Pregnenolone and Mental Function
Pregnenolone is the precursor
(building-block) for all other steroid hormones. It is converted
directly into DHEA and/or progesterone. DHEA converts to
testosterone and estrogens; progesterone converts to estrogens,
cortisol, and aldosterone. It is this succession of conversions
that makes human life possible. Without pregnenolone, there can
be no human steroid hormone production.
Made from cholesterol, pregnenolone is a natural steroid hormone
produced primarily in the adrenal glands, but in smaller amounts
by many other organs and tissues of the human body, including
liver, brain, skin, gonads, and even the retina of the eye.
Like many health-promoting hormones, levels of pregnenolone drop
with age. Although the data are not as abundant or definitive
for pregnenolone as they are for DHEA, Dr. Eugene Roberts, a
pioneer in hormone research, believes that the age-related drop
in pregnenolone is as dramatic as the drop in DHEA. At 75, our
bodies typically make 60% less pregnenolone than at age 35. This
is a point of great concern, considering pregnenolones numerous
protective, health-promoting properties.
Energizing, Anti-stress Benefits
Some of the earliest investigations of pregnenolones many
benefits showed it to be an energizing, anti-stress biochemical.
During the 1940s, Drs. Pincus and Hoagland gave 50-100 mg/day of
pregnenolone to various types of factory workers, as well as
pilots and students trained to use a flight simulator. The
factory workers noted improved production rates while taking
pregnenolone. They felt less fatigued, better able to cope with
their jobs and experienced an enhanced sense of happiness and
well-being. Interestingly, workers in stressful job environments
improved more with pregnenolone than those with less demanding
The flight simulation machine was designed to test hand-eye
coordination, learning, memory and stamina. The subjects were to
'fly' the 'plane' correctly, avoiding obstacles and crashes.
Half the subjects were airplane pilots; half were not. Tests
conducted over several weeks showed that the ability of all
subjects to 'fly' the simulated airplane improved significantly
after taking 50 mg pregnenolone before each test run. The
improvement was especially noticeable after the subjects had
taken pregnenolone for at least two weeks. This suggests
pregnenolones anti-stress benefits may be cumulative. Also, the
professional pilots reported that they performed better in their
real flying jobs and that they suffered less fatigue during
their pregnenolone-supplementing period.
Animal studies by Isaacson, Flood, Morely and Roberts have shown
that injection of as few as 15 to 145 molecules (!) of
pregnenolone directly into the areas of the brain that are
thought to www.e memory improved the ability of mice to more
quickly remember the way out of a maze that they had run before.
Preliminary results of St. Louis School of Medicine researcher
R. Sih have shown definite memory enhancement with pregnenolone.
Dr. Sih gave 500 mg pregnenolone or a placebo to men and women
three hours before they were asked to perform 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.
Pregnenolone is known to modulate at least two key nerve
receptor systems in the brain: NMDA receptors and GABA
receptors. NMDA receptors, which weaken with age, are involved
in learning, memory, and alertness. Pregnenolone enhances NMDA
receptor function. GABA receptors promote relaxation, mental
slowing, sedation and sleep. Benzodiazepine drugs (Valium,
Librium, Xanax, etc.) activate GABA receptors, while
pregnenolone inhibits GABA receptors. Thus, too little NMDA
activity combined with excessive GABA activity would tend to
promote mental sluggishness and depression. Since pregnenolone
raises NMDA activity and lowers excessive GABA activity,
pregnenolone seems to be a natural antidepressant. Indeed a
recent study of 27 depressed patients found that their
cerebrospinal fluid (which circulates through the brain and
spinal cord) was significantly lower in pregnenolone than in 10
non-depressed volunteers. Cerebrospinal fluid levels are
generally believed to accurately reflect levels of various
biochemicals in the brain.
During the 1940s, pregnenolone was used successfully as a
treatment for rheumatoid arthritis. A 1950 review article on
pregnenolone reported on a study by Henderson and colleagues
which found that 300 mg pregnenolone/day for 40 days resulted in
a significant decrease in joint pain, tenderness, and spasticity,
with improved strength and range of motion. Another study by
Freeman and colleagues, with 64 patients, used 500 mg of
pregnenolone daily for periods of 2 to 30 weeks. 24 patients
showed striking improvements, and 20 showed minor improvements.
Unfortunately, the advent of the 'wonder drug' cortisone (Cortisol)
in the 1950s caused pregnenolone to be passed by for arthritis
treatment, since pregnenolones results were much slower to
manifest. 'Coincidentally', pregnenolone couldnt be patented by
the drug companies whereas synthetic variants of cortisone could
be (and were) patented. By the time the nightmarish side-effects
of excessive cortisone were widely known by the medical
community in the 1960s (these side effects could include
psychotic breakdown, adrenal failure, and even death),
pregnenolone had been completely forgotten.
