A Review of the GHB Scientific Literature

A Review of the GHB Scientific Literature

GHB's history is unusual in that it was synthesized, (created in the laboratory) before it was discovered as a naturally-occurring molecule. This is the reverse of what typically occurs in science.

The scientific study of GHB began in the early 1960s in Paris. Dr. Henri-Marie Laborit, who was then Director of the Laboratoire d'Eutonologie, Boucic ut Hospital, was interested in the function of the natural amino acid, butyric acid, in cell metabolism and in the central nervous system. Butyric acid had caught Laborit's eye because it had a definite hypnotic (sleep-inducing) action when given to experimental animals. However, very little of the butyric acid seemed to be getting into the brain. Rather, nearly all of it was being oxidized and excreted in the urine.1

In an attempt to improve the ability of the butyric acid molecule to survive oxidation and thus increase its chances of getting into the brain, Laborit modified it slightly, adding an OH (hydroxyl) group to the fourth carbon atom. This change resulted in a molecule called 4- (or gamma-) hydroxybutyrate (GHB), which was a less attractive target for oxidation.

Laborit had another goal in creating the GHB molecule. He was interested in studying gamma aminobutyric acid (GABA), which has since been shown to be an important inhibitory neurotransmitter in the brain. The effects of GABA are difficult to study because when administered to experimental animals, it does not readily enter brain tissue, because it cannot cross the blood-brain barrier. Laborit hoped that GHB would function as a precursor to GABA. Thus, by giving GHB, he thought he might be able to increase brain levels of GABA.

What Laborit did not know at the time was that the GHB molecule he had created was actually a natural precursor to GABA, (as well as a metabolite of GABA) position previously indicated. Natural GHB was discovered in physiological amounts in the normal brain shortly after Laborit had created synthetic GHB. The natural and synthetic GHB molecules were identical in structure. (2)

What Happens to GHB in the Body?

The research on GHB's many metabolic roles has probably only just scratched the surface. Much of the GHB research was done 30 to 35 years ago, before many of the computerized, high-tech devices now used for biochemical analysis were available. There is undoubtedly much to be learned about how GHB works in the body at the molecular level.

In a 1969 review of GHB research, Vickers lamented the fact that the bulk of Laborit's work on GHB metabolism was unknown to most English-speaking scientists, because they did not read the French language. "There is no doubt," he wrote, "that Laborit has been able to assemble a great deal of experimental pharmacological evidence,... and if it were not for the translation difficulty, more interest would certainly exist in this matter among anesthetists in the English-speaking countries." (3)

Metabolism of GHB

Intravenously administered GHB passes very rapidly from the bloodstream across the blood-brain barrier and into the brain. A dose that produces anesthesia in dogs and cats was found to raise the level of GHB in the brain to 100 times its natural level. The GHB does not stick around very long, however, as it passes rapidly back into the bloodstream via the cerebrospinal fluid. This explains the rather short-term sleep-inducing effects of GHB.

As it circulates throughout the body, GHB is metabolized into carbon dioxide (CO2) (80 to 90%) and water (10 to 20%). The CO2 is excreted via the lungs, and the water passes out through the kidneys as urine. As with most natural substances, GHB metabolism is a very "clean" process. No psychoactive or toxic metabolites are formed to cause unpleasant side effects, or worse. (3, 4)

Laborit initially thought that once GHB got into the brain, it would increase levels of GABA. However, he found that the picture is a little more complicated. Certainly, GHB is capable of forming GABA. (5, 6) But when labeled GHB is injected into mice, GABA levels in the brain do not rise, even though labeled GHB is found in the brain.7 On the other hand, when labeled GABA is injected into cerebrospinal fluid, GHB levels increase, suggesting that GABA is serving as a precursor to GHB. (8)

Although no such direct evidence is available from humans, one study did find that people who are in a deep GHB-induced sleep did not have elevated levels of GABA. This suggests that whatever GHB is doing to produce its profound psychoactive effects, it seems to be doing it by some mechanism of its own, without elevating GABA levels. (3)

