Scientific Research of Cortisol & Sleep Formula

CLINICAL STUDIES ON THE FOLLOWING INGREDIENTS:

ASHWAGANDHA

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

Abstract

Stress is a state of mental or emotional strain that can lead to underperformance and adverse clinical conditions, and adaptogens are herbs that help the body combat it. This study evaluated the safety and efficacy of a high-concentration full-spectrum Ashwagandha root extract (KSM-66) in reducing stress and anxiety, and in improving the general well-being, of adults under chronic stress.

Methods: A total of 64 subjects with a history of chronic stress were enrolled in this single-center, prospective, double-blind, randomized, placebo-controlled trial. Subjects were randomized 1:1 to receive either 300 mg of high-concentration full-spectrum Ashwagandha root extract or a placebo, taken twice daily for 60 days. Stress was assessed at baseline and Day 60 using serum cortisol levels and three standardized questionnaires: the Perceived Stress Scale (PSS), the General Health Questionnaire-28 (GHQ-28), and the Depression Anxiety Stress Scale (DASS). Compliance and adverse events were tracked via follow-up calls on Days 15, 30, and 45.

Results: The Ashwagandha group showed a significant reduction (P<0.0001) in scores across all stress-assessment scales by Day 60 relative to placebo, including a 44.0% reduction in PSS scores (vs. 5.5% for placebo) and reductions of 64.2%–79.2% across the DASS and GHQ-28 subscales (vs. changes of –10.6% to 11.6% for placebo). Serum cortisol levels were also substantially reduced in the Ashwagandha group compared to placebo (27.9% vs. 7.9% reduction, P=0.002). Adverse effects were mild and comparable between groups, with no serious adverse events reported.

Conclusion: A high-concentration full-spectrum Ashwagandha root extract safely and effectively improved resistance to stress and self-assessed quality of life in adults with chronic stress, with significant reductions in both psychological stress measures and serum cortisol.

Source: K Chandrasekhar, Jyoti Kapoor, Sridhar Anishetty. "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." Indian Journal of Psychological Medicine, 2012, 34(3). PMCID: PMC3573577; PMID: 23439798.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3573577/

Effects of Ashwagandha (Withania Somnifera) on Stress and Anxiety: A Systematic Review and Meta-Analysis

Abstract

Ashwagandha (Withania somnifera) is an adaptogenic herb used to prevent and treat psychosomatic disorders. This systematic review and meta-analysis evaluated the effects and safety of Ashwagandha on psychosomatic functions related to stress and anxiety among patients.

Methods: A comprehensive search was conducted across MEDLINE, EMBASE, PubMed, PsychINFO, and the Cochrane Library for articles published between January 2000 and January 2022. Randomized controlled trials examining the effects of Ashwagandha on stress and anxiety were included, with two authors independently extracting data. Both subjective and objective measures of stress and anxiety were assessed as outcome variables.

Results: Nine randomized controlled trials involving 558 patients were eligible for the meta-analysis. Ashwagandha formulations showed a significant effect on the Perceived Stress Scale (MD = -4.72, 95% CI = -8.45 to -0.99), the Hamilton Anxiety Scale (MD = -2.19, 95% CI = -3.83 to -0.55), and serum cortisol levels (MD = -2.58, 95% CI = -4.99 to -0.16) compared to placebo. Doses across the included studies ranged from 125–600 mg daily for 30–90 days, using both root-only and root-and-leaf combination formulations. Four of the included studies reported mild to moderate adverse events.

Conclusion: Ashwagandha formulations have beneficial effects on stress and anxiety, with significant reductions in perceived stress, anxiety, and serum cortisol compared to placebo. Adverse effects were limited, though further research is needed to confirm safety with long-term use.

Source: Velan Arumugam, Venugopal Vijayakumar, Arthi Balakrishnan, Rudra B Bhandari, Deenadayalan Boopalan, Ramesh Ponnurangam, Venkateswaran Sankaralingam Thirupathy, Maheshkumar Kuppusamy. "Effects of Ashwagandha (Withania Somnifera) on Stress and Anxiety: A Systematic Review and Meta-Analysis." Explore, 2024. DOI: 10.1016/j.explore.2024.103062.
https://www.sciencedirect.com/science/article/abs/pii/S1550830724001691

A Randomized, Double Blind, Placebo Controlled Study to Evaluate the Effects of Ashwagandha (Withania somnifera) Extract on Sleep Quality in Healthy Adults

Abstract

Non-restorative sleep (NRS) affects roughly 10% of people worldwide, leading to poor sleep quality and physical and cognitive fatigue. This was the first human study to evaluate an ashwagandha (Withania somnifera) extract for its effects on overall sleep quality in subjects with NRS.

Methods: In this randomized, double-blind, placebo-controlled trial, 150 healthy subjects scoring high on non-restorative sleep measures were given 120 mg of standardized ashwagandha extract (Shoden®) once daily for six weeks. Subjects were evaluated using the Restorative Sleep Questionnaire-weekly version and the WHO Quality of Life-Bref (WHOQOL) scale, while sleep actigraphy measured sleep onset latency, sleep efficiency, total sleep time, and wake after sleep onset. Safety was assessed through vitals, hematology, biochemistry, and urinalysis.

Results: A total of 144 subjects completed the study with no dropouts due to adverse events. Self-reported sleep quality improved by 72% in the ashwagandha group compared to 29% in the placebo group (p<0.001). Activity monitoring showed significant improvements in sleep efficiency (p<0.01), total sleep time (p<0.001), sleep latency (p<0.01), and wake after sleep onset (p<0.05) versus placebo after six weeks. Quality of life scores also improved significantly in the physical (p<0.001), psychological (p<0.001), and environmental (p<0.01) domains.

Conclusion: Six weeks of supplementation with standardized ashwagandha extract improved overall sleep quality by significantly easing non-restorative sleep in healthy subjects, with no treatment-related adverse events reported.

Source: Abhijit Deshpande, Nushafreen Irani, Ratna Balkrishnan, Irin Rosanna Benny. "A Randomized, Double Blind, Placebo Controlled Study to Evaluate the Effects of Ashwagandha (Withania somnifera) Extract on Sleep Quality in Healthy Adults." Sleep Medicine, 2020. DOI: 10.1016/j.sleep.2020.03.012.
https://www.sciencedirect.com/science/article/abs/pii/S1389945720301246

Effect of Ashwagandha (Withania somnifera) Extract on Sleep: A Systematic Review and Meta-Analysis

Abstract

This systematic review and meta-analysis aimed to determine the effect of Ashwagandha extract on sleep in adults.

Methods: A comprehensive search was conducted across CENTRAL, MEDLINE, SCOPUS, Google Scholar, the WHO Trials Portal, ClinicalTrials.gov, the Clinical Trial Registry of India, and the AYUSH Research Portal through February 2021. Randomized controlled trials comparing Ashwagandha extract to placebo on sleep outcomes in adults 18 years and older were included. Two authors independently extracted data, with primary outcomes of sleep quantity and quality, and secondary outcomes of mental alertness on rising, anxiety level, and quality of life.

