Pregnenolone Uses, Side Effects & Safety

Pregnenolone: What You Need to Know

Pregnenolone Uses, Side Effects & Safety

In the latest installment of our Ask the Scientists blog, we sat down with our resident experts to answer some of the most commonly asked questions concerning the use of Pregnenolone.

What is Pregnenolone?

Pregnenolone is a hormone naturally produced in the body by the adrenal gland.  Pregnenolone is also made from cholesterol, and is the starting material in the production of testosterone, progesterone, cortisol, estrogen and other hormones.  Because the body uses it biochemically as starting material, pregnenolone is sometimes referred to as a “precursor” or “pro-hormone”.

What about Pregnenolone in dietary supplements?

The legal status of pregnenolone in dietary supplements has not been explicitly stated by the FDA, and is often determined on a case by case basis.

If pregnenolone is present in a dietary supplement as a constituent or extract of adrenal glands, then the FDA may conclude it qualifies as a dietary supplement ingredient. On the other hand, the FDA may have a different opinion on synthetically produced pregnenolone.

The FDA issued a warning letter to a compounding pharmacy for illegally compounding with pregnenolone (to see the warning letter, go to and search for “American Hormones Warning Letter”)[1].

In this warning letter, the FDA makes it clear that it considers pregnenolone an unapproved new drug [2]. Furthermore, it appears it was once an approved topical drug, which may also preclude it from use in dietary supplements.

What is Pregnenolone used for?

There has been interest in pregnenolone for a long time as an anti-aging compound, for hormone replacement and to treat a myriad of medical conditions.

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 a banned substance?

Pregnenolone is not on the World Anti-Doping Agency (WADA) Prohibited List. However, WADA reviews and updates the List annually and substances can be added to the List at any time. Therefore, you should always double check the current status of any substance on before using it.

Since Pregnenolone is not prohibited, can I go ahead and use it?

Yes, you may use pregnenolone without incurring an anti-doping rule violation. However, by doing so you also must accept all risks inherent to the supplement and compounding industry.

USADA considers the use of any dietary supplement that claims to deliver or “boost” hormones to be especially risky. To learn more about risks associated with the supplement industry, visit

You can also read more about compound pharmacies.

Can I get a Therapeutic Use Exemption for a compounded formulation of Pregnenolone?

No. A TUE is not required for pregnenolone because it is not prohibited.


[2]See section 201(ff)(3)(B)(i) of the Federal Food, Drug, and Cosmetic Act

*Original article posted September 2, 2015. This article was amended on June 14, 2017, and again on 6/29/2019. 


Benefits of Pregnenolone: What Is It & Why You Should Be Taking It

Pregnenolone Uses, Side Effects & Safety

In order to achieve balance and good health, it is essential to consider every possible factor that could be causing you to feel unwell or sync. One of the important steroid hormones to take into account is pregnenolone, which when properly balanced can have a whole host of important benefits.

Pregnenolone is the main steroid produced in your body from cholesterol and is produced in the brain, gonads and adrenal glands, it is also the main precursor of other steroid hormones, including allopregnanolone.

There are many benefits to supplementing your body’s natural pregnenolone production, including mood, brain function, memory and sleep, but it is essential that it is prescribed to you by your doctor to ensure its use is properly monitored.

1. Cognitive & Memory Function

Taking pregnenolone can have a fantastic effect on your cognitive function, as it helps to increase the growth of neurons in the brain. By enhancing the production of myelin, a fatty layer that insulates nerves and boosts their function, it leads to the formation of new synapses and acts as a neuroprotector. Studies have also shown that pregnenolone improves learning and memory.

2. Improves Mood, Depression & Anxiety

It has been shown that low levels of pregnenolone and allopregnanolone are linked to depression and anxiety and therefore supplementing their levels can have significant mood-boosting effects. Not only that, but it has also been proven to help control emotions, reduce negative emotional responses and improve function in social and emotional situations.

3 Improves Sleep Performance

Studies have shown that pregnenolone and its derivative allopregnanolone, can stimulate deep sleep, making it ideal for patients who suffer from sleep disturbance or insomnia.

Human studies have shown that supplementing with pregnenolone increases the amount of time that a person spends in deep sleep (slow wave sleep). This, in turn, can have a positive impact on mood, anxiety and even memory, helping to consolidate the other benefits of pregnenolone.

4. Aids Weight Loss

Pregnenolone inhibits the production of cortisol, which is one of the reasons it is such an effective stress reducer. This has the added benefit of aiding weight loss, as cortisol increases stomach fat. Similarly, by reducing cortisol levels, pregnenolone has the effect of naturally boosting testosterone levels which can increase metabolism and lead to weight loss.

Pregnenolone Side Effects

As with all supplements, we recommend that they are taken under the supervision of a doctor or qualified expert, as improper use can cause unwanted side effects. With pregnenolone, this is particularly important, as it has such a key role to play in the day to day function of your body.