GHB works much better on an empty stomach. Laborit and his colleagues gave the same dose of GHB via gastric intubation, (a tube into the stomach) to two groups of animals: Fed animals that had just finished a meal, and Fasted animals that had not eaten in 36 hours. The Fed animals slept only briefly, while the Fasted animals went into a long, deep sleep. (1)

It is known is that GHB activates a metabolic process known as the pentose pathway, which plays an important role in the synthesis of protein in the body.9 In addition, GHB appears to have a "protein-sparing" effect. Without getting into the complexities of the Krebs Cycle, the central energy-producing mechanism of the body, suffice it to say that GHB helps reduce the rate at which the body breaks down its own proteins, including muscle tissue. (1)

Growth Hormone Release

A very significant metabolic effect of GHB is its ability to cause the release of growth hormone (GH) from the pituitary gland. This was demonstrated in a Japanese study in which six healthy male volunteers received intravenous injections of 2.5 g of GHB.10 Significant increases in plasma GH were observed at 30, 45, 60, and 90 minutes later.

Growth hormone, of course, has been the subject of intense research over the last decade because of its demonstrated anti-aging capabilities, including building bone and muscle, reducing fat, and making skin thicker and more flexible. When GHB was officially condemned by the FDA in 1990, its primary users were body builders and weight lifters, who were buying GHB in health food stores and taking a couple of grams before bed every night to enhance their natural growth hormone release in hope of building bigger muscles without steroids.

It was its association with large-muscled men and women that got GHB tagged with the "steroid substitute" label by ignorant media and police/regulatory authorities, who wouldn't know Growth Hormone (GH) from General Hospital (GH). Their "scientific" reasoning seems to go something like this: "Because steroids help build muscles and are dangerous drugs (they're really not, when properly used--eds.), therefore, anything that helps build muscles must be a dangerous drug."

But by removing this safe and effective option to naturally stimulate the release of growth hormone by using GHB, the FDA/DEA has probably had the paradoxical effect of increasing the use of steroids. Anabolic steroids remain even more readily available than "street GHB" to any serious athlete who wants them, despite their official prohibition. Such are the fruits of regulation!

Central Nervous System Effects of GHB

GHB has a variety of complex effects on brain function, only a few of which have been well-elucidated.

Dopaminergic Effects

Among the best studied is its effect on the neurotransmitter dopamine (DA). Early on it was discovered that IV administration of GHB (1-2 g/kg) to rats induces sleep and results in a doubling of DA levels after about 1 hour.11, 12 Upon awakening, the rats' DA levels return to normal. The increases in DA were most pronounced in the region of the brain known as the caudate nucleus. More recently, it has been found that subanesthetic doses stimulate the firing rate of DA neurons in the substantia nigra region of the brain, whereas high doses suppress these neurons.13 L-DOPA, a precursor to DA, which also increases DA levels, has been shown to potentiate GHB's hypnotic effects.14 Parkinson's disease is a debilitating and cognitive-impairing illness that is in large part due to a reduction of DA production by the substantia nigra. Several FDA-sanctioned clinical studies have been conducted to evaluate the potential of GHB to restore the DA-producing functions of the substantia nigra, and thereby alleviate Parkinson's disease.

Serotonergic Effects

High doses of GHB also increase brain levels of the neurotransmitter serotonin, (4) although these increases are smaller than those seen with DA.12 Since serotonin is be involved in the induction of sleep, it is thought that this mechanism may contribute to GHB's ability to induce sleep. (15)

Antidepressive Effects

It is this same mechanism, that undoubtedly contributes to GHB's profound anti-depressive effects. Among the "hottest" of new pharmacological agents are the serotonin-reuptake inhibitors like Prozac ®, Paxil ®, and Zoloft, all of which act to increase levels of serotonin in the brain by blocking the uptake of serotonin by receptor sites in brain neurons. It also may be this effect of GHB which is the reason for its persecution.