Results: Five randomized controlled trials with 400 participants were analyzed. Ashwagandha extract showed a small but significant improvement in overall sleep compared to placebo (Standardized Mean Difference -0.59; 95% CI -0.75 to -0.42). The effect was more pronounced in adults with diagnosed insomnia, at treatment doses of 600 mg/day or higher, and with treatment durations of 8 weeks or more. Ashwagandha extract also significantly improved mental alertness on rising and anxiety level, though no significant effect on quality of life was found. No serious adverse effects were reported across any of the five trials.

Conclusion: Ashwagandha extract appears to have a beneficial effect on sleep in adults, both subjectively and objectively, and seems relatively safe for this use, with effects more pronounced at doses of 600 mg/day or more and durations of 8 weeks or longer. Further research is needed to establish its long-term safety.

Source: Kae Ling Cheah, Mohd Noor Norhayati, Lili Husniati Yaacob, Razlina Abdul Rahman. "Effect of Ashwagandha (Withania somnifera) Extract on Sleep: A Systematic Review and Meta-Analysis." PLOS ONE, 2021. PMCID: PMC8462692; PMID: 34559859.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8462692/

Effects of Ashwagandha Supplements on Cortisol, Stress, and Anxiety Levels in Adults: A Systematic Review and Meta-Analysis

Abstract

Withania somnifera, widely known as Ashwagandha, is a key treatment herb in Indian traditional medicine with anti-inflammatory, neuroprotective, adaptogenic, and immunomodulatory activities. This systematic review and meta-analysis evaluated its effects on cortisol, stress, and anxiety levels in adults.

Methods: Researchers searched PubMed, Web of Science, Scopus, and Cochrane databases from inception through September 8, 2024, for randomized controlled trials conducted on adults with stress and/or anxiety that compared Ashwagandha supplementation with a placebo or other active treatments and reported outcomes using validated stress and anxiety measures. Two reviewers independently extracted data, and the analysis was carried out using R with the metafor package.

Results: A total of 15 studies with a combined sample size of 873 patients were included. Ashwagandha supplementation significantly reduced anxiety on the Hamilton Anxiety Rating Scale both before 8 weeks (μ=-1.55, 95% CI: -2.45 to -0.65, p=0.0007) and at 8 weeks of treatment (μ=-3.52, 95% CI: -6.00 to -1.04, p=0.0053). It also significantly reduced stress on the Perceived Stress Scale (μ=-4.88, 95% CI: -7.84 to -1.91, p=0.0013) and cortisol levels (μ=-2.36, 95% CI: -3.26 to -1.46, p<0.0001) at 8 weeks of treatment. No significant improvement was observed in quality of life (μ=-1.76, 95% CI: -5.61 to 2.09, p=0.3698).

Conclusion: Ashwagandha supplementation is safe and effective in reducing stress and anxiety in adults, with statistically significant reductions in cortisol levels, Perceived Stress Scale scores, and Hamilton Anxiety Rating Scale scores. No statistically significant improvement was found in quality of life.

Source: George Bachour, Abdullah Samir, Saddik Haddad, Mohamed Amine Houssaini, Menatallah El Radad. "Effects of Ashwagandha Supplements on Cortisol, Stress, and Anxiety Levels in Adults: A Systematic Review and Meta-Analysis." BJPsych Open, 2025, 11(Suppl S1), S39. DOI: 10.1192/bjo.2025.10136.
https://www.cambridge.org/core/journals/bjpsych-open/article/effects-of-ashwagandha-supplements-on-cortisol-stress-and-anxiety-levels-in-adults-a-systematic-review-and-metaanalysis/6F2D7847C1F64707F2034A45FD6CF0C0

Effects of Ashwagandha (Withania somnifera) on Mental Health in Adults: A Systematic Review and Dose–Response Meta-Analysis of Randomized Controlled Trials

Abstract

Ashwagandha (Withania somnifera) has been increasingly recognized for its role in mental health management, particularly in reducing stress and anxiety, reflecting the growing relevance of complementary and alternative medicine in psychological well-being. This study aimed to investigate its effectiveness by pooling evidence from existing randomized controlled trials.

Methods: A systematic search of PubMed, Scopus, and Web of Science Core Collection was conducted from inception to June 2025 for randomized controlled trials in adults aged 18 and older comparing ashwagandha supplementation to placebo on stress, anxiety, and depression outcomes, with an intervention duration of more than two weeks. Meta-analysis, meta-regression, non-linear dose-response analysis, and subgroup analyses were conducted using standardized mean differences (SMDs), with risk of bias assessed via the Cochrane Risk of Bias Tool and certainty of evidence graded using GRADE. The study protocol was registered with PROSPERO.

Results: Twenty-two studies with a combined sample of 1,391 participants met the eligibility criteria. Ashwagandha supplementation significantly improved stress (SMD = -5.88; 95% CI: -8.15 to -3.60), depression (SMD = -5.68; 95% CI: -8.43 to -2.94), and anxiety (SMD = -6.87; 95% CI: -8.77 to -4.97) compared to placebo. A significant linear (coefficient = 0.005, P = 0.031) and non-linear (P-nonlinearity = 0.005) dose-response relationship was found between ashwagandha dosage and stress levels, with lower daily doses (≤500 mg/day) and longer intervention durations (>8 weeks) generally associated with greater benefits, and effects more pronounced in participants with pre-existing psychological conditions. The overall certainty of evidence was rated very low due to substantial heterogeneity and publication bias.

Conclusion: Ashwagandha supplementation may help reduce symptoms of stress, anxiety, and depression in adults, with a dose-response relationship observed for stress specifically. However, given the very low certainty of evidence, ashwagandha should be regarded as a promising complementary strategy rather than a definitive treatment, and further high-quality, standardized trials are needed to establish optimal dosing and duration.

Source: Saleh A. Alsanie, Fahad Saad Alhodieb, Moein Askarpour. "Effects of Ashwagandha (Withania somnifera) on Mental Health in Adults: A Systematic Review and Dose–Response Meta-Analysis of Randomized Controlled Trials." Complementary Therapies in Medicine, 2026. DOI: 10.1016/j.ctim.2026.103325.
https://www.sciencedirect.com/science/article/pii/S0965229926000087

SAFFRON FLOWER

Saffron and Sleep Quality: A Systematic Review of Randomized Controlled Trials

Abstract

Sleep quality reflects an individual's satisfaction with their overall sleep experience, and poor sleep quality carries significant adverse health consequences. While pharmaceutical sleep aids exist, herbal treatments such as saffron (derived from the Crocus sativus flower) may offer a lower-side-effect alternative. This review is the first to critically evaluate saffron's effect on sleep quality improvement.

