VALPROIC ACID induces hair regeneration …

You likely know this already.

Valproic acid induces hair regeneration in murine model and activates alkaline phosphatase activity in human dermal papilla cells.

“Interestingly, VPA induced expression of the hair follicular stem cell markers ketatin 15 and CD34 during hair formation and wound-induced growth. VPA is known to induce CD34 expression and enhance stemness [35], [36]. The bald scalps of men with androgenetic alopecia lack CD200-rich, CD34-positive hair follicle progenitor cells, and have a defect in conversion of hair follicle stem cells to progenitor cells, which play a role in the pathogenesis of androgenetic alopecia [37]. The results of our study indicate that small molecules that activate the Wnt/beta-catenin pathway, such as VPA, can potentially be applied for the development of drugs to accelerate hair cycle and stimulate hair re-growth.”

“VPA is an antiepileptic drug frequently prescribed due to its safety and effectiveness [10], [11]. Prolonged use of VPA resulted in several side effects including hair loss by oral intake; these adverse effects are attributed to zinc and biotinidase depletion [31]. We did not observe hair re-growth effects when VPA was orally administered to C57BL/6 mice (Figures S11A and S11B). However, topical application of VPA significantly promoted hair formation in murine models. The levels of beta-catenin in the mice skin were specifically increased by topical application of VPA (Figure S11C).”

“The histomorphometrical analyses showed that VPA promoted telogen-anagen transition (Figure 1B). Especially, the hair follicles of mice treated with VPA were transformed to middle- or late-anagen (Figure 1B). Immunohistochemical analysis confirmed that expression of filaggrin and loricrin was increased by VPA or MNX (Figure 2A, data for different drug treatment times are shown in Figures S2B and S2C). We did not observe any significant abnormal phenotypes in the epidermis, hair follicles, or other skin structures aside from hair re-growth following application of VPA or MNX (Figure 1A). In contrast to the epidermis of mouse skin treated with VPA, skin that was treated with LiCl revealed critical abnormal changes including an increase in the thickness of the epidermis (Figure S3), where expression of filaggrin, loricrin, and keratin 14 was also abnormally elevated as shown by immunohistochemistry (Figure S3).“

“In this study, we demonstrated that GSK3-beta inhibitors that activate the Wnt/beta-catenin pathway [17], [18], [25], [32] could potentially be developed as drugs to treat hair loss and baldness involving defects in hair follicles. Among these, VPA was identified as the most potent hair re-growth factor without causing skin abnormalities in mice. Alternative inhibitors of GSK3-beta, LiCl or BeCl2, also stimulated hair re-growth and returned the hair cycle to the anagen phase, but abnormally increased the thickness of the epidermis with hyper-activation of terminally differentiated epidermal markers. In contrast to the epidermis of mouse skin treated with other GSK3-beta inhibitor, skin of C3H mice treated with VPA didn’t reveal any significant abnormal phenotypes in the epidermis.“

“The thickness of the epidermis increased slightly and the number of hair follicles increased 7 d after application of VPA or MNX (Figure S4A, upper panel).”

“Interestingly, VPA, but not MNX, greatly increased the expression of beta-catenin in the hair follicles of C3H mice (Figure 2B). We also observed significant induction of ALP in the dermal papilla following application of VPA, but not MNX (Figures 2B and S4B). Moreover, we confirmed specific activation of the Wnt/beta-catenin pathway in the pre-cortex regions [4] of the skin of TOP-Gal Wnt reporter mice treated for 7 d with VPA, but not MNX (Figure S4C). Interestingly, Keratin 15 and CD34, the hair follicular stem cell markers, were induced in bulge cells by application of VPA for 7 d (Figure 2C), but not by application of MNX.“

Valproic Acid seems to be a very promising active agent which is likely superior to Minoxidil.
Some years ago some people tried LiCl, I wonder if they had success. However, from this publication we learn that Valproic Acid is the better choice since LiCl caused skin abnormalities. One has to keep into mind, that increasing beta-catenin bears the danger of tumor development (cancer). However, Valproic Acid only slightly increased skin thickness. Some years ago I was also interested in LiCl and Valproic Acid but the danger of cancer and the fact that orally used LiCl and Valproic Acid cause hair loss demotivated me. I did not know why they cause hair loss orally but in this publication the riddle finally gets solved; the authors explain it by zinc and biotin depletion and give this reference:

However, I would like to mention also the following publications which draw a little bit different picture:

The influence of valproic acid and carbamazepine treatment on serum biotin and zinc levels and on biotinidase activity.

