Valproic Acid

Potential Benefits of Valproic Acid

• Reduces seizures [1-12]
• Fights hair loss [13-20]
• Treats migraines [21-33]
• Improves mood [34-58]
• Improves cognitive function [59-70]

What is Valproic Acid?

Valproic acid is an anticonvulsant medication that is primarily used to treat epilepsy, bipolar disorder, neuropathic pain, migraine, attention deficit hyperactivity disorder (ADHD), and other psychological disorders. It exerts its therapeutic effect by affecting certain brain chemicals or neurotransmitters, thus improving overall brain health.

How Valproic Acid Works?

Valproic acid achieves its desired effects through the following important mechanisms:

1. It increases the levels of gamma-aminobutyric acid (GABA), a neurotransmitter that reduces overstimulation in the brain.
2. It restores communication between neurons (nerve cells) by reducing overactivity and blocking certain pathways in the brain.
3. It protects new brain cells by blocking certain enzymes responsible for gene alteration.

Chemical Structure of Valproic Acid

Research on Valproic Acid

Reduces Seizures

Treating seizures is the earliest and most prominent use of this anticonvulsant medication, and it is still prescribed for this condition today. Numerous clinical trials support the safety and efficacy of valproic acid in reducing the prevalence of seizure attacks:

1. In epileptic children, valproic acid exhibited similar effectiveness to ethosuximide, the current gold standard for treating epileptic seizures. [1]
2. In patients with glioblastoma multiforme, a deadly brain cancer, valproic acid administration reduced seizure attacks and resulted in a 2-month longer survival. [2]
3. In late-onset post-stroke epilepsy patients, valproic acid administration was associated with better seizure control. [3]
4. In patients with chronic seizures, valproic acid was found to be effective at reducing the incidence of attacks. [4]
5. In patients with idiopathic generalized epilepsies, valproic acid provided superior control of epileptic seizures and was associated with fewer hospitalizations and emergency department visits. [5]
6. In patients with hemorrhagic stroke (caused by blood vessel rupture), valproic acid reduced the occurrence of seizures in the early period. [6]
7. In patients with uncontrolled seizures of a generalized or partial type, valproic acid administration was associated with a significant reduction in seizure frequency ranging from 25 to 100%. [7]
8. In patients with poorly controlled complex partial seizures, valproic acid treatment significantly reduced seizures by 50%. [8]
9. Valproic acid was found to be similar in efficacy to other antiepileptic drugs such as carbamazepine, phenytoin, phenobarbital, and ethosuximide in the treatment of generalized, partial, and absence seizures. [9-10]
10. In patients with juvenile myoclonic epilepsy, valproic acid significantly reduced the incidence of seizure attacks. [11]
11. In patients with generalized tonic-clonic seizures, valproic acid administration alone demonstrated greater efficacy at reducing attacks. [12]

Fights Hair Loss

Valproic acid is not just indicated for seizure disorders. Evidence suggests that it can help stimulate hair regeneration and treat the root cause of hair loss:

1. In male patients with androgenetic alopecia, a type of hair loss common in both genders, valproic acid spray treatment for 24 weeks significantly increased total hair count compared to placebo spray. [13]
2. In participants with hair baldness, treatment with 7.2% of valproic acid spray on the scalp twice a day (morning and evening) for 24 weeks increased linear hair growth rate and final hair density. [14]
3. In patients with alopecia, administration of valproic acid induced hair growth on bald areas. [15]
4. A study found that implantation of valproic acid-encapsulated dissolving microneedles stimulated hair follicle regrowth. [16]
5. A cell study also found that valproic acid has the ability to inhibit glycogen synthase kinase 3ß and activation of the Wnt/βcatenin pathway, which in turn induces hair regeneration and hair growth phase (anagen). [17]
6. In male patients with moderate androgenic alopecia, valproic acid spray treatment for 24 weeks significantly increased total hair count without any adverse side effects. [18]
7. Treatment of human dermal papilla cells (hair follicles) with valproic acid induced hair regeneration. [19]
8. Administration of valproic acid in patients with alopecia increased hair count by boosting the production of biotin, a protein that promotes hair growth. [20]

