Enhancing Cognitive Function with PregnenoloneNovember 2007
By Julius G. Goepp, MD
Combating Mental Health Disorders
There is increasing evidence that lower levels of pregnenolone are associated with a variety of mental health conditions beyond anxiety, including depression, phobias, and even schizophrenia.9,47-49 In fact, one study published just this year revealed that schizophrenic patients with the lowest levels of pregnenolone were also most likely to have high levels of anxiety.50
Overcoming Chemical Dependency
Many of the addictive substances humans consume can have potent negative effects on learning and memory—effects that are exacerbated by aging. Both alcohol and nicotine impair learning and leave long-term marks on memory as well. However, a number of studies have shown that pregnenolone sulfate overcomes the memory impairment caused by addictive substances such as alcohol and nicotine.51,52
These impressive findings have been echoed by another study looking into the effects of neuro-steroids in nicotine and morphine dependence—two problems that are faced by millions of older adults.53 Again, pregnenolone and other neurosteroids were shown to counteract the anxiety-like behavior that is associated with nicotine or morphine withdrawal. In fact, this study together with the recent discovery that pregnenolone and other neuro-steroids have potent effects on the so-called sigma receptors, which have long been associated with addictive behaviors,36 have generated tremendous excitement in the scientific community with the prospect that neurosteroids such as pregnenolone may offer powerful relief to sufferers of these tragic conditions.22
The possibility that thousands of older adults may suffer from low pregnenolone levels is of concern. However, there is plenty of evidence favoring careful supplementation to prevent or mitigate memory loss and a host of other mental and emotional health issues. Because cancers of the breast, uterus, ovaries, and prostate may grow faster in the presence of sex hormones derived from pregnenolone,54-59 it’s important to collaborate with your health care provider if you have any such conditions, to be sure that supplementation is right for you.
Our knowledge of pregnenolone and its “family members,” the neurohormones, is at an exciting early stage. What we know is that these powerful molecules exert rapid and profound effects on vital brain structures, intimately affecting how we think, learn, and remember. It’s fair to say that studies of pregnenolone and other neurosteroids are changing the way we think about steroids and the actions of hormones in general. Animal studies and early human trials show promising results of supplementation with this exceptionally versatile natural substance. Furthermore, dozens of new trials that are now in progress will surely shed even more light in the future on how pregnenolone can help protect and promote healthy brain function.
If you have any questions on the scientific content of this article, please call a Life Extension Health Advisor at 1-800-226-2370.
1. Flood JF, Morley JE, Roberts E. Pregnenolone sulfate enhances post-training memory processes when injected in very low doses into limbic system structures: the amygdala is by far the most sensitive. Proc Natl Acad Sci USA. 1995 Nov 7;92(23):10806-10.
2. Nikitin VP. A new mechanism of synapse-specific neuronal plasticity. Neurosci Behav Physiol. 2007 Jul;37(6):559-70.
3. Wojtal K, Trojnar MK, Czuczwar SJ. Endogenous neuroprotective factors: neurosteroids. Pharmacol Rep. 2006 May;58(3):335-40.
4. Gibbs TT, Russek SJ, Farb DH. Sulfated steroids as endogenous neuromodulators. Pharmacol Biochem Behav. 2006 Aug;84(4):555-67.
5. Maurice T, Phan VL, Urani A, et al. Neuroactive neurosteroids as endogenous effectors for the sigma1 (sigma1) receptor: pharmacological evidence and therapeutic opportunities. Jpn J Pharmacol. 1999 Oct;81(2):125-55.
6. Paul SM, Purdy RH. Neuroactive steroids. FASEB J. 1992 Mar;6(6):2311-22.
7. Baulieu EE. Neurosteroids: a new function in the brain. Biol Cell. 1991;71(1-2):3-10.
8. Baulieu EE. Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Prog Horm Res. 1997;5:21-32.
9. Dubrovsky BO. Steroids, neuroactive steroids and neurosteroids in psychopathology. Prog Neuropsychopharmacol Biol Psychiatry. 2005 Feb;29(2):169-92.
10. Wu FS, Gibbs TT, Farb DH. Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor. Mol Pharmacol. 1991 Sep;40(3):333-6.
11. Mellon SH. Neurosteroid regulation of central nervous system development. Pharmacol Ther. 2007 Jun 16.
12. Mukai H, Takata N, Ishii HT, et al. Hippocampal synthesis of estrogens and androgens which are paracrine modulators of synaptic plasticity: synaptocrinology. Neuroscience. 2006;138(3):757-64.
13. Mellon SH, Griffin LD, Compagnone NA. Biosynthesis and action of neurosteroids. Brain Res Brain Res Rev. 2001 Nov;37(1-3):3-12.
