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          Cognitive Nutrition Update: GHB (gamma-hydroxybutyrate)
                      by John Morgenthaler and Dan Joy
        Published in the Ceri Newsletter Vol. 3 No. 6 September 1994
          Transcribed to the electronic media by Swedish Infomania

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        GHB, or gamma-hydroxybutyrate, is a normal component of mammalian
metabolism. It is found naturally in every cell in the human body and is
most properly considered a nutrient. In the brain, the highest amounts are
found in the hypothalamus and basal ganglia [Gallimberti,1989). GHB is
found in greater concentrations in kidney, heart, skeletal muscles, and
brown fat tissues [Chin and Kreutzer,1992]. It is believed to be a
neurotransmitter, although the jury is still out as to whether it exhibits
all of the properties required for fulfillment of this funetion (Chin and
Kreutzer, 1992]. It is both a metabolite and precursor of the inhibitory
neurotransmitter GABA (gamma-aminobutyric acid, or gamma-aminobutyrate),
another nutrient to which it bears a close structural relationship. GHB,
however, does not act directly on GABA receptor sites [Chin and
Kreutzer,1992].
        GHB was first synthesized about thirty years ago by Dr. H. Laborit,
a French researcher interested in exploring the effects of GABA in the
brain. Because little or no GABA crosses the blood-brain barrier, Laborit
synthesized GHB, which substitutes a hydroxy group for an amino group (see
Figure 1). This difference allows GHB to cross the blood brain barrier
where some of it is metabolized into GABA (Vickers,1969].
        As it turned out, Laborit found that GHB exhibited a range of
effects beyond those expected from GABA. Over the intervening years,
numerous researehers have extensively studied GHB's effects. It is has come
to be used in Europe as a general anesthetic, a treatment for insomnia and
narcolepsy (a daytime sleeping disorder), an aid to childbirth (increasing
strength of contractions, decreasing pain, and inereasing dilation of the
cervix), a treatment for alcoholism and alcohol withdrawal syndrome, and
for many other uses.
        During the 1980s, GHB was widely available over-the-counter in
health-food stores, purchased largely by body-builders for its ability to
stimulate growth hormone release which aids in fat reduction and muscle
building. In the last few years it has been gaining popularity as a
"recreational" drug offering a pleasant, alcohnl-like, hangover-free "high"
with potent prosexual effects.
        For the thirty years prior to 1990, the scientific papers on GHB
were unanimous in reporting numerous beneficial physiological effects and
the absence of long-term negative effects. In 1964, Laborit listed "very
low toxicity" as one of the "principle elements" of the compound's
pharmacology. In a 1969 report on GHB's anesthetic uses, Vickers referred
to GHB as "a truly nontoxic hypnotic" and repeatedly emphasized its "lack
of toxicity." Vickers cited evidence that GHB demonstrates "no toxic
effects on the liver and kidney." In 1972 Laborit described the body's
metabolism of GHB and stressed "the absence of any need of detoxification
by the organism."
        As recently as 1989, this scientific consensus on GHB's benign
nature remained unchanged. Gallimberti's study from that year on its uses
in treating alcohol withdrawal in humans notes that "GHB's action ...seems
to be without serious side effects." His almost off-hand reference to the
"safety of GHB" shows how well-established this property of the nutrient
had become.
        Then, on November 8th,1990, the FDA banned the over-the-countersale
of GHB in the United States. In 1991, two scientists from the California
Department of Health Services wrote a report on ten "poisonings" associated
with GHB. The authors, Chin and Kreutzer, warned of GHB's "tremendous
potential for abuse." They observed that "all interviewed patients reported
a pleasurable sensation or a `high.' Several of them...continued taking
[GHB] because it made them `feel good'." Apparently, the authors construed
feeling good in and of itself as a potential threat to public health.
Despite such dire language, the report acknowledged that "there are no
documented reports of long-term [detrimental] effects. Nor is there any
evidence for physiologic addiction."
        Of the ten "poisonings" reported, four involved "unknown doses,"
four featured the "coingestion" of other drugs, (usually alcohol), one
involved unmedicated epilepsy, and another a history of grand mal seizures.