Treats Migraines

There’s also increasing evidence supporting the pain-relieving properties of valproic acid:

1. In patients with chronic (recurring) migraines, valproic acid administration at daily doses of 500 to 600 mg reduced migraine frequency. [21]
2. Larger clinical trials confirmed the benefit of valproic acid on migraine attacks and the FDA approved the use of this drug. [22-23]
3. Valproic acid administration in patients with recurrent migraines was associated with better clinical response. [24]
4. A study found that a low dose of valproic acid (10 mg/kg) for 6 months may be helpful in preventing migraine in pediatric patients. [25]
5. In patients with severe migraine headaches, administration of intravenous valproic acid seems to be safe and rapidly effective at alleviating symptoms. [26]
6. A study found that valproic acid treats migraine by increasing brain GABA levels. [27]
7. In adult patients with episodic migraine, valproic acid reduced headache frequency and was reasonably well tolerated. [28]
8. In patients with refractory migraine, a type of migraine not relieved or prevented by acute migraine therapies, valproic acid administration at a dose of 1,250 mg daily reduced headache severity. [29]
9. In migraine sufferers, valproic acid administration at a dose of 100–600 mg/day was consistent in alleviating symptoms. [30]
10. Administration of 400 mg valproic acid twice daily for 8 weeks in patients with migraine was effective in reducing the frequency, severity, and duration of the attacks. [31]
11. Administration of 70 to 120 mg/L of valproic acid in patients with migraine headaches was associated with significantly lesser functional restriction and symptoms. [32]
12. Valproic acid appeared to be equivalent in efficacy and safety to topiramate, an anti-epileptic drug, in reducing the duration, monthly frequency, and intensity of headaches. [33]

Improves Mood

There’s also a good amount of evidence demonstrating the safety and efficacy of valproic acid in stabilizing the mood of patients with various psychological disorders:

1. In patients with neurosis, a mild mental illness characterized by stress, depression, anxiety, and obsessive behavior, valproic acid significantly improved scores in various tests assessing symptoms such as the Clinical Global Impression Scale for panic severity, the Hamilton Psychiatric Rating Scale for Anxiety, and the panic factor of the SCL-90. [34-35]
2. In patients with panic disorder who failed to respond to conventional treatment, valproic acid reduced symptoms of anxiety and improved low and unstable mood. [36]
3. In patients with social anxiety disorder, valproic acid administration at 500-2500 mg for 12 weeks improved scores on the Liebowitz Social Anxiety Scale (LSAS), a measure of anxiety symptoms. [37]
4. In patients with a generalized anxiety disorder that is resistant to antidepressants, valproic acid improved symptoms by increasing the efficiency of gamma-aminobutyric acid. [38]
5. In a human model of anxiety behavior, valproic acid treatment reduced subjective ratings of anxiety. [39]
6. In bipolar patients, valproic acid administration at a dose range of 50-300 mg/day for 8 weeks appears to reduce anxiety. [40]
7. In patients with major depressive disorder, valproic acid significantly improved scores on the Hamilton Rating Scale for Depression (HRSD). [41]
8. In patients with major depressive disorder who are resistant to antidepressant medications, valproic acid administration provided substantial clinical improvement. [42]
9. In patients with long-lasting depressive and anxiety symptoms, valproic acid administration at 100–1250 mg/day significantly reduced symptoms. [43-45]
10. In patients with acute bipolar depression, valproic acid administration significantly reduced symptoms without any adverse effects. [46-50]
11. In patients with acute mania, a mental illness characterized by great excitement, delusions, and overactivity, valproic acid was similar in efficacy to the antipsychotic drug haloperidol in treating manic episodes. [51]
12. In patients with schizophrenia, a mental disorder characterized by cognitive impairment and detachment from reality, short-term valproic acid treatment improved psychotic symptoms. [52-55]
13. In patients with schizoaffective disorder, a mental condition like schizophrenia but with depression and mania symptoms, valproic acid reduced symptoms and was found to be more effective than other antipsychotic drugs such as lithium. [56-57]
14. Valproic acid treatment was also associated with reduced length and intensity of symptoms as well as fewer and shorter hospital stays. [58]

