Safr'Inside® - Clinical Research Data Summary
Safr'Inside™ Standardized Saffron Extract (Crocus sativus L.)
Safr'Inside™ is a clinically studied ingredient used in the following Silver Fern™ Brand product:
- Stress Complex – https://www.silverfernbrand.com/products/stress-complex
Introduction
Safr'Inside™ is a standardized saffron (Crocus sativus L.) extract that has been evaluated in multiple clinical and preclinical studies for its potential role in supporting emotional well-being, healthy stress response, sleep quality, and overall mental wellness. Research suggests that saffron extract may help support healthy mood balance, stress resilience, and sleep quality through several complementary biological pathways, including support for neurotransmitter activity involved in emotional balance, maintenance of healthy stress-response signaling, and interactions with biological systems that influence sleep and nervous system regulation.*
Human randomized, double-blind, placebo-controlled studies have evaluated standardized saffron extract at daily doses of approximately 20–30 mg and reported improvements in measures related to mood, emotional well-being, perceived stress, and sleep quality in adults. Mechanistic research also suggests that saffron-derived metabolites may support neuronal health, antioxidant defenses, and communication along the gut–brain axis.*
These are the studies for Safr'Inside™. Below, we provided a summary of each key data for each study, along with a link to the complete clinical research.
- Summary of Study 1 – Full Study: https://pubmed.ncbi.nlm.nih.gov/29332222/
- Summary of Study 2 – Full Study: https://journals.lww.com/jaanp/abstract/2015/01000/the_efficacy_and_tolerability_of_ssri_snris_in_the.10.aspx
- Summary of Study 3 – Full Study: https://obgyn.onlinelibrary.wiley.com/doi/10.1111/j.1471-0528.2007.01652.x
- Summary of Study 4 – Full Study: https://www.sciencedirect.com/science/article/abs/pii/S0944711310004071?via%3Dihub
- Summary of Study 5 – Full Study: https://www.sciencedirect.com/science/article/abs/pii/S187638201530010X?via%3Dihub
- Summary of Study 6 – Full Study: https://www.mdpi.com/2072-6643/15/13/2921
- Summary of Study 7 – Full Study: https://www.mdpi.com/2072-6643/14/7/1511
- Summary of Study 8 – Full Study: https://www.mdpi.com/2072-6643/13/3/904
- Summary of Study 9A – Full Study: https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2020.606124/full
- Summary of Study 9B – Full Study: https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2020.606124/full
- Summary of Study 10 – Full Study: https://pubs.rsc.org/en/content/articlelanding/2022/fo/d2fo02739a
- Summary of Study 11 – Full Study: https://www.medrxiv.org/content/10.1101/2025.02.20.25322405v1
Ingredient Manufacturer Link: https://activinside.com/ingredients/safrinside/
Study 1 Summary
Complete Study Information: https://pubmed.ncbi.nlm.nih.gov/29332222/
Efficacy of Crocus sativus (Saffron) in Support of Mood and Comfort in Post-Menopausal Women: A Double-Blind, Randomized, Placebo-Controlled Trial
Arch Gynecol Obstet. 2018 Mar;297(3):717-724. doi: 10.1007/s00404-018-4655-2. PMID: 29332222.
A randomized, double-blind, placebo-controlled clinical study evaluated 30 mg/day saffron extract (15 mg twice daily) in post-menopausal women over six weeks, assessing validated mood assessment scores and the impact of hot flashes on daily activities.
