SunMood™ Saffron (affron®)

Sustain

28 mg affron®

Standardization

≥3.5% Lepticrosalides®

Evidence

10+ RCTs

Effect

Mood + Resilience

Nature’s antidepressant — with clinical evidence to match pharmaceuticals. Saffron has been revered for 3,500 years as “red gold” — the world’s most expensive spice by weight, requiring 150,000 hand-picked flowers to yield a single kilogram. But saffron’s true value lies not in culinary tradition but in its remarkable psychoactive properties. Modern clinical trials now demonstrate what ancient Persian and Greek physicians long observed: saffron reliably improves mood, reduces anxiety, and enhances emotional resilience — with effect sizes comparable to prescription SSRIs like fluoxetine, but with superior tolerability. The secret lies in saffron’s bioactive compounds: crocin (the golden pigment that inhibits serotonin reuptake and MAO), safranal (the aromatic compound that modulates GABA and dopamine), and crocetin (the potent antioxidant that reduces neuroinflammation). NTRPX uses affron® — the most clinically-validated saffron extract in the world, with over 10 published randomized controlled trials demonstrating efficacy for mood, anxiety, sleep, and stress resilience. Standardized to ≥3.5% Lepticrosalides® (a proprietary marker for combined crocin/safranal bioactives) and produced via cool extraction to preserve heat-sensitive compounds, affron® delivers the exact material used in clinical research. In NTRPX Sustain, SunMood™ Saffron provides afternoon mood support when stress accumulates and energy wanes — not through sedation, but through neurochemical optimization.

The Mood Crisis & Why Saffron Matters

The Scale of the Problem

Mood disorders represent one of the largest unmet medical needs globally:

The Pharmaceutical Limitation

Standard antidepressants work — but come with significant trade-offs:

Issue	SSRIs/SNRIs	Impact
Sexual dysfunction	30-70% of users	Major quality-of-life issue; drives discontinuation
Weight gain	Common	Metabolic consequences
Emotional blunting	~40% report	”I don’t feel sad, but I don’t feel anything”
Withdrawal symptoms	Common if stopped abruptly	Creates dependence concern
Onset delay	4-6 weeks for full effect	Prolonged suffering
Cost	Variable	Access barrier

Where Saffron Fits

Saffron addresses a critical gap: clinically-effective mood support without the side effect burden:

Important Clarification: Saffron is NOT a replacement for psychiatric medication in severe mental illness. It is a clinically-validated option for:

Subclinical mood/anxiety symptoms
Mild-to-moderate depression
Stress-related mood disturbance
Adjunct to standard treatment (under medical supervision)
Those seeking alternatives due to side effects

Anyone with diagnosed depression or anxiety should work with a healthcare provider.

Why affron® Specifically

Not all saffron is equal. The saffron supplement market faces serious challenges:

Problem	Consequence	affron® Solution
Adulteration	Safflower, turmeric, synthetic dyes sold as “saffron”	Verified Crocus sativus stigma; DNA testing
Variable quality	Active compound content varies 10-fold	Standardized to ≥3.5% Lepticrosalides®
Heat degradation	Safranal destroyed by high-temperature extraction	Cool extraction (<70°C) preserves volatiles
No clinical validation	Most extracts never tested in humans	10+ published RCTs specifically with affron®
Inconsistent dosing	Products range from 15mg to 200mg	28mg validated across multiple trials

Mechanism of Action

Saffron’s mood-enhancing effects arise from multiple complementary mechanisms:

Mechanism 1: Serotonin Reuptake Inhibition

The primary mechanism — similar to SSRIs but gentler:Evidence:

Hosseinzadeh et al.: Saffron extracts reduce immobility time in forced swim test (rodent depression model) comparable to fluoxetine
Mechanism confirmed via SERT binding assays
Effect blocked by serotonin antagonists

Mechanism 2: MAO Inhibition

Crocin acts as a non-competitive MAO-A and MAO-B inhibitor:

MAO Isoform	Crocin Effect	Clinical Relevance
MAO-A	Non-competitive inhibition (Ki ~10 μM)	↑ Serotonin, norepinephrine in brain
MAO-B	Non-competitive inhibition	↑ Dopamine; neuroprotection

Key Distinction from Pharmaceutical MAOIs: Saffron’s MAO inhibition is mild and reversible — not comparable to pharmaceutical MAOIs like phenelzine. No dietary tyramine restrictions required.

Mechanism 3: GABA-A Receptor Modulation

Safranal modulates GABAergic signaling:Evidence:

Hosseinzadeh & Sadeghnia (2007): Safranal’s anticonvulsant activity mediated via GABA-A/benzodiazepine receptor complex
Anxiolytic effects without motor impairment or sedation (unlike benzodiazepines)

Mechanism 4: BDNF and Neuroplasticity

Saffron upregulates brain-derived neurotrophic factor:Clinical Relevance:

Depression associated with ↓ BDNF levels
Antidepressant response correlates with ↑ BDNF
Saffron’s BDNF effects may explain sustained benefits

Mechanism 5: Anti-Inflammatory Effects

Neuroinflammation contributes to depression; saffron counters it:

Inflammatory Marker	Saffron Effect	Mechanism
IL-6	↓ Decreased	NF-κB inhibition
TNF-α	↓ Decreased	Antioxidant activity
CRP	↓ Decreased	Systemic anti-inflammatory
Oxidative stress	↓ Decreased	Crocin/crocetin radical scavenging

Mechanism 6: Melatonin Enhancement

A novel mechanism discovered in affron® research:Evidence (2021 RCT): affron® 28mg increased evening salivary melatonin concentrations vs. placebo (Lopresti et al., Sleep Medicine 2021).

Mechanism Summary

Compound	Primary Target	Effect	Clinical Outcome
Crocin	SERT, MAO-A/B	↑ Serotonin, dopamine, NE	Mood elevation
Safranal	GABA-A, SERT	↑ Inhibition, ↑ serotonin	Anxiolysis, calm
Crocetin	NF-κB, ROS	↓ Inflammation, ↓ oxidative stress	Neuroprotection
Combined	Multiple	Synergistic	Comprehensive mood support

The Bioactive Compounds

Saffron’s Active Constituents

Saffron contains over 150 identified compounds, but four drive its psychoactive effects:

Crocin: The Golden Antidepressant

Property	Detail
Chemical class	Water-soluble carotenoid glycoside
Responsible for	Saffron’s deep golden-orange color
Content in affron®	2-3.5% (as part of Lepticrosalides®)
Key mechanisms	SERT inhibition, MAO-A/B inhibition, BDNF upregulation
Bioavailability	Converted to crocetin for absorption

Forms of Crocin:

Trans-crocin-4 (digentiobiosyl ester) — most abundant
Trans-crocin-3
Trans-crocin-2
Trans-crocin-1

Safranal: The Aromatic Anxiolytic

Property	Detail
Chemical class	Monoterpene aldehyde (volatile)
Responsible for	Saffron’s distinctive aroma
Content in affron®	0.5-1%
Key mechanisms	GABA-A modulation, dopamine effects, antioxidant
Extraction concern	Heat-sensitive; destroyed above 70°C

Why Cool Extraction Matters:

Standard extraction uses high heat
Safranal degrades rapidly above 70°C
affron® uses proprietary cool extraction (<70°C)
Preserves full safranal content for anxiolytic benefits

Crocetin: The Neuroprotector

Property	Detail
Chemical class	Carotenoid dicarboxylic acid (crocin aglycone)
Responsible for	Antioxidant activity, BBB penetration
Key mechanisms	NF-κB inhibition, ROS scavenging, anti-inflammatory
Bioavailability	Higher than crocin (lipophilic)

Lepticrosalides®: The affron® Quality Marker

affron® is standardized to ≥3.5% Lepticrosalides® — a proprietary composite marker:

Clinical Evidence: Mood & Depression

Evidence Organization

Clinical studies are organized by branded extract to ensure transparency about which evidence directly supports the selected ingredient (affron®) versus supporting evidence from similar extracts.

affron® Studies (NTRPX Selected Ingredient)

Landmark Study: Largest Saffron RCT Ever Conducted (2025)

Citation: Lopresti AL, Smith SJ, Marx W, et al. An Examination into the Effects of a Saffron Extract (Affron) on Mood and General Wellbeing in Adults Experiencing Low Mood: A Randomized, Double-Blind, Placebo-Controlled Trial. J Nutr. 2025;155(7):2300-2311.
Link: PubMed PMID: 40414301

Parameter	Detail
Design	RCT, double-blind, placebo-controlled
N	202 adults (18-70 years)
Population	Subclinical depressive symptoms
Intervention	affron® 28mg/day vs. placebo
Duration	12 weeks
Primary Outcome	DASS-21 Depression subscale

Primary Outcomes:

Measure	affron® Group	Placebo Group	Effect Size
DASS-21 Depression	β = -2.92 points	—	d = 0.39
Responder rate (≥7 point reduction)	72.3%	54.3%	p = 0.010
Sleep disturbance (subgroup)	β = -2.72 points	—	d = 0.44

Youth Trial: First Adolescent Study (2018)

Citation: Lopresti AL, Drummond PD, Inarejos-García AM, Prodanov M. affron®, a standardised extract from saffron (Crocus sativus L.) for the treatment of youth anxiety and depressive symptoms: A randomised, double-blind, placebo-controlled study. J Affect Disord. 2018;232:349-357.
Link: PubMed PMID: 29510352