Improves Cognitive Function

Studies also support that valproic acid has a positive impact on cognitive health:

1. In patients with epilepsy, valproic acid treatment was associated with better scores on memory tasks. [59]
2. In young patients with epilepsy, administration of valproic acid improved attention and memory. [60]
3. In elderly patients, valproic acid treatment improved attention, concentration, psychomotor speed, and memory. [61]
4. Valproic acid treatment was also associated with improved attention, memory, and visuomotor function among epileptic patients. [62]
5. In patients with juvenile myoclonic epilepsy, valproic acid improved neuropsychological performance on different cognitive functions such as attention, short-term memory, processing speed, and verbal fluency. [63]
6. In HIV-infected individuals with cognitive impairment, valproic acid improved mental performance. [64]
7. In a rat model of convulsive status epilepticus, valproic acid significantly improved spatial cognitive dysfunction. [65]
8. In rats, valproic acid administration after traumatic brain injury improved cognitive function by protecting brain nerve cells. [66]
9. In a rat model of Parkinson’s disease, valproic acid prevented the death of brain neurons. [67]
10. Animal and cell studies found that valproic acid may help reverse the progression of Alzheimer’s disease by stimulating the growth and development of new neurons. [68-69]
11. In a rat model of stroke, valproic acid protected against the loss of cognitive function via inhibition of oxidative stress and inflammation. [70]

Associated Side Effects of Valproic Acid

Valproic acid side effects are very uncommon. There have been some side effects associated with the use of this drug wherein the patient had one of the issues listed below at some point while being on valproic acid. However, these side effects weren’t confirmed to be associated with the treatment and could have been a coincidence and not related to the use of valproic acid. Despite this, it was listed as a side effect associated with valproic acid even though these associated side effects are very uncommon.

Side effects associated with valproic acid may include the following:

• Breathing problems
• Confusion
• Diarrhea
• Dizziness
• Dry or sore mouth
• Feeling tired or sleepy
• Headaches
• Irregular or delayed periods
• Muscle weakness
• Nausea
• Passing out
• Stomach pain
• Swollen gums
• Thinning hair or changes in the color or texture of the hair
• Tremors
• Unusual eye movements
• Vomiting
• Weight gain