Since alcohol and other central nervous system (CNS) depressants are not
recommended with GHB, and because GHB is contraindicated for epileptics,
such cases are not unexpected. Chin and Kreutzer acknowledge that the "more
severe reactions...generally occurred when patients took an unmeasured
dose, a particularly large dose, or several doses within a short period of
time." Such problems are easily avoided by following the directions for
GHB's use.
        Although the specific clinical details of these ten cases are too
lengthy to go into here, one point needs addressing - the use of the terms
"coma" and "seizures" in deseriptions of these cases. At a sufficiently
high dose, GHB can cause clonus, a rapid, rhythmic contraction and
relaxation of muscles which would be better described as muscle spasm or
uncontrollable twitching than a seizure. GHB can also cause intense
drowsiness, abrupt sedation, and deep sleep which is probably better
deseribed as unarrousability or deep sedation than coma. Vickers [1969)
deseribed it as a "nontoxic coma," which blunts some of the inflammatory
connotations of the term coma.
        Regardless of their alarmist tone, the authors confirm that "there
have not been any reported deaths" and that "if product use is
discontinued, full recovery with no long-term side effects is universal."
They coneluded that "the prognosis for people who experience GHB poisoning
is quite good."
        The degree to which the pleasant state of GHB euphoria may be
psychologically addicting may not be fully appreciated. Anybody with known
attraction or addiction to tranquilizers or alcohol should pay special heed
to this possibility. In the few cases of GHB abuse that we have
investigated, there were pre-existing use/abuse patterns with alcohol
and/or tranquilizers. Ironically, it was GHB's lack of toxicity that led to
increased frequency of use (numerous times per day) that characterized what
can only be called classic cases of psychological addiction. Without the
dehydration and CNS irritation of alcohol, or the side effects of
tranquilizers, there was no incentive to moderate or curtail GHB use.
Fortunately, few people seem to have such overwhelming attraction to the
GHB state. Even Chin and Kreutzer minimize GHB's abuse potential by
stating, "No investigator [has] reported any long-term adverse effects,
addictive or dependent qualities associated with discontinued usage of the
drug."
        It seems likely, then, that at least some of the motives behind the
1990 FDA ban of GHB were other than those of public safety. Such a ban
constitutes the only means of Federal control of a substance neither
scheduled by the DEA nor approved by the FDA as a drug. In the absence ofa
genuine public-health concern, such control might have been motivated by a
desire to protect the pharmaceutical industry (with which the FDA is
closely intertwined) from competition from a safer, more effective and less
expensive alternative to sleeping pills. Is it a coincidence that the FDA
has also banned L-tryptophan, another nutrient that functions as a safe and
effective sleep aid?
        As with most substances, unpleasant and possibly dangerous side
effects can be associated with excessive doses of GHB. A dose usually only
about twice the amount required for relaxation or a prosexual effect can,
as one user put it, "knock you out but fast." In this respect, GHB is
probably comparable to alcohol: if you drink twice as much as you normally
would, you probably wouldn't function very well. Despite its general safety
and lack of toxicity, the safe use of GHB requires information,
preparation, caution, and good judgment. In other words, follow the usage
guidelines!
        Most users find that GHB induces a pleasant state of relaxation and
tranyuility. Frequent effects are placidity, sensuality, mild euphoria, and
a tendency to verbalize. Anxieties and inhibitions tend to dissolve into a
feeling of emotional warmth, wellbeing, and pleasant drowsiness.
        The "morning after" effects of GHB lack the unpleasant or
debilitating characteristics associated with alcohol and other
relaxation-oriented drugs. In fact, many users report feeling particularly
refreshed, even energized, the next day.
        The effects of GHB can generally be felt within five to twenty
minutes after ingestion. They usually last no more than one and a half to
three hours, although they can be indefinitely prolonged through repeated
dosing. The effects of GHB are very dosedependent. Small increases in the
amount ingested lead to significant intensification of the effect. Higher
levels feature greater giddiness, silliness, and interference with mobility
and verbal coherence, and maybe even dizziness. Even higher doses usually
induce sleep.
