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Ghb and narcolepsy.

Soap, G, Easy Lay, Liquid Ecstasy, Grievous Bodily Harm, and Georgia Home Boy are its names on the street where it is used as an aphrodisiac or for a quick high at parties. Alternative health care advocates consider it a safe alternative to anabolic steroids. After falling out of favor as a general anesthetic, it has found other uses in medical settings such as enhancing dilation of the cervix during labor. Orphan Medical, Inc.-the only company approved by the Food and Drug Administration (FDA) to manufacture it-sells it under the trade name Xyrem and generic name, sodium oxybate. Its chemical name is gamma-hydroxybutyrate or GHB.

In the 1980s in America, GHB could easily be obtained in health food stores. Because it increases growth hormone levels, body builders used it to increase muscle mass. By 1990, a few reports of it causing seizure and coma caused the FDA to label GHB as a dangerous drug and withdraw it from over-the-counter use. By then, GHB had also become a party drug.

GHB's label as a dangerous drug and its use as a party drug has left it with a negative reputation. Until recently, this reputation barred narcoleptics from an effective treatment. Research studies have found that GHB can relieve symptoms of narcolepsy.

GHB was first synthesized in 1961 by French scientists Henri Laborit and Camille-Georges Wermuth. Seeking to understand better how the then recently discovered neurotransmitter gamma-aminobutyric acid (GABA) functioned, Laborit wanted a substance which had properties similar to GABA that could cross the blood-brain barrier. Wermuth, a pharmacologist, synthesized GHB for Laborit.

Laborit found that GHB could induce a deep sleep quickly. This property resulted in its being used as a general anesthetic. However, GHB had drawbacks. One, the pain threshold is not diminished with GHB. A person physiologically reacts to pain during surgery (i.e., increased heart rate). Second, a person awakens abruptly (sometimes combatively) from GHB. Third, the action of GHB is short-lived; its effects wear off after 2-4 hours. These drawbacks caused scientists to discontinue using GHB as a general anesthetic.

In the 1970s, scientists began consider using GHB to treat narcolepsy. This interest came about inadvertently from research with insomniacs. Roger Broughton and Mortimer Mamelakl were investigating the effect of GHB on insomnia. In their study, a subject reported being paralyzed just before going to sleep. This meant that GHB had unexpectedly induced sleep paralysis--one symptom of narcolepsy. This prompted their interest in determining if GHB could somehow be used to treat narcolepsy.

Narcolepsy comes from two Greek words meaning "benumbing seizure." It is a disorder characterized by uncontrollable brief episodes of sleep (sleep attacks), hypnagogic hallucinations, cataplexy, and sleep paralysis. Hypnagogic hallucinations are vivid, sometimes realistic, dream imagery that occurs just as a person is going to sleep. Cataplexy is the sudden onset of muscle weakness which often occurs in association with strong emotion. Sleep paralysis is the result of a phenomenon which would normally occur during REM sleep. During REM sleep, muscles lose all tone which prevents a person acting out dreams that occur in that stage. However, this lack of muscle tone can remain briefly during the sleep-wake transition and a person awakens unable to move.

Some scientists believe that symptoms of narcolepsy are the result of REM sleep deprivation since the REM sleep of narcoleptics is interrupted by frequent arousals during the night. Even in a non-narcoleptic person, REM sleep deprivation can result in phenomena such as hallucinating while awake (i.e., hypnagogic hallucination). In a similar fashion, symptoms seen in narcolepsy are elements of REM sleep intruding into wake.

The sleep of narcoleptics is abnormal and characterized by: a short sleep latency; frequent sleep onset REM periods (i.e., REM sleep begins within 30 minutes of going to sleep); REM period interrupted by arousals; higher than normal amount of time spent in stage 1 but less than normal amount Spent in slow wave sleep; and frequent arousals from sleep.

GHB counteracts these abnormalities by increasing slow wave sleep, lessening stage 1 sleep, and reducing arousals from rapid eye movement (REM) sleep. Its ability to counter sleep abnormalities has lead scientists to a new speculation: narcolepsy may be the result of impaired GHB metabolism.

