DEEP DIVE:
Strategies to Increase Allopregnanolone
A Comprehensive Review for Mental Health Support
Strategies to Increase Allopregnanolone
A Comprehensive Review for Mental Health Support
1. What is Allopregnanolone?
Allopregnanolone (ALLO) is a neurosteroid synthesized from progesterone that acts as a potent positive allosteric modulator of GABA-A receptors. [1,2] Its potency at enhancing GABAergic transmission far exceeds that of benzodiazepines, making it one of the most powerful endogenous anxiolytic compounds in the human body. [3]Why are we discussing allopregnanolone in a TRT forum? Please read background information about how some men get shocked that they unfortunately feel anxious or have brain fog when starting TRT instead of getting all the good benefits they hear about: Why Some Men on TRT Experience Anxiety and Brain Fog Despite Optimal Testosterone Levels - Excel Male Health Forum
Key Effects: Allopregnanolone possesses antidepressant, anxiolytic, stress-reducing, rewarding, prosocial, antiaggressive, prosexual, sedative, pro-sleep, cognitive and memory-modulating, analgesic, anesthetic, anticonvulsant, neuroprotective, and neurogenic properties. [1,3,23]
1.1 Biosynthesis Pathway
The biosynthesis of allopregnanolone follows a two-step enzymatic process: [16,24]• Progesterone is converted to 5α-dihydroprogesterone (5α-DHP) by 5α-reductase (rate-limiting step) [16]
• 5α-DHP is then converted to allopregnanolone by 3α-hydroxysteroid dehydrogenase (3α-HSD) [5,24]
Rate-Limiting Step: The 5α-reductase enzyme is rate-limiting. This explains why 5α-reductase inhibitors (finasteride/dutasteride) can cause mood disturbances. [17,21]
1.2 Biphasic Effects
Allopregnanolone possesses biphasic, U-shaped actions at the GABA-A receptor. Moderate increases (equivalent to luteal phase levels of 1.5-2 nmol/L) actually inhibit receptor activity, while both lower and higher concentrations stimulate it. [14] This explains why low doses of progesterone can paradoxically worsen mood. [3,14]
2. Strategies to Increase Allopregnanolone
2.1 Precursor Hormone Supplementation
Oral Micronized Progesterone (Most Direct Approach)
Oral progesterone serves as a "prodrug" for allopregnanolone due to first-pass hepatic metabolism. [12,15] This is the most direct approach to raising ALLO levels.Mechanism: Oral capsules undergo first-pass metabolism in the liver, converting to allopregnanolone which modulates GABA-A receptors. [12]
Evidence:
• 20 mg oral micronized progesterone increased allopregnanolone AUC by 196% [14]
• 100-300 mg produces luteal-phase equivalent levels [15]
• 300 mg in men produced sleep effects resembling GABA-A agonists [13]
Dosing: Women: 50-200 mg at bedtime. Men: 5-10 mg at bedtime (under medical supervision). [12,15] Note: Creams/troches bypass first-pass metabolism and don't produce the same ALLO boost. [12]
Pregnenolone Supplementation
Pregnenolone serves as the "mother hormone" from which all steroid hormones derive. [26]• 400 mg oral pregnenolone tripled serum allopregnanolone within ~2 hours [26]
• 500 mg/day in mood disorder patients increased ALLO approximately five-fold [26]
• Also increases progesterone (4×) and pregnenolone sulfate (3×) [26]
Practical Dosing: Start low (10-30 mg), titrate up. OTC doses typically 10-50 mg. Higher doses (100-500 mg) require medical supervision. [28,29]
DHEA Supplementation
While not directly in the allopregnanolone pathway, DHEA supports the broader neurosteroid milieu. [27] TRT often suppresses endogenous DHEA production.Typical dose: 25-50 mg/day for men (lower for women). Monitor DHEA-S levels via blood test. [28]
2.2 Pharmaceutical Approaches
SSRIs as Selective Brain Steroidogenic Stimulants (SBSSs)
A major finding in neurosteroid research: SSRIs have neurosteroidogenic properties independent of serotonin effects: [5,6,7]• Fluoxetine, sertraline, and paroxetine decrease the Km of 3α-HSD type III by 10-30 fold [5]
• Effects occur at doses well below those affecting serotonin systems (as low as 2.5 mg fluoxetine) [7]
• S-norfluoxetine's neurosteroidogenic potency is 55× higher than its serotonin reuptake inhibition [7]
• Tricyclic antidepressants do NOT show this neurosteroidogenic effect [5]
Clinical Significance: CSF allopregnanolone normalization in SSRI-treated depressed patients appears sufficient to mediate anxiolytic and antidysphoric effects. [3,7]
Brexanolone (Zulresso)
The first synthetic allopregnanolone, FDA-approved in 2019 for postpartum depression. Administered as a 60-hour IV infusion in healthcare settings due to sedation risks. [10]Zuranolone (SAGE-217/Zurzuvae)
