A technIcal primer on Over-The-Counter Pregnenolone vs Prescription Allopregnanolone and Their Use in Psychiatric and Pain Disorders
Pregnenolone (PREG) is a prohormone synthesized in the adrenal glands. It is called a prohormone because it is a precursor to other hormones such as cortisol, estrogen, testosterone, and progesterone. Given it affects many chemical processes and chemicals in the brain, it has an important role in psychiatric diseases including postpartum depression, major depression, and post-traumatic stress disorder (PTSD). 
PREG is also a neurosteroid. More broadly, steroids affect cellular functions by binding to cytosolic and nuclear receptors that bind to DNA and induce changes in gene transcription. More specifically neurosteroids are most often synthesized from cholesterol in the CNS independently of the endocrine system. Neurosteroids pharmacologically modulate neurotransmission by non-genomic mechanisms through specific interactions with neurotransmitter receptors. Pregnenolone modulates N-methyl-D-aspartate (NMDA), γ-aminobutyric acid type A (GABAA), glycine, and calcium-permeable transient receptor potential (TRP) channels. PREG stimulates the trafficking of functional NMDA receptors to the cell surface at relatively low nanomolar concentrations, resulting in a delayed onset of potentiation of the NMDA response, consistent with its overall role as a potentiator of excitatory synaptic activity. PREG likely plays a significant role in the modulation of glutamatergic excitatory synaptic transmission that underlies learning and memory. The burden of evidence supports PREG as an antidepressant and cognitive enhancer for a range of neurological disorders. 
INTRAVENOUS ALLOPREGNANOLONE (APREG)
One of the most important applications of the neurosteroid allopregnanolone (APREG) is the treatment of postpartum depression (PPD). APREG is one of the many derivatives of PREG. Confusing as it is, APREG is called brexanolone when used as a medication and Zulresso when marketed by the drug company. For our purposes we will refer to all of the above as APREG.
APREG has neurogenetic, neuroprotective, antidepressant, and anxiolytic effects. Decreased levels of APREG are associated with major depression, anxiety disorders, premenstrual dysphoric disorder, and Alzheimer's disease.  In trials for the treatment of postpartum depression, APREG yielded positive results as a positive modulator of the GABAA receptor. [2,3,4] APREG is thought to mimic the progesterone metabolite that fluctuates after childbirth). 
In one study, two double-blind, randomized, placebo-controlled phase 3 trials were conducted at 30 clinical research centers and specialized psychiatric units in the United States. Eligible women were aged 18-45 years, with postpartum depression and qualifying Hamilton Depression Rating Scale (HAM-D). At the end of the study, the administration of APREG injection for postpartum depression resulted in a significant and clinically significant reduction in the HAM-D total score compared to placebo. APREG is a drug with a rapid onset of action and a sustained response to treatment during the study period. The results suggested intravenous APREG therapy has significant potential in treating women with with postpartum depression.  The rapid onset of action of APREG is faster than most FDA-indicated treatments and may lead to improved quality of life for both mother and child. APREG was designated a breakthrough treatment by the FDA and is a 2019 FDA-approved drug for PPD.
ORAL PREGNENOLONE (PREG)
Although allopregnanolone (APREG) is currently only available as a prescription intravenous therapy, APREG levels also increase with the use of pregnenolone (PREG). Pregnenolone is available as a non-prescription-needed or over-the-counter drug. The usual therapeutic dose is 50 or 100 mg, taken early in the morning. Certainly, pregnenolone therapy should be under the supervision of a doctor.
Pregnenolone and Mood:
In a clinical trial comparing PREG with placebo (19 PREG subjects, 18 placebo subjects), PREG supplementation resulted in significantly greater reductions in depressive symptoms in mono- and bipolar depressed patients with a history of substance abuse.
Pregnenolone was also studied in a 2014 study. It has been used at a dose of 500 mg per day for 12 weeks in patients suffering from bipolar depression. The comparison group received a placebo. Depression remission rates were higher in the PREG group (61%) compared to the placebo group (37%). The authors concluded that the results suggest that PREG can improve symptoms of depression in patients with bipolar disorder and that it can be safely administered because it is well tolerated. 
Steroid compounds may act as neuromodulators in various functions of the central nervous system. One study analyzed the levels of the neuroactive steroids pregnenolone and progesterone, as well as the neuropeptide diazepam binding inhibitor from the cerebrospinal fluid obtained by lumbar puncture from 27 people with affective illness vs 10 healthy volunteers. Subjects with a mood disorder who were clinically depressed had a lower cerebrospinal fluid (CSF) PREG compared with healthy volunteers. In addition, PREG was lower in all affectively ill subjects, regardless of mood state at the time of lumbar puncture, than in healthy volunteers. No differences were found for progesterone or neuropeptide diazepam binding inhibitor levels by mood state or diagnosis. The study authors concluded that CSF PREG is reduced in individuals with affective illness, particularly during episodes of active depression. 
Pregnenolone and Pain:
Ninety-four war veterans with chronic low back pain participated in the research in North Carolina. Pregnenolone and placebo were administered in escalating doses of 100 mg for one week, 300 mg for one week, and 500 mg for two weeks. After only four weeks of treatment, there was a significant improvement in pain and mobility. Side effects were negligible. The authors of this study concluded that PREG might be a safe and potentially effective treatment for chronic low back pain. 