Study Design Highlights
- Study design: Randomized, double-blind, placebo-controlled
- Population: Post-menopausal women experiencing hot flashes and low mood
- Dose: 30 mg/day saffron extract (15 mg twice daily)
- Duration: 6 weeks
Key Findings (What the Study Showed)
Hot Flash–Related Daily Interference (HFRDIS)
- Saffron: ~75% reduction from baseline by week 6
- Placebo: ~49% reduction
- Statistically significant at weeks 2, 4, and 6 (p ≤ 0.001), with large effect sizes (Cohen's d ≈ 1.0)
Mood-Related Questionnaire Scores (HDRS)
- ~46% greater reduction in Hamilton Depression Rating Scale scores vs. placebo at week 6 (p = 0.007)
- Remission-range scores (HDRS ≤7) observed in 53.6% of saffron group vs. 14.3% placebo
- Improvements statistically significant as early as week 2
Benefits of Safr'Inside™ Demonstrated by This Study
Based directly on the clinical outcomes, saffron extract at 30 mg/day was shown to:
✓ Support a ~75% reduction in hot flash–related daily interference vs. ~49% placebo
✓ Support ~46% greater improvement in mood-related questionnaire scores vs. placebo
✓ Achieve remission-range mood scores in 53.6% of participants vs. 14.3% placebo
✓ Produce statistically significant improvements as early as week 2
✓ Be well tolerated with adverse events mild and comparable to placebo
Why This Study Matters
This study demonstrates that saffron extract may support both mood-related measures and physical comfort during the menopausal transition through a well-tolerated, non-hormonal nutritional approach.*
Reference Link: https://pubmed.ncbi.nlm.nih.gov/29332222/
Study 2 Summary
Complete Study Information: https://journals.lww.com/jaanp/abstract/2015/01000/the_efficacy_and_tolerability_of_ssri_snris_in_the.10.aspx
The Efficacy and Tolerability of SSRI/SNRIs in the Treatment of Vasomotor Symptoms in Menopausal Women: A Systematic Review
Journal of the American Association of Nurse Practitioners 27(1):54-61, January 2015. doi: 10.1002/2327-6924.12137.
A systematic review examined multiple randomized controlled trials evaluating commonly used non-hormonal approaches for supporting comfort during menopause. These findings provide context for understanding the types of outcomes that are often evaluated when assessing approaches that support women during hormonal transitions.
Key Findings (Contextual Reference Data)
- Across reviewed trials, hot flash frequency and severity were reduced by ~40–65% with effective agents
- Paroxetine: up to 62–64% reduction in hot flash scores
- Citalopram: 49–55% reduction vs. ~23% placebo
- Escitalopram: ~47% reduction vs. ~33% placebo
- Venlafaxine: 41–61% reduction depending on dose
- Improvements frequently observed within days to 1 week of intervention
- These outcomes provide a clinical benchmark for evaluating other approaches supporting comfort during menopause
Why This Study Matters
This systematic review provides contextual reference data for understanding the types of outcomes commonly measured in menopause research. When viewed alongside Study 1, saffron extract's observed ~75% reduction in hot flash–related daily interference is notable relative to the ~40–65% range reported here for pharmaceutical comparators.*
Reference Link: https://journals.lww.com/jaanp/abstract/2015/01000/the_efficacy_and_tolerability_of_ssri_snris_in_the.10.aspx
Study 3 Summary
Complete Study Information: https://obgyn.onlinelibrary.wiley.com/doi/10.1111/j.1471-0528.2007.01652.x
Crocus sativus L. (Saffron) in the Support of Premenstrual Symptom Scores: A Double-Blind, Randomised and Placebo-Controlled Trial
BJOG: An International Journal of Obstetrics & Gynaecology, 115: 515-519.
A randomized, double-blind, placebo-controlled study evaluated 30 mg/day saffron extract (15 mg twice daily) in women experiencing premenstrual symptoms over two menstrual cycles, assessing improvements in validated symptom scores related to emotional and physical discomfort.
Study Design Highlights
- Study design: Randomized, double-blind, placebo-controlled
- Population: Women experiencing premenstrual symptoms
- Dose: 30 mg/day saffron extract (15 mg twice daily)
- Duration: Two menstrual cycles (~8 weeks)
Key Findings (What the Study Showed)
- Overall symptom responders: 76% experienced ≥50% improvement in validated scores vs. 8% placebo (NNT: 1.47)
- Mood-related scores: 60% experienced ≥50% improvement vs. 4% placebo (p < 0.0001; NNT: 1.78)
- Improvements observed after the first cycle and continued through the second
- No serious adverse events; mild effects infrequent and comparable to placebo
Benefits of Safr'Inside™ Demonstrated by This Study
Based directly on the clinical outcomes, saffron extract at 30 mg/day was shown to:
✓ Support ≥50% symptom improvement in 76% of participants vs. 8% placebo (NNT: 1.47)
✓ Support ≥50% mood-related score improvement in 60% of participants vs. 4% placebo
✓ Produce improvements within one to two menstrual cycles
✓ Be well tolerated with safety outcomes comparable to placebo
Why This Study Matters
The high response rates (NNT of 1.47) and dramatic differences between saffron and placebo groups make this one of the most striking studies in the Safr'Inside™ evidence base, supporting saffron extract's role in maintaining emotional and physical comfort during the menstrual cycle.*
Reference Link: https://obgyn.onlinelibrary.wiley.com/doi/10.1111/j.1471-0528.2007.01652.x
Study 4 Summary
Complete Study Information: https://www.sciencedirect.com/science/article/abs/pii/S0944711310004071?via%3Dihub
Psychological and Neuroendocrinological Effects of Odor of Saffron (Crocus sativus)
Phytomedicine. 2011;18:726–730.
