Shoden® (Ashwagandha, Withania somnifera)

“The World’s Most Bioactive Ashwagandha”

Overview

• Shoden® is a new Ashwagandha option that stands out from the rest it contains an industry leading 35% withanolide glycosides - including 21 diverse withanolide glycosides
• The withanolides are harvested from the root and leaves through a two-step extraction process using ethanol-water and no excipients/carriers
• Demonstrates superior bioavailability when compared with other commercial ashwagandha extracts, even when normalizing for withanolide content. Therefore, offering health benefits at a lower efficacious dose.
• Shoden® has been clinically studied for the following health benefits: Stress, Anxiety, restorative sleep, immune health, testosterone, vitality, exercise, endurance and more.
• Country of origin: India
• Shoden® is nonGMO, gluten free, and free of allergens
• Proposed shelf life of 2 years (Stability data available)

REASON FOR USE IN FORMULA

Cognitive function: Although there has been interest in using oral ashwagandha for cognitive function, there is insufficient reliable information about the clinical effects of ashwagandha for this condition. Ashwagandha works by bringing the body to homeostasis. Stress, anxiety, and sleep are important aspects for maintaining healthy brain function. Ashwagandha helps to manage occasional stress, anxiety, and sleep disturbances that may support general cognitive improvement overtime. Cognitive function has mostly been evaluated as a secondary outcome and/or part of subjective questionnaires in human published ashwagandha studies. Preclinical evidence shows that ashwagandha may exhibit molecular effects, such as neurogenic properties that protect cognitive function

Composition:

Ashwagandha root and leaf extract (Withania somnifera) (standardized to 35% Withanolide Glycosides) (Shoden spec)

What is special about Shoden®? It is considered to be the most potent ashwagandha extract on the market (std. to 35% withanolide glycosides). It also contains the highest amount of specific withanolide glycosides with a total of 21. Shoden® showed significantly greater bioavailability and retention for 24+ hours in the circulating blood. Shoden’s® ability to stay over 24 hours circulating in the blood appears to be driven by the diversity of the higher amount of specific withanolides, allowing for a lower efficacious dose.

(Shoden® Ashwagandha - Bioavailability).

Natural Medicines Database Safety, Effectiveness & Interaction Analysis

POSSIBLY SAFE ...when used orally and appropriately, short-term. Ashwagandha has been used with apparent safety in doses of up to 1250 mg daily for up to 6 months

PREGNANCY: LIKELY UNSAFE ...when used orally. Ashwagandha has abortifacient effects

LACTATION: Insufficient reliable information available; avoid using.

General: Orally, ashwagandha seems to be well-tolerated. Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

Most Common Adverse Effects:

Orally: Diarrhea, gastrointestinal upset, nausea, and vomiting. However, these adverse effects do not commonly occur with typical doses.

Drug Interactions…Ashwagandha has moderate drug interactions with the following classes: antidiabetic, antihypertensive, benzos, CNS depressants, immunosuppressants, thyroid hormone. These are theoretical interactions as ashwagandha has been shown in preclinical research to have similar effects

Herbs & Supplements with hypotensive and sedative properties… These are theoretical interactions as ashwagandha has been shown in preclinical research to have similar effects

Research summary:

Bioavailability study

• Unpublished Shoden® Ashwagandha – Bioavailability Study

Preclinical data (MOA): Generic studies were used to support mechanism of action (MOA), with the exception of Murthy et al, 2022.

• Sleep: Murthy et al, 2022. (in vitro – In vivo experimental models using Shoden®) Ashwagandha’s calming properties work by interacting with the brain's GABA receptors which control your circadian rhythm and regulate your sleep-wake cycle.
• Additional references
• Candelario et al, 2015.
• Cognitive: Gupta, 2019. (In vivo and in vitro animal model) Ashwagandha may have neuroprotective properties by supporting neuronal activity.
• Stress and neuroprotection: Bhatnagar, 2009. (Animal model) Animal research suggests after exposure to stress, ashwagandha may be neuroprotective by bringing bodily functions into balance.

Human Studies to support general cognitive health (Shoden® published research)

• Sleep: Deshpande et al, 2020. A randomized, double blind, placebo-controlled study in healthy subjects for 6 weeks.
• Stress & anxiety:
• Confidential. Unpublished (paper is in peer review status). Shoden Manuscript. Shoden® promotes relief from stress and anxiety: A randomized, double-blind, placebo-controlled Study in Healthy Subjects with High Stress Levels
• Additional references:
• Lopresti et al, 2019. A randomized, double-blind, placebo-controlled study in healthy subjects for 60 days (240 mg/d dose)
• Shoden® Dosing for Anxiety – Scientific Rationale
• Sleep Study, Deshpande et al, 2020.
• Testosterone & vitality in men: Lopresti et al, 2019.

Totality of the evidence: this search criteria was PubMed, targeted search criteria for all data (note, this type of search does not bring up every branded ingredient study as most are not open access)

• Ashwagandha = 1,623 results with no filters or specified search criteria
• Ashwagandha supplementation = 63 results with no filters
• Ashwagandha = 35 results with randomized controlled trial as the filter
• Ashwagandha supplementation = 8 results with randomized controlled trial as the filter

Bioavailability study

Unpublished Shoden® Ashwagandha – Bioavailability Study

Purpose: To compare the bioavailability of various Ashwagandha materials

Population: n= 14 healthy subjects

Treatment: At least 14 healthy individual subjects were given a single dose of the test ashwagandha extract, following overnight fasting.

Design: Four different ashwagandha extracts were evaluated with a 7-day washout period between each test in a randomized, mono-centric, double-blind, placebo-controlled, clinical study

Composition: Since each extract contained different amounts of total withanolides, the extracