Potential clinical use
Total dose of 50–250 mg of kavalactonesper day, approximating 50–60 mg of kavalactones contained in a tablet
Kavalactones: Formulations higher in kavain and dihydrokavain with lower levels of dihydromethysticin preferred
Mainly positive RCTs and a meta-analysis showing a significant anxiolytic effect over placebo
Very rare potential of liver toxicity; sedation and motor coordination issues at higher doses. High doses and long-term use may cause dermopathy
General anxiety and GAD; potential use in social anxiety; No data on OCD, panic disorder or PTSD (but may have a supportive role); useful for benzodiazepine withdrawal and anxiety presenting with insomnia
Use intermittently and monitor via occasional LFTs if warranted; use recommended dose and avoid co-use with benzodiazepines and alcohol
Chronic dose: dried herb 1–3 g per day standardized to benzoflavones
Acute dose: 500–700 mg standardised to benzoflavones
Benzoflavone, potentially chyrsin
Several positive RCTs showing efficacy in generalised anxiety and preoperative anxiety
Considered quite safe. No interaction found with anaesthetic medication
Generalized anxiety, GAD, preoperative anxiety. No data on OCD, panic disorder, or PTSD; however, may have a supportive role. May be useful for social anxiety given the demonstrated acute effects
A generally safe herbal medicine that can be combined with a range of other anxiolytic and adaptogenic herbal medicines. Monitor adjunctive use with benzodiazepines and SSRIs due to possible potentiation of effect
Chamomile (Matricaria recutita)
Dried herb 1–2 g per day standardized to apigenin
An isolated RCT showed efficacy of standardised chamomile in capsule form in GAD
Considered very safe ad commonly used as a tea
GAD and mild anxiety and nervous tension
A generally safe herbal medicine although caution needed for people with asteracea plant family allergies
Galphimia (Galphimia glauca)
Dried herb 0.6–1 g per day standardized to 0.175–0.348 mg of galphimine B
Clinical trials showing equivalence to synthetic anxiolytics
No adverse reactions found in studies
Generalized anxiety, GAD
While emerging data is encouraging, further placebo-controlled studies are needed. May be challenging to source from South America
Skullcap (Scutellaria officinalis)
Dried herb 1–2 g per day (no establizhed standardization markers)
A range of constituents, including phenolics
Minor research and traditional use detailing potential use as an anxiolytic
No adverse reactions found in studies
Generalised anxiety and stress, nervous and physical tension
May have an adjunctive role in presentations of muscular tension. More research needed
Valerian (Valeriana spp.)
Dried herb 1–3 g per day standardized to valepotriates and/or valerenic acid
Valepotriates and valerenic acid
Minor research. Not strongly supportive of anxiolytic effects. Hypnotic (sleep) effects also mixed evidence for insomnia
May cause excitation, stimulation, and vivid dreams
Generalised anxiety, physical tension, insomnia
May have an adjunctive role in presentations of insomnia and/or muscular tension. May however cause excitation in some individuals. Taste and scent may be unpleasant for some
2.2 Kava (Piper methysticum)
Apart from Kava’s (Piper methysticum) traditional use for cultural, social, and religious occasions, the plant also has a role as a medicine, and has been used in Western society for its effects on anxiety via physiological and psychological relaxation . It should be noted that while kava is detailed under this section of plants with “sedative actions,” this effect is varied, with some consumers potentially experiencing a mentally stimulating effect alongside physiological sedation (due to the combination of GABAergic and noradrenergic effects) . The use of kava has been popularised since the 1990s, with dozens of kava products (of varying quality) being used worldwide for the treatment of anxiety. While selective serotonin re-uptake inhibitors (SSRIs) and benzodiazepines are effective first-line pharmacological treatments of anxiety disorders , both agents have unwanted side effects. While there is compelling evidence in support of kava for the treatment of anxiety , concerns over hepatotoxicity led to its withdrawal or restriction in many countries since 2002 (overturned by a German court ruling in 2015) . Although not confirmed, reasons for previous liver toxicity may have included: the use of low-quality and inexpensive plant materials (e.g. plant peelings rather than the traditional peeled rhizomes), incorrect use of kava cultivars, and the use of dangerous chemical solvents during extraction .