Methods: Researchers searched PubMed, Central, Google Scholar, and Scopus for studies published up to 2022 using terms related to saffron, Crocus sativus, and sleep quality. Only full human clinical trial reports were included (abstracts excluded), and risk of bias was assessed using the Cochrane Risk of Bias Tool alongside the Stevinson and Ernst methodological criteria.

Results: Five randomized clinical trials with a combined 379 participants from three countries (Australia, Iran, and Japan) were identified, with study durations of 4 to 8 weeks and saffron doses ranging from 0.6 mg to 28 mg/day. Four of the five trials reported a positive impact of saffron on sleep quality. Findings included significant improvements in Insomnia Severity Index scores, Restorative Sleep Questionnaire scores, and Pittsburgh Sleep Diary sleep quality ratings at doses of 14–28 mg/day, along with reductions in anxiety and combined depression-anxiety symptoms at 15 mg twice daily over 8 weeks. Saffron was also associated with increased evening melatonin concentrations compared to placebo, and sleep-quality improvements were observed as early as the first 7 days of treatment in one trial.

Conclusion: Saffron, along with its active constituents crocin and safranal, appears to have a beneficial influence on sleep duration and quality, with research to date providing initial support for its safety and effectiveness as a sleep aid.

Source: Seyyed Kiarash Sadat Rafiei, Setare Abolghasemi, Mahsa Frashidi, Shiva Ebrahimi, Fatemeh Gharei, Zahra Razmkhah, Najmeh Tavousi, Behnaz Mahmoudvand, Melika Faani, Narges Karimi, Amir Abdi, Mahsa Soleimanzadeh, Mahya Ahmadpour Youshanlui, Sayedeh-Fatemeh Sadatmadani, Reyhaneh Alikhani, Yasamin Pishkari, Niloofar Deravi. "Saffron and Sleep Quality: A Systematic Review of Randomized Controlled Trials." PMCID: PMC10357048; PMID: 37484523.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10357048/

Effect of a Saffron Extract on Sleep Quality in Adults with Moderate Insomnia: A Decentralized, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Natural interventions for sleep disturbances, such as saffron extract, are gaining scientific and clinical interest. This three-arm, randomized, double-blind, placebo-controlled trial examined the effect of a standardized saffron extract (Safr'Inside™) on sleep, stress, and other psychological outcomes in 165 adults reporting moderate insomnia.

Methods: Participants received 30 mg, 20 mg of saffron extract, or placebo nightly for 4 weeks. The primary endpoint was change in insomnia symptoms via the Athens Insomnia Scale (AIS). Secondary outcomes included the Single-Item Sleep Quality Scale (SQS), Perceived Stress Scale (PSS), Patient Health Questionnaire-4 (PHQ-4), Positive and Negative Affect Schedule (PANAS), Epworth Sleepiness Scale (ESS), and WHO Quality of Life (WHOQOL) measures. Analyses followed an intention-to-treat approach with per-protocol confirmation.

Results: Among 150 completers, saffron extract led to a greater reduction in insomnia symptoms than placebo (adjusted mean difference β = -0.95, 95% CI: -1.79 to -0.11, P<.05). Sleep quality improved significantly after 3 weeks and was sustained at week 4 in both saffron groups compared to placebo (30 mg: β=0.82, P=.004; 20 mg: β=1.02, P<.001). Perceived stress was significantly reduced with both the 30 mg and 20 mg doses compared to placebo (30 mg: β=-1.87, P=.01; 20 mg: β=-1.89, P=.04). The 30 mg dose also showed improvement in psychological symptoms on the PHQ-4 (β=-0.79, P=.03) compared to placebo. No significant differences were found for daytime sleepiness, mood, or quality of life measures. No serious adverse events occurred, with gastrointestinal discomfort the most common mild side effect.

Conclusion: Four weeks of 20 mg or 30 mg saffron extract may reduce insomnia symptoms and perceived stress in middle-aged adults with moderate insomnia, with the 30 mg dose showing additional benefit for psychological well-being. Future research should explore longer interventions and identify which subgroups benefit most.

Source: Julius Schuster, Christin Mundhenke, Hannah Nordsieck, Camille Pouchieu, Line Pourtau, Andreas Hahn. "Effect of a Saffron Extract on Sleep Quality in Adults with Moderate Insomnia: A Decentralized, Randomized, Double-Blind, Placebo-Controlled Trial." Sleep Medicine: X, 2025. DOI: 10.1016/j.sleepx.2025.100147.
https://www.sciencedirect.com/science/article/pii/S2590142725000102

Effect of Saffron Extract Supplementation on Mood in Healthy Adults with Subclinical Symptoms of Depression: A Randomized, Double-Blind Placebo-Controlled Study

Abstract

Subclinical depressive symptoms, including low mood, fatigue, and anxiety, are clinically relevant manifestations that don't meet criteria for major depressive disorder but can still affect quality of life and predispose individuals to chronic mental health issues. This study evaluated the efficacy of 6 weeks of saffron extract supplementation on mood in healthy individuals with subclinical neuropsychiatric symptoms and explored the underlying mechanisms.

Methods: This randomized, double-blind, placebo-controlled study involved 51 healthy adults who received either 30 mg/day of saffron extract or a placebo for 6 weeks. The primary outcome was a composite z-score combining standardized scores of depression (Beck Depression Inventory-II), anxiety (State-Trait Anxiety Inventory), and fatigue (Multidimensional Fatigue Inventory-20). Secondary outcomes included neuropsychiatric scores, quality of life, inflammatory markers (IL-6, CRP), HPA axis reactivity (via salivary cortisol awakening response), and blood amino acid metabolomics.

Results: Saffron extract did not significantly affect the primary composite outcome or individual depression, anxiety, or fatigue scores compared to placebo, with both groups showing similar improvement over time. However, saffron supplementation was associated with a significant improvement in self-perceived mental health on the Short-Form 12 questionnaire compared to placebo (P=0.04 for the time × treatment interaction; P=0.017 at 6 weeks). No significant effects were found on inflammatory markers or HPA axis reactivity. Metabolomic analysis revealed that saffron significantly reduced circulating N-acetyl-phenylalanine, a metabolite that correlated with mood severity.

Conclusion: Saffron extract supplementation did not significantly improve subclinical depressive, anxiety, or fatigue symptoms as a composite score or individually, though a potential benefit for self-perceived mental health was observed and warrants further replication in larger, well-powered trials.

Source: Camille Amadieu, Quentin Leyrolle, Milena Farneti, Andrea Anesi, Eva Bruchet, Juliette Montet, Sandra Dexpert, David Gaudout, Fulvio Mattivi, Line Pourtau, Nathalie Castanon, Lucile Capuron. "Effect of Saffron Extract Supplementation on Mood in Healthy Adults with Subclinical Symptoms of Depression: A Randomized, Double-Blind Placebo-Controlled Study." The American Journal of Clinical Nutrition, 2025. DOI: 10.1016/j.ajcnut.2025.09.050.
https://www.sciencedirect.com/science/article/pii/S0002916525006033

L-THEANINE

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

Abstract

L-theanine is a non-protein amino acid found in green tea with a structure resembling glutamic acid, giving it potential as a nutraceutical ingredient for mitigating stress-related symptoms. This randomized, placebo-controlled, crossover, double-blind trial examined the effects of 4 weeks of L-theanine administration on stress-related symptoms and cognitive function in healthy adults.

Methods: Thirty participants (9 men, 21 women; mean age 48.3 years) without major psychiatric illness received 200 mg/day of L-theanine or a placebo nightly for 4 weeks in a crossover design, with a 2-week washout period between phases. Stress-related symptoms were assessed using the Self-rating Depression Scale (SDS), the State-Trait Anxiety Inventory (STAI), and the Pittsburgh Sleep Quality Index (PSQI). Cognitive function was evaluated using the Trail-Making Test, the Stroop test, and the Brief Assessment of Cognition in Schizophrenia (BACS). Serum and salivary cortisol, immunoglobulin-A, and serum L-theanine concentrations were also measured.

Results: SDS, STAI-trait, and PSQI scores significantly decreased after L-theanine administration (p=0.019, 0.006, and 0.013, respectively), with no significant change after placebo. Among PSQI subscales, reductions in sleep latency, sleep disturbance, and use of sleep medication were significantly greater with L-theanine than placebo (all p<0.05). BACS verbal fluency and executive function scores significantly improved after L-theanine administration (p=0.001 and 0.031, respectively), with the largest gains in letter fluency seen among participants with lower baseline cognitive scores. No significant changes were observed in cortisol or immunoglobulin-A levels, body mass index, or other biochemical markers, and no adverse events were reported.

Conclusion: Four weeks of L-theanine administration improved stress-related symptoms (depression, anxiety, and sleep quality) and certain cognitive functions (verbal fluency and executive function) in healthy adults, with no significant safety concerns, suggesting L-theanine may be a suitable nutraceutical ingredient for supporting mental health in the general population.

Source: Shinsuke Hidese, Shintaro Ogawa, Miho Ota, Ikki Ishida, Zenta Yasukawa, Makoto Ozeki, Hiroshi Kunugi. "Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial." Nutrients, 2019. PMCID: PMC6836118; PMID: 31623400.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6836118/

L-Theanine: From Tea Leaf to Trending Supplement – Does the Science Match the Hype for Brain Health and Relaxation?

Abstract

L-theanine is a unique non-protein amino acid found abundantly in tea leaves, and interest in its use as a dietary supplement has surged, particularly around claims of relaxation and cognitive enhancement. This review surveys the chemistry, metabolism, and purported biological activities of l-theanine, concluding that while it is well absorbed and crosses the blood-brain barrier, the evidence supporting many popular health claims remains limited and often inconsistent.

Methods: This is a narrative literature review surveying the chemistry, metabolism, and biological activity research on l-theanine, drawing on preclinical (animal and cell-based) studies as well as available human clinical trials related to relaxation, cognition, stress, anxiety, sleep, and safety.

Results: Some studies suggest l-theanine may increase alpha brain waves associated with relaxation and selective attention, reduce stress and anxiety, and improve sleep quality, but findings across the literature are frequently inconsistent. Benefits related to relaxation and attention were typically only observed in individuals with higher baseline anxiety, with little to no effect seen in those with lower anxiety levels. A network meta-analysis of herbal anxiety treatments found that l-theanine did not outperform placebo, in contrast to other standard treatments. When combined with caffeine, l-theanine may improve cognitive performance, alertness, and focus, with more consistent supporting evidence than for l-theanine alone. L-theanine showed a favorable toxicology and safety profile across animal studies, with no evidence of genotoxicity or carcinogenicity even at high doses.

Conclusion: The current evidence supporting many of l-theanine's popular health claims remains limited, particularly due to a lack of rigorous, well-designed human clinical trials; the authors urge caution regarding its purported benefits for brain health and relaxation until stronger scientific substantiation emerges, concluding that "the science does not yet match the hype" for this trending supplement.

Source: Roderick Dashwood, Francesco Visioli. "L-Theanine: From Tea Leaf to Trending Supplement – Does the Science Match the Hype for Brain Health and Relaxation?" Nutrition Research, 2024. DOI: 10.1016/j.nutres.2024.12.008.
https://www.sciencedirect.com/science/article/pii/S0271531724001684

The Effects of L-Theanine Consumption on Sleep Outcomes: A Systematic Review and Meta-Analysis

Abstract

This systematic review and meta-analysis aimed to evaluate the effects of L-theanine, a non-proteinogenic amino acid found in tea, on sleep outcomes.

Methods: Literature searches were conducted across five databases (APA PsycINFO, CINAHL, Medline, Scopus, Web of Science) and one register (Cochrane Central Register of Controlled Trials) from inception until September 2024. Randomized controlled trials investigating L-theanine supplementation's effects on sleep quality in humans of all ages and health statuses were included, with risk of bias assessed using the Cochrane Risk of Bias 2 tool.

Results: Nineteen articles (897 participants) were included in the systematic review, with 18 entered into the meta-analysis. L-theanine significantly improved subjective sleep onset latency (SMD=0.15, 95% CI: 0.01 to 0.29, p=0.04), subjective daytime dysfunction (SMD=0.33, 95% CI: 0.16 to 0.49, p<0.001), and overall subjective sleep quality (SMD=0.43, 95% CI: 0.04 to 0.83, p=0.03). However, no significant improvements were found for objective sleep onset latency, subjective or objective sleep efficiency, sleep duration, or sleep disturbances. Secondary outcomes on depression, stress, and anxiety showed mixed results across studies, and no significant improvement was found for salivary cortisol, blood pressure, or heart rate variability. L-theanine was generally well tolerated, with headaches and gastrointestinal symptoms the most commonly reported mild adverse events.

Conclusion: L-theanine supplementation shows potential for managing sleep disturbances, with positive effects on subjective measures of sleep onset latency, daytime dysfunction, and overall sleep quality, despite a lack of improvement in objective sleep measures. The limited number of studies using "pure" L-theanine (rather than blends with other ingredients) and variation in study design warrant further well-designed dose-response research.

Source: Amanda Bulman, Nathan M. D'Cunha, Wolfgang Marx, Murray Turner, Andrew McKune, Nenad Naumovski. "The Effects of L-Theanine Consumption on Sleep Outcomes: A Systematic Review and Meta-Analysis." Sleep Medicine Reviews, 2025. DOI: 10.1016/j.smrv.2025.102076.
https://www.sciencedirect.com/science/article/pii/S1087079225000292

A Novel Theanine Complex, Mg-L-Theanine, Improves Sleep Quality via Regulating Brain Electrochemical Activity

Abstract

L-theanine is commonly used to improve sleep quality through inhibitory neurotransmitters, while magnesium (Mg2+), a natural NMDA antagonist and GABA agonist, plays a critical role in sleep regulation. This study investigated the effects of L-theanine and two novel Mg-L-theanine compounds (with different magnesium concentrations) on brain electrical activity, neurotransmitter receptor expression, and sleep in mouse models.

