Pregnenolone: A Comprehensive Reference
1. Identity and Chemical Characterization
Names and Chemical Classification
Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineralocorticoids. Pregnenolone (pregn-5-en-3β-ol-20-one) is a neurosteroid with pleiotropic effects that regulates descending brain functions as a neuromodulator and neurotransmitter.
Pregnenolone is the C21 steroid closest in structure to cholesterol, which is the most abundant sterol in the Eutheria. Pregnenolone is a steroid, the 3-hydroxy analogue of progesterone, appearing in the penultimate stage of the oxidative preparation of progesterone. Its IUPAC systematic name is 3β-hydroxypregn-5-en-20-one, and it carries the CAS registry number 145-13-1. Pregnenolone is the generic name of the drug and its INN (International Nonproprietary Name), BAN (British Approved Name), DCF (Dénomination Commune Française), and JAN (Japanese Accepted Name).
Endogenous Biosynthesis and Natural Sources
In humans, the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1). Pregnenolone accumulation is the first, rate-limiting, and hormonally regulated step of mammalian steroidogenesis.
In mammals, pregnenolone is synthesized primarily in the gonads, placenta, and adrenal cortex, as well as in the cells of the nervous system and heart. Pregnenolone and dehydroepiandrosterone (DHEA) accumulate in the brain as unconjugated steroids and their sulfate and fatty acid esters. Immunocytochemical and biochemical evidence supports pregnenolone biosynthesis by differentiated oligodendrocytes.
This C21 steroid is by far the major precursor of all the steroid hormones in the adrenal gland, ovary, and testis. In addition, pregnenolone is biologically active in its own right, acting as a neurosteroid.
Age-Related Changes in Endogenous Levels
Serum pregnenolone peaks in the mid-20s to mid-30s and then declines at approximately 1 to 2% per year, mirroring the pattern of DHEA-S (which is directly downstream of pregnenolone via the delta-5 pathway). Pregnenolone levels decline with age, with a 78% decrease in men and a 45% decrease in women. It should be noted that most clinical evidence does not show that pregnenolone levels decrease with age (Rustichelli, J Headache Pain 2021; Akamatsu, Asia Oceania J Obstet Gynaecol 1992; Meldrum, Obstet Gynecol 1981), indicating that the degree of age-related decline remains a point of ongoing debate in the scientific literature.
Supplement and Pharmaceutical Forms
Pregnenolone, sold under the brand name Enelone among others, is a medication and supplement as well as a naturally occurring and endogenous steroid. Pregnenolone can be taken by mouth, as a topical medication, or by injection into muscle. Pregnenolone acetate was available as Enelone in the form of 100 mg oral tablets and as a 100 mg/mL crystalline aqueous suspension in 10 mL vials.
As a dietary supplement available in the contemporary market, pregnenolone is most commonly sold in oral capsule or tablet form in doses ranging from 5 mg to 500 mg. Pregnenolone is sold in the United States as a dietary supplement, meaning it is not subjected to the same rigorous testing and approval process as prescription drugs. The FDA does not verify the purity, potency, or quality of dietary supplements before they are sold; consequently, the actual amount of pregnenolone in a purchased supplement may not match the dosage listed on the label.
2. Traditional and Historical Use
Early Medical Investigation (1940s–1950s)
Pregnenolone does not have a documented history of use in traditional herbal or ethnomedicinal systems such as Ayurveda, Traditional Chinese Medicine, or Western botanical traditions, because it is an endogenous mammalian steroid rather than a plant-derived substance. Its historical use is therefore rooted in early 20th-century biomedical investigation rather than folk medicine.
Because the body uses pregnenolone to make many hormones, pregnenolone was studied for stress, fatigue, and arthritis in the 1940s before lab-made hormones became available. A variety of studies were done on humans in the 1940s, specifically testing pregnenolone's effect on rheumatoid arthritis and other autoimmune conditions as well as its effect as an anti-fatigue factor in factory workers.
It was first used in medicine, as an anti-inflammatory medication, in the 1940s. Historically, in the 1950s, pregnenolone was investigated and briefly employed as a pharmaceutical medication for the treatment of rheumatoid arthritis and soft-tissue rheumatism, primarily due to its observed anti-inflammatory effects. Early clinical investigations positioned it as a potential alternative or adjunct to emerging steroid therapies like cortisone and ACTH, given its role as a steroid precursor and its capacity to alleviate fatigue and inflammation in animal models.
