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Sleep Formula


American Skullcap (Scutellaria lateriflora)

An Investigation Into The Efficacy Of Scutellaria Lateriflora In Healthy Volunteers*


Scutellaria lateriflora is an herbal medicine with long-standing traditional use as a relaxing nervine. There has been controversy in the literature with regards to its efficacy, and this study was designed to clarify its effectiveness in reducing anxiety, one of the phytotherapeutic indications. A double blind, placebo-controlled study of healthy subjects demonstrated noteworthy anxiolytic effects. The use of phytomedicines for the treatment of anxiety is reviewed, as is the published literature on S. lateriflora and its putative toxicity.

Source: P Wolfson, D L Hoffmann. “An investigation into the efficacy of Scutellaria lateriflora in healthy volunteers” Alternative Therapies in Health and Medicine (2003): 9(2):74-8.

American Skullcap (Scutellaria Lateriflora): A Randomised, Double-Blind Placebo-Controlled Crossover Study Of Its Effects On Mood In Healthy Volunteers*


Scutellaria lateriflora, a traditional herbal remedy for stress and anxiety, was tested on human volunteers for its effects on mood. In a placebo-controlled, double-blind, crossover study, 43 healthy participants were randomised to a sequence of three times daily S. lateriflora (350 mg) or placebo, each over two weeks. In this relatively non-anxious population (81% were mildly anxious or less, i.e. Beck Anxiety Inventory (BAI) scores ≤ 15), there was no significant difference between skullcap and placebo with BAI (p = 0.191). However, there was a significant group effect (p = 0.049), suggesting a carryover effect of skullcap. For Total Mood Disturbance measured by the Profile of Mood States, there was a highly significant (p ≤ 0.001) decrease from pre-test scores with skullcap but not placebo (p = 0.072). The limitations of carryover effect, generally low anxiety scores and differences in anxiety levels between groups at baseline (p = 0.022), may have reduced the chances of statistical significance in this study. However, as S. lateriflora significantly enhanced global mood without a reduction in energy or cognition, further study assessing its putative anxiolytic effects in notably anxious subjects with co-morbid depression is warranted.

Source: Christine Brock, Julie Whitehouse, Ihab Tewfik, Tony Towell. “American Skullcap (Scutellaria lateriflora): a randomised, double-blind placebo-controlled crossover study of its effects on mood in healthy volunteers” Phytotherapy Research (2014): 28(5):692-8.

Biphasic Effects Of Baicalin, An Active Constituent Of Scutellaria Baicalensis Georgi, In The Spontaneous Sleep-Wake Regulation*


Aim of the study: Baicalin is an active compound originating from the root of Scutellaria baicalensis Georgi, which has been used for anti-inflammation, anti-bacteria, anti-hypertension, anti-allergy and sedation since ancient China, though the neuronal mechanisms involved in the sedative effect is still unclear. Baicalin possesses the ability to decrease the expression of pro-inflammatory cytokines and nuclear factor (NF)-κB activity. Furthermore, baicalin has demonstrated an anxiolytic-like effect via activation of γ-aminobutyric acid-A (GABA(A)) receptors. Pro-inflammatory cytokines (e.g. interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α) and the GABAergic system promote sleep. This study was designed to determine whether the GABA(A) receptor activation and/or the suppression of pro-inflammatory cytokines mediate(s) baicalin-induced sleep alterations.

Materials and methods: Baicalin was intracerebroventricularly (ICV) administered 20 min either prior to the beginning of the light period or before the onset of the dark period. Electroencephalogram (EEG) and gross body movement were acquired for sleep analysis. Pharmacological blockade of IL-1 and GABA(A) receptors were employed to elucidate the involvements of IL-1 and GABA(A) receptors in baicalin-induced sleep alterations. IL-1β concentrations obtained after baicalin administration in several distinct brain regions were determined by ELISA.

Results: ICV administration of baicalin decreased slow wave sleep (SWS) during the first 2h of the light period. Rapid eye movement sleep (REMS) was not altered. The blockade of IL-1β-induced SWS enhancement by baicalin suggests that the antagonism of IL-1 receptors is involved in baicalin-induced SWS decrement during the light period. However, IL-1β concentrations during the light period were not altered after baicalin administration. In contrast, baicalin increased both SWS and REMS during hours 8-10 of the dark (active) period when baicalin was administered at the beginning of the dark period, and its effects were blocked by the GABA(A) receptor antagonist bicuculline.

Conclusion: Baicalin exhibits biphasic effects on sleep-wake regulation; the decrease of SWS during the light period and increases of SWS and REMS during the dark period. Inhibition of IL-1 action and enhancement of GABA(A) receptor activity may mediate baicalin's effects during the light and dark period, respectively.

Source: Han-Han Chang , Pei-Lu Yi, Chiung-Hsiang Cheng, Chin-Yu Lu, Yi-Tse Hsiao, Yi-Fong Tsai, Chia-Ling Li, Fang-Chia Chang “Biphasic effects of baicalin, an active constituent of Scutellaria baicalensis Georgi, in the spontaneous sleep-wake regulation” Journal of Ethnopharmacology. (2011): 135(2):359-68.

Herbal Medicine For Anxiety, Depression And Insomnia*


The prevalence and comorbidity of psychiatric disorders such as depression, anxiety and insomnia are very common. These well-known forms of psychiatric disorders have been affecting many people from all around the world. Herb alone, as well as herbal formula, is commonly prescribed for the therapies of mental illnesses. Since various adverse events of western medication exist, the number of people who use herbs to benefit their health is increasing. Over the past decades, the exploration in the area of herbal psychopharmacology has received much attention. Literatures showed a variety of herbal mechanisms of action used for the therapy of depression, anxiety and insomnia, involving re-uptake of monoamines, affecting neuroreceptor binding and channel transporter activity, modulating neuronal communication or hypothalamic-pituitary adrenal axis (HPA) etc. Nonetheless, a systematic review on herbal pharmacology in depression, anxiety and insomnia is still lacking. This review has been performed to further identify modes of action of different herbal medicine, and thus provides useful information for the application of herbal medicine.

2.3. Herbal Hypnotics and Insomnia

Insomnia, the most common sleep disorder, is often neglected. It is evaluated that almost one-third of the whole population suffer from a long-term derangement of sleep and wakefulness [92]. Multiple medicinal herbs and complex formulas are commonly used for insomnia. The mechanism of sleep disorders are generally caused by abnormalities in various pathways, such as GABA receptor, cortisol level, cytokines, circadian rhythm (melatonin secretion, adenosine receptors) and excitatory amino acid (glutamate and aspartate) [93, 94].

