by

Chloe Shum

Valeriana officinalis L. is a perennial herb that can be found in many parts of Northern Europe and parts of Asia, as well as an introduced species in North and South American continents. It has been used throughout the ages to treat many health problems, but the main uses are as a sleep aid, calming agent and muscle relaxant. Usually the underground organs are used medicinally, popularly in the form of a tea or an alcoholic tincture and a range of regulated (licensed or registered) products are available as over the counter medicines. Valerian owes its medicinal benefits to certain plant metabolites found within them, namely valepotriates, terpenes, lignanes and – less well documented – very small amounts of alkaloids. Like all drugs, these natural molecules are able to bind with receptors in the body to induce effects such as effects on the central nervous system. Some of the underlying mechanisms of action of valerian are still unknown, thus it is important to be aware of drug-herb or herb-herb interactions that may occur. Valerian is a natural alternative to the widely prescribed benzodiazepines, with fewer side effects, however, that is not to say it poses no risks. Valerian can be found growing in damp regions, but they readily grow in other climates. These numerous species are genetically and morphologically different, along with having certain similarities. The flowers are in bloom from May to September. The formulation of the extracts has a significant impact on how it affects the consumer, aqueous extracts are more sedative whereas alcoholic extracts are anxiolytic. It can be found in the medical herb spiral at Mecklenburg Square Garden as well as in the small medicinal plant garden next to the School of Pharmacy (UCL) on Brunswick Square nearby.

The genus is a morphologically diverse one, found north-western Europe, norther Asia, including Japan, India and North America including México (Grieve, 2013). Not only do the differing climates affect the morphology of the plants, but may also vary in the number of chromosomes they possess.

History and Contemporary use

Most important is Valeriana officinalis L. Reports on valerian and its uses have existed since the Greek and Roman times. According to the European Pharmacopeia valerian is used to treat nervous disorders, such as sleeplessness, restlessness, nervousness and tension. Aside from having potent CNS effects, valerian was also used to treat gastrointestinal problems (Grieve, 2013).

By the mid-19^th century, valerian extracts had grown in popularity in Europe and the United States. It was prescribed by physicians and administered as home remedies. It was indicated in treating a variety of ailments, including anxiety, heart palpitations, menstrual cramps, headaches, hypertension, seizures and adolescent learning disorders. According to the German Commission E monograph 1985, valerian was traditionally administered as a tincture, commonly alcoholic extracts and tea infusions (WHO, 2009). Valerian has been in the British Pharmacopeia since 1988 and is currently given status of well-established use in Europe (BP, 1988).

Biological characteristics and identification

Valeriana officinalis is an erect perennial herb that can grow up to 1.5 meters tall. It grows from a small wrinkly brownish-yellow rhizome that has fibrous roots emerging from it. The dentate leaves are divided into lanceolate sections. As the leaves ascend on the hollow stem, the petioles become shorter. Some of the leaves have tiny hairs on the underside, and they are pinnate and opposite in pairs of 7 to 21. The upward facing side of the leaves are a light green, while the opposite side is dark green. The main stem growing from the rhizome splits into smaller flowering stems. The inflorescences of the flowers are presented in an umbel shape, with small white or pink flowers. They blossom in May to late August. Each flower measures about 4 mm in length. The bracts are also lanceolate shaped. Flowers appear from June to August, but seed formation occurs in September. There are three stamens and fruit found in a capsule, which holds an oblong-ovate shaped seed. Odour of the fresh plant is usually pleasant, however over time the dried plant material oxides and releases isovaleric acid which has an unpleasant scent. The taste is mildly sweet and spicy, with a hint of bitterness. In nature, valerian can be found growing in varying climates however, they grow better in damp places like near streams and rivers. The plants found in mountain regions are more aromatic than those grown in swamp lands.

In powdered roots, the volatile oil is less than 1%; however, it can reach up to 5% in ethanolic extracts (Houghton, 1999). V. officinalis is the only one of the species where the three sesquiterpenoids are found ubiquitously, those being valerenic acid, acetoxyvalerenihc acid and valerenal. This distinction makes it possible to distinguish it chemically from V. edulis Nutt. and V. wallichii DC. (WHO, 2009).