Possible side effects include:

  • Becoming drowsy (it should, therefore, be taken at night, before bed)
  • It can increase anxiety, despite its anti-anxiety properties in the majority of cases

However, it has been shown that pregnenolone is safe for humans and has minimal side effects, making it a great option for many patients. If you are taking pregnenolone and experience side effects, it is best to consult your doctor and reduce or stop your dose until the side effects go away.



Pregnenolone Uses, Side Effects & Safety
Vitamins & Supplements

  • Overview
  • Uses
  • Side Effects
  • Interactions
  • Dosing

Overview Pregnenolone is a chemical that is found in our bodies. It can also be made in a laboratory.

People use it for medicine.

Pregnenolone is taken by mouth to improve symptoms of schizophrenia. It is also used to help fight fatigue, increase energy, enhance memory, and improve mood.

But there is limited scientific research to support these other uses.

In the body, pregnenolone is used to make steroid hormones. Pregnenolone affects many different chemicals in the brain and may play a role in certain psychiatric illnesses. Uses More evidence is needed to rate the effectiveness of pregnenolone for these uses. Side Effects Pregnenolone is POSSIBLY SAFE for most people when taken by mouth for up to 12 weeks.

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 palpitations (irregular heart beat), depressed mood, both increased or decreased appetite, or muscle pain.

Not enough is known about the safety of long-term use of pregnenolone. Stick with short-term use.

Hormone-sensitive conditions 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.

Pregnancy and breast-feeding: There is not enough reliable information about the safety of taking pregnenolone by mouth if you are pregnant or breast-feeding. Stay on the safe side and avoid use.


  • Estrogens interacts with PREGNENOLONEPregnenolone is used in the body to make hormones including estrogen. Taking estrogen along with pregnenolone might cause too much estrogen to be in the body.

    Some estrogen pills include conjugated equine estrogens (Premarin), ethinyl estradiol, estradiol, and others.

  • Progestin interacts with PREGNENOLONEProgestins are a group of hormones. Taking other hormones along with progesterone pills might cause too much hormones in the body. This could increase the effects and side effects of hormone pills.
  • Testosterone interacts with PREGNENOLONEThe body changes pregnenolone into testosterone. Taking pregnenolone along with a testosterone pill might cause too much testosterone in the body. This might increase the chance of testosterone side effects.


The appropriate dose of pregnenolone depends on several factors such as the user's age, health, and several other conditions.

At this time there is not enough scientific information to determine an appropriate range of doses for pregnenolone. Keep in mind that natural products are not always necessarily safe and dosages can be important.

Be sure to follow relevant directions on product labels and consult your pharmacist or physician or other healthcare professional before using.

View References

  • Brown ES, Park J, Marx CE, et al. A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology 2014;39(12):2867-73. View abstract.
  • Devlin TM, ed. Textbook of Biochemistry With Clinical Correlations. third ed. New York: Wiley-Liss Inc., 1992.
  • Fung LK, Libove RA, Phillips J, Haddad F, Hardan AY.Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder. J Autism Dev Disord 2014;44(11):2971-7. View abstract.
  • George MS, Guidotti A, Rubinow D, et al. CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI. Biol Psych 1994;35:775-80.
  • Kardashev A, Ratner Y, Ritsner MS.Add-on pregnenolone with L-theanine to antipsychotic therapy relieves negative and anxiety symptoms of schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. Clin Schizophr Relat Psychoses. 2018;12(1):31-41. doi: 10.3371/CSRP.KARA.070415. View abstract.


Mother of All Hormones?

Pregnenolone Uses, Side Effects & Safety

Yes, you read that right, and we're not talking DHEA here. Without this “mother” hormone your body couldn't produce other hormones estrogen, progesterone, testosterone, cortisol, or dehydroepiandrosterone (DHEA), for that matter.

This neuroprotective hormone — that nobody is really talking about — has really powerful effects on aging, memory, mood, sexuality, and even sleep.

It is the critical building block in the production of all other hormones that you have heard me writing, talking, or blogging about these days.

In fact, this uber-hormone may be the ultimate raw material in your entire body. It's so essential to health that it's produced not only in the adrenal glands and sex organs, but also in the brain and spinal cord.

There's solid science to back up all the benefits of pregnenolone:

Brain function: Pregnenolone helps raise brain levels of acetylcholine, the neurotransmitter needed for thought processes that is typically low in Alzheimers' patients.

Memory enhancement: It can not only boost memory but also prevent its loss and support memory-protecting sleep, according to animal studies.

Depression and anxiety: Several studies, including two at the University of California, San Francisco, show that pregnenolone can help relieve depression and anxiety. Schizophrenia patients, who are very anxious, generally have the lowest levels of pregnenolone.

Stress and fatigue: Pregnenolone helps counter the effects of stress to lessen fatigue and increase endurance.

Joint pain: Scientists believe it can relieve joint pain as well as rheumatoid arthritis and gout, even when conventional therapies may not help.

PMS and menopause: Researchers conclude that pregnenolone plays a promising role in the pathophysiology of PMS, and according to my colleague and hormone expert Ray Sahelian, M.D., it can help alleviate PMS and menopause symptoms, particularly hot flashes and loss of libido.