Changes in the expressing level of GABA receptor expression are considered to be related to the perturbations in GABAergic function, which are not only involved in the mechanism of depression and anxious behavior but also contribute to the sleep disorder, and such alterations in the GABA receptor subunits are related to the sedative-hypnotic effects of some drugs. As perhaps the most frequently prescribed herbal medicine to cure sleep disorders, Semen Ziziphi Spinosae (SZS) is widely used in China, Japan, Korea and other oriental countries [95, 96]. SZS and its major active compound (Jujuboside A (JuA)) are described as improving sleep quality, prolonging sleep time and remarkably increasing non-rapid eye movement sleep [97], which appears to be a safe sedative/hypnotic choice in patients. In the recent years, JuA has been proved to change GABAA 1, 5, 2 subunit genes expressions as a section of the molecular mechanism underlying its sedative-hypnotic activities [98]. A large number of prescription drugs are also employed to cure insomnia. Extracts of valerian (Valeriana officinalis L., Valerianaceae) and valerenic acid are applied to treat insomnia as well as restlessness as 5-HT5a receptor activators [84]. On the other hand, Valerian has an activity like adenosine and promotes falling into sleep. The regulation of the sleep-wake rhythm triggers sleep when the time-related interaction functions properly, which is intimately associated with the endogenous secretion of melatonin [99]. Lactuca sativa (garden lettuce), a member of the Compositae family, is a commonly used herb for salad in Egypt, which has already been applied for centuries as a folk herb to aid in sleeping and to ameliorate pains as well as inflammation [100]. The oil from the seed of L. sativa could ameliorate the symptoms of sleeping and disorders of patients, in particular those who are old [101]. The generally used saffron, which is the stigma of Crocus sativus L (a stemless perennial herb belonging to the Iridaceae family) has demonstrated various effects upon the central nervous system. A study focused on the neuropharmacological activities of water extracts of saffron and its components in mice demonstrated that safranal possesses neuropharmacological activities [102]. The literature search revealed that several other herbal medicines, such as Passifloraincanata (passionflower), Eschscholzia californica (California poppy), P. methysticum, and Scutellaria lateriflora (scullcap) also showed to be potentially beneficial to insomnia.

Source: Lei Liu,Changhong Liu, Yicun Wang, Pu Wang, Yuxin Li, Bingjin Li. “Herbal Medicine for Anxiety, Depression and Insomnia” Curr Neuropharmacol. (2015) 13(4): 481–493.

Valerian (Valeriana Officinalis)

Valerian for Sleep: A Systematic Review and Meta-Analysis*


Insomnia affects approximately one-third of the adult population and contributes to increased rates of absenteeism, health care use, and social disability. Extracts of the roots of valerian (Valeriana officinalis) are widely used for inducing sleep and improving sleep quality. A systematic review of randomized, placebo-controlled trials of valerian for improving sleep quality is presented. An extensive literature search identified 16 eligible studies examining a total of 1093 patients. Most studies had significant methodologic problems, and the valerian doses, preparations, and length of treatment varied considerably. A dichotomous outcome of sleep quality (improved or not) was reported by 6 studies and showed a statistically significant benefit (relative risk of improved sleep = 1.8, 95% confidence interval, 1.2-2.9), but there was evidence of publication bias in this summary measure. The available evidence suggests that valerian might improve sleep quality without producing side effects. Future studies should assess a range of doses of standardized preparations of valerian and include standard measures of sleep quality and safety.

Source: Stephen Bent, MD, Amy Padula, MS, Dan Moore, PhD, Michael Patterson, MS, and Wolf Mehling, MD. “Valerian for Sleep: A Systematic Review and Meta-Analysis” The American Journal of Medicine (2006): 119(12): 1005–1012.

Critical Evaluation Of The Effect Of Valerian Extract On Sleep Structure And Sleep Quality*


A carefully designed study assessed the short-term (single dose) and long-term (14 days with multiple dosages) effects of a valerian extract on both objective and subjective sleep parameters. The investigation was performed as a randomized, double-blind, placebo-controlled, cross-over study. Sixteen patients (4 male, 12 female) with previously established psychophysiological insomnia (ICSD-code 1.A.1.), and with a median age of 49 (range: 22 to 55), were included in the study. The main inclusion criteria were reported primary insomnia according to ICSD criteria, which was confirmed by polysomnographic recording, and the absence of acute diseases. During the study, the patients underwent 8 polysomnographic recordings: i.e., 2 recordings (baseline and study night) at each time point at which the short and long-term effects of placebo and valerian were tested. The target variable of the study was sleep efficiency. Other parameters describing objective sleep structure were the usual features of sleep-stage analysis, based on the rules of Rechtschaffen and Kales (1968), and the arousal index (scored according to ASDA criteria, 1992) as a sleep microstructure parameter. Subjective parameters such as sleep quality, morning feeling, daytime performance, subjectively perceived duration of sleep latency, and sleep period time were assessed by means of questionnaires. After a single dose of valerian, no effects on sleep structure and subjective sleep assessment were observed. After multiple-dose treatment, sleep efficiency showed a significant increase for both the placebo and the valerian condition in comparison with baseline polysomnography. We confirmed significant differences between valerian and placebo for parameters describing slow-wave sleep. In comparison with the placebo, slow-wave sleep latency was reduced after administration of valerian (21.3 vs. 13.5 min respectively, p<0.05). The SWS percentage of time in bed (TIB) was increased after long-term valerian treatment, in comparison to baseline (9.8 vs. 8.1% respectively, p<0.05). At the same time point, a tendency for shorter subjective sleep latency, as well as a higher correlation coefficient between subjective and objective sleep latencies, were observed under valerian treatment. Other improvements in sleep structure – such as an increase in REM percentage and a decrease in NREM1 percentage – took place simultaneously under placebo and valerian treatment. A remarkable finding of the study was the extremely low number of adverse events during the valerian treatment periods (3 vs. 18 in the placebo period). In conclusion, treatment with a herbal extract of radix valerian are demonstrated positive effects on sleep structure and sleep perception of insomnia patients, and can, therefore, be recommended for the treatment of patients with mild psychophysiological insomnia.

Source: Donath, F., et al. “Critical evaluation of the effect of valerian extract on sleep structure and sleep quality.” Pharmacopsychiatry 33.2 (2000): 47-53

Hops (Humulus Lupulus)

The Sedative Effects Of Hops (Humulus Lupulus), A Component Of Beer, On The Activity/Rest Rhythm*


The hop (Humulus lupulus), a component of beer, is a sedative plant whose pharmacological activity is due principally to its bitter resins, especially to the α-acid component 2-methyl-3-buten-2-ol. The mechanism of action of the resin of hop consists of increasing the activity of the neurotransmitter γ-aminobutyric (GABA), inhibiting the central nervous system (CNS).

Objectives: To analyze in an experimental model of diurnal animal the sedative effect of hop, a component of beer, on the activity/rest rhythm.

Methods: Experiments were performed with common quail (Coturnix coturnix) similar to humans in the sleep-wake rhythm, isolated in 25 × 25 × 25 cm methacrylate cages, with food and water ad libitum, in a room with artificial ventilation (22 ± 1 °C) and a lighting cycle of 12L/12D (n = 5). The doses administered, close to the content of non-alcoholic beer, were 1, 2 and 11 mg extract of hop as one capsule per day, at 18:00 h for one week. A control group received capsules only with a methylcellulose excipient and a basal group received no treatment. The chronobiological analysis of the animals' activity captured and logged by the software DAS24 was performed using the Ritme computer program (cosinor methods).