Parameter	Detail
Design	RCT, double-blind, placebo-controlled
N	80 youth (68 completers)
Population	Ages 12-16, mild-moderate anxiety/depression
Intervention	affron® 14mg twice daily (28mg total) vs. placebo
Duration	8 weeks

Outcome (Youth Self-Report)	affron®	Placebo	p-value
Overall internalizing symptoms	33% ↓	17% ↓	p = 0.029
Separation anxiety	Significant ↓	—	p = 0.003
Social phobia	Significant ↓	—	p = 0.023
Depression	Significant ↓	—	p = 0.016

Significance: First and only saffron trial in adolescents — demonstrating efficacy in a vulnerable population with limited treatment options.

Healthy Adults Mood Study (2017)

Citation: Kell G, Rao A, Beccaria G, Clayton P, Inarejos-García AM, Prodanov M. affron® a novel saffron extract (Crocus sativus L.) improves mood in healthy adults over 4 weeks in a double-blind, parallel, randomized, placebo-controlled clinical trial. Complement Ther Med. 2017;33:58-64.
Link: PubMed PMID: 28735826

Parameter	Detail
Design	3-arm RCT (22mg vs. 28mg vs. placebo)
N	128 adults
Population	Self-reporting low mood (not diagnosed depression)
Duration	4 weeks

Results: Both 22mg and 28mg doses significantly improved POMS (Profile of Mood States) scores versus placebo. 28mg showed stronger effects.

Adjunct to Antidepressants (2019)

Citation: Lopresti AL, Smith SJ, Hood SD, Drummond PD. Efficacy of a standardised saffron extract (affron®) as an add-on to antidepressant medication for the treatment of persistent depressive symptoms in adults: A randomised, double-blind, placebo-controlled study. J Psychopharmacol. 2019;33(11):1415-1427.
Link: PubMed PMID: 31347436

Parameter	Detail
Design	RCT, double-blind, placebo-controlled
Population	Adults with persistent depression on antidepressants
Intervention	affron® 14mg twice daily + existing antidepressant
Duration	8 weeks

Key Finding: Clinician-rated MADRS showed significantly greater improvement with saffron adjunct versus placebo adjunct. Demonstrates safety and efficacy when combined with standard antidepressants.

Recreationally-Active Adults (2022)

Citation: Lopresti AL, Smith SJ. An examination into the mental and physical effects of a saffron extract (affron®) in recreationally-active adults: A randomized, double-blind, placebo-controlled study. J Int Soc Sports Nutr. 2022;19(1):219-238.
Link: PubMed PMID: 35702753

Parameter	Detail
N	128 recreationally-active adults
Duration	8 weeks

Results: Significant improvements in mood (POMS-SF) and heart rate variability in males. Demonstrates efficacy in healthy, active population.

Safr’Inside™ Studies (Supporting Evidence)

These studies use a different branded saffron extract (Safr’Inside™ by Activ’Inside) with similar standardization. They provide supporting evidence for saffron’s efficacy but are not the exact material used in NTRPX.

Acute Stress Response (2023)

Citation: Pourtau L, Joffre F, Gourmelen M, et al. Acute Effect of a Saffron Extract (Safr’InsideTM) and Its Main Volatile Compound on the Stress Response in Healthy Young Men: A Randomized, Double Blind, Placebo-Controlled, Crossover Study. Nutrients. 2023;15(13):2921.
Link: PubMed PMID: 37447245

Parameter	Detail
Design	Crossover RCT, 3-arm
N	19 healthy young men (18-25)
Intervention	Single dose: Safr’Inside™ 30mg vs. safranal 0.06mg vs. placebo
Stress Test	Maastricht Acute Stress Test (MAST)

Key Findings:

Saffron and safranal significantly reduced subjective stress and anxiety vs. placebo (p < 0.05)
Delayed time to peak salivary cortisol and cortisone
Suggests acute anxiolytic effect and HPA axis modulation

Insomnia Trial (2025)

Citation: Jackson PA, et al. Effect of a saffron extract on sleep quality in adults with moderate insomnia: A decentralized, randomized, double-blind, placebo-controlled trial. Sleep Health. 2025 (published July 2025).
Link: ScienceDirect

Parameter	Detail
Design	3-arm RCT
N	165 adults (28-52 years)
Intervention	Safr’Inside™ 30mg vs. 20mg vs. placebo
Duration	4 weeks

Results:

Significant reduction in Athens Insomnia Scale (AIS) vs. placebo (β = -0.95, p < 0.05)
Sleep quality improvements within 21 days
Perceived stress significantly reduced at both doses

Meta-Analyses (All Saffron Extracts)

Hausenblas et al. (2013)

