The Science Speaks For Itself

The ingredients in SLEEP are backed by numerous published reviews and studies.

Browse the following peer-reviewed research to see for yourself!

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The effect of magnesium supplementation on primary insomnia in elderly: A double-blind placebo-controlled clinical trial - PMC ( "Supplementation of magnesium bisglycinate appears to improve subjective measures of insomnia such as ISI score, sleep efficiency, sleep time and sleep onset latency, early morning awakening, and likewise, insomnia objective measures such as concentration of serum renin, melatonin, and serum cortisol, in elderly people.”

Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: an open pilot study - PubMed ( "Periodic limb movements during sleep (PLMS), with or without symptoms of restless legs syndrome (RLS), may cause sleep disturbances. Our study indicates that magnesium treatment may be a useful alternative therapy in patients with mild or moderate RLS-or PLMS-related insomnia.”

Oral magnesium supplementation for insomnia in older adults: a Systematic Review & Meta-Analysis - PubMed ( "This review confirms that the quality of literature is substandard for physicians to make well-informed recommendations on usage of oral magnesium for older adults with insomnia.”

The Role of Magnesium in Sleep Health: a Systematic Review of Available Literature - PubMed ( "This systematic review revealed an association between magnesium status and sleep quality (daytime falling asleep, sleepiness, snoring, and sleep duration) according to the observational studies.”

Zinc and Magnesium Levels of Pregnant Women with Restless Leg Syndrome and Their Relationship with Anxiety: A Case-Control Study - PubMed ( "This is the first study to show that magnesium and zinc deficiency may play a role in the etiology of RLS (restless leg syndrome) during pregnancy.”

The Importance of Magnesium in Clinical Healthcare - PubMed ( "Level I evidence supports the use of magnesium in the prevention and treatment of many common health conditions including migraine headache, metabolic syndrome, diabetes, hyperlipidemia, asthma, premenstrual syndrome, preeclampsia, and various cardiac arrhythmias. Magnesium may also be considered for prevention of renal calculi and cataract formation, as an adjunct or treatment for depression, and as a therapeutic intervention for many other health-related disorders.”

Association of magnesium intake with sleep duration and sleep quality: findings from the CARDIA study | SLEEP | Oxford Academic ( "As an antagonist of calcium (Ca), magnesium (Mg) has been implicated in the regulation of sleep. Findings from this longitudinal study support the hypothesis that Mg intake was associated with better sleep quality and the recommended sleep duration (i.e. 7–9 h), particularly among the participants without depressive disorders. After adjustment for potential confounders, magnesium intake was borderline associated with better sleep quality. The present study suggested that individuals with higher Mg intake are more likely to have the recommended duration of sleep.”

Magnesium Intake and Sleep Disorder Symptoms: Findings from the Jiangsu Nutrition Study of Chinese Adults at Five-Year Follow-Up - PubMed ( "In clinical trials, dietary magnesium use can improve insomnia symptoms. However, little is known about the association between dietary magnesium consumption and sleep disorder symptoms including daytime falling asleep, sleepiness and snoring at the population level. Conclusions: Dietary magnesium intake may have long-term benefits in reducing the likelihood of daytime falling asleep in women.”

Magnesium supplementation improves indicators of low magnesium status and inflammatory stress in adults older than 51 years with poor quality sleep - PubMed ( "Low magnesium status has been associated with numerous conditions characterized as having a chronic inflammatory stress component. Some animal findings indicate that a moderate magnesium deficiency, similar to which apparently commonly occurs in humans, may enhance inflammatory or oxidative stress induced by other factors, including disrupted sleep/sleep deprivation. The findings suggest an association between magnesium status and sleep quality that needs further study to definitively determine whether a low magnesium status is a cause or an effect of poor sleep quality.”

Serum Magnesium Levels in Patients with Obstructive Sleep Apnoea: A Systematic Review and Meta-Analysis - PubMed ( "Magnesium (Mg) is an essential mineral and a potent antioxidant. Mg deficiency can worsen oxidative stress caused by sleep deprivation or disorders. Conclusions: Sleep deprivation appears to deplete Mg levels of OSA patients, making them at risk of Mg deficiency, which potentially increases systemic inflammation and the risk of cardiovascular and metabolic diseases.”

Vitamin B6

[Pyridoxine (vitamin B6) influence on endogenic melatonin production during the experiment] - PubMed ( "The purpose of the study was to investigate the role of vitamin B6 in the process of melatonin biosynthesis. It is found that, B6 vitamin injections strengthens melatonin biosynthesis; consequently strengthening of melatonin biosynthesis influences positive therapeutic effects.”

A combination of melatonin, vitamin B6 and medicinal plants in the treatment of mild-to-moderate insomnia: A prospective pilot study - PubMed ( "This pilot study suggests that the combination of vitamin B6 and medicinal plants may be beneficial in mild-to-moderate insomnia.”