        GHB temporarily inhibits the release of dopamine in the brain. This
may cause increased dopamine storage, and later inereased dopamine release
when the GHB influence wears off [Chin and Kreutzer, 1992]. This effect
could account for the middle-of-the-night wakings common with use of higher
GHB doses, and the general feelings of inereased well-being, alertness and
arousal the next day.
        GHB also stimules pituitary growth hormone (GH) release. One
methodologically rigorous Japanese study reported ninefold and sixteen-fold
increases in growth hormone 30 and 60 minutes respectively after
intravenous administration of 2.5 grams of GHB in six healthy men between
the ages of twenty-five and forty (Takahara, 1977). GH levels were still
seven-fold higher at 120 minutes.
        The mechanism by which GHB stimulates growth-hormone release is not
known. Dopamine activity in the hypothalamus is known to stimulate
pituitary release of growth hormone, but GHB inhibits dopamine release at
the same time that it stimulates GH release. This suggests that GHB's
GH-releasing effect takes place through an entirely different mechanism
[Takahara,1977].
        At the same time GH is being released, prolactin levels also rise.
Serum prolactin levels increase in a similar time-dependent manner as GH,
peaking at five-fold above baseline at 60 minutes. [Takahara, 1977). This
effect, unlike the release of GH, is entirely consistent with GHB's
inhibition of dopamine. Other compounds which lessen dopamine activity in
the brain (such as the neuroleptic Thorazine) have been shown to result in
prolactin release. Although prolactin tends to counteract many of the
beneficial effects of GH, the sixteen-fold inereases in GH probably
overwhelm the five-fold inereases in prolactin.
        GHB induces "remarkable hypotonia" (musele relaxation) [Vickers,
1969). It is now gaining popularity in France and Italy as an aid to
childbirth. GHB causes "spectacular action on the dilation of the cervix,"
decreased anxiety, greater intensity and frequency of uterine contractions,
inereased sensitivity to oxytocic drugs (used to induce contractions),
preservation of reflexes, a lack of respiratory depression in the fetus,
and protection against fetal cardiac anoxia (especially in cases where the
umbilical cord wraps around the fetus' neck) (Vickers, 1969; Laborit,
1964].
        GHB is completely metabolized into carbon dioxide and water,
leaving absolutely no residue of toxic metabolites (Vickers, 1969;
Laborit,1972). Metabolism is so efficient that GHB can no longer be
detected in urine four to five hours after it is taken by injection
(Laborit,1964).
        GHB activates a metabolic process known as the "pentose pathway"
which plays an important role in the synthesis of protein within the body
(Laboril, 1972). lt also causes a "protein sparing" effect [Laborit, 1964]
which reduces the rate at which the body breaks down its own proteins.
These properties, along with GHB's effect on growth hormone, underlie its
common use as an aid to muscle-building and fat loss.
        Anesthetic (large) doses of GHB are accompanied by a small increase
in blood sugar levels, and a significant decrease in cholesterol.
Respiration becomes slower and deeper. Blood pressure may rise or fall
slightly, or remain stable, but a moderate bradycardia (slowing of the
heart) is consistent [Vickers,1969; Laborit,1964). A slight drop in body
temperature also occurs (Laborit, 1964].
        GHB also stimulates the release of acetylcholine in the brain
[Gallimberti, 1989).
        GHB has been called "almost an ideal sleep inducing substance"
[Smart Drugs II, p. 245). Small doses produce relaxation, tranquility and
drowsiness which make it extremely easy to fall asleep naturally. Higher
doses inerease the drowsiness effect and decrease the time it takes to fall
asleep. A sufficiently large dose of GHB will induce sudden sleep within
five to ten minutes [Laborit, 1964).