A placebo-controlled human study examined psychological and hormonal responses to 20 minutes of saffron aroma exposure, assessing measures of perceived stress, anxiety, and salivary hormone levels.
Study Design Highlights
- Study type: Placebo-controlled human acute exposure study
- Intervention: Saffron odor (volatile compounds, primarily safranal) vs. ethanol odor placebo
- Exposure: 20 minutes (olfactory)
- Outcomes: Cortisol, estradiol, testosterone, anxiety (STAI scores)
Key Findings (What the Study Showed)
- Cortisol: Significantly decreased after 20 minutes of saffron odor exposure in both follicular and luteal phases; increased in placebo group
- Estradiol: Significantly increased following saffron odor exposure; decreased in control group
- Anxiety (STAI): Significant reductions in state anxiety scores; anxiety scores increased in placebo group
- No adverse effects; non-invasive intervention
Why This Study Matters
Changes in stress-related biological markers were observed following just 20 minutes of saffron aroma exposure without ingestion, suggesting that saffron-derived volatile compounds (particularly safranal) may interact with neuroendocrine pathways associated with stress response and emotional balance.*
Reference Link: https://www.sciencedirect.com/science/article/abs/pii/S0944711310004071?via%3Dihub
Study 5 Summary
Complete Study Information: https://www.sciencedirect.com/science/article/abs/pii/S187638201530010X?via%3Dihub
The Effect of Crocus sativus (Saffron) on the Severity of Premenstrual Symptom Scores
European Journal of Integrative Medicine. 2016;8:55–61.
A randomized, triple-blind, placebo-controlled clinical trial evaluated 30 mg/day saffron extract (once daily with lunch) in women experiencing premenstrual symptoms over two menstrual cycles, assessing validated symptom severity scores.
Study Design Highlights
- Study design: Randomized, triple-blind, placebo-controlled
- Dose: 30 mg/day saffron stigma extract (oral capsule, once daily)
- Duration: Two menstrual cycles (~8 weeks)
Key Findings (What the Study Showed)
- SPAF total score: ~31% reduction after 1 cycle; ~45% reduction after 2 cycles
- Reductions in symptom severity significantly greater than placebo (p < 0.001)
- Meaningful improvement observed after one cycle, with continued improvement after the second
- No serious adverse events; mild effects comparable to placebo
Benefits of Safr'Inside™ Demonstrated by This Study
Based directly on the clinical outcomes, saffron extract at 30 mg/day was shown to:
✓ Support ~31% reduction in validated symptom severity scores after one cycle
✓ Support ~45% reduction after two cycles
✓ Demonstrate progressive symptom improvement with continued use
✓ Be well tolerated throughout the study period
Why This Study Matters
This triple-blind design adds methodological rigor to the premenstrual comfort evidence, confirming dose-related and time-dependent improvements in validated symptom scores with once-daily 30 mg saffron supplementation.*
Reference Link: https://www.sciencedirect.com/science/article/abs/pii/S187638201530010X?via%3Dihub
Study 6 Summary
Complete Study Information: https://www.mdpi.com/2072-6643/15/13/2921
Acute Effect of a Saffron Extract (Safr'Inside™) and Its Main Volatile Compound on the Stress Response in Healthy Young Men: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study
Nutrients. 2023;15:2921.
A randomized, double-blind, placebo-controlled crossover study evaluated the acute effects of a single 30 mg dose of Safr'Inside™ or its volatile compound safranal on psychological and biological responses to a validated laboratory stress test in healthy adults.