An oral neurosteroid analog with better bioavailability than natural allopregnanolone. FDA-approved 2023 for postpartum depression. [11] A 14-day treatment course shows rapid antidepressant effects. [8,9]LYT-300 (In Development)
PureTech Health is developing an oral allopregnanolone using lymphatic delivery. Phase 1 trials achieved blood levels ninefold greater than standard oral allopregnanolone. [2]2.3 Lifestyle Interventions
Exercise
• Low-intensity exercise increased brain allopregnanolone in aged rodents [22]• Exercise-induced pain relief was blocked by allopregnanolone synthesis inhibitors [22]
• Recommendation: Moderate regular exercise; avoid chronic overtraining (elevates cortisol) [23]
Sleep
• Quality sleep (7-9 hours) supports the brain's natural neurosteroid rhythm [23]• Sleep disturbances linked to hormonal irregularities and reduced neurosteroids [23]
• Oral progesterone at bedtime aids sleep via allopregnanolone's soporific effects [13]
Stress Management
• Chronic stress downregulates allopregnanolone biosynthesis in corticolimbic circuits [25]• Acute stress transiently elevates ALLO (adaptive); chronic stress depletes it (maladaptive) [3,25]
• High cortisol diverts pregnenolone away from sex hormones ("pregnenolone steal") [24]
• Interventions: meditation, yoga, deep breathing reduce cortisol [23]
Diet and Nutrition
• Palmitoylethanolamide (PEA): Found in peanuts, soy lecithin, egg yolks — increases brain ALLO, pregnenolone, progesterone [4]• Healthy fats/cholesterol: Provide steroid hormone precursors [24]
• Key cofactors: Zinc, magnesium, B-vitamins (B5, B6), vitamin C [23]
• Omega-3 fatty acids: Anti-inflammatory, support neurosteroid environment [4]
• PPAR-agonist nutrients (omega-3s, polyphenols) may enhance neurosteroidogenesis [4]
2.4 Critical Avoidances
5α-Reductase Inhibitors (Finasteride/Dutasteride)
CRITICAL WARNING: These drugs block allopregnanolone synthesis. [17,21]• Finasteride inhibits conversion of progesterone → 5α-DHP → ALLO [17]
• Associated with depression, anxiety, cognitive problems ("post-finasteride syndrome") [17,19]
• Studies show decreased ALLO, DHT, pregnenolone in treated patients [21]
• 64% of finasteride users had moderate/severe depression vs 0% controls [18]
• 44% had suicidal thoughts vs 3% controls [20]
Alternatives for hair loss: Topical minoxidil, low-level laser therapy, topical finasteride with limited systemic absorption. [29]
Chronic Alcohol Use
Acute alcohol transiently increases allopregnanolone (contributes to relaxing effects). Chronic heavy use dysregulates the neurosteroid system, causes tolerance, and withdrawal crashes ALLO levels. [1,3]2.5 TRT-Specific Considerations
Men on testosterone replacement therapy face unique challenges: [29]• TRT suppresses LH/FSH via negative feedback, reducing testicular production of pregnenolone and progesterone (ALLO precursors) [29]
• Men on TRT commonly have lower pregnenolone, progesterone, and DHEA vs age-matched controls [28,29]
• High T → DHT conversion may "burn out" 5α-reductase availability for progesterone → ALLO conversion [29]
• Result: Adequate testosterone but deficient neurosteroids → anxiety, brain fog despite optimal T levels [29]
Solutions for TRT Patients: [28,29]
• Monitor upstream hormones: pregnenolone, progesterone, DHEA-S (not standard TRT panels)
• hCG add-back therapy: 500-1500 IU 2-3×/week stimulates testicular steroidogenesis
• Supplement precursors: Pregnenolone 25-50 mg + DHEA 25-50 mg daily
• Low-dose progesterone: 5-10 mg oral/cream at bedtime (experimental, requires supervision)
• Absolutely avoid finasteride/dutasteride [17,21]
• Consider low-dose SSRI if clinically indicated (balance neurosteroid benefits vs sexual side effects) [7]
3. Summary of Interventions
Intervention | Mechanism | Evidence | Refs |
Oral micronized progesterone | Direct precursor; first-pass conversion | Strong | 12-15 |
Pregnenolone | Upstream precursor hormone | Strong | 26 |
Low-dose SSRIs | Enzyme activation (3α-HSD) | Strong | 5-7 |
Zuranolone | Direct GABA-A modulation | Strong (FDA) | 8-11 |
Avoid 5α-RI drugs | Preserve enzyme activity | Strong | 17-21 |
hCG (TRT patients) | Stimulates testicular steroidogenesis | Moderate | 29 |
Moderate exercise | Increases brain ALLO | Moderate | 22 |
Quality sleep | Supports neurosteroid rhythm | Moderate | 13,23 |
DHEA | Supports neurosteroid milieu | Moderate | 27,28 |
PEA supplementation | Increases multiple neurosteroids | Preliminary | 4 |
4. References
1. Wikipedia. Allopregnanolone. Allopregnanolone - Wikipedia2. Rupa Health. Allopregnanolone Biomarker Overview. Allopregnanolone | Rupa Health