        Many other hypnotics interfere with various stages of the sleep
cycle thus preventing the body from achieving a complete and balanced
session of rest and recuperation. The most remarkable facet of GHB-induced
sleep is its physiological resemblance to normal sleep. For instance, GHB
sleep is characterized by increased levels of carbon dioxide in the
arteries, as in normal sleep (Vickers, 1969). During normal and GHB sleep,
the CNS continues to be responsive to "noxious stimuli" (pain and other
irritations), a factor which sets limits on GHB's uses in anesthesia
(Vickers 1969). GHB facilitates both REM (rapid eye movement) sleep, and
"slow-wave" (non-REM) sleep, the stage of sleep featuring increased release
of growth hormone [Laborit, 1972]. And unlike the unconsciousness induced
by other anesthetics, that triggered by GHB does not feature a systemic
decrease in oxygen consumption [Laborit, 1964).
        The primary disadvantage to GHB's use as a sleep aid is it's
short-term influence about three hours. During GHB's influence, sleep is
deeper and more restful, but after the GHB has worn off, people have a
tendency to wake up. The higher the dose, the greater is this tendency.
Some have called this pattern the "dawn effect" and have speculated that it
is related to the release of stored-up dopamine. Some people minimize this
effect by taking minimal doses of GHB. Others take advantage of this effect
by getting a couple of hours of work done in the middle of the night. Still
others choose to take a second dose of GHB to sleep for another three
hours.
        It should be noted that not everyone can be put to sleep by GHB. We
have spoken to three men who have never achieved sleep even with the doses
normally used for such purposes. In addition, Takahara [1977] reported that
one of the six men in the growth hormone study cited above remained
conscious even though he had received two and a halfgrams of GHB
intravenously, a dosage which rendered the rest of the participants
unconscious.

        GHB shows great promise in the treatment of alcoholism. In Europe,
one of its primary uses is to relieve withdrawal symptoms, cravings, and
anxiety among alcoholics.
        In laboratory rats addicted to alcohol, withdrawal symptoms closely
resemble those exhibited by humans, including tremors, convulsions, and
hypersensitivity to sound. All of these symptoms were blocked by
sufficiently high doses of GHB [Fadda,1989). Administration of GHB has also
been found to prevent alcohol consumption among rats that voluntarily
ingest alcohol [Fadda,1989; Gallimberti,1989].
        In a rigorous, double-blind, placebo-controlled study conducted of
human alcoholics, "nearly all withdrawal symptoms disappeared within two to
seven hours" after administration of GHB. On a severe-moderate-mild-or-none
scale, withdrawal symptoms remained below moderate during the entire
period. The only side effect observed was slight, occasional, and transient
dizziness. The researehers concluded, "the results clearly indicated that
GHB is effective for the suppression of withdrawal symptoms in alcoholics"
(Gallimberti,1989].
        GHB has a decades long track record of use as a general anesthetic.
Administered intravenously, an anesthetic dose of GHB is in the range of
4-5 grams for a 150-pound person [Vickers,1969]. Its advantages as an
anesthetic include low toxicity, relatively few contraindications, slowing
of the heart rate without loss of blood pressure, the absence of irritation
to the veins with intravenous administration, musele relaxation, absence of
respiratory depression (usually), reduction of body temperature
(hypothermia), and various protective and anti-shock actions
(Laborit,1964]. However, GHB can almost never be used in anesthesia without
the additional administration ofother drugs (Vickers,1969J because it does
not produce complete surgical anesthesia except in children (Laborit,
1964). The autonomic nervous system remains active during GHB-induced
anesthetic coma, and thus the body continues to respond to surgical stimuli
through inereases in heart rate, blood pressure, and cardiac output, as
well as through sweating, peripheral vasoconstriction, vocalization, and
relax muscle action (Vickers,1969). Local anesthetics or other drugs which
suppress these responses must therefore also be used, like the way a
dentist or orthodontic surgeon might use Novocaine to kill pain along with
nitrous oxide to render a patient unconscious.
        It is suspected that part of GHB's protective function involves a
slowing of the metabolism of brain cells, thus reducing their requirements
for oxygen and glucose [Chin and Kreutzer, 1992; Artru, 1980]. Another
factor in GHB's anti-shock capability may be the marked vasodilation
induced in the liver and kidney, thus inereasing blood flow to those vital
organs.