Cholinergic Effects

GHB also increases the synthesis of the neurotransmitter acetylcholine (ACh). Deficiency of acetylcholine has been proposed as one of the primary causes of Alzheimer's disease. ACh is also believed to be involved in the production of rapid-eye movement (REM) sleep. When rats are deprived of REM sleep, their brain levels of ACh decrease, but during REM sleep, they increase. Although this research is preliminary, it suggests a possible mechanism by which GHB may enhance REM sleep. (15) It also may provide a rationale for testing the effectiveness of GHB on Alzheimer's disease.

EEG Effects

The effects of GHB on brain function as measured by the electroencephalogram (EEG) are confusing, contradictory, poorly understood, and, not surprisingly, controversial. Some evidence suggests that GHB may promote seizure activity in the brain, while other evidence suggests that GHB prevents seizures.

Studies in cats, (16) rats, (17) rabbits, (18) and monkeys, (19) have found that anesthetic doses of GHB may result in EEG recordings that resemble non-convulsive epilepsy. In one cat study, though, tactile stimulation following GHB administration was associated with convulsions. (20) Taken together, these data have led some researchers to theorize that GHB might play a role in the etiology of absence seizures (petit mal epilepsy) in humans21 and/or that GHB-induced seizures in animals might be a model for human petit mal epilepsy. (22, 23)

On the other hand, several animal studies have shown that GHB has anti-convulsive properties. In one of the first experiments ever done with GHB, for example, the results showed that in rats, it prevented convulsions caused by the drugs strychnine, cardiazol, isoniazide, and ammonium chloride. (24)

In a 1994 review of GHB research, Dr. Christopher D. Cash of the Centre de Neurochemie in Strasbourg, France, argued that, while the EEG and behavioral aspects of absence epilepsy in the rat resemble those observed in human petit mal epilepsy--especially in children--the rat model may have little or nothing to do with what happens in the human brain. "The petit mal epileptic symptoms induced by peripheral administration of GHB [in animals are] not applicable to humans," Cash wrote. (4)

To give you an idea just how difficult it is to interpret the results of these types of experiments and then extrapolate them to humans, consider a recent study by Brankack, and colleagues, from the University of Kuopio, in Finland. (25) These researchers recorded the frontal cortical EEG from freely moving rats with a genetic form of absence epilepsy. They knew that systemically administered (eg, oral or IV) GHB can induce a "rhythmic spike and wave" pattern of brain waves that resembles petit mal epilepsy. They wanted to see what would happen to these waves when they put GHB directly into discreet regions of the brain (intracerebral administration) of animals that were genetically predisposed petit mal seizures.

Before they applied the GHB to the rats' brain, the researchers recorded a baseline EEG. They noted that while most of the animals were exhibiting the characteristic spontaneous high voltage spindles (HVS group), another group did not have these spindles (no-HVS group). When a tiny amount of GHB was placed directly into their cerebral cortex, animals in both groups reacted similarly with an EEG pattern that featured epileptogenic spikes and discharges accompanied by occasional muscle jerks, convulsions, and seizures. Oddly, though, GHB did not cause the HVS or spike-and-wave pattern characteristic of petit mal epilepsy that occurs after systemic administration. Even stranger, in the animals with spontaneous HVS activity, GHB actually suppressed the abnormal EEG activity. The Finnish researchers concluded that in these animals, genetic petit mal epilepsy and the epileptic discharges induced by GHB had different origins and different mechanisms of action.

Human studies don't clarify the picture much, either. Oral administration of a dose of GHB has been reported to be an "excellent hypnotic with few side effects" that induces sleep that is "indistinguishable from natural sleep" as determined by both behavioral criteria and EEG analysis. (26, 27) No EEG abnormalities were observed in these studies.

In his 1969 review of GHB research, Vickers3 acknowledges that people in a deep GHB-induced sleep, frequently exhibit "random clonic movements of the limbs or face." However, these movements are "not accompanied by an epileptic discharge" (Italics added). It seems likely these are the types of movements that EMS personnel have identified as "seizures" in some people who have been found in GHB-induced "comas."

