Side Effects of Pregnenolone

Pregnenolone is advertised as a mild "natural" supplement, and in small clinical studies it was indeed generally well tolerated. But "well tolerated in an 8-week study under a doctor's supervision" and "safe for long-term independent use" are different statements. The editorial team explains which side effects are documented, which follow from the pharmacology of pregnenolone, and where the evidence base still has gaps.

What clinical studies say

Most modern data on the safety of pregnenolone in humans come from randomized studies in psychiatry. In the works of Marx and colleagues (schizophrenia), Ritsner and colleagues (schizophrenia and schizoaffective disorder), and Brown and colleagues (bipolar depression), pregnenolone was tolerated generally satisfactorily, without a significant difference in the frequency of side effects compared with placebo.

However, these studies have significant limitations for assessing safety. They lasted mostly 8–12 weeks, included dozens rather than thousands of participants, and were conducted under regular medical supervision. Rare or distant side effects are impossible to detect under such conditions.

In addition, the participants of these studies simultaneously received psychotropic drugs, which complicates the assessment of pregnenolone itself. Healthy people who buy the supplement on their own are a different population with a different risk profile.

Thus, the honest conclusion is this: short-term use in the studied amounts under a doctor's supervision was not accompanied by alarming signals, but the long-term safety of pregnenolone in healthy people has not been studied.

Hormonal effects through metabolites

Pregnenolone is the starting point of steroidogenesis. In the body it can be converted into progesterone, 17-hydroxypregnenolone, DHEA, and further into androgens and estrogens. The scale of such conversion after oral intake varies from person to person and is poorly predictable.

Therefore, theoretically, effects characteristic of an excess of the corresponding hormones are possible. For the androgenic direction — oily skin, acne, increased hair growth in women. For the estrogenic and progesterone direction — breast tissue sensitivity, menstrual cycle changes, fluid retention.

These reactions are described in reviews and manufacturers' instructions mainly as possible, rather than as often recorded in controlled studies. However, experience with DHEA, which has a better-studied profile, shows that androgenic effects in women are quite real when the level of precursors rises.

Taking pregnenolone also changes the results of hormonal tests. If a person does not inform the doctor about the supplement, this may lead to a false interpretation of the levels of progesterone, DHEA-S, or other steroids.

Effect on the nervous system: sleep, mood, anxiety

Pregnenolone and its metabolites are neurosteroids with an opposite direction of action. Pregnenolone sulfate enhances the operation of NMDA receptors and weakens GABA-A receptors, that is, it has a conditionally "excitatory" profile. Allopregnanolone, formed through progesterone, on the contrary, enhances inhibitory GABA-A transmission.

Because of this, opposite reactions are possible in different people: some feel increased energy, irritability, anxiety, or difficulty falling asleep, others — drowsiness and sluggishness. Which one prevails depends on individual metabolism and the amount taken.

For people with anxiety disorders, bipolar disorder, or epilepsy, such fluctuations may have clinical significance. Pregnenolone sulfate has proconvulsant properties in animal models, so independent use is inappropriate for people prone to seizures.

Other described nonspecific complaints are headache, palpitations, muscle tension. Their frequency is unknown, since there are no systematic data on independent use.

Hormone-dependent tissues and risk groups

Since pregnenolone can be a source of progesterone, androgens, and estrogens, its use is inappropriate in hormone-dependent tumors — cancer of the breast, endometrium, ovaries, prostate — currently or in history. This logic is analogous to the warnings regarding DHEA.

During pregnancy and breastfeeding pregnenolone is not recommended due to the lack of safety data. It is also not indicated for children and adolescents: puberty is sensitive to any changes in steroid metabolism.

Caution is needed for women with endometriosis, uterine fibroids, polycystic ovary syndrome, and also for men with prostate diseases. In these conditions, even moderate changes in the hormonal background may be significant.

• hormone-dependent tumors in history;
• pregnancy, breastfeeding, age under 18;
• endometriosis, fibroids, PCOS;
• epilepsy, bipolar disorder, marked anxiety;
• taking hormonal or psychotropic drugs.

Interactions and product quality

The simultaneous intake of pregnenolone with hormone therapy, contraceptives, DHEA, or other steroid precursors may create additive hormonal effects. Together with drugs that act on GABA-A receptors — benzodiazepines, sleeping pills, alcohol — unpredictable changes in sedation are theoretically possible.

People taking antipsychotics, antidepressants, or mood stabilizers should make the decision about pregnenolone only together with a psychiatrist. It is precisely in this population that the main studies were conducted, but under careful supervision.

As with other supplements, the actual content of the active substance in products may differ from what is declared, and some preparations contain mixtures with DHEA or plant extracts. This complicates the assessment of both effectiveness and adverse reactions.

Athletes should take into account the risk of contamination and a possible effect on the steroid profile during doping control, even if pregnenolone itself is not directly named on the WADA Prohibited List.

Editorial conclusions

In short clinical studies under a doctor's supervision, pregnenolone was tolerated generally well, but long-term safety data in healthy people are absent.

Possible side effects are associated with conversion into sex hormones (acne, cycle changes) and with neurosteroid action (insomnia, anxiety, or drowsiness).

Particular caution is required for people with hormone-dependent conditions, mental disorders, epilepsy, and also those who take hormonal or psychotropic drugs.

Also read our materials "Pregnenolone: What It Is and How It Works," "How to Take Pregnenolone: Dosage, Timing, Duration," and "Side Effects of DHEA."

References

1. Marx CE, Keefe RS, Buchanan RW, et al. Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacology. 2009;34(8):1885–1903.
2. Ritsner MS, Gibel A, Shleifer T, et al. Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia and schizoaffective disorder: an 8-week, double-blind, randomized, controlled, 2-center, parallel-group trial. J Clin Psychiatry. 2010;71(10):1351–1362.
3. Brown ES, Park J, Marx CE, et al. A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology. 2014;39(12):2867–2873.
4. Osuji IJ, Vera-Bolaños E, Carmody TJ, Brown ES. Pregnenolone for cognition and mood in dual diagnosis patients. Psychiatry Res. 2010;178(2):309–312.
5. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32(1):81–151.
6. Roberts E. Pregnenolone — from Selye to Alzheimer and a model of the pregnenolone sulfate binding site on the GABA_A receptor. Biochem Pharmacol. 1995;49(1):1–16.