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Excerpted from the July 20th issue of Smart Life News. Copyright (c) 1999-2000. All rights reserved.

Question: In the Life Extension magazine’s Q&A column, Tom Matthews wrote that gamma-butyrolactone (GBL) “should not be taken supplementally but should only be used in the synthesis of GHB outside the body.” He then cited an oral LD-50 of 17.2 ml/kg for GBL in rats. Any comments? ——CF

Answer: A dose of 17.2 ml/kg in a 50 kg (112 lb) person would be 860 ml of GBL, which is about 170 teaspoons! That’s nearly a quart of GBL! Since the average person using GBL would be expected to use approximately 1/4-1/2 tsp. (1-2 ml), this represents a theoretical safety margin of 400:1, which is exceedingly high by almost any standard. There is no obvious reason for citing such a high LD-50 as apparent justification for an absolute dis-recommendation for GBL. Scientifically, that would be like citing the danger of sunburn as a basis for trashing the use of 100 watt light bulbs.

In a long-term dosing experiment in rodents, very high doses of butyrolactone showed a surprising lack of toxicity [NTIS, 1992]. The researchers gave 0, 112 and 225 mg/kg GBL to male rats; 0, 225 and 450 mg/kg GBL to female rats; and 0, 262 and 526 mg/kg GBL to both male and female mice. Scaled to human body size, these rodent dosages are about ten times what humans would use. The GBL was administered 5 days per week by gavage (stomach tube).

At the end of 2 years (old age, for rats), the survival of male rats was 48% for the control group, 54% for the intermediate-dose group and 64% for the high-dose group. That’s right, the GBL-treated male rats lived longer! This was attributed to a decreased incidence of mononuclear leukemia. In the female rats receiving double the dose of the male rats, the survival was not significantly different between the three groups: 56%, 54% and 54% respectively. However, the body weight of the GBL-dosed females was 10-20% lower than that of the controls.

In the mice, body weights were reduced in both sexes, 6% in the males and 14-17% in the females. Female survival at two years (also old age for mice) was 76% in the control group, 68% in the intermediate-dose group and 76% in the high-dose group. Male survival was a disaster. Survival was 70% in the control group, 60% in the intermediate-dose group and 24% in the high-dose group. The higher mortality was attributed entirely to fighting and bite wounds inflicted during recovery from GBL-induced sedation. At week 67, the high-dose males were transferred from group cages to individual cages, thus eliminating fighting-related deaths and allowing males to gain back some of their lost weight.

GBL administration caused no increased incidence of neoplasms (tumors) or lesions (tissue damage) in the male rats. Female rats showed a decrease in the incidence of mammary cysts (84%, 70% and 46%), pituitary cysts (50%, 35% and 22%) and mammary fibroadenomas (44%, 28% and 12%), which were all attributed to GBL. GBL-treated male mice showed a reduced incidence of hepatocellular adenoma (liver tumor) (48%, 16% and 18%) and an increased incidence of pheochromacytoma (adrenal tumor) (4%, 12% and 8%).

What does all this mean? The predominance of strong positive effects over weak adverse effects at such high dosages establishes that GBL is fundamentally safe and potentially beneficial.

Despite the illogic of Matthew’s presentation, there may be some wisdom in his advice. There is certainly a lot we do not know about exactly how we might adapt to long-term use of butyrolactone in different circumstances. I have two concerns. The first is acidosis. Every molecule of GBL that is hydrolyzed by lactonase generates one molecule of GHB-acid [newsletter illustration not shown here], or, equivalently, consumes one molecule of hydroxide [newsletter sidebar not shown here]. This can alter pH (acidity-alkalinity) in the blood stream. In some people, blood acidification might be a problem. While it is true that 1-2 grams of an organic acid is not a very large acidification effect in absolute terms, it happens in a relatively short period of time and may have subtle effects on pH-dependent systems. For example, blood pH is critical for regulating the binding and release of oxygen from hemoglobin. This might affect somebody with emphysema (with deficient oxygen absorption) or diabetes (with higher risk of lactic acidosis) more than somebody in good health. Similarly, food choices affect blood acidity. Somebody eating an extreme diet might be more susceptible to circulatory acidosis than somebody eating a mixed diet. Since rats and mice tolerate this acidification effect at a ten-times greater magnitude, it is not likely to be a problem in normal, healthy people. However, it is a general rule that the average lab rat eats a more nutritious diet than the average person. So, this could be a problem in some people.

Another concern of mine is the potential problem of frequent use (multiple times per day), which has not been adequately studied. All of the people who have reported withdrawal symptoms to me had used GBL (or GHB) on a semi-continuous basis. The dopamine suppression/rebound effect from GBL and GHB can be a powerful motivational influence. Excess dopamine is compulsive. It can make people obsess. It magnifies our response to stimulation. It is not unreasonable to suggest that rebound dopamine might have been responsible for the increased fighting among male mice in the above study.

While the effect of rebound dopamine is only transitory when GBL is given once a day, it may become magnified when subsequent doses are used in rapid succession to suppress the dopamine rebound [newsletter illustration not shown here]. There may be even longer-term adaptations to dopamine suppression that might occur if dopamine is suppressed for days or weeks at a time. Upregulation of dopamine receptors is one possibility.

One way to monitor potential long-term adaptations to GBL is to take periodic breaks: one day off per week, one week off per month, one month off per year, etc.

If we lived in a rational world, GHB would be readily available and butyrolactone use would be unnecessary. But the reality of the situation is that medical use of GHB in the United States has been rendered all but impossible. Despite the avowed “intentions” of legislators who stated in hearings that they had no wish to prevent legitimate medical use of GHB, GHB has become unavailable. Patients needing GHB are not able to get their prescriptions filled anywhere in the USA. The use of butyrolactone may be a second-choice solution, but it may be better than doing without GHB or butyrolactone. Certainly, the FDA and police will have a harder time eliminating butyrolactone because of wide-spread industrial uses that must be sacrificed to accomplish a zero-tolerance policy. So far, GHB prohibitionists show no sign if recognizing the immense economic costs of criminalizing butyrolactone. Florida has already passed their anti-butyrolactone bill, and California’s bill is already out of Committee in the Assembly. It’s full steam ahead on the Titanic with the captain asleep and no iceberg early-warning system in sight. ——SWF

This study was conducted under the auspices of the National Toxicology Program and is available through the National Toxicological Information Service, #PB92-189323, March 1992 (available at