Journal of Medicinal Plants

Evidence Based Herbal Medicine and Mental Health

Hajiaghaee R (Ph.D.)1, Akhondzadeh S (Ph.D.)2*

1- Pharmacognosy & Pharmaceutics Department of Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran 2- Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran * Corresponding author: Psychiatric Research Center, Roozbeh Hospital, South Kargar Street, Tehran 13337, Iran Tel: +98-21-88281866, Fax: +98-21-55419113 Email: [email protected]

Received: 21 Aug. 2012 Accepted: 16 Nov. 2012

Abstract

Many cultures have developed folk herbal remedies for various symptoms of mental illness. An evidence base now is being developed for some of these “alternative” herbal remedies. There has been an increase in the number and proportion of clinical trials of complementary medicine, which suggests a trend toward an evidence-based approach. This review presents the scientific information regarding herbal medicine with evidence based approaches for saffron. Keywords: Crocus sativus, Evidence Based Herbal Medicine, Mental health

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Introduction and available in hospitals. Nevertheless, many Complementary medicine are interventions people using herbal medicines find the health that are not widely taught in medical schools care alternatives are more congruent with their and are not part of the usual arsenal of own values, beliefs and philosophical treatments and medications recommended and orientations toward health and life. Similarly, prescribed by physicians and available in it seems likely that many people feel that hospitals. Use of Complementary medicine is herbal medicines are empowering by allowing dependent, not on dissatisfaction with them to treat themselves without seeing a conventional medicine as it is most commonly physician. The danger is that, many people used in association with conventional believe that herbal medicines have no toxicity medicine, but on philosophical orientations problems or even side effects. In addition, they towards health and life [1]. A vast quantity of are not aware of many possible interactions of information of varying quality exists in the herbal medicine with concurrent prescribed media and on the internet. There are concerns, medications [1]. however, that the media and internet provide Herbal medicines include a range of too rosy a picture of complementary medicine pharmacologically active compounds: in some and downplay adverse reactions to cases it is not well understood which complementary medicine, which can be ingredients are important for a therapeutic dangerous and potentially fatal. These factors effect. The supporters of herbal medicine suggest that significant improvements need to believe that isolated ingredients in the majority be made to knowledge translation mechanisms of cases have weaker clinical effects than for the public, healthcare professionals, and whole plant extract, a claim that would policy makers. The response of the medical obviously require proof in each case. and scientific community has been an Generalizations about the efficacy of herbal increasing interest in complementary medicine medicines are clearly not possible. Each one issues [1]. There has been an increase in the needs systematic research including a variety number and proportion of clinical trials of of animal studies and also randomized clinical complementary medicine, which suggests a trials. Indeed, clinical trials of herbal trend toward an evidence-based approach. One medicines are feasible much in the same way of main branches of complementary medicine, as for other drugs [1]. Numerous randomized is herbal medicine. Herbal medicine has seen a clinical trials of herbal medicines have been growth in scientifically referenced texts in the published and systematic review and meta- past twenty years. However, herbal medicines analyses of these studies have been available. are interventions that are not widely taught in Many of today’s synthetic drugs originated medical schools and are not part of the usual from the plant kingdom, and only about two arsenal of treatments and medications centuries ago the major pharmacopoeias were recommended and prescribed by physicians

2 Journal of Medicinal Plants, Volume 11, No. 43, Summer 2012 Hajiaghaee & Akhondzadeh dominated by herbal drugs. It has been anticholinergic side effects). Subsequently, reported that most patients with a mental saffron was compared to placebo in a six-week disorder sought herbal medicine treatment for randomized controlled trial of 40 adult patients somatic problems rather than for their mental with mild to moderate depression. Saffron and emotional symptoms and the best example resulted in about 12-point reduction on is somatic symptoms of depression [1]. Hamilton depression rating scale (HDRS) Physicians need to understand the compared with only five points seen with the biochemical and evidential bases for the use of placebo. Tolerability profile of saffron was herbs and nutrients to diagnose and treat similar to the placebo [3]. Later, several patients safely and effectively, to avoid studies provided evidence for antidepressant interactions with standard medications, and to effects of different Crocus sativus L. provide patients with the benefits of alternative constituents compared with both placebo and treatments [1]. This review will present saffron fluoxetine. Both petal and stigma of Crocus as example for evidence based herbal sativus L. have shown beneficial effects for medicine. treatment of depression [3, 4]. The mechanism of action of antidepressant effects of saffron is Saffron (Crocus sativus) not clearly understood. However, reuptake Saffron is the world’s most expensive spice, inhibition of monoamines, NMDA derived from the flower of Crocus sativus. antagonism, and possibly improved BDNF Each saffron crocus grows to 20 – 30 cm and signaling might be implicated in its bears up to four flowers, each with three vivid mechanism of action [5, 6]. In summary, crimson stigmas [1]. Indeed, it is a Persian saffron extract with a dose of 20 mg twice herb with a history as long as the Persian daily, seems to be as efficacious and tolerable Empire itself. Iran, the world's largest producer as fluoxetine for short-term treatment of mild of saffron has been investing in research into to moderate depression [7]. Long-term studies saffron's potential medicinal uses. for comparison of relapse rates are still lacking. Interestingly, saffron does not cause Depression sexual side effects generally associated with To date, five published randomized fluoxetine use; indeed it can prevent or treat controlled trials have been published about some aspects of fluoxetine induced sexual effects of saffron on depression. The first impairment [8]. evidence-based study on this subject was published in 2004 showing that saffron was as Anxiety and sleep problems efficacious as imipramine in the short-term Published studies on anti-anxiety effects of treatment of mild to moderate depression in saffron are limited to animal experiments [9, adults [2]. Importantly, saffron was more 10]. Activation of GABA-A receptors might tolerable than imipramine (which often causes explain the anxiolytic effects of saffron [11].