Methods: Using a caffeine-induced brain electrical activity model in mice, researchers measured electrocorticography (ECoG) patterns, GABAergic and serotonergic receptor expression, and dopamine, serotonin, and melatonin levels following administration of L-theanine or two Mg-L-theanine compounds (8% and 18% magnesium). Sleep latency and duration were evaluated using a pentobarbital-induced sleep model, both with and without prior caffeine-induced sleep disturbance.

Results: L-theanine and, more prominently, its Mg-L-theanine complexes increased the expression of GABAergic, serotonergic, and glutamatergic receptors, which corresponded with decreased ECoG spike frequency, increased amplitude, and enhanced delta wave power (associated with deep sleep). Both compounds increased dopamine, serotonin, and melatonin levels, decreased the oxidative stress marker MDA, and increased antioxidant enzyme activity, with Mg-L-theanine complexes showing stronger effects than L-theanine alone. In the sleep models, L-theanine and Mg-L-theanine compounds increased sleep duration and decreased sleep latency after pentobarbital administration, including in the presence of caffeine-induced sleep disturbance, with the higher-magnesium Mg-T2 compound showing the greatest effect.

Conclusion: L-theanine reverses caffeine's disruptive effects on sleep and related brain chemistry, while novel Mg-L-theanine compounds showed even greater improvements in sleep quality and associated neurochemical changes, suggesting a synergistic effect between magnesium and L-theanine on sleep regulation.

Source: Muhammed Furkan Dasdelen, Sezgin Er, Berkan Kaplan, Suleyman Celik, Mustafa Caglar Beker, Cemal Orhan, Mehmet Tuzcu, Nurhan Sahin, Havakhanum Mamedova, Sarah Sylla, James Komorowski, Sara Perez Ojalvo, Kazim Sahin, Ertugrul Kilic. "A Novel Theanine Complex, Mg-L-Theanine, Improves Sleep Quality via Regulating Brain Electrochemical Activity." Frontiers in Nutrition, 2022. PMCID: PMC9017334; PMID: 35449538.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9017334/

MAGNESIUM

The Role of Magnesium in Sleep Health: A Systematic Review of Available Literature

Abstract

No prior study had critically reviewed the literature on the association between magnesium and sleep health. This systematic review assessed the association between magnesium status and sleep patterns in adults through both observational and interventional studies.

Methods: Researchers searched PubMed, Scopus, and ISI Web of Science from the earliest available date through November 2021, using a PI(E)CO framework: adult populations, high dietary intake or supplementation of magnesium as the exposure/intervention, low dietary intake or placebo as the comparison, and sleep patterns (duration, sleep-onset latency, night awakenings, sleep stages, and sleep phases) as the outcome.

Results: Nine published cross-sectional, cohort, and randomized controlled trial studies involving a combined 7,582 subjects were systematically reviewed for links between magnesium and sleep quality (daytime sleepiness, snoring, and sleep duration). Observational studies suggested an association between magnesium status and sleep quality, but the randomized controlled trials reported contradictory and uncertain findings.

Conclusion: While observational data point to an association between magnesium status and sleep quality, randomized clinical trials show an uncertain association between magnesium supplementation and sleep outcomes. Larger, well-designed randomized trials with longer follow-up periods (more than 12 weeks) are needed to clarify this relationship.

Source: Arman Arab, Nahid Rafie, Reza Amani, Fatemeh Shirani. "The Role of Magnesium in Sleep Health: A Systematic Review of Available Literature." Biological Trace Element Research, 2023. DOI: 10.1007/s12011-022-03162-1. PMID: 35184264.
https://pubmed.ncbi.nlm.nih.gov/35184264/

Effectiveness of Magnesium Supplementation on Sleep Quality and Mood for Adults with Poor Sleep Quality: A Randomized Double-Blind Placebo-Controlled Crossover Pilot Trial

Abstract

This randomized, double-blind, placebo-controlled crossover pilot trial examined the effectiveness of magnesium supplementation on sleep quality and mood in adults with nonclinical insomnia symptoms.

Methods: Thirty-one adults (mean age 46) were randomized to receive either 1 g/day of magnesium (Upgraded Magnesium™) or a placebo for 2 weeks, followed by a 2-week washout period before crossing over to the alternate condition. Standardized self-report measures included the Insomnia Severity Index, Pittsburgh Sleep Quality Index, Restorative Sleep Questionnaire, Pain and Sleep Questionnaire, Flinders Fatigue Scale, Trait Anxiety Inventory, Perceived Stress Scale, and Profile of Mood States, alongside daily objective sleep and activity measures collected via Oura Ring.

Results: The magnesium condition showed significant improvements over placebo across several sleep quality, mood, and activity outcomes, including sleep duration, deep sleep, sleep efficiency, readiness, activity balance, and heart rate variability readiness (all p<.05). Improvements with magnesium were not statistically significant compared to placebo for the Restorative Sleep Questionnaire, Trait Anxiety Inventory, Perceived Stress Scale, or Flinders Fatigue Scale (all p>.05). No adverse events were reported, and adherence was 100%.

Conclusion: Magnesium supplementation may be an effective nonpharmacological intervention for promoting sleep and mood, though longer-term clinical trials across varied populations and settings are needed to confirm these pilot findings.

Source: Michael J. Breus, Stephanie Hooper, Tarah Lynch, Heather A. Hausenblas. "Effectiveness of Magnesium Supplementation on Sleep Quality and Mood for Adults with Poor Sleep Quality: A Randomized Double-Blind Placebo-Controlled Crossover Pilot Trial." Medical Research Archives, 2024, 12(7). DOI: 10.18103/mra.v12i7.5410.
https://esmed.org/MRA/mra/article/view/5410

Magnesium Status and Stress: The Vicious Circle Concept Revisited

Abstract

Magnesium deficiency and stress are both common conditions that can increase the risk of health consequences over time. This review revisits the "magnesium and stress vicious circle" concept first introduced in the early 1990s, examining how magnesium interacts with key mediators of the physiological stress response and how low magnesium status has been reported in subjects suffering from psychological stress, suggesting a bidirectional relationship: stress increases magnesium loss, and magnesium deficiency increases susceptibility to stress.

Methods: This is a narrative review synthesizing pre-clinical (animal) and clinical (human) studies on the biological role of magnesium, its dietary requirements, the impact of stress on magnesium homeostasis, and the impact of magnesium status on stress susceptibility, drawing on neurobiological stress models including the HPA axis and the Generalized Unsafety Theory of Stress.