2.2.2 Mechanisms of Action
The pharmacodynamic anxiolytic mechanism is thought to be attributable to the lipophilic constituents of kava, known as kavalactones . Collectively, kavalactones are concentrated mainly within the rhizomes, roots and root stems of the plant [10, 11]. The distribution of kavalactones progressively decreases towards the aerial parts of the plant . The aerial parts of the plant often contain toxic alkaloids such as piper methystine, and are not used in traditional consumption . Eighteen different kavalactones have been identified to date, with approximately 96 % of the total pharmacological activity attributed to the presence of six kavalactones: methysticin, dihydromethysticin, kavain, dihydrokavain, demethoxy yangonin and yangonin [2, 11].
Several studies have documented a wide spectrum of pharmacological effects of kava including anxiolytic , anti-stress , sedative , analgesic , muscle relaxant , anti-thrombotic , neuroprotective , mild anaesthetic , hypnotic , and anticonvulsant . As briefly detailed in Table 2.1, numerous in vivo and in vitro studies from animals and humans suggest possible mechanisms, which may mediate the actions of kava extract and specific kavalactones including: blockade of voltage-gated sodium ion channels, reduced excitatory neurotransmitter release due to blockade of calcium ion channels, enhanced ligand binding to GABA type A receptors, reversible inhibition of monoamine oxidase B, and reduced neuronal re-uptake of noradrenaline (norepinephrine) and dopamine . Unlike benzodiazepines, kavalactones do not bind directly to GABA receptors, and appear to achieve GABAergic effects via modulation of the GABA channels, increased binding to and upregulation of GABA binding sites [14, 20]. Davies and colleagues  found no significant interactions between GABA or benzodiazepine binding sites and the pharmacological activities of kava within rodents; and Boonen and Häberlein  discovered that kavalactones dihydromethysticin, dihydrokavain, methysticin and kavain also did not bind with GABA-α receptors in an animal model (and did not antagonise flunitrazepam binding to benzodiazepine sites).
2.2.3 Evidence of Efficacy
A Cochrane review has been undertaken of 11 RCTs of rigorous methodology using kava monopreparations (60–280 mg of kavalactones) in anxiety . Results revealed significant anxiolytic activity of kava compared with placebo in all but one trial. A meta-analysis of seven placebo-controlled trials using the Hamilton Anxiety Scale (HAMA) found significant reductions in anxiety, with a strong clinical effect. Moderate heterogeneity was reported in respect to the type of extract used (acetone, ethanol, and type of standardization), dosage used (60–280 mg kavalactones), and the sample treated (preoperative anxiety, climacteric anxiety, state–trait or GAD diagnoses). The methodological quality of the trials was generally sound, with four of the seven trials having the maximum Jadad score of five. Similar findings were also demonstrated in another meta-analysis by Witte and colleagues , that included six placebo-controlled, randomized trials utilizing a standardized kava extract WS1490 in non-psychotic anxiety disorders (assessed via HAMA).
In response to safety concerns, the WHO commissioned a report in 2007 assessing the risk of kava products . Recommendation 2.1.3 suggested that products from water-based suspensions should be studied and used preferentially over acetone and ethanol extracts. This approach is supported theoretically by evidence of safety from traditional use, and aqueous extracts being rich in hepatoprotective glutathione . Due to this, recent research has been conducted following these guidelines. In 2009, the Kava Anxiety Depression Spectrum Study (KADSS) was published; a 3-week placebo-controlled, double-blind, crossover trial that recruited 60 adult participants with 1 month or more of elevated generalized anxiety . The results revealed aqueous extract of kava (standardised to 250 mg of kavalactones per day) significantly (p < 0.001) reduced anxiety and depression levels on HAMA with a very large effect size (Cohen’s d), d = 2.24. The aqueous extract was found to be safe and well-tolerated and importantly displayed no serious adverse effects, and no clinical liver toxicity. The qualitative research component of the study revealed that the key themes of kava consumption were a reduction in anxiety and stress, and calming or relaxing mental effects . Other themes related to improvement in sleep and in somatic anxiety symptoms. Kava use did not cause any serious adverse reactions, although a few respondents reported nausea or other gastrointestinal side effects.
