Cognitive Anxiolytics


Herbal medicine

Dosage

Major/active constituents

Key evidence

Potential adverse effects

Potential clinical use

Clinical advice

Brahmi (Bacopa monnieri)

Acute: 320 mg or 640 mg of Brahmi extract

Chronic: 300 mg/d or 450 mg/d of Brahmi extract for 12 weeks or 6 months

Bacosides A and B

Some positive Randomised Controlled Trials (RCTs) and two meta-analyses showing significant reductions in trait anxiety and improvements in cognitive function (executive function, processing speed, free recall) versus placebo

No adverse reactions found in studies

Non-clinical stress or anxiety, anxiety-induced insomnia, anxiety associated with cognitive decline. Further research needed on individuals with clinical anxiety disorders

Some suggestion it may have equivalent effects to benzodiazepines and therefore may be a useful alternative to these

Generally safe, though currently no data on potential interactions with psychotropic medications. Use with care

Ginkgo (Ginkgo biloba)

Standardised ginkgo extract: EGb 761

240 mg/d or 480 mg/d for 4 weeks or 24 weeks

Flavonoids (kaempferol, quercetin, and isorhamnetin)

Terpenoids (ginkgolides A, B, C, J, and bilobalide)

Some positive RCTs for anxiety and cognitive function, though several meta-analyses have concluded null effects

No adverse reactions found in studies

GAD, anxiety associated with adjustment disorder, anxiety associated with mild cognitive impairment (MCI)

Generally safe, though currently no data on potential interactions with psychotropic medications. Can lead to excessive bleeding and bruising when used with antiplatelet aggregators. Has known effects on neurotransmitters (particularly serotonin, norepinephrine, and dopamine), therefore, use with care

Lemon balm (Melissa officinalis)

Acute: 300, 600, or 900 mg of lemon balm extract

Chronic: 60 drops/d of lemon balm extract for 16 weeks; standardised lemon balm extract (Cyracos®) for 15 days

Flavonoids (e.g., luteolin).

Phenolic acids (e.g., rosmarinic acid, caffeic acid, and chlorogenic acids). Tanins.

Triterpenic acids

Some positive RCTs for anxiety and cognitive function (attention, processing speed, memory)

No adverse reactions found in studies; commonly added to food as flavouring or consumed as a tea

Mild-to-moderate clinical anxiety (DMS-IV-TR), insomnia, agitation, and anxiety associated with dementia (including AD).

Some suggestion it may have equivalent effects to benzodiazepines and therefore may be a useful alternative to these

Generally safe and widely consumed

Tea (Camellia sinensis)

Acute: 75 mg caffeine ±50 mg L-theanine.

Chronic: 8 weeks of 400 mg/day L-theanine

Polyphenols (e.g., catechins).

Amino acids (e.g., L-theanine).

Caffeine

Some positive RCTs on cognitive function (alertness, attentional switching) and anxiety for constituents of tea (particularly L-theanine + caffeine), however, overall meta-analyses have failed to confirm the cognitive anxiolytic effects

No adverse reactions found in studies; commonly consumed as a drink

Non-clinical stress, tension, or anxiety, anxiety associated with schizophrenia or schizoaffective disorder. Further research needed on individuals with clinical anxiety disorders.

The cognitive anxiolytic effects are currently questionable and further research is needed prior to formal recommendations. It is also currently unclear which combination of L-theanine and caffeine is ideal

Generally safe and widely consumed

Sage (Salvia spp.)

