Pregnenolone is a “master” precursor for numerous other important hormones in the body, including dehydroepiandrosterone (DHEA), progesterone, testosterone, estrogen, and cortisol. It is synthesized from cholesterol, and peaks around age 30, after which there is a steady decline until ~age 55 at which point it significantly declines. In fact, one study reported that pregnenolone levels were as much as 60% lower for individuals in their mid-70s compared with those in their mid-30s.
Following diminished pregnenolone production, there is a subsequent (and expected) decline in its downstream hormones -- DHEA, testosterone, and estrogen, in particular. Consequences of these low hormone levels include:
- Brain fog
- Low energy
- Low libido
- Achy joints
- Poor sleep
- Increased risk of cardiovascular events
To combat declining hormone levels (particularly sex hormones), hormone replacement therapy (HRT) has become incredibly popular, not only with aging adults but younger adults looking to resist the effects of aging (“biohackers”), build more muscle, and optimize body composition. Typical hormones used in HRT protocols include testosterone, estrogen, and progesterone. While these are beneficial, prolonged used of them has been known to lead to various complications, including (but not limited to):
- Endometrial bleeding
- Prostatic hypertrophy
Pregnenolone is often overlooked by hormone/anti-aging clinics, yet researchers posit that utilizing a combination of pregnenolone with “relatively small amounts of sex steroids might give the same physiological effects as would administration of larger amounts of the latter alone.” This, in turn, could achieve the same end result/benefits with less risk of adverse side effects.
As a result, pregnenolone supplements may be an option to support optimal hormone levels and promote healthy aging, as it is the “mother” hormone. In fact, the anti-inflammatory and anti-fatigability properties of pregnenolone have been recognized since the 1930s.[20,21]
Here are some of the top benefits of pregnenolone supplements:
Primary Benefits of Pregnenolone Supplements
Anti-Stress & Anti-Fatigue
Stress is inherent to the human condition, which means there’s no getting around it -- there will be instances (physical, emotional, psychological, etc.) that stress your mind and/or body. Now, it’s important to realize that not all stress is bad. In fact, some stress is not only beneficial (e.g. resistance training, HIIT, etc.) but necessary as it serves as a powerful signal to our physiology that it needs to “batten down the hatches” after which it will become stronger and more resilient.
Where stress goes “bad” is when the volume and/or magnitude of stress exceeds the body’s ability to recover. This leads to chronically elevated of cortisol (the body’s primary stress hormone), which has numerous deleterious effects, including:
- Disrupted sleep
- Impaired energy metabolism / nutrient storage
- Poor mood
- Reduced feelings of well-being
- Decreased motivation & productivity
- Lower libido and testosterone levels
- Decreased athletic performance and recovery
- Elevated blood pressure
- Impaired immune function
In addition to making the requisite lifestyle changes (diet, sleep, exercise, stress management, breaking up with a batshit crazy girlfriend, leaving a job that makes you miserable, etc.), certain supplements may also help alleviate feelings of stress and anxiety. Common ones I’ve discussed before include L-Theanine, Ashwagandha, Lemon Balm, and Magnolia Bark.
Pregnenolone is another stress-relief supplement that doesn’t get the attention it deserves but does offer some interesting stress-relief benefits.
Up top, I mentioned that pregnenolone is a precursor to cortisol, and this might make you think that supplementing with pregnenolone might increase baseline cortisol levels, but that’s a bit of an oversimplification.
Pregnenolone, in addition to facilitating steroid hormone synthesis, also exerts a number of other effects throughout the body. One of those many actions is as a neurosteroid.
Research notes the pregnenolone sulfate (the primary form of pregnenolone found in the body as well as that which is included in dietary supplements) acts as both a negative modulator of GABA and a positive modulator of the N-Methyl-D-Aspartate (NMDA).[2,3,4,5]
Note: GABA is the body’s primary inhibitory neurotransmitter, and NMDA is an excitatory neurotransmitter (and NMDA receptors are a binding site for glutamate -- another major excitatory neurotransmitter).
