Valerian
FAMILY: Valerianaceae.
HABITAT: It is common in damp undergrowth, at the edge of ditches and watercourses throughout Europe.
USED PART: the rhizome with the rootlets.
RECOMMENDED PHARMACEUTICAL PREPARATION: nebulised dry extract titrated in total sesquiterpene acids calculated as valerenic acid min. 0.42% (Italian Pharmacopoeia X). The daily dosage used in studies published in the literature is 4-6 mg/kg/day, divided into two doses, the last of which should be taken about 30 minutes before bedtime. The above-mentioned studies were done using the dry extract with the above-mentioned title for the most part.
CHEMICAL COMPOSITION: is a drug rich in substances of a terpenic nature, particularly sesquiterpenes and iridoids. The sesquiterpenes are acidic (valerenic acid, hydroxyvalerenic acid, acetoxyvalerenic acid), ketone (valeranone), alcoholic (maaliol, valerianol, kessyl alcohol) and aldehydic (valerenal) compounds. Valerenic acids are only present in Valeriana officinalis, but not in other species of the genus Valeriana. Iridoids are characteristic and typical of the species, and are lipophilic esters of triols derived from iridane. The potassium content ranges from 0.5 to 1.2 %, but these compounds are highly unstable and decompose rapidly, turning into unsaturated aldehydes such as baldrinal and isopropylbaldrinal. It also contains moderate amounts of essential oil, about 0.5 per cent of the dry drug weight, composed of both monoterpenes and sesquiterpenes.
THERAPEUTIC PROPERTIES:
Action on the central nervous system: is a drug active on the central nervous system, on which it exerts sedative and hypnoinductive action. In vivo studies in animal models actually show a decrease in locomotor activity, aggression and were generically tranquillising.
These properties have been attributed to valepotriates, but these are very labile compounds and are present in valerian extracts in very small quantities. Furthermore, they are destroyed by gastric juice, although the degradation products formed, such as baldrin, appear to have pharmacological activity on the central nervous system.
The sesquiterpenes also appear to have a central sedative action, possibly due in part to inhibition of GABA transaminase, which leads to an increase in this amino acid with potent sedative activity, and in part to the fact that these substances appear to be able to bind to brain receptors for benzodiazepines.
Studies have also been done on the ability of aqueous Valerian extract to influence the capture and/or release of GABA in synaptosomes isolated from the rat cerebral cortex. It has been noted that the drug inhibits capture and stimulates the release of GABA.
Very interesting is the observation that total valerian extract is able to compete with fluorodiazepam in binding to benzodiazepine receptors in the hamster brain. The intensity of this competition is about seven times greater for valepotriates and sesquiterpenes taken in isolation than for total valerian extract.
Even more recent data indicate that at low doses valerian promotes the binding of flunitrazepam to its receptors, while at higher doses it has an antagonistic effect on this binding.
Other data indicate that valerian stimulates GABA production by hippocampal cells and inhibits GABA recapture by synaptosomes.
Experiments in the rat have shown that sesquiterpenes, and in particular valerenic acid, significantly reduce the animal's motility through a depressant action on the central nervous system. This seems further confirmed by the fact that these substances enhance the central depressant action of barbiturates and prolong the sleep induced by these substances.
Also interesting is the observation that the Valerian phytocomplex may enhance the hypnotic action of melatonin on the central nervous system.
The effects on the central nervous system of the Valerian phytocomplex have also been compared to those of diazepam and chlorpromazine, and it has been noted that they are similar to those of these drugs, but their intensity is considerably less.
In this study, the action of valerian extract mediated by adenosine A1 receptors on postsynaptic potentials in pyramidal cells of the rat cingulate cortex was evaluated. It was observed that N(6)-cyclopentyladenosine (CPA, 0.01 - 10 muM), an A1 adenosine receptor agonist, inhibited postsynaptic potentials in a concentration-dependent manner. This inhibition was overridden by 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.1 muM), an adenosine A1 receptor antagonist. Valerian extract Ze 911 inhibited postsynaptic potentials in a concentration-dependent manner starting at a concentration of 0.1 mg/ml in the presence of an adenosine A2 receptor antagonist such as 1,3,7-trimethyl-8-(3-chlorostyril) xanthine (CSC, 0.2 muM). The maximum inhibition occurred at a concentration of 10 mg/ml was completely antagonised by DPCPX at a concentration of 0.1 muM. These data indicate that activation of the A1 adenosine receptor is involved in the pharmacological effect of valerian.