Cholesterol: In one study, pregnenolone helped decrease subjects' total average cholesterol levels from 263.5 mg/dL to 187.9 mg/dL, suggesting that balanced hormone levels may stabilize the body's production of excess cholesterol.

Addiction and chemical dependency: A study in the Journal of Pharmacological Science finds that pregnenolone can help combat addictive behaviors and chemical dependency. Researchers at the University of North Carolina at Chapel Hill find that pregnenolone plays an important role in alcohol tolerance and withdrawal.

Overlooked, But Oh So Essential

If this hormone is as terrific as it sounds, why haven't you heard of it before? Good question.

Because pregnenolone is the precursor of the more-familiar hormones cortisol, estrogen, progesterone, testosterone, and DHEA, it seems to have been ignored and overlooked. But, I find the research on this “mother” hormone incredibly compelling.

Over the years, I have come to regard it as an adaptogen that will transform itself into whatever your body actually needs, hormone-wise.

I have found that so many of my clients do really well on low doses of this supplement — especially when estrogen levels need some support. I have been working with salivary hormone testing for nearly a decade. Raising low estrogen levels without resorting to synthetic hormones (which are not tolerated well by many women) has been very challenging. I find that pregnenolone can help.

In the body, pregnenolone is made from cholesterol. In the laboratory it is derived from wild yam — so it is not a steroid-based product. Perhaps this is why a growing number of health professionals are recommending it as a natural alternative to other types of hormone replacement.

I generally recommend that people start with one tablet of 5 milligrams of pregnenolone per day and slowly progress up to two per day — max.

The body's production of this “mother” of all hormones declines with age, stress, depression, hypothyroidism, and environmental toxins. It is outstanding for memory enhancement — perhaps because it can cross the blood-brain barrier!

For more by Ann Louise Gittleman, Ph.D., CNS, click here.

For more on women's health, click here.


What is DHEA and Pregnenolone?

Pregnenolone Uses, Side Effects & Safety

DHEA is the most abundant hormone found in the bloodstream with production peaking around the age of 20-25 when production wanes. By the age of 80, people are thought to have only ten percent of the DHEA they had at 20.

  • Support the body with stress, asthma, arthritis,inflammation, constipation, candida
  • Detoxifies the body
  • Promotes better blood circulation
  • Helps muscle & leg cramps back pain
  • Permits muscles to heal faster
  • Promotes energy, alertness. mental calmness, ability to concentrate
  • Free radical scavenger relieves allergies to foods pollens
  • Helps liver produce choline
  • Helps control acidity & ulcers in stomach
  • Coats intestinal tract so parasites lose ability to hang on
  • Helps with hypersensitivity to drugs
  • Support the body's ability to produce insulin important for carbohydrate metabolism
  • Speeds wound healing

Pregnenolone is the ultimate parent steroid compound.

All steroid hormones in the body (including cortisone, testosterone, estrogen, progesterone, DHEA and others) are produced from pregnenolone, which in turn is synthesized from cholesterol.

Progesterone and DHEA are also parent steroids in the sense that they can give rise to a number of other steroid species, but only pregnenolone is the ultimate precursor of all other steroid hormones.

Levels of endogenous (made in the body) pregnenolone decline with age, as do levels of DHEA. However, normal levels of pregnenolone at various ages for each gender in humans have not been as clearly established as with DHEA.

The pathways from pregnenolone to the many other steroids and the interrelationships among these steroids is complex. While some benefits can be attributed to the relatively direct action of pregnenolone as a memory enhancer, for example many other benefits are a result of one or more of pregnenolone's direct or indirect offspring.

There seem to be many factors that determine how much of the pregnenolone in the body is: 1) used as pregnenolone; 2) converted to and used as DHEA; 3) converted to and used as progesterone; and 4) converted to either DHEA or progesterone and then converted into one or more other hormones (cortisol, testosterone, and the various forms of estrogen). One of those factors is gender. Other factors are more variable throughout life such as the many factors collectively referred to as lifestyle (diet, stress level, exercise habits), the presence of one or more diseases/health conditions, and stage of life (i.e. post menopausal).

Our superior sublingual delivery system assures that you will receive maximum benefit as it absorbed immediately through the mucous membranes and does not need to be processed by the digestive system.

Relative to DHEA, particularly in large amounts, pregnenolone is less ly to create masculinizing effects in women (such as facial hair) because it is less ly to increase testosterone levels in women. Pregnenolone does not seem to have any negative side effects.

However, please consult a health care professional before using pregnenolone if you are pregnant or nursing.

DHEA (dehydroepiandrosterone) is produced by the adrenal glands, which sit atop the kidneys. It is the precursor to the estrogen and testosterone and cortisol pathway.

Much human growth hormone (HGH) and melatonin two other hormones now known to have anti-aging properties DHEA is produced in abundance during youth, peaking around the age of 20-25.

Over stimulation of the adrenals from past abuse (dieting, stimulants, high stress levels, etc.) can exhaust the adrenal synthesis of DHEA.