Effects of Vitamin B6 (Pyridoxine) and a B Complex Preparation on Dreaming and Sleep - PubMed ( "Anecdotal evidence indicates that supplementation with vitamin B6 (pyridoxine) before bed can enhance dream vividness and recall. In a single pilot study, Ebben, Lequerica, and Spielman (2002) found that vitamin B6 had a dose-dependent effect of increasing scores on a composite measure of dream vividness, bizarreness, emotionality, and color. We found that vitamin B6 significantly increased the amount of dream content participants recalled.”

Therapeutic effects of magnesium and vitamin B6 in alleviating the symptoms of restless legs syndrome: a randomized controlled clinical trial - PubMed ( "Conclusion: Taking magnesium and vitamin B6 supplements can reduce the severity of symptoms of RLS/WED (Restless legs syndrome/Willis-Ekbom Disease) patients and improve their sleep quality.”

The Effects of Magnesium - Melatonin - Vit B Complex Supplementation in Treatment of Insomnia - PubMed ( "Our findings indicate that 3 months of the Magnesium- melatonin vitamin B (10 mg Vit B6) supplementation has a beneficial effect in the treatment of insomnia regardless of cause.”

Systemic Manifestations in Pyridox(am)ine 5'-Phosphate Oxidase Deficiency - PubMed ( "Pyridoxine is converted to its biologically active form pyridoxal-5-phosphate (P5P) by the enzyme pyridox(am)ine 5'-phosphate oxidase and serves as a cofactor in nearly 200 reactions in the central nervous system. In addition to the well-described epileptic encephalopathy, P5P deficiency causes a range of neurological and systemic manifestations.”

Association of Pyridoxal 5'-Phosphate with Sleep-Related Problems in a General Population - PubMed ( "The average serum P5P concentrations were higher in people with normal sleep duration, suggesting a non-linear dose-response relationship.”

Influence of pyridoxal 5'-phosphate alone and in combination with vigabatrin on brain GABA measured by 1H-NMR-spectroscopy - PubMed ( "Both iso-forms of the gamma-aminobutyric acid (GABA) synthesizing enzyme and also the GABA degrading enzyme need pyridoxal 5'-phosphate (PP) as co-enzyme.”

Structures of gamma-aminobutyric acid (GABA) aminotransferase, a pyridoxal 5'-phosphate, and [2Fe-2S] cluster-containing enzyme, complexed with gamma-ethynyl-GABA and with the antiepilepsy drug vigabatrin - PubMed ( "Gamma-aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5'-phosphate-dependent enzyme responsible for the degradation of the inhibitory neurotransmitter GABA.”

New Insights Emerging from Recent Investigations on Human Group II Pyridoxal 5'-Phosphate Decarboxylases - PubMed ( "Aromatic amino acid, cysteine sulfinic acid, glutamate and histidine decarboxylases, belonging to group II of pyridoxal 5' phosphate-dependent enzymes, catalyze the synthesis of dopamine/serotonin.”

Vitamin B-6 and depressive symptomatology, over time, in older Latino adults - PubMed ( "Low vitamin B-6 status has been linked to depressive symptomatology. We examined the longitudinal association of vitamin B-6 status with depressive symptomatology across 3-time points over ∼5-7 years in a cohort of older Hispanic adults. Conclusions: Suboptimal plasma PLP is associated with higher depressive symptomatology in older Hispanic of Puerto Rican descent and this appears to persist over time. Our data suggest that identification and treatment of vitamin B-6 deficiency may be a useful preventive approach in this population.”


5-Hydroxytryptophan (5-HTP): Natural Occurrence, Analysis, Biosynthesis, Biotechnology, Physiology and Toxicology - PubMed ( "L-5-hydroxytryptophan (5-HTP) is both a drug and a natural component of some dietary supplements. 5-HTP is produced from tryptophan by tryptophan hydroxylase (TPH), which is present in two isoforms (TPH1 and TPH2). Decarboxylation of 5-HTP yields serotonin (5-hydroxytryptamine, 5-HT) that is further transformed to melatonin (N-acetyl-5-methoxytryptamine). 5-HTP plays a major role both in neurologic and metabolic diseases and its synthesis from tryptophan represents the limiting step in serotonin and melatonin biosynthesis.

5-Hydroxytryptophan: a clinically-effective serotonin precursor - PubMed ( "5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia.”

Pharmacotherapeutic management of sleep disorders in children with neurodevelopmental disorders - PubMed ( "Sleep disturbances are highly prevalent in children with neurodevelopmental disabilities. Without appropriate treatment, sleep disorders can become chronic and last for many years. Supplements (iron, vitamin D, and 5-hydroxytryptophan) might be helpful.”

