Pregnenolone and Mental Function
This article first appeared in the
January, 1997
issue of VRP's Nutritional News
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 pregnenolone's numerous protective, health-promoting properties.
Energizing, Anti-stress Benefits
Some of the earliest investigations of pregnenolone's many benefits showed it
to be an energizing, anti-stress biochemical. During the 1940's, 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 tasks.
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 pregnenolone's 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.
Pro-memory Effects
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 which are thought to mediate 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.
Mood Elevation
Pregnenolone is known to modulate at least two key nerve receptor systems in
the brain NMDA receptors and GABA receptors. NMDA receptors, which decrease
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.
Anti-arthritis Effects
During the 1940's, 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 1950's caused
pregnenolone to be passed by for arthritis treatment, since pregnenolone's
results were much slower to manifest. "Coincidentally",
pregnenolone couldn't 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 1960's (these side effects could include psychotic
breakdown, adrenal failure, and even death), pregnenolone had been completely
forgotten.
Pregnenolone's 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.
Excessive Cortisol
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 in memory;
(3) impaired wound healing, poor skin quality and excessive scar tissue;
(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 chronic stress.
Chemo-protective Action
A major determinant of the body's 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 system's 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.
Safety
Fortunately, pregnenolone is amazingly safer than other steroids.
Pregnenolone researchers working with both human and animal subjects since
the 1940's have consistently commented on pregnenolone's 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; 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 Alzheimer's
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 1940's, found no toxic reactions with pregnenolone used by hundreds of
men and women at dosages of 100 mg/day for four months.
Dosage
The classic studies on pregnenolone and stress in the 1940's 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 a personal note, I have taken 100 - 1,000 mg
pregnenolone/day intermittently since 1987, with no discernible negative side
effects.
Contraindications
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 doctor's 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 pregnenolone's 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 doctor's 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, etc.
Those wishing more detailed information
on pregnenolone, or a good collection of scientific references on
pregnenolone, should consult Pregnenolone
- A Practical Guide by Ray Sahelian, M.D (available from VRP), or chapter 2,
"Pregnenolone - The Superhormone for Your Brain," in The
Superhormone Promise (soon to be available from VRP) by W. Regelson, M.D. and
C. Colman (Simon and Schuster).
References:
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 Nat Acad Sci USA. 91(25):
12308-12, 1994.
Henderson, E., et al. Pregnenolone. J Clin Endocrinol 10: 455-74, 1950.
Maione, S., et al. Pregnenolone sulfate increases the convulsant potency of
NMDA in mice. Eur J Pharmacol 219 (3): 477-9, 1992.
Majewska, et al. Neurosteroid pregnenolone sulfate antagonizes
electrophysiological responses to GABA in neurons. Neuroscience Letters 90:
279-84, 1990.
Pincus, G. and Hoagland, H. Effects of administered pregnenolone on fatiguing
psychomotor performance J Aviation Med 15: 98-115, 1944.
Pincus, G. and Hoagland, H. Effects on industrial production of the
administration of delta 5 pregnenolone to factory workers. Psychosom Med 7:
342-46, 1945.
Regelson, W. and Colman, C. Pregnenolone: "The Superhormone for Your
Brain" [material on Dr. R. Sih] in The Superhormone Promise, Simon and
Schuster, 1996.
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: neuroendocrine
functions. Front Neuroendocrinol 16(3): 224-36, 1995.
Wu, F., et al. Pregnenolone sulfate: a positive allosteric modulator at the
NMDA receptor. Mol Pharmacol 40: 333-6, 1991.