A 1950 review published in The Journal of Clinical Endocrinology & Metabolism by Henderson, Weinberg, and Wright summarized the evidence of the era. Among the steroids then being studied, pregnenolone appeared to have certain advantages that should mark this compound as worthy of careful inquiry. It had an extremely low order of toxicity; it had not shown any adverse effect on endocrine physiology; and it had shown some promise in the treatment of rheumatoid arthritis.
A key preliminary study by Freeman et al. (1950) evaluated the therapeutic efficacy of Δ5-pregnenolone in patients diagnosed with definite rheumatoid arthritis according to New York Rheumatism Association criteria. The trial reported reductions in fatigue and improvements in joint symptoms, such as decreased pain and enhanced mobility, in several participants, suggesting potential benefits for symptom management in active disease cases, though later studies showed mixed results.
Dosage protocols from mid-20th century studies typically ranged from 25 to 500 mg daily, with common regimens of 50–100 mg administered orally for rheumatism, as documented in reviews and trials from that period showing tolerability and targeted relief of arthritic symptoms.
Decline in Pharmaceutical Use
Pregnenolone was approved for use as a pharmaceutical medication in the treatment of rheumatoid arthritis and soft-tissue rheumatism in the 1950s. It is no longer used today. When a pharmaceutical agent named cortisone, introduced by Merck in 1949, was touted as a cure-all for rheumatoid arthritis, more potent synthetic steroids like dexamethasone and prednisone were developed, overshadowing pregnenolone. Despite the initial successes of pregnenolone, research came to a halt in the 1950s due to the popularity of these synthetic alternatives. It is described as a neurosteroid and anti-inflammatory drug and was used in the treatment of rheumatoid arthritis and soft-tissue rheumatism in the 1950s and is no longer prescribed today, but remains available as a supplement.
3. Key Constituents, Active Forms, and Mechanisms of Action
Pregnenolone and Its Principal Active Metabolites
Pregnenolone itself is active, but its biological effects are also mediated through a number of key metabolites generated in vivo. Pregnenolone serves as a precursor to downstream neurosteroids, including allopregnanolone, pregnanolone, and dehydroepiandrosterone (DHEA). Pregnenolone sulfate (PregS or PS), the sulfated form, is particularly important for neuromodulatory activity and is found in measurable concentrations in brain tissue. Treatment with pregnenolone elevates allopregnanolone (a neurosteroid that enhances GABAA receptor responses) and pregnenolone sulfate (a positive NMDA receptor modulator).
Steroidogenic Cascade: Pregnenolone as "Mother Steroid"
Pregnenolone is a naturally occurring steroid hormone synthesized in the body from cholesterol, often referred to as the "grandmother of all steroid hormones" due to its role as a precursor for other key hormones like testosterone and estrogen. Through two principal enzymatic pathways — the Δ5 (delta-5) pathway and the Δ4 (delta-4) pathway — pregnenolone is converted downstream to progesterone, DHEA, androstenedione, testosterone, estradiol, cortisol, aldosterone, and allopregnanolone.
Pregnenolone has low bioavailability and is subject to high metabolism. Oral administration of 50 or 100 mg pregnenolone has been found to have minimal or negligible effect on urinary levels of testosterone and testosterone metabolites, including androsterone, etiocholanolone, 5β-androstanediol, androstadienol, and androstenol (and/or their conjugates), suggesting that only a small amount of pregnenolone is converted into testosterone. This is in accordance with findings on the conversion of DHEA into testosterone, in which only 1.5% of an oral dose of DHEA was found to be converted into testosterone.
GABAA Receptor Modulation
Pregnenolone sulfate (PS) is a sulfated neurosteroid which reduces the responses of the γ-aminobutyric acid A (GABAA) receptor. PS reduced the duration of clusters of single-channel activity. PS had no discernible effect on rapid processes — no effects were apparent on channel opening and closing, nor on GABA affinity, and a rapidly recovering desensitized state was not affected. Instead, PS produced a slowly developing block which occurred at a similar rate for receptors with open or closed channels. This negative allosteric modulation of GABAA receptors by pregnenolone sulfate is the opposite of the action of its downstream metabolite allopregnanolone, which is a potent positive modulator of the same receptor.
