Gamma-Hydroxybutyrate

By: Par Deus

Background

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 market 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).

In the real world, reports of the subjective experience of doses this high are that it causes rapid onset of sleep -- which does not agree with the effects typically seen from increased dopamine release. As GHB has been found to effect several other systems, perhaps one of them is overriding the stimulant effect that would be expected to occur.

GHB has also been shown to increase mRNA for dopamine receptors D1 and D2 (22).
Serotonin

It is not known whether GHB influence serotonergic systems directly, or indirectly via dopamine or GABA, but it is known that pharmacological doses cause an increase in serotonin turnover, due to increased uptake of tryptophan (23). This action on serotonin probably at least partially accounts for its ability to stimulate growth hormone release, as co-administration with the serotonin receptor antagonist, metergoline, significantly reduced this increase (23). Metergoline has also been shown to lower GH levels in acromegaly patients (24). It seems quite possible that this system is involved in the sedating and antidepressant effects observed with GHB treatment.
Opioid

GHB has been found to increase brain levels of the endogenous opiods, dynorphin and beta-endorphin (25). The opiod receptor antagonist, nalaxone, significantly reduces the metabolic and pharmacological effects of GHB (including dopaminergic) -- leading some to suggest that the opiod system modulates its activity on dopamine (26). In addition, GHB induced EEG changes are mimicked by administration of morphine and beta-endorphin (26). As with serotonin, GHB induced sedating and antidepressant/euphoric effects could be be mediated by the opiod system.
GABA

Since its creation as a hopeful GABA analogue, it has been a common misconception that GHB exerts much of its action through binding with GABA receptors -- however its affinity is 1/1000th that of GABA, thus binding does not occur under physiological conditions (27). Nonetheless, GHB's effects are thought to be mediated, to some extent, by the GABAergic system. First, GHB is both a precursor to, and metabolite of, GABA. In addition, GHB receptors are found on GABAergic neurons, suggesting that it modulates it release (28). As GABA is the brain's primary inhibitory neurotransmitter, it is quite likely that the sedating properties of GHB are mediated by this system.
Benzodiazepine

Benzodiazepine action is mediated through the GABA(A) receptor (29), and since GHB metabolizes to GABA and also stimulates its release, it would be expected to activate this system. And, indeed, the anxiolytic effects of low dose GHB is antagonized by the benzodiazepine receptor antagonist flumazenil (29). Flumazenil also blunts the growth hormone response of GHB (30). Again, this system could be involved in the sedative/anxiolytic/antidepressant effects of GHB.


Acetylcholine

GHB has no effect on acetylcholine, though its precursor, gammabutyrolactone, has been shown to increase brain levels at high doses, suggesting that some amounts may escape hydrolysis and enter the CNS (31).
Norepinephrine

The majority of the literature suggests GHB has no effect on central norepinephrine levels, however Persson found increases in synthesis and utilization (32).


GHB and Bodybuilding

Direct Effects

Does GHB truly have a place in a bodybuilder's arsenal, or is the whole GH thing just an excuse to get twisted?? I believe it does have a place -- though, as I will show, many of its positive effects on body composition are more indirect than direct.

The first thing we should look at is its most commonly touted effect -- its stimulation of Growth Hormone release. It has, in fact, been found to raise growth hormone levels sharply in numerous studies (23, 30, 33). Some have claimed that these increases are only with intravenous administration or are the indirect result of GHB inducing sleep, as the onset of slow wave sleep is associated with increased GH levels. However, studies using oral delivery, have indeed shown increases in conscious subjects (23,30). With administration of 1.5 g of GHB, GH levels begin to rise almost immediately, reaching a peak of 3 times normal levels within 45 minutes, then rapidly falling back to within 25% of baseline by the 90 minute mark. Clearly, it does increase growth hormone.

Nonetheless, reports in both the literature and the real world on body composition, even with growth hormone injections, have been something less than spectacular. In the literature, GH has been shown to increase protein synthesis, however, it is not contractile protein (muscle) but rather visceral (organs) (34). Data on fat loss and muscle sparing with GH is a bit better. It has been shown to inhibit protein breakdown during dieting and fasting, leading to increased retention of muscle mass (35) . It is also known to be lipolytic (36). Real world reports of GH run along the same lines -- it not effective on its own for increasing muscle, but an increase it fat loss is definitely noticeable. But, again, this is with injections. Once a day use of GHB is not likely to mirror these effects. However, if someone would like to take 1.5 grams every 90 minutes for an extended period, please report back with your results.