Study Design Highlights
- Study design: Randomized, double-blind, placebo-controlled, crossover
- Population: Healthy young men
- Dose: Single 30 mg dose Safr'Inside™ or 0.06 mg safranal (sublingual capsule)
- Design: Acute single-dose prior to validated laboratory stress test
Key Findings (What the Study Showed)
Perceived Stress and Anxiety (VAS)
- Perceived anxiety (AUC): Significantly lower after saffron and safranal vs. placebo (p = 0.04); safranal vs. placebo p = 0.01
- Perceived stress (AUC): Significantly reduced after saffron and safranal vs. placebo (p = 0.03); safranal vs. placebo p = 0.01
Cortisol Response Timing (HPA-Axis)
- Time to peak cortisol (Tmax): Increased from 11 min (placebo) to 26 min with saffron (~136% delay; p = 0.04)
- Time to peak cortisone (Tmax): Delayed from 15 min (placebo) to 31 min (~107% delay; p = 0.04)
- Peak hormone levels (Cmax) were not increased — indicating modulation, not suppression, of the stress response
Benefits of Safr'Inside™ Demonstrated by This Study
Based directly on the clinical outcomes, a single 30 mg dose of Safr'Inside™ was shown to:
✓ Support significantly reduced perceived stress and anxiety vs. placebo following acute stress challenge
✓ Support ~136% delay in cortisol peak timing without increasing peak cortisol levels
✓ Demonstrate rapid-onset effects within 30–75 minutes of administration
✓ Modulate the stress response without suppressing it
✓ Be well tolerated with no adverse effects reported
Why This Study Matters
A single dose of Safr'Inside™ supported meaningful reductions in perceived stress and anxiety during a validated acute stress challenge. The cortisol timing modulation — delaying but not increasing peak levels — suggests interaction with the body's adaptive stress pathways rather than blunting the stress response entirely.*
Reference Link: https://www.mdpi.com/2072-6643/15/13/2921
Study 7 Summary
Complete Study Information: https://www.mdpi.com/2072-6643/14/7/1511
Circulating Human Serum Metabolites Derived from the Intake of a Saffron Extract (Safr'Inside™) Protect Neurons from Oxidative Stress
Nutrients. 2022;14:1511.
A mechanistic study examined whether circulating metabolites produced after saffron extract intake could influence neuronal health. Human serum collected approximately 90 minutes after a single oral dose of saffron extract was applied to neuronal cells exposed to oxidative stress.
Study Design Highlights
- Study type: Mechanistic study using human serum applied to neuronal cell cultures
- Human intake: Single oral dose (300 mg saffron extract; corresponding to ~30 mg/day dose at standard dilution)
- Serum collection: ~90 minutes post-ingestion (peak crocetin levels)
Key Findings (What the Study Showed)
- Neuronal viability maintained under oxidative stress conditions with saffron-metabolite serum
- Significant reductions in intracellular reactive oxygen species (ROS)
- Increased basal BDNF (brain-derived neurotrophic factor) and prevention of stress-related BDNF reductions
- Increased serotonin release; reduced serotonin breakdown (5-HIAA); reduced serotonin transporter (SERT) expression
- Increased dopamine release under both baseline and oxidative stress conditions
Benefits of Safr'Inside™ Demonstrated by This Study
Based directly on the mechanistic findings, saffron-derived metabolites from human intake were shown to:
✓ Support neuronal cell viability under oxidative stress conditions
✓ Support reductions in intracellular ROS
✓ Support BDNF levels associated with neuronal health
✓ Support serotonin and dopamine signaling pathways
✓ Demonstrate multi-pathway neurotransmitter activity using human metabolites (not isolated compounds)
Why This Study Matters
This study provides mechanistic insight into how saffron extract may support neurological function and emotional well-being through multiple biological pathways simultaneously — serotonin, dopamine, BDNF, and antioxidant defenses — using human-derived serum rather than isolated compounds, strengthening its biological relevance.*
Reference Link: https://www.mdpi.com/2072-6643/14/7/1511
Study 8 Summary
Complete Study Information: https://www.mdpi.com/2072-6643/13/3/904
Saffron Extract–Induced Improvement of Stress-Related Behavior in Mice Is Associated with Modulation of Monoaminergic Neurotransmission
Nutrients. 2021;13:904.
A preclinical study evaluated the behavioral and neurobiological effects of saffron extract in a mouse model commonly used to study emotional behavior, assessing neurotransmitter pathways, inflammatory markers, and synaptic proteins.