References

1. Glauser TA, Cnaan A, Shinnar S, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med. 2010;362(9):790-9.
2. Kerkhof M, Dielemans JC, Van breemen MS, et al. Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. Neuro-oncology. 2013;15(7):961-7.
3. Huang YH, Chi NF, Kuan YC, et al. Efficacy of phenytoin, valproic acid, carbamazepine and new antiepileptic drugs on control of late-onset post-stroke epilepsy in Taiwan. Eur J Neurol. 2015;22(11):1459-68.
4. Sasidaran K, Singhi S, Singhi P. Management of acute seizure and status epilepticus in pediatric emergency. Indian J Pediatr. 2012;79(4):510-7.
5. Miró J, Aiguabella M, Veciana M, et al. Low-dose sodium valproate in the treatment of idiopathic generalized epilepsies. Acta Neurol Scand. 2014;129(5):e20-3.
6. Gilad R, Boaz M, Dabby R, Sadeh M, Lampl Y. Are post intracerebral hemorrhage seizures prevented by anti-epileptic treatment?. Epilepsy Res. 2011;95(3):227-31.
7. Mattson RH, Cramer JA, Williamson PD, Novelly RA. Valproic acid in epilepsy: clinical and pharmacological effects. Ann Neurol. 1978;3(1):20-5.
8. Bruni J, Albright P. Valproic acid therapy for complex partial seizures. Its efficacy and toxic effects. Arch Neurol. 1983;40(3):135-7.
9. Davis R, Peters DH, Mctavish D. Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs. 1994;47(2):332-72.
10. Löscher W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs. 2002;16(10):669-94.
11. Prasad A, Kuzniecky RI, Knowlton RC, et al. Evolving antiepileptic drug treatment in juvenile myoclonic epilepsy. Arch Neurol. 2003;60(8):1100-5.
12. Wilder BJ, Rangel RJ. Review of valproate monotherapy in the treatment of generalized tonic-clonic seizures. Am J Med. 1988;84(1A):7-13.
13. Jo SJ, Shin H, Park YW, et al. Topical valproic acid increases the hair count in male patients with androgenetic alopecia: a randomized, comparative, clinical feasibility study using phototrichogram analysis. J Dermatol. 2014;41(4):285-91.
14. Available from https://clinicaltrials.gov/ct2/show/NCT01548066.
15. Agrawal AK, Das S. Valproic acid and alopecia: A two-edged sword. Asian J Psychiatr. 2017;29:39-40.
16. Fakhraei lahiji S, Seo SH, Kim S, et al. Transcutaneous implantation of valproic acid-encapsulated dissolving microneedles induces hair regrowth. Biomaterials. 2018;167:69-79.
17. Kakunje A, Prabhu A, Sindhu Priya ES, et al. Valproate: It’s Effects on Hair. Int J Trichology. 2018;10(4):150–153. doi:10.4103/ijt.ijt_10_18.
18. Choi SY, Kim HD, Kim BJ, Kim MN, Han DH. A case of androgenetic alopecia treated with valproic acid. Int J Dermatol. 2014;53:e214–5.
19. Lee SH, Yoon J, Shin SH, et al. Valproic acid induces hair regeneration in murine model and activates alkaline phosphatase activity in human dermal papilla cells. PLoS One. ;7(4):e34152. doi:10.1371/journal.pone.0034152.
20. Available from https://jddonline.com/articles/evidence-for-supplemental-treatments-in-androgenetic-alopecia-S1545961614P0809X/.
21. Kinze S, Clauss M, Reuter U, et al. Valproic acid is effective in migraine prophylaxis at low serum levels: a prospective open-label study. Headache. 2001;41(8):774-8.
22. Shelton CE, Connelly JF. Valproic acid: a migraine prophylaxis alternative. Ann Pharmacother. 1996;30(7-8):865-6.
23. Shelton CE, Connelly JF. Valproic acid: a migraine prophylaxis alternative. Ann Pharmacother. 1996;30(7-8):865-6.
24. Ichikawa M, Katoh H, Kurihara T, Ishii M. Clinical Response to Valproate in Patients with Migraine. J Clin Neurol. 2016;12(4):468–475. doi:10.3988/jcn.2016.12.4.468.
25. Fusco C, Pisani F, Capone C, Faienza C. Valproic acid in migraine prophylaxis of young patients. Three new reports. Acta Biomed. 2002;73(3-4):47-51.
