Pregnenolone Supplement Benefits: What Research Shows

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.[1] 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.[2] 

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
• Osteoporosis
• 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)[2]:

• Endometrial bleeding
• Prostatic hypertrophy
• Carcinogenesis 

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.”[2] 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
• Depression
• 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.”[2]

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.[2] 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.[8] 

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.[9]

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.

 

In addition to modulating GABA, pregnenolone Other research indicates that GABA-A antagonists facilitate LTP while diazepam blocks LTP in hippocampal slices.[10]

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.[14] 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.[15]

To top it off, pregnenolone (as well as allopregnanolone) are considered by researchers to have “immense neuroprotective potential.”[16]

Previous studies conducted in mouse hippocampus cells noted that allopregnanolone offered neuroprotective properties against glutamate and amyloid beta protein neurotoxicity.[17]

A recent 2022 animal study found that pregnenolone also reduced the neurological impairments via reducing mitochondrial reactive oxygen species (ROS).[18] In case you weren’t aware, ROS are a contributing factor towards inflammation (including neuroinflammation) as well as cognitive decline.

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.[22] 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.[25]

Pregnenolone may also protect the brain against the intoxicating effects of marijuana.[27] 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.[28] Animal studies found that injections of  pregnenolone inhibited the increase in food-intake and memory impairment, commonly seen with marijuana use.[27]

 

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

Immune Support

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).[19] 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.[19]

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).

Joint Support

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)![29]

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.”

Deeper Sleep

Animal studies indicate that pregnenolone sulfate may increase REM sleep without affecting slow-wave sleep or wakefulness.[30]

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.

Takeaway

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.