Sleep-promoting effects of the GABA/5-HTP mixture in vertebrate models - PubMed ( "The aim of this study was to investigate the sleep-promoting effect of combined γ-aminobutyric acid (GABA) and 5-hydroxytryptophan (5-HTP) on sleep quality and quantity in vertebrate models. Our available evidence suggests that the GABA/5-HTP mixture modulates both GABAergic and serotonergic signaling. Moreover, the sleep architecture can be controlled by the regulation of GABAA receptor and GABA content with 5-HTP.”

Preliminary finding of a randomized, double-blind, placebo-controlled, crossover study to evaluate the safety and efficacy of 5-hydroxytryptophan on REM sleep behavior disorder in Parkinson's disease - PubMed ( "5-HTP produced an increase in the total percentage of stage REM sleep without a related increase of RBD episodes, as well as a marginal, non-significant reduction in both arousal index and wake after sleep onset. This study provides evidence that 5-HTP is safe and effective in improving sleep stability in PD, contributing to ameliorate patients' global sleep quality.”

Efficacy and safety of 5-hydroxytryptophan on depression and apathy in Parkinson's disease: a preliminary finding - PubMed ( "Several studies have indicated that altered serotonergic neurotransmission may contribute to non-motor features commonly associated with Parkinson's disease (PD) such as apathy and depression. This study provides preliminary evidence of clinical benefit of 5-HTP for treating depressive symptoms in PD.”

Advances in the Microbial Synthesis of 5-Hydroxytryptophan - PubMed ( "5-Hydroxytryptophan (5-HTP) plays an important role in the regulation of emotion, behavior, sleep, pain, body temperature, and other physiological functions. It is used in the treatment of depression, insomnia, migraine, and other diseases.”

The Impact of 5-Hydroxytryptophan Supplementation on Sleep Quality of Older Adults in Singapore: A Randomized Controlled Trial - PMC ( "5-Hydroxytryptophan (5-HTP) is known as a precursor of the sleep regulating serotonin and melatonin. Conclusions: Older adults had poor sleep quality and 5-HTP supplementation helped reduce sleep latency for up to 8 weeks.”


Safety and Efficacy of Gamma-Aminobutyric Acid from Fermented Rice Germ in Patients with Insomnia Symptoms: A Randomized, Double-Blind Trial - PubMed ( "This study shows that treatment with unpolished-rice-germ-derived GABA improved not only the subjective sleep quality but also the objective sleep efficacy without severe adverse events.”

An Updated Review on Pharmaceutical Properties of Gamma-Aminobutyric Acid - PubMed ( "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.”

Supplementation of gamma-aminobutyric acid (GABA) affects temporal, but not spatial visual attention - PubMed ( "In a randomized, double-blind, and placebo-controlled experiment, the acute effects of gamma-aminobutyric acid (GABA) supplementation on temporal and spatial attention in young healthy adults were investigated. Although there is controversy about whether oral GABA can cross the blood-brain barrier, our results offer preliminary evidence that GABA
intake might help to distribute limited attentional resources more efficiently, and can specifically improve the identification and ordering of visual events that occur in close temporal succession.”

Oral intake of γ-aminobutyric acid affects mood and activities of central nervous system during stressed condition induced by mental tasks - PubMed ( "γ-Aminobutyric acid (GABA) is a kind of amino acid contained in green tea leaves and other foods. Several reports have shown that GABA might affect brain protein synthesis, improve many brain functions such as memory and study capability, lower the blood pressure of spontaneously hypertensive rats, and may also have a relaxation effect in humans. That is to say, GABA might have alleviated the stress induced by the mental tasks. This effect also corresponded with the results of the POMS scores.”

The role of glutamate and GABA in cognitive dysfunction in schizophrenia and mood disorders - A systematic review of magnetic resonance spectroscopy studies - PubMed ( "Epidemiologic, genetic, and neurobiological studies suggest considerable overlap between schizophrenia and mood disorders. Importantly, both disorders are associated with a broad range of cognitive deficits as well as altered glutamatergic and GABAergic neurometabolism. We found that alterations in glutamatergic and GABAergic neurotransmission have been identified relatively consistently in both schizophrenia and mood disorders.”

Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies - PubMed ( "The inhibitory gamma-aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). In conclusion, this meta-analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls.”

Effects of gamma-aminobutyric acid on working memory and attention: A randomized, double-blinded, placebo-controlled, crossover trial - Ahmet Al tınok, Aytaç Karabay, Joost de Jong, Gülşen Balta, Elkan G Akyürek, 2023 ( "γ-Aminobutyric acid (GABA) is a primary inhibitory neurotransmitter that plays a significant role in the central nervous system. Studies on both animals and humans show that GABA has the pharmacological potential for reducing the impact of cognitive disorders, as well as enhancing cognitive functions and mood.”


L-theanine, unique amino acid of tea, and its metabolism, health effects, and safety - PubMed ( "It has been known that the theanine amino acid in tea has positive effects especially on relaxing, cognitive performance, emotional status, sleep quality, cancer, cardiovascular diseases, obesity, and common cold. The results of acute and chronic toxicity tests conducted on the safety of theanine express that L-theanine is reliable in general even if it is consumed too much with diet.”

