EXCLI Journal 2011;10:192-197 – ISSN 1611-2156 Received: August 31, 2011, accepted: October 03, 2011, published: October 10, 2011

Mini review:

SEDATIVE AND HYPNOTIC EFFECTS OF IRANIAN TRADITIONAL MEDICINAL HERBS USED FOR TREATMENT OF INSOMNIA

Sasan Andalib1, Ali Vaseghi2, Golnaz Vaseghi3,*, Azadeh Motavallian Naeini3

1 School of Veterinary Medicine, Islamic Azad University of Tabriz, Tabriz, Iran 2 Department of General Sciences, Capilano University, Vancouver, BC, Canada 3 Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

* corresponding author: email: [email protected]; Contact No.: +983117922628; Fax: +983116680011

ABSTRACT

For tens of centuries, plants have been highly valued and regularly used as medicine amongst the masses. Insomnia, a loss of sleep, is mostly treated by synthetic sleeping tablets these days. However, questions have been raised about the safety of prolonged use of artificial sedatives due to their deleterious side effects such as physical dependence. In recent years, there has been an increasing propensity to preclude insomnia by herbal medicines throughout the world. Many herbs have a lengthy background in terms of insomnia treatment in Iran. This paper gives an account of previously published research on sedative and hypnotic effects of medicinal herbs used for treatment of insomnia in Iranian traditional medicine.

Keywords: Iranian medicinal herbs, Iranian traditional medicine, insomnia, sedative effect, hypnotic effect

INTRODUCTION cines. Some insomniacs rely on sleeping tablets such as benzodiazepines and newer Nowadays, insomnia has been a con- nonbenzodiazepines to get rest (Smith and spicuous problem or disease in our restless Tett, 2010; Richey and Krystal, 2011). De- society. It has been reported that 10 to spite clinical success, these medicines have 20 percent of adults across cultures suffer a number of problems in use. Apart from from chronic insomnia (Lamberg, 2005). daytime fatigue and cognitive impairment Insomnia is often defined by sleeping prob- as side effects of these sedatives (Zlott and lems. People who suffer from insomnia Byrne, 2010; Hendler et al., 1980), they may encounter difficulty of getting to sleep may engender physical dependence (Blais or staying asleep, or having non-refreshing and Petit, 1990). On the other hand, insom- sleep, to some degree. The poor quality of nia can be treated by herbal remedies. Some sleep is naturally followed by functional insomniacs are inclined to take medicinal impairment while awake (Scott et al., plants owing to low frequency of side ef- 2011). Insomnia is secondary to other con- fects. Several medicinal herbs have been ditions. Indeed, it may stem from life used throughout the world (Wing, 2001). events, mental disorders, pain, hormone Moreover, the usage of herbal medicines shift and alcohol usage, to name but a few. has come to Iranian people since ancient Insomnia can be treated by synthetic medi- times and apparently still serves a key role 192 EXCLI Journal 2011;10:192-197 – ISSN 1611-2156 Received: August 31, 2011, accepted: October 03, 2011, published: October 10, 2011