GHB is created in the human brain as a metabolite of the inhibitory neurotransmitter gamma-arninobutyric acid (GABA). GHB is also an inhibitory neurotransmitter. Scientists do not know at what point the metabolism of GHB may be going awry in order to cause symptoms of narcolepsy. Through animal research, scientists do have some clues on how GHB is utilized in the brain.

GHB has a paradoxical effect on dopamine. In animal studies, GHB increases dopamine levels in the brain but it also inhibits the brain's ability to utilize dopamine. It may be this inhibition which allows GHB to promote REM sleep by reducing dopamine's ability to suppress REM sleep. GHB enhances the release of the neurotransmitter acetylcholine in the striatal region of the brain (i.e., caudate nucleus & lentiform nucleus). Acetylcholine plays a role in onset of REM sleep.

GHB causes tryptophan to accumulate in the brain. Excess levels in turn stimulate the production of the sleep-promoting neurotransmitter serotonin. Scientists are not sure if GHB directly or indirectly causes tryptophan to accumulate in the brain.

Because it is a metabolite of GABA synthesis, scientists did not realize until the early 1980s that GHB was in fact a neurotransmitter. This came about when researchers such as Maitre noted that some brain receptors had a high affinity for GHB. That is, the receptors responded only to GHB but not to GABA which is similar in structure. The presence of such receptors meant that GHB itself was a neurotransmitter.

REM sleep is controlled by certain areas in the brainstem. Most GHB receptors should be located in the brainstem since GHB has a profound effect on this stage. Ironically, the brain-stern does not contain many receptors with a high affinity for GHB. The hypothalamus however does contain these receptors and seems to be the site where GHB is synthesized. This finding is in keeping with the hypothalamus' apparent role in modulating REM sleep. Injury to the hypothalamus from tumor, surgery, or other cause can induce problems with REM sleep: sleep paralysis, hypnagogic hallucination, sleep onset REM period, and muscle atonia.

High concentration of GHB are also found in the basal ganglia especially those structures of the basal ganglia that lie near the hippocampus. These structures play a role in emotion as well as movement. Altered function may result in cataplexy, the sudden muscular weakness which occurs in association with strong emotion in narcoleptics. GHB treatment has a high rate of success in reducing cataplexy, sleep attacks, sleep paralysis, and hypnagogic hallucinations. Of these symptoms, cataplexy and sleep attacks take longer to resolve. In some people, GHB treatment initially intensifies sleep paralysis, sleep attacks, and cataplexy. A rare short-term initial effect in some people is enuresis. These problems subside after about a week.

Unlike sleep medications and stimulant drugs, GHB does not lose efficacy with long-term use (9 months or more). While investigating long-term effects of GHB, Mamelak et al noted three groups of people who do not benefit from GHB treatment:

(1) people who are on tricyclic antidepressants;

(2) people whose sleep-wake schedule changes frequently or who work the night shift; and

(3) people who have a physiological problem which alters sleep (for example, certain types of head trauma).

GHB appears to have no toxic effect on the liver, kidneys, blood, or heart. An adverse effect which is not necessarily due to toxicity is that GHB use may cause a person to become more emotional or suffer confusion. A drawback of GHB use is that it improves sleep but does not improve daytime alertness. A person may still need to take stimulants to maintain daytime alertness.

On July 17, 2002, the FDA gave its approval for GHB to be used to treat symptoms of narcolepsy. This approval came with severe restrictions. Narcolepsy is the only disorder it is approved for. Doctors prescribing GHB have to provide the name and medical progress of the person to whom it is prescribed to a registry monitored by the FDA. The drug is sent directly to the home of the registered person by Federal Express.

With the legal but restricted availability of GHB, people with narcolepsy have an effective treatment available. More information about Xyrem can be found at

by Regina Patrick, RPSGT
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Title Annotation:SLEEP MEDICINE
Author:Patrick, Regina
Publication:FOCUS: Journal for Respiratory Care & Sleep Medicine
Date:Jun 22, 2013
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