NMDA Receptor Potentiation
The neurosteroid pregnenolone sulphate (PS) potentiates N-methyl-D-aspartate (NMDA) receptor mediated responses in various neuronal preparations. Whereas PS potentiated NMDA-, glutamate-, and glycine-induced currents of NR1/NR2A and NR1/NR2B receptors, it was inhibitory at NR1/NR2C and NR1/NR2D receptors. PS, a sulphated neurosteroid, is synthesized in brain and exerts modulatory effects upon NMDA, glycine, and GABAA receptors. Decreased levels of PS in the hippocampus of aged rats are correlated with cognitive impairment, which can be transiently reversed by intraperitoneal or intrahippocampal injection of PS, suggesting that PS plays a role in cognition.
Sigma-1 Receptor Interaction
NMDA receptor-potentiating neurosteroid pregnenolone sulfate has also been shown to potentiate glutamate release in a variety of preparations, targeting metabotropic σ1 receptors, presynaptic NMDA receptors, or transient receptor potential channels to increase presynaptic Ca2+ influx and enhance glutamate release. Sigma-1 receptor engagement is considered one of the routes by which pregnenolone sulfate exerts broader effects on neuronal excitability and neuroprotection.
Non-Genomic Neuromodulation
Nanomolar concentrations of neurosteroids (PregS, 10 nM; PREG, 50 nM) induce the release of endozepines from mouse primary astrocytes within 5 min, indicating a non-genomic mechanism. Recent studies provide additional evidence that pregnenolone sulfate may function as an endogenous neurotransmitter or neuromodulator, creating renewed interest in the identification of novel neuroactive steroid targets for pharmacological intervention.
Microtubule Stabilization and Neuroprotection
Pregnenolone is neuroprotective and enhances learning and memory, myelination, and microtubule polymerization. Microtubule stabilization is a mechanism that has been proposed to underlie some of pregnenolone's cognitive and possibly antidepressant effects, as microtubule dynamics are important for neuronal plasticity and axonal transport.
4. Scientific Evidence by Area of Use
4.1 Cognitive Function and Memory
Animal studies have consistently documented that pregnenolone and its sulfated metabolite enhance memory. The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. The level of PS is reduced in the hippocampus of some aged rats, and there is a correlation between the reduction in PS levels and reduced performance in a behavioural test for memory of a novel place, which could be restored by injection of PS. Even in young adult rats, injection of PS into the brain can improve performance on multiple tests of memory.
Human evidence remains limited and mixed. In the late 2010s and early 2020s, research expanded on the therapeutic uses of pregnenolone. Human studies indicated it may improve memory and facilitate learning. Researchers reported that pregnenolone showed promise in brain-based health benefits related to increasing cognitive function. 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 definitively improve memory and the cognitive health of humans.
Evidence strength: Preclinical evidence is robust; human clinical evidence is preliminary and largely derived from small trials, often as secondary endpoints in psychiatric populations. No large-scale, adequately powered RCT has established pregnenolone as an effective cognitive enhancer in healthy human adults.
4.2 Schizophrenia and Schizoaffective Disorder
The most extensively studied clinical application in recent decades is as an adjunctive treatment for schizophrenia. Preclinical and clinical data suggest that pregnenolone may be a promising therapeutic in schizophrenia. Pregnenolone could potentially mitigate GABA dysregulation and/or NMDA receptor hypofunction in schizophrenia via metabolism to other neurosteroids.
A widely cited proof-of-concept RCT was conducted by Marx et al. (published in Neuropsychopharmacology, 2009). The investigators investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics, in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo for 8 weeks. Primary endpoints were changes in BACS and MCCB composite and total SANS scores. Increases in serum pregnenolone following treatment were correlated with improvements in cognitive performance as assessed by composite BACS z-scores; increases in serum allopregnanolone were also correlated with cognitive improvement.
The combination of pregnenolone (30 mg/day) with DHEA was more effective than placebo for positive symptoms and cognition in schizophrenia and schizoaffective disorder. Another report in patients with schizophrenia or schizoaffective disorder suggested that pregnenolone (500 mg/day) reduced negative symptoms (e.g., anhedonia, affective blunting) of the illness. Changes in Brief Assessment of Cognition in Schizophrenia (BACS) scores correlated with increases in pregnenolone levels.