Acute: 25 μL or 50 μL (essential oil) of S. lavandulaefolia OR 300 mg or 600 mg (dried leaf) of S. officinalis

Chronic: 6 weeks oral administration (50 μL essential oil up to 3 times per day) of S. lavandulaefolia OR 16 weeks oral administration of 60 drops per day of 1:1 plant extract (i.e., 1 kg leaf: 1 L 45 % alcohol) of S. officinalis

Terpenoids (e.g., 1,8-cineole, α- and β-pinene, camphor, bornyl acetate, 3-carene)

Pre-clinical research and traditional use suggest potential anxiolytic effects; two positive RCTs in humans demonstrating acute anxiolytic effects

RCTs in MCI and AD suggest cognitive-enhancing effects

No adverse reactions found in studies; commonly used in cooking

Non-clinical stress or anxiety, agitation and anxiety associated with cognitive decline (MCI, AD). Further research needed on individuals with clinical anxiety disorders

Generally safe and widely consumed

Rosemary (Rosmarinus officinalis)

Acute: aromatherapy essential oil inhalation (3–4 drops on cotton wool) or massage (20 min)

Rosmarinic acid

Terpenoids (e.g., 1,8-cineole, α-pinene, camphor)

A systematic review suggests positive anxiolytic effects, though the unique effects of rosemary versus aromatherapy in general (including lavender) remains unclear

Some positive RCTs indicate acute improvements in cognitive function (e.g., alertness, memory)

No adverse reactions found in studies; commonly used in cooking and aromatherapy

Non-clinical stress or anxiety, test anxiety, anxiety associated with medical conditions or an adjustment disorder. Further research needed on individuals with clinical anxiety disorders

Some suggestion in pre-clinical research that it may have equivalent effects to benzodiazepines and therefore may be a useful alternative to these

Generally safe and widely consumed





4.5.2 Mechanisms of Action



4.5.2.1 Constituents


The primary bioactive constituents of tea are polyphenols, amino acids, and caffeine [62]. Between 30 and 42 % of the dry weight of green tea is formed from catechins; caffeine and L-theanine (amino acid) respectively account for around 2 to 5 % and 3 %. Its chief catechin polyphenol, epigallocatechin gallate (EGCG), contributes 50 to 80 % of total catechins [63], and has neuroprotective effects due to its antioxidant action, suppressing inflammatory processes and inhibiting cell proliferation [64]. Other prominent catechins include epigallocatechin (EGC), epicatechin gallate (ECG), and epicatechin (EC), although these are present in smaller quantities. L-theanine is a non-protein amino acid analogue of γ-N-ethyl-L-glutamine, and has been shown to bind to AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), N-Methyl-D-aspartate (NMDA), group I metabotropic glutamate, and kainate receptors, inhibiting glutamate reuptake and potentiating GABA, dopamine, and serotonin [6567]. L-theanine is thought to have anxiolytic properties due to potentiation of GABA [68], the primary inhibitory neurotransmitter in the brain. Caffeine inhibits adenosine (A1 and A2a) receptors, increasing dopamine transmission and ACh, resulting in increased arousal and enhanced cognition [69]. These three constituents are thought to interact, resulting in the overall cognitive-enhancing and anxiolytic effects of tea, with some evidence that L-Theanine inhibits caffeine’s stimulatory effects [70].


4.5.3 Evidence of Efficacy



4.5.3.1 Preclinical


Animal studies have demonstrated effects of green tea extract and its individual constituents on cognition and anxiety. Work on green tea extract has demonstrated effects after both chronic and acute administration. Improvements in motor coordination (Morris water maze, rota rod test, locomotor activity measured with actophotometer, and negative geotaxis measured with mid-air righting) and reduced anxiety (elevated plus maze, open field test) in valproic acid induced oxidative stress model mice were seen after 300 mg/kg of green tea extract [71]. In addition, enhanced learning and memory in aged rats were observed after 8 weeks of 0.5 % green tea extract, measured by elevated plus maze and passive avoidance tests [72]. Other acute research on individual constituents showed that standardised EGCG extract (10 mg/kg) reduced cognitive dysfunction and improved positive mood in Parkinson’s disease model rats [73], and that 100 μml/20 g of EGCG resulted in amnestic and anxiolytic effects on behaviour in mice in elevated plus maze test [74]. However, Stringer, Abeysekera, Dria, Roper, and Goodlett [75] did not show cognitive improvement in Down syndrome model mice following chronic administration of EGCG (~20 mg/kg/day) for 3 or 7 weeks. Heese et al. [68] found that acute 10 mg/kg L-theanine alone did not exert anxiolytic effects; however, when combined with midazolam, a synergistic/additive effect occurred, resulting in decreased anxiety and motor movements on the elevated plus maze. L-theanine has also been shown to reduce opioid withdrawal signs in rhesus monkeys (e.g., fighting), and produce anxiolytic effects in mice without affecting motor behaviour [70].


4.5.3.2 Clinical


Work examining the combined and separate effects of acute L-theanine and caffeine on human cognition and mood has demonstrated that L-theanine suppresses the stimulatory effect of caffeine. For example, a study on the acute effects of caffeine and L-theanine in habitual (n = 12) and non-habitual (n = 12) caffeine drinkers demonstrated that 75 mg caffeine alone improved attention and positive mood (VAS), reduced oxygenated haemoglobin, and increased deoxygenated haemoglobin [76]. When 75 mg caffeine and 50 mg L-theanine were combined, increased deoxygenated haemoglobin was still apparent; however, this was somewhat attenuated compared to caffeine alone. Those authors concluded that caffeine and L-theanine interact, and the presence of L-theanine results in the attenuation of the vasoconstrictive and behavioural effects of caffeine. Further research is required to identify which constituent contributes to the positive effects on mood. Another study (n = 48) showed that acute dosing of caffeine (250 mg) increased alertness, jitteriness, and blood pressure, but when combined with 200 mg L-theanine, caffeine’s effect on blood pressure was attenuated; L-theanine alone slowed reaction times on a visual probe task [77]. Importantly, Camfield et al. [78] conducted a meta-analysis on 11 randomised placebo-controlled trials to determine the acute effects of EGCG, L-Theanine, and caffeine. Combined caffeine and L-theanine was found to improve cognition (alertness and attentional switching accuracy); however, a subsequent analysis showed a trend towards an enhanced effect for caffeine compared to L-theanine.

Other research utilising L-theanine alone has demonstrated anxiolytic effects. A randomised controlled trial (n = 60) on 8 weeks of 400 mg/day L-theanine administration significantly reduced anxiety and positive psychopathology scores (on the Positive and Negative Affect Schedule [PANAS]) in participants with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder [79]. In relation to acute studies, Lu et al. [65] demonstrated that 200 mg L-theanine exerts calming effects under resting conditions (measured on visual analogue mood scale [VAMS]), however does not demonstrate anxiolytic effects under increased anxiety conditions (n = 16). Further, a recent study (n = 34) on the effects of an L-theanine-based nutrient drink (197 mg L-theanine) on responses to a cognitive stressor demonstrated a reduced salivary cortisol response and increased magnetoencephalogram (MEG) alpha activity (indicating decreased cortical arousal) following treatment, cf. placebo, for individuals higher in trait anxiety (STAI) [80]. Other work has shown that 200 mg L-theanine significantly attenuates task-related blood-pressure increases in labile individuals (n = 14), and reduced tension-anxiety scores measured on the Profile of Mood States (POMS) [81]. In the meta-analysis by Camfield et al. [78], no overall acute effects on anxiety were found in the first two hours post-dose, as measured by the STAI. However, isolated studies [77, 82] that were included in the review did report anxiolytic effects for 200 mg L-theanine in comparison to placebo (with standardised mean differences [SMDs] from 0.42 to 0.84).

The flavonoid EGCG has received less attention in human trials. A double-blind, placebo-controlled, cross-over design study (n = 31) reported that acute administration of 300 mg EGCG increased electroencephalogram (EEG) alpha, beta, and theta activity, increased self-reported calmness, and reduced self-reported stress [83]. Wightman, Haskell, Forster, Veasey, and Kennedy [84] found that 135 mg acute administration of EGCG reduced heart rate, oxygenated and total haemoglobin in the frontal cortex, but did not affect cognitive performance or mood (n = 27). An fMRI study (n = 12) found an acute dose-dependent effect of green tea extract in a milk whey based soft drink (0.05 % extract/250 ml or 500 ml) on increased activation in the dorso-lateral prefrontal cortex cf. controls, in a working memory task [85].


