only a minor route of metabolism and its significance to the pharmacological action of GHB is not known, although there is likely to be some increase in GABA levels when GHB is consumed in quantity.


Also note that both of the metabolic breakdown pathways shown for GHB can run in either direction depending on the concentrations of the substances involved, so the body can make its own GHB either from GABA or from succinic semialdehyde. Under normal physiological conditions the concentration of GHB in the body is rather low, and the pathways would run in the reverse direction to what is shown here to produce endogenous GHB. However, when GHB is consumed for medical or recreational purposes its concentration in the body is much higher than normal, which changes the enzyme kinetics so that these pathways operate to metabolise GHB rather than producing it.

Leave a Reply

Your email address will not be published. Required fields are marked *