At doses of 2.5 - 3.5 grams, GHB causes increased release of prolactin, doubling levels by the 45 minute mark, followed by a gradual return to baseline (33). Increases in prolactin have been shown to proportionally raise leptin levels, so this represents a possible positive effect on fat loss and muscle retention (37). Unfortunately, similar doses also raise cortisol levels, which has exactly the opposite effect of leptin on body composition (33). This antagonism might account for the lack of effects observed with GHB, and could perhaps be remedied with a drugs or supplement such as Cytadren or phosphatidylserine.

In addition to these, there are several other lesser known effects of GHB which have implications for bodybuilders. It increases gastric emptying (38), which is likely what causes the temporary increase in appetite observed with GHB use . Obviously, this is not particularly beneficial on a diet, though it might be on a mass phase. It also would likely make a good addition to a post-workout drink, as it would make glucose and amino acids available more quickly. Increased protein synthesis in brain and gastric tissues has been reported, whether this is accompanied by increased skeletal muscle synthesis is not known (39). Obese rats were found to have lower brain levels of GHB than their lean counterparts, despite identical diet, which suggests GHB as a potential signaler in the regulation of bodyweight (40) -- GHB metabolite GABA increases with fat feeding, which lends further support to this hypothesis. It has been shown to function as a powerful an antioxidant, blocking free-radical formation and lipid peroxidation (10). This could aid in recovery, as well as in overall health.

One of the more fascinating possibilities, comes from a study in rats (21) which showed a remarkable increase in body temperature after administration of very low doses. Following intraperitoneal injection of 5mg/kg, body temperature rose rapidly to 1.8 degrees Fahrenheit above normal at 15 minutes, and reached a peak of almost 2.2 degrees at the hour mark. It was still elevated by 2 degrees at the 75 minute mark, and dropping only quite gradually -- in humans, this would be a profound thermogenic effect (Clenbuterol might raise body temperature by 1 degree).

Considering GHB has a half-life of 5 minutes after injection (41), it would seem that GHB was not directly mediating these effects, but rather caused the release of something with a longer half-life. I am going to go out on a limb a bit and propose that the mediator might be norepinephrine -- which has a peripheral half-life of several hours -- as long as 12 in some tissues (42 ).

As mentioned above, GHB does not seem to effect central norepinephrine levels, however it HAS been shown to effect peripheral levels -- with high doses causing profound depletion of heart and brown fat norepinephrine levels (10). And, perhaps not coincidentally, in contrast to the increase in body temperature with the low dose, these high doses consistently cause a DECREASE in body temperature (21, 43). As we have seen, GHB has been conclusively shown to exert a biphasic effect on dopamine, so the possibility certainly exists with this compound.

I want to make clear that the above is very speculative, both as to why it occurred and to its having any relevancy toward humans. First, it is only one study. Second, it used intraperitoneal injections rather than oral administration. Third, the mechanisms were not looked at. And fourth, rats have much higher levels of brown fat, thus the thermogenic effects of an increase in norepinephrine would be exaggerated compared to humans.

Nonetheless, it is certainly enticing enough to give a try, with a couple of adjustments that take into account the use of human subjects (I would not expect the pharmacokinetics of oral and i.p. administration to be significantly different with this low of doses). GHB is metabolized by rats much faster than humans, thus a lower dose would be recommended. I would estimate 1-2mg/kg at most -- meaning around 100-200 mg for a 200 lb person -- this is a tiny dose -- one which would produce no subjective psychological effects and, in fact, probably no increase in brain GHB levels (21).
Indirect Effects

Perhaps the most important applications of GHB for bodybuilders do not involve direct effects on hormones or hormone systems, anabolic or otherwise. The first is that GHB is a MAGNIFICENT sleep aid. As mentioned previously, at sufficient doses, it rapidly and predictably causes the onset of a sedation which has been characterized as identical to human sleep (17), but with a greater portion of the time spent in stage IV and R.E.M. sleep (44), which are the most beneficial for recovery. I trust I do not need to mention the importance of sleep for a bodybuilder. I trust I also do not need to mention the detrimental effect on sleep of certain common components of the bodybuilding arsenal such as EC and androgens. I will mention that GHB makes waking up in the middle of the night for a protein shake much more feasible. And, again, I trust that I do not have to mention the effects of a 6-10 hour fast on the anabolic/catabolic state of the body.

The other application for GHB is as an alcohol substitute. In addition to containing 105 calories per drink -- more if you are having beer, alcohol lowers testosterone (45) and has a tendency to cause less than optimal workouts the following day. As dedicated as we might be to improving our bodies, most of us do not want to be a slave to this pursuit when it comes to socializing/partying.