Due to this dual-action on opposing neurotransmitter systems, researchers note that “PREG-S (pregnenolone sulfate) could exert a remarkable synergistic amplification of excitatory transmission at much lower concentrations than would be expected from effects of PREG on either the inhibitory or excitatory system alone.”
Additional studies investigating doses ranging from 25-75mg pregnenolone found improvements in performance under stressful conditions (i.e. greater productivity), less fatigue, and improved feelings of well-being. Research also noted that the effects seemed to compound with time with no adverse side effects.
Another thing to note is that pregnenolone may also be converted to allopregnanolone, and researchers have found it may offer some interesting results based on the dosage used in animal studies. In particular, low doses of allopregnanolone may have an adverse, anxiogenic effect. This effect decreases with increasing doses of allopregnanolone and the beneficial and calming property occurs.[6,7]
These calming properties are, in part, due to the way allopregnanolone interacts with GABA-A receptors.
Memory & Cognition
As is the case with natural hormone production, many other aspects of life decline with age (let alone the other lifestyle factors -- drinking, smoking, stress, sleep deprivation, etc. -- that can accelerate said degradation).
Two such critical components of daily life that decline with age are memory and cognitive function. Chronic stress and sex steroids are also known to adversely impact memory and are also linked to the development of dementia.
My fascination (“obsession”) with brain health/performance has led me to explore numerous nootropics over the years that not only improve cognitive function in the short term, but also help combat cognitive decline and support healthy aging. I’ve covered many of these over the years, but it wasn’t until doing research for this article (courtesy of long-time listener/reader Devin) that I was aware of the brain-boosting benefits of pregnenolone.
Figure3: Cholesterol Metabolism
In addition to modulating GABA, pregnenolone Other research indicates that GABA-A antagonists facilitate LTP while diazepam blocks LTP in hippocampal slices.
Research has shown that Alzheimer’s patients have lower levels of pregnenolone, allopregnanolone (a pregnenolone metabolite) and DHEA-sulfate in all key memory-related areas of their brains, compared to individuals without Alzheimer’s.[11,12,13]
Supplementing with pregnenolone is a viable option to help increase the body’s pregnenolone “reservoir” which can then be used to produce the downstream hormones.
Additionally, pregnenolone has also been shown to increase acetylcholine levels. Acetylcholine (dubbed the “learning neurotransmitter”) is heavily involved in memory, learning, muscle contractions, and the mind-muscle connection.
Animal studies have also found that infusions of pregnenolone sulfate stimulate neurogenesis -- the process by which new neurons are produced.
To top it off, pregnenolone (as well as allopregnanolone) are considered by researchers to have “immense neuroprotective potential.”
Previous studies conducted in mouse hippocampus cells noted that allopregnanolone offered neuroprotective properties against glutamate and amyloid beta protein neurotoxicity.
A recent 2022 animal study found that pregnenolone also reduced the neurological impairments via reducing mitochondrial reactive oxygen species (ROS). In case you weren’t aware, ROS are a contributing factor towards inflammation (including neuroinflammation) as well as cognitive decline.
Pregnenolone provides neuroprotection by reducing reactive oxygen species (ROS).
Combating Drug Abuse Side Effects
Research has found that cocaine-using individuals supplementing with 500 mg/day of pregnenolone demonstrated lower stress-induced heart rate and blood pressure. Furthermore, pregnenolone supplementation also may help decrease cocaine cue-provoked craving and anxiety and reduces stress-induced autonomic arousal in individuals with CUD.
Animal studies have shown that pregnenolone sulfate injections may attenuate memory impairment caused by alcohol and nicotine.[23,24] Remember that chronic excessive alcohol intake downregulates GABAergic transmission and reduces levels of neuroactive steroids.
Newly published research, appearing in the January 2023 edition of Psychopharmacology, found that humans with alcohol use disorder consuming 300mg/day pregnenolone decreased stress- and alcohol cue-induced craving and reduced stress-induced anxiety.
Pregnenolone may also protect the brain against the intoxicating effects of marijuana. Cannabinoid drugs, including marijuana, modulate brain activity and behavior principally by activating cannabinoid-1 (CB1) receptors. This, in turn, inhibits the release of several neurotransmitters, in particular GABA and glutamate. Animal studies found that injections of pregnenolone inhibited the increase in food-intake and memory impairment, commonly seen with marijuana use.