Scientific Evidence – Pharmacology and Phytochemistry

The pharmacologically active constituents of valerian consist primarily of terpenoids. They are secondary metabolites of the plant, in other words they play roles that increase the competitiveness of the plants but do not play primary roles in their survival. In 1957 Stoll et al. discovered that the essential oils of V. officinalis were composed of twelve monoterpenes and seventeen sesquiterpenes, which are volatile. The majority of this oil is bornyl acetate and isovalerate. Sesquiterpene like valerenic acid was indicated in the sedative action of the plant. It does this by increasing the net levels of GABA through inhibiting its enzymatic breakdown which leads to central nervous system (CNS) depression. Gamma amino butyric acid, known as GABA is the main inhibitory neurotransmitter of the CNS. Valerenic acid also allosterically binds to the GABA receptor, meaning that after it binds to the receptor, it causes the neurotransmitter GABA to bind more efficiently, leading to greater activation (Edwards et al 2015).

Some extracts with low volatile oil content have still been shown to produce sedative effects, suggesting that there must be other compounds causing these effects. Pharmacological and chemical studies led to researchers discovering sedative and tranquilizing effects of iridoids, more specifically valepotriates. These are a group of metabolites considered non-glycosidic iridoids, as they are not bound to a sugar molecule, but esterified instead. The spasmolytic effects of valerian are due to valtrate and didrovaltrate (Wagner & Jurcic, 1979). Valtrate and isovaltrate were similar to antidepressants in treating mood disorders while didrovaltrate dampened the output activity of the hippocampus resulting in tranquilizing activity (Houghton, 1987).

Extracts of varying compositions have been seen to have different effects. Aqueous extracts with or without alcohol induce sleepiness or sedation, whereas dilute alcoholic extracts contain high amounts of valepotriates which are responsible for the tranquilizing effects. Extracts of stronger alcoholic strength yield higher concentration of volatile oils [Bisset (1994) cited in Houghton, 1988].

The sesquiterpenes valerenic acid and kessyl glycol are exclusive to Valerianaceae. Other compounds are found in different species of Valerian, like valeronone in V. wallichiana DC. Valerenic acid is found in higher abundances in European valerian, whereas kessane types are more common in Asian species (Houghton, 1988).

A small number of alkaloids were isolated from the roots or root stocks, such as 1-hydroxypinoresiniol (Bodesheim & Holzl, 1997), but the compounds may actually be produced during the drying of the botanical material prior to extraction. It inhibits the hydroxytryptamine receptor activation which may also contribute to the CNS effects. It also has a slight affinity to the benzodiazepine receptors (Bodesheim, 1997). Some of these alkaloids such as actinidine have been postulated to possess anticholinergic effects which may manifest as lethargy (Torssell, 1967).

Preclinical data / pharmacology

It is important to note that the majority of reports citing that valerian products were toxic only were conducted in vitro, i.e. cell lines. If valerian is administrated orally, even at a very high concentrations (1350mg/kg) no significant toxicity was observed. This may be due to the bioavailability of the drug in vivo (inefficient absorption and distribution), thus the in vitro reports do not reflect its true nature (Houghton, 1988). The lipophilic extracts were more potent and effective than hydrophilic extracts (Wagner et al., 1980). Aqueous extracts seem to be more effective against insomnia symptoms and are able to elevate levels of GABA in the brain. Less polar extracts contain more of the terpenes and valepotriates, which results in greater sedation and relaxation. Valepotriates are indicated for anxiety, thus they can be classified as a tranquilizer rather than a sedative.

Depending on the cultivar, the rhizomes and roots contain up to 1.2% w/w of valepotriates. Valepotriates decay quickly and result in homobaldrinal, which can also be caused by gut microflora. Wagner et al. studied these compounds and discovered that homobaldrinal had a greater influence on spontaneous motility in mice, indicating that it may be a pro drug (Wagner, 1980). Similarly, it was more efficient that its precursor didrovaltrate on spontaneous motility (Vieth et al., 1986). The observed spasmolytic effect is due to valepotriates, yet at such low doses, exert no effects on the CNS which would explain its use for gastrointestinal irritation.

Cautions

At higher doses, people have experienced dependency and withdrawal symptoms when they ceased taking valerian. Certain people lacking the digestive enzymes to break down valerian can have opposing effects such as agitation and increased energy (Kelber et al., 2014). Of course, due to the nature of its pharmacological effects, caution must be taken when driving or working with machines.

