Healthy sleep is a fundamental component to comprehensive wellness. The essential nature of sleep can be well-summarized in the following statistic: the average human spends approximately one-third of life asleep. Quality of rest, sleep-wake cycle, and circadian rhythm reflect a complex web of external factors, bodily systems, and biochemical processes. Imbalances (or disturbances) to these can result in sleep disorders, which can negatively affect quality of life in many ways. And while the amount of sleep required varies from person to person, healthy sleep is vital for everyone.
But what exactly is sleep?
Your sleep is a dynamic, multistage process which “cycles” several times on a typical night. Throughout these sleep stages, cells rejuvenate, tissues are restored, and the brain’s plasticity is renewed. A biological clock in the brain controls circadian rhythm to promote quality rest. Sleep disorders affect all ages, and these become even more common in older adults. As we age our melatonin production declines. However, external factors like stress, excessive alcohol use, overuse of artificial light at night, and inconsistent sleep habits can cause numerous sleep issues.
nox super sleep is professionally formulated to work with the body and its natural processes by promoting mitochondrial function, calm restlessness, aid the metabolic function of melatonin synthesis and support the regulation of the natural sleep-wake cycle. Liquid delivery allows for a customized dosage to fit every individual. Our packaging includes BPA free ultraviolet glass for superior preservation, as well as FSC mix box material and soy-based inks to help protect forests and promote sustainable practices in the packaging industry.
It's not just sleep. It’s Super Sleep.
Adults take one serving (7 pumps) before bed or as directed by your healthcare professional. Avoid contact with pump dispenser to preserve freshness. Store in a cool dry place away from direct sunlight. Do not use if tamper- evident packaging is broken or missing. Shake well before use.
Analysis of Natural Sleep Supplements: Mechanisms, Efficacy, and Safety*
This comprehensive analysis explores the mechanisms, efficacy, and safety of inositol, GABA, melatonin, L-theanine, pyridoxyl-5-phosphate, L-glycine, 5-hydroxytryptophan, lavender flower extract, passion flower extract, and chamomile extract, synthesizing current research findings, highlighting the role of each supplement in enhancing sleep, its physiological mechanisms, and its effectiveness in various populations. By examining the interplay between these compounds and sleep-related neurochemical pathways, circadian rhythms, and sleep architecture, this study provides valuable insights into non-pharmacological approaches to improving sleep quality and addressing various sleep disorders.
Inositol: Potential Role in Sleep Regulation
Inositol has been explored for sleep enhancement, focusing on its involvement in physiological processes, such as signal transduction and ion-channel permeability, which are critical for neurotransmitter activity and hormone signaling in sleep-wake cycles. Inositol phosphate acts as a secondary messenger, potentially influencing sleep-related processes. Myo-inositol’s significance in neuronal function and brain health is highlighted, with lower levels associated with sleep disturbances and depressive symptoms in adolescents (1), suggesting it as a potential biomarker for sleep quality. Interactions with neurochemical pathways, including glutamatergic function and circadian rhythms (2, 3, 4) and orexin pathways (5), underscore its role in sleep architecture. Efficacy is suggested by the potential alleviation of anxiety and depression* (6), with mechanisms involving phosphorylation cascades and calcium signaling that affect slow-wave sleep. (7, 8) Metabolic health and circadian rhythm benefits have been noted. (9, 10, 11)
GABA: Inhibitory Neurotransmitter for Sleep Improvement
GABA, the primary inhibitory neurotransmitter, has been detailed for its role in sleep enhancement, with supplementation showing promise in reducing sleep latency and enhancing non-REM sleep quality. Mechanisms involve GABA receptor interactions, specifically GABAA and GABAB, modulating inhibitory synaptic transmission by enhancing chloride influx, reducing neuronal excitability, and fostering a sedative state. (12, 13) In various model organisms, such as mouse studies, an ameliorating effect of caffeine on sleep disturbances has been revealed. (14) Human trials have shown a decreased latency (15), while other studies address oral efficacy. (16) Synergy with L-Theanine significantly reduces latency and increases REM/NREM sleep (17), with clinical trials reporting improved subjective quality and next-day cognition. (18, 19) Safety is favorable (20, 21, 22), highlighting its potential as a non-pharmacological option.