Does GHB cause seizures? Clearly, there is no good answer to that question, yet. It is interesting to note that in those cases in which seizures were reported by Chin, Kreutzer, and Dyer, in their oft-quoted review of "acute poisoning" from GHB, it did not appear to be GHB, by itself, that was causing the problem: (28)

Case 1 was a 39-year-old woman who developed a range of symptoms, including "uncontrollable twitching" in her arms and legs that may have lasted for 45 minutes, as well as intense drowsiness, confusion, difficulty breathing, and speech problems. She had been taking low doses (about « teaspoon daily) of GHB for about a month with no incidents. Then, one day she took three to four such doses over the course of the day. It was the last dose, taken at bedtime that apparently triggered her symptoms. When she was brought to the emergency room, her pulse, blood pressure, and respiration were normal. Except for occasional leg twitches and a tendency to alternately wake up and fall back to sleep, she appeared normal.

In addition to GHB, the woman had also been taking ibuprofen and the combination pain killer (Vicodin ) which contains hydrocodone bitartrate and acetaminophen. Hydrocodone is a narcotic drug related to codeine. Like other opioid (opium-like) drugs, hydrocodone is a powerful central nervous system (CNS) depressant. Although the woman admitted to being an alcoholic and illicit drug user, Chin, et al, report that she denied ingesting alcohol or using illicit drugs at the same time as GHB. Apparently, no tests were done at the time to confirm this, however.

Combining GHB with any CNS depressant, including opioids, (e.g., codeine, morphine, heroin, Demerol, and others), benzodiazepines (e.g., Valium, Xanax, Halcyon, and others) and alcohol, is recognized as being potentially dangerous because of an apparent synergy of CNS depressive effects that may occur when two or more such drugs are taken together. It is probably just as dangerous to mix Xanax and alcohol, or Halcyon and morphine. Nevertheless, Chin, et al, reported, the woman "experienced a full recovery with no lasting symptoms." (28)

Case 3 was a 28-year-old woman who reportedly took GHB at a nightclub along with "some mixed drinks." She soon experienced "uncontrollable shaking, followed by seizure and then coma. A witness stated that she was banging her head on a wall before becoming unconscious."(28)

When she arrived at the ER, her respiratory effort was described as "good" but with "long apneic periods." Despite this, she was put on mechanical ventilation. Her EEG was normal. Although her toxicologic screen was negative, she had apparently been doing some serious drinking when she took GHB. Her blood alcohol level was found to be 80 mg/dL, [WHICH IS MORE THAN TWICE THE FATAL DOSE!] Nevertheless, Chin et al reported, "No adverse effects have been observed since she stopped taking GHB." (28)

Case 4 was a 47-year-old man who had been taking about 1 teaspoon of GHB "every once in a while" for about 2 months without apparent incident. Then one day he took 1 teaspoon every 2 hours for a total dose of 4 teaspoons. Shortly after the last dose, he was found "immobile and having difficulty breathing." Paramedics reported "uncontrollable shaking" which they described as a "seizure." In the ER, he was found to be "initially lethargic but later became awake and alert." His physical examination, ECG (electrocardiogram), CAT scan, and blood tests were normal, and he was released after 3 hours. Two weeks later, a follow-up neurologic exam and EEG were normal.

It is questionable whether this patient actually suffered seizures. It is known, though, that he may have been predisposed to seizures, because he reported that 20 years earlier he "may have had a seizure" after drinking excessively and swallowing a "few pills." Nevertheless, Chin, et al, conceded that "The patient has had no symptoms since discontinuing GHB use." (28)

If GHB does increase the risk of seizures, it is certainly not clear from these reports. However, given the uncertainty that surrounds the potential seizure risk, and until further definitive knowledge is obtained, prudence would dictate that:

  1. GHB should not be combined with any other CNS depressant.
  2. Those with a personal or family history of epilepsy or other seizure disorder should probably avoid using GHB.