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Animal studies also demonstrated on the international index of erectile function improvement of non-rapid eye movement (IIEF) questionnaire [18]. In a recent study, (non-REM) sleep following safranal and saffron 15 mg twice daily was used to treat crocin administration in mice [12, 13]. fluoxetine-induced sexual dysfunction in male Safranal enhanced non-REM sleep probably patients with major depression. The authors by activation of the sleep center in the found significant improvement in the erectile ventrolateral preoptic nucleus and the function and intercourse satisfaction (but not inhibition of the histaminergic desire and orgasmic function) domains of IIEF tuberomammillary nuclei [12]. in the saffron group. Sixty percent of patients in the saffron group compared with only 7% of Reproductive and sexual problems patients in the placebo group achieved normal The only clinical trial on the effect of erectile function at the end of the study [8]. In saffron on premenstrual syndrome showed that a parallel safety study on the same patients, use of saffron 15 mg twice daily for two saffron did not affect liver, kidney, and blood menstrual cycles was significantly more tests. Moreover, frequency of adverse events effective than placebo in improvement of in the saffron group was similar to that of the depression and premenstrual daily symptoms placebo [19]. In a similar study which was [14]. In an open label study, saffron odor carried out on women with fluoxetine- reduced cortisol levels and anxiety, and associated sexual dysfunction, saffron resulted increased estrogen levels in both follicular and in improvement of arousal, pain and luteal phases [15]. A clinical trial compared lubrication domains while it did not affect the effect of placebo, mefenamic acid, and an satisfaction, orgasm, and desire (under herbal drug (composed of saffron, celery seed, review). and anise) on primary dysmenorrhea in young women. After two or three cycles, patients in Neurotoxicity and Alzheimer’s disease the herbal drug group reported significantly Several constituents of saffron including lower pain scores than patients in other groups safranal, crocin, crocetin, and carotenoids have [16]. shown neuroprotective properties in animal Traditionally, saffron was thought to models of ischemic, oxidative, traumatic, and improve sexual functioning. From an inflammatory brain injury. Among several evidence-based point of view, Crocus sativus constituent of saffron, crocin showed the L. and its constituents improved all highest neuroprotective activity in one study. components of sexual function in male rats The neuroprotective activity of crocin is [17]. Administration of high dose of saffron probably secondary to enhancement of (200 mg/day) for ten days to 20 patients with glutathione (GSH) synthesis through erectile dysfunction, significantly improved increasing expression of gamma- nocturnal penile tumescence as well as score glutamylcysteinyl synthase (gamma-GCS). In

4 Journal of Medicinal Plants, Volume 11, No. 43, Summer 2012 Hajiaghaee & Akhondzadeh a hemi-parkinsonian mouse model, crocetin The mechanism of action of cognitive pretreatment preserved levels of GSH, enhancement by saffron merits further dopamine, and activity of antioxidant consideration. Saffron seems to both enzymes, and protected neurons of substantia antagonize glutamatergic activity on NMDA nigra [21]. receptors (similar to memantine) [5,32,33] and Crocus sativus L. is increasingly being to inhibit acetylcholinesterases (similar to studied as a memory enhancer. Saffron can donepezil) [34]. AD is associated with attenuate the deleterious effect of ethanol on inflammatory activation in the brain as shown memory registration and retrieval, and prevent by several studies. Saffron (particularly its ethanol-induced inhibition of hippocampal crocin and crocetin constituents) effectively long-term potentiation [23, 24]. Crocin seems inhibited glial activation induced by interferon to be involved in spatial memory and and amyloid beta, and reduced levels of recognition and blocked scopolamine-induced several inflammatory markers in the rat brain performance deficits in the step-through [37]. passive avoidance and radial water maze tests [25, 26]. Saffron showed similar protective Adverse effects and toxicity effects on recognition and spatial memory in In a double-blind, placebo-controlled study, chronic stress and hypoperfusion models of three groups of volunteers received placebo, memory impairment [27, 28]. 200 mg/day, or 400 mg/day saffron tablets for In an animal model of AD induced by one week. High dose saffron reduced systolic intraventricular injection of streptozocin, blood pressure and mean arterial pressures Khalili et al. showed that administration of significantly. Moreover, saffron slightly crocin resulted in significantly better results in reduced or increased some hematological and passive avoidance test [29]. In a 16-week biochemical parameters (hemoglobin, placebo-controlled study, 46 patients with mild hematocrit, platelets, sodium, blood urea to moderate AD were assigned to saffron 15 nitrogen and creatinine). None of the mg twice daily or placebo. At the end of the mentioned changes had clinical significance trial, saffron was associated with a [39]. It should be emphasized that with the significantly better outcome on cognitive doses used in the clinical setting (usually less function than placebo. Importantly, tolerability than 100 and often less than 60 mg/day) of saffron was similar to placebo [30]. In a 22- saffron is generally no less tolerable than week donepezil-controlled study, saffron 15 placebo. A case of proven anaphylaxis mg twice daily was compared to donepezil 5 following eating rice cooked with saffron has mg twice daily. Saffron was as efficacious as been reported. The authors recommended that donepezil, but was associated with lower saffron should be regarded as an allergen when frequency of side effects than donepezil [31]. investigating the causes of allergies.

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