Research has shown that DHEA has many functions in the body pertaining to health and longevity. Among other things, it helps to generate the sex hormones estrogen and testosterone; increases the percentage of muscle mass; decreases the percentage of body fat; and stimulates bone deposition, thereby helping to prevent osteoporosis.

As DHEA production declines with age, the structures and systems of the body appear to decline with it.

This leaves the body vulnerable to various cancers, including cancer of the breast, prostate, and bladder; as well as to arteriosclerosis, high blood pressure Parkinson disease, diabetes, nerve degeneration, and other age-related conditions.

Previously only available with a doctor's prescription, as a result of the FDA's Dietary Supplement Health and Education Act (DSHEA) ruling in 1995, it is now available as a natural extract which falls into the neutraceutical category.

Most of the DHEA that you buy is made in laboratories from substances extracted from wild yams. Wild yam extract alone is not shown to convert into active DHEA in the body only the specific enzymatically extracted DHEA molecule itself is proven effective.

Being that it is not the entire yam with all its constituents, this is considered to be natural semi synthetic because it is molecularly extracted. The DHEA we sell is identical to the body's DHEA.

While many companies now make it available, Super Good Stuff is the best value because of the potency, delivery system, and price.

It is important to take supplements of antioxidants vitamin C, vitamin E and selenium (or Perfect Plus, containing more than 74 antioxidants) while taking DHEA to prevent oxidative damage.

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A Randomized, Double-Blind, Placebo-Controlled Trial of Pregnenolone for Bipolar Depression

Pregnenolone Uses, Side Effects & Safety

Depression in bipolar disorder (BPD) is challenging to treat. Therefore, additional medication options are needed. In the current report, the effect of the neurosteroid pregnenolone on depressive symptoms in BPD was examined.

Adults (n=80) with BPD, depressed mood state, were randomized to pregnenolone (titrated to 500 mg/day) or placebo, as add-on therapy, for 12 weeks.

Outcome measures included the 17-item Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology—Self-Report (IDS-SR), Hamilton Rating Scale for Anxiety (HRSA), and Young Mania Rating Scale (YMRS). Serum neurosteroid levels were assessed at baseline and week 12.

Data were analyzed using a mixed model ANCOVA with a between factor of treatment assignment, a within factor (repeated) of visit, and the baseline value, as well as age and gender, as covariates. In participants with at least one postbaseline visit (n=73), a significant treatment by week interaction for the HRSD (F(5,288)=2.61, p=0.

025), but not IDS-SR, was observed. Depression remission rates were greater in the pregnenolone group (61%) compared with the placebo group (37%), as assessed by the IDS-SR (χ2(1)=3.99, p=0.046), but not the HRSD. Large baseline-to-exit changes in neurosteroid levels were observed in the pregnenolone group but not in the placebo group.

In the pregnenolone group, baseline-to-exit change in the HRSA correlated negatively with changes in allopregnanolone (r(22)=−0.43, p=0.036) and pregNANolone (r(22)=−0.48, p=0.019) levels. Pregnenolone was well tolerated. The results suggest that pregnenolone may improve depressive symptoms in patients with BPD and can be safely administered.

Bipolar disorder (BPD) is a highly prevalent, challenging-to-treat psychiatric disorder that can greatly impact daily functioning (Goetzel et al, 2003; Kleinman et al, 2003). BPD is present in 1–5% of the worldwide population (Angst, 1998; Ferrari et al, 2011; Merikangas et al, 2007).

Patients with either bipolar I or II disorders are more ly to experience depressive rather than manic symptoms over the course of the illness (Judd et al, 2003; Mitchell et al, 2011) and also frequently experience subsyndromal depressive symptoms (Judd et al, 2003).

Longitudinal studies suggest that individuals with BPD experience even more cumulative depressive episodes than those with major depressive disorder (Mitchell et al, 2011; Perlis et al, 2006; Schaffer et al, 2010).

Furthermore, individuals with BPD are more ly to seek treatment when experiencing a depressed, rather than a manic, episode (Bschor et al, 2012; Ghaemi et al, 2000; Hoertel et al, 2013).

Some traditional antidepressants may be ineffective for bipolar depression (Sachs et al, 2007) and perhaps detrimental to long-term mood stability (Daray et al, 2010; El-Mallakh et al, 2008; Ghaemi et al, 2010; Pacchiarotti et al, 2013; Post et al, 2012). Therefore, additional treatment options for bipolar depression are needed.

Both preclinical and human data suggest that pregnenolone may be a promising treatment for bipolar depression (Carta et al, 2012; Marx et al, 2009; Ritsner et al, 2010). Pregnenolone is an endogenous neurosteroid (Baulieu, 1998) that is a precursor to numerous other downstream steroids, including cortisol, allopregnanolone, dehydroepiandrosterone (DHEA), and progesterone.

Preclinical findings suggest that pregnenolone may have a role in anxiety and depression-regulatory mechanisms (Espallergues et al, 2012; Nothdurfter et al, 2012).