Results: Symptoms of magnesium deficiency (fatigue, irritability, mild anxiety, muscle weakness, headache, sleep disturbances) closely mirror common stress symptoms. Studies in stressed populations have found subclinical chronic magnesium deficiency in roughly 22–60% of subjects examined, depending on the population. Magnesium has been shown to inhibit glutamatergic transmission, enhance GABA and serotonin activity, and indirectly reduce ACTH and cortisol release, supporting a mechanistic role in dampening the stress response. In supplementation studies, magnesium (250 mg/day for 4 weeks) reduced serum cortisol in stressed male students, 400 mg/day improved heart rate variability under stress, and 300 mg/day (with or without 30 mg vitamin B6) reduced Depression Anxiety Stress Scale scores by up to 45% from baseline in subjects with severe baseline stress.

Conclusion: Growing evidence from animal and human studies supports a bidirectional link between magnesium deficiency and stress susceptibility, and magnesium supplementation has shown benefits for stress-related symptoms in stressed populations. However, the authors note that the effect of magnesium supplementation specifically on stress has been less thoroughly documented than its effects on depression and anxiety disorders, and further well-designed research is needed.

Source: Gisèle Pickering, André Mazur, Marion Trousselard, Przemyslaw Bienkowski, Natalia Yaltsewa, Mohamed Amessou, Lionel Noah, Etienne Pouteau. "Magnesium Status and Stress: The Vicious Circle Concept Revisited." Nutrients, 2020. PMCID: PMC7761127; PMID: 33260549.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7761127/

The Effects of Magnesium Supplementation on Subjective Anxiety and Stress—A Systematic Review

Abstract

Anxiety-related conditions are the most common affective disorders in the general population, with a lifetime prevalence over 15%. Since magnesium status is associated with subjective anxiety, this systematic review examined the available evidence for the efficacy of magnesium supplementation in alleviating subjective measures of anxiety and stress.

Methods: A systematic search of magnesium interventions (alone or combined with up to 5 additional ingredients) was conducted in May 2016 across Ovid Medline, PsycInfo, Embase, CINAHL, and Cochrane databases, supplemented by a grey literature review. Eighteen studies met inclusion criteria, all recruiting samples based on a pre-existing vulnerability to anxiety: mild anxiety, premenstrual syndrome (PMS), postpartum status, or hypertension.

Results: Positive effects of magnesium on subjective anxiety were reported in 4 of 8 studies in anxious samples, 4 of 7 studies in PMS samples, and 1 of 2 studies in hypertensive samples; magnesium had no effect on postpartum anxiety. No study used a validated measure of subjective stress as an outcome. Studies reporting positive effects in anxious samples generally combined magnesium with additional ingredients (commonly vitamin B6), and all placebo-controlled studies showed substantial placebo effects. No clear dose-response relationship emerged, and evidence was undermined by methodological weaknesses including inconsistent PMS diagnostic criteria, lack of placebo controls in some studies, and small or unreliable subsamples.

Conclusion: Existing evidence suggestively but inconclusively supports a beneficial effect of magnesium on subjective anxiety in anxiety-vulnerable populations (particularly those with mild anxiety or PMS symptoms), but the overall quality of evidence is poor, and well-designed randomized controlled trials are needed to confirm efficacy. No study has assessed magnesium's effect on stress using a validated stress measure.

Source: Neil Bernard Boyle, Clare Lawton, Louise Dye. "The Effects of Magnesium Supplementation on Subjective Anxiety and Stress—A Systematic Review." Nutrients, 2017, 9(5), 429. DOI: 10.3390/nu9050429.
https://www.mdpi.com/2072-6643/9/5/429

VITAMIN B6

Vitamins and Sleep: An Exploratory Study

Abstract

This exploratory study examined whether common vitamins and minerals are associated with sleep-promoting or sleep-inhibiting effects, an area with no prior published research at the time.

Methods: Data came from a larger epidemiological survey of 772 randomly recruited adults (ages 20–98) in Shelby County, Tennessee, with vitamin use information collected from 519 participants. Sleep was assessed via 14-day sleep diaries measuring sleep onset latency, number of awakenings, wake time after sleep onset, sleep efficiency, total sleep time, and subjective sleep quality. Participants were grouped by vitamin use (no vitamin, multivitamin, single vitamin, multiple vitamins, vitamin E) and compared using MANOVA, with insomnia classified using standardized diagnostic criteria (subjective complaint, impaired daytime functioning, and objective sleep diary criteria).

Results: Initial comparison across five vitamin-use groups found no significant differences in sleep variables. However, when regrouped into "no vitamin" versus "multivitamin/multiple vitamins," the multi-vitamin group reported significantly more nighttime awakenings (mean 1.8 vs. 1.4, p<0.001) and more wake time after sleep onset (mean 29.3 vs. 24.2 minutes, p<0.05) than non-users. This association was reduced but remained marginally significant after controlling for age, gender, and ethnicity. Insomniacs were marginally over-represented among multivitamin/multiple-vitamin users compared to non-users.

Conclusion: Use of a multivitamin or multiple individual vitamins was associated with poorer sleep maintenance (more awakenings, more wake time) compared to non-users, though the cross-sectional design cannot establish causation — the authors note several equally plausible explanations, including that poor sleepers may simply be more likely to take vitamins in the first place. The findings are described as preliminary and in need of replication.

Source: Kenneth L. Lichstein, Kristen L. Payne, James P. Soeffing, H. Heith Durrence, Daniel J. Taylor, Brant W. Riedel, Andrew J. Bush. "Vitamins and Sleep: An Exploratory Study." Sleep Medicine, 2007. PMCID: PMC2174691; PMID: 17825610.
https://pmc.ncbi.nlm.nih.gov/articles/PMC2174691/

Effect of Magnesium and Vitamin B6 Supplementation on Mental Health and Quality of Life in Stressed Healthy Adults: Post-Hoc Analysis of a Randomised Controlled Trial

Abstract

Magnesium status and vitamin B6 intake have both been linked to mental health and quality of life. This post-hoc secondary analysis of an 8-week Phase IV randomized controlled trial explored the effect of magnesium, with and without vitamin B6, on depression, anxiety, and quality of life in stressed but otherwise healthy adults with suboptimal magnesium levels.

Methods: Adults with a Depression Anxiety Stress Scales (DASS-42) stress subscale score above 18 and suboptimal serum magnesium (0.66–0.84 mmol/L) were randomized 1:1 to receive either magnesium plus vitamin B6 (300 mg and 30 mg daily, respectively) or magnesium alone (300 mg daily) for 8 weeks. Outcomes included changes in DASS-42 depression and anxiety scores and quality of life via the Short Form-36 Health Survey (SF-36), assessed at baseline, week 4, and week 8 in the intent-to-treat population (264 participants).