14. Verkhratsky A, Kirchhoff F. NMDA Receptors in glia. Neuroscientist. 2007 Feb;13(1):28-37.
15. Castner SA, Williams GV. Tuning the engine of cognition: a focus on NMDA/D1 receptor interactions in prefrontal cortex. Brain Cogn. 2007 Mar;63(2):94-122.
16. Cosman KM, Boyle LL, Porsteinsson AP. Memantine in the treatment of mild-to-moderate Alzheimer’s disease. Expert Opin Pharmacother. 2007 Feb;8(2):203-14.
17. Wenk GL. Neuropathologic changes in Alzheimer’s disease: potential targets for treatment. J Clin Psychiatry. 2006;67 Suppl 33-7.
18. Hige T, Fujiyoshi Y, Takahashi T. Neurosteroid pregnenolone sulfate enhances glutamatergic synaptic transmission by facilitating presynaptic calcium currents at the calyx of Held of immature rats. Eur J Neurosci. 2006 Oct;24(7):1955-66.
19. Sliwinski A, Monnet FP, Schumacher M, Morin-Surun MP. Pregnenolone sulfate enhances long-term potentiation in CA1 in rat hippocampus slices through the modulation of N-methyl-D-aspartate receptors. J Neurosci Res. 2004 Dec 1;78(5):691-701.
20. Sabeti J, Nelson TE, Purdy RH, Gruol DL. Steroid pregnenolone sulfate enhances NMDA-receptor-independent long-term potentiation at hippocampal CA1 synapses: role for L-type calcium channels and sigma-receptors. Hippocampus. 2007;17(5):349-69.
21. Maurice T, Gregoire C, Espallergues J. Neuro(active)steroids actions at the neuromodulatory sigma1 (sigma1) receptor: biochemical and physiological evidences, consequences in neuroprotection. Pharmacol Biochem Behav. 2006 Aug;84(4):581-97.
22. Maurice T, Urani A, Phan VL, Romieu P. The interaction between neuroactive steroids and the sigma1 receptor function: behavioral consequences and therapeutic opportunities. Brain Res Brain Res Rev. 2001 Nov;37(1-3):116-32.
23. Vajda FJ. Neuroprotection and neurodegenerative disease. J Clin Neurosci. 2002 Jan;9(1):4-8.
24. Vallee M, Mayo W, Le MM. Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging. Brain Res Brain Res Rev. 2001 Nov;37(1-3):301-12.
25. Stomati M, Monteleone P, Casarosa E, et al. Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecol Endocrinol. 2000 Oct;14(5):342-63.
26. Vallee M, Purdy RH, Mayo W, Koob GF, Le MM. Neuroactive steroids: new biomarkers of cognitive aging. J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):329-35.
27. Vallee M, Mayo W, Darnaudery M, et al. Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus. Proc Natl Acad Sci USA. 1997 Dec 23;94(26):14865-70.
28. Urani A, Romieu P, Roman FJ, Maurice T. Enhanced antidepressant effect of sigma(1) (sigma(1)) receptor agonists in beta(25-35)-amyloid peptide-treated mice. Behav Brain Res. 2002 Aug 21;134(1-2):239-47.
29. Urani A, Romieu P, Roman FJ, et al. Enhanced antidepressant efficacy of sigma1 receptor agonists in rats after chronic intracerebroventricular infusion of beta-amyloid-(1-40) protein. Eur J Pharmacol. 2004 Feb 20;486(2):151-61.
30. Schumacher M, Weill-Engerer S, Liere P, et al. Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog Neurobiol. 2003 Sep;71(1):3-29.
31. Weill-Engerer S, David JP, Sazdovitch V, et al. Neurosteroid quantification in human brain regions: comparison between Alzheimer’s and nondemented patients. J Clin Endocrinol Metab. 2002 Nov;87(11):5138-43.
32. Marx CE, Trost WT, Shampine LJ, et al. The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer’s disease. Biol Psychiatry. 2006 Dec 15;60(12):1287-94.
33. Mayo W, Le MM, Abrous DN. Pregnenolone sulfate and aging of cognitive functions: behavioral, neurochemical, and morphological investigations. Horm Behav. 2001 Sep;40(2):215-7.
34. Mayo W, George O, Darbra S, et al. Individual differences in cognitive aging: implication of pregnenolone sulfate. Prog Neurobiol. 2003 Sep;71(1):43-8.
35. Mayo W, Lemaire V, Malaterre J, et al. Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus. Neurobiol Aging. 2005 Jan;26(1):103-14.
36. Monnet FP, Maurice T. The sigma1 protein as a target for the non-genomic effects of neuro(active)steroids: molecular, physiological, and behavioral aspects. J Pharmacol Sci. 2006 Feb;100(2):93-118.
37. Roberts E, Bologa L, Flood JF, Smith GE. Effects of dehydroepiandrosterone and its sulfate on brain tissue in culture and on memory in mice. Brain Res. 1987 Mar 17;406(1-2):357-62.