An in vitro study examined the effects of three valerian extracts (methanolic, ethanolic and ethylacetic) on postsynaptic potentials in cortical neurons of the cingulate cortex. It was seen that the methanolic extract induced a strong inhibition of the aforementioned potentials at concentrations between 0.1 and 15 mg/ml, while the ethanolic extract had very little effect. The inhibition induced by the methanolic extract was abolished by 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.1 microm), an A1 receptor antagonist for adenosine. The ethanolic extract increased postsynaptic potentials, and this effect was blocked by picrotoxin, a selective GABA-A receptor antagonist. The study indicates that the activation of A1 receptors for adenosine and GABA-A receptors is mediated by different compounds present in the valerian phytocomplex, and that both of these mechanisms are useful for the sedative and hypnoinductive action of this drug.
A study in the rat evaluated the effect of three different valerian extracts (45% methanol or 70% ethanol or 35% ethanol) on the central nervous system, particularly with regard to sedative and anxiolytic action. It was seen that even at very high doses of 500 mg/kg/day none of the extracts tested had a sedative action, but the methanolic and ethanolic 35% extracts exhibited a clear anxiolytic action at doses between 100 and 500 mg/kg/day. In addition, the 36% ethanol extract also showed antidepressant action in the forced swimming test. None of the extracts studied had a muscle relaxant action at the doses tested. The study indicates that the methanolic and especially the 35% ethanolic extract of valerian have a significant anxiolytic and partly also antidepressant action in the rat.
An in vitro study evaluated the antioxidant action of valerian on brain tissue. In particular, we examined the effect of this drug at concentrations between 0 and 60 mug/ml on lipoperoxidation induced by various pro-oxidants such as quinolinic acid, 3-nitropropionic acid, sodium nitroprusside, iron sulphate and Fe2+EDTA in a brain tissue homogenate. The effect of valerian on deoxyribose degradation and ROS production was also examined. Valerian extract was found to inhibit the formation of thiobarbituric acid caused by all the above-mentioned pro-oxidants in a concentration-dependent manner. It also caused a significant reduction in lipoperoxidation and deoxyribose degradation. ROS production was also inhibited by valerian extract. The study indicates that this extract reduces pro-oxidant-induced lipoperoxidation and ROS formation in brain tissue, and that this effect may be important in explaining valerian's pharmacological action on the CNS.
Spasmolytic action: Both valepotriates and sesquiterpenes are endowed with spasmolytic action on the smooth muscles of the gastrointestinal tract. Valepotriates and valeranone in the essential oil have been shown to cause a reduction in rhythmic contractions of the guinea pig ileum in vivo and reduce potassium- and BaCl2-induced contractions in vitro.
Valerian is also able to consistently reduce potassium-induced smooth muscle fibrocell contractions in vitro, even when the autonomic receptors are blocked by specific receptors, with an efficacy similar to that of papaverine in inhibiting BaCl2 contractions. Therefore, this drug relaxes smooth muscle probably acting as a musculotropic agent and not interacting with autonomic nervous system receptors.
Main indications: anxiety syndrome, sleep disorders.
Prevalent action: sedative-anxiolytic and hypnoinductive.
Other actions: visceral antispasmodic.
SIDE EFFECTS: Recently, some cases of delirium and supraventricular tachycardia-type cardiac complications with fibrillatory arrhythmias have been reported in patients taking high doses (900 mg/day) of titrated valerian dry extract for prolonged periods of time.
CONTRAINDICATIONS: At high doses it may cause moderate liver damage, with moderate elevation of transaminases and GT gamma.
At high doses (12 mg/kg) these substances can cause a delay in ossification in the foetus, without altering the duration and course of pregnancy. No significant changes were observed in the histological appearance of the animal's various organs and in the values of the haematochemical tests performed. It is therefore contraindicated during pregnancy and lactation. Do not administer in children under 6 years of age.
DRUG INTERACTIONS: Valerian should not be used in conjunction with barbiturates because excessive sedation may occur.
A study in the rat assessed whether the combination of valerian and haloperidol could induce alterations in liver and/or kidney function. Valerian alone had no toxic effect, while haloperidol alone reduced reduced glutathione levels in the liver but not in the kidney. The combination of the two substances caused an increase in lipoperoxidation and dichlorofluorescein-reactive substances in liver tissue, without altering the activity of endogenous antioxidant enzymes in the liver and kidney. Valerian and haloperidol alone did not alter the activity of the renal enzyme delta aminolevulinate dehydratase, whereas the two drugs in combination caused its inhibition. Plasma transaminase levels were higher in rats treated with haloperidol alone and even higher in those receiving combination therapy. The study indicates that valerian given together with haloperidol may potentiate its hepato- and nephrotoxic action (51).