Results: With the dose of 2 mg, there was a statistically significant (p < 0.05) reduction of the arithmetic mean nocturnal activity (23 ± 3.0) with respect to the basal (38.56 ± 2.79), control (38.1 ± 2.8) and other doses groups 1 mg (52.04 ± 3.65) and 11 mg (47.47 ± 5.88). This dose of 2 mg, similar to the concentration in beer, was more effective in reducing nocturnal activity than the other doses of 1 and 11 mg, as well as preserving the circadian activity/rest rhythm.

Conclusion: The concentration of 2 mg of hop extract effectively decreased nocturnal activity in the circadian activity rhythm. On the basis of this investigation, administration of non-alcoholic beer would be recommended due to its hop content and consequent sedative action, which would be an aid to nocturnal sleep.

Source: L Franco, C Sánchez, R Bravo, A Rodriguez, C Barriga, Javier Cubero Juánez. “The sedative effects of hops (Humulus lupulus), a component of beer, on the activity/rest rhythm” Acta Physiologica Hungarica (2012): 99(2):133-9.

Valerian (Valeriana officinalis) & Hops (Humulus lupulus)

Evaluation Of Effectiveness And Safety Of An Herbal Compound In Primary Insomnia Symptoms And Sleep Disturbances Not Related To Medical Or Psychiatric Causes*


Repetitive administrations of valerian/hops combinations have been widely used for self-administered therapy of sleep disturbances. This investigation focuses on the question if a single administration can be an effective sleep aid. Two parallel groups of n = 20 (verum) and n = 22 (placebo) were tested. Each subject spent two consecutive nights in the lab (reference night and medication night). Medication consisted in giving verum or placebo to poor sleepers identified by a validated sleep questionnaire (Schlaffragebogen SF-B). Two ml of the liquid ex?tract or similar smelling placebo were diluted in 50 ml water (flavoured with honey) and administered 15 minutes before EEG recording during the medication night. The data analysis is based on the electrohypnogram - a method derived from a validated computer assisted automatic analysis for depth of sleep. Differences between the reference nights and medication nights were evaluated and tested for significance. Time spent in sleep (values of the sleep frequency index "SFx" of the electrohypnogram of 74% or lower) was significantly higher for the verum group in comparison to the placebo group (p<0.01). The difference with respect to time spent in deeper sleep (i.e. 68% and lower or 62% and lower) between reference and medication night was also statistically significant at p<0.01. This parameter correlated with the difference in quality of sleep between the two consecutive nights as derived from the sleep inventory SF-A sub-score (subjects evaluation) with r = 0.48 at p<0.0001. The EEG derived parameter "sleep quantity" as calculated from the electrohypnogram proved superiority of the valerian/hops combination over placebo. Thus, the present investigation has shown evidence that a valerian/hops fluid extract can be used successfully using a single administration.

Source: Wilfried Dimpfel, A Suter. “Sleep improving effects of a single dose administration of a valerian/hops fluid extract - a double blind, randomized, placebo-controlled sleep-EEG study in a parallel design using electrohypnograms” European Journal of Medical Research (2008): 26;13(5):200-4.

Treating Primary Insomnia - The Efficacy Of Valerian And Hops*


Objective: To evaluate the efficacy of valerian and hops in the treatment of primary insomnia.

Methods: The AMED and MEDLINE databases were searched for primary sources of literature published between 1950 and 2009, using keywords: herbal medicine, medicinal plants, herbal, Valeriana officinalis, valerian, Humulus lupulus, hops, sleep, insomnia. Studies were included if they evaluated the efficacy of valerian or hops in improving primary insomnia in adults: sixteen studies met the inclusion criteria. Twelve of these found that the use of valerian, on its own, or in combination with hops, is associated with improvements in some sleep parameters (eg. sleep latency and quality of sleep). However, these results need to be interpreted cautiously as there were significant differences in design between the studies.

Conclusion: Further randomised, double blind, placebo-controlled trials are needed before such herbal treatments can be confidently recommended for the treatment of primary insomnia.

Source: Shanah Salter, Sonya Brownie. “Treating primary insomnia - the efficacy of valerian and hops” Australian Family Physician (2010): ;39(6):433-7.

A Randomized, Double Blind, Placebo-Controlled, Prospective Clinical Study To Demonstrate Clinical Efficacy Of A Fixed Valerian Hops Extract Combination (Ze 91019) In Patients Suffering From Non-Organic Sleep Disorder*


Valerian and hops are traditionally used as sleep aids. Since the fixed extract combination (Ze 91019) as a whole is considered the active compound, the clinical efficacy must be demonstrated for this extract combination. The present clinical study aimed to demonstrate superiority of the fixed extract combination in comparison with placebo in patients suffering from non-organic insomnia (ICD 10, F 51.0-51.2). Objective sleep parameters were registered by means of a transportable home recorder system (QUISI). The primary outcome was the reduction in sleep latency (SL2) which had to be prolonged at baseline (>/=30 min) as an inclusion criterion. The treatment period lasted for 4 weeks with either placebo, single valerian extract (Ze 911) or the fixed valerian hops extract combination (Ze 91019). The amount of the single valerian extract was identical to that amount contained in the fixed extract combination, i.e. 500 mg valerian extract siccum. In the extract combination 120 mg hops extract siccum was added. Both the extracts were prepared with 45% methanol m/m with a drug-extract ratio of 5.3:1 (valerian) and 6.6:1 (hops), respectively. The fixed extract combination was significantly superior to the placebo in reducing the sleep latency whilst the single valerian extract failed to be superior to the placebo. The result underlined the plausibility for adding hops extract to the valerian extract.

Source: U Koetter, E Schrader, R Käufeler, A Brattström. “A randomized, double blind, placebo-controlled, prospective clinical study to demonstrate clinical efficacy of a fixed valerian hops extract combination (Ze 91019) in patients suffering from non-organic sleep disorder” Phytotherapy Research (2007): 21(9):847-51.

Effect of Valerian/Hop Mixture on Sleep-Related Behaviors in Drosophila Melanogaster*


The aim of this study was to investigate the sleep-promoting effect of a Valerian/Hops mixture in fruit flies. The HPLC analysis showed that Valerenic acid (1260.53 µg/g of extract) and Xanthohumol (Cascade: 827.49 µg/g, Hallertau: 763.60 µg/g, Saaz: 186.93 µg/g) were contained in Valerian and Hop, respectively. The sleep patterns of fruit flies on the Valerian/Hops were examined in both baseline and caffeine-treated conditions. Total activities of flies significantly decreased in 20 mg/mL Valerian (74%), 10 mg/mL Cascade (25%), and 5 mg/mL Hallertau (11%) during nighttime or daytime compared with the control. Valerian/Cascade mixture showed longer sleeping time (ca. 20%) than control group. This mixture-mediated effect was partly observed in caffeine-treated flies. Valerian/Cascade mixture upregulated mRNA expressions of gamma-aminobutyric acid (GABA) receptors and serotonin receptor, and GABA receptors were more strongly regulated than serotonin receptor. In competitive GABA receptor binding assay, Valerian/Cascade mixture extract showed a higher binding ability on GABA receptor than Valerenic acid or/and Xanthohumol which are estimated to be active compounds in the extract. This study demonstrates that a Valerian/Cascade mixture extract improves sleep-related behaviors, including sleeping time, by modulating GABAergic/serotonergic signaling.