Study Design Highlights
- Study type: Preclinical animal model study
- Dose: Human-equivalent dose of saffron extract
- Assessment points: Behavioral effects observed within 30 minutes; sustained with 4 weeks of supplementation
Key Findings (What the Study Showed)
- Approximately 61% reduction in high-immobility behavior vs. control animals
- Behavioral effects observed within 30 minutes and persisted with 4 weeks of supplementation
- Reduced serotonin transporter (SERT) gene expression in the hippocampus
- Increased dopamine levels in the striatum (~50%); reduced dopamine degradation markers (DOPAC, HVA)
- Reduced markers associated with inflammatory signaling and microglial activation
- Restoration of synaptic proteins associated with neuronal signaling
- No increases in anxiety-related behavior, corticosterone levels, or locomotor activity
Why This Study Matters
This preclinical study demonstrates biological effects at doses comparable to those evaluated in human studies, highlighting multi-pathway activity involving serotonin and dopamine signaling alongside both rapid and sustained behavioral responses — without increases in stress hormone markers or hyperactivity. This provides mechanistic support for observations reported in human clinical research.*
Reference Link: https://www.mdpi.com/2072-6643/13/3/904
Study 9A Summary
Studies 9A and 9B represent different outcome domains derived from the same randomized controlled trial.
Complete Study Information: https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2020.606124/full
Effects of Saffron Extract Supplementation on Mood, Well-Being, and Response to a Psychosocial Stressor in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Trial — Psychological and Inflammatory Outcomes
Frontiers in Nutrition. 2020;7:606124.
A randomized, double-blind, placebo-controlled clinical study evaluated 30 mg/day Safr'Inside™ (oral capsule, once daily) for 4 weeks in healthy adults, assessing mood, emotional well-being, and biological responses to stress including inflammatory markers.
Study Design Highlights
- Study design: Randomized, double-blind, placebo-controlled
- Dose: 30 mg/day Safr'Inside™ (oral capsule, once daily)
- Duration: 4 weeks
- Safety: Well tolerated with no significant adverse events; compliance >95%
Key Findings (What the Study Showed)
- Significant reductions in negative mood scores vs. placebo (p < 0.05), particularly under stress conditions
- Improvements in positive affect and emotional balance measures (p < 0.05)
- Reduced inflammatory response following psychosocial stress exposure
- Cortisol responses were not increased while downstream inflammatory signaling associated with stress appeared moderated
Benefits of Safr'Inside™ Demonstrated by This Study
Based directly on the clinical outcomes, Safr'Inside™ at 30 mg/day for 4 weeks was shown to:
✓ Support significant reductions in negative mood scores vs. placebo under stress conditions
✓ Support improvements in positive affect and emotional balance
✓ Influence inflammatory response markers following psychosocial stress
✓ Demonstrate activity across immune, endocrine, and nervous system pathways simultaneously
Why This Study Matters
This study supports the body's adaptive response to psychological stress while demonstrating improvements in emotional well-being measures — providing evidence relevant for individuals experiencing elevated stress in daily life.*
Reference Link: https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2020.606124/full
Study 9B Summary
Studies 9A and 9B represent different outcome domains derived from the same randomized controlled trial.
Complete Study Information: https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2020.606124/full
Effects of Saffron Extract Supplementation on Mood, Well-Being, and Response to a Psychosocial Stressor in Healthy Adults — Nervous System and Autonomic Outcomes
Frontiers in Nutrition. 2021;7:606124.
In a related analysis of the same clinical trial, researchers evaluated nervous system responses to acute stress in participants taking 30 mg/day Safr'Inside™ (15 mg twice daily, morning and evening) for 8 weeks. Heart rate variability (HRV) was measured during laboratory stress testing.
Study Design Highlights
- Study design: Randomized, double-blind, parallel group clinical trial (same parent trial as 9A)
- Dose: 30 mg/day Safr'Inside™ (15 mg twice daily)
- Duration: 8 weeks
- Safety: Well tolerated; high compliance (~96–97%)
Key Findings (What the Study Showed)
- Mood scores: Greater reductions in mood-related questionnaire scores vs. placebo (p = 0.05); moderately correlated with urinary crocetin levels
- Social well-being: Significant improvements in social relationship scores (p = 0.007)
- HRV (RMSSD): Placebo participants showed typical reduction in HRV during stress testing; saffron group maintained HRV levels, suggesting preserved parasympathetic nervous system activity during stress
- Cortisol response: Altered cortisol timing without increasing peak cortisol levels
Benefits of Safr'Inside™ Demonstrated by This Study
Based directly on the clinical outcomes, Safr'Inside™ at 30 mg/day for 8 weeks was shown to:
✓ Support improvements in mood-related questionnaire scores vs. placebo
✓ Support significant improvements in social well-being measures
✓ Support maintenance of HRV during stress testing, suggesting preserved parasympathetic balance
✓ Modulate cortisol timing without increasing peak levels
✓ Demonstrate biological exposure relationship via urinary crocetin correlation
Why This Study Matters
The maintenance of HRV during acute stress testing is a measurable physiological indicator of autonomic nervous system balance — linking emotional well-being with biological markers of nervous system regulation and providing support for stress adaptability without sedative effects.*
Reference Link: https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2020.606124/full
Study 10 Summary
Complete Study Information: https://pubs.rsc.org/en/content/articlelanding/2022/fo/d2fo02739a
Saffron Extract (Safr'Inside™) Improves Stress-Related Behaviour in a Mouse Model of Low-Grade Inflammation Through the Modulation of the Microbiota and Gut-Derived Metabolites
Food & Function. 2022;13:12219–12233.