        GHB's efficacy for treating anxiety has been positively
demonstrated in tests involving schizophrenic subjects [Laborit, 1964]. Its
sedative properties have earned it a role as a psychotherapeutic adjunct
(Vickers, 1969]. It has also been used to assist the process of
"abreaction," or the release (usually through verbalization) of repressed
emotion [Vickers,1969). Unlike other "anxiolytic" (or anti-anxiety) drugs,
GHB's effect is non-toxic. Furthermore GHB's reduction ofinhibitions, its
tendency to encourage verbalization, and the typical lack of fear during
the GHB experience would seem to provide an ideal context for the verbal
exploration of difficult emotional territory during therapy.
        Scientists and doctors have traditionally been reluctant to ascribe
aphrodisiac properties to any substance, although this tendency may have
abated somewhat in recent years. It is a testament, then, to the power the
GHB's sexual effects that they were clearly acknowledged in the scientific
literature by 1972. Dr. Laborit wrote:

`A last point should still be mentioned: the (GHB) action on Man which
could be called 'aphrodisiac.' We cannot present any animal experiments on
this subject. However the oral form has now been sufficiently used so that,
as generally agreed, no doubt can subsist as to its existence. "

        We have identified four main prosexual properties:
1) disinhibition, 2) heightening of the sense of touch (tactility),
3) enhancement of male erectile capacity, and 4) increased intensity of
orgasm.
        Perhaps the foremost prosexual property of GHB is disinhibition.
Some users suggest that GHB's other sexual benefits are secondary effects,
made possible (or at least amplified) by this loosening of psychosomatic
constraint. A number of people have commented that this disinhibition is
particularly marked among women.
        Women often report that GHB makes their orgasms longer and more
intense, as well as more difficult or time-consuming to achieve, especially
at higher doses. As with its other effects, GHB's impact on female orgasm
seems highly sensitive to small adjustments in dosage.
        GHB is not approved in the US and has been banned from
over-the-counter sale by the FDA. GHB has not yet been "scheduled" as a
"controlled substance" by the DEA, and therefore simple possession is not
illegal. GHB continues to be sold to legitimate laboratories and scientists
for researeh purposes, but selling it specifically for human consumption,
especially while making claims about its health benefits, is a violation of
current FDA regulations and policy.
        In some European countries, GHB is an approved drug available by
preseription. Local doctors, pharmacists and government bureaucrats should
be able to provide country-by-country specifics.
        GHB is growing in popularity and seems to be widely available in
the underground "gray market." Since most of the GHB available through such
channels is of the "bootleg" variety, manufactured by non-professional
"kitehen" chemists, concerns about quality and purity should be kept in
mind. Caveat emptor (buyer beware)!
        As has been emphasized, the overall safety of GHB is
well-established, and no deaths attributable to GHB have been reported over
the thirty year period that this compound has been in use [Vickers,1969;
Chin and Kreutzer, 1992]. In fact, as of 1990, only forty-six adverse
reactions had been reported in the United States surely constituting only
an infinitesimal fraction of actual usage, all followed by rapid and
complete recovery (Chin and Kreutzer, 1992]. Unlike a large proportion of
other drugs including alcohol and even Tylenol, GHB has no toxic effects on
the liver, kidney or other organs [Vickers, 1969; Chin and Kreutzer, 1992].
One program of sleep therapy using six to eight grams daily for a period of
eight to ten days produced no side effects. Vickers [1969] even reports
that doses as high as twenty to thirty grams per twenty-four hour period
have been used for several days without negative consequences (don't do
this at home kids!). In the Canadian studies of narcolepsy mentioned
earlier, the nightly use of two to six teaspoons (one teaspoon equaling
roughly 2.5 grams) for several years resulted in no reports of long-term
adverse effects, or problems with issues of addiction or dependence. In one
of these studies, one patient inadvertently ingested fifteen teaspoons
without adverse consequence "other than deep sedation and headache the next
day" [Chin and Kreutzer,1992). And in France, sub-anesthetic oral doses
were used by "a large number of patients for about six years" without
untoward effect [Laborit,1972].
