Herbs and mood disorders
Numerous herbs are known to contain bioactive substances, although the clinical significance of these needs further investigation.57 Research in phytomedicine has been generating considerable amounts of new data on the chemical, pharmacological, and clinical aspects of herbs in mood disorders.58,59

St John’s wort
St John’s wort contains two bioactive substances, ie, hyperforin and hypericin, and has been used effectively in the treatment of major depression.57 Although initial reports of its use were hampered by inadequate concentrations of hyperforin,60 subsequent comparative, randomized, double-blind, placebo-controlled trials using better standardized St John’s wort (Kira® [LI-160 extract], 1800 mg/day, Klosterfrau Healthcare Group, Germany; Remotiv®, Flordis Natural Medicines, Australia; or Ze 117®, 500 mg/day Zeller AG, Switzerland) found it to be as effective as imipramine 150 mg/day and fluoxetine 20 mg/day for all severity levels of depression, but with fewer gastrointestinal side effects.61,62 A widely cited randomized, multicenter, placebo-controlled study of inpatients with depression given St John’s wort Kira® (LI-160 extract) 900 mg/day for 4 weeks, then increased to 1200 mg/day for another 4 weeks, found Kira® (LI-160 extract) to be no better than placebo. However, this negative result could be explained by the use of subtherapeutic doses of the bioactive substances in St John’s wort.63 The greater severity and resistant nature of depression might also have contributed to lack of effectiveness, but this is unlikely, given the results from Phase II of the study.64 In another study of severely depressed patients given Kira® (LI-160, 900–1500 mg/day), sertraline (50–100 mg/day), or placebo, found that neither sertraline nor St John’s wort showed more efficacy than placebo.65 In a randomized, placebo-controlled multicenter study of outpatients with mild-to-moderate depression, Kira® (LI-160 extract) and fluoxetine did not differ significantly with regard to efficacy measures except for remission rates (24% for Kira® [LI-160 extract], 28% for fluoxetine, and 7% for placebo). It was concluded that Kira® (LI-160 extract) and fluoxetine were no more effective than placebo in the short-term treatment of mild-to-moderate depression.66 The results of this study are supported by other researchers.67
In another randomized study of patients with major depression, Kira® (LI-160 extract, 900 mg/day) was more effective than fluoxetine (20 mg/day) and showed a trend towards superiority over placebo.68 The remission rates were higher for Kira® (LI-160 extract) compared with fluoxetine and placebo.68 A reanalysis of earlier data suggested that patients’ beliefs regarding treatment may have a stronger effect on clinical outcome than the actual medication received, depending on what treatment patients thought they were receiving and what they actually received.69 Recent well controlled studies, meta-analyses, and consensus guidelines support the efficacy of St John’s wort in patients with mild-to moderate-depression in particular.33,37,43,70,71
In another double-blind, randomized, placebo-controlled, long-term trial, Kasper et al70 reported the beneficial effects of Hypericum extract (WS® 5570, Dr. Willmar Schwabe Pharmaceuticals, Germany) in adult outpatients who had recovered from an acute episode of moderate depression. Patients treated with WS® 5570 showed more favorable time courses to resolution of symptoms and greater overall improvement than those randomized to placebo. Used as long-term maintenance therapy, WS® 5570 was reported to have a prophylactic effect in patients with early-onset depression and in those with a high degree of chronicity. WS® 5570 also showed a beneficial effect in preventing relapse after recovery from acute depression.70
St John’s wort has also been used in primary care psychiatric settings and in patients with seasonal affective disorder, and examined with regard to relapse rates in those who responded, all with good results. For example, Szegedi et al reported that 71% of patients with moderate-to-severe depression treated in primary care responded to 900 mg/day Hypericum extract WS® 5570, and that 900–1800 mg/day was as effective as paroxetine 20–40 mg/day, but without side effects.72 Patients with mild seasonal affective disorder have also been reported to benefit from Kira® (LI-160 extract).37,73 With regard to relapse, reanalysis of data from 154 patients with mild-to-moderate depression treated with St John’s wort (STW 3-VI; Laif®, Steigerwald Arzneimittelwerk GmbH, Germany) 900 mg, citalopram 20 mg, or placebo once daily found that relapse rates were highest in the citalopram group, followed by the St John’s wort and placebo groups, with no difference in the severity of relapse.74 Further, the duration of response was longest for the St John’s wort group, intermediate for the citalopram group, and shortest for the placebo group. Researchers concluded that 3-VI had the longest duration of response and was more effective than citalopram and placebo in decreasing relapse and recurrence rates.74 However, in a 12-week study of minor depression, St John’s wort (Cederroth International, Sweden, 810 mg/day) was not superior to citalopram 20 mg/day or placebo, and the authors called for more research to identify better treatment options for patients with minor depression.75 In a review of commonly used botanicals in the treatment of anxiety and mood disorders, St John’s wort (5 of 7 trials), black cohosh (all studies reviewed), and ginseng (1 trial) have been reported to improve symptoms of depression and anxiety in menopausal and postmenopausal women.76
St John’s wort is generally used as a second-line option, except in women with a history of response to low doses of an SSRI.57 St John’s wort has potential side effects that increase with higher doses. These include phototoxic rash, SSRI-like effects, serotonin syndrome, and induced mania.77 The side effect profile and dropout rates in the range of 0%–5.7% for patients receiving St John’s wort are not different from placebo, and have been reported to be similar to those of tricyclic antidepressants and slightly lower than those of the SSRIs.77 A study that reanalyzed data from four clinical trials found that St John’s wort extract (WS® 5570) was associated with fewer adverse events than SSRIs.78 Nevertheless, St John’s wort reduces circulating levels of a large number of drugs, including digoxin, warfarin, and oral contraceptives, because it induces cytochrome P450 (CYP) 3A4 and CYP 1A2 enzymes as well as P-glycoprotein in the intestinal wall.77,79 According to one study, the information available on websites selling St John’s wort is not of good quality and consumers should bear this in mind when considering buying the product.80 Another study that evaluated safety information provided in the labeling of St John’s wort products found that the majority of producers failed to address safety issues adequately.81 Health care providers and consumers will benefit if the US Food and Drug Administration and similar regulatory bodies elsewhere re-examine the labeling requirements for dietary supplements.81