in the arsenal of medicines in modern extract was assumed to be mainly responsi- medicine. In fact, various climates in Iran ble for the hypnotic effect. exert a crucial role in distribution of plants used in traditional medicine. To date, sev- Rosa damascene eral reviews have been published with re- Rosa damascene is cultivated in central spect to hypnotic impacts of herbal reme- Iran and known as Gole Sorkh. It is an erect dies throughout the world (Kim et al., 2011; shrub that grows about 1 to 2 meters with LaFrance et al., 2000). We previously pub- colorful and large flowers. In Iranian tradi- lished a review on Persian herbal medicines tional medicine, flowers, petals and hips are with anxiolytic properties (Rabbani et al., administered to treat insomnia. It was 2011). Nonetheless, a comprehensive re- shown that not only did R. damascene in- view has been absent with regard to hyp- hibit the reactivity of the hypothalamus and notic effects of herbs used in Iranian tradi- pituitary systems in rats, but also it sup- tional medicine. Therefore, this paper re- pressed the activity of the central nervous views the literature pertaining to medicinal system (Libster, 2002). Rakhshandah and herbs used for treatment of insomnia in Hosseini (2006) examined the hypnotic ef- Iran. fect of ethanolic, aqueous and chloroformic extracts of R. damascene by means of pento- Coriandrum sativum barbital-induced sleeping time test Coriandrum sativum is an herb which is (30 mg/kg, i.p.) in mice and demonstrated currently cultivated in Iran. It is popularly that this herb can relive insomnia. Intraperi- referred as Geshniz in Persian. In addition toneal doses of 500 and 1000 mg/kg of to the extensive use of Coriander leaves in ethanolic and aqueous extracts were demon- Iranian recipes, various parts of this plant strated to produce hypnotic effect which such as seed, leaf, flower and fruit have was comparable to diazepam. The hypnotic been used in Iranian traditional medicine effect of aqueous extract was induced dose (Pathak Nimish et al., 2011). Emamghorei- dependently, notwithstanding the maximum shi et al. (2005) reported that coriander effect of this extract at the dose of seeds led to a decrease in spontaneous ac- 500 mg/kg. Chloroformic extract-treated tivity in mice and therefore exhibited a mice did not show any hypnotic effect. In sedative effect. Thereafter, Emamghoreishi another study, hypnotic effect of R. damas- and Heidari-Hamedani (2006) investigated cene extract and fractions (ethanol extract, the hypnotic and sedative activities of N-butanol fraction, ethyl acetate fraction, aqueous or hydro-alcoholic extracts and aqueous fraction) was assessed based on essential oil of coriander seeds in male al- prolongation of pentobarbital (diazepam)- bino mice by means of pentobarbital- induced sleeping time in mice (Rakhshan- induced sleeping time test and Animex ac- dah et al. 2007). They found that ethanol tivity meter. Aqueous extract with doses of extract and fractions of R. damascena at 200, 400 and 600 mg/kg, hydro-alcoholic doses of 250 and 500 mg/kg increased the extract with doses of 400 and 600 mg/kg, sleeping time in mice. Aqueous fraction of and essential oil with a dose of 600 mg/kg R. damascene had the minimum hypnotic were found to increase pentobarbital- influence. However, ethyl acetate fraction induced sleeping time. It was also demon- showed maximum hypnotic influence at a strated that aqueous extract at doses of 50, dose of 500 mg/kg. 100 and 500 mg/kg significantly declined To date, no single study has covered the spontaneous locomotor activity. They mechanism in which R. damascene extract pointed out that although the extracts and or fractions produce their hypnotic effect. essential oil of coriander seeds exerted Nevertheless, Noguerira and Vassilieff sedative and hypnotic influence, aqueous studied the hypnotic effect of the other gen- iuses of Rosaceae family, that is, Rubus

193 EXCLI Journal 2011;10:192-197 – ISSN 1611-2156 Received: August 31, 2011, accepted: October 03, 2011, published: October 10, 2011

brasiliensis and suggested that a benzodi- means of thiopental-hypnosis test. Aqueous azepine-like principle in hexanic fraction of decoction extract at intraperitoneal doses of this herb induced the hypnotic effect 1.15 and 1.57 g/kg was shown to slightly through GABAa system (Nogueira and increase the total sleeping time up to Vassilieff, 2000). 20.58 minutes versus 63.67 minutes in di- azepam (3 mg/kg). Relaxation of skeletal Crocus sativus muscles was also assessed by traction test. Saffron stigma (Crocus sativus), is the An intraperitoneal treatment of the extract world’s most expensive herb. It is cultivated (0.29-2.87 mg/kg) caused relaxation in in north east of Iran and called as Zafaran in muscles; even so, muscle relaxation in- Persian. Saffron, a spice derived from the duced by the extract with a low dose of flower of the saffron crocus, is found almost 0.29 mg/kg was found to be as effective as in every kitchen in Iran. Additionally, Saf- relaxation produced by diazepam fron stigma has traditionally been adminis- (1 mg/kg). In another study, preliminary tered in order to prevent insomnia. Sedative phytochemical test showed that the extract and hypnotic effects of Saffron aqueous ex- was composed of low amount of flavonoid, tract and its constituents, crocin and safranal but enriched with tannin and saponin formed the central focus of a study by (Hosseinzadeh and Hassan Zadeh, 2001). Hosseinzadeh and Noraei (2009) in which Nevertheless, the mechanism in which they the authors found that Saffron aqueous ex- produce effect has not been well character- tract and Safranal showed sedative and hyp- ized. notic effects. They administered agents in- traperitoneally to mice before tests of sodium Salvia reuterana pentobarbital-induced sleeping time Salvia reuterana, which is commonly (30 mg/kg) and locomotor activity (open known as Mariam Goli Esfahani in Iran, field test). It was then mentioned that the has been mostly found in highlands of center decline in locomotor activity caused by of Iran. The aerial parts of this herb have aqueous extract was dose dependent, and been used in Iranian traditional medicine ow- Saffron only with a dose of 0.56 g/kg pro- ing to its sedative and anxiolytic effects. longed the total sleeping time in the hyp- Perry et al. (2003) reported that the mecha- notic test. Crocin was identified to have no nism of inhibition of acetylcholinesterase anxiolytic, hypnotic or myorelaxation ef- by constituents of S. reuterana was respon- fects. Safranal was shown to increase the sible for its sedative effects. In addition, it total sleeping time dose dependently. How- was reported that Miltirone inhibited the ever, at lower doses (0.05 and 0.15 mL/kg), binding of [3H]flunitrazepam to central it decreased some parameters of locomotion benzodiazepine receptor; and elucidated a activity. It was also demonstrated that major role for GABA receptor in its Safranal had no effects on motor coordina- mechanism (Lee et al., 1991). Another tion. study investigated volatile constituents of S. reuterana and showed that there are 21 Salvia leriifolia components in the oil of plant (Mirza and Salvia leriifolia, which is known as Sefidkon, 1999). The authors found that Noruzak, is endemic to Khorasan province (E)-β-Ocimene (32.3 %), α-gurjunene of Iran. It has traditionally been used for its (14.1 %), germacrene-d (11.2 %) and hexyl various health benefits. It is generally acetate (7.6 %) were the major constituents thought that it can relive pain, decrease in the oil of S. reuterana (Mirza and Sefid- blood sugar and treat inflammation and in- kon, 1999). In our previous study, we as- somnia. Hosseinzadeh and Hassan Zadeh sessed sedative effect of hydroalcoholic ex- (2001) investigated sedative and hypnotic tract of S. reuterana in mice by means of effects of extract of S. leriifolia on mice by spontaneous locomotor activity test at a