After KADSS, a follow-up, double-blind placebo controlled trial in 75 participants with GAD (DSM-IV diagnosed) in the absence of mood disorders, administered kava (120/240 mg of kavalactones/day depending on response) over a 6-week period . Intention-to-treat (ITT) analysis was performed on 58 participants who met inclusion criteria after an initial 1-week placebo run-in phase. A significant treatment effect of moderate effect size was found for kava (p = 0.046, Cohen’s d = 0.62). Among participants with moderate to severe diagnosed GAD (assessed by the MINI Plus) this effect was larger (p = 0.02; d = 0.82). Within the kava group GABA transporter polymorphisms rs2601126 (p = 0.046) and rs2697153 (p = 0.02) were associated with greater HAMA reduction. Kava also demonstrated equivalent efficacy to synthetic agents buspirone and opipramol in an 8-week 3-arm clinical trial (n = 129) for the treatment of ICD-10 diagnosed GAD . This demonstration of equivocal efficacy is noteworthy (although the lack of a placebo arm limits a firm conclusion) as kava may provide an advantage over synthetic comparators such as benzodiazepines, in respect to limiting daytime sedation and cognitive impairment . Preferential use of kava may have less potential for addiction, and be associated with less withdrawal and rebound problems compared to chronic benzodiazepine use.
188.8.131.52 Mental Function
Acute (n = 9) and chronic (n = 3) cognitive effects of kava have been measured across 12 clinical trials. All trials adopted cognitive measures, which similarly assessed visual attention, memory retrieval, and psychomotor function. Four out of ten studies suggested improved accuracy and performance on visual attention and working memory measures [31–34], while 5 out of 11 studies found kava to have little or no negative effect on cognitive processes [35–40]. One study reported kava to impair reaction time . Therefore, the current evidence suggests that kava has a positive or benign effect on cognition, while impairing motor skills at higher doses. Acute RCTs that have suggested that kava significantly enhances cognitive performance attribute these effects to specific short-term physiological processes. For example, Thompson and colleagues  found kava improved performance in the Sperling partial report, and recognition tasks, improving the ability of selective attention, visual processing speed and the efficiency of memory retrieval . The authors speculated that kava may decrease the rate of decay for images held in iconic memory, while increasing the time taken for items to be transferred to a more permanent memory trace. Response accuracy was also increased, indicating that kava may have beneficial effects on working memory and retrieval processes. This study, however, found that reaction time was reduced by 40 % in comparison to placebo, suggesting a possible negative effect on motor-skill-based tasks such as driving.
The ability of kava to inhibit the re-uptake of noradrenaline is a novel pharmacological mechanism which may differentiate it from synthetic anxiolytics (e.g. benzodiazepine) . A 2012 Australian RCT  compared the acute neurocognitive, anxiolytic, and thymoleptic effects of a medicinal dose of kava to a benzodiazepine, and explored for the first time specific genetic polymorphisms, which may affect psychotropic activity. Twenty-two moderately anxious adults aged 18–65 years were randomized to receive an acute dose of kava (180 mg of kavalactones), oxazepam (30 mg), or placebo 1 week apart in a crossover trial. Kava and oxazepam were not found to impair cognitive performance on a computerised battery of six tests: Simple Reaction Time, Digit Vigilance Task, Choice Reaction Time, Numeric Working Memory, Rapid Visual Information Processing, and Corsi Blocks. As mentioned above, psychophysiological effects of kava vary according to a range of factors that include: the specific cultivar (extract), the dose, the method of preparation, and the person’s genetics and biochemistry (in addition to potential dispositional differences).