Melatonin: Circadian Rhythm Regulator for Sleep
Melatonin’s role in sleep enhancement is well-documented, regulating circadian rhythms and promoting sleep onset/maintenance without altering architecture. Low-dose treatment advances or delays the circadian clock phase, which is beneficial for insomnia and rhythm disorders. (23, 24) It has also shown efficacy in chronic insomnia, rheumatoid arthritis, autism, and cancer patients*. (25, 26, 27, 28) Children with neurodevelopmental disorders exhibit improved initiation and duration* (29, 30), with mechanisms that involve phase-shifting and evolutionary conservation. (31) Dosage ranges from 1 to 10 mg, with 3 mg being optimal. (28, 30, 32, 33) However, the sustaining sleep effects are less clear. (34, 35) Short and long-term usage in adults is well tolerated, without significant adverse effects (36, 37), while long-term usage in adolescents raises safety concerns at natural levels and puberty disruption. (38, 39)
L-Theanine: Relaxation Promoter for Sleep
L-Theanine enhances sleep through anxiolytic effects, reducing stress and promoting relaxation via alpha brain wave induction. It elevates GABA levels through mechanisms that modulate GABAergic activity, thereby decreasing pre-sleep anxiety. (40, 41, 42) Efficacy varies, improving satisfaction and reducing disturbances in MDD/GAD (43), but less in ADHD (44), with PSQI scores lowered for latency and disturbance. (45) Synergy with GABA increases REM/non-REM sleep. (17) Notably, long-term use of L-theanine has been evaluated, with studies demonstrating no significant adverse long-term effects over periods extending to 28 days or more, supporting its safety for extended use. (40, 41) Overall, existing literature supports L-theanine as a safe adjunct or alternative for improving sleep quality in various populations, including those suffering from anxiety or sleep disturbances. Further research may continue to elucidate its full potential and safety profile in long-term applications. (46, 47)
Pyridoxyl-5-phosphate: Promising Sleep Link
Pyridoxyl-5-phosphate (PLP), vitamin B6’s active form, acts as a cofactor for serotonin/GABA synthesis, crucial for sleep cycles. (48) Deficiencies are linked to disrupted patterns (48), with potential benefits for chronic issues (49, 50), and support for the circadian rhythm through serotonin. (51) Mechanisms involve metabolic/neurochemical pathways, with parallels to vitamin D (49, 50), but evidence for these needs additional research (52), with calls for further study to confirm efficacy. (50, 53, 54) PLP is generally recognized as safe for human consumption, displaying minimal side effects even at therapeutic doses. (55) Novel vitamin B6 toxicity has been noted in a rare case of pyridox(am)ine-5-phosphate oxidase deficiency, an inborn error of vitamin B6 metabolism. (56)
L-Glycine: Sleep Quality Enhancer
L-Glycine improves sleep quality, reducing awakenings and enhancing next-day cognition, especially in active individuals. It acts as an inhibitory neurotransmitter, modulating NMDA receptors and decreasing body temperature, facilitating sleep onset. (57, 58) Polysomnography studies show sleep benefits (59), with affordability and safety noted. (57, 58, 59, 60, 61) It increases NREM sleep, with efficacy in older adults (60, 61), and potential synergy with protein diets (62, 63), suggesting a feasible, safe supplement, with future research needed for standardization.