Source: Hyeon-Son Choi, Bong Soo Ko, Hae Dun Kim, Ki-Bae Hong, Hyung Joo Suh. “Effect of Valerian/Hop Mixture on Sleep-Related Behaviors in Drosophila melanogaster” Biological and Pharmaceutical Bulletin (2017): 40(7):1101-1110.

GABA (Gamma-Aminobutyric Acid)

Anxiety Disorders And GABA Neurotransmission: A Disturbance Of Modulation*


Lines of evidence coming from many branches of neuroscience indicate that anxiety disorders arise from a dysfunction in the modulation of brain circuits which regulate emotional responses to potentially threatening stimuli. The concept of anxiety disorders as a disturbance of emotional response regulation is a useful one as it allows anxiety to be explained in terms of a more general model of aberrant salience and also because it identifies avenues for developing psychological, behavioral, and pharmacological strategies for the treatment of anxiety disorder. These circuits involve bottom-up activity from the amygdala, indicating the presence of potentially threatening stimuli, and top-down control mechanisms originating in the prefrontal cortex, signaling the emotional salience of stimuli. Understanding the factors that control cortical mechanisms may open the way to identification of more effective cognitive behavioral strategies for managing anxiety disorders. The brain circuits in the amygdala are thought to comprise inhibitory networks of γ-aminobutyric acid-ergic (GABAergic) interneurons and this neurotransmitter thus plays a key role in the modulation of anxiety responses both in the normal and pathological state. The presence of allosteric sites on the GABAA receptor allows the level of inhibition of neurons in the amygdala to be regulated with exquisite precision, and these sites are the molecular targets of the principal classes of anxiolytic drugs. Changes in the levels of endogenous modulators of these allosteric sites as well as changes in the subunit composition of the GABAA receptor may represent mechanisms whereby the level of neuronal inhibition is downregulated in pathological anxiety states. Neurosteroids are synthesized in the brain and act as allosteric modulators of the GABAA receptor. Since their synthesis is itself regulated by stress and by anxiogenic stimuli, targeting the neurosteroid-GABAA receptor axis represents an attractive target for the modulation of anxiety.

Source: Philippe Nuss. “Anxiety disorders and GABA neurotransmission: a disturbance of modulation” Neuropsychiatric Disease and Treatment (2015):11:165-175.

An Updated Review on Pharmaceutical Properties of Gamma-Aminobutyric Acid*


Gamma-aminobutyric acid (Gaba) is a non-proteinogenic amino acid that is widely present in microorganisms, plants, and vertebrates. So far, Gaba is well known as a main inhibitory neurotransmitter in the central nervous system. Its physiological roles are related to the modulation of synaptic transmission, the promotion of neuronal development and relaxation, and the prevention of sleeplessness and depression. Besides, various pharmaceutical properties of Gaba on non-neuronal peripheral tissues and organs were also reported due to anti-hypertension, anti-diabetes, anti-cancer, antioxidant, anti-inflammation, anti-microbial, anti-allergy, hepato-protection, reno-protection, and intestinal protection. Therefore, Gaba may be considered as potential alternative therapeutics for prevention and treatment of various diseases. Accordingly, this updated review was mainly focused to describe the pharmaceutical properties of Gaba as well as emphasize its important role regarding human health.

Source: Dai-Hung Ngo and Thanh Sang Vo. “An Updated Review on Pharmaceutical Properties of Gamma-Aminobutyric Acid” Molecules (2019): 24(15): 2678.

GABA Mechanisms and Sleep*


GABA is the main inhibitory neurotransmitter of the CNS. It is well established that activation of GABA(A) receptors favors sleep. Three generations of hypnotics are based on these GABA(A) receptor-mediated inhibitory processes. The first and second generation of hypnotics (barbiturates and benzodiazepines respectively) decrease waking, increase slow-wave sleep and enhance the intermediate stage situated between slow-wave sleep and paradoxical sleep, at the expense of this last sleep stage. The third generation of hypnotics (imidazopyridines and cyclopyrrolones) act similarly on waking and slow-wave sleep but the slight decrease of paradoxical sleep during the first hours does not result from an increase of the intermediate stage. It has been shown that GABA(B) receptor antagonists increase brain-activated behavioral states (waking and paradoxical sleep: dreaming stage). Recently, a specific GABA(C) receptor antagonist was synthesized and found by i.c.v. infusion to increase waking at the expense of slow-wave sleep and paradoxical sleep. Since the sensitivity of GABA(C) receptors for GABA is higher than that of GABA(A) and GABA(B) receptors, GABA(C) receptor agonists and antagonists, when available for clinical practice, could open up a new era for therapy of troubles such as insomnia, epilepsy and narcolepsy. They could possibly act at lower doses, with fewer side effects than currently used drugs. This paper reviews the influence of different kinds of molecules that affect sleep and waking by acting on GABA receptors.

Source: Claude Gottesmann. “GABA mechanisms and sleep” Neuroscience. (2002): 111(2):231-9.


Effects of chronic l-theanine administration in patients with major depressive disorder: an open-label study*


Objective: L-theanine, an amino acid uniquely contained in green tea (Camellia sinensis), has been suggested to have various psychotropic effects. This study aimed to examine whether l-theanine is effective for patients with major depressive disorder (MDD) in an open-label clinical trial.

Methods: Subjects were 20 patients with MDD (four males; mean age: 41.0±14.1 years, 16 females; 42.9±12.0 years). l-theanine (250 mg/day) was added to the current medication of each participant for 8 weeks. Symptoms and cognitive functions were assessed at baseline, 4, and 8 weeks after l-theanine administration by the 21-item version of the Hamilton Depression Rating Scale (HAMD-21), State-Trait Anxiety Inventory (STAI), Pittsburgh Sleep Quality Index (PSQI), Stroop test, and Brief Assessment of Cognition in Schizophrenia (BACS).

Results: HAMD-21 score was reduced after l-theanine administration (p=0.007). This reduction was observed in unremitted patients (HAMD-21>7; p=0.004) at baseline. Anxiety-trait scores decreased after l-theanine administration (p=0.012) in the STAI test. PSQI scores also decreased after l-theanine administration (p=0.030) in the unremitted patients at baseline. Regarding cognitive functions, response latency (p=0.001) and error rate (p=0.036) decreased in the Stroop test, and verbal memory (p=0.005) and executive function (p=0.016) were enhanced in the BACS test after l-theanine administration.

Conclusion: Our study suggests that chronic (8-week) l-theanine administration is safe and has multiple beneficial effects on depressive symptoms, anxiety, sleep disturbance and cognitive impairments in patients with MDD. However, since this is an open-label study, placebo-controlled studies are required to consolidate the effects.

Source: Shinsuke Hidese Miho Ota, Chisato Wakabayashi, Takamasa Noda, Hayato Ozawa, Tsutomu Okubo, Hiroshi Kunugi. “Effects of chronic l-theanine administration in patients with major depressive disorder: an open-label study” Acta Neuropsychiatrica. (2017): 29(2):72-79.

Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial*


This randomized, placebo-controlled, crossover, and double-blind trial aimed to examine the possible effects of four weeks L-theanine administration on stress-related symptoms and cognitive functions in healthy adults. Participants were 30 individuals (nine men and 21 women; age: 48.3 ± 11.9 years) who had no major psychiatric illness. L-theanine (200 mg/day) or placebo tablets were randomly and blindly assigned for four-week administration. For stress-related symptoms, Self-rating Depression Scale, State-Trait Anxiety Inventory-trait, and Pittsburgh Sleep Quality Index (PSQI) scores decreased after L-theanine administration (p = 0.019, 0.006, and 0.013, respectively). The PSQI subscale scores for sleep latency, sleep disturbance, and use of sleep medication reduced after L-theanine administration, compared to the placebo administration (all p < 0.05). For cognitive functions, verbal fluency and executive function scores improved after L-theanine administration (p = 0.001 and 0.031, respectively). Stratified analyses revealed that scores for verbal fluency (p = 0.002), especially letter fluency (p = 0.002), increased after L-theanine administration, compared to the placebo administration, in individuals who were sub-grouped into the lower half by the median split based on the mean pretreatment scores. Our findings suggest that L-theanine has the potential to promote mental health in the general population with stress-related ailments and cognitive impairments.

Source: Shinsuke Hidese, Shintaro Ogawa, Miho Ota, Ikki Ishida, Zenta Yasukawa, Makoto Ozeki, and Hiroshi Kunugi. “Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial” Nutrients (2019): 11(10): 2362.

In Search of a Safe Natural Sleep Aid*


Sleep deprivation is associated with an elevated risk of various diseases and leads to a poor quality of life and negative socioeconomic consequences. Sleep inducers such as drugs and herbal medicines may often lead to dependence and other side effects. L-Theanine (γ-glutamylethylamide), an amino acid naturally found abundant in tea leaves, has anxiolytic effects via the induction of α brain waves without additive and other side effects associated with conventional sleep inducers. Anxiolysis is required for the initiation of high-quality sleep. In this study, we review the mechanism(s), safety, and efficacy of L-theanine. Collectively, sleep studies based on an actigraph, the obstructive sleep apnea (OSA) sleep inventory questionnaire, wakeup after sleep onset (WASO) and automatic nervous system (ANS) assessment, sympathetic and parasympathetic nerve activities, and a pediatric sleep questionnaire (PSQ) suggest that the administration of 200 mg of L-theanine before bed may support improved sleep quality not by sedation but through anxiolysis. Because L-theanine does not induce daytime drowsiness, it may be useful at any time of the day. The no observable adverse effect level (NOAEL) for the oral administration of L-theanine was determined to be above 2000 mg/kg bw/day. KEY TEACHING POINTS: Sleep deprivation-associated morbidity is an increasing public health concern posing a substantial socioeconomic burden. Chronic sleep disorders may seriously affect quality of life and may be etiological factors in a number of chronic diseases such as depression, obesity, diabetes, and cardiovascular diseases. Most sleep inducers are sedatives and are often associated with addiction and other side effects. L-Theanine promotes relaxation without drowsiness. Unlike conventional sleep inducers, L-theanine is not a sedative but promotes good quality of sleep through anxiolysis. This review suggests that L-theanine is a safe natural sleep aid.

Source: Theertham P Rao, Motoko Ozeki, Lekh R Juneja. “In Search of a Safe Natural Sleep Aid” Journal of the American College of Nutrition (2015): 34(5):436-47.

GABA (Gamma-Aminobutyric Acid) & L-Theanine

GABA and L-Theanine Mixture Decreases Sleep Latency And Improves NREM Sleep*


Context: γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter and it is well established that activation of GABAA receptors favours sleep. L-Theanine, a naturally occurring amino acid first discovered in green tea, is a well-known anti-anxiety supplement with proven relaxation benefits.

Objective: This study investigated the potential synergistic sleep enhancement effect of GABA/L-theanine mixture.

Materials and methods: Pentobarbital-induced sleep test was applied to find proper concentration for sleep-promoting effect in ICR mice. Electroencephalogram (EEG) analysis was performed to investigate total sleeping time and sleep quality in normal SD rats and caffeine-induced awareness model. Real-time polymerase chain reaction (RT-PCR) was applied to investigate whether the sleep-promoting mechanism of GABA/L-theanine mixture involved transcriptional processes.

Results: GABA/L-theanine mixture (100/20 mg/kg) showed a decrease in sleep latency (20.7 and 14.9%) and an increase in sleep duration (87.3 and 26.8%) compared to GABA or theanine alone. GABA/L-theanine mixture led to a significant increase in rapid eye movement (REM) (99.6%) and non-REM (NREM) (20.6%) compared to controls. The use of GABA/L-theanine mixture rather than GABA or L-theanine alone restored to normal levels sleep time and quality in the arousal animal model. The administration of GABA/L-theanine led to increased expression of GABA and the glutamate GluN1 receptor subunit.

Conclusions: GABA/L-theanine mixture has a positive synergistic effect on sleep quality and duration as compared to the GABA or L-theanine alone. The increase in GABA receptor and GluN1 expression is attributed to the potential neuromodulatory properties of GABA/L-theanine combination, which seems to affect sleep behaviour.

Source: Suhyeon Kim, Kyungae Jo, Ki-Bae Hong, Sung Hee Han, and Hyung Joo Suh. “ GABA and l-theanine mixture decreases sleep latency and improves NREM sleep” Pharmaceutical Biologoy (2019): 57(1): 65–73.

Chamomile flower (Matricaria recutita)

Therapeutic efficacy and safety of chamomile for state anxiety, generalized anxiety disorder, insomnia, and sleep quality: A systematic review and meta-analysis of randomized trials and quasi-randomized trials*


This systematic review and meta-analysis aimed to study the efficacy and safety of chamomile for the treatment of state anxiety, generalized anxiety disorders (GADs), sleep quality, and insomnia in human. Eleven databases including PubMed, Science Direct, Cochrane Central, and Scopus were searched to retrieve relevant randomized control trials (RCTs), and 12 RCTs were included. Random effect meta-analysis was performed by meta package of R statistical software version 3.4.3 and RevMan version 5.3. Our meta-analysis of three RCTs did not show any difference in case of anxiety (standardized mean difference = -0.15, 95% CI [-0.46, 0.16], P = 0.4214). Moreover, there is only one RCT that evaluated the effect of chamomile on insomnia and it found no significant change in insomnia severity index (P > 0.05). By using HAM-A scale, there was a significant improvement in GAD after 2 and 4 weeks of treatment (mean difference = -1.43, 95% CI [-2.47, -0.39], P = 0.007), (MD = -1.79, 95% CI [-3.14, -0.43], P = 0.0097), respectively. Noteworthy, our meta-analysis showed a significant improvement in sleep quality after chamomile administration (standardized mean difference = -0.73, 95% CI [-1.23, -0.23], P < 0.005). Mild adverse events were only reported by three RCTs. Chamomile appears to be efficacious and safe for sleep quality and GAD. Little evidence is there to show its effect on anxiety and insomnia. Larger RCTs are needed to ascertain these findings.