A preclinical study explored the relationship between Safr'Inside™ saffron extract, gut microbiota composition, and behavioral responses associated with stress in a mouse model of low-grade inflammation. Dietary dosing at ~4.5 mg/kg body weight/day (human-equivalent ~22 mg/day for a 60 kg adult) was administered for 8 weeks.
Key Findings (What the Study Showed)
Behavioral Outcomes
- Mice receiving saffron extract spent 62% more time in the center of the open-field arena vs. controls (p < 0.05)
- Total distance traveled unchanged — indicating effects were not related to sedation
Gut Microbiome Effects
- Increased microbial richness (Chao1 alpha diversity, p < 0.01)
- Changes in microbial taxa including Akkermansia, Muribaculaceae, Christensenellaceae, and Alloprevotella
Gut-Derived Metabolites and Brain Signaling
- Reduced dimethylamine (DMA) levels; DMA levels correlated with behavioral outcomes
- 17 brain proteins associated with neuronal signaling and stress response were modulated
Why This Study Matters
This preclinical study demonstrates that saffron extract may influence behavioral markers associated with stress through interactions across microbiome, metabolic, and neurological pathways simultaneously — providing mechanistic support for the gut–brain axis connection observed in human sleep research (Study 11).*
Reference Link: https://pubs.rsc.org/en/content/articlelanding/2022/fo/d2fo02739a
Study 11 Summary
Complete Study Information: https://www.medrxiv.org/content/10.1101/2025.02.20.25322405v1
A Standardized Saffron Extract Improves Subjective and Objective Sleep Quality in Healthy Adults with Sleep Complaints: Results from the Gut–Sleep–Brain Axis Randomized, Double-Blind, Placebo-Controlled Studies
medRxiv. 2025;2025.02.20.25322405.
Randomized, double-blind, placebo-controlled clinical studies evaluated Safr'Inside™ supplementation (20–30 mg/day, taken 30–60 minutes before bedtime) on sleep quality in adults experiencing sleep complaints over 28 days. Assessment included validated questionnaires, objective portable EEG/sleep tracker monitoring, and gut microbiome analysis.
Study Design Highlights
- Study design: Randomized, double-blind, placebo-controlled
- Population: Healthy adults experiencing sleep complaints
- Doses: 20 mg/day and 30 mg/day Safr'Inside™
- Duration: 28 days; taken 30–60 minutes before bedtime
- Delivery: Capsule or gummy (clinical validation included gummy format)
Key Findings (What the Study Showed)
Subjective Sleep Outcomes
- Pittsburgh Sleep Quality Index (PSQI): 21.3% reduction vs. placebo after 28 days
- Single-item Sleep Quality Scale (SQS): 24.3% improvement at 20 mg/day; 27.2% improvement at 30 mg/day
- Improvements in perceived sleep quality reported as early as day 21
Objective Sleep Outcomes (EEG/Sleep Tracker)
- Sleep Onset Latency (SOL): 35.4% reduction vs. placebo
- Latency to Persistent Sleep: 35.9% reduction vs. placebo
- Wake Duration (WASO): 43.2% reduction vs. placebo
Gut Microbiome Modulation
- Dialister: ↓ 67–68%
- Turicibacter: ↓ ~67%
- UBA1819: ↑ ~34%
- Changes in microbial taxa correlated with improvements in sleep onset latency and wake duration
Benefits of Safr'Inside™ Demonstrated by This Study
Based directly on the clinical outcomes, Safr'Inside™ at 20–30 mg/day for 28 days was shown to:
✓ Support 21.3% improvement in PSQI sleep quality scores vs. placebo
✓ Support 24–27% improvement in subjective sleep quality measures
✓ Support 35.4% reduction in sleep onset latency (objective measurement)
✓ Support 43.2% reduction in wake duration (WASO) (objective measurement)
✓ Produce improvements in perceived sleep quality by approximately day 21
✓ Show gut microbiome changes correlated with sleep improvements
✓ Be well tolerated with no serious adverse events in both capsule and gummy formats
Why This Study Matters
This study demonstrates improvements in both subjective and objective sleep measures simultaneously, supporting healthy sleep onset and sleep maintenance without sedative effects. The gut microbiome changes correlated with sleep improvements provide clinical evidence for gut–brain axis involvement in sleep regulation, connecting preclinical findings (Study 10) with human outcomes.*
Reference Link: https://www.medrxiv.org/content/10.1101/2025.02.20.25322405v1
Big-Picture Integration with Other Studies
- Study 1: A 6-week RCT found saffron (30 mg/day) significantly reduced hot flash–related daily interference (~75% vs. ~49% placebo) and improved mood scores in post-menopausal women with good tolerability.