A separate larger RCT (Ritsner et al., 2014, published in Psychiatry and Clinical Neurosciences) evaluated pregnenolone as an add-on treatment in recent-onset schizophrenia and found reductions in negative symptom severity. Clinical trials using pregnenolone as a therapeutic agent for schizophrenia have been encouraging to date, showing increases in attention, verbal and working memory, and decreases in negative symptoms.
Following a placebo lead-in, 120 participants were randomized to pregnenolone or placebo for 8 weeks. Primary endpoints were changes in MATRICS Consensus Cognitive Battery (MCCB) composite scores and UCSD Performance-based Skills Assessment—Brief.
Evidence strength: Moderate-to-preliminary. Multiple small-to-medium RCTs have reported encouraging signals for cognitive and negative symptoms. However, sample sizes have generally been small, trials short (typically 8 weeks), and findings remain to be replicated in larger definitive trials.
4.3 Depression and Mood Disorders
Interest in pregnenolone for depression stems from both neurobiological rationale and early observational data. Studies from the 1950s suggested pregnenolone was associated with improvement in irritability, insomnia, depression, and anxiety. Decreased levels of pregnenolone have been reported in the cerebrospinal fluid of depressed patients. A first clinical investigation on the effects of pregnenolone in healthy volunteers revealed a general tendency of reduced subjective depression ratings (Meieran et al., Psychoneuroendocrinology, 2004).
Pregnenolone was also studied for its mental health benefits. A small study showed pregnenolone eased depression symptoms in patients with bipolar disorder, and other studies showed it to alleviate symptoms of schizophrenia. A principal investigator (Brown) has conducted two placebo-controlled trials of pregnenolone in patients with mood disorders with positive findings.
Evidence strength: Preliminary. Human clinical evidence consists largely of small, pilot, or proof-of-concept studies. While findings are directionally positive, robust evidence from large, adequately powered RCTs is lacking.
4.4 Post-Traumatic Stress Disorder (PTSD)
Pregnenolone is a neurosteroid and an over-the-counter supplement that has shown promise in clinical studies of stress-related disorders, such as anxiety, depression, and posttraumatic stress disorder (PTSD). Several clinical trials have been registered with ClinicalTrials.gov to evaluate pregnenolone for PTSD, including in Veterans.
An 8-week open-label pilot trial at UT Southwestern Medical Center titrated participants with co-occurring PTSD and alcohol use disorder to 800 mg/day of pregnenolone over the course of 4 weeks, maintaining this dose for the remainder of the study.
The US Department of Defense has funded a Phase 2 randomized controlled clinical trial. Marx and her team are conducting a phase 2 randomized controlled clinical trial (RCT) to evaluate whether a neurosteroid (pregnenolone) can improve psychological health, PTSD, and pain symptoms that are associated with chronic complex TBI. Building on this phase 2 study, Marx's team plans to conduct a larger, pivotal phase 3 trial and explore intramuscular or transdermal patch delivery of pregnenolone.
Evidence strength: Early-stage. Most available PTSD-specific data come from pilot trials, uncontrolled studies, and registered trials whose results have not yet been fully published. Evidence is insufficient to draw clinical conclusions.
4.5 Chronic Pain
A clinical study among 94 U.S. veterans with chronic low back pain (average age 38) showed that taking pregnenolone, titrated from 100 mg daily to 500 mg daily (which is much higher than common supplement dosages of 50 to 100 mg daily) for 4 weeks, reduced self-reported pain intensity by 20% compared to 6% for those who received a placebo, but there were no significant improvements in measures of sleep, depression, working memory, executive function, or physical function (Naylor, JAMA Network Open, 2020).
Evidence strength: Very preliminary. A single published RCT with a specific veteran population showed a statistically significant but clinically modest reduction in pain intensity. No other independent replication exists. The result should be considered hypothesis-generating only.
4.6 Cannabis Use Disorder and Substance Dependence
In animal models, levels of the neurosteroid pregnenolone increase after tetrahydrocannabinol (THC) administration, and pregnenolone appears to attenuate the brain 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.
A pilot trial published on medRxiv investigated the effect of pregnenolone on provoked craving and cocaine use in men and women with cocaine use disorder. Inclusion criteria included men and women 18–60 years old with current cocaine use disorder. Preclinical and clinical evidence shows that pregnenolone and allopregnanolone, operating according to different or common pharmacological profiles involving GABAergic and/or endocannabinoid systems, may be relevant biomarkers of psychiatric conditions.