Source: Truong Hong Hieu, Mahmoud Dibas, Kadek Agus Surya Dila, Nourin Ali Sherif, Muhammad Usman Hashmi, Mostafa Mahmoud, Nguyen Thi Thuy Trang, Lava Abdullah , Thai Le Ba Nghia, Mai Nhu Y, Kenji Hirayama, Nguyen Tien Huy. “Therapeutic efficacy and safety of chamomile for state anxiety, generalized anxiety disorder, insomnia, and sleep quality: A systematic review and meta-analysis of randomized trials and quasi-randomized trials” Phytotherapy Research. (2019) 33(6):1604-1615.

Chamomile: A herbal medicine of the past with bright future*


Chamomile is one of the most ancient medicinal herbs known to mankind. It is a member of Asteraceae/Compositae family and represented by two common varieties viz. German Chamomile (Chamomilla recutita) and Roman Chamomile (Chamaemelum nobile). The dried flowers of chamomile contain many terpenoids and flavonoids contributing to its medicinal properties. Chamomile preparations are commonly used for many human ailments such as hay fever, inflammation, muscle spasms, menstrual disorders, insomnia, ulcers, wounds, gastrointestinal disorders, rheumatic pain, and hemorrhoids. Essential oils of chamomile are used extensively in cosmetics and aromatherapy. Many different preparations of chamomile have been developed, the most popular of which is in the form of herbal tea consumed more than one million cups per day. In this review we describe the use of chamomile in traditional medicine with regard to evaluating its curative and preventive properties, highlight recent findings for its development as a therapeutic agent promoting human health.

Source: Janmejai K Srivastava, Eswar Shankar, and Sanjay Gupta. “Chamomile: A herbal medicine of the past with bright future” Molecular Medicine Reports (2010): 3(6): 895–901.

The effects of chamomile extract on sleep quality among elderly people: A clinical trial*


Background: The prevalence of insomnia increases with age. Chamomile is among the medicinal plants which are used as tranquilizer. Yet, there is inadequate experimental and clinical evidence regarding its hypnotic effects. This study sought to evaluate the effects of chamomile extract on sleep quality among elderly people.

Design: A single-blind randomized controlled trial was performed.

Setting: A convenient sample of sixty elderly people who aged sixty or more and lived in Kahrizak day care nursing home, Karaj, Iran, were randomly allocated to a control and a treatment group. The treatment group received chamomile extract capsules (200mg) twice a day for 28 consecutive days while the control group received wheat flour capsules (200mg) in the same manner. Using the Pittsburgh Sleep Quality Index, sleep quality was assessed immediately before, two weeks after beginning, immediately after the completion, and two weeks after the completion of the intervention. The data were analyzed via the independent-sample t, Chi-square, and Fisher's exact tests as well as the repeated measures analysis of variance.

Results: The means of age in the control and the treatment groups were 70.73±6.44 and 69.36±4.99, respectively. Except for the habitual sleep efficiency component of the Sleep Quality Index, the study groups did not differ significantly from each other at baseline regarding the scores of the other components of the index. Moreover, at baseline, sleep quality in both groups was low, with no statistically significant between-group difference (P=0.639). However, after the intervention, sleep quality in the treatment group was significantly better than the control group (P<0.05).

Conclusion: The use of chamomile extract can significantly improve sleep quality among elderly people. Thus, it can be used as a safe modality for promoting elderly people's sleep.

Source: Mohsen Adib-Hajbaghery, Seyedeh Nesa Mousavi. “The effects of chamomile extract on sleep quality among elderly people: A clinical trial” Complementary Therapies in Medicine (2017): 35:109-114.

Passion Flower (Passiflora incarnata)

Effect of a medicinal plant (Passiflora incarnata L) on sleep*

Introduction: Extracts of the plant Passiflora incarnata L. (Passifloraceae) were administered intraperitoneally in order to test its effects on sleep.

Method: Experiments were carried out on chronically implanted male adult wistar rats to obtain cerebral (EEG), ocular (EOG) and muscular (EMG) activities throughout their states of vigilance. Polygraphic recordings were taken during 9 continuous hours before and after the extract administration (500 mg/kg).

Results: Passiflora incarnata induced a significant increment in the total sleep time (p<0.05). This increment was due to an increase in the time spent by animals in slow wave sleep (SWS). Concomitantly, a significant decrement in wakefulness (W) was observed (p<0.05). In contrast, time spent in rapid eye movement (REM) sleep showed a decreasing tendency, since both its frequency and mean duration were reduced.

Conclusions: The extracts obtained from Passiflora incarnata can be considered as appropriated sleep inducers.

Source: Fructuoso Ayala Guerrero, Graciela Mexicano Medina. “Effect of a medicinal plant (Passiflora incarnata L) on sleep” Sleep Science. (2017): 10(3): 96–100.

A double-blind, placebo-controlled investigation of the effects of Passiflora incarnata (passionflower) herbal tea on subjective sleep quality*


Passiflora incarnata is a traditional herbal sedative, anxiolytic and a popular sleep aid used for the treatment of sleep disturbance. Several controlled experiments have demonstrated enhanced sleep in laboratory animals, but clinical trials in humans are lacking. The aim of the present study was to investigate the efficacy of Passiflora incarnata herbal tea on human sleep, as measured using sleep diaries validated by polysomnography (PSG). This study featured a double-blind, placebo-controlled, repeated-measures design with a counterbalanced order of treatments (passionflower vs placebo tea), separated by a 1 week 'washout' period. Forty-one participants (18-35 years) were exposed to each treatment for a week, whereby they consumed a cup of the tea and filled out a sleep diary for 7 days, and completed Spielberger's state-trait anxiety inventory on the seventh morning. Ten participants also underwent overnight PSG on the last night of each treatment period. Of six sleep-diary measures analysed, sleep quality showed a significantly better rating for passionflower compared with placebo (t(40) = 2.70, p < 0.01). These initial findings suggest that the consumption of a low dose of Passiflora incarnata, in the form of tea, yields short-term subjective sleep benefits for healthy adults with mild fluctuations in sleep quality.

Source: A Ngan, R Conduit. “A double-blind, placebo-controlled investigation of the effects of Passiflora incarnata (passionflower) herbal tea on subjective sleep quality” Physiotherapy Research (2011) 25(8):1153-9.

Effect of a medicinal plant (Passiflora incarnata L) on sleep*


Introduction: Extracts of the plant Passiflora incarnata L. (Passifloraceae) were administered intraperitoneally in order to test its effects on sleep.

Method: Experiments were carried out on chronically implanted male adult wistar rats to obtain cerebral (EEG), ocular (EOG) and muscular (EMG) activities throughout their states of vigilance. Polygraphic recordings were taken during 9 continuous hours before and after the extract administration (500 mg/kg).

Results: Passiflora incarnata induced a significant increment in the total sleep time (p<0.05). This increment was due to an increase in the time spent by animals in slow wave sleep (SWS). Concomitantly, a significant decrement in wakefulness (W) was observed (p<0.05). In contrast, time spent in rapid eye movement (REM) sleep showed a decreasing tendency, since both its frequency and mean duration were reduced.

Conclusions: The extracts obtained from Passiflora incarnata can be considered as appropriated sleep inducers.

Source: Fructuoso Ayala Guerrero, Graciela Mexicano Medina. “Effect of a medicinal plant (Passiflora incarnata L) on sleep” Sleep Science (2017): 10(3):96-100.