2.3 Passionflower (Passiflora incarnata)
The herbal medicine passionflower (also known as maypop) has a long history of traditional use in stress, sleep, and anxiety disorders [42, 43]. It is claimed that the medicinal properties of passionflower were first described in 1569 by a Spanish researcher in Peru . Felter and Lloyd  state that passionflower was first introduced as a medicine to America around 1840, with the first trials of passionflower recorded in the New Orleans Medical Journal around that time. In their well-regarded materia medica King’s American Dispensatory , Felter and Lloyd (p. 1440) describe passionflower’s medicinal action as being “exerted chiefly upon the nervous system,” and state that “it is specifically useful to allay restlessness and overcome wakefulness, when these are the result of exhaustion, or the nervous excitement of debility.” In addition, they state “It gives sleep to those who are labouring under the effects of mental worry or from mental overwork.” These traditional descriptions have informed modern research on passionflower’s anxiolytic effects.
There are a number of passionflower species used traditionally; however, research has focused on Passiflora incarnata (unless specified otherwise below), as it has a well-documented history of traditional use, and exhibits the strongest anxiolytic effect in comparison to other species . The aerial parts of the plant have been used traditionally, with the leaves being identified as having the strongest anxiolytic action .
2.3.2 Mechanisms of Action
Passionflower has been found to have numerous bioactive constituents, which include amino acids , various β-carboline alkaloids, and flavonoids [48–50]. The flavonoid chrysin is a benzodiazapine receptor ligand [51–53]; however, it appears to have a low binding affinity to this receptor; therefore, it is suggested that other mechanisms involving the GABAA receptor could better explain passionflower’s anxiolytic activity [49, 50]. While the benzoflavone compound (BZF) is considered a main active anxiolytic constituent of passionflower , consensus in the literature has not been reached . Despite this dispute, passionflower is typically standardized to BZF content, although the amount has varied when used in clinical trials from 1.01/500 mg  to 2.8 mg/5 ml . Results from in vitro studies using passionflower whole leaf extract have also been inconsistent. GABA transaminase was preferentially inhibited in one in vitro study . In contrast, another study on rats found no effect on GABA transaminase, GABA release or the benzodiazapine receptor, while the uptake of [3-H]-GABA into rat cortical synaptosomes was inhibited . The exact mechanism of action remains unclear due to inconsistencies across studies regarding the preparations used, the experimental conditions, dosage, and routes of administration, which vary considerably across studies.
184.108.40.206 In Vivo Studies
A number of studies have used animal behavioural models to measure the anxiolytic effects associated with Passiflora spp. whole plant extracts [43, 46, 48, 51, 54, 58–66]. All included studies demonstrated anxiolytic effects, although different preparations were used, with an anxiolytic effect seen a different doses, and sedative effects observed at higher doses [64, 66]. This section will focus on Passiflora incarnata, as the majority of in vivo studies have investigated this species, and it is the only species to be researched in clinical trials. Dhawan and colleagues conducted a series of acute dose escalation studies in mice [43, 46, 48, 59], all of which demonstrated that a passionflower methanol extract (methanol fraction only) was associated with a statistically significant reduction in acute anxiety in mice. There was a dose-dependent decrease in anxiety with the maximum benefit observed at 125 mg/kg, which was an equivalent effect to 2 mg/kg of diazepam . The highest dose of 300 mg/kg showed no anxiolytic effect . Sampath and colleagues  demonstrated a number of fractions of passionflower hydroethanol extract to have anxiolytic effects in mice. Using three behavioural models another study demonstrated passionflower to have dose-dependent effects in mice, with anxiolytic and sedative effects occurring at 400 mg/kg, and a sedative but non-anxiolytic effect seen at 800 mg/kg . Two mice studies by Grundmann and colleagues [60, 61] confirmed two different preparations of passionflower extract to have an acute dose-dependent (375 mg/kg) anxiolytic effect comparable to diazepam.
