Pregnenolone is a prohormone used by the body to produce other steroid hormones, such as testosterone, estrogens, progesterone, cortisone, and many others.1 But pregnenolone is also an important brain neurosteroid — that is, a hormonal substance that is both formed and accumulated in the nervous system and is active there. As such, pregnenolone is involved in learning and memory, aggression and epilepsy, and modulation of responses to stress, anxiety and depression.2
Before it was pushed aside by the promotion of other hormones, pregnenolone had been shown to have a wide range of beneficial actions for people who were sick or under stress. These included ameliorating arthritis, countering fatigue, and generally improving the quality of life.2
Experiments in the 1940s showed that 50-100 mg/day of pregnenolone given to factory workers resulted in improved production rates, less fatigue, and an increase in happiness and well-being. Pilots reported also reported less fatigue and an improved ability to fly airplanes. These effects occurred after about two weeks of pregnenolone usage.2
Also during the 1940s, rheumatoid arthritis was successfully treated with pregnenolone. At 300 mg/day for 40 days patients experienced “a significant decrease in joint pain, tenderness, and spasticity, with improved strength and range of motion”.2
In the 1950s, however, a raft of new stimulants, painkillers and anti-inflammatories hit the market, and pregnenolone simply got swept into the backwaters of the pharmaceutical world as the medical profession got caught up in the excitement of new drugs and the money they bring in. It was later discovered that the long-term use of these newer drugs led to serious side effects, but by then pregnenolone had become an unfashionable research topic.
During the past two decades, however, pregnenolone and its sulfate ester have been receiving renewed attention. Many scientific studies give strong experimental support to claims that pregnenolone can be used to enhance memory and reduce stress. There is also evidence that it lessens depression,3 controls ‘bipolar disorder’,4,3 and reduces schizophrenic symptoms5.
The term ‘neurosteroid’ was introduced in the 1980s to refer to pregnenolone and other steroids that can be produced in the brain. Since then, hundreds of studies have been published about these substances and their potential value as treatments for psychiatric illnesses.
Pregnenolone is made from cholesterol in many tissues of the body besides the brain.6 Pregnenolone is the master steroid hormone from which whole families of other hormones are made, including the corticoids, androgens, estrogens, and progestins.1
When pregnenolone is taken orally much of it is absorbed from the digestive tract. Some of it is immediately converted to pregnenolone sulfate which dissolves in the circulating blood, some of it remains unconverted and is thought to be transported in the blood by a carrier protein. When it reaches the brain, some of the circulating pregnenolone and pregnenolone sulfate passes through the blood-brain-barrier into the nervous system,7 whereupon further conversion of pregnenolone to its sulfate is carried out.8 Hence, oral supplements of pregnenolone can elevate the concentrations of pregnenolone and pregnenolone sulfate in the brain beyond what the brain would do on its own.
Experiments have clearly shown that pregnenolone is a powerful stimulator of memory formation.9 So strong is the effect that significant memory-enhancing effects have been seen in mice when just a few dozen molecules of pregnenolone sulfate are injected into certain regions of the brain.10
But does pregnenolone really enhance memory when you take it orally? Incredible as it may seem, neither the medical research establishment nor the supplement industry has bothered to do a clinical study and publish the results. The studies that were performed and published in the 1940s showed definite improvements in mental functions, but they did not specifically measure memory enhancement.
One study of memory enhancement is said to have been done recently at the St. Louis School of Medicine, USA: 500 mg pregnenolone or a placebo were given to volunteers three hours before they performed standard memory tests. “Pregnenolone resulted in improved memory in both men and women, improved spatial memory and perception in men, and improved verbal recall memory in women.”2 The work, however, has not been published in a medical journal.
But we do not have to wait for formal studies to be done before we can reap the memory benefits which pregnenolone presumably has to offer — this supplement is available, affordable, and safe to use in the amounts that are typically recommended for memory enhancement: 50 to 500 mg/day.
Studies in patients with anxiety disorders have shown that higher anxiety levels correlate with lower pregnenolone levels in the blood.11,12 More to the point, experiments with mice demonstrated that when pregnenolone sulfate is administered directly to the brain, anxiety symptoms decrease.13,14 But at very high doses (10 to 100 times the effective dose), mice experienced increased anxiety.
The one published clinical study that has been done in humans used very low oral doses of pregnenolone (15-30 mg/day) and showed no effects on anxiety,15 thereby establishing a lower bound on the effective dose range. In view of the studies on mental function done in the 1940s, these results suggest that anxiety therapy using pregnenolone may require doses in the range of 50-200 mg/day.
Depression and manic-depression (‘bipolar disorder’)
It was reported in 1994 that patients with bipolar disorder have depressed pregnenolone levels in their cerebrospinal fluid.3 Since then, dozens of studies have been performed in mice and rats in an effort to understand how neurosteroids affect brain function. Many investigators have concluded that these substances hold great promise as treatment options for psychiatric illnesses, including depression and bipolar disorder.16,17 Yet, to the discredit of the psychiatric profession, only one clinical trial has been conducted to test this concept18 and the results have not been published.
