244/GAMMA-BUTYROLACTONE (GBL) PDR FOR NUTRITIONAL SUPPLEMENTS

The reason GBL was introduced into the dietary supplementmarketplace is because it is easily converted into gamma-hydroxybutyrate (GHB) after ingestion and is used as aprodrug of GHB (See Gamma-Hydroxybutyrate).

GBL is also known chemically as dihydro-2 (3H)-furanone;butyrolactone; 1,2-butanolide; 1,4-butanolide; gamma-hy-droxybutyric acid lactone; 3-hydroxybutyric acid lactone and4-hydroxybutanoic acid lactone. The chemical structure is asfollows:

Gamma-Butyrolactone

GHB has been classified as a Schedule I substance and isillegal to use except for the treatment of narcolepsy, forwhich it is approved by the FDA (GHB is a Schedule IIIdrug in that case), and in FDA-allowed clinical trials.

FDA has asked all GBL dietary supplement producers torecall their products.

Another organic solvent, 1,4 butanediol or -130, also getsconverted to gamma-hydroxybutyrate upon ingestion. FDAhas issued a warning regarding products that contain BD.

For more information on this substance, refer to the Gamma-Hydroxybutyrate (GHB) monograph.

LITERATURE

Centers for Disease Comtrol and Prevention. Adverse eventsassociated with ingestion of gamma-butyro]actone-Minnesota,New Mexico, and Texas, 1998-]999. MMWR Morh MortalWkly Rep. 1999;48:137-140.

FDA. Warning on dietary supplements. lAMA. 1999;282:] 218.

Lo Vecchio F, Curry SC, Bagnasco T. Butyrolactone-inducedcentral nervous system depression after ingestion ofRenewTrient,a "dietary supplement."N Engl 1 Med.J998;339:847-848.

Poldrugo F, Snead OC 3d. ], 4 Butanediol gamma-hydroxybutyricacid and ethanol. Neuropharmacology.1984;23:109-113.

Ramburg-Schepens MO, Buffet M, Durak C, Mathieu-Nolf M.Gamma-butyro]actone poisoning and its similarities to gamma-hydroxybutyricacid: two cases. Vet Hun Toxicol. 1997;39:234-235.

Wood OM, Warren-Gash C, Ashraf T, et al. Medical and legalconfusion surrounding gamma-hydroxybutyrate (GHB) and itsprecursors gamma-butyrolactone (GBL) and 1,4-butanediol(I,4BD). QlM. 2008;101(1):23-29.

Gamma - Hydroxyb utyra te(GHB)

It is illegal to use or possess GHB except if enrolledin certain FDA-allowed clinical trials or for FDA-approved indications. GHB is a central nervous systemdepressant with abuse potential.

DESCRIPTION

Gamma-hydroxybutyrate or GHB was sold in the 1980s as anutritional supplement. It was used mainly as a claimed aidto bodybuilding and sleep. In November 1990, FDA bannedthe OTC sale of GHB following reports of severe illness,including seizures-and coma associated with use of GHB. InFebruary 2000, the U.S. House of Representatives approvedfederal legislation making GHB illegal while allowingmedical formulations to be available for clinical testing andpotential medical use. Illicitly made GHB is now a Schedule1 substance in company. with heroin, LSD and cocaine.Medically formulated GHB, such as' that developed andapproved by the FDA for excessive daytime sleepiness andcataplexy in patients with narcolepsy, is classified as aSchedule III drug. GHB is the only drug to be on two drugschedules at once under U.S. law. GHB, marketed as Xyrem(sodium oxybate) by Jazz Pharmaceuticals, Inc. and pre-scribed for specific conditions, is on Schedule Ill. ScheduleIII'drugs are considered safe when used properly and have alower potential for abuse than do Schedule I and Schedule IIdrugs. A Schedule I drug is considered a highly dangerousand addictive drug.

Gamma-hydroxybutyrate is also known chemically as 4-hydroxybutyrate and oxybate and is represented by thefollowing chemical formula:

Gamma-Hydroxybutyric acid (GHB)

It typically is in the form of sodium oxybate (sodiumgamma-hydroxybutyrate or sodium 4-hydroxybutyrate). Oth-er names used for GHB have been liquid ecstasy, liquid X,somatomax PM and Gamma-OH. Some of the effects ofGHB are reported to be similar to the effects of 3,4-methylenedioxymethamphetamine or MDMA, more com-monly known as ecstasy.

GHB is found naturally in animal tissues, including thebrain, kidney, heart muscle and fat. It was synthesized in1969 and used in Europe as an intravenous anesthetic agent.It was also found to be useful for narcolepsy and has beendeveloped and approved for that use in the U.S.

SUPPLEMENT MONOGRAPHS GAMMA-HYDROXYBUTYRATE (GHB) /245

ACTIONS AND PHARMACOLOGY

ACTIONS

GHB is a central nervous system depressant and hasanesthetic and hypnotic actions. It also has activity againstexcessive daytime sleepiness and cataplexy. (Cataplexy is acondition characterized by weak or paralyzed muscles.)