Pregnenolone injections inhibited the increase in food-intake in (A) ad-libitum fed Wistar rats [F(3,94) = 3.65; p < 0.02] and in (B) 24h-food deprived C57Bl/6N mice, as well as (C) the memory impairment [F(3,23) = 24.6, p < 0.001] induced by THC in C57Bl/6N mice.
Interestingly, marijuana increases levels of pregnenolone. This naturally made researchers curious as to why pregnenolone injections demonstrated protective effects. They surmised that:
“Pregnenolone then, acting as a signaling specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals an unknown paracrine/autocrine loop protecting the brain from CB1 receptor over-activation that could open an unforeseen novel approach for the treatment of cannabis intoxication and addiction.”
Additional Benefits of Pregnenolone
In addition to serving as a precursor for steroid (including neurosteroid) hormones, pregnenolone is also a precursor for hormones involved with lymphocytes (white blood cells). Researchers have also shown that chronic stress, sleep deprivation, systemic inflammation, and a whole host of other factors contribute to increased infection and reduced immune function.
Cell studies indicate that pregnenolone, allopregnanolone, and progesterone (a derivative of pregnenolone) may significantly suppress LPS- or Pam3CSK4-induced TNF-α (an inflammatory cytokine) in macrophages.
Pregnenolone may also help reduce feelings of stress and chronically elevated cortisol levels (two factors known to impair immune function and increase risk of infection).
Early research on pregnenolone suggests it may also benefit individuals with arthritis.[2,26] This is likely due, at least in part, to its anti-inflammatory effects discussed above. Doses varied quite wildly in arthritic research from 100-300mg per day (as pregnenolone acetate) all the way up to 12,000mg (12 grams)!
Researchers noted that “Clinically, it is apparent that some patients who eventually respond well may not exhibit any change at all during the first few weeks of treatment. It seems advisable, therefore, for treatment to be continued for three to four weeks before final evaluation is attempted in any one patient.”
Animal studies indicate that pregnenolone sulfate may increase REM sleep without affecting slow-wave sleep or wakefulness.
Suggested Dosage of Pregnenolone
A wide range of dosages of pregnenolone have been investigated in humans over the past several decades, from as low as 50mg all the way up to 12,000mg per day.
Pregnenolone supplementation, as described in research, is generally well-tolerated and without significant side effects for the majority of individuals. A 1950 review on pregnenolone concluded that, “The substance has an extraordinarily low order of toxicity…It appears, moreover, that very large doses can be employed without danger of side-effects.”
Pregenonolone supplements also appear to be most beneficial when taken consistently ("daily" for several weeks at a time) as opposed to occasionally.
Most supplements on the market today include between 50-100mg pregnenolone sulfate.
Pregnenolone is a neurosteroid naturally produced by the body that serves as the “mother” hormones for numerous other hormones in the body that exert a multitude of effects. Based on the current body of research, pregnenolone possesses a high safety profile and seems like a viable option to support mood, mental energy, stress levels, and brain health.