5-Hydroxytryptophan (5-HTP): REM Sleep Booster
5-Hydroxytryptophan (5-HTP), a serotonin precursor that is convertible to melatonin, may enhance REM sleep and quality, with mechanisms involving serotonergic and GABAergic pathways. (64, 65) Meloni et al. (2021) demonstrated benefits in Parkinson’s patients,* increasing REM sleep without exacerbating REM sleep behavior disorder (RBD), and reducing wake time. (66) Efficacy varies, with daytime administration reportedly enhancing non-REM sleep; however, these findings are not conclusive. (67) 5-HTP is generally considered safe for both short-term and long-term use, with minimal side effects reported in various clinical studies. The safety of 5-HTP, particularly in the context of depression treatment, has been highlighted in studies with doses ranging from 20 to 3,250 mg per day. (68) Furthermore, 5-HTP has been linked to improved sleep patterns by enhancing melatonin synthesis, which is crucial for regulating sleep-wake cycles. (69) Additionally, the chronic use of 5-HTP does not seem to exacerbate the risk of serotonin syndrome, particularly when used cautiously and monitored for interactions with other serotonergic medications. (70) Ultimately, the evidence suggests that 5-HTP is a promising natural remedy for sleep issues, with established safety and effectiveness. (71)
Lavender Flower Extract: Targeted Sleep Aid
Lavender flower extract enhances sleep, particularly in postmenopausal women and the elderly, via GABA modulation, promoting relaxation. (20) A dose of 500 mg capsules has been shown to improve sleep quality (72), with systematic reviews noting its safety for mild insomnia. (73) Efficacy is supported in cardiac patients (74), with benefits from aromatherapy (75); however, some studies show non-significant differences. (76) Although more research is needed, Lavender flower extract is a safe and effective option for sleep treatment. (77, 78)
Passion Flower Extract: Anxiolytic Sleep Support
Passion Flower extract reduces sleep latency and improves quality through GABA modulation, with anxiolytic effects. (20) Additionally, it has a prolonged stress reduction effect, benefiting users in both wake and sleep states. (79, 80) Efficacy compares to oxazepam with fewer side effects* (81), but chemical variability poses challenges. (82) Safety is good (83), with potential synergies (73, 84), suggesting a natural alternative and a needed standardization.
Chamomile Extract: Mixed Sleep Benefits
Chamomile extract exhibits mixed results, with sedative effects attributed to apigenin’s interaction with GABA receptors (85, 86). A study in rats showed a reduced latency (87), with human benefits in postpartum women (88), but modest for chronic insomnia. (89) Mechanisms involve melatonin modulation with safety for mild issues. (90, 91) Chamomile extract and its variations are generally considered safe and suitable for addressing mild sleep issues. (85, 92)
Conclusion: Synergistic Effects
The combination of Inositol, GABA, Melatonin, L-Theanine, Pyridoxyl-5-Phosphate, L-Glycine, 5-Hydroxytryptophan (5-HTP), Lavender Flower Extract, Passion Flower Extract, and Chamomile Extract offers a multifaceted approach to enhancing sleep quality by targeting neurotransmitter regulation, circadian rhythm modulation, and anxiety reduction. Research suggests these supplements work synergistically, with GABA and L-Theanine notably reducing sleep latency by 14.9–20.7% and increasing sleep duration by 26.8–87.3%, boosting REM and non-REM sleep through enhanced GABA and glutamate receptor activity. (17) Melatonin, a regulator of the circadian rhythm, complements 5-HTP, a precursor to serotonin and melatonin, potentially enhancing sleep onset and quality; however, caution is advised due to the risks of serotonin syndrome when combined with serotonergic agents. (25, 71) Herbal extracts, including lavender, Passionflower, and chamomile, modulate GABAergic pathways, reducing anxiety and promoting relaxation. Systematic reviews indicate better outcomes in combination than when used individually. (73) Lavender’s efficacy in postmenopausal women and chamomile’s sedative effects, attributed to apigenin, highlight their roles in alleviating mild insomnia. (72, 85) Passion Flower’s anxiolytic properties, comparable to oxazepam,* further support sleep initiation. (81) Inositol and Pyridoxyl-5-Phosphate contribute indirectly by supporting serotonin and GABA synthesis, potentially stabilizing neurochemical pathways crucial for sleep. (1, 48) L-Glycine enhances sleep quality by reducing awakenings and lowering body temperature, with benefits in active individuals. (59)
The interplay of these compounds suggests a holistic strategy: GABA and L-Theanine reduce neural excitability, Melatonin and 5-HTP regulate sleep-wake cycles, and herbal extracts alleviate pre-sleep anxiety, while Inositol, Pyridoxyl-5-Phosphate, and L-Glycine support underlying metabolic and neurotransmitter balance.
*The Food and Drug Administration has not evaluated this literature review and therefore the information contained herein is not intended to diagnose, treat, cure, or prevent any disease. According to the FDA, only drugs can make those claims.
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