Evidence strength: Very preliminary. Animal model data are supportive, but human evidence consists only of small pilot trials. Definitive conclusions cannot be drawn.
4.7 Rheumatoid Arthritis and Inflammation (Historical Evidence)
Pregnenolone is described as a neurosteroid and anti-inflammatory drug and was used in the treatment of rheumatoid arthritis and soft-tissue rheumatism in the 1950s. The mid-century clinical trials reported symptomatic benefit, but were conducted without modern methodological standards (randomization, blinding, placebo control, standardized outcome measures).
The Freeman et al. trial reported reductions in fatigue and improvements in joint symptoms, such as decreased pain and enhanced mobility, in several participants, suggesting potential benefits for symptom management in active disease cases, though later studies showed mixed results. No modern RCT has re-evaluated pregnenolone specifically for rheumatoid arthritis according to contemporary methodological standards.
Evidence strength: Historically suggestive but scientifically insufficient by modern criteria. The 1940s–1950s evidence cannot be used to draw contemporary evidence-based conclusions.
4.8 Aging and Hormonal Decline
Pregnenolone is widely marketed for anti-aging purposes, based on its role as the upstream precursor to multiple hormones that decline with age. However, there is very little clinical research evaluating the efficacy of pregnenolone for any condition. Proponents often recommend pregnenolone for signs of aging by suggesting that pregnenolone levels decline with age, along with many other hormones. There is no evidence that pregnenolone supplements increase the levels of sex hormones. There is also no evidence that these supplements can reduce the effects of aging or increase energy levels.
Evidence strength: No clinical trial evidence supports supplementation specifically for aging or hormone optimization in healthy older adults.
4.9 Traumatic Brain Injury (TBI)
Traumatic brain injury frequently involves co-occurring psychological health challenges such as depression and PTSD, as well as pain and neurological difficulties. Although civilians are also affected, military Service Members have a higher risk of sustaining a TBI, with more than 450,000 U.S. Service Members having been diagnosed with a TBI between 2000 and 2021. Currently, there are no FDA-approved medications for TBI treatment. Marx and her team are evaluating pregnenolone treatment for psychological health, cognition, pain, PTSD, depression symptoms, and functional outcomes associated with TBI in Veterans of Operations Enduring Freedom, Iraqi Freedom, and New Dawn.
Evidence strength: Investigational. Trials are ongoing; published efficacy data for TBI specifically are not yet available.
5. Body Systems and Health Areas
- Endocrine / Steroidogenic System: Pregnenolone is the universal upstream precursor of all steroid hormones. Its conversion governs downstream availability of sex hormones, glucocorticoids, and mineralocorticoids. Declining pregnenolone production reduces the substrate available for DHEA, progesterone, cortisol, and ultimately testosterone and estradiol synthesis. A patient with low testosterone, low DHEA-S, low progesterone, and relative adrenal cortisol response impairment may have a single upstream driver: reduced pregnenolone production from declining mitochondrial CYP11A1 activity in the adrenal cortex.
- Central Nervous System / Neurosteroid Activity: Neurosteroids are synthesized in the central nervous system and accumulate in the brain at physiologically relevant concentrations. In rodents, these neurosteroids are present in the CNS in higher levels than in the periphery, and are known to have diverse actions in the CNS, including effects on cognition, anxiety, and depression.
- Immune and Inflammatory System: The historical evidence from the 1940s–1950s positioned pregnenolone as an anti-inflammatory agent, though the molecular mechanism remains incompletely characterized. Pregnenolone is neuroprotective and enhances learning and memory, myelination, and microtubule polymerization.
- Cardiovascular System: Irregularities of heart rhythm and heart palpitations have been reported, even on as low a dose as 5 mg. This can be serious in the elderly or those with heart rhythm disturbances.
- Reproductive System: Because pregnenolone is converted to sex hormones including estrogen, progesterone, and testosterone, its supplementation can theoretically influence reproductive hormonal balance. Pregnenolone supplementation may increase the levels of progesterone and DHEA in the body and possibly the levels of other hormones (testosterone and estradiol).