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Does pregnenolone really work? ›
Since pregnenolone is a precursor in the synthesis of other hormones, sometimes it is advertised to boost the production of other hormones and may make people feel more energetic and younger. There is no clear scientific evidence that pregnenolone is effective for this purpose.Is pregnenolone approved by FDA? ›
Pregnenolone is not available as an FDA-approved product. Pregnenolone is available as an oral and sublingual OTC supplement in the US.What does pregnenolone do for the brain? ›
Pregnenolone and its metabolic derivatives have been shown to have beneficial effects in the brain, including enhancing memory and learning, reversing depressive disorders, and modulating cognitive functions.What are the dangers of pregnenolone? ›
In some people, pregnenolone can cause skin rashes, acne, hair loss, diarrhea or constipation, problems sleeping, restlessness, agitation, sweating, or tremor. It may also cause irregular heartbeat, depressed mood, a change in appetite, or muscle pain.How do I know if I need pregnenolone? ›
If you feel that you suffer from poor memory and concentration, frequent fatigue, dry skin, joint and muscle pain, or decreased sex drive, then you may want to consider a dietary supplement for hormones.Which is better pregnenolone or DHEA? ›
DHEA is better known and many people know a little about it. It is even used in higher doses for fertility in women. Pregnenolone is not well researched and a lot more needs to be done. It is known as the 'brain' hormone as that's one of its main function.Is pregnenolone anti aging? ›
We now know pregnenolone may help prevent or ease many of the effects of aging. For some, improved memory, increased energy levels, or elevated mood may be just what the doctor ordered. For others, preventing the onset of Alzheimer's disease, arthritis, or coronary heart disease are important health goals.Does pregnenolone block cortisol? ›
Pregnenolone can inhibit the production of cortisol, meaning it is an effective stress reducer, can aid with weight loss and helps immunity. By reducing cortisol levels, pregnenolone has the effect of naturally boosting testosterone levels which can increase metabolism and lead to weight loss.Should I be taking pregnenolone? ›
Stay on the safe side and avoid use. Hormone-sensitive condition such as breast cancer, uterine cancer, ovarian cancer, endometriosis, or uterine fibroids: Pregnenolone is converted by the body to estrogen. If you have any condition that might be made worse by exposure to estrogen, don't take supplemental pregnenolone.How does pregnenolone make you feel? ›
Possible Side Effects
However, there's some concern that pregnenolone may trigger a number of side effects, including insomnia, anxiety, mood changes, headache, and irregular heart rhythm. It also has the potential to cause facial hair growth or hair loss.
Why is pregnenolone called the mother of all steroid hormones? ›
One of the hormones you probably have not heard of is PREGNENOLONE (P). It is a hormone made in the adrenal gland and is considered the mother of steroid hormones because it is the precursor or the first hormone that then becomes the hormones testosterone, DHEA, estradiol, cortisol and progesterone.What happens when you stop taking pregnenolone? ›
You may experience restlessness, high levels of anxiety, and nervousness. Some people report depression, fatigue, and even paranoia when stopping the supplement. The safest way of withdrawing from this supplement is to reduce your dosage by no more than 10mg per day.Does pregnenolone increase dopamine? ›
Pregnenolone sulphate dose-dependently increased dopamine release in the nucleus accumbens. Furthermore, this hormone doubled the dopaminergic response to morphine. These effects were observed for Preg-S doses of 100, 200, and 400 pmol injected intracerebroventricularly.What happens when your pregnenolone is low? ›
What does it mean if your Pregnenolone result is too low? Pregnenolone levels naturally decrease as a person ages. A deficiency in pregnenolone can result in deficiency in other hormones. Symptoms can include decreased sex drive, depression, fatigue, impaired memory, loss of bone density and decreased muscle mass.Does pregnenolone affect thyroid? ›
Pregnenolone-16α-carbonitrile (PCN) and Aroclor 1254 (PCB) both reduce serum thyroid hormone levels in rats, but only PCN consistently produces an increase in serum thyrotropin (TSH).Can pregnenolone cause hair growth? ›
Apart from the natural aging process, another reason for taking pregnenolone is to promote a rise in other steroid hormones like testosterone. However, too much can lead to alarming hair growth on the face and body.Can pregnenolone cause blood clots? ›
On the contrary, the use of oral contraceptives has been known to aggravate the issue of blood clotting. Likewise, taking hormones, such as pregnenolone and estrogen, results in the same. In actuality, oral contraceptive usage and hormone therapy play a role in worsening the risk of clotting.What depletes pregnenolone? ›
A high-stress lifestyle can lead to an increase in cortisol which can deplete pregnenolone, causing supplementation to be needed to replace the prohormone.What causes pregnenolone deficiency? ›
But sometimes your pregnenolone levels become low. This could happen because of various reasons. Menopause is one reason. Another is adrenal fatigue and the adrenal's inability to convert cholesterol to pregnenolone.Does pregnenolone help adrenal fatigue? ›
Either pregnenolone or progesterone can better be used to raise the hormonal levels in both men and women, and decrease some aspects of adrenal fatigue.