The Effects of Green Tea Amino Acid L-Theanine Consumption on the Ability to Manage Stress and Anxiety Levels: a Systematic Review - PubMed ( "The green tea amino acid, L-theanine (L-THE) is associated with several health benefits, including improvements in mood, cognition and a reduction of stress and anxiety-like symptoms. Our findings suggest that supplementation of 200-400 mg/day of L-THE may assist in the reduction of stress and anxiety in people exposed to stressful conditions.”

A Novel Theanine Complex, Mg-L-Theanine Improves Sleep Quality via Regulating Brain Electrochemical Activity - PMC ( "l-Theanine is commonly used to improve sleep quality through inhibitory neurotransmitters. As a result, our data indicate that Mg-l-theanine compounds potentiate the effect of l-theanine on sleep by boosting slow-brain waves, regulating brain electrical activity, and increasing neurotransmitter and GABA receptor levels.”

Effects of L-theanine or caffeine intake on changes in blood pressure under physical and psychological stresses - PubMed ( "The results after the mental tasks showed that L-theanine significantly inhibited the blood-pressure increases in a high-response group, which consisted of participants whose blood pressure increased more than average by a performance of a mental task after placebo intake. The findings above denote that L-theanine not only reduces anxiety but also attenuates the blood-pressure increase in high-stress-response adults.”

Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial - PubMed ( "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. Our findings suggest that L-theanine has the potential to promote mental health in the general population with stress-related ailments and cognitive impairments.”

Effects of chronic l-theanine administration in patients with major depressive disorder: an open-label study - PubMed ( "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.”

L-theanine improves neurophysiological measures of attention in a dose-dependent manner: a double-blind, placebo-controlled, crossover study - PubMed ( "L-theanine, a non-proteinic amino acid found in tea, is known to enhance attention particularly in high doses, with no reported adverse effects. The findings indicate L-theanine can increase attentional processing of auditory information in a dose-dependent manner.”

Effects of l-Theanine on Cognitive Function in Middle-Aged and Older Subjects: A Randomized Placebo-Controlled Study - PubMed ( "l-theanine (γ-glutamylethylamide), an amino acid in green tea, has been shown to affect brain functions by relieving stress disorders, improving mood, and maintaining normal sleep. In conclusion, our study indicated that l-theanine may contribute to improving attention, thus enhancing working memory and executive functions.”

The deployment of intersensory selective attention: a high-density electrical mapping study of the effects of theanine - PubMed ( "Ingestion of the nonproteinic amino acid theanine (5-N-ethylglutamine) has been shown to increase oscillatory brain activity in the so-called alpha band (8-14 Hz) during resting electroencephalographic recordings in humans. This increase of attention-related anticipatory alpha over the right parieto-occipital scalp suggests that theanine may have a specific effect on the brain's attention circuitry. We conclude that theanine has clear psychoactive properties, and that it represents a potentially interesting, naturally occurring compound for further study, as it relates to the brain's attentional system.”


Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects - PubMed ( "The results reported in this paper demonstrate that apigenin is a ligand for the central benzodiazepine receptors exerting anxiolytic and slight sedative effects but not being anticonvulsant or myorelaxant.”

β-Amyloid Formation, Memory, and Learning Decline Following Long-term Ovariectomy and Its Inhibition by Systemic Administration of Apigenin and β-Estradiol - PubMed ( "The increasing cases of Alzheimer Disease (AD) has caused numerous problems. The risk of developing AD increases in menopausal women, too. Apigenin and β-estradiol are effective antioxidant and neuroprotective agents. Accordingly, β-estradiol and apigenin could have more potent therapeutic effects on AD.”

Neuroimmunomodulatory and Neuroprotective Effects of the Flavonoid Apigenin in in vitro Models of Neuroinflammation Associated With Alzheimer's Disease - PubMed ( "Apigenin (4,5,7-trihydroxyflavone) is a flavonoid found in abundance in many fruits and vegetables, that has shown important effects upon controlling the inflammatory response. This study evaluated the neuroprotective and neuroimmunomodulatory potential of apigenin using in vitro models of neuroinflammation associated with Alzheimer’s Disease (AD). Together these data demonstrate that apigenin presents neuroprotective and anti-inflammatory effects in vitro and might represent an important neuroimmunomodulatory agent for the treatment of neurodegenerative conditions.”

Antioxidant, anti-inflammatory, and enzyme inhibitory activity of natural plant flavonoids and their synthesized derivatives - PubMed ( "The synthesized flavonoid derivatives were examined for their antioxidant, anti-inflammatory, xanthine oxidase (XO), urease inhibitory activity, and cytotoxicity. The flavonoids luteolin, apigenin, diosmetin, chrysin, O3Ꞌ , O7 -dihexyl diosmetin, O4Ꞌ, O7 -dihexyl apigenin, and O7 -hexyl chrysin, showed an inhibition with IC50 values (4.5-8.1 μg/mL), more than allopurinol (8.5 μg/mL) at 5 μM against XO and showing more than 50% inhibition at a final concentration (5 mM) with an IC50 value of ranging from 4.8 to 7.2 (μg/mL) in comparison with the positive control thiourea (5.8 μg/mL) for urease inhibition. Thus, the flavonoid derivatives may be considered as potential antioxidant and antigout agents.”

Apigenin inhibits tumor necrosis factor-induced intercellular adhesion molecule-1 upregulation in vivo - PubMed ( "Apigenin is a flavonoid that effectively blocks intercellular adhesion molecule-1 (ICAM-1) upregulation and leukocyte adhesion in response to cytokines in vitro. TNF-induced ICAM-1 upregulation in vivo effectively is blocked by apigenin through a mechanism that is unrelated to free radical scavenging or leukocyte function.”

Modulation of Th17 Proliferation and IL-17A Gene Expression by Acetylated Form of Apigenin in Patients with Multiple Sclerosis - PubMed ( "The presence of Th17 cells in CNS lesion of MS patients due to their inflammatory cytokines secretion is in line with the deterioration of the disease. Currently, the use of natural compounds with anti-inflammatory properties such as flavonoids have been considered to reduce inflammation in these patients, but the remaining issue is how deliver these compounds to the site of inflammation. The results showed that Apigenin 3-Acetate inhibited Th17 cells proliferation (P value: 0.018) at 80 µM concentration after 48 hr. Additionally, IL-17A gene expression significantly (P value≤ 0.0001) inhibited by Apigenin, Apigenin 3-Acetate and Methyl Prednisolone Acetate in 80 µM, 80 µM and 2.5 µM (selected dose in IC50 determination) respectively. These results demonstrate that Acetate increases anti-inflammatory effects of Apigenin on Th17 cells.”

Apigenin suppresses cancer cell growth through ERbeta - PubMed ( "Two flavonoids, genistein and apigenin, have been implicated as chemopreventive agents against prostate and breast cancers.  Our data unveil, for the first time, that the anticancer action of apigenin is mediated, in part, by ERbeta.”

Inhibitory effect of apigenin, a plant flavonoid, on epidermal ornithine decarboxylase and skin tumor promotion in mice - PubMed ( "This investigation studied the effect of topical application of apigenin on skin tumorigenesis initiated by 7,12 dimethylbenz(a)anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA) in SENCAR mice. These data indicate that apigenin inhibited skin papillomas and showed the tendency to decrease conversion of papillomas to carcinomas.”

Effect of apigenin on neurodegenerative diseases - PubMed ( "Neurodegenerative diseases (NDDs), such as Alzheimer's and Parkinson's, are the most frequent age-related illnesses affecting millions worldwide. This review discusses evidence from different research models and clinical trials on the therapeutic potential of one promising flavonoid, apigenin, and how it can be helpful for NDDs in the future prospects.”

The Therapeutic Potential of Apigenin - PMC ( "Several plant bioactive compounds have exhibited functional activities that suggest they could play a remarkable role in preventing a wide range of chronic diseases. The largest group of naturally-occurring polyphenols are the flavonoids, including apigenin. The beneficial indications are reported and discussed in detail, including effects in diabetes, amnesia and Alzheimer’s disease, depression and insomnia, cancer, etc. Apigenin may induce muscle relaxation and sedation depending on the dose, and it is also active as an antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing substance with interesting potential in the treatment/prevention of Alzheimer’s disease.”

Pharmacological profile of apigenin, a flavonoid isolated from Matricaria chamomilla - ScienceDirect "In traditional medicine, the dried flower heads of M. chamomilla are widely used to obtain sedative, spasmolytic, and anti-inflammatory effects. One of the compounds [in the extract of M. chamomilla] was identified by HPLC–ESI–MS/MS analysis as apigenin, as determined by comparing the spectra shown in Fig. 1 with those of synthetic apigenin.”

Sleep-Aids Derived from Natural Products - PMC ( "Apigenin (from Circium japonicum, Asteraceae) found in many plants, is a natural product belonging to flavonoids that are the aglycone of several naturally occurring glycosides. Apigenin
is a weak ligand for central benzodiazepine receptors in vitro and exerts anxiolytic and slight sedative effects in an animal model (Viola et al., 1995). Apigenin shows second-order positive modulatory activity at GABAA receptors (Campbell et al., 2004Rosi et al., 2004). It was reported that enhancement of pentobarbital-induced sleep by apigenin is mediated by GABAA receptors through Cl− channel complex activation (Kim et al., 2012).”