Results: Both treatment groups showed significant improvement in DASS-42 anxiety and depression scores from baseline to week 8, with depression and anxiety scores dropping from moderate/severe levels to near-normal, and most improvement occurring within the first 4 weeks. However, no significant difference was found between the magnesium-plus-B6 group and the magnesium-alone group for either anxiety or depression at week 4 or week 8. Quality of life improved across nearly all SF-36 domains in both groups over the 8 weeks, with the most pronounced gains in mental health domains. The magnesium-plus-B6 group showed significantly greater improvement than magnesium alone in physical role functioning (perceived capacity for daily activities) at week 4, while magnesium alone showed significantly greater improvement in general health perception at week 4; both differences were not significant by week 8.

Conclusion: Magnesium supplementation, with or without vitamin B6, may provide a meaningful clinical benefit for stress-related anxiety, depression, and quality of life in adults with suboptimal magnesium levels and stress, though this analysis did not find an added benefit of vitamin B6 over magnesium alone for anxiety or depression specifically (in contrast to earlier findings on the combination's effect on overall stress).

Source: Lionel Noah, Louise Dye, Béatrice Bois De Fer, André Mazur, Gisèle Pickering, Etienne Pouteau. "Effect of Magnesium and Vitamin B6 Supplementation on Mental Health and Quality of Life in Stressed Healthy Adults: Post-Hoc Analysis of a Randomised Controlled Trial." Brain and Behavior, 2021. PMCID: PMC9292249; PMID: 33864354.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9292249/

High-Dose Pyridoxine as an 'Anti-Stress' Strategy

Abstract

Pyridoxine (vitamin B6) status has a significant and selective modulatory effect on the brain's production of serotonin and GABA — neurotransmitters that regulate depression, pain perception, and anxiety — because the enzymes that produce these neurotransmitters have a relatively low affinity for pyridoxal phosphate (PLP), the active form of vitamin B6.

Methods: This is a hypothesis paper (not an original study), synthesizing existing mechanistic and animal evidence to propose that high-dose pyridoxine supplementation could function as an "anti-stress" intervention.

Results: The author notes that pyridoxine deficiency increases sympathetic nervous system output and causes hypertension in rodents, plausibly due to reduced serotonin/GABA production, while supplemental pyridoxine lowers blood pressure in animal models of hypertension, with preliminary evidence of similar effects in humans. Physiological PLP levels were also found to interact with glucocorticoid receptors to down-regulate their activity, suggesting a mechanism by which high-dose pyridoxine could blunt the physiological impact of cortisol and other corticosteroids.

Conclusion: Given evidence that chronic dysphoria (particularly with hopelessness or cynicism) negatively affects morbidity and mortality across many conditions, the author proposes that high intakes of pyridoxine may improve mental state and prognosis, with an added cardiovascular benefit through homocysteine reduction — a hypothesis the author argues is consistent with epidemiological correlations between plasma PLP levels and vascular event risk and survival.

Source: M.F. McCarty. "High-Dose Pyridoxine as an 'Anti-Stress' Strategy." Medical Hypotheses, 1999. DOI: 10.1054/mehy.1999.0955.
https://www.sciencedirect.com/science/article/abs/pii/S0306987799909556

High-Dose Vitamin B6 Supplementation Reduces Anxiety and Strengthens Visual Surround Suppression

Abstract

Vitamins B6 and B12 are involved in metabolic processes that decrease neural excitation and increase inhibition in the brain. This double-blind study investigated the effects of 1 month of high-dose B6 or B12 supplementation, compared to placebo, on a range of behavioral outcomes connected to the balance between neural inhibition and excitation.

Methods: A total of 478 young adults (mainly students, 381 female, mean age 23) were recruited across five linked study phases and randomized to receive a high-dose Vitamin B6 tablet (100 mg, well above the 1.3 mg RDA), a high-dose Vitamin B12 tablet (1000 µg, well above the 2.4 µg RDA), or a placebo daily for 30–35 days. Self-reported anxiety (SCAARED questionnaire) and depression (Mood and Feelings Questionnaire) were assessed at baseline and post-supplementation, alongside several sensory tests of inhibitory neural function measured only post-supplementation: visual contrast detection with a suppressive surround mask, binocular rivalry reversal rate, and a tactile sensitivity battery.

Results: Vitamin B6 supplementation significantly reduced self-reported anxiety compared to baseline (driven by a significant drop in the B6 group, with no significant change in placebo), with the largest effect on generalized anxiety symptoms. B6 also significantly increased visual contrast thresholds specifically in the presence of a suppressive surround — a pattern consistent with increased GABA-mediated neural inhibition — but had no effect when the surround was absent. B6 showed only a non-significant trend toward reduced depression, and no significant effects on binocular rivalry or tactile sensitivity measures. Vitamin B12 produced only non-significant trends toward reduced anxiety and altered visual processing.

Conclusion: High-dose Vitamin B6 supplementation appears to increase inhibitory GABAergic neural activity, consistent with its known role in GABA synthesis, and this may explain its observed anxiety-reducing effect; B12's effects were inconclusive in this study.

Source: David T. Field, Rebekah O. Cracknell, Jessica R. Eastwood, Peter Scarfe, Claire M. Williams, Ying Zheng, Teresa Tavassoli. "High-Dose Vitamin B6 Supplementation Reduces Anxiety and Strengthens Visual Surround Suppression." Human Psychopharmacology: Clinical and Experimental, 2020. PMCID: PMC9787829; PMID: 35851507.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9787829/

BLACK PEPPER

Effect of Black Pepper (Piper nigrum) Extract on Caffeine-Induced Sleep Disruption and Excitation in Mice

Abstract

Insomnia is increasingly prevalent worldwide, and caffeine intake is a major contributing trigger. This study investigated whether black pepper (Piper nigrum) extract (PE) could inhibit caffeine-induced sleep disruption and excitation in mice.

Methods: Mice were tested using a pentobarbital-induced sleep model (measuring sleep duration after caffeine with or without co-administered PE at 100, 250, or 500 mg/kg), an EEG/EMG-based sleep architecture analysis comparing caffeine alone, caffeine plus PE, and caffeine plus the prescription hypnotic zolpidem, and an open-field test measuring caffeine-induced hyperlocomotion and anxiety-related behavior with or without PE.

Results: Caffeine significantly reduced sleep duration, increased sleep onset time, and decreased non-rapid eye movement sleep (NREMS) compared to vehicle controls. Co-administering PE with caffeine significantly increased sleep duration compared to caffeine alone, and normalized sleep onset, total sleep time, and the wake/NREMS balance to near-vehicle levels — effects comparable to those produced by zolpidem. In the open-field test, caffeine significantly increased time in the center zone and total distance traveled (markers of excitation/anxiety-related hyperactivity), and PE significantly reduced these caffeine-induced behavioral effects.

Conclusion: Black pepper (Piper nigrum) extract attenuated caffeine-induced sleep disruption and hyperlocomotion in mice, with effects similar to the hypnotic drug zolpidem, suggesting potential value as a natural agent for counteracting caffeine-related sleep disturbance and excitation.