Pregnenolones Cortisol-neutralizing Power
Small amounts of cortisol are essential to promote health and
even for life itself. Yet under the prodding of chronic stress
and aging, our adrenal glands often over-produce cortisol.
Indeed, cortisol is the only steroid hormone whose levels tend
to increase with age. The level of all other steroids, including
pregnenolone, tend to decrease (often radically) with age.
Excessive cortisol promotes a host of negative side-effects.
High cortisol levels promote depression, as does chronic,
unremitting stress in many people (which results in chronically
elevated cortisol). Experimental subjects such as factory
workers and airplane pilots who were given pregnenolone under
stressful conditions actually reported an enhanced sense of
well-being and happiness.
The following are indications of an excessive cortisol level:
(1) accelerated skin aging and deterioration;
(2) damaged structure and function of mid-brain regions involved
(3) impaired wound healing, poor skin quality and excessive scar
(4) excess fluid retention and puffy, flabby skin.
(5) poor quality of sleep.
Most of these adverse effects of cortisol are directly
counteracted by pregnenolone. For example, Papa and Kligman
reported in 1965 that topical application of a pregnenolone-containing
skin cream restored youthful properties to aged skin.
Experiments with humans and animals show that pregnenolone
enhances the function of the same pro-memory areas of the
mid-brain that are damaged by cortisol. A 1994 report by Guth
and colleagues found that pregnenolone actually promoted
successful healing of otherwise crippling spinal cord injuries
in rats. Ray Peat, Ph.D., has reported successful use of
pregnenolone to rid the body of cortisol-induced excessive fluid
and puffiness, promoting a more lean and taut, youthful
appearance to the face. Steiger (1993) used a mere 1 mg of
pregnenolone in human volunteers to increase the restorative
delta, slow-wave, stage IV sleep. (Larger doses of pregnenolone
taken inappropriately at night may, however, also promote
insomnia through 'over-energization'). Thus, pregnenolone seems
in many ways to be a natural 'antidote' to the 'dark side' of
cortisol, which tends to manifest ever more with aging and
A major determinant of the bodys ability to detoxify poisonous
chemicals -- such as pesticides, medical drugs, industrial
contaminants and auto exhaust -- is the health and effectiveness
of the Cytochrome P450 enzyme system in the liver. This is one
of the most broad-spectrum, universal detoxifying enzyme systems
possessed by all mammals, including humans. Moderate levels of
cortisol (the 'state-of-siege' anti-stress hormone) promote the
activity of this detox system. However, larger amounts of
cortisol (which is all-too-often over-produced by our adrenal
glands due to aging or prolonged stress) degrade the P450
systems anti-toxin effects. Although pregnenolone does not
affect the rate of synthesis of the enzymes in the P450 system,
it does stabilize these enzymes against the digestive activity
of liver proteolytic enzymes which would tend to break down the
P450 enzymes. Pregnenolone thus increases overall P450 detox
enzyme power by promoting conservation of existing P450 enzymes.
Fortunately, pregnenolone is amazingly safer than other
steroids. Pregnenolone researchers working with both human and
animal subjects since the 1940s have consistently commented on
pregnenolones virtual absence of toxicity. For example, the
classic review article on pregnenolone by Henderson and
colleagues in 1950 states: 'It [pregnenolone] has an extremely
low order of toxicity; [it] has not shown any adverse effects on
endocrine [hormone] physiology ....'
Pregnenolone has been given orally to humans at doses as high as
500 mg/day for as long as 30 weeks without evidence of adverse
effects. Mice given 5 grams (1/6 ounce) per kilogram (2.2
pounds) of body weight suffered no ill effects. This would be
equivalent to a 154 pound (70 kilogram) human ingesting 350
grams (approximately 3/4 pound) per day! In a long-term study,
mice that were given one gram pregnenolone per kilogram of body
weight three times weekly for 50 doses suffered no toxic
reactions -- including no changes in the size and condition of
offspring produced after the 50 doses.
In one human study, eight people received 50 to 150 milligrams
per day by intramuscular injection for 75 days, with no reported
side effects. Dr. Eugene Roberts gave 20 Alzheimers patients 525
mg/day for three months with no toxicity. During rheumatoid
arthritis experiments with pregnenolone, Dr. H. Freeman and
colleagues gave 500 mg pregnenolone/day for up to 30 weeks, with
no toxicity. And Drs. Pincus and Hoagland, two of the pioneer
researchers on pregnenolone use by humans in the 1940s, found no
toxic reactions with pregnenolone used by hundreds of men and
women at dosages of 100 mg/day for four months.