4.5.4 Conclusion


A small number of human trials have focused on the combined and separate effects of EGCG, L-theanine, and caffeine on cognition and anxiety, and reported findings consistent with anecdotal reasons for tea consumption. This work has demonstrated that the active constituents of tea have cognitive anxiolytic properties, particularly when administered in combination. Further work is needed to elucidate the mechanisms underpinning these combined/synergistic effects.



4.6 Sage (Salvia spp.)



4.6.1 Overview


Commonly referred to as Sage, the Salvia genus (e.g., S. officinalis, S. lavandulaefolia, and S. elegans) belongs to the mint (Lamiaceae) family and includes almost 1000 species from across the world. Common uses include cooking or traditional medicinal herbs, ornamental plants, and occasionally religious ceremonies. More recent clinical applications of sage typically take the form of a standardised essential oil extract in combination with an inactive agent (e.g., sunflower oil) or dried plant extract in an alcohol solution, for oral administration [42, 86].


4.6.2 Mechanisms of Action



4.6.2.1 Constituents


The main active constituents of sage, relevant to anxiety, are the class of terpenoids (e.g., 1,8-cineole, α- and β-pinene, camphor, bornyl acetate, 3-carene), which are AChE and butyrylcholinesterase (BuChE) inhibitors [42]. Even very low concentrations of sage (S. officinalis or S. lavandulaefolia) have demonstrated anti-AChE activity both in vitro [87, 88] and in vivo [89], and anti-BuChE activity in vitro [90]. These, and other constituents (e.g., carvacrol, luteolin, and rosmarinic acid), have also reliably demonstrated antioxidant, anti-inflammatory, and oestrogenic activities in vivo [91].


4.6.3 Evidence of Efficacy



4.6.3.1 Anxiety


Despite traditional uses, relatively few empirical studies have investigated the anxiolytic properties of sage in humans. The pre-clinical research on S. elegans [92, 93], S. leriifolia [94], S. reuterana [95], and S. miltiorrhiza [96] has demonstrated clinically significant anxiolytic effects using mouse and rat models and the elevated plus maze. In healthy (non-clinical) humans, one randomised, placebo-controlled, double-blind, balanced, cross-over design study in young adults (n = 24; M age = 23.2 years) demonstrated significant increases in subjective feelings of ‘calmness’ (Bond-Lader mood scale) following a single dose (25 μL or 50 μL essential oil) of S. lavandulaefolia [97]. A similarly designed study in non-clinical young adults (n = 30; M age = 24.4 years) demonstrated acute (up to, but not beyond 20 min) anxiolytic effects (Bond-Lader mood scale, STAI-state) of a single dose (300 mg or 600 mg dried leaf) of S. officinalis [98], though a more recent study with a similar design failed to find any anxiolytic effects of S. lavandulaefolia [99].


4.6.3.2 Cognitive Function


In pre-clinical research, S. officinalis increased memory retention in rats in a passive avoidance learning paradigm [100]. In healthy humans, randomised, placebo-controlled, double-blind, balanced, cross-over design studies in young (approx. M age = 23–24 years) [9799, 101] and older (n = 20; M age = 73.0 years) [102] adults have demonstrated significant improvements in measures of attention, alertness, processing speed, and memory (including immediate and delayed word recall, picture recognition, and speed of memory) from a single dose of either S. lavandulaefolia or S. officinalis. Interestingly, to date the only clinical trials of sage have investigated their efficacy for use in dementia populations, including individuals with MCI and AD. One pilot open-label study demonstrated significant improvements in attention following 6-week oral administration (50 μL essential oil up to 3 times per day) of S. lavandulaefolia to individuals (n = 11; aged 76–95 years) with mild to moderate AD [91]. Similarly, a parallel group, placebo-controlled, double-blind clinical trial demonstrated significant improvements in overall cognitive function (including measures of attention, memory, orientation, and problem-solving) following 16-week oral administration of 60 drops per day of 1:1 plant extract (i.e., 1 kg leaf: 1 L 45 % alcohol) of S. officinalis to individuals (n = 42; aged 65–80 years) with mild to moderate AD [103]. This study also found a potential ad hoc side effect of reduced agitation in comparison to the placebo group, suggesting potential anxiolytic effects. However, one pre-clinical study demonstrated impairments to cognitive function (despite anxiolytic effects) following administration of S. elegans [93].