38. Flood JF, Morley JE, Roberts E. Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc Natl Acad Sci USA. 1992 Mar 1;89(5):1567-71.
39. Meziane H, Mathis C, Paul SM, Ungerer A. The neurosteroid pregnenolone sulfate reduces learning deficits induced by scopolamine and has promnestic effects in mice performing an appetitive learning task. Psychopharmacology (Berl). 1996 Aug;126(4):323-30.
40. Murakami K, Fellous A, Baulieu EE, Robel P. Pregnenolone binds to microtubule-associated protein 2 and stimulates microtubule assembly. Proc Natl Acad Sci USA. 2000 Mar 28;97(7):3579-84.
41. Bicikova M, Ripova D, Hill M, et al. Plasma levels of 7-hydroxylated dehydroepiandrosterone (DHEA) metabolites and selected amino-thiols as discriminatory tools of Alzheimer’s disease and vascular dementia. Clin Chem Lab Med. 2004 May;42(5):518-24.
42. Savic MM, Obradovic DI, Ugresic ND, Bokonjic DR. Memory effects of benzodiazepines: memory stages and types versus binding-site subtypes. Neural Plast. 2005;12(4):289-98.
43. Reddy DS. Pharmacology of endogenous neuroactive steroids. Crit Rev Neurobiol. 2003;15(3-4):197-234.
44. Reddy DS, Kulkarni SK. Neurosteroid coadministration prevents development of tolerance and augments recovery from benzodiazepine withdrawal anxiety and hyperactivity in mice. Methods Find Exp Clin Pharmacol. 1997 Jul;19(6):395-405.
45. Brambilla F, Biggio G, Pisu MG, et al. Plasma concentrations of anxiolytic neurosteroids in men with normal anxiety scores: a correlation analysis. Neuropsychobiology. 2004;50(1):6-9.
46. Meieran SE, Reus VI, Webster R, Shafton R, Wolkowitz OM. Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. Psychoneuroendocrinology. 2004 May;29(4):486-500.
47. Baghai TC, di MF, Schule C, et al. Plasma concentrations of neuroactive steroids before and after electroconvulsive therapy in major depression. Neuropsychopharmacology. 2005 Jun;30(6):1181-6.
48. Dubrovsky B. Neurosteroids, neuroactive steroids, and symptoms of affective disorders. Pharmacol Biochem Behav. 2006 Aug;84(4):644-55.
49. Strohle A, Romeo E, di MF, et al. GABA(A) receptor-modulating neuroactive steroid composition in patients with panic disorder before and during paroxetine treatment. Am J Psychiatry. 2002 Jan;159(1):145-7.
50. Ritsner M, Maayan R, Gibel A, Weizman A. Differences in blood pregnenolone and dehydroepiandrosterone levels between schizophrenia patients and healthy subjects. Eur Neuropsychopharmacol. 2007 Apr;17(5):358-65.
51. Martin-Garcia E, Pallares M. The neurosteroid pregnenolone sulfate neutralized the learning impairment induced by intrahippocampal nicotine in alcohol-drinking rats. Neuroscience. 2005;136(4):1109-19.
52. Martin-Garcia E, Pallares M. Intrahippocampal nicotine and neurosteroids effects on the anxiety-like behaviour in voluntary and chronic alcohol-drinking rats. Behav Brain Res. 2005 Oct 14;164(1):117-27.
53. Concas A, Sogliano C, Porcu P, et al. Neurosteroids in nicotine and morphine dependence. Psychopharmacology (Berl). 2006 Jun;186(3):281-92.
54. Fiet J, Dore JC, Go AL, Ojasoo T, Raynaud JP. Multivariate analysis of plasma hormones in patients with metastatic prostate cancer receiving combined LHRH-analog and antiandrogen therapy. Prostate. 1993;23(4):291-313.
55. Geldof AA, Dijkstra I, Newling DW, Rao BR. Inhibition of 3 beta-hydroxysteroid-dehydrogenase: an approach for prostate cancer treatment? Anticancer Res. 1995 Jul;15(4):1349-54.
56. Bicikova M, Szamel I, Hill M, Tallova J, Starka L. Allopregnanolone, pregnenolone sulfate, and epitestosterone in breast cyst fluid. Steroids. 2001 Jan;66(1):55-7.
57. Angeli A, Dogliotti L, Naldoni C, et al. Steroid biochemistry and categorization of breast cyst fluid: relation to breast cancer risk. J Steroid Biochem Mol Biol. 1994 Jun;49(4-6):333-9.
58. Bradlow HL, Hershcopf R, Martucci C, Fishman J. 16 alpha-hydroxylation of estradiol: a possible risk marker for breast cancer. Ann NY Acad Sci. 1986;464:138-51.
59. Chen YH, Huang LH, Chen TM. Differential effects of progestins and estrogens on long control regions of human papillomavirus types 16 and 18. Biochem Biophys Res Commun. 1996 Jul 25;224(3):651-9.