Crocus sativus L. (Saffron)

The stigmas of Crocus sativus L. contain a number of potentially bioactive compounds including a number of carotenoids (crocins), monoterpenes and flavonoids, including quercetin and kaempferol. Rodent behaviour models have demonstrated that Crocus sativus extracts can ameliorate scopolamine-induced memory performance and that crocins can enhance memory performance and attenuate scopolamine-induced memory deficits.

In humans, four double-blind, controlled trials, each with relatively small samples of 40 patients with mild-to-moderate depression, have demonstrated that 6-8 weeks of administration of dried ethanol extracts of Crocus sativus stigmas (15 mg) and petals (30 mg) are more effective than placebo and as effective as fluoxetine (but with no placebo control) in ameliorating the symptoms of depression, as assessed by the Hamilton Depression Rating Scale. While Crocus sativus has been included on the basis that these studies show some promise, the evidence base requires research conducted in larger cohorts.

Hypericum perforatum L. (St John’s wort)

Hypericum perforatum L. has been in recorded medicinal use from the time of the ancient Greeks. Hypericum extracts contain a number of groups of potentially bioactive constituents including flavonoids, phenolic acids, naphthodianthrones and phloroglucinols.

The bioactive properties of St John’s wort include inhibition of the neuronal re-uptake of serotonin, dopamine, noradrenaline, Ύ-aminobutyric acid (GABA) and L-glutamate, and increased neurotransmitter sensitivity and receptor binding. These effects have been variously attributed over time to the naphthodianthrones, e.g. hypericin, pseudohypericin, protohypericin and protopseudohypericin, the phloroglucinol hyperforin and the range of flavonoid constituents.

Given their ability to modulate a wide range of neurotransmitter systems, it is not surprising that extracts and constituents have been shown to exert a plethora of effects relevant to behaviour in animal models. These include neuroprotective effects, an attenuation of cognitive impairment and improved cognitive performance.

In humans the vast majority of research has focused on the antidepressant effects of Hypericum perforatum extracts. In this domain a number of reviews and meta-analyses summarising the evidence have been published in the past 8 or 9 years. The two most recent reviews adequately encompass the considerable body of work in this area. In the first of these meta-analyses, Roder et al, (2004) assessed the evidence from randomised, controlled trials for the efficacy of standardised extracts (dosage: 300-1200 mg/day) in the treatment of mild-to-moderate depression. They concluded that these extracts had a significant effect on symptoms in comparison with placebo, and performed as well as synthetic antidepressants.

A subsequent Cochrane review by Linde et al. (2005) included a total of 37 trials judged to be methodologically adequate that had assessed St John’s wort in comparison with either placebo or standard antidepressants. In common with Roder et al. (2004), the authors conclude that the extracts seems to be more effective than placebo and as effective as standard antidepressants for treating mild-to-moderate depressive symptoms. However, beneficial effects for treating major depression appear minimal, although this latter conclusion may reflect a simple lack of research addressing this question. A subsequent review of reviews and meta-analyses also confirmed the general consensus that St John’s wort is effective in the treatment of depression.

Given evidence of similar levels of efficacy as synthetic antidepressants, a further advantage of Hypericum perforatum extracts is that they are generally found to be better tolerated. However, they can affect the metabolism of several medications resulting in reduced plasma concentrations.

Melissa officinalis L. (Lemon balm)

Melissa officinalis is a perennial, lemon-scented herb, used medicinally for over 2000 years, particularly for improved memory and mental function. Its contemporary usage includes as a mild sedative, in disturbed sleep, and in the attenuation of the symptoms of nervous disorders, including the reduction of excitability, anxiety, and stress.

Potentially active constituents include a number of monoterpenoid aldehydes (including citronellal, neral and geranial), flavonoids and polyphenolic compounds (most notably rosmarinic acid) and monoterpene glycosides.

Extracts have been shown to have both nicotinic and muscarinic cholinergic receptor-binding properties in human brain homogenates and essential oils have appreciable acetylcholinesterase-inhibitory properties. Extracts also have antioxidant properties which are putatively attributable to their flavonoid content.

In behavioural terms, a number of studies involving rodents suggest specific ‘calming’ or sedative effects following both essential oil and an hydroalchoholic extract of Melissa officinalis.