MECHANISM OF ACTION

The precise mechanism of action of GHB is unclear. GHB isderived from the neurotransmitter gamma-aminobutyric acid(GAB A) and is also converted to GABA. GHB is thought tofunction as an inhibitory chemical transmitter in the centralnervous system. Further, it is thought that its central nervoussystem depressant effect is probably mediated throughspecific receptors for GHB as well as interaction with theGABA (B) receptor.

GHB is also thought to be a specific inhibitor of centraldopamine release. And, under certain conditions, e.g. duringsedation or anesthesia or in the presence of a highconcentration of calcium, GHB may stimulate dopaminerelease.

GHB has been found to stimulate the release of growthhormone when administered intravenously in healthy malevolunteers. The mechanism of this possible activity isunknown.

PHARMACOKINETICS

Following oral ingestion, GHB is rapidly absorbed from thegastrointestinal tract and transported by the portal circulationto the liver where most of it gets metabolized to carbondioxide and water by first-pass metabolism pathways. Acertain amount crosses the blood-brain barrier. Mean valuefor the terminal half life ranges from 20 to 23 minutes.

INDICATIONS AND USAGE

GHB is approved by the FDA for the treatment ofnarcolepsy. There are no indications for its use as asupplement. It is illegal to use it as a supplement.

RESEARCH SUMMARY

GHB has been approved by the FDA as an orphan drug forthe treatment of narcolepsy, but banned by it as a supple-ment. There are, however, products being sold that containgamma-butyrolactone (GBL) for which many claims aremade. GBL is converted in the body to GHB. Claims forGBL include anti-depressive effects, sleep aid, growth-hormone releaser, sexual and athletic enhancers. None ofthese claims has been proved. Several cases of GBL toxicityhave been reported, manifestations of which include brady-cardia, hypothermia, central nervous system depression anduncontrolled movements. Use of any GBL/GHB products-excluding the approved drug form of GHB-is inadvisableand illegal.

CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS

CONTRA INDICA TlONS

GHB is contraindicated in those with seizure disorders; thosebeing treated with sedative hypnotic agents; those withbradycardia and other conditions associated with defects ofcardiac conduction; those with cardiovascular disease, Cush-ing's syndrome, severe hypertension and hyperprolactine-mia; and those with severe illness of any kind.

PRECAUTIONS

GHB is illegal to use except if enrolled in certain FDA-allowed clinical trials or for FDA-approved indications. Theonly indication that is presently approved by the FDA is forthe treatment of narcolepsy. Gamma-butyrolactone (GBL)and 1,4 butanediol (BD) are chemicals that may be available.GBL and BD are metabolized to GHB in the body andshould be avoided by all.

Under no conditions should GHB, GBL or BD be used withalcohol, benzodiazepines, skeletal muscle relaxants, opioids,antihistamines, barbiturates, anticonvulsants, major tranquil-izers or protease inhibitors.

ADVERSE REACTIONS

The most common adverse events reported in patientsparticipating in U.S. clinical trials of the effects of sodiumoxybate (sodium gamma-hydroxybutyrate) for the treatmentof narcolepsy are dizziness, nausea, headache and enuresis.In these trials, subjects were randomized to doses of 3, 6 or 9grams daily, and the side effects appeared to be dose-related.

Other adverse effects reported in those taking GHB includevomiting, lightheadedness, confusion, abnormal musclemovements, bradycardia, drowsiness, incoordination, ortho-static hypotension, diarrhea, loss of bladder control, loss ofconsciousness, temporary amnesia, sleepwalking and sei-zure-like activity.

INTERACTIONS

GHB taken with any of the following drugs may lead to life-threatening situations: alcohol, anticonvulsants, benzodiaze-pines, antihistamines (particularly sedating antihistamines),skeletal muscle relaxants, major tranquilizers, opioids andprotease inhibitors used for the treatment of HIV.

OVERDOSAGE

It is unclear whether GHB ingestion alone can be fatal(without co-ingesting other CNS depressant agents or otherdrugs). Symptoms of GHB overdosage include markedlydecreased levels of consciousness, bradycardia, hypothermia,respiratory acidosis and emesis. Patients typically regainconsciousness spontaneously within five hours of ingestion.

GHB ingestion in a patient taking the protease inhibitorsritonavir and saquinavir caused a near-fatal reaction. Co-ingestion of GHB and alcohol and other "recreational drugs"

246/GAMMA-HYDROXYBUTYRATE (GHB) PDR FOR NUTRITIONAL SUPPLEMENTS

has been associated with low respiratory rates (at timesrequiring intubation), coma and death. Over 145 cases ofGHB poisoning, including eight deaths, have been reported.Typically, those involved were using other CNS-depressantagents such as alcohol along with GHB. These reportsinclude ingestions of substances such as gamma-butyrolac-tone (GB) and 1,4 butanediol, both of which are converted toGHB in the body.