2.3.3 Evidence of Efficacy
220.127.116.11 Clinical Studies
Passiflora incarnata has demonstrated significant reductions in anxiety symptoms in three studies [42, 55, 56]. One of the studies focused on chronic anxiety, while the other two investigated acute symptoms. A 4-week double-blind RCT used two comparison groups: passionflower extract at 45 drops/day plus placebo tablet, and placebo drops plus oxazepam at 30 mg/day, in 36 outpatients with a GAD diagnosis (DSM IV) . Reductions in total mean HAMA scores (p < 0.01) were observed in both groups, although no significant differences were found between groups at 4 weeks. The passionflower group took longer (7 days) to demonstrate a significant reduction in HAMA scores compared to the oxazepam group (4 days). No differences in the frequency of side effects were observed; although, increased impairment in job performance was noted for the oxzepam group.
Two RCTs in preoperative patients demonstrated an acute anxiolytic effect with two different preparations of passionflower [55, 56]. The first study orally administered either a tablet containing 500 mg (1.01 mg BZF) of passionflower or placebo to patients 90 min before surgery . Anxiety was measured at preoperative baseline, 10, 30, 60 and 90 min following administration, and a significant reduction in anxiety was found in both groups over time. There was also a significant difference between the two groups, with passionflower demonstrating a greater reduction in anxiety over time compared to placebo. Reduced anxiety was reported from 10 min post-dose, and peaked at 30 min. The second study used an aqueous extract of passionflower standardized to 2.8 mg BZF per 5 ml of extract (700 mg/5 ml) that was administered 30 min prior to spinal anaesthesia . A significant reduction in preoperative anxiety compared to placebo—as measured by the STAI-S—was found prior to spinal anaesthesia for BZF in comparison to placebo. The anxiolytic effects similarly peaked at 30 min. Neither of these acute studies reported sedative effects or reduced psychomotor function.
While these studies provide preliminary evidence of efficacy for passionflower as an anxiolytic using chronic and acute dosing, further research is required in order to establish efficacy across a range of anxiety disorders.
2.4 Chamomile (Matricaria recutita)
Chamomile (Matricaria recutita) is a medicinal herb with a long history of traditional use for its calming effect. Felter and Lloyd  describe its action as “affecting both the sensory and motor nerves”(p. 1246) being specifically indicated for “nervous irritability, with peevishness, fretfulness, discontent, and impatience” (p. 1247). The flowering tops are the plant part most commonly used for their medicinal action. Chamomile is also widely consumed as tea for a relaxing effect , and is used therapeutically in tablet, capsule, liquid extract, and in essential oil form.
2.4.2 Mechanisms of Action
Preclinical research on chamomile has reported a range of anxiolytic effects involving the GABA system [3, 68]; however, the exact pharmacology and number of active constituents are yet to be determined. Flavonoids contained in chamomile have been found to act on the GABA system [3, 68]. The flavone apigenin is suggested to be a benzodiazepine receptor ligand with anxiolytic activity [52, 69]; however, it has not consistently shown an interaction with the benzodiazepine receptor , and it is argued that its binding affinity is low .
One study found apigenin to have a sedative rather than anxiolytic effect, and it was concluded that the sedative effect is related to activation of the GABAA receptor . The authors suggested that other constituents with benzodiazepine-like activity are involved in the sedative effect rather than apigenin. Chamomile whole plant extract was found to inhibit both glutamic acid decarboxylase and GABA transaminase; however, inhibition of glutamic acid decarboxylase was greater than that of GABA transaminase, indicating that CNS excitation could occur . This suggests that other yet to be determined mechanisms are most likely involved in chamomile’s anxiolytic and sedative effects.
2.4.3 Evidence of Efficacy
A number of animal behavioural studies have explored the anxiolytic effects of isolated constituents of chamomile [50, 52, 68, 69]; however, there has been no animal model using the whole plant extract to date.