Cardiovascular Effects

GHB's effects on the function of the heart and blood vessels tend to be beneficial, overall. Laborit observed that injection of 2 to 4 gm of GHB had no effect on blood pressure except in certain rare instances. (1) In animals, a slowing of the heart beat (bradycardia) has been observed. While heart rate may decrease, Laborit noted, pulse pressure "increases substantially," so that the net effect is little or no reduction in cardiac output.

GHB administration does not affect the autonomic nervous system's control of cardiovascular function. This means that, even though GHB may slow the baseline heart rate, the heart and blood vessels remain responsive to stimulation, such as those that might occur during surgery. (3) This situation is similar to that which occurs with regard to respiration (see below).

GHB's major cardiovascular benefit may lie in its ability to protect the body against low tissue oxygen levels and shock. Studies have demonstrated a clinically important protective action of GHB against various types of cardiac arrhythmia and states of anoxia (low oxygen levels). "In the animal," wrote Laborit, "we have observed a strong hepatic and renal vasodilating action which is particularly marked during hemorrhage. This property explains in part its anti-shock activity, clearly observed in the animal and frequently seen in man."(1)

Cash suggested that a low dose of GHB in combination with other anesthetic agents could be beneficial in human surgery where there is a danger of damage from ischemia (loss of blood flow due to an obstructed or ruptured artery). (4) Higher doses of GHB have been shown to protect the heart from injury that occurs due to the accumulation of fat droplets in heart muscle fibers following cerebral ischemia. (29)

Another animal study also demonstrated that GHB can prevent complications and improve the chances of survival following severe loss of blood due to hemorrhage. In hamsters, hemorrhage was induced to the point that they had lost 37% of their blood volume. Blood was then restored. In non-treated animals, blood flow in the intestines came to a standstill two hours later ("complete intestinal microvascular stasis"). In animals treated with GHB, however, microvascular stasis was completely prevented. In a second group of animals (rats), when GHB was given after hemorrhage, blood pressure and cardiac output rapidly returned to pre-hemorrhage levels even though the shed blood was not returned. (30) This is a remarkable result that may have extremely important implications for the treatment of shock due to blood loss.

As a cardiovascular bonus, in these cholesterol-conscious times, GHB has been shown to reduce blood cholesterol levels. In a study of 100 patients in Poland, GHB administration was associated with a constant drop in blood cholesterol levels. (31)

Respiratory Effects

As noted, much has been made of the decrease in respiratory rate associated with high doses of GHB. When people are brought to the ER in deep GHB-induced sleep (misdiagnosed as coma), they are often inappropriately placed on mechanical ventilation, because the ER doctor assumes they are about to go into respiratory arrest (despite normal levels of oxygen in the blood).

Laborit found that while hypnotic (sleep-inducing) doses of GHB reduce the rate of breathing, at the same time they increase the amplitude (depth) of each breath. As a result, wrote Laborit, "Both in animals and man, the sleep induced by 4-hydroxybutyrate is not accompanied by a decrease in O2 consumption."

High doses of GHB were found to induce a Cheyne-Stokes rhythm (waxing and waning of the depth of respiration, with regular periods of apnea [arrested breathing]) which is often seen in real coma. While ER physicians and EMS personnel who are not knowledgeable about GHB may think that people in this state are in a coma and require mechanical ventilation, Laborit stated that, even at high doses, GHB does not cause people to stop breathing. The reason is that the respiratory center in the brain remains sensitive to high levels of carbon dioxide (CO2) which build up as respiration slows and always trigger a new breath.