Pregnenolone for schizophrenia:
Use of pregnenolone has also produced positive results in schizophrenia both in reducing negative and positive symptoms, while simultaneously increasing serum levels of PREG, PregS, AlloP, DHEAS, and progesterone. 
Highly sensitive and specific methods are starting to elucidate different steroid metabolomes. Multiple studies have reported more significant changes in PREG than other steroids in extra physiological or pathological conditions, suggesting that PREG plays a highly functional role.  Beneficial effects of oral PREG have been demonstrated in preclinical and clinical studies but do they compare to the intravenous APREG treatment that has been FDA approved? Only time will tell as more evidence emerges. Drug and administration costs for APREG are over $38,000  whereas a bottle of PREG may cost less than $20. At this time, PREG is highly accessible to patients as an over-the-counter nutraceutical, and we predict its use will rapidly increase given its unique mechanism that is unlike most prescription and over-the-counter therapies. Therein, both providers and interested patients should understand the differences between the risks/benefits of both therapies.
Please consult your psychiatric provider before treatment with any therapy. If you need a psychiatric provider in the state of Florida, please visit www.cpc.care or call 561-531-7818
1. Smith CC, Gibbs TT, Farb DH. Pregnenolone sulfate as a modulator of synaptic plasticity. Psychopharmacology (Berl). 2014 Sep;231(17):3537-56. doi: 10.1007/s00213-014-3643-x. Epub 2014 Jul 6. PMID: 24997854; PMCID: PMC4625978.
2. ZULRESSO Prescribing Information. Cambridge, MA: Sage Therapeutics, Inc; 6/2019.
3. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62.
4. Powell JG, Garland S, Preston K, Piszczatoski C. Brexanolone (Zulresso): Finally, an FDA-Approved Treatment for Postpartum Depression. Ann Pharmacother. 2020 Feb;54(2):157-163. doi: 10.1177/1060028019873320. Epub 2019 Sep 3. PMID: 31476884.
5. Meltzer-Brody S, Colquhoun H, Riesenberg R, Epperson CN, Deligiannidis KM, Rubinow DR, Li H, Sankoh AJ, Clemson C, Schacterle A, Jonas J, Kanes S. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. 2018 Sep 22;392(10152):1058-1070. doi: 10.1016/S0140-6736(18)31551-4. Epub 2018 Aug 31. Erratum in: Lancet. 2018 Sep 29;392(10153):1116. PMID: 30177236
6. Edinoff AN, Odisho AS, Lewis K, Kaskas A, Hunt G, Cornett EM, Kaye AD, Kaye A, Morgan J, Barrilleaux PS, Lewis D, Viswanath O, Urits I. Brexanolone, a GABAA Modulator, in the Treatment of Postpartum Depression in Adults: A Comprehensive Review. Front Psychiatry. 2021 Sep 14;12:699740. doi: 10.3389/fpsyt.2021.699740. PMID: 34594247; PMCID: PMC8477036.
7. Tsutsui K, Haraguchi S. Subchapter 96C – Allopregnanolone. Handbook of Hormones, Academic Press, 2016, Pages 544-e96C-3, ISBN 9780128010280. https://doi.org/10.1016/B978-0-12-801028-0.00235-X.
8. Naylor JC, Kilts JD, Shampine LJ, Parke GJ, Wagner HR, Szabo ST, Smith KD, Allen TB, Telford-Marx EG, Dunn CE, Cuffe BT, O'Loughlin SH, Marx CE. Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans: A Randomized Clinical Trial. JAMA Netw Open. 2020 Mar 2;3(3):e200287. doi: 10.1001/jamanetworkopen.2020.0287. PMID: 32119096; PMCID: PMC7052727.
9. Brown ES, Park J, Marx CE, Hynan LS, Gardner C, Davila D, Nakamura A, Sunderajan P, Lo A, Holmes T. A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology. 2014 Nov;39(12):2867-73. doi: 10.1038/npp.2014.138. Epub 2014 Jun 11. PMID: 24917198; PMCID: PMC4200497.
10. George MS, Guidotti A, Rubinow D, Pan B, Mikalauskas K, Post RM. CSF neuroactive steroids in affective disorders: Pregnenolone, progesterone, and DBI. Biological Psychiatry, Volume 35, Issue 10, 1994,Pages 775-780,ISSN 0006-3223. https://doi.org/10.1016/0006-3223(94)91139-8.
11. Vallée M. Neurosteroids and potential therapeutics: Focus on pregnenolone. J Steroid Biochem Mol Biol. 2016 Jun;160:78-87. doi: 10.1016/j.jsbmb.2015.09.030. Epub 2015 Oct 1. PMID: 26433186.
13. Eldar-Lissai A, Cohen JT, Meltzer-Brody S, Gerbasi ME, Chertavian E, Hodgkins P, Bond JC, Johnson SJ. Cost-Effectiveness of Brexanolone Versus Selective Serotonin Reuptake Inhibitors for the Treatment of Postpartum Depression in the United States. J Manag Care Spec Pharm. 2020 May;26(5):627-638. doi: 10.18553/jmcp.2020.19306. Epub 2020 Mar 19. PMID: 32191592.
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