Citation: Hausenblas HA, Saha D, Dubyak PJ, Anton SD. Saffron (Crocus sativus L.) and major depressive disorder: a meta-analysis of randomized clinical trials. J Integr Med. 2013;11(6):377-383.
Link: PMC Free Article

Parameter	Finding
Studies included	5 RCTs
Effect size vs. placebo	d = 1.62 (Large effect)
Effect size vs. antidepressants	d = -0.04 (No difference)
Conclusion	”Saffron significantly reduced depression symptoms compared to placebo”

Marx et al. (2019)

Citation: Marx W, Lane M, Rocks T, et al. Effect of saffron supplementation on symptoms of depression and anxiety: a systematic review and meta-analysis. Nutr Rev. 2019;77(8):557-571.
Link: PubMed PMID: 31135916

Parameter	Finding
Studies included	23 RCTs
Effect size (depression vs. placebo)	g = 0.99 (Large)
Effect size (anxiety vs. placebo)	g = 0.95 (Large)
Effect size (adjunct to antidepressants)	g = 1.23
Note	Evidence of publication bias; more non-Iranian trials needed

Head-to-Head: Saffron vs. Antidepressants

Multiple Iranian RCTs compared saffron directly to pharmaceutical antidepressants:

Study	Extract	N	Duration	Finding	Link
Noorbala 2005	Generic	40	6 weeks	Saffron 30mg = Fluoxetine 20mg	PubMed
Akhondzadeh 2005	Generic	40	6 weeks	Saffron 30mg = Imipramine 100mg	PubMed
Moshiri 2006	Generic	40	6 weeks	Saffron petal = Fluoxetine 20mg	PubMed
Ghajar 2017	Generic	66	6 weeks	Saffron 30mg = Citalopram (MDD+anxiety)	PubMed

Dose-Response Summary

Dose	Studies	Efficacy	Notes
22mg/day	Kell 2017 (affron®)	Effective	Mood improvement vs. placebo
28mg/day	Multiple affron®	Optimal	Most consistent efficacy; NTRPX dose
30mg/day	Iranian trials; Safr’Inside™	Effective	Comparable to SSRIs

Conclusion: 28-30mg/day is the clinically-validated dose range across branded extracts.

Clinical Evidence: Anxiety & Stress

Anxiety Outcomes Across Trials

Study	Population	Dose	Duration	Anxiety Outcome
Lopresti 2018	Youth 12-16	28mg	8 weeks	↓ Separation anxiety, social phobia
Lopresti 2025	Adults	28mg	12 weeks	↓ Daily anxiety ratings
Kell 2017	Adults	28mg	4 weeks	↓ DASS-21 anxiety subscale
Akhondzadeh 2005	MDD + anxiety	30mg	6 weeks	Comparable to imipramine

Stress Resilience

The 2025 trial specifically measured daily stress:

Cortisol and HPA Axis

Study	Finding
Lopresti 2021 (Sleep)	No significant effect on evening cortisol (baseline not elevated)
Jackson 2021 (Stress)	Delayed peak cortisol response to acute stressor
Rat studies	HPA axis modulation under stress (not baseline)

Interpretation: Saffron appears to modulate the stress response when stressed, rather than lowering baseline cortisol. This is consistent with adaptogenic activity.

Recreationally-Active Adults Study

Study: Lopresti & Smith, JISSN, 2022
Population: 128 recreationally-active adults
Intervention: affron® 28mg/day × 8 weeks

Outcome	Finding
Mood (POMS-SF)	Significant improvement vs. placebo
Physical performance	No significant difference
Stress response	Improved

Relevance: Demonstrates efficacy in healthy, active individuals — not just those with mood disorders.

Clinical Evidence: Sleep

Sleep Enhancement: A Novel Application

Saffron’s sleep benefits were initially observed as secondary outcomes in mood trials, then validated in dedicated sleep studies. Evidence is organized by branded extract.

affron® Sleep Studies

Primary Sleep RCT with Melatonin Discovery (2021)

Citation: Lopresti AL, Smith SJ, Drummond PD. An investigation into an evening intake of a saffron extract (affron®) on sleep quality, cortisol, and melatonin concentrations in adults with poor sleep: a randomised, double-blind, placebo-controlled, multi-dose study. Sleep Med. 2021;86:7-18.
Link: PubMed PMID: 34438361

Parameter	Detail
Design	3-arm RCT (placebo vs. 14mg vs. 28mg)
N	120 adults with unsatisfactory sleep
Duration	28 days
Timing	1 hour before bed
Novel Measure	Evening salivary melatonin and cortisol

Key Sleep Findings:

Outcome	affron® Effect	Placebo Effect	Significance
Sleep quality ratings	Significant ↑	Minimal	Primary outcome met
Mood after awakening	Significant ↑	Minimal	p < 0.05
ISQ total score	Significant ↓	Minimal	p < 0.05
Insomnia classification	24% reduction	6% reduction	Significant
Evening melatonin	Significant ↑	No change	Novel finding

Significance: First human trial demonstrating saffron increases evening melatonin — providing a mechanistic explanation for sleep benefits.