        According to Dr. Gallimberti (1989), the action of GHB is "without
serious side effects." Some research programs have reported no side effects
at all. Nonetheless, it's clear that some minor side effects can occur.
Those most commonly experienced are drowsiness, dizziness, nausea, and
sometimes vomiting. As a sedative-hypnotic, GHB's effects bear some
similarity to those of alcohol and tranquilizers. GHB not only "may cause
drowsiness" like these other drugs, it will almost invariably do so.
Ataxia, or incoordination, can also be a side effect of GHB. Do not drive a
vehicle or operate dangerous machinery while under the influence of GHB.
        As mentioned, clonic movements (muscle contractions or "seizures")
have been observed during the onset of GHB-induced sleep. Headache is
sometimes reported. A moderate slowing of the heart rate is a consistent
effect, and small changes in blood pressure can take place. Likewise,
orthostatic hypotension (a sudden drop in blood pressure caused by standing
up quickly) has also been reported. Sometimes this is experienced as brief
dizziness, and rarely people can brietly lose consciousness. At very high
doses, cardiac and respiratory depression can occur.
        Sufficiently large doses of GHB can cause sudden sedation and loss
of consciousness. Do not take such doses except when reclining on a bed or
sofa. It is also a bad idea to take such doses in the presence of people
who don't know anything about GHB. You may alarm your family or friends and
wake up in an emergency room (with a large medical bill).
        More unusual and extreme reactions have included diarrhea, lack of
bladder control, temporary amnesia, and sleepwalking. Whatever side effects
may be noted, they are often much more severe when GHB is combined with
other central nervous system depressants [Chin and Kreutzer, 1992,
Gallimberti, 1989; Takahara,1977; Vickers,1969].
        Although contraindications for GHB have been described as
"remarkably few" (Vickers, 1969], those who suffer from any of the
following conditions should not use GHB: severe illness of any kind,
epilepsy, eclampsia (convulsions), bradycardia (slowed heart-beat) due to
conduction problems (left-bundle-branch-block is an example of conduction
difficulty], Cushing's syndrome, severe cardiovascular disease,
hyperprolactinemia, and severe hypertension (Gallimberti, 1989; Vickers,
1969].
        Severe alcoholism is sometimes mentioned as a contraindication for
GHB (Smnrt Drugs II, page 244) even though GHB has been used quite
successfully in the treatment of withdrawal symptoms. The explanation for
this seeming contradiction probably lies in the likelihood that severe
alcoholics may combine GHB with alcohol.
        GHB should not be used with benzodiazepines ("minor tranquilizers"
such as Valium and Xanax), phenothiazines ("major tranquilizers" like
Thorazine and Stellazine), various painkillers (barbiturates and opiates),
alcohol, anticonvulsants (Dilantin and phenobarbital) and even many
over-the-counter allergy and sleep remedies - without direct medical
supervision.
        Determining the ideal dose is probably the trickiest aspect of
working with GHB. The amount required for a given level of effect will vary
from person to person, and the dose-response curve is fairly steep.
Overestimating the dose can have consequences ranging in seriousness from
ruining your plans for the evening to waking up in the emergency ward as a
result of panic on the part of concerned-but-uninformed friends or
relatives.
        Once you have found the levels that give you the effects you
desire, they will remain consistent. Tolerance to GHB does not develop.
However, recent (not current) alcohol consumption may decrease the effect
of a given dose of GHB [Fadda,1989].
        Most people find that a dose in the range of 0.75-1.5 grams is
suitable for prosexual purposes, and that a quantity in the range of 2.5
grams is sufficient to force sleep.
        Some people think that GHB might lower potassium levels and should
therefore be taken with potassium supplementation. Some research papers
have identified such an effect, others have not. If you want to play it
safe, take a potassium supplement equal to 10% of the GHB dose.

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This article is excerpted and adapted from a special report on GHB written
by the authors and available from Smart Publications, PO Box 4667,
Petaluma, CA 94955 (phone: 707-769-8078, Fax: 707-769-1062,
CompuServe: 71221,1427).

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