Rhodiola rosea
The use of medicinal herbs had been widespread across many cultures since ancient times. A recent university student survey83 found that most herb use was self-prescribed (60%) and undisclosed to health providers (75%), 34% of users took herbs to treat a mood disorder, 13% of herb users were taking concurrent prescription medication, and those who took both herbs and prescription medications had higher depression and anxiety scores than other herb users. Detailed patient interviews are necessary to prevent adverse herb-drug interactions.82
Rhodiola rosea, recommended in many conditions, including irregular menopause,83,84 has also been reported to be effective in the treatment of mild-to-moderate depression.85 One trial used a standardized extract of Rhodiola rosea (SHR-5, Swedish Herbal Institute, Sweden) at doses of 340 mg and 680 mg daily for six weeks with no reports of side effects.85 A systematic review has also supported the antidepressant effects of Rhodiola rosea.86 Its mechanism of action in major depression is thought to be via beta-endorphins, tryptophan, and serotonin in the brain.57,88 Rosiridin is the bioactive ingredient of Rhodiola rosea, which is reported to inhibit monoamine oxidases A and B and may also be useful in dementia.83
Having no addictive potential, Rhodiola rosea is a mild stimulant, so should be taken in the morning to avoid sleep problems. It may induce temporary vivid dreams and mild nausea. It also binds with the estrogen receptor, so women with a personal or family history of estrogen-sensitive breast cancer should exercise caution in using Rhodiola rosea, although this issue needs further study.88 Products containing 3% rosavins and 1% salidrosides were found to be effective in a randomized controlled trial, and may be used to enhance the clinical effectiveness of Rhodiola rosea.57 Panossian et al provide detailed information on its traditional use, chemical composition, pharmacology, side effect profile, and clinical efficacy.84

Saffron and other herbs
A systematic review of herbs used in major depression and other mood disorders identified nine clinical trials that met all eligibility criteria.89 Three of these trials found saffron stigma extract to be more effective than placebo and equivalent in effect to fluoxetine and imipramine. Two studies found that saffron petal extract was significantly more effective than placebo and was equivalent to fluoxetine and saffron stigma extract. Lavender was found to be less effective than imipramine, but the combination of lavender and imipramine was significantly more effective than imipramine alone. When compared with placebo, Echium extract was found to decrease depression scores markedly at week 4, although this effect had disappeared by week 6. According to this review, saffron, lavender, Echium, and Rhodiola rosea when used alone or in combination with antidepressants showed good results in mild-to-moderate depression.89 Another critical review that identified 21 phytomedicines and 66 clinical trials involving 11 phytomedicines reported positive results of the aforementioned herbs in mild-to-moderate depression, anxiety, and sleep disorders.90 In a clinical trial of Free and Easy Wanderer Plus (FEWP, Golden Flower, People’s Republic of China; a Chinese herbal extract formula), fluoxetine, and placebo, 150 patients with post-stroke depression showed significant improvement with both FEWP and fluoxetine compared with placebo.91 At the end of the trial, subjects on FEWP showed greater improvement than those on fluoxetine at week 2 and performed better than patients receiving fluoxetine in activities of daily living. This study suggests that FEWP can be used safely with few side effects in patients with post-stroke depression.91
Caution is important when using herbs and dietary supplements. Rai et al92 analyzed the heavy metal content in nine plant species used for the preparation of herbs in India and found that most samples had a heavy metal content exceeding the upper limits set by the World Health Organization. Further, heavy metals and organochlorine pesticides have been found in some dietary supplements in the US.93 In traditional Chinese medicine (Table 2), cases of heavy metal poisoning has been reported by several investigators.94 There is a large body of literature concerning the heavy metal content of herbal supplements used in CAM, including mercury, lead, chromium, cadmium, arsenic, cobalt, and pesticides, including dioxin.95–100 Quality control measures, including standardized doses and regulations, are needed for herbal products used for health reasons.40