- "Pregnenolone Steal" Hypothesis: In the context of chronic stress, the "pregnenolone steal" hypothesis suggests that the body preferentially converts pregnenolone toward cortisol production at the expense of sex hormones (DHEA, testosterone, oestrogen). This concept, while popular in integrative medicine, has not been definitively validated in human clinical studies.
6. Dosage Forms and Dosages Reported in Studies
Pregnenolone seems to be well tolerated when taken at a dose of no more than 50 mg daily. Clinical studies, however, have used a substantially wider range of doses:
- 30 mg/day (oral): The combination of pregnenolone (30 mg/day) with DHEA was more effective than placebo for positive symptoms and cognition in schizophrenia and schizoaffective disorder.
- 500 mg/day (oral, escalating): Patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo for 8 weeks. The reported side effects in clinical trials using the 500 mg/day pregnenolone dose were primarily mild restlessness, mild muscle pain or stiffness, and mild coldness in the extremities.
- 100–500 mg/day (titrated), chronic pain: A clinical study among 94 U.S. veterans with chronic low back pain showed that taking pregnenolone titrated from 100 mg daily to 500 mg daily for 4 weeks reduced self-reported pain intensity by 20% compared to 6% for placebo.
- 800 mg/day (titrated), PTSD/AUD: All participants in the PTSD/AUD feasibility trial were titrated to 800 mg/day of pregnenolone over the course of 4 weeks and maintained this dose for the remainder of the study.
- Historical rheumatism studies: Dosage protocols from mid-20th century studies typically ranged from 25 to 500 mg daily, with common regimens of 50–100 mg administered orally.
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.
7. Safety Considerations and Interactions
General Tolerability
Pregnenolone has a favorable safety and tolerability profile when used in the dose ranges examined in short-duration clinical trials. It has an extremely low order of toxicity and has not shown any adverse effect on endocrine physiology according to mid-20th century clinical reviews. In more recent trials at higher doses (500 mg/day), the reported side effects were primarily mild restlessness, mild muscle pain or stiffness, and mild coldness in the extremities.
Steroid-Like Adverse Effects
Higher doses may cause steroid-like side effects including overstimulation, insomnia, irritability, anger, anxiety, acne, headache, negative mood changes, facial hair growth, hair loss, and irregular heart rhythm. Due to the lack of comprehensive, long-term safety data from large clinical trials, the full risk profile of prolonged supplementation remains unknown.
Hormone-Sensitive Conditions
A significant contraindication for use is the presence of hormone-sensitive conditions, such as breast, ovarian, or uterine cancers, endometriosis, or uterine fibroids. Since pregnenolone can be converted into estrogen, it may stimulate the growth or progression of these conditions. Pregnenolone supplementation may cause disruption in the endocrine system, which may manifest as changes in the menstrual cycle or the development or aggravation of hormone-sensitive diseases (including breast and prostate cancer).
Seizure Risk
Due to its antagonistic effects on the GABA receptor in the central nervous system, supplementation with pregnenolone could cause problems in people with a history of seizures.
Cardiovascular Considerations
Irregularities of heart rhythm and heart palpitations have been reported, even on doses as low as 5 mg. This can be serious in the elderly or those with heart rhythm disturbances.
Pregnancy and Lactation
Not enough is known about the use of pregnenolone during pregnancy and breast-feeding. The precautionary approach is to avoid use.
Drug and Supplement Interactions
Pregnenolone may interact with certain drugs and supplements. Moderate interactions have been reported with benzodiazepines, estrogens, progesterone, progestin, and testosterone. Caution is advised when combining pregnenolone with these medications.
Taking pregnenolone alongside hormone replacement therapy, birth control pills, or other pro-hormones like DHEA or testosterone can result in excessively high hormone levels, increasing the risk of adverse effects. It may also interact with certain psychiatric medications, decreasing the effectiveness of sedative drugs like benzodiazepines.
It is theoretically possible that pregnenolone (due to its neurosteroid properties) could interact with oral contraceptive agents; thus, women taking oral contraceptive medications containing progestin may need to be excluded from trials.
Regulatory Status
Pregnenolone is promoted online with false claims that it can treat a variety of health conditions including cancer, arthritis, and multiple sclerosis. In many regions (e.g., U.S.), pregnenolone is classified as a dietary supplement rather than a prescription drug. This classification means it undergoes less stringent regulation and safety oversight compared to pharmaceutical medications.
References
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