Efficacy and Safety of Ashwagandha (Withania somnifera) Root Extract in Insomnia and Anxiety: A Double-blind, Randomized, Placebo-controlled Study – PubMed ( "Insomnia is a prevalent sleep disorder that can profoundly impact a person's physical health and mental wellbeing. Ashwagandha, a proven "Rasayana" from ancient Ayurveda has the required potential to treat insomnia. Ashwagandha root extract is a natural compound with sleep-inducing potential, well tolerated and improves sleep quality and sleep onset latency in patients with insomnia. It could be of potential use to improve sleep parameters in patients with insomnia and anxiety, but need further large-scale studies.”

Pharmacological evaluation of Ashwagandha highlighting its healthcare claims, safety, and toxicity aspects - PubMed ( "Withania somnifera, commonly known as "Ashwagandha" or "Indian ginseng" is an essential therapeutic plant of Indian subcontinent regions. W. somnifera has demonstrated various biological actions such as anti-cancer, anti-inflammatory, anti-diabetic, anti-microbial, anti-arthritic, anti-stress/adaptogenic, neuro-protective, cardio-protective, hepato-protective, immunomodulatory properties. Furthermore, W. somnifera has revealed the capability to decrease reactive oxygen species and inflammation, modulation of mitochondrial function, apoptosis regulation and improve endothelial function.”

Withania somnifera (L.) Dunal (Ashwagandha): A comprehensive review on ethnopharmacology, pharmacotherapeutics, biomedicinal and toxicological aspects - PubMed ( "Clinical studies and toxicological considerations of its extracts and constituents are also elucidated. Comparative analysis of relevant in-vitro, in-vivo, and clinical investigations indicated potent bioactivity of W. somnifera [Ashwagandha] extracts and phytochemicals as anti-cancer, anti-inflammatory, apoptotic, immunomodulatory, antimicrobial, anti-diabetic, hepatoprotective, hypoglycaemic, hypolipidemic, cardio-protective and spermatogenic agents. W. somnifera was found to be especially active against many neurological and psychological conditions like Parkinson's disease, Alzheimer's disease, Huntington's disease, ischemic stroke, sleep deprivation, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, bipolar disorder, anxiety, depression, schizophrenia and obsessive-compulsive disorder.”

Does Ashwagandha supplementation have a beneficial effect on the management of anxiety and stress? A systematic review and meta-analysis of randomized controlled trials - PubMed ( "We found that Ashwagandha supplementation
significantly reduced anxiety (SMD: -1.55, 95% CI: -2.37, -0.74; p = .005; I2 = 93.8%) and stress level (SMD: -1.75; 95% CI: -2.29, -1.22; p = .005; I2 = 83.1%) compared to the placebo. The current systematic review and dose-response meta-analysis of RCTs revealed a beneficial effect in both stress and anxiety following Ashwagandha supplementation.”

Medicinal herbs for the treatment of anxiety: A systematic review and network meta-analysis - PubMed ( "Anxiety disorder is a common psychiatric illness. Ginkgo biloba (MD: -4.63, 95% CrI: -9.01 to -0.23) and Withania somnifera [Ashwagandha] (MD: -4.90, 95% CrI: -9.70 to -0.17) were efficacious, as measured by HAMA scores but the trials were limited by their small sample sizes. Medicinal herbs have become a field of interest in the treatment of anxiety. Medicinal herbs may be promising for the treatment of anxiety.”

An alternative treatment for anxiety: a systematic review of human trial results reported for the Ayurvedic herb ashwagandha (Withania somnifera) - PubMed
"ObjectiveTo assess existing reported human trials of Withania somnifera (WS; common name, ashwagandha) for the treatment of anxiety. ConclusionsAll five studies concluded that WS intervention resulted in greater score improvements (significantly in most cases) than placebo in outcomes on anxiety or stress scales.”

Assessment of the Efficacy of Withania somnifera Root Extract in Patients with Generalized Anxiety Disorder: A Randomized Double-blind Placebo- Controlled Trial - PubMed ( "Conclusion: W. somnifera extract offers some potential advantages as a safe and effective adjunctive therapy to SSRIs in Generalized Anxiety Disorder (GAD).”

An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract: A randomized, double-blind, placebo-controlled study - PubMed ( "Ashwagandha (Withania somnifera (L.) Dunal) is a herb traditionally used to reduce stress and enhance wellbeing. Conclusions: These findings suggest that ashwagandha's stress-relieving effects may occur via its moderating effect on the hypothalamus-pituitary-adrenal axis.”

Efficacy and Safety of Ashwagandha Root Extract on Cognitive Functions in Healthy, Stressed Adults: A Randomized, Double-Blind, Placebo-Controlled Study - PubMed
"Ashwagandha (Withania somnifera (L.) Dunal), an essential medicine in Ayurveda, is reportedly beneficial in reducing stress and improving memory. This is the first clinical study assessing Ashwagandha SR for its safety and efficacy. Treatment with one Ashwagandha SR capsule once daily for 90 days improved memory and focus, psychological well-being, and sleep quality, reduced stress levels, and was safe and well-tolerated.”