26. Shahien R, Saleh SA, Bowirrat A. Intravenous sodium valproate aborts migraine headaches rapidly. Acta Neurol Scand. 2011;123(4):257-65.
27. Cutrer FM, Limmroth V, Moskowitz MA. Possible mechanisms of valproate in migraine prophylaxis. Cephalalgia. 1997;17(2):93-100.
28. Linde M, Mulleners WM, Chronicle EP, Mccrory DC. Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev. 2013;(6):CD010611.
29. Erdemoglu AK, Ozbakir S. Valproic acid in prophylaxis of refractory migraine. Acta Neurol Scand. 2000;102(6):354-8.
30. Takeshima T, Nishikawa W, Yoneda H, Kanki R, Yamashita S, Kikui S. Efficacy and safety of valproate in a series of Japanese migraine sufferers (in Japanese) Japanese J Headache. 2013;39:306–311.
31. Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia. 1992;12(2):81-4.
32. Mathew NT, Saper JR, Silberstein SD, et al. Migraine prophylaxis with divalproex. Arch Neurol. 1995;52(3):281-6.
33. Shaygannejad V, Janghorbani M, Ghorbani A, Ashtary F, Zakizade N, Nasr V. Comparison of the effect of topiramate and sodium valporate in migraine prevention: a randomized blinded crossover study. Headache. 2006;46(4):642-8.
34. Primeau F, Fontaine R, Beauclair L. Valproic acid and panic disorder. Can J Psychiatry. 1990;35(3):248-50.
35. Raevskiĭ KS, Aleksandrovskiĭ IuA, Poiurovskiĭ MV, Kharlamov AN, Neznamov GG. [Anxiolytic action of sodium valproate (possible role of gamma-aminobutyric acid in affective disorders)]. Zh Nevropatol Psikhiatr Im S S Korsakova. 1985;85(4):574-9.
36. Baetz M, Bowen RC. Efficacy of divalproex sodium in patients with panic disorder and mood instability who have not responded to conventional therapy. Can J Psychiatry. 1998;43(1):73-7.
37. Kinrys G, Pollack MH, Simon NM, Worthington JJ, Nardi AE, Versiani M. Valproic acid for the treatment of social anxiety disorder. Int Clin Psychopharmacol. 2003;18(3):169-72.
38. Available from https://www.tandfonline.com/doi/full/10.1080/24750573.2017.1317382.
39. Bach DR, Korn CW, Vunder J, Bantel A. Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial. Transl Psychiatry. 2018;8(1):157. Published 2018 Aug 16. doi:10.1038/s41398-018-0206-7.
40. Sheehan DV, Harnett-sheehan K, Hidalgo RB, et al. Randomized, placebo-controlled trial of quetiapine XR and divalproex ER monotherapies in the treatment of the anxious bipolar patient. J Affect Disord. 2013;145(1):83-94.
41. Davis LL, Kabel D, Patel D, et al. Valproate as an antidepressant in major depressive disorder. Psychopharmacol Bull. 1996;32(4):647-52.
42. Ghabrash MF, Comai S, Tabaka J, Saint-laurent M, Booij L, Gobbi G. Valproate augmentation in a subgroup of patients with treatment-resistant unipolar depression. World J Biol Psychiatry. 2016;17(2):165-70.
43. Liu CC. Adjuvant valproate therapy for patients with suspected mixed-depressive features. Ther Adv Psychopharmacol. 2014;4(4):143–148. doi:10.1177/2045125314532868.
44. Vigo DV, Baldessarini RJ. Anticonvulsants in the treatment of major depressive disorder: an overview. Harv Rev Psychiatry. 2009;17(4):231-41.
45. Kemp LI. Sodium valproate as an antidepressant. Br J Psychiatry. 1992;160:121-3.
46. Smith LA, Cornelius VR, Azorin JM, et al. Valproate for the treatment of acute bipolar depression: systematic review and meta-analysis. J Affect Disord. 2010;122(1-2):1-9.
47. Haeberle A, Greil W, Russmann S, Grohmann R. Mono- and combination drug therapies in hospitalized patients with bipolar depression. Data from the European drug surveillance program AMSP. BMC Psychiatry. 2012;12:153.
48. Bond DJ, Lam RW, Yatham LN. Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis. J Affect Disord. 2010;124(3):228-34.
49. Selle V, Schalkwijk S, Vázquez GH, Baldessarini RJ. Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics. Pharmacopsychiatry. 2014;47(2):43-52.