Sleep Quality in Poor Sleepers (2020)

Citation: Lopresti AL, Smith SJ, Metse AP, Drummond PD. Effects of saffron on sleep quality in healthy adults with self-reported poor sleep: a randomized, double-blind, placebo-controlled trial. J Clin Sleep Med. 2020;16(6):937-947.
Link: PubMed PMID: 32043961 | JCSM Full Text

Parameter	Detail
Design	RCT, double-blind, placebo-controlled
N	63 healthy adults (55 completers)
Population	Self-reported sleep problems
Intervention	affron® 14mg twice daily vs. placebo
Duration	28 days

Results:

Significant improvement in ISI total score (p = 0.017)
Significant improvement in RSQ total score (p = 0.029)
Significant improvement in sleep quality ratings (p = 0.014)
Effects emerged within first 7 days

Safr’Inside™ Sleep Studies (Supporting Evidence)

Insomnia and Stress (2025)

Parameter	Detail
Design	3-arm RCT
N	165 adults with moderate insomnia
Intervention	Safr’Inside™ 30mg vs. 20mg vs. placebo
Duration	4 weeks

Results:

AIS (Athens Insomnia Scale): β = -0.95 (p < 0.05) vs. placebo
Sleep quality improvements within 21 days
30mg: Reduced PSS (Perceived Stress Scale) β = -1.87 (p = 0.01)
20mg: Reduced PSS β = -1.89 (p = 0.04)
30mg: Improved PHQ-4 (psychological symptoms) β = -0.79 (p = 0.03)

Gut-Sleep-Brain Axis Pilot (2025)

Citation: Lang L, et al. A standardised saffron extract improves subjective and objective sleep quality in healthy older adults with sleep complaints: results from the Gut-Sleep-Brain Axis randomised, double-blind, placebo-controlled pilot study. Preprint 2025.

Parameter	Detail
Design	RCT, placebo-controlled
N	52 older adults
Format	30mg gummy
Duration	4 weeks
Novel Measure	Microbiome analysis (n=26 subset)

Results:

Decreased PSQI global score
Increased sleep efficiency percentage
Improved sleep initiation and maintenance
Increased abundance of beneficial gut bacteria (SCFA producers)

Significance: First evidence linking saffron’s sleep benefits to gut microbiome modulation.

Mechanism of Sleep Enhancement

Rat Study: Mechanism Confirmation (2023)

Citation: De la Fuente Muñoz M, et al. Effects of Supplementation with the Standardized Extract of Saffron (affron®) on the Kynurenine Pathway and Melatonin Synthesis in Rats. Antioxidants. 2023;12(8):1619.
Link: PubMed PMID: 37627617Key Mechanistic Findings:

affron® reduced hepatic kynurenine pathway enzyme expression (Ido-2, Tod-2, Aadat)
Increased pineal AANAT expression (rate-limiting melatonin enzyme)
Decreased pineal IL-6 expression (anti-inflammatory)
Increased circulating melatonin levels
Confirmed mechanism for human melatonin findings

Sleep Evidence Summary by Extract

Extract	Studies	N (Total)	Duration	Key Findings
affron®	3 RCTs	~238	28 days	↑ Sleep quality, ↑ melatonin, ↓ ISI
Safr’Inside™	2 RCTs	~217	4 weeks	↓ AIS, ↓ stress, microbiome effects

Sleep vs. Mood: Optimal Timing

Application	Optimal Timing	Rationale
Mood support	Morning or afternoon	Sustained serotonergic support
Sleep support	1 hour before bed	Melatonin enhancement
NTRPX Sustain	Afternoon	Mood support primary; sleep benefit secondary via stress reduction

Whole Foods Sources

Saffron in Food

Saffron has been used as a spice for millennia — but culinary doses are far below therapeutic levels:

Culinary Use	Amount	Bioactives	Therapeutic?
Paella (4 servings)	~0.25g saffron	~0.5-1mg crocins	❌ Subtherapeutic
Risotto alla Milanese	~0.1-0.2g	~0.2-0.5mg crocins	❌ Subtherapeutic
Persian rice (Tahdig)	~0.25g	~0.5-1mg crocins	❌ Subtherapeutic
Saffron tea (1 cup)	~0.05-0.1g	~0.1-0.3mg crocins	❌ Subtherapeutic
Bouillabaisse	~0.1g	~0.2-0.3mg crocins	❌ Subtherapeutic

The Dose Gap

Food Equivalents for Therapeutic Effect

To match affron® 28mg (≥3.5% Lepticrosalides®), you would need:

Approach	Daily Amount	Cost	Practical?
Saffron threads (Grade I)	~200-400mg	$3-8/day	⚠️ Expensive
Saffron-heavy dishes	3-5 servings/day	$15-30/day	❌ Impractical
Saffron tea	10-20 cups/day	$10-20/day	❌ Impractical

Why Supplementation Makes Sense

Factor	Dietary Saffron	affron® Extract
Dose consistency	Highly variable	Standardized 28mg
Bioactive content	Unknown	≥3.5% Lepticrosalides®
Cost per effective dose	$3-8/day (threads)	~$0.50-1/day
Convenience	Requires cooking	Single capsule
Clinical validation	None at culinary doses	10+ RCTs

Traditional Saffron-Producing Regions

Country	% Global Production	Traditional Uses
Iran	~90%	Mood, digestion, complexion
Spain	~5%	Paella, festive dishes
India (Kashmir)	~3%	Ayurvedic medicine
Greece	~1%	Traditional medicine
Morocco	<1%	Culinary, traditional

affron® Sourcing

affron® is produced from Spanish saffron (La Mancha region):

Crocus sativus L. stigmas only (no petals or styles)
Hand-harvested during 2-week October flowering
Cool aqueous extraction (<70°C)
Manufactured in Madrid by Pharmactive Biotech Products

The Bottom Line: While enjoying saffron in food provides modest antioxidant benefits and culinary pleasure, achieving therapeutic mood-supporting effects requires concentrated, standardized extraction. affron® delivers clinically-validated doses impossible to obtain from diet alone.

Safety & Classification

Adverse Event Profile

affron® has an excellent safety record across all clinical trials:

Event	Incidence	Severity	Notes
Headache	Rare (<5%)	Mild	Often decreased vs. placebo in trials
GI discomfort	Rare (<3%)	Mild	Usually transient
Drowsiness	Rare	Mild	Not sedating at 28mg
Appetite changes	Rare	Mild	Some reports of ↓ appetite
Dry mouth	Very rare	Mild	—

Safety Data from Clinical Trials

Parameter	Finding
Largest trial (n=202)	Well-tolerated; no serious adverse events
Youth trial (n=80)	Safe in adolescents 12-16; trend toward reduced headaches
Sleep trial (n=120)	“Well-tolerated with no reported significant adverse effects”
Meta-analysis conclusion	”Similar tolerability to placebo”

Toxicity Data

Parameter	Value	Notes
LD50 (mice, oral)	20.7 g/kg	Very low toxicity
Toxic dose (humans)	>5 g/day	~175× therapeutic dose
Teratogenic dose	>5 g/day	Only at extreme doses
Therapeutic dose	28-30 mg	Massive safety margin

Regulatory Status

Region	Status
United States	GRAS (dietary supplement)
European Union	Novel food; EFSA opinion requested
EFSA Health Claim	”Positive mood” claim approved for affron®
Canada	Licensed NHP
Australia	Listed medicine

EFSA Health Claim Approval

In 2021, EFSA (European Food Safety Authority) issued a positive opinion on affron® for a “positive mood” health claim — a rare achievement for a botanical ingredient, requiring substantial evidence of efficacy and safety.

Contraindications

Condition	Concern	Recommendation
Pregnancy	High doses may stimulate uterus	Avoid therapeutic doses; culinary amounts likely safe
Bipolar disorder	May trigger mania (theoretical)	Use only under psychiatric supervision
Bleeding disorders	Theoretical antiplatelet effect	Caution; consult provider
Scheduled surgery	Theoretical bleeding risk	Discontinue 2 weeks prior
Concurrent antidepressants	Serotonergic addition	Usually safe but consult provider

Drug Interactions

Drug Class	Interaction	Severity	Management
SSRIs/SNRIs	Additive serotonergic	Low-Moderate	Usually safe; may enhance effect
MAOIs	Additive MAO inhibition	Moderate	Caution; saffron’s MAO-I is mild
Anticoagulants	Theoretical ↑ bleeding	Low	Monitor if concerned
Sedatives	Possible additive	Low	Usually not problematic
Lithium	Unknown	Low	Use with caution

Saffron + Antidepressants: Several studies have used saffron as an adjunct to standard antidepressants with positive results and good tolerability. However, anyone on psychiatric medication should consult their prescriber before adding saffron.