DOSAGE AND ADMINISTRATION

It is illegal to use or possess GHB except if enrolled incertain FDA-allowed clinical trials or for the FDA-approvedindication of narcolepsy.

LITERATURE

Centers for Disease Control and Prevention. Gamma-hydroxybutyrate use-New York and Texas, 1995-1996.MMWR. 1997;46:281-283.

Centers for Disease Control and Prevention. Multistate outbreakof poisonings associated with illicit use of gamma-hydroxy butyrate. MMWR. 1990;39:861-863.

Chin RL, Spores KA, Cullison B. Clinical course of gamma-hydroxybutyrate overdose. Ann Emerg Med. 1998;31:716-722.

FDA. Warning on dietary supplements. JAMA. 1999;282:1218.

Harrington RD, Woodward JA, Hooton TM, et al. Life-threatening interactions between HIV-I protease inhibitors andthe illicit drugs MOMA and gamma-hydroxybutyrate. ArchIntern Med. 1999;159:2221-2224.

Lammers GL, Arends J, Declerck AC, et aI. Gamma-hydroxybutyrate and narcolepsy: a double-blind, placebo-controlled study. Sleep. 1993;16:216-220.

Mamclak M, Scharf MB, Woods M. Treatment of narcolepsywith gamma-hydroxybutyrate. A review of clinical and sleeplaboratory findings. Sleep. 1986;9(1 pt 2):285-289.

Takahara J, Yunoki S, Yakushiji W, et aI. Stimulatory effectsof gamma-hydroxybutyric acid on growth hormone andprolactin release in humans. J Clin Endocrinol Metab.1977;44: 1014-1017.

Tunnicliff G. Sites of action of gamma-hydroxybutyrate(GHB)-aneuroactive drug with abuse potential. J Toxicol Clin Toxicol.1997;35:581-590.

Wood OM, Warren-Gash C, Ashraf T, et al. Medical and legalconfusion surrounding gamma-hydroxybutyrate (GHB) and itsprecursors gamma-butyrolactone (GBL) and 1,4-butanediol(I,4BD). QJM. 2008;101(1):23-29.

Gamma-Linolenic Acid(GLA)DESCRIPTION

Gamma-linolenic acid or GLA is an n-6 (omega-6) polyun-saturated fatty acid. It is comprised of 18 carbon atoms and

three double bonds. GLA is an all-cis n-6 polyunsaturatedfatty acid also known as GLA, 18: 3n-6; 6,9,12-octadeca-trienoic acid; (Z, Z, Z)- 6,9, l2-octadecatrienoic acid; cis-6,cis-9, cis-12-octadecatrienoic acid, and gamolenic acid. Thestructural formula of GLA is:

GLA (gamma-linolenic acid)

GLA is found naturally to varying extents in the fatty acidfraction of some plant seed oils. In evening primrose seedoil, it is present in concentrations of 7 to 14% of total fattyacids; in borage seed oil, 20 to 27%; and in blackcurrant seedoil, 15 to 20%. GLA is also found in some fungal sources.GLA is produced naturally in the body as the delta 6-desaturase metabolite of the essential fatty acid linoleic acid.Under certain conditions, e.g. decreased activity of the delta-6 desaturase enzyme, GLA may become a conditionallyessential fatty acid. GLA is present naturally in the form oftriacylglycerols (TAGs). The stereospecificity of GLA variesamong different oil sources. GLA is concentrated in the sn-3position of evening primrose seed oil and blackcurrant seedoil and in the sn-2 position in borage seed oil. GLA isconcentrated evenly in both the sn-2 and sn-3 positions offungal oil.

ACTIONS AND PHARMACOLOGY

ACTIONS

GLA may have anti-inflammatory and anti thrombotic ac-tions. It may also have lipid-lowering activity.

MECHANISM OF ACTION

The anti-inflammatory and anti-aggregatory actions can beaccounted for by reviewing its role in eicosanoid bio-syntheses. GLA is a precursor in the synthesis of prostaglan-din EI (PGE1) as well as the series-3 prostaglandins. It alsoserves as a precursor in the synthesis of eicosapentaenoicacid (EPA). EPA is a precursor of the series-3 prostaglan-dins, the series-5 leukotrienes and the series-3 thromboxanes.These eicosanoids have anti-thrombogenic, anti-inflammato-ry and anti-atherogenic properties. PGEI inhibits plateletaggregation and has a vasodilation action. The incorporationof GLA and it metabolites in cell membranes may also playarole in the possible anti-inflammatory and anti-proliferativeactions of GLA.

PHARMACOKINETICS

GLA-Iaden triacylglycerols (TAGs) following ingestionundergo hydrolysis via lipases to form monoglycerides andfree fatty acids. Once formed, the monoglycerides and freefatty acids are absorbed by the enterocytes. In the entero-cytes, a reacylation takes place reforming TAGs that are then