In animal models, social isolation is associated with anxiety, depression, and decreased pregnenolone levels, (Serra et al, 2000) whereas pregnenolone administration is associated with improved performance on cognitive tasks (Flood et al, 1992; Isaacson et al, 1994).

Pregnenolone may act through multiple mechanisms (Roth et al, 2004; Zorumski et al, 2013b), including microtubules (Bianchi and Baulieu, 2012; Fontaine-Lenoir et al, 2006; Murakami et al, 2000) and the CB1 (endocannabinoid) receptor (Vallee et al, 2014), as well as through downstream neurosteroids. Thus, pregnenolone may exert antidepressant effects through novel mechanisms.

In humans, George et al (1994) found that patients experiencing a depressive episode, either unipolar or bipolar type, had lower cerebrospinal fluid (CSF) pregnenolone levels than healthy controls.

More recent work has suggested that pregnenolone and its metabolites modulate functional connectivity in the human amygdala (Sripada et al, 2014) and enhance activation of neurocircuits pertinent to mood and emotions (Sripada et al, 2013).

Clinical trials suggest that pregnenolone and its derivatives, such as allopregnanolone, have potential in treating schizophrenia (Marx et al, 2009; Ritsner et al, 2010; Zorumski et al, 2013b). However, the sample sizes in these studies have been small.

The combination of pregnenolone (30 mg/day) with DHEA was more effective than placebo for positive symptoms and cognition in patients with schizophrenia (Ritsner et al, 2010). Another report in patients with schizophrenia suggested that pregnenolone (500 mg/day) reduced negative symptoms (eg, anhedonia, alogia, affective blunting) of the illness (Marx et al, 2009).

A small study that included both unipolar and bipolar depressed patients suggested improvement in depressive symptoms with pregnenolone (100 mg/day) as compared with placebo (Osuji et al, 2010). Given these data, pregnenolone and other neurosteroids have been suggested as potential therapeutic targets for neuropsychiatric disorders (Sripada et al, 2013; Torrey and Davis, 2012; Zorumski and Mennerick, 2013a; Zorumski et al, 2013b).

We report results from a randomized, double-blind, placebo-controlled trial of pregnenolone (500 mg/day) as an add-on therapy in outpatients with bipolar depression.

The primary aim of this study was to examine the effects of pregnenolone supplementation on depressive symptoms in persons with BPD, depressed phase.

Secondary aims included examining the impact of pregnenolone on anxiety and manic/hypomanic symptoms, as well as exploring the relationship between serum neurosteroid levels and mood symptoms.

Outpatients between the ages of 18 and 75 years who had a diagnosis of bipolar I, II, or NOS disorder and met criteria for a major depressive episode a Structured Clinical Interview for DSM-IV (SCID) (First et al, 1995) and a baseline Hamilton Rating Scale for Depression (HRSD, 17-item version, clinician-rated depression) (Hamilton, 1960) score⩾15 at the time of baseline evaluation were enrolled. Recruitment methods included flyers placed in the Dallas area describing the study, newspaper advertisements in local publications, as well as links to our website. Exclusion criteria included active suicidal ideation with plan and intent, treatment-resistant depression (failure of two adequate antidepressant trials or electroconvulsive therapy (ECT) during current episode), any psychotropic medication changes in the past 10 days, severe or life-threatening medical condition, vulnerable populations (eg, pregnant, incarcerated), heart disease or arrhythmias, current systemic corticosteroid, hormone replacement, warfarin or oral contraceptive use, history of allergic reaction or side effects with previous pregnenolone use, and current substance-use disorder defined as meeting criteria for abuse or dependence the SCID interview and self-reported use within the past 3 months or a positive baseline urine drug screen. Discontinuation criteria included the development of active suicidal or homicidal ideation with plan and intent or clear and progressive worsening of psychiatric symptoms that makes continued care within the research study unsafe in the opinion of the investigator, development of severe or life-threatening medical condition or pregnancy or psychiatric hospitalization, and withdrawal of informed consent by the participant. The study was approved by the UT Southwestern IRB and monitored by a Data and Safety Monitoring Board. After complete description of the study to the participants, written informed consent was obtained. Participants were paid for participation.

At the baseline visit, 80 participants were randomized on a 1 : 1 basis to receive either pregnenolone or matching placebo, both orally administered, as an add-on medication. Commercially available pregnenolone with >99% purity a certificate of analysis was used in the study.

Pregnenolone was encapsulated and the placebo was prepared (using Microcrystalline Cellulose (USP) as an inert substance) by Abram's Pharmacy, Dallas, Texas.

Study medication was initiated at 50 mg twice daily (100 mg/d total), titrated to 150 mg twice daily (300 mg/d) at week 2, and then to 250 mg twice daily (500 mg/d) at week 4, allowing slower upward titration or decreased dose, clinician judgment, and performed in a blinded fashion, side effects and tolerability.

The placebo was identical in appearance to the active medication. Randomization was performed using a random number sequence and assigned by a member of the research team who had no direct contact with study participants. All direct care staff (ie, study physicians and raters) and participants were blinded to treatment assignment.