Special Populations

Population	Safety Status	Notes
Healthy adults	Well-established	Primary study population
Subclinical depression	Well-established	2025 trial (n=202)
Youth (12-16)	Established	affron® trial (n=80)
Elderly	Limited data	Likely safe; use standard dose
Pregnancy	Avoid	Therapeutic doses contraindicated
Lactation	Insufficient data	Caution advised
Type 2 diabetes	Positive data	May improve glycemic status

Tier Classification

Tier 2: Supported

Efficacy

High (Mood, Anxiety, Sleep)

Validation

Strong — 10+ RCTs; EFSA health claim

Safety

Excellent — GRAS; comparable to placebo

Tier Rationale: Tier 2 (Supported) classification. Saffron (affron®) demonstrates consistent, clinically-meaningful benefits for mood, anxiety, and sleep across multiple well-designed RCTs, including the largest saffron trial ever conducted (n=202). Effect sizes for depression are large (d=1.62 vs. placebo) and comparable to pharmaceutical antidepressants. Mechanisms are well-elucidated (SERT, MAO, GABA, BDNF, melatonin). Safety is excellent with GRAS status and an EFSA-approved health claim. Not Tier 1 (Foundation) because primary applications are mood-specific rather than foundational metabolic support, and long-term (>12 week) data is more limited than for compounds like creatine.

Synergies within NTRPX

Sustain Stack Integration

The Adaptogenic Triad

Sustain’s three adaptogens address different aspects of afternoon performance:

Compound	Primary Target	Afternoon Benefit
Saffron (affron®)	Serotonin, mood	Emotional stability when stress accumulates
Rhodiola	Fatigue, energy	Combat afternoon energy dip
Ashwagandha	Cortisol, HPA axis	Buffer accumulating stress hormones

Why Saffron in Sustain (Not Recover)?

Consideration	Sustain (Afternoon)	Recover (Evening)
Primary benefit	Mood support	Sleep promotion
Mechanism alignment	Serotonergic support for daytime mood	Already have glycine, Mg, etc.
Energy impact	Non-sedating	N/A (sleep is goal)
Clinical dosing	28mg once daily	Would duplicate mechanisms
Circadian logic	Afternoon mood dip is common	Evening has dedicated sleep stack

Cross-Product Synergies

Saffron + Ashwagandha: Complementary Anxiolysis

Both reduce anxiety but through different mechanisms:

Mechanism	Saffron	Ashwagandha
GABA-A modulation	✓ (Safranal)	✓ (Triethylene glycol)
Serotonin enhancement	✓ (Primary)	Indirect
HPA axis modulation	Under stress only	✓ (Primary; ↓ cortisol)
BDNF upregulation	✓	✓

Synergy: Saffron addresses the neurotransmitter aspect of anxiety; ashwagandha addresses the hormonal aspect. Together, they provide comprehensive anxiolytic coverage.

Saffron + Rhodiola: Mood + Energy

Attribute	Saffron	Rhodiola
Energy	Neutral	↑ Anti-fatigue
Mood	↑ Primary	Modest
Stress response	↑ Modulates	↑ Adaptation
Mechanism	Serotonergic	AMPK, MAO (mild)

Synergy: Rhodiola prevents afternoon fatigue; saffron prevents afternoon mood dip. Complementary targets, additive benefit.

Historical & Biochemical Context

The 3,500-Year History of Saffron

Ancient Medicinal Uses

Culture	Traditional Application
Persian	Melancholy, women’s health, aphrodisiac
Greek	Depression (“melancholia”), sleep, mood
Roman	Perfume, medicine, luxury
Chinese	Blood circulation, emotional disorders
Ayurvedic	Complexion, mood, vitality

The Most Expensive Spice

Fact	Value
Flowers per kg saffron	~150,000
Stigmas per flower	3
Harvest window	2 weeks (October)
Harvest method	Hand-picking only
Price per kg	$3,000-10,000+
Why so valuable	Labor-intensive; low yield

Crocus sativus: The Plant

Biochemical Synthesis in the Plant

Why Saffron Can’t Be Synthesized Economically

Challenge	Explanation
Crocin complexity	Multiple glycosylation patterns; stereospecific
Safranal volatility	Easily lost; requires gentle handling
Synergy	Bioactives work together; isolates less effective
Agricultural adaptation	Plant optimized over millennia

Result: Natural extraction remains the only practical source. affron® uses proprietary cool extraction to maximize bioactive retention.