TOXICOLOGICAL DATA: The acute toxicity of an ethanolic extract of valerian administered intraperitoneally to the rat is very low at 3.3 g/kg. Doses of 600 mg/kg also administered intraperitoneally for 45 consecutive days did not cause changes in the weight of the animals or in their blood and urinary biochemical parameters. The administration of 400 mg/kg of pure valerenic acid intraperitoneally to rats resulted in the death of 6 out of 7 animals due to the onset of convulsions.
It can be found in Vagonotte® e Vagonotte® Mel
Bibliography
1)Leathwood P.D. et al. Aqueous extract of valerian reduces latency to fall asleep in man. Planta Med. 52, 144-147, 1985
2)Leathwood P.D. et al. Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man. Pharmacol. Biochem. Behav. 17, 65-71, 1982
3)Cavadas C. et al. In vitro study on the interaction of Valeriana officinalis L. extracts and their amino acids on GABAA receptor in rat brain. Arzneim. Forsch. 45, 753-755, 1995.
4)Willey L.B. et al. Valerian overdose: a case report. Vet. Hum. Toxicol. 37, 364-365, 1995.
5)Volz H.P. et al. Efficacy of valerian extract on human sleep. Review of published studies on probands and patients. Psychopharmakoterapie 4, 18-22, 1997.
6)Bourin A.U. et al. A combination of plant extracts in the treatment of outpatients with adjustment disorders with anxious mood: controlled study versus placebo. Fundam. Clin. Pharmacol. 11, 127-132, 1997.
7)Kubitschek J. Valerian influences the effect of melatonin. Pharm. Ztg. 1
8)Freund T. High doses valerian extract in sleep disorders. Z. Allg. Med. 72, 715-716, 1996.
9)Rabezzana G. Treatment of mild and moderate anxiety disorders with natural products: evaluation, efficacy and tolerability of Sedatol. Riv. REP. Biol. Med. 15, 126-133, 1995.
10)Herber K.W. Side effects of plant sedatives. Results and findings after administration of a valerian-hop-balm combination. Z. Allg. Med. 72, 234-240, 1996.
11)Quandt J. Successful therapy of anxiety and depression with combination of some plant-based drugs. Therapiewoche 44, 292-299, 1994.
12)Schulz H. et al. The effect of valerian extract on sleep polygraphy in poor sleepers: a pilot study. Pharmacopsychiatry 27, 147-151, 1994.
13)Cott J. NCEU update. Natural product formulations available in Europe for psychotropic indications. Psychopharmacol. Bull. 31, 745-751, 1995.
14)Gerhard U. et al. Acute sedative effect of a herbal relaxation tablet as compared to that of bromazepam. Schweiz Rundsch. Med. Prax. 80, 1481-1486, 1991.
15)Gerhard U. et al. Vigilance-decreasing effects of 2 plant derived sedatives. Schweiz Rundsch. Med. Prax. 85, 473-481, 1996.
16)Balderer G. et al. Effect of valerian in human sleep. Psychopharmacol. 87, 406-409, 1985.
17)Miller L.G. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch. Intern. Med. 158, 2200-2211, 1998.
18)Garges H.P. et al. Cardiac complication and delirium associated with valerian root withdrawal. J. Am. Med. Ass. 280, 1566-1567, 1998.
19)Ortiz J.G. et al. Effects of Valeriana officinalis extracts on [3H]flunitrazepam binding, synaptosomal [3H]GABA uptake, and hippocampal [3H]GABA release. Neurochem. Res. 24, 1373-1378, 1999.
20)Houghton P.J. The scientific basis for the reputed activity of Valerian. J. Pharm. Pharmacol. 51, 505-512, 1999.
21)Donath F. et al. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. Pharmacopsychiatry 33, 47-53, 2000.
22)Dominguez R.A. et al. Valerian as a hypnotic for Hispanic patients. Cultur Divers. Ethni. Minor Psychol. 6, 84-92, 2000.
23)Dorn M. et al. Efficacy and tolerability of Baldrian versus oxazepam in non-organic and non-psychiatric insomniacs: a randomised, double-blind, clinical, comparative study. Forsch. Komplementarmed. Klass Naturheilkd. 7, 79-84, 2000.
24)Poyares D.R. et al. Can valerian improve the sleep of insomniacs after benzodiazepine withdrawal? Prog.Neuropsychopharmacol.Biol.Psychiatry 26, 539-545, 2002.