GHB is a life saver here. Its biochemical, electrophysiological, and and pharmacological effects are quite similar to alcohol (46, 47). And, in fact, it has been successfully used clinically in the treatment of alcohol dependency, where it is thought to work through a substitution mechanism -- meaning it mimics alcohol's actions on the central nervous system (46). Both activate the dopamine system -- a characteristic commonly shared by drugs of abuse, they exhibit cross-tolerance -- meaning frequent consumption of one causes tolerance to the other, and both are preferentially (vs. water) self-administered by rats (16).

Subjectively, the effects are not identical. Some prefer a GHB intoxication to alcohol, some the vice versa. I find GHB to be more sedating and slightly less uninhibiting than alcohol, but I know others for whom the opposite is true. Without question, one feels considerably better the next day with GHB vs. alcohol.

A combination of the two can allow a a ****faced intoxication subjectively quite similar to that produced by alcohol, but with the consumption of only a few drinks, thus only a few hundred calories. It is typically strongly suggested that the two not be combined, with the argument that they have synergistic effects. However, based both on experience and the available scientific data, I tend to think the effects are mostly additive. Thus, I do not necessarily consider this activity contraindicated. The problem is that downing a "cap full" of GHB is like bonging a 6 pack, so for someone who is already quite intoxicated, this can put them over the edge.

Also, keep in mind that the metabolism of the two drugs are different -- GHB's in not saturable at typically utilized doses, thus it has a half-life (of probably 1 hr when taken orally), while alcohol's is quite saturable, thus only one drink is metabolized per hour -- meaning if one has 6g of GHB and 6 drinks at hour one (do not do this), at hour three, you would have only 1.5g of GHB in your system, but 4 drinks. As you can see, if one kept drinking, as the night went on, it would get a bit complicated, so if you do experiment with this combination, start with small amounts until you get a feel for it.
Safety

The overall safety of GHB is well-established in experimental and clinical use. Doses as high as 30 grams a day have been used in humans (48). And acute doses of as much as 1g/kg have been used in monkeys (10). Both without ill effects. It has no toxic effects on the liver, kidneys or other organs (48, 49). In narcolepsy studies, nightly use of 2.5 to 15 grams for several years resulted in no long-term adverse effects, nor did it result in addiction/dependence.

Side effects can include dizziness, nausea, and sometimes vomiting -- particularly on an empty stomach. It almost invariably causes drowsiness, so don't take it and then hop in the bathtub. Ataxia (loss of coordination) is more severe than with alcohol, so driving could be considered contraindicated.
Maximizing Recreational Value

With our new understanding of GHB pharmacology, coupled with a basic understanding of the mechanisms of other drugs, it is apparent that we could readily manipulate our subjective experience to suit our tastes. However, an in-depth analysis is beyond the scope of this article -- though, it will likely be the subject of a future one.
Availability

Scandalously, sale or possession of GHB is now illegal in all 50 states. It is currently a "Schedule I" drug -- meaning it has no legitimate medical uses, despite over thirty years of use in Europe in everything from drug addiction treatment to childbirth.

Both gammabutyrolactone (GBL) and 1,4 butanediol (BDO) are converted into GHB upon ingestion (both are naturally occurring precursors in the human brain), and were being sold as nutritional supplements for a while (RenewTrient, SomatoPro, Blue Nitro, etc.). However, their sale for human use has now been banned as well.

GHB can be readily synthesized from GBL, however, it has been designated as a "List 1" chemical, meaning a distributor must obtain a DEA # and report all sales, along with appropriate paperwork. Thus, it is, for all intents and purposes, unavailable as well.

If none of these can be readily obtained, what is the point of all this...???
The Good News

I have recently discovered a substance which, upon ingestion, is converted via lactonase catalysed hydrolysis (same mechanism as GBL) to a GHB analogue that was found to bind to the receptor with 15% GREATER affinity GHB itself. And, not only is it perfectly legal in all 50 states for sale, possession, and ingestion, but it also is Generally Regarded as Safe (G.R.A.S) by the FDA.

This product, Tranquili-G, is now available through Avant Labs. I am taking steps, as we speak, to obtain a use patent on it as a sleep aid, growth hormone releaser, anxiolytic, and good-time party drink. Until that time, I will be unable to reveal the actual name of the chemical, for obvious reasons.

[Tranquili-G is available now at Bodybuilding.com, click here!]



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Par Deus