Adaptogenic and Anxiolytic Effects of Ashwagandha Root Extract in Healthy Adults: A Double-blind, Randomized, Placebo-controlled Clinical Study - PubMed ( "Compared to the placebo group participants, the participants receiving Ashwagandha had significant improvement in sleep quality. Conclusion: Ashwagandha root aqueous extract was beneficial in reducing stress and anxiety.”

A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults - PubMed ( "The findings of this study suggest that Ashwagandha root extract safely and effectively improves an individual's resistance towards stress and thereby improves self assessed quality of life.”

Body Weight Management in Adults Under Chronic Stress Through Treatment With Ashwagandha Root Extract: A Double-Blind, Randomized, Placebo-Controlled Trial - PubMed ( "The treatment with Ashwagandha resulted in significant improvements in primary and secondary measures. Also, the extract was found to be safe and tolerable. The outcome of this study suggests that Ashwagandha root extract can be used for body weight management in adults under chronic stress.”

Valerian Root

Effect of valerian on sleep quality in postmenopausal women: a randomized placebo-controlled clinical trial - PubMed ( "The aim of the present study was to evaluate the effects of valerian extract taken nightly on the improvement of sleep quality in postmenopausal women experiencing insomnia. Conclusions: Valerian improves the quality of sleep in women with menopause who are experiencing insomnia. Findings from this study add support to the reported effectiveness of valerian in the clinical management of insomnia.”

Effectiveness of Valerian on insomnia: a meta-analysis of randomized placebo-controlled trials - PubMed ( "ConclusionThe qualitative dichotomous results suggest that valerian would be effective for a subjective improvement of insomnia, although its effectiveness has not been demonstrated with
quantitative or objective measurements.”

Aqueous extract of valerian reduces latency to fall asleep in man - PubMed ( "Subjective sleep ratings were assessed by questionnaire and movements were recorded throughout the night with wrist-worn activity meters. Using the first period of 5 consecutive minutes without movement as a criterion of sleep onset, there was a significant decrease in sleep latency with valerian compared to placebo (15.8 ± 2.2 min vs 9.0 ± 1.5 min; paired “t” = 3.37;p < 0.01). The higher dose of valerian produced no further improvement in sleep latency.”

Valerian Root in Treating Sleep Problems and Associated Disorders-A Systematic Review and Meta-Analysis - PubMed ( "In addition, therapeutic benefits could be optimized when it was combined with appropriate herbal partners. There were no severe adverse events associated with valerian intake in subjects aged between 7 and 80 years. In conclusion, valerian could be a safe and effective herb to promote sleep and prevent associated disorders.”

Valerian for sleep: a systematic review and meta-analysis - PubMed ( "Extracts of the roots of valerian (Valeriana officinalis) are widely used for inducing sleep and improving sleep quality. The available evidence suggests that valerian might improve sleep quality without producing side effects.”

Lemon Balm

Pilot trial of Melissa officinalis L. leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances - PubMed ( "Melissa officinalis L. [Lemon Balm] has been shown as an anti-stress and anxiolytic agent. Our study demonstrates, for the first time that chronic administration of Melissa officinalis L. relieves stress-related effects.”

Effect of Melissa officinalis capsule on the mental health of female adolescents with premenstrual syndrome: a clinical trial study - PubMed ( "Conclusion: Based on the findings of this study, Melissa officinalis can decrease psychosomatic symptoms, sleeping disorder and anxiety, depression and disorder in social function in female adolescents.”

The effects of lemon balm (Melissa officinalis L.) on depression and anxiety in clinical trials: A systematic review and meta analysis - PubMed ( "A systematic review and a meta analytic approach were considered to investigate the effects of lemon balm as a medicinal herb on anxiety and depression in clinical trials and its side effects. Current evidence suggests that lemon balm may be effective in improving anxiety and depressive symptoms, particularly in the acute setting.”

A double-blind, randomized pilot study for comparison of Melissa officinalis L. and Lavandula angustifolia Mill. with Fluoxetine for the treatment of depression - PubMed ( "Melissa officinalis L and Lavandula angustifolia Mill have been traditionally used in Asia for the treatment of depression. Our study showed that M. officinalis and L. angustifolia effect similar to fluoxetine in mild to moderate depression.”

Effect of Melissa officinalis Capsule on the Intensity of Premenstrual Syndrome Symptoms in High School Girl Students - PubMed ( "The current study aimed to assess the effect of M. officinalis capsule on the intensity of PMS in high-school girls. Conclusions: M. officinalis capsules were effective in reduction of the PMS symptoms.”

Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (Lemon Balm) - PubMed ( "Melissa officinalis (lemon balm) is contemporaneously used as a mild sedative and/or calming agent. Conclusion: These results suggest that the potential for M. officinalis to mitigate the effects of stress deserves further investigation.”