- Study 2: A systematic review of 18 RCTs evaluated non-hormonal approaches commonly used to support comfort during menopause, reporting ~40–65% reductions in hot flash frequency — providing context for saffron's observed outcomes.
- Study 3: In a double-blind RCT, saffron (30 mg/day) improved premenstrual symptom scores in 76% of participants vs. 8% placebo (NNT: 1.47) after two cycles.
- Study 4: Short-term exposure to saffron aroma influenced cortisol and anxiety scores within 20 minutes, supporting neuroendocrine pathway interactions.
- Study 5: Daily saffron (30 mg/day) improved premenstrual symptom severity scores by ~31% after one cycle and ~45% after two cycles vs. placebo.
- Study 6: A single 30 mg dose of Safr'Inside™ significantly reduced perceived stress and anxiety and delayed cortisol peak by ~136% following an acute stress challenge vs. placebo.
- Study 7: Human serum collected after saffron intake helped protect neuronal cells from oxidative stress while supporting BDNF, serotonin, and dopamine signaling pathways.
- Study 8: In a preclinical model, saffron extract produced ~61% reduction in stress-related behavioral markers alongside multi-pathway neurotransmitter modulation at human-equivalent doses.
- Study 9A: Four weeks of Safr'Inside™ (30 mg/day) improved mood and emotional well-being scores and moderated inflammatory responses to psychosocial stress in healthy adults.
- Study 9B: Eight weeks of Safr'Inside™ (30 mg/day) improved mood scores and supported maintenance of HRV (parasympathetic balance) during acute stress testing.
- Study 10: In a preclinical model, Safr'Inside™ improved stress-related behavioral markers while modulating gut microbiome composition, DMA metabolites, and 17 brain proteins associated with stress response.
- Study 11: Four weeks of Safr'Inside™ (20–30 mg/day) improved PSQI scores by 21.3%, reduced sleep onset latency by 35.4%, and reduced wake duration by 43.2% vs. placebo, with correlated gut microbiome changes.
Safr'Inside™ Ingredient Summary & Real-World Relevance
Safr'Inside™ is a clinically studied saffron extract that has been evaluated for its potential role in supporting emotional well-being, healthy stress response, and sleep quality. Research across human and preclinical studies suggests that saffron extract may help support healthy mood balance, emotional well-being, stress resilience, healthy sleep patterns, nervous system balance, and communication along the gut–brain axis.*
These effects appear to involve multiple biological pathways, including neurotransmitter activity (serotonin, dopamine, BDNF), antioxidant protection, nervous system regulation (HRV, HPA-axis timing), and interactions with the microbiome. Safr'Inside™ has been studied at daily doses of approximately 20–30 mg and has demonstrated good tolerability in human clinical trials. By supporting the body's natural regulatory systems rather than acting as a sedative, saffron extract may be incorporated into a daily wellness routine aimed at maintaining emotional balance, stress resilience, and restorative sleep.*
Ingredient Manufacturer Link: https://activinside.com/ingredients/safrinside/
Safr'Inside™ is a clinically studied ingredient used in the following Silver Fern™ Brand product:
*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.