Lemon Balm (Melissa officinalis)

Sleep Promoting Effects of IQP-AO-101: A Double-Blind, Randomized, Placebo-Controlled Exploratory Trial*

Objective: The purpose of this study was to explore the clinical benefit and tolerability of IQP-AO-101 in healthy subjects with sleep complaints.

Methods: This double-blind, randomized, placebo-controlled trial involved fifty subjects with sleep complaints. Subjects with a Pittsburgh Sleep Quality Index (PSQI) score between 6 and 15 were randomized to receive either IQP-AO-101 or placebo for 6 weeks, following a run-in period of one week. Sleep parameters were assessed at baseline and after 1, 4, and 6 weeks using the modified Athens Insomnia Scale (mAIS). Subjects were also instructed to wear an activity tracker and keep a sleep diary during the study. Other questionnaires administered were the Frankfurt Attention Inventory (FAIR-2) and the Profile of Mood States (POMS-65). Blood samples for safety laboratory parameters were taken before and at the end of the study.

Results: After 6 weeks, subjects who consumed IQP-AO-101 reported significant improvements in mAIS scores compared with placebo, including mAIS total score (11.76 ± 6.85 vs 4.00 ± 4.80; p < 0.001); night parameters composite score (5.20 ± 3.80 vs 2.04 ± 3.16; p = 0.001); and day parameters composite score (6.56 ± 4.10 vs 1.96 ± 2.65; p < 0.001). All individual parameters (Items 1 to 8) were also significantly improved from baseline after 6 weeks of IQP-AO-101 intake. Analysis of variance with baseline values as covariates showed statistically significant improvements across all individual parameters for IQP-AO-101 when compared to placebo. The measurements using the activity tracker, sleep diary, FAIR-2, and POMS did not reveal any significant differences between groups. No adverse effects related to the intake of IQP-AO-101 were reported. Tolerability was rated as very good by all the subjects and by the investigator for all cases.

Conclusions: In this study, IQP-AO-101 was well tolerated and efficacious for promoting sleep and enhancing daytime performance in subjects with moderate sleep disturbances.

Source: Udo Bongartz, Bee-Kwan Tan, Stephanie Seibt, Gordana Bothe, Ralf Uebelhack, Pee-Win Chong, Natalia Wszelaki. “Sleep Promoting Effects of IQP-AO-101: A Double-Blind, Randomized, Placebo-Controlled Exploratory Trial” Evidence Based Complementary Alternative Medicine. (2019): 9178218

Effects of Herbal combination (Melissa officinalis L. and Nepeta menthoides Boiss. & Buhse) on insomnia severity, anxiety and depression in insomniacs: Randomized placebo controlled trial*


Background: Insomnia is a prevalent disorder leading to psychological problems such as anxiety and depression.

Methods: This study investigates the effect of a combination of herbs (Melissa officinalis L. and Nepeta menthoides Boiss. & Buhse) on anxiety and depression for insomniacs and on insomnia severity. This study is a double-blind randomized placebo-controlled clinical trial. A total number of 67 participants met the inclusion criteria who were diagnosed as cases of insomnia. The patients were randomized into the herbal treatment or placebo groups. The herbal treatment group received a combination of Melissa officinalis and Nepeta menthoides Boiss. & Buhse. The primary outcomes were insomnia, depression and anxiety. We used per-protocol analysis.

Results: The all outcomes of herbal treatment were significantly improved compared with placebo in the ISI, BAI and BDI scores after four weeks’ treatment (p value: 0.008, 0.005 and <0.001 respectively).

Conclusion: A combination of Melissa officinalis L. and Nepeta menthoides Boiss. & Buhse may improve insomnia and its comorbid depression and anxiety.

Source: Maryam Ranjbar, Ali Firoozabadi Alireza Salehi, Zahra Ghorbanifar, Mohammad M. Zarshenas, Khosro Sadeghniiat-Haghighi, Hossein Rezaeizadeh. Integrative Medicine Research (2018): 7(4): 328–332.

Pilot trial of Melissa officinalis L. leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances*

Botanicals are an alternative option to prescription drugs for the alleviation of symptoms due to anxiety disorders and insomnia. Melissa officinalis L. has been shown as an anti-stress and anxiolytic agent. We previously reported moderate stress improvement in mice in which Cyracos®, a standardized Melissa officinalis L. extract, was administrated. Cyracos® contains phytochemicals that inhibit gamma-aminobutyric acid catabolism. This was a prospective, open-label, 15-day study to evaluate the efficacy of Cyracos® on stressed volunteers, who have mild-to-moderate anxiety disorders and sleep disturbances. Using clinician rating criteria, primary outcomes showed improvement of symptoms. Cyracos® reduced anxiety manifestations by 18% (p < 0.01), ameliorated anxiety-associated symptoms by 15% (p < 0.01) and lowered insomnia by 42% (p < 0.01). As much as 95% of subjects (19/20) responded to treatment, of which 70% (14/20) achieved full remission for anxiety, 85% (17/20) for insomnia, and 70% (14/20) for both. Our study demonstrates, for the first time that chronic administration of Melissa officinalis L. relieves stress-related effects. It is critical that further studies incorporate a placebo and investigate physiological stress markers.

Source: Julien Cases, Alvin Ibarra, Nicolas Feuillère, Marc Roller, Samir G. Sukkar. “Pilot trial of Melissa officinalis L. leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances” Medical Journal of Nutrition Metabolism. (2011): 4(3): 211–218.

Valarian, Chamomile, Hops, Lemon Balm, GABA, & Passion Flower – More Effective Combined

Alternative and Complementary Therapies*


Anxiety is a common ailment in our society. However, the drugs available to treat mild-to-moderate anxiety, particularly benzodiazepines, are problematic because they can cause injury, produce side-effects, and create dependence. Nervine herbs have been widely used historically to treat mild to- moderate cases of anxiety, and these herbs appear to be very safe, nonaddictive but their properties as anxiolytics have been poorly researched.

This article discusses the clinical uses of a number of nervines: oat seed (Avena spp.), Hawthorn (Crataegus spp.), California poppy (Eschscholzia californica), lavender (Lavandula spp.), chamomile (Matricaria recutita), lemon balm (Melissa officinalis), passionflower (Passiflora spp.), skullcap (Scutellaria lateriflora), and verbena (also called vervain; Verbena spp.).

Source: Abascal, Kathy, and Eric Yarnell. “Nervine herbs for treating anxiety.” Alternative & Complementary Therapies 10.6 (2004): 309-315.

GABA-modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence*


Anxiety disorders are chronic and functionally disabling conditions with high psychological stress, characterised by cognitive symptoms of excessive worry and focus difficulties and physiological symptoms such as muscle tension and insomnia. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter within the central nervous system and is a key target of pharmacotherapies in the treatment of anxiety. Although current pharmaceutical treatments are often efficacious, they may cause undesirable side effects including cognitive decrements and withdrawal symptoms. Plant-based "phytomedicines" may provide novel treatment options, to act as an adjunctive or alternative to existing anxiolytic medications. As such, we conducted a systematic review to assess the current body of literature on anxiolytic phytomedicines and/or phytoconstituents. An open-ended search to 5 July 2017 was conducted using MEDLINE (PubMed), Scopus, and Cochrane library online databases and performed in a stepped format from preclinical to clinical investigations. Eligible studies must have had (a) in vitro evidence of GABA-modulating activity, (b) animal studies using anxiety models to test an anxiolytic effect, and (c) human clinical trials. Ten phytomedicines were identified as having preclinical investigations showing interaction with the GABA system, in addition to human clinical trials: kava, valerian, pennywort, hops, chamomile, Ginkgo biloba, passionflower, ashwagandha, skullcap, and lemon balm. Collectively, the literature reveals preclinical and clinical evidence for various phytomedicines modulating GABA-pathways, with comparative anxiolytic effect to the current array of pharmaceuticals, along with good safety and tolerability profiles.