18.104.22.168 Clinical Studies
A single, double-blind, dose escalation RCT investigated the effects of chamomile on symptoms of GAD. chamomile extract standardized to 1.2 % apigenin was found to reduce anxiety symptoms in individuals (n = 57) with a DSM-IV diagnosis of GAD . Doses ranged from 220 to 1100 mg. For participants who demonstrated a 50 % or less reduction in total HAMA scores from weeks 3 to 4, and 5 to 8, doses were increased to between three and five capsules daily. Following 8 weeks of treatment, chamomile was demonstrated to significantly reduce anxiety symptoms (mean total HAMA scores) compared to placebo (−3.17; 95 % CI: −6.26, −0.45, p = 0.047) . Chamomile was well-tolerated with no increase in adverse events at higher doses, compared to placebo. The study provided preliminary evidence to suggest that chamomile may reduce anxiety symptoms associated with GAD; however, further research is needed to replicate these findings and determine the most effective dose.
The above study also measured the antidepressant effects of chamomile, and found a statistically significant greater reduction in depressive symptoms (mean HAMD scores) for chamomile in comparison to placebo. It is possible that the antidepressant effects occurred as a secondary effect following the reduction of anxiety symptoms, and was not directly related to an antidepressant effect of chamomile. Further research on chamomile should be considered in the treatment of GAD with co-morbid depression. In regard to the use of chamomile in other anxiety disorders, preliminary research is yet to be conducted.
2.5 Galphimia (Galphimia glauca)
The use of galphimia (Galphimia glauca) as a medicinal plant is reported to date back to the sixteenth century . It is a plant medicine indigenous to Mexico, with the leaves and stem traditionally used in the treatment of a range of ailments including asthma, allergies, and nervous disorders. It is specifically indicated for treating “nervous excitement” and is considered a sedative in Mexican folk medicine . Galphimia is the most widely studied herbal treatment for anxiety in Mexico.
2.5.2 Mechanisms of Action
Galphimines have been identified as active compounds in galphimia, with the nor-secotriterpenes galphimine A and galphimine B, being shown to have the strongest anxiolytic activity . Galphimine B has been considered the primary active constituent for galphimia’s anxiolytic and sedative effect, and is the constituent standardized for clinical trials. Galphimine B has been shown to interact with serotonergic transmission in the dorsal hippocampus in rats. This occurs by increasing the frequency of neuronal discharge in CA1 cells, resulting in activation of 5HT(1A) receptors . One study in mice demonstrated that galphimines cross the blood–brain barrier, with galphimine A found to have an effect on the central nervous system .
2.5.3 Evidence of Efficacy
A number of galphimine constituents, including galphimine B, were evaluated for their anxiolytic effects in mice using the EPM . Mice were intraperitoneally administered 15 mg/kg of a galaphimine derivative 1 hour before testing. An anxiolytic-like effect in the mice was found for both galphimine A and galphimine B, with a significant increase in the time spent in and number of entries into the open arm in the EPM. A second study on mice used a methanolic extract (standardized for galphimine B, 8.3 mg/g) at different doses (125, 250, 500, 1000 and 2000 mg/kg), which were orally administered at three different times (24, 18 and 1 hour before the test). Significant anxiolytic-like effects were found in the light–dark paradigm test and the EPM, but not the forced swimming test .
Two clinical trials have found galphimia to be an effective anxiolytic. The first was a 4-week, positive-controlled double-blind RCT, with a cohort of 152 patients with a DSM-IV diagnosis of GAD and HAMA scores ≥19 . The two groups received either galphimia aqueous extract (310 mg standardized to 0.348 mg of galphimine B), or the benzodiazepine lorazepam (1 mg). Each treatment was administered in capsule form (identical in appearance) twice daily. Both groups demonstrated a significant reduction in anxiety symptoms. There were no significant side effects reported in the galphimia group, which contrasted with the lorazepam group, in which over 21 % of people reported excessive sedation.