Baseline evaluation included a medical history, the clinician version of the SCID (First et al, 1995), HRSD17 (Hamilton, 1960), Inventory of Depressive Symptomatology-Self Report (IDS-SR30, self-rated depression) (Rush et al, 2000), Hamilton Rating Scale for Anxiety (HRSA, clinician-rated anxiety) (Hamilton, 1959), and Young Mania Rating Scale (YMRS, clinician-rated manic symptoms) (Young et al, 1978). Possible side effects were evaluated with the Psychobiology of Recovery in Depression III—Somatic Symptom Scale (PRD-III), a 24-item side effects' rating scale developed for a longitudinal depression study at the University of Pittsburgh (Thase et al, 1996).

Blood samples were obtained for routine laboratory analyses at baseline, week 6, and exit.

Serum pregnenolone, allopregnanolone, pregnanolone (spelled pregNANolone throughout the manuscript to distinguish it from pregnenolone), and androsterone levels were assessed at baseline and week 12 at the Durham VA Medical Center/Duke University Medical Center using a highly sensitive and specific gas chromatography/mass spectrometry method as described previously with modifications (Marx et al, 2006a, 2006b). The electron impact ionization mode was utilized rather than negative ion chemical ionization. Mean intra-assay coefficients of variation were 1.8% for pregnenolone, 2.0% for pregNANolone, 4.0% for androsterone, and 3.7% allopregnanolone. Limits of detection were 1 pg for each neurosteroid.

Continuous, approximately normally distributed measures are shown as mean±SD, and percentages describe categorical measures. Baseline characteristics were compared between groups using Student's t-tests for continuous data and chi-square tests for categorical data.

Scores on the HRSD (primary outcome measure) and IDS-SR (secondary outcome measure) were compared between the treatment groups using a mixed model analysis of covariance (ANCOVA) with time (visit week 2, 4, 6, 8, 10, 12) as the within-subjects factor, treatment group (pregnenolone vs placebo) as the between-subjects factor, and baseline measurement, gender, and age as covariates. Additional outcome measures HRSA, YMRS, and PRD-III were analyzed using the same statistical methodology. The hypothesis was tested by the significance of the treatment group by time interaction effect or the treatment group main effect. Covariates were included in the model if p


How Taking Pregnenolone Might Boost Brain Health

Pregnenolone Uses, Side Effects & Safety

Pregnenolone is a steroid hormone that plays a key role in the production of other steroid hormones, including progesterone, DHEA, and estrogen. The substance is found naturally in the body, but some people also take it in supplement form to help keep memory sharp through the years.

Verywell / Cindy Chung

Proponents claim that taking pregnenolone supplements can help to combat age-related memory impairment, as well as protect against a variety of health conditions.

In alternative medicine, pregnenolone is said to aid in the treatment of the following health problems:

  • Alzheimer's disease
  • allergies
  • arthritis
  • depression
  • endometriosis
  • fatigue
  • fibrocystic breast condition
  • menopausal symptoms
  • multiple sclerosis
  • premenstrual syndrome
  • psoriasis
  • scleroderma

Pregnenolone is also used to sharpen memory, reduce stress, stimulate the immune system, promote detox, prevent heart disease, and slow the aging process.

Although a number of animal and human studies published in the 1940s indicated that pregnenolone may help manage arthritis and reduce stress, more recent research on pregnenolone is fairly limited.

However, several studies published in recent years suggest that pregnenolone may offer certain health benefits. Here's a look at some key findings from those studies.

Preliminary research shows that pregnenolone may help protect against aging-related memory impairment. In a 2001 report published in Brain Research Reviews, for instance, investigators analyzed the available studies on steroid hormones and their effects on learning and memory in the aging brain.

But while research in animals demonstrated that pregnenolone may enhance memory, the report's authors note that human-based studies on pregnenolone and memory have yielded mixed results.

Pregnenolone may help alleviate depression, according to an animal-based study published in the Proceedings of the National Academy of Sciences of the United States of America in 2012. In tests on rats, the study's authors determined that pregnenolone may help relieve depression by treating abnormalities in certain components of brain cells.

Pregnenolone shows promise in the treatment of schizophrenia, according to a report published in Neuroscience in 2011.

In their analysis of the available research on pregnenolone and schizophrenia (including a number of animal-based studies and several pilot studies in humans), the report's authors found that pregnenolone may benefit schizophrenia patients by affecting steroid compounds in the brain. The report also indicates that pregnenolone may aid in schizophrenia treatment by increasing brain levels of gamma-aminobutyric acid.

Due to a lack of research, little is known about the safety of long-term or regular use of pregnenolone supplements. 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.

Since pregnenolone can influence hormone levels, avoid using pregnenolone if you have or are at risk for hormone-sensitive conditions (such as breast cancer, prostate cancer, endometriosis, and uterine fibroids). California requires a label regarding a possible risk of promoting hormone-dependent cancers.

There is not enough scientific data to provide a recommended dose of pregnenolone. Due to the limited research, it's too soon to recommend pregnenolone as a treatment for any condition.