In addition, doses that induce unconsciousness do not abolish pharyngeal and laryngeal reflexes. As Vickers pointed out, "In this state, respiratory obstruction does not occur, and indeed, deliberate attempts to produce it result in active movements by the subject to preserve the airway." With high doses, however, some depression of these reflexes does occur. Laborit observed, however, that this effect can be beneficial, because it makes it easier to anesthetize a still-breathing patient by facilitating insertion of a ventilator tube into the airway without a need to paralyze the larynx and pharynx with curare or other drugs. (15)

Laborit hypothesized that the decreased rate of breathing associated with high doses of GHB was due to a decrease in the sensitivity of pulmonary stretch receptors rather than a central depression of respiratory centers in the brain, as is the case with virtually all other hypnotic, and anesthetic drugs.1 "One of the most striking features of gammahydroxybutyric acid narcosis [sleep]," wrote Vickers, reviewing the data on GHB, is "the brisk responsiveness of the brainstem centers and of the autonomic centers to a noxious stimulus... In contrast to barbiturates, there is little or no depression of the reticular-activating system." (3)

GHB Toxicity and Adverse Effects

Chin, et al, erroneously considered GHB to have "documented clinical actions consistent with severe neurotoxicity." (28) Their conclusion, based on a second-analysis of cases reported by medical officials who knew nothing about GHB, stands in stark contrast to the 30 years of research by Laborit and other GHB experts. In fact, it appears that GHB is one of the least toxic psychoactive substances known.

Laborit found that the LD50 (the dose that kills 50% of the animals) in rats was 1.7 gm/kg, and the LD100 was 2 gm/kg. The rats died of respiratory depression. If they were placed on artificial ventilation, though, they could tolerate as much as 7 gm/kg! In order to test for long-term toxicity, Laborit gave a group of rats 1/10 of the LD50 daily. After 70 days, the GHB-treated rats were no different in terms of weight, bone marrow, or liver or kidney function from untreated controls. (1)

Of course, similar studies cannot be performed on humans. But, as noted, extrapolation of rat data to humans yields an LD50 of 116 gm for an average human. This contrasts with therapeutic doses that typically range from 2 to 8 gm. [There has been one reported case of a person who took daily doses of 15 gm with no adverse effects. (32) There are numerous reports of patients who took 30 grams per day for months on end without adverse effects. Also, see the French package insert for the human LD50 of 4.28 gm per kg!! (= about 300 gm as an LD50)]

Laborit observed that GHB was generally well-tolerated, causing no neurological, physiological, or EEG abnormalities. "In the Emergency and Intensive Care Department of the Fernand Vidal Hospital in Paris," he wrote, "no patient has ever tried to commit suicide when treated with GHB alone." (15)

Side effects known to occur in conjunction with GHB use, according to Laborit, include "variously located myoclonias" (the muscle twitching often misidentified as seizure activity), nausea (most often in alcoholics or people with liver disorders), mild hypokalemia (loss of serum potassium), and, of course, "respiratory intermittence," which may be "very intense at the time of sleep induction, but it gradually subsides or disappears completely." (15)

Despite their characterization of GHB activity as "severe neurotoxicity," it is worth re-emphasizing that Chin and colleagues concluded their paper by stating, "The prognosis for those who experience GHB poisoning is quite good. There are no documented or anecdotal reports of long-term adverse effects or fatalities, nor any evidence for physiologic addiction." (28)

Even the US government's Centers for Disease Control and Prevention (CDC), which has issued at least two warnings regarding the dangers of illegal GHB use, acknowledges GHB's basic lack of toxicity. In a 1991 letter published in the Journal of the American Medical Association, the CDC scientists wrote, "The GHB was ingested for questionable purposes in uncontrolled dosages without physician supervision, sometimes in conjunction with other drugs that affect the central nervous system. The reported toxic effects were what would be expected from GHB on a dose-response basis.33 (Italics added for emphasis.) In other words, the "toxicity" problems related to GHB use that have been reported by the CDC, FDA, and DEA, have nothing to do with GHB, per se. Rather, when real, they have probably been caused by the use of "street GHB" of unknown purity and potency and by lack of information about GHB's actual effects. The basis of both of these problems, of course, can be traced directly to the criminalization of GHB.

References

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