Modulation of mood and cognitive performance following acute administration of single doses of Melissa officinalis (Lemon balm) with human CNS nicotinic and
muscarinic receptor-binding properties - PubMed (
"Melissa officinalis (Lemon balm) is a herbal medicine that has traditionally been attributed with memory-enhancing properties, but which is currently more widely used as a mild sedative and sleep aid. These results suggest that doses of Melissa officinalis at or above the maximum employed here can improve cognitive performance and mood and may therefore be a valuable adjunct in the treatment of Alzheimer's disease.”

Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm) - PubMed ( "Results, utilizing the cognitive factors previously derived from the CDR battery, included a sustained improvement in Accuracy of Attention following Melissa officinalis and time- and dose-specific reductions in both Secondary Memory and Working Memory factors.”

Magnolia Bark

Honokiol promotes non-rapid eye movement sleep via the benzodiazepine site of the GABA(A) receptor in mice - PubMed ( "Decoctions of the Chinese herb houpu contain honokiol and are used to treat a variety of mental disorders, including depression. Honokiol promoted NREM sleep by modulating the benzodiazepine site of the GABA(A) receptor, suggesting potential applications in the treatment of insomnia, especially for patients who experience difficulty in falling and staying asleep.”

Biological activity and toxicity of the Chinese herb Magnolia officinalis Rehder & E. Wilson (Houpo) and its constituents - PubMed ( "The bark of Magnolia officinalis Rehder & E. Wilson, known under the pinyin name "Houpo", has been traditionally used in Chinese and Japanese medicines for the treatment of anxiety, asthma, depression, gastrointestinal disorders, headache, and more. Much pharmacological activity has been reported for this herb and its major compounds, notably antioxidant, anti-inflammatory, antibiotic and antispasmodic effects.”

Neuro-modulating effects of honokiol: a review - PubMed ( "Honokiol [compound in Magnolia Bark] is a poly-phenolic compound that exerts neuroprotective properties through a variety of mechanisms. It has therapeutic potential in anxiety, pain, cerebrovascular injury, epilepsy, and cognitive disorders including Alzheimer's disease.”

Therapeutic applications of compounds in the Magnolia family - PubMed ( "The bark and/or seed cones of the Magnolia tree have been used in traditional herbal medicines in Korea, China and Japan. Bioactive ingredients such as magnolol, honokiol, 4-O methylhonokiol and obovatol have received great attention, judging by the large number of investigators who have studied their pharmacological effects for the treatment of various diseases. Recently, many investigators reported the anti-cancer, anti-stress, anti-anxiety, anti-depressant, anti-oxidant, anti-inflammatory and hepatoprotective effects as well as toxicities and pharmacokinetics data.”

Antidepressant-like effects of the mixture of honokiol and magnolol from the barks of Magnolia officinalis in stressed rodents - PubMed ( "Honokiol and magnolol are the main constituents simultaneously identified in the barks of Magnolia officinalis, which have been used in traditional Chinese medicine to treat a variety of mental disorders including depression. These results suggested that the mixture of honokiol and magnolol possessed potent antidepressant-like properties in behaviors involved in normalization of biochemical abnormalities in brain 5-HT and 5-HIAA, serum corticosterone levels and platelet AC activity in the CMS rats. Our findings could provide a basis for examining directly the interaction of the serotonergic system, the HPA axis and AC-cAMP pathway underlying the link between depression and treatment with the mixture of honokiol and magnolol.”

Honokiol and magnolol as multifunctional antioxidative molecules for dermatologic disorders - PubMed ( "Honokiol is a small-molecule polyphenol isolated from the genus Magnolia. It is accompanied by other related polyphenols, including magnolol, with which it shares certain biological properties. Recently, honokiol and magnolol have been found to have anti-oxidative, anti-inflammatory, anti-tumor, and anti-microbial properties in preclinical models, without appreciable toxicity.”

Effects of honokiol and magnolol on acute and inflammatory pain models in mice - PubMed ( "The antinociceptive actions of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, were evaluated using tail-flick, hot-plate and formalin tests in mice. These results demonstrate that honokiol and magnolol effectively alleviate the formalin-induced inflammatory pain without motor and cognitive side effects, suggesting their therapeutic potential in the treatment of inflammatory pain.”

Gastroprotective Effect of Ethanol Extracts from Bark of Magnolia officinalis on Ethanol-Induced Gastric Mucosal Damage in Rats - PubMed ( "Magnolia officinalis Rehd. and Wils. is widely used in Asian countries because of its multiple pharmacological effects. This study investigated the gastroprotective effect and mechanisms of the ethanol extracts from the bark of Magnolia officinalis (MOE) against ethanol-induced gastric mucosal damage in rats. Conclusions. The gastroprotective effect of MOE was attributed to the inhibition of oxidative stress and the NF-κB inflammatory pathway. The results provided substantial evidence that MOE could be a promising phytomedicine for gastric ulcer prevention.”

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