 It's also important to note that self-treating a condition and avoiding or delaying standard care may have serious consequences.

If you're considering using it for any health purpose, make sure to consult your physician first.

Keep in mind that supplements haven't been tested for safety and dietary supplements are largely unregulated. In some cases, the product may deliver doses that differ from the specified amount for each herb.

In other cases, the product may be contaminated with other substances such as metals.

 Also, the safety of supplements in pregnant women, nursing mothers, children, and those with medical conditions or who are taking medications has not been established.

If you're seeking a natural remedy to help preserve memory, some studies show that increasing your intake of antioxidants and omega-3 fatty acids may have memory-enhancing effects.

A number of alternative therapies may also aid in the treatment of depression. For example, herbs such as St. John's wort might help relieve symptoms of depression, while mind-body practices acupuncture and meditation could help improve mood. Additionally, regular exercise and time spent outdoors have been shown to reduce stress and improve mood.

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  • Pregnenolone. Natural Medicines Database. Professional Monograph. 3/4/2019
  • Bianchi M, Baulieu EE. “3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders.” Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1713-8.
  • Marx CE, Bradford DW, Hamer RM, Naylor JC, Allen TB, Lieberman JA, Strauss JL, Kilts JD. “Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence.” Neuroscience. 2011 Sep 15;191:78-90.
  • Vallée M, Mayo W, Le Moal M. “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.


Pregnenolone: A ‘Prohormone’ that May Help Relieve Depression

Pregnenolone Uses, Side Effects & Safety

Are you concerned about your memory performance as you age? Maybe you are looking to boost your cognitive health and want to use natural sources to stay mentally sharp. Aside from brain foods that boost focus and memory, a steroid called pregnenolone is gaining attention for its potential neuroprotective effects.

Pregnenolone supplements are said to aid in the treatment of several health conditions, including depression, anxiety, schizophrenia and Alzheimer’s disease.

What does the scientific research suggest about the efficacy and safety of this supplement? Before you order a bottle, read up on the latest pregnenolone research.

You may be surprised to find out how little is actually known about the uses of pregnenolone supplements for humans.

There seems to be a lot of potential for it as a therapeutic agent, but there are some uncertainties that remain in question.

What Is Pregnenolone?

Pregnenolone is a prohormone that serves as a precursor (or “starting material”) for numerous steroids, including cortisol, progesterone, dehydroepiandrosterone (DHEA) and allopregnanolone. It’s used to make steroid hormones that play an important role in modulating brain activity and behavior. Steroids are also needed to regulate physiological activities memory, mood, food intake, wakening and reproduction.

Pregnenolone is the main steroid that’s synthesized from cholesterol in humans and animals. It has three main sources of synthesis: the brain, adrenal glands and gonads. (1)

Studies show that this compound may have a role in regulating the mechanisms of anxiety and depression. There’s also evidence to suggest that pregnenolone administration is associated with improved performance on cognitive tasks and aging-related impairments. (2)

4 Potential Pregnenolone Benefits

  1. Helps Improve Depression
  2. May Reduce Symptoms of Schizophrenia
  3. May Improve Memory
  4. Potentially Reduces the Effects of THC

1. Helps Improve Depression

Research conducted in the last decade shows that pregnenolone may have beneficial effects on mood and cognition. In fact, it may work as a natural remedy for depression.

A 2014 randomized, double-blind and placebo-controlled trial conducted at the University of Texas Southwestern Medical Center in Dallas found that pregnenolone may improve depressive symptoms in patients with bipolar disorder or manic depression.

When adults with bipolar disorder and depressed mood were randomized into two groups — one receiving 500 milligrams a day of pregnenolone and one receiving placebo — as a add-on therapy for 12 weeks, those taking the prohormone displayed greater depression remission rates.


Another study involving patients with bipolar disorder or recurrent major depressive disorder and a history of substance abuse sought to determine whether or not pregnenolone is useful for improved cognition and mood.

Seventy patients were randomly assigned to receive the prohormone or a placebo for eight weeks. The pregnenolone group ended up showing trends toward greater improvement compared to the placebo group.

This suggests that the prohormone may be associated with some improvement in manic and depressive symptoms. However, it didn’t display major benefits for cognition in this study. (4)

2. May Reduce Symptoms of Schizophrenia 

Because pregnenolone is a neurosteroid, it’s been studied for its potential therapeutic role for neuropsychiatric disorders, including schizophrenia.

In 2010, research published in the Journal of Clinical Psychiatry found that when patients with chronic schizophrenia or schizoaffective disorder were given 30 milligrams of pregnenolone a day for an eight-week period, they experienced significant reductions in symptoms. The patients also saw improvement in attention and working memory performance. (5)

In 2009, researchers at Duke University Medical Center’s Department of Psychiatry and Behavioral Sciences found that taking 500 milligrams of pregnenolone a day for an eight-week period led to significant improvements in symptoms of schizophrenia, such as the inability to feel pleasure (anhedonia), lack of speech and lack of emotions. (6)

3. May Improve Memory

Studies involving rodents have showed that pregnenolone positively affects learning and memory.