Source: Karen Savage, Joseph Firth, Con Stough, Jerome Sarris. “GABA-modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence” Phytotherapy Research (2018): 32(1):3-18.


Melatonin replacement therapy of elderly insomniacs*


Changes in sleep-wake patterns are among the hallmarks of biological aging. Previously, we reported that impaired melatonin secretion is associated with sleep disorders in old age. In this study, we investigated the effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs. The study comprised a running-in, no-treatment period and four experimental periods. During the second, third and fourth periods, subjects were administered tablets for 7 consecutive days, 2 hours before the desired bedtime. The tablets were either 2 mg melatonin administered as sustained-release or fast-release formulations or an identical-looking placebo. The fifth period, which concluded the study, was a 2-month period of daily administration of 1 mg sustained-release melatonin 2 hours before the desired bedtime. During each of these five experimental periods, sleep-wake patterns were monitored by wrist-worn actigraphs. Analysis of the first three 1-week periods revealed that a 1-week treatment with 2 mg sustained-release melatonin was effective for sleep maintenance (i.e. sleep efficiency and activity level) of elderly insomniacs, while sleep initiation was improved by the fast-release melatonin treatment. Sleep maintenance and initiation were further improved following the 2-month 1-mg sustained-release melatonin treatment, indicating that tolerance had not developed. After cessation of treatment, sleep quality deteriorated. Our findings suggest that for melatonin-deficient elderly insomniacs, melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep.

Source: Haimov, Iris, et al. “Melatonin replacement therapy of elderly insomniacs.” Sleep 18.7 (1995): 598-603.

Improvement of sleep quality in elderly people by controlled-release melatonin*


Melatonin, produced by the pineal gland at night, has a role in the regulation of the sleep-wake cycle. Among elderly people, even those who are healthy, the frequency of sleep disorders is high and there is an association with impairment of melatonin production. We investigated the effect of a controlled-release formulation of melatonin on sleep quality in 12 elderly subjects (aged 76 [SD 8] years) who were receiving various medications for chronic illnesses and who complained of insomnia. In all 12 subjects, the peak excretion of the main melatonin metabolite 6-sulphatoxymelatonin during the night was lower than normal and/or delayed in comparison with non-insomniac elderly people. In a randomized, double-blind, crossover study the subjects were treated for 3 weeks with 2 mg per night of controlled-release melatonin and for 3 weeks with placebo, with a week’s washout period. Sleep quality was objectively monitored by wrist actigraphy. Sleep efficiency was significantly greater after melatonin than after placebo (83 [SE 4] vs 75 [3]%, p<0·001) and wake time after sleep onset was significantly shorter (49 [14] vs 73 [13] min, p<0·001). Sleep latency decreased, but not significantly (19 [5] vs 33 [7] min, p=0·088). Total sleep time was not affected. The only adverse effects reported were two cases of pruritus, one during melatonin and one during placebo treatment; both resolved spontaneously. Melatonin deficiency may have an important role in the high frequency of insomnia among elderly people. Controlled-release melatonin replacement therapy effectively improves sleep quality in this population.

Source : Garfinkel, D., et al. “Improvement of sleep quality in elderly people by controlled-release melatonin.” The Lancet 346.8974 (1995): 541-544.

Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders*

Study Objectives: To investigate the efficacy of melatonin compared to placebo in improving sleep parameters in patients with primary sleep disorders.

Design: PubMed was searched for randomized, placebo-controlled trials examining the effects of melatonin for the treatment of primary sleep disorders. Primary outcomes examined were improvement in sleep latency, sleep quality and total sleep time. Meta-regression was performed to examine the influence of dose and duration of melatonin on reported efficacy. Participants: Adults and children diagnosed with primary sleep disorders.

Interventions: Melatonin compared to placebo.

Results: Nineteen studies involving 1683 subjects were included in this meta-analysis. Melatonin demonstrated significant efficacy in reducing sleep latency (weighted mean difference (WMD) = 7.06 minutes [95% CI 4.37 to 9.75], Z = 5.15, p<0.001) and increasing total sleep time (WMD = 8.25 minutes [95% CI 1.74 to 14.75], Z = 2.48, p = 0.013). Trials with longer duration and using higher doses of melatonin demonstrated greater effects on decreasing sleep latency and increasing total sleep time. Overall sleep quality was significantly improved in subjects taking melatonin (standardized mean difference = 0.22 [95% CI: 0.12 to 0.32], Z = 4.52, p<0.001) compared to placebo. No significant effects of trial duration and melatonin dose were observed on sleep quality.

Conclusion: This meta-analysis demonstrates that melatonin decreases sleep onset latency, increases total sleep time and improves overall sleep quality. The effects of melatonin on sleep are modest but do not appear to dissipate with continued melatonin use. Although the absolute benefit of melatonin compared to placebo is smaller than other pharmacological treatments for insomnia, melatonin may have a role in the treatment of insomnia given its relatively benign side-effect profile compared to these agents.

Source: Eduardo Ferracioli-Oda, Ahmad Qawasmi, Michael H. Bloch. “Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders” PLoS One. (2013): 8(5): e63773.

The effectiveness of melatonin for promoting healthy sleep: a rapid evidence assessment of the literature*


A systematic review was conducted using Samueli Institute’s Rapid Evidence Assessment of the Literature (REAL©) process to determine the evidence base for melatonin as an agent to optimize sleep or improve sleep quality, and generalize the results to a military, civilian, or other healthy, active, adult population. Multiple databases were searched yielding 35 randomized controlled trials (RCTs) meeting the review’s inclusion criteria, which were assessed for methodological quality as well as for melatonin effectiveness. The majority of included studies were high quality (83.0%). Overall, according to Grading Recommendations, Assessment Development and Evaluation (GRADE) methodology, weak recommendations were made for preventing phase shifts from jet lag, for improving insomnia in both healthy volunteers and individuals with a history of insomnia, and for initiating sleep and/or improving sleep efficacy. Based on the literature to date, no recommendations for use in shift workers or to improve hormonal phase shift changes in healthy people can be made at this time. Larger and longer-duration RCTs utilizing well characterized products are needed to warrant melatonin recommendations in young, healthy adults.

Source: Rebecca B Costello, Cynthia V Lentino, Courtney C Boyd, Meghan L O’Connell, Cindy C Crawford,Meredith L Sprengel, and Patricia A Deuster. “The effectiveness of melatonin for promoting healthy sleep: a rapid evidence assessment of the literature” Nutrition Journal (2014): 13: 106.