3. Pinna G, Rasmusson AM. Allopregnanolone, the Neuromodulator Turned Therapeutic Agent: Thank You, Next? Front Endocrinol (Lausanne). 2020;11:236. PMC7240001
4. Locci A, Pinna G. PPAR and functional foods: Rationale for natural neurosteroid-based interventions for postpartum depression. Prog Neuropsychopharmacol Biol Psychiatry. 2020;98:109838. PMID: 32426424
5. Griffin LD, Mellon SH. Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci USA. 1999;96(23):13512-7. PMC23979
6. Lovick T. SSRIs and the female brain—potential for utilizing steroid-stimulating properties to treat menstrual cycle-linked dysphorias. J Psychopharmacol. 2013;27(12):1113-20
7. Pinna G, Costa E, Guidotti A. SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake. Curr Drug Targets. 2006;7(2):177-185. PMC2670606
8. Gunduz-Bruce H, Silber C, Kaber I, et al. Trial of SAGE-217 in Patients with Major Depressive Disorder. N Engl J Med. 2019;381(10):903-911
9. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Clinical efficacy and safety of Zuranolone (SAGE-217) in individuals with major depressive disorder. J Affect Disord. 2023;338:370-379. PMID: 37557991
10. Edinoff AN, Odisho AS, Lewis K, et al. Review of Allopregnanolone Agonist Therapy for the Treatment of Depressive Disorders. Ment Health Clin. 2021;11(3):141-147. PMC8276990
11. Deligiannidis KM, Citrome L, Gunduz-Bruce H. Zuranolone for the Treatment of Postpartum Depression. Ann Pharmacother. 2024. PMC11559899
12. Strive Pharmacy. Progesterone in Practice: What Every Provider Should Know. 2025. Progesterone in Practice: What Every Provider Should Know | Strive Pharmacy Blog
13. Soderpalm AH, Lindsey S, Purdy RH, et al. Administration of progesterone produces mild sedative-like effects in men and women. Psychoneuroendocrinology. 2004;29(2):339-54
14. Porcu P, Barron AM, Frye CA, et al. The Allopregnanolone to Progesterone Ratio Across the Menstrual Cycle and in Menopause. Psychoneuroendocrinology. 2020;112:104512. PMC6935417
15. Genazzani AR, Pluchino N. Diagnostic and therapeutic use of oral micronized progesterone in endocrinology. Rev Endocr Metab Disord. 2024;25(4):881-894
16. Corpechot C, Robel P, Axelson M, et al. Allopregnanolone: An overview on its synthesis and effects. J Neuroendocrinol. 2022;34(2):e12996. PMC9285581
17. Diviccaro S, Melcangi RC, Giatti S. The connection of 5-alpha reductase inhibitors to the development of depression. Biomed Pharmacother. 2021;142:111946
18. Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki A. Finasteride induced depression: a prospective study. BMC Clin Pharmacol. 2006;6:7. PMC1622749
19. Romer B, Gass P. Finasteride-induced depression: new insights into possible pathomechanisms. J Cosmet Dermatol. 2010;9(4):331-2. PMID: 21122055
20. Fertig R, Shapiro J, Bergfeld W, Tosti A. Suicidality Risks Associated with Finasteride: An Evaluation of Real-World Data from the FDA Adverse Event Reports. Pharmaceuticals. 2025;18(7):957
21. Traish AM, Hassani J, Guay AT, et al. The Dark Side of 5α-Reductase Inhibitors' Therapy: Sexual Dysfunction, High Gleason Grade Prostate Cancer and Depression. Korean J Urol. 2014;55(6):367-379. PMC4064044
22. Aoyama K, Shimizu T, Hayakawa M, et al. Role of neurosteroid allopregnanolone on age-related differences in exercise-induced hypoalgesia in rats. J Pharmacol Sci. 2019;139(1):20-26. PMID: 30579760
23. Reddy DS. Neurosteroids: a lifelong impact on brain health. Front Behav Neurosci. 2025;19:1644615. PMC12518332
24. Liang JJ, Rasmusson AM. Overview of the Molecular Steps in Steroidogenesis of the GABAergic Neurosteroids Allopregnanolone and Pregnanolone. Chronic Stress. 2018;2:2470547018818555
25. Pinna G, Dong E, Matsumoto K, et al. Upregulation of neurosteroid biosynthesis as a pharmacological strategy to improve behavioral deficits in a putative mouse model of PTSD. J Neuroendocrinol. 2008;20(7):1128-1138. PMC3245370
26. Marx CE, Bradford DW, Hamer RM, et al. Allopregnanolone Elevations Following Pregnenolone Administration are Associated with Enhanced Activation of Emotion Regulation Neurocircuits. Psychopharmacology (Berl). 2014;231(17):3481-95. PMC3648625
27. Sripada RK, Marx CE, King AP, et al. The neurosteroids allopregnanolone and dehydroepiandrosterone modulate resting-state amygdala connectivity. Hum Brain Mapp. 2014;35(7):3249-61. PMC4739102
28. Empower Pharmacy. Compounded DHEA/Pregnenolone Capsules. DHEA / Pregnenolone Capsules
29. Excel Male Health Forum. How Can I Increase My Allopregnanolone? How Can I Increase My Allopregnanolone ? - Excel Male Health Forum
Document prepared January 2026
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