25)Ziegler G. et al. Efficacy and Tolerability of Valerian Extract LI 156 Compared with Oxazepam in the Treatment of Non-organic Insomnia A Randomized, Double-blind, Comparative Clinical Study. Eur J Med Res 7(11):480-6, 2002.
26)Glass J.R. et al. Acute Pharmacological Effects of Temazepam, Diphenhydramine, and Valerian in Healthy Elderly Subjects. J Clin Psychopharmacol. 23(3):260-268, 2003.
27)Hallam K.T. et al. Comparative cognitive and psychomotor effects of single doses of Valeriana officianalis and triazolam in healthy volunteers. Hum Psychopharmacol. 18(8):619-25, 2003.
28)Gutierrez S. Et al. Assessing subjective and psychomotor effects of the herbal medication valerian in healthy volunteers. Pharmacol Biochem Behav. 78(1):57-64, 2004.
29)Vissiennon Z. et al. Valerian extract ze 911 inhibits postsynaptic potentials by activation of adenosine A1 receptors in rat cortical neurons. Planta Med. 72(7):579-83, 2006.
30) Bent S. et al. Valerian for sleep: a systematic review and meta-analysis. Am J Med. 119(12):1005-12, 2006.
31) Miyasaka M.S. et al. Valerian for anxiety disorders. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD004515.
32)Sichardt K. et al. Modulation of postsynaptic potentials in rat cortical neurons by valerian extracts macerated with different alcohols: involvement of adenosine A(1)- and GABA(A)-receptors. Phytother Res. 2007 Jun 20; [Epub ahead of print].
33)Taibi D.M. et al. A systematic review of valerian as a sleep aid: Safe but not effective. Sleep Med Rev. 11(3):209-30, 2007.
34)Koetter U. et al. A randomised, double blind, placebo-controlled, prospective clinical study to demonstrate clinical efficacy of a fixed valerian hops extract combination (Ze 91019) in patients suffering from non-organic sleep disorder. Phytother Res. 2007 May 8. [Epub ahead of print]
35)Taibi D.L. et al. A randomised clinical trial of valerian fails to improve self-reported, polysomnographic, and actigraphic sleep in older women with insomnia. Sleep Med. 2008 May 13. [Epub ahead of print]
36)From Court C.L. et al. Potentially adverse interactions between haloperidol and valerian. Food Chem Toxicol. 46(7):2369-75, 2008.
37)Taibi D.M. et al. A Feasibility Study of Valerian Extract for Sleep Disturbance in Person With Arthritis. Biol Res Nurs. 2008 Dec 28. [Epub ahead of print]
38)Sudati J.H. et al. In vitro Antioxidant Activity of Valeriana officinalis Against Different Neurotoxic Agents. Neurochem Res. 2009 Feb;4 [Epub ahead of print]
39)Cuellar N.G. et al. Does valerian improve sleepiness and symptom severity in people with restless legs syndrome. Altern Ther Health Med. 15(2):22-8, 2009.
40)Fernandez San Martin M.I. et al. Effectiveness of Valerian on insomnia: A meta-analysis of randomized placebo-controlled trials. Sleep Med. - 2010 MAR 25 [Epub ahead of print]
41)Anderson G.D. et al. Pharmacokinetics of valerenic acid after single and multiple doses of valerian in older women. Phytother Res. 24(10):1442-6, 2010.
42)Del Valle-Mojica L.M. et al. Selective Interactions of Valeriana officinalis Extracts and Valerenic Acid with [H]Glutamate Binding to Rat Synaptic Membranes. Evid Based Complement Alternat Med. 2011:403591, 2011.
43)Taavoni S. et al. Effect of valerian on sleep quality in postmenopausal women: a randomised placebo-controlled clinical trial. Menopause. 2011 Sep;18(9):951-5, 2011.
44)Sampath C. et al. Pharmacokinetics of Valerenic Acid in Rats after Intravenous and Oral Administrations. Planta Med. - 2012 MAR 12 [Epub ahead of print]
45)Yoo D.Y. et al. Valeriana officinalis Extracts Ameliorate Neuronal Damage by Suppressing Lipid Peroxidation in the Gerbil Hippocampus Following Transient Cerebral Ischemia. J Med Food. - 2015 MAR 18 [Epub ahead of print]
46)Jung H.Y. et al. Valerenic Acid Protects Against Physical and Psychological Stress by Reducing the Turnover of Serotonin and Norepinephrine in Mouse Hippocampus-Amygdala Region. J Med Food. 15 Jul 2015. [Epub ahead of print]