“We determined the serum concentration of biotin, zinc, antiepileptic drugs, and biotinidase enzyme activity in 20 children treated with valproic acid, in 10 children treated with carbamazepine, and in 75 age- and sex-matched healthy controls. There were no significant differences in the serum levels of biotin, and biotinidase enzyme activity between the patients treated with valproic acid, the patients treated with carbamazepine, and the control group. Zinc serum levels were lower in the patients treated with valproic acid and with carbamazepine than in the control group, but within the normal range. Hair loss was observed in 3 patients treated with valproic acid, with normal serum levels of biotin, zinc, and biotinidase activity, and the alopecia disappeared with the oral administration of biotin (10 mg/d) in 3 months. These results suggest that the treatment with valproic acid does not alter the serum levels of biotin, zinc, and biotinidase enzyme activity.”

Serum biotinidase activity in children treated with valproic acid and carbamazepine.

“Hyperammonemia was detected in 8 patients treated with valproic acid. Hair loss was observed in 3 female patients treated with valproic acid, and the alopecia disappeared with the oral administration of biotin (10 mg/ d) in 3 months.”

Although only oral Valproic Acid caused hair loss in the above publication, it still may be a good idea to use Biotin in a topical along with Valproic Acid, in case someone is so bold to use it at all. Biotin is anyway a good idea.
I want to point out, that it is best to wait for human clinical trials and a thoroughly tested product instead of trying to use a self-made topical. Although Valproic Acid seems to be less dangerous than LiCl in the above mentioned publication, it still can turn out to be dangerous. Even if one takes into account that Valproic Acid may be used against cancer in the future since it is a histone deacetylase inhibitor:

“VPA is a histone deacetylase inhibitor and is under investigation for treatment of HIV and various cancers.”

However, since I already saw people boldly using LiCl in the past without even any paper on hair growth and concentrations around, I am pretty sure some people will try VPA in their home-made topicals. I want to help that they at least get the concentrations right, although I again advise to wait for a professional product after the necessary safety tests were done.

However, if you can´t resist, do the calculations and compare them with mine (I may made some mistakes, so better check it anyway, it is late in the night here while I am writing this):

Valproic Acid solution

Vehicle: 50 ml Ethanol, 30 ml Water, 20 ml Propylene Glycol (PG)

They used a 500 mMol = 0.5 Mol solution of Valproic Acid.

The Molar mass of VPA is: 144.211 g/Mol

100 mL = 0.1 L

0.5 Mol/L * 144.211 g/Mol * 0.1 L = 7.21 g

So you have to toss about 7 g of Valproic Acid into 100 mL of the above mentioned vehicle.
They applied the solution topically daily for up to 28 days. Since you may want to use it longer, you may want to reduce the concentration which is anyway a good idea with regard to safety (however, it is still bold and dangerous to try it at all). However, as one can see in the publication, a ten times lower concentration and a 100 times lower concentration did not promote hair growth; so reducing the concentration too much may lead to no results.
They applied 300 µL of the solution once per day to the shaved back of the mice, which is usually an area of approximately 4 cm2. That is 75 µL per cm2. You have to determine the area you want to apply the solution to and then calculate the amount you have to use per application.

Also, keep in mind that the experiments in this publication were in mice not humans. There are many differences, for example, the skin of mice is thinner than the skin of humans.

Again, better wait for human clinical trials and a tested product; the above calculations are only for those who will try this anyway.