A series of randomised, double-blind, placebo-controlled, balanced-crossover trials have also assessed the cognitive and mood effects of single doses of Melissa officinalis in humans. Two of these studies assessed the effects of a commercial lemon-balm methanolic, which lacked in-vitro nicotinic and muscarinic receptor-binding properties. In the first, three separate, single doses of Melissa officinalis extract (300 mg, 600 mg, and 900 mg) were compared with placebo, with 20 participants undergoing weekly assessments. The results demonstrated a dose-dependent impairment of memory function, with concomitant reductions in ratings of ‘alertness’ restricted to the highest dose and increased ‘calmness’ following the lowest dose.

In the second study, the two lower doses (300 mg, 600 mg) were investigated using a multitasking laboratory stressor paradigm, with the highest dose again leading to reduced ratings of alertness and increased ratings of calmness during the stressor battery. The pattern of results from these two studies is broadly in line with the traditional mildly sedative and calming properties of these extracts.

To assess the effects of Melissa officinalis with cholinergic receptor-binding properties, a further experiment was conducted in two distinct phases. In the first phase, cholinergic receptor-binding properties were established across a number of samples, with the dried leaf with the highest nicotinic and muscarinic receptor-binding properties being administered in a placebo-controlled, double-blind, balanced crossover study assessing the cognitive performance and mood effects of several single doses (600, 1000, 1600 mg dried leaf). In this case, while the lowest of the three doses evinced similar memory decrements as those seen in the previous study, the highest dose both increased ‘calmness’ and improved memory performance. The results from these three studies suggest that lemon balm owes its mildly sedative properties to something other than cholinergic receptor binding.

Two recent double-blind, placebo-controlled studies have also assessed the effects of Melissa officinalis in patients with dementia. Ballard et al. (2003) examined the effect of essential oil aromatherapy (in comparison with vegetable oil) on ratings of agitation and quality of life of 71 patients with severe dementia. After 4 weeks’ treatment, patients in the active treatment group were rated, in comparison with the placebo group, as being less agitated, less socially withdrawn, and as engaging in more time spent in constructive activities. Akhondzadeh et al. (2003) also assessed the effects of 60 drops/day of a tincture in 35 patients with mild-to-moderate dementia (20 verum, 15 placebo) who completed their 16-week trial. At the study endpoint, the results showed a clear cognitive advantage (ADAS-cog and Clinical Dementia Rating) and reduced agitation for the group taking the tincture.

Piper methysticum L.f. (Kava)

Drinks and extracts made from the rhizome and roots of kava have been used for millennia in the South Pacific both recreationally and medicinally to reduce fatigue and induce relaxation and sleep.

The major bioactive constituents of kava are styryl α-pyrones generally referred to as kava-pyrones or, more commonly, kavalactones. Contemporary commercial Kava extracts are generally standardised to contain approximately 30-70% of kavalactones. It should be noted that leaves and stem contain potentially hepatotoxic alkaloids but these are not generally considered to be responsible for the severe liver toxicity in a few individuals reported in recent years, which has led to severe curtailment of its use in many countries.

The exact mechanism underlying the central nervous system effects of kavalactones is poorly delineated to date. Kavalactones have been shown, at the most fundamental level, to modulate neuronal excitability via voltage-dependent calcium channels. They also modulate activity in the serotonergic, glutamatergic and dopaminergic neurotransmitter systems. In addition, kava’s anxyolitic properties have been attributed to interactions with N-methyl-D-aspartic acid and GABA receptors, although the evidence regarding the latter is inconsistent. Modulation of P-adrenergic activity may also play a role in their behavioural effects.

With regards to kava’s anxiolytic effects, Pittler and Ernst’s (2003) Cochrane review meta-analysed the randomised, controlled trials extant at that time. Twelve studies met their inclusion criteria and they concluded that, in comparison with placebo, kava extracts (administered for between 1 day and 24 weeks and containing between 105 and 280 mg of kavalactones) were associated with a significant reduction in anxiety on the Hamilton Anxiety (HAM-A) scale. Witte et al. (2005) went on to meta-analyse the six studies included in the latter analysis that had administered the standardised acetonic extract WS1490, and again found a significant treatment-related anxiolytic effect in comparison with placebo. With regards to behaviour, Cairney et al. (2002) note that a number of small studies have assessed the cognitive effects of kava. However, because of the methodology employed in these studies, the question is largely unresolved.

The focus of recent research has shifted away from efficacy and firmly towards putative negative side-effects and potential drug interactions of kava, since the publication of several case reports of treatment-related liver failure. These reports led to the withdrawal of kava by many national authorities, although the strength of the evidence on which these decisions were based is contested by many. Similary, it has been suggested that kava is capable of a host of theoretical drug interactions, for which hard evidence of specific cases is lacking.

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