Source: Minseok Yoon, Jonghoon Jung, Minjung Kim, Changho Lee, Suengmok Cho, Minyoung Um. "Effect of Black Pepper (Piper nigrum) Extract on Caffeine-Induced Sleep Disruption and Excitation in Mice." Nutrients, 2022. PMCID: PMC9183155; PMID: 35684048.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9183155/

Black Pepper and Health Claims: A Comprehensive Treatise

Abstract

Spices have been integral to human diets and commerce for millennia, with growing recognition of diet-health linkages bolstering their dietary importance. Black pepper (Piper nigrum L.) is highlighted as an important functional food owing to its antioxidant, antimicrobial, and gastro-protective properties, with piperine as its key bioactive alkaloid.

Methods: This is a narrative review (treatise) synthesizing cell-culture studies and animal modeling research on the phytochemistry and biological activities of black pepper and its active compound, piperine.

Results: The review describes evidence for black pepper's free-radical scavenging activity (potentially relevant to chemoprevention and tumor growth control), as well as antioxidant, antimicrobial, anti-inflammatory, gastro-protective, and antidepressant activities, primarily drawn from animal and cell-culture studies. Piperine is specifically noted for its role in supporting cognitive brain function, boosting nutrient absorption, and improving gastrointestinal functionality, along with synergistic interactions when combined with other drugs and nutrients.

Conclusion: While black pepper and piperine show a range of health-promoting properties, the authors explicitly state these benefits have so far been demonstrated mainly in animal models, and they call for controlled randomized human trials, cohort studies, and meta-analyses before recommending black pepper for use in diet-based regimens to prevent disease.

Source: Masood Sadiq Butt, Imran Pasha, Muhammad Tauseef Sultan, Muhammad Atif Randhawa, Farhan Saeed, Waqas Ahmed. "Black Pepper and Health Claims: A Comprehensive Treatise." Critical Reviews in Food Science and Nutrition, 2013. DOI: 10.1080/10408398.2011.571799. PMID: 23768180.
https://pubmed.ncbi.nlm.nih.gov/23768180/

Bioactive Properties, Bioavailability Profiles, and Clinical Evidence of the Potential Benefits of Black Pepper (Piper nigrum) and Red Pepper (Capsicum annum) Against Diverse Metabolic Complications

Abstract

Regular intake of pepper is increasingly studied for its potential to protect against metabolic complications. This review searched major databases to compile clinical evidence linking black pepper and red pepper intake with improvements in metabolic disorders.

Methods: A systematic literature search was conducted using PubMed, Scopus, and Google Scholar from inception until June 2023, using keywords related to "pepper" and "metabolic diseases." The search yielded 14 human studies on black pepper/piperine and 16 human studies on red pepper/capsaicin, predominantly in overweight, obese, or metabolic syndrome populations.

Results: Black pepper and piperine showed evidence for improving blood lipid profiles (reducing total cholesterol, LDL cholesterol, and triglycerides) in overweight and obese individuals, and for enhancing antioxidant/anti-inflammatory status (increasing superoxide dismutase, reducing malondialdehyde and C-reactive protein) in people with metabolic syndrome, typically when combined with other bioactive compounds like curcumin or green tea extract rather than used alone. Piperine doses in the human studies reviewed ranged from roughly 2–15 mg/day in most formulations. Red pepper and capsaicin showed evidence for promoting energy expenditure and limiting energy intake, contributing to reduced fat mass in some studies. Emerging evidence also suggested potential benefits for osteoarthritis, swallowing difficulty, digestive bloating, hemodialysis-related inflammation, and exercise-related neuromuscular fatigue. Notably, piperine's bioavailability is limited by poor water solubility, though absorption can be enhanced via the same nanoparticle/encapsulation delivery systems discussed for other compounds in this review.

Conclusion: Black pepper and red pepper, along with their respective active compounds piperine and capsaicin, show several potential benefits against metabolic complications, with effects more pronounced when combined with other bioactive compounds rather than used in isolation; further high-quality clinical trials, particularly in individuals with metabolic syndrome, are needed.

Source: Phiwayinkosi V. Dludla, Ilenia Cirilli, Fabio Marcheggiani, Sonia Silvestri, Patrick Orlando, Ndivhuwo Muvhulawa, Marakiya T. Moetlediwa, Bongani B. Nkambule, Sithandiwe E. Mazibuko-Mbeje, Nokulunga Hlengwa, Sidney Hanser, Duduzile Ndwandwe, Jeanine L. Marnewick, Albertus K. Basson, Luca Tiano. "Bioactive Properties, Bioavailability Profiles, and Clinical Evidence of the Potential Benefits of Black Pepper (Piper nigrum) and Red Pepper (Capsicum annum) Against Diverse Metabolic Complications." Plants (Basel), 2023. PMCID: PMC10534530; PMID: 37764345.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10534530/

 

References:

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC3573577/
2. https://www.sciencedirect.com/science/article/abs/pii/S1550830724001691
3. https://www.sciencedirect.com/science/article/abs/pii/S1389945720301246
4. https://pmc.ncbi.nlm.nih.gov/articles/PMC8462692/
5. https://www.cambridge.org/core/journals/bjpsych-open/article/effects-of-ashwagandha-supplements-on-cortisol-stress-and-anxiety-levels-in-adults-a-systematic-review-and-metaanalysis/6F2D7847C1F64707F2034A45FD6CF0C0
6. https://www.sciencedirect.com/science/article/pii/S0965229926000087
7. https://pmc.ncbi.nlm.nih.gov/articles/PMC10357048/
8. https://www.sciencedirect.com/science/article/pii/S2590142725000102
9. https://www.sciencedirect.com/science/article/pii/S0002916525006033
10. https://pmc.ncbi.nlm.nih.gov/articles/PMC6836118/
11. https://www.sciencedirect.com/science/article/pii/S0271531724001684
12. https://www.sciencedirect.com/science/article/pii/S1087079225000292
13. https://pmc.ncbi.nlm.nih.gov/articles/PMC9017334/
14. https://pubmed.ncbi.nlm.nih.gov/35184264/
15. https://esmed.org/MRA/mra/article/view/5410
16. https://pmc.ncbi.nlm.nih.gov/articles/PMC7761127/
17. https://www.mdpi.com/2072-6643/9/5/429
18. https://pmc.ncbi.nlm.nih.gov/articles/PMC2174691/
19. https://pmc.ncbi.nlm.nih.gov/articles/PMC9292249/
20. https://www.sciencedirect.com/science/article/abs/pii/S0306987799909556
21. https://pmc.ncbi.nlm.nih.gov/articles/PMC9787829/
22. https://pmc.ncbi.nlm.nih.gov/articles/PMC9183155/
23. https://pubmed.ncbi.nlm.nih.gov/23768180/
24. https://pmc.ncbi.nlm.nih.gov/articles/PMC10534530/