References

1. Havlíková, H., Hill, M., Hampl, R., & Stárka, L. (2002). Sex- and Age-Related Changes in Epitestosterone in Relation to Pregnenolone Sulfate and Testosterone in Normal Subjects. The Journal of Clinical Endocrinology & Metabolism, 87(5), 2225–2231. doi:10.1210/jcem.87.5.8499 
2. Roberts, E. (1995). Pregnenolone—from selye to Alzheimer and a model of the pregnenolone sulfate binding site on the GABAA receptor. Biochemical Pharmacology, 49(1), 1–16. doi:10.1016/0006-2952(94)00258-n
3. Woodward RM. Polenzani L and Miledi R, Effects of steroids on y-aminobutyric acid receptors expressed in Xenopus oocytes by poly(A)+ RNA from mammalian brain and retina. Mol Pharmacol 41: 89-103, 1992. 
4. Wu F-S, Gibbs TI and Farb DH, Pregnenolone sulfate: A positive allosteric modulator at the N-methyl-D-aspartate receptor. Mol Pharmacol 40: 333-336, 1991. 
5. Bowlby MR, Pregnenolone sulfate potentiation of N methyl-D-aspartate receptor channels in hippocampal neurons. Mol Pharmacol43: 813-819, 1993. 
6. Beauchamp M. H., Ormerod B. K., Jhamandas K., Boegman R. J., Beninger R. J. (2000). Neurosteroids and reward: allopregnanolone produces a conditioned place aversion in rats. Pharmacol. Biochem. Behav. 67, 29–35 10.1016/S0091-3057(00)00299-9
7. Fish E. W., Faccidomo S., DeBold J. F., Miczek K. A. (2001). Alcohol, allopregnanolone and aggression in mice. Psychopharmacology (Berl.) 153, 473–483 10.1007/s002130000587
8. Wang M. Neurosteroids and GABA-A Receptor Function. Front Endocrinol (Lausanne). 2011 Oct 4;2:44. doi: 10.3389/fendo.2011.00044. PMID: 22654809; PMCID: PMC3356040.
9. Shumaker S. A., Legault C., Rapp S. R., Thal L., Wallace R. B., Ockene J. K., Hendrix S. L., Jones B. N., III, Assaf A. R., Jackson R. D., Kotchen J. M., Wassertheil-Smoller S., Wactawski-Wende J. (2003). Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 289, 2651–2662 10.1001/jama.289.20.2651
10. Brioni, J.D. (1993), Role of GABA during the multiple consolidation of memory. Drug Dev. Res., 28: 3-27. https://doi.org/10.1002/ddr.430280103
11. Schumacher M, Weill-Engerer S, Liere P, et al. Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog Neurobiol. 2003 Sep;71(1):3-29.
12. Weill-Engerer S, David JP, Sazdovitch V, et al. Neurosteroid quantification in human brain regions: comparison between Alzheimer’s and nondemented patients. J Clin Endocrinol Metab. 2002 Nov;87(11):5138-43.
13. Marx CE, Trost WT, Shampine LJ, et al. The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer’s disease. Biol Psychiatry. 2006 Dec 15;60(12):1287-94.
14. Mayo W, George O, Darbra S, et al. Individual differences in cognitive aging: implication of pregnenolone sulfate. Prog Neurobiol. 2003 Sep;71(1):43-8.
15. Mayo W, Lemaire V, Malaterre J, Rodriguez JJ, Cayre M, Stewart MG, Kharouby M, Rougon G, Le Moal M, Piazza PV, Abrous DN. Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus. Neurobiol Aging. 2005 Jan;26(1):103-14. doi: 10.1016/j.neurobiolaging.2004.03.013. PMID: 15585350.
16. Rossetti, M. F.; Cambiasso, M. J.; Holschbach, M. A.; Cabrera, R. Oestrogens and Progestagens: Synthesis and Action in the Brain. J. Neuroendocrinol. 2016, 28,  DOI: 10.1111/jne.12402
17. Froger, N. Potentialités thérapeutiques des neurostéroïdes en psychiatrie [New therapeutic avenues for neurosteroids in psychiatric diseases]. Biol. Aujourdhui. 2019, 213, 131– 140,  DOI: 10.1051/jbio/2019023
18. Syed Suhail Andrabi, Pooja Kaushik, Sayed Md Mumtaz, Mohammad Mumtaz Alam, Heena Tabassum, and Suhel Parvez. ACS Omega 2022 7 (23), 19122-19130. DOI: 10.1021/acsomega.1c07016
19. Murugan S, Jakka P, Namani S, Mujumdar V, Radhakrishnan G. The neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation. J Biol Chem. 2019 Mar 22;294(12):4596-4607. doi: 10.1074/jbc.RA118.005543. Epub 2019 Jan 15. PMID: 30647133; PMCID: PMC6433066.
20. Henderson E., Weinberg M., and Wright W. A. (1950) Pregnenolone. J. Clin. Endocrinol. Metab. 10, 455–474 10.1210/jcem-10-4-455
21. Hoagland H. (1944) Adventures in Biological Engineering. Science 100, 63–67 10.1126/science.100.2587.63
22. Milivojevic V, Charron L, Fogelman N, Hermes G, Sinha R. Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder. Biomolecules. 2022 Oct 29;12(11):1593. doi: 10.3390/biom12111593. PMID: 36358943; PMCID: PMC9687893.
23. Martin-Garcia E, Pallares M. The neurosteroid pregnenolone sulfate neutralized the learning impairment induced by intrahippocampal nicotine in alcohol-drinking rats. Neuroscience. 2005;136(4):1109-19.
24. Martin-Garcia E, Pallares M. Intrahippocampal nicotine and neurosteroids effects on the anxiety-like behaviour in voluntary and chronic alcohol-drinking rats. Behav Brain Res. 2005 Oct 14;164(1):117-27.
25. Milivojevic V, Sullivan L, Tiber J, Fogelman N, Simpson C, Hermes G, Sinha R. Pregnenolone effects on provoked alcohol craving, anxiety, HPA axis, and autonomic arousal in individuals with alcohol use disorder. Psychopharmacology (Berl). 2023 Jan;240(1):101-114. doi: 10.1007/s00213-022-06278-3. Epub 2022 Nov 29. PMID: 36445398.
26. McGavack TH, Chevalley J, Weissberg J. The use of delta 5-pregnenolone in various clinical disorders. J Clin Endocrinol Metab. 1951 Jun;11(6):559-77.
27. Vallée M, Vitiello S, Bellocchio L, Hébert-Chatelain E, Monlezun S, Martin-Garcia E, Kasanetz F, Baillie GL, Panin F, Cathala A, Roullot-Lacarrière V, Fabre S, Hurst DP, Lynch DL, Shore DM, Deroche-Gamonet V, Spampinato U, Revest JM, Maldonado R, Reggio PH, Ross RA, Marsicano G, Piazza PV. Pregnenolone can protect the brain from cannabis intoxication. Science. 2014 Jan 3;343(6166):94-8. doi: 10.1126/science.1243985. Erratum in: Science. 2014 Feb 28;343(6174):969. PMID: 24385629; PMCID: PMC4057431.
28. Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Physiol Rev. 2009;89:309–380.
29. Henderson, E., Weinberg, M., & Wright, W. A. (1950). Endocrine Review - Pregnenolone. J Clin Endocrinol Metab., 10(4), 455–474.
30. Darnaudéry, M., Bouyer, J.-J., Pallarés, M., Le Moal, M., and Mayo, W. (1999). The promnesic neurosteroid pregnenolone sulfate increases paradoxical sleep in rats. Brain Res. 818, 492–498.