The classic studies on pregnenolone and stress in the 1940s by
Pincus and Hoagland generally used only 50 mg/day to achieve
excellent results, while arthritis studies typically used
200-500 mg daily. Thus, although pregnenolone appears amazingly
safe and beneficial, there are still many unanswered questions
regarding proper dosage, metabolism, and clinical effects.
Keeping these uncertainties in mind, here are some
recommendations for dosage.
For those wishing to err on the side of caution, 50 to 100 mg
pregnenolone per day would probably be suitable for use without
physician monitoring. Perhaps an additional safety margin (for
this already amazingly-safe substance) could be achieved through
discontinuing use for one week every month. Those wishing to use
the higher, anti-arthritis doses (200 - 500 mg/day) should
probably do so only under the supervision of their physician,
even though many human clinical studies with arthritis at these
dosages yielded no problems or toxicities. Morning is the
perfect time to take pregnenolone, and a single daily dose is
probably best, since pregnenolone is fat-soluble, and probably
follows the circadian highs and lows of DHEA and cortisol
(highest in the morning, with a drop to baseline by late
afternoon). On an anecdotal note, there have been patients
taking 100 - 1,000 mg pregnenolone/day intermittently since
1987, with no discernible negative side effects.
While there has been no definite information published as to who
should not take pregnenolone, on theoretical grounds, a few
cautions can be suggested. Since pregnenolone (especially at
high doses) may (in some people) increase estrogen or
testosterone levels, I believe that men with prostate cancer
(which may be worsened by testosterone) and women with breast or
ovarian cancer (which may be worsened by estrogen) should
probably take pregnenolone only with their doctors consent and
supervision. Men with high PSA (prostate specific antigen) blood
levels (possible indicator for undiagnosed or future prostate
cancer) should also proceed with caution with pregnenolone use.
Lastly, because of pregnenolones anti-GABA, pro-NMDA action,
persons known to suffer from epileptic seizures or who are
taking an anti-seizure medication such as Dilantin, Depakote or
Tegretol should probably only use pregnenolone with their
doctors supervision. Finally, as we age, the body produces
ever-less of the enzyme which converts pregnenolone to DHEA.
Thus, while supplementary pregnenolone taken during middle age
and beyond will produce at least some normalization back toward
more youthful (and healthful) levels of other steroid hormones,
pregnenolone will not completely substitute for other steroid
hormone supplements in those with medically demonstrated needs
for various specific steroids i.e., DHEA, cortisol, estrogen,
source of nutrients and supplements.
did we qualify them ?
Davison, R., et al. Effects of delta 5 pregnenolone in
rheumatoid arthritis. Arch Int Med 85: 365-88, 1950.
Flood, J. et al. Pregnenolone sulfate enhances post-training
memory processes when injected in very low doses into limbic
system structures. Proc Nat Acad Sci USA 92: 10806-10, 1995.
Freeman, H., et al. Therapeutic efficacy of delta 5 pregnenolone
in rheumatoid arthritis. JAMA 143: 338-44, 1950.
George, M., et al. CSF neuroactive steroids in affective
disorders: pregnenolone, progesterone, and DBI Biol Psych
35(10): 775-80, 1994.
Guth, L., et al. Key role for pregnenolone in combination
therapy that promotes recovery after spinal cord injury. Proc
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Henderson, E., et al. Pregnenolone. J Clin Endocrinol 10:
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potency of NMDA in mice. Eur J Pharmacol 219 (3): 477-9, 1992.
Majewska, et al. Neurosteroid pregnenolone sulfate antagonizes
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Pincus, G. and Hoagland, H. Effects of administered pregnenolone
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Pincus, G. and Hoagland, H. Effects on industrial production of
the administration of delta 5 pregnenolone to factory workers.
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Regelson, W. and Colman, C. Pregnenolone: 'The Superhormone for
Your Brain' [material on Dr. R. Sih] in The Superhormone
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Roberts E. Pregnenolonefrom Selye to Alzheimer and a model of
the pregnenolone sulfate binding site on the GABA-A receptor.
Biochem Pharmacol 49: 1-16, 1995.
Steiger, A., et al. Neurosteroid pregnenolone induces sleep EEG
changes in man compatible with inverse agonistic GABA-A receptor
modulation. Brain Res 615: 267-74, 1993.
Warner, M. and Gustaffson, J. Cytochrome P450 in the brain:
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