194 EXCLI Journal 2011;10:192-197 – ISSN 1611-2156 Received: August 31, 2011, accepted: October 03, 2011, published: October 10, 2011

dose of 100 mg/kg (Rabbani et al., 2005). phenyl propanoid glycoside (Basaran et al., The total locomotor activity count meas- 1988; Sezik and Basaran, 1985). ured in 15 minutes of the test was found to be significantly decreased in animals which CONCLUSION received diazepam pretreatment and S. Insomnia is a major health concern reuterana extract treatment. It is interesting throughout the world and a highly prevalent to note that a decline in locomotor activity sleep disorder in Iran. To elude deleterious was also evident in 5 minutes. We also ob- side effects of artificial medicines abating served that an increase in the dose of the insomnia, there has been a propensity for plant extract leaded to higher sedative herbal remedies. Despite the fact that plants properties. have been used in Iranian traditional medi- cine in order to preclude insomnia for cen- Stachys lavandulifolia turies, special attention has recently been Stachys lavandulifolia is widely distrib- devoted to them as alternatives for synthetic uted in Iran and known as Chaye Kuhi. As medicines in Iran. In fact, plausible justifi- well as being administered for several me- cation provided by previously mentioned dicinal purposes, the traditional use of S. Iranian studies has made it difficult to trivi- lavandulifolia for its hypnotic and sedative alize the role of these medicinal herbs in effects has been of great importance. Rab- treatment of insomnia. Various herbs have bani et al. (2003) studied the impacts of S. been used for reliving insomnia in Iranian lavandulifolia extracts upon ketamine- traditional medicine, Valeriana officinalis, induced sleeping time and locomotor activ- Blue violte, Salix aegyptiaca, lotus flower, ity tests in mice and demonstrated that the lettuce, and Echium amoenum, to name but extract produced hypnotic and sedative ac- a few. It is interesting to note that in our tivities. It was shown that intraperitoneal previous study, we investigated the sedative doses of 100 and 300 mg/kg of S. lavan- and hypnotic effects of E. amoenum by dulifolia extract significantly prolonged the means of locomotor activity and ketamin- duration of sleep by 28 and 42 percent, re- induced sleeping tests. The ethanolic ex- spectively. It was also reported that a treat- tract of this plant increased the latency time ment with plant extract at doses of 100 or and excreted no effect on total sleeping 300 mg/kg (30 minutes prior to ketamine time. This extract also did not produce a treatment), significantly shortened the ini- significant effect in locomotor activity test. tiation of induced sleep (latency time) by 24 As a result, we suggested that this herb did and 25 %, respectively. Moreover, they not exhibit sedative and hypnotic effects mentioned that the locomotor activity sig- (Rabbani et al., 2004). nificantly diminished in S. lavandulifolia- Considering the fact that reviewed stud- treated mice at a dose of 100 mg/kg. The ies have been carried out on animals, fur- authors then demonstrated that at all three ther research on human provides a better time intervals (5, 10 and 15 minutes), the insight concerning hypnotic and sedative decline in locomotor activity was evident; effects of herbal medicines and approves even so, greatest decline in locomotor activ- their efficacy. Nonetheless, many pharma- ity was found to be during the initial 5 min- cological and toxicological studies are utes. needed to be conducted prior to clinical tri- Moreover, the mechanism of action of als. In fact, more work should be done to constituents of S. lavandulifolia has not yet establish active constituents of these herbal been completely worked out, and only a medicines used for insomnia treatment. few studies have been carried out on its ac- What has to be finally considered is that tive constituents. It was demonstrated that these medicinal herbs have not yet been ap- S. lavandulifolia contained volatile oil and a proved. Therefore, they should undergo several approval processes. Indeed, there is

195 EXCLI Journal 2011;10:192-197 – ISSN 1611-2156 Received: August 31, 2011, accepted: October 03, 2011, published: October 10, 2011

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