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We believe fully that 4-DHEA is legal to sell under U.S. law. It is a naturally occurring product that is legal under DSHEA. It is a naturally occurring metabolite of androstenedione due to reversal of the 3-beta hydroxysteroid dehydrogenase/isomerase reaction and can be found in rabbits and sheep – both of which are components of the human diet as well as in rats suggesting that this reaction is common in mammals (1, 2). As DHEA is metabolized in large quantities to androstenedione, 4-DHEA can also be considered to be a metabolite of DHEA, a dietary supplement that was marketed in the United States prior to October 15, 1994.

To make dietary supplements compliant under current DSHEA regulation, a supplement must be naturally occurring and part of the food supply where the food has not been chemically altered. The endogenous formation of androstenedione has been well documented in healthy human and animal tissues. Under DSHEA, 4-DHEA is a natural metabolite of androstenedione and DHEA that is proven to occur in rabbits, sheep and rats(1,2). Rabbit and sheep flesh and organ tissue has been consumed by humans since antiquity. This ingredient, though standardized has not been chemically altered from the animal tissues where it is found.

Name of Ingredient

4-dehydroepiandrosterone

Safety of the ingredient

DHEA has a long history of use in healthy and diseased humans (4,5,6,8) and has been shown to be safe in doses up to 200 mg per day for 24 weeks (9) and 2250 mg for 16 weeks (7) with minimal side effects. The side effects that are encountered are due, in large part to the formation of estrogen and potent 5-alpha reduced metabolites (3,9,10). DHEA has been shown to act as a direct agonist of the estrogen receptor while there is no evidence that 4-DHEA has this activity. Numerous opinions have been written showing that comparing an ingredient to one that is already on the market is a valid and defensible form of showing safety. The numerous benefits of 4-DHEA over standard 5-DHEA make this certainly more safe and effective as a means of increasing adrenal hormones.

Conclusion

The presence of 4-DHEA in animal tissues normally consumed in the diet qualify it as a DSHEA compliant nutritional supplement that is reasonably expected to be as safe or safer than DHEA, also a DSHEA compliant dietary supplement.

References

  1. BREUER H, DAHM K, NORYMBERSKI JK. ENZYMIC FORMATION OF 3-BETA-HYDROXYANDROST-4-EN-17-ONE. J Endocrinol. 1963 Nov;27:357-8.
  2. THOMAS PZ, DORFMAN RI. METABOLISM OF ANDROST-4-ENE-3,17-DIONE-4-14C BY RABBIT SKELETAL MUSCLE SUPERNATANT FRACTION. ISOLATION OF 3BETA-HYDROXYANDROST-4-EN-17-ONE-14C AND TESTOSTERONE-14C. J Biol Chem. 1964 Mar;239:766-72.
  3. Longcope C, Bourget C, Flood C. The production and aromatization of dehydroepiandrosterone in post-menopausal women. Maturitas. Dec;4(4):325-32, 1982.
  4. Milewich L, Hendricks TS, Johnson AR. Metabolism of dehydroisoandrosterone and androstenedione in human pulmonary endothelial cells in culture. J Clin Endocrinol Metab. May;56(5):930-5, 1983.
  5. Rabkin JG, McElhiney MC, Rabkin R, McGrath PJ, Ferrando SJ. Placebo-controlled trial of dehydroepiandrosterone (DHEA) for treatment of nonmajor depression in patients with HIV/AIDS. Am J Psychiatry. Jan;163(1):59-66, 2006.
  6. Piketty C, Jayle D, Leplege A, Castiel P, Ecosse E, Gonzalez-Canali G, Sabatier B, Boulle N, Debuire B, Le Bouc Y, Baulieu EE, Kazatchkine MD. Double-blind placebo-controlled trial of oral dehydroepiandrosterone in patients with advanced HIV disease. Clin Endocrinol (Oxf). Sep;55(3):325-30, 2001.
  7. 18Dyner TS, Lang W, Geaga J, Golub A, Stites D, Winger E, Galmarini M, Masterson J, Jacobson MA. An open-label dose-escalation trial of oral dehydroepiandrosterone tolerance and pharmacokinetics in patients with HIV disease. J Acquir Immune Defic Syndr. May;6(5):459-65, 1993.
  8. Alhaj HA, Massey AE, McAllister-Williams RH. Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study. Psychopharmacology (Berl). Oct 18;:1-11, 2005.
  9. 20Chang DM, Lan JL, Lin HY, Luo SF. Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: a multicenter randomized, double-blind, placebo-controlled trial. Arthritis Rheum. Nov;46(11):2924-7, 2002.
  10. 21Acacio BD, Stanczyk FZ, Mullin P, Saadat P, Jafarian N, Sokol RZ. Pharmacokinetics of dehydroepiandrosterone and its metabolites after long-term daily oral administration to healthy young men. Fertil Steril. Mar;81(3):595-604, 2004.

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