In 1992, researchers the Veterans Administration Medical Center in Saint Louis found that the administration of this prohormone to male mice improved memory when using a “footshock” experiment. Mice given pregnenolone and pregnenolone sulfate showed the best improvements in avoiding footback, or a mild electrical shock to the feet. (7)

A 2010 study published in the European Journal of Pharmacology suggests that intranasal administration of this neurosteroid improved memory and displayed central nervous system effects. (8)

Although evidence indicates that memory performance is correlated with pregnenolone levels in the brains of rodents, studies involving humans have mixed results. More research is needed to determine whether or not it can definitely improve memory and the cognitive health of humans. (9)

4. Potentially Reduces the Effects of THC

Because pregnenolone is an inactive precursor of all steroid hormones, it can modulate brain activity and behavior. This physiological activity may be helpful for patients who are dealing with drug dependence, especially cannabis.

Recent research suggests that THC, the psychoactive agent in cannabis and cannabis oil, significantly increases the synthesis of pregnenolone in the brain by activating a specific receptor called type-1 cannabinoid (CB1).

Then, because pregnenolone acts as a signaling inhibitor for CB1, it reduces the effects of THC.

This is called “negative feedback,” and it’s the brain’s way of protecting itself from the over-activation of receptors that are affected by THC and cannabis intoxication.

Although THC causes an increase in food cravings that can promote food intake and cause a decrease in memory performance, researchers found that pregnenolone administration actually blocked these behavioral changes in rodents.

When brain samples from rats were analyzed in a lab after being pre-treated with this neurosteroid, scientists found that the steroid significantly attenuated the effects of THC.

Researchers suggest that given its effects on THC and the side effects of cannabis use, pregnenolone may have supplementary advantages for the treatment of drug dependence.

Un orthosteric antagonists that are used to treat drug addiction and tend to cause profound discomfort, aren’t well-tolerated by drug-dependent patients and can be overcome by taking higher doses of a drug, pregnenolone appears to be better tolerated and cannot be overcome by increasing drug intake. (10)

On top of that, this prohormone doesn’t appear to inhibit all CB1 receptor activities, so, in theory, you can still get CBD benefits when using cannabis medicinally and you won’t feel the psychoactive effects of THC.

However, more research in this area is needed to understand the potential of this neurosteroid for cannabis drug abuse.

For one, studies have only been done in rodents or labs, and it’s difficult to administer the hormone to humans without it transforming to other steroids once it hits the bloodstream.

Make sure to keep an eye out for more studies pertaining to this potential pregnenolone benefit.

Pregnenolone is also believed to be beneficial for arthritis, fatigue, endometriosis and aging-related disorders, but more research is needed on the efficacy of the hormone for these conditions before it can be recommended.

Pregnenolone Dosage and How to Use

Pregnenolone supplements are available in capsule and tablet forms. Pregnenolone dosage varies, with 10- to 50-milligram supplements available and instructed to be taken one or more times daily. This is a health care professional’s recommendation.

These supplements are used to increase steroid hormone levels, including estrogen, testosterone and progesterone. They are also used to relieve signs of depression, reduce stress, promote restful sleep and improve fatigue.

Pregnenolone is also used for weight loss. The scientific data pertaining to this neurosteroid and these health conditions is minimal and mostly conducted on rodents.

That means we can’t be sure whether or not these supplements will actually benefit any of these concerns.

Keep in mind that pregnenolone supplements are not regulated by the United States Food and Drug Administration, and the safety of these supplements has not been proven with scientific research.

Possible Pregnenolone Dangers and Side Effects

Little is known about the safety of taking pregnenolone supplements. There is some concern that this prohormone can cause steroid- side effects, such as irritability, overstimulation, trouble sleeping, anxiety, anger, acne, mood changes, headaches, irregular heartbeat and hair loss.

People with hormone-sensitive conditions should not use these supplements, especially conditions that may worsen because of exposure to estrogen. Pregnenolone is converted into estrogen and other sex hormones by the body, so people with endometriosis, uterine fibroids, breast cancer and uterine cancer should consult their health care providers before using this type of supplement.

There isn’t any research to support the safety of pregnenolone use for women who are pregnant or nursing, so it should be avoided to be on the safe side.

In addition, these supplements should not be taken with any kind of hormones, birth control pills, estrogen pills or testosterone pills, because they may cause too much of a particular hormone in your body.

Final Thoughts

  • Pregnenolone is a prohormone that serves as the starting material for numerous steroids, including cortisol, progesterone, DHEA and testosterone.
  • There are quite a few supplement companies that market it as an answer to health conditions depression, anxiety, fatigue, insomnia, obesity and even hormone-related disorders endometriosis.

    However, when you review the scientific evidence pertaining to these type of supplements, it’s clear that we really don’t know enough yet to make any appropriate recommendations.

  • the research that is available, this prohormone neurosteroid seems to be effective for reducing symptoms of depression. It may also help improve memory, relieve symptoms of schizophrenia and reduce the effects of THC. However, more human studies are needed on these potential benefits.