What is the mother of all hormones? ›
San Diego - The hormone dehydroepiandrosterone (DHEA), also known as the mother of all hormones, is the precursor of androgens and estrogens and is tagged by some physicians as a wonder drug when supplements are taken for certain disease states and in certain doses.How much pregnenolone should a woman take? ›
P2. A typical recommended dosage of pregnenolone is 30 mg daily, but some studies have used as much as 700 mg.When is the best time to take pregnenolone? ›
Pregnenolone is a powerful steroid hormone that acts to reduce the effects of stress on the body. Take as indicated per day with a meal in the morning or early afternoon‚ preferably on an empty stomach. For best results, take it in the morning.Does progesterone keep you looking younger? ›
Estrogen and progesterone have many characteristics that aid in preventing aging signs on your skin. For example, they naturally increase hyaluronic acid (HA) and prevent the loss of collagen and elastin.What hormones stop aging? ›
Human growth hormone is described by some as the key to slowing the aging process. Get the facts about these claims. Growth hormone fuels childhood growth and helps maintain tissues and organs throughout life. It's produced by the pea-sized pituitary gland — located at the base of the brain.Which hormone is responsible for aging? ›
Solution : ABA is a plant growth inhibitor. It promotes senescence and ageing in plant parts.Does pregnenolone increase GABA? ›
Pregnenolone sulfate (PS) is a sulfated neurosteroid which reduces the responses of the γ-aminobutyric acid A (GABAA) receptor.Can pregnenolone help with anxiety? ›
Recent basic science and clinical evidence indicate that GABAergic neuroactive steroids and their neuroactive precursor pregnenolone (PREG) normalize the stress response and reduce drug craving, anxiety, and drug intake [9–12], suggesting that PREG may be acting by normalizing stress system upregulation and potentially ...What is the grandmother hormone? ›
Nicknamed the “grandmother hormone,” pregnenolone is a precursuor to DHEA, which in turn can convert to testosterone, estrogen, and progesterone. It is a sterioid manufactured from cholesterol and is produced in the brain and the adrenal cortex. It works to keep the brain functioning at peak capacity.What foods are high in pregnenolone? ›
That is why it is important to eat more healthy fats such as avocados, coconut oil, olive oil, walnuts, fish, chia seeds, and flax seeds. When the body metabolizes these fats, a hormone called pregnenolone is formed. Pregnenolone is a precursor to estrogen, progesterone, DHEA, testosterone, and cortisol.
Can pregnenolone balance hormones? ›
Pregnenolone plays a key role in hormonal balance as a key precursor to cortisol, progesterone, and DHEA, which can later convert into estrogens and testosterone. Pregnenolone helps to maintain balance in the body's stress response system.Can pregnenolone make you gain weight? ›
Pregnenolone Aids Weight Loss
Additionally, because cortisol is closely related to gaining visceral abdominal fat, using pregnenolone supplements may also prevent weight gain due to the fact that pregnenolone inhibits cortisol overproduction.
DHEA is better known and many people know a little about it. It is even used in higher doses for fertility in women. Pregnenolone is not well researched and a lot more needs to be done. It is known as the 'brain' hormone as that's one of its main function.Does pregnenolone help balance hormones? ›
It is vital to have a healthy pregnenolone balance in the body in order to balance other hormones. When pregnenolone levels are low, your body can not create enough other hormones, causing hormonal imbalances which can affect your daily functioning.Why is pregnenolone the mother of all hormones? ›
Pregnenolone is a vital hormone that is manufactured in the body. It is nicknamed “The Mother Hormone” because it is the first hormone in the pathway that generates a host of key neurohormones in the brain that affect cell growth. Because of Pregnenolone's balancing effect, it may be one of the most important hormones.Is hair loss a side effect of pregnenolone? ›
Women may have facial hair or hair loss if there is too much pregnenolone in the body. This is because pregnenolone, the mother of all steroid hormones in our body, is a precursor to testosterone. Testosterone then is converted to DHT which causes hair loss.How do I get rid of my hormonal belly? ›
Before you rush to your doctor to get a prescription for your hormonal belly, there are natural ways to readjust your levels. Reducing sugar intake, eliminating processed foods from your diet, and avoiding things like dairy, alcohol, and caffeine can all help reset your blood sugar and insulin levels.