Fortunately, the snail’s pace at which the medical world moves is no obstacle to people who want to use pregnenolone. They can easily and safely buy pregnenolone and try it for themselves, and many do — in the U.S. at least, where the right of individuals to buy it is protected by an act of Congress.20
Researchers investigating the detailed mechanism by which pregnenolone influences brain function consider pregnenolone a promising treatment for schizophrenia, drug abuse and dementia.16
In a clinical trial conducted in 2005, schizophrenia patients were given pregnenolone for 8 weeks in escalating doses from 100 to 500 mg/day. During the trial the researchers reported that patients “who have been on the higher dose (500 mg/d) have felt better, with an improved sense of energy. Even when blinded to treatment, high-dose patients have asked to remain on pregnenolone.” But the results of the study remain unpublished as of 2007.5
Schizophrenia is a complex illness for which the causal factors may vary somewhat from one patient to another. One would expect that optimum treatments would vary somewhat also. Pregnenolone may be a useful therapy for some patients and not for others. It would be nice to have some clinical data to use as a guide, but the psychiatric profession’s lack of interest in exploring ‘outside the box’ makes it unlikely that we will have this data any time soon. Schizophrenia patients must therefore try pregnenolone on their own if they want an answer to the question “Is pregnenolone right for me?”
Are pregnenolone supplements useful for the conditions and purposes mentioned above? We aren’t allowed to tell you, so you should take a look at some of the references cited here, and then decide for yourself.
A clear, non-technical overview of pregnenolone as a supplement is the one by PDR Health.1 A slightly more technical discussion of pregnenolone and its relationship to other steriods is available in the Wikipedia.19 The article on the Intelegen website offers a broad perspective.2
Warning: Pregnenolone should be avoided by those who are at risk for hormonally related cancers, or who are lactating or pregnant.
 PDRhealth website
 Pregnenolone and Mental Function Intelegen.com website
 CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI. Biol Psychiatry. 1994 May 15; 35(10):775-80 George MS, Guidotti A, Rubinow D, Pan B, Mikalauskas K, Post RM
 Pregnenolone for Bipolar II disorder: Community ratings Revolution Health website. 2005
 A DOSE-FINDING STUDY OF PREGNENOLONE IN PATIENTS WITH SCHIZOPHRENIA Schizophr Bull. 2005 Apr; 31(2):183-575 A. J. Savitz, K. E. Carpiniello, S. M. Silverstein
 Rates of sterol synthesis and uptake in the major organs of the rat in vivo. J Lipid Res. 1981 May; 22(4):551-69 Turley SD, Andersen JM, Dietschy JM
 The regional brain distribution of the neurosteroids pregnenolone and pregnenolone sulfate following intravenous infusion. J Steroid Biochem Mol Biol. 1997 Jul; 62(4):299-306 Wang MD, Wahlström G, Bäckström T
 Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus. Proc Natl Acad Sci U S A. 1997 Dec 23; 94(26):14865-70 Vallée M, Mayo W, Darnaudéry M, Corpéchot C, Young J, Koehl M, Le Moal M, Baulieu EE, Robel P, Simon H
 Neurosteroids and cholinergic systems: implications for sleep and cognitive processes and potential role of age-related changes. Psychopharmacology (Berl). 2006 Jun; 186(3):402-13 George O, Vallée M, Le Moal M, Mayo W
 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 U S A. 1995 Nov 7; 92(23):10806-10 Flood JF, Morley JE, Roberts E
 Neuroactive steroid levels in patients with generalized anxiety disorder. J Neuropsychiatry Clin Neurosci. 2001; 13(3):396-8 Semeniuk T, Jhangri GS, Le Mellédo JM
 Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia. Psychol Med. 2002 Jul; 32(5):929-33 Heydari B, Le Mellédo JM
 Differential anxiolytic effects of neurosteroids in the mirrored chamber behavior test in mice. Brain Res. 1997 Mar 28; 752(1-2):61-71 Reddy DS, Kulkarni SK
 Pregnenolone and pregnenolone sulfate, alone and with ethanol, in mice on the plus-maze. Pharmacol Biochem Behav. 1994 Aug; 48(4):893-7 Melchior CL, Ritzmann RF
 Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. Psychoneuroendocrinology. 2004 May; 29(4):486-500 Meieran SE, Reus VI, Webster R, Shafton R, Wolkowitz OM
 [Effects of sigma receptor ligands on psychiatric disorders] Nihon Shinkei Seishin Yakurigaku Zasshi. 2003 Oct; 23(5):187-96 Kamei H, Noda Y, Nabeshima T, Yamada K
 The antidepressant-like effect induced by sigma(1)-receptor agonists and neuroactive steroids in mice submitted to the forced swimming test. J Pharmacol Exp Ther. 2001 Sep; 298(3):1269-79 Urani A, Roman FJ, Phan VL, Su TP, Maurice T
 Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics. Neuropsychopharmacology. 2006 Jun; 31(6):1249-63 Marx CE, Stevens RD, Shampine LJ, Uzunova V, Trost WT, Butterfield MI, Massing MW, Hamer RM, Morrow AL, Lieberman JA
 Pregnenolone Wikipedia website
 Dietary Supplement Health And Education Act of 1994 Website of the Commission on Dietary Supplement Labels