4.6.4 Conclusion


Preliminary findings suggest promising effects after oral administration of sage (particularly S. officinalis or S. lavandulaefolia) as a cognitive enhancer in individuals with AD and an anxiolytic in healthy, non-clinical individuals. However, to date no studies have investigated the effects of sage as a cognitive anxiolytic in individuals with a clinical anxiety disorder. Nor have studies investigated the long-term effects of sage on cognitive function. Further research is needed.


4.7 Rosemary (Rosmarinus officinalis)



4.7.1 Overview


Commonly referred to as Rosemary, Rosmarinus officinalis is also a member of the mint (Lamiaceae) family. Recent clinical applications of rosemary involve aromatherapy of the essential oil via the skin (massage) or olfactory system (inhalation).


4.7.2 Mechanisms of Action



4.7.2.1 Constituents


The main active constituents of rosemary relevant to anxiety are the phenolic acid rosmarinic acid and the terpenoids 1,8-cineole, α-pinene, and camphor, which have been shown to increase ACh and produce differential effects on AChE [104, 105]. Inhalation and oral administration of rosemary oil resulted in increases in blood levels of 1,8-cineole in mice [106]. Intragastric administration of either R. officinalis plant extract or rosmarinic acid resulted in an inhibition of AChE but an increase in BuChE activity in the hippocampus and frontal cortex of rats [107].


4.7.3 Evidence of Efficacy



4.7.3.1 Cognitive Function


In pre-clinical research, intragastric administration of R. officinalis extract improved long-term memory and reversed chemically induced (scopolamine) memory impairment in rats [107]. In healthy humans, skin application of 1,8-cineole was associated with faster reaction time on a vigilance task than (±)-linalool [108]. Similarly, a large (n = 144) randomised, parallel-group study of healthy young adults demonstrated significantly increased alertness and higher performance on multiple memory tests (including immediate and delayed word recall, word and picture recognition, and working memory) following acute administration of rosemary aromatherapy inhalation compared to either the lavender or control groups [109]. Acute administration of rosemary aromatherapy inhalation was also associated with a significant decrease in frontal EEG alpha power (suggesting increased alertness) compared to lavender aromatherapy [110].


4.7.3.2 Anxiety


In pre-clinical research, rosemary oils have exhibited clinically significant anxiolytic effects using rodent models and the elevated plus maze [see 111 for systematic review]. More specifically, either long-term oral [112] or acute intraperitoneal [113] administration of R. officinalis plant extract have demonstrated anxiolytic effects in mice using the elevated plus maze (and equivalence to diazepam) [113]. In healthy (non-clinical) humans (n = 40), acute aromatherapy inhalation of rosemary essential oil was associated with significantly lower test anxiety (test anxiety inventory [TAI]) and heart rate than the control (no aromatherapy) condition [114]. A quasi-experimental, control group, pretest-posttest design study of healthy older adults (65–85 years; n = 36) demonstrated significantly greater reduction in state anxiety (STAI) following tri-weekly, 20 min aromatherapy massage of rosemary (with lavender, chamomile, and lemon, in an essential oil diluted with jojoba) for a total of 6 weeks, than those who received no intervention [115]. A systematic review of 16 randomised controlled trials confirmed that aromatherapy (typically rosemary and/or lavender) had significant anxiolytic effects in individuals with anxiety symptoms [e.g., medical patients; 116]. However, relatively few studies have investigated the unique anxiolytic effects of rosemary as compared to another aromatherapy essential oil such as lavender. One study suggested that acute administration of lavender aromatherapy inhalation but not rosemary has significant anxiolytic effects [117], whereas other work has demonstrated comparable anxiolytic effects of acute administration of rosemary versus lavender [110].

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Apr 12, 2018 | Posted by in PSYCHIATRY | Comments Off on Cognitive Anxiolytics

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