50. Cipriani A, Reid K, Young AH, Macritchie K, Geddes J. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev. 2013;(10):CD003196.
51. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306-15.
52. Tseng PT, Chen YW, Chung W, et al. Significant Effect of Valproate Augmentation Therapy in Patients With Schizophrenia: A Meta-analysis Study. Medicine (Baltimore). 2016;95(4):e2475.
53. Suzuki T, Uchida H, Takeuchi H, et al. Augmentation of atypical antipsychotics with valproic acid. An open-label study for most difficult patients with schizophrenia. Hum Psychopharmacol. 2009;24(8):628-38.
54. Sajatovic M, Coconcea N, Ignacio RV, et al. Adjunct extended-release valproate semisodium in late life schizophrenia. Int J Geriatr Psychiatry. 2008;23(2):142-7.
55. Yoshimura R, Shinkai K, Ueda N, Nakamura J. Valproic acid improves psychotic agitation without influencing plasma risperidone levels in schizophrenic patients. Pharmacopsychiatry. 2007;40(1):9-13.
56. Schaff MR, Fawcett J, Zajecka JM. Divalproex sodium in the treatment of refractory affective disorders. J Clin Psychiatry. 1993;54(10):380-4.
57. Bogan AM, Brown ES, Suppes T. Efficacy of divalproex therapy for schizoaffective disorder. J Clin Psychopharmacol. 2000;20(5):520-2.
58. Puzyński S, Kłosiewicz L. Valproic acid amide in the treatment of affective and schizoaffective disorders. J Affect Disord. 1984;6(1):115-21.
59. Forsythe I., Butler R., Berg I., McGuire R. (1991) Cognitive impairment in new cases of epilepsy randomly assigned to carbamazepine, phenytoin and sodium valproate. Dev Med Child Neurol 33: 524–534.
60. Coenen A.M.L., Konings G.M.L.G., Aldenkamp A.P., Reiner W.O., van Luijtelaar E.L.J.M. (1995) Effects of chronic use of carbamazepine and valproate on cognitive processes. J Epilepsy 8: 250–254.
61. Craig I, Tallis R. Impact of valproate and phenytoin on cognitive function in elderly patients: results of a single-blind randomized comparative study. Epilepsia. 1994;35(2):381-90.
62. Stores G, Williams PL, Styles E, Zaiwalla Z. Psychological effects of sodium valproate and carbamazepine in epilepsy. Arch Dis Child. 1992;67(11):1330-7.
63. De araujo filho GM, Pascalicchio TF, Lin K, Sousa PS, Yacubian EM. Neuropsychiatric profiles of patients with juvenile myoclonic epilepsy treated with valproate or topiramate. Epilepsy Behav. 2006;8(3):606-9.
64. Schifitto G, Peterson DR, Zhong J, et al. Valproic acid adjunctive therapy for HIV-associated cognitive impairment: a first report. Neurology. 2006;66(6):919-21.
65. Wu P, Hong S, Zhong M, Guo Y, Chen H, Jiang L. Effect of Sodium Valproate on Cognitive Function and Hippocampus of Rats After Convulsive Status Epilepticus. Med Sci Monit. 2016;22:5197–5205. Published 2016 Dec 29. doi:10.12659/MSM.898859.
66. Dash PK, Orsi SA, Zhang M, et al. Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats. PLoS ONE. 2010;5(6):e11383.
67. Zhang C, Yuan X, Hu Z, et al. Valproic Acid Protects Primary Dopamine Neurons from MPP+-Induced Neurotoxicity: Involvement of GSK3β Phosphorylation by Akt and ERK through the Mitochondrial Intrinsic Apoptotic Pathway. Biomed Res Int. 2017;2017:8124501. doi:10.1155/2017/8124501.
68. Zhang XZ, Li XJ, Zhang HY. Valproic acid as a promising agent to combat Alzheimer’s disease. Brain Res Bull. 2010;81(1):3-6.
69. Zaky A, Mahmoud M, Awad D, El Sabaa BM, Kandeel KM, Bassiouny AR. Valproic acid potentiates curcumin-mediated neuroprotection in lipopolysaccharide induced rats. Front Cell Neurosci. 2014;8:337. Published 2014 Oct 21. doi:10.3389/fncel.2014.00337.
70. Suda S, Katsura K, Kanamaru T, Saito M, Katayama Y. Valproic acid attenuates ischemia-reperfusion injury in the rat brain through inhibition of oxidative stress and inflammation. Eur J Pharmacol. 2013;707(1-3):26-31.