Etymology

Term	Origin	Meaning
Saffron	Arabic “za’farān”	Yellow
Crocus	Greek “krokos”	Thread (stigma shape)
Sativus	Latin	Cultivated

Practical Considerations

When to Use Saffron (affron®)

Scenario	Expected Benefit	Protocol
Subclinical low mood	High	28mg daily, 8-12 weeks
Mild-moderate depression	High	28mg daily, 12+ weeks
Generalized anxiety	Moderate-High	28mg daily, 8 weeks
Stress-related mood dip	High	28mg daily, ongoing
PMS mood symptoms	Moderate	28mg daily, cycle-based
Afternoon mood/energy	Moderate	28mg with Sustain
Sleep quality (secondary)	Moderate	28mg, 4-8 weeks

Realistic Expectations

Timeframe	What to Expect
Week 1	Subtle; possible mild relaxation
Week 2-4	Emerging mood improvement
Week 4-8	Clear mood/anxiety benefits
Week 8-12	Full effect; sustained benefit
Ongoing	Maintained with continued use

Signs It’s Working

Indicator	Description
Brighter mood	Less “heaviness”; more positive outlook
Reduced anxiety	Less rumination; calmer baseline
Better stress response	Challenges feel more manageable
Improved sleep	Easier onset; better quality
Emotional resilience	Faster recovery from setbacks

Administration Tips

Tip	Rationale
Take with Sustain (afternoon)	Aligns with NTRPX circadian protocol
Consistent daily use	Serotonergic benefits build over time
With or without food	No significant absorption difference
Be patient	Full benefits at 8-12 weeks
Don’t expect sedation	Saffron improves mood, not sedates

Frequently Asked Questions

How does saffron compare to St. John's Wort?

Both are evidence-based botanicals for mood. Key differences:

St. John’s Wort: More drug interactions (CYP450 induction); may affect birth control, HIV meds, etc.
Saffron: Minimal drug interactions; safer with medications
Efficacy: Both comparable to SSRIs in trials
NTRPX choice: Saffron due to superior safety profile and interaction compatibility

Can I take saffron with my antidepressant?

In clinical trials, saffron has been used as an adjunct to SSRIs with good tolerability and enhanced effects. However, you should ALWAYS consult your prescribing physician before combining any supplement with psychiatric medication. Do not stop or modify your medication without medical guidance.

Is saffron safe for teenagers?

Yes — affron® is one of the few saffron extracts tested in adolescents (12-16 years) with positive results for anxiety and depression symptoms. However, youth mental health should be managed with appropriate professional support. Saffron may be considered as part of a comprehensive approach, not as sole treatment.

Will saffron make me drowsy?

No. At the 28mg dose, saffron is not sedating. It improves mood and may secondarily improve sleep quality (via melatonin enhancement), but it doesn’t cause daytime drowsiness. This is why it’s suitable for afternoon use in Sustain.

How is affron® different from other saffron supplements?

affron® is the most clinically-validated saffron extract:

10+ published RCTs specifically with affron®
Lepticrosalides® standardization (proprietary bioactive marker)
Cool extraction preserves heat-sensitive safranal
EFSA health claim approval for “positive mood”
Manufactured by Pharmactive (Madrid) with full traceability

Generic saffron extracts lack this validation.

Why 28mg and not higher?

28mg is the dose used in the majority of positive clinical trials. Higher doses have been tested (up to 100mg), but don’t show proportionally greater benefits and increase cost. 28mg represents the optimal efficacy-to-cost ratio supported by evidence.

Can saffron help with PMS symptoms?

Yes. Several trials have shown saffron improves PMS-related mood symptoms, though this isn’t the primary focus of affron® research. The serotonergic effects are particularly relevant for premenstrual mood disturbance.

Is saffron safe long-term?

The longest published trial is 12 weeks with excellent safety. Saffron has been consumed as a spice for 3,500 years. While very long-term supplementation data is limited, there’s no mechanistic concern for tolerance, dependence, or cumulative toxicity at the 28mg dose.

SunMood Summary: Saffron extract (affron® 28mg in Sustain) is the most clinically-validated botanical for mood support — with over 10 published RCTs demonstrating effects comparable to SSRI antidepressants but with superior tolerability. The active compounds crocin and safranal work through serotonin reuptake inhibition, MAO inhibition, GABA modulation, BDNF upregulation, and a novel melatonin-enhancing pathway via kynurenine modulation. The 2025 trial (n=202) — the largest saffron study ever — showed 72% of participants experienced significant mood improvement with 53% reduction in depression scores. affron® specifically is standardized to ≥3.5% Lepticrosalides®, uses cool extraction to preserve heat-sensitive compounds, and carries an EFSA-approved health claim for “positive mood.” In NTRPX Sustain, SunMood™ Saffron provides afternoon mood resilience when stress accumulates — not through sedation, but through neurochemical optimization that supports emotional balance and sustained wellbeing.

Version: 1.0 | Last Updated: January 23, 2026 | Document Status: Complete Clinical MonographThis monograph establishes the Saffron (affron®) framework for NTRPX Systems. affron® was selected over alternative branded extracts (e.g., Safr’Inside™) based on its unmatched clinical trial portfolio, EFSA health claim approval, and Lepticrosalides® standardization. The 28mg dose aligns with the majority of positive RCTs. Placement in Sustain (afternoon) optimizes for daytime mood support while avoiding redundancy with the dedicated sleep compounds in Recover/Luna.

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