The valepotriates have structural similarities to some compounds with cytotoxic effects on cell lines, thus their toxicity was studied intensively. They interfered with amino acids incorporating into DNA which eventually lead to death (Braun et al., 1982, Bounthanh et al., 1988). Valepotriates are potentially carcinogenic since they contain an epoxide group, which is three cyclically bonded carbon atoms with an ether, but there is no evidence for this.

The German Commission E monograph states there are no contraindications, side effects or known drug interactions. Many Western physicians caution pregnant women against using valerian as there could be harm to the fetus. With increased knowledge of this plant, it is recommended that valerian is taken without concomitant use of other CNS depressants like benzodiazepines and alcohol.

The true nature of valerian’s toxicity has yet to be fully investigated, thus it should still be taken with caution. There is still the possibility of an adverse reaction, especially with chronic use, such as uneasiness, headaches, excitability, and difficulty sleeping (Houghton, 1998).

Clinical Evidence

In 2006, Bent and colleagues conducted a systematic review on placebo-controlled double blind studies that included a total of 1093 patients. In one of the studies, 121 participants (mean age: 47) who suffered from non-organic insomnia were given a 600 mg alcoholic extract of dried valerian root for 28 days. They saw an increase in clinical global impression, sleep rating, and improvements in the Zerssen’s well-being scale (Vorbach et al., 1996). Significant and constant therapeutic effects were only observed 2-4 weeks after continuous use. Of their study group, 66% given valerian had improvements in sleep compared to 26% of the placebo group. This was one of the in vivo trials that showed significant improvements in sleep upon taking valerian extracts.

In a German study, 202 patients were treated with 600mg/day of valerian extract or 10mg/day oxazepam, a benzodiazepine (Ziegler et al. 2002). After six weeks, similar positive results on their sleep quality, measured by psychological questionnaires. The sleep quality was shown to be just as good in the valerian group compared to the oxazepam group. In the oxazepam treated group 36% of patients had adverse effects to the drug, compared to 28% of the valerian group, although all were considered slight or mild (Ziegler, 2002).

In a systematic review by the University of Washington, a meta-analysis was initially intended; however, the variability of the studies made it implausible. 29 studies that fit the criteria (random, placebo controlled studies) out of the 592 found at first concluded that there was no significant difference between the placebo-treated and valerian (Taibi, 2007). They postulated that the differences between plants can be so varying, dosages are problematic to standardize, which leads to a range of outcomes at the patient level. More rigorous studies will have to be carried out with less variables, to determine the efficacy of valerian.

In another meta-analysis by Fernández-San-Martín and colleagues in 2010, they assessed the outcomes of eighteen randomized clinical trials (RCTs) looking at qualitative sleep improvements. Many of the studies exhibited greater JADED scores, which means subjective improvements of sleep were experienced, however this is not quantitative data. Once again, they suggested that more methodical studies must be conducted in order to evaluate the efficacy of valerian.

Conclusion

Valeriana officinalis is a polyvalent plant that combines multiple mechanisms of action to have an overall effect of sedation, relaxation and faster onset of sleep. Its array of secondary metabolites allows it to target various parts of the body to exert a multi-faceted effect. The composition of V. officinalis can be problematic since higher concentrations of certain secondary metabolites can create distinct responses, thus the discrepancies in the literature. Valerian products have been used since antiquity or even before, thus the relevance in multiple cultures throughout history implies that there must be some efficacy. Through scientific study, the individual metabolites and their effects can be more carefully studied, so far showing that these molecules indeed have pharmacological effects. Studies comparing valerian to benzodiazepines or other pharmaceutical sedatives have shown that it is just as much, if not more efficacious, with less side effects.

Within Mecklenburg Square Gardens, the plant can be found in the garden spiral and it also grows in the School of Pharmacy Medicinal Plant Garden (UCL) on Brunswick Square.

Disclaimer: In this essay, we do not intend to advise or recommend herbs for medicinal or health use. This information is for educational purposes only and should not be considered as a recommendation or an endorsement of any particular medical or health treatment. The use of any such product should be based on the appropriate advice of a health care professional or based on the information available in the patient information leaflets (i.e. for THR products). The information provided should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

About the author: My name is Chloe Shum, I am a MSc student (2015 – 2016) studying natural products at the School of Pharmacy. I am interested in how our current healthcare issues can be helped with natural remedies or plant based therapies. My passion is to study the science of cannabinoids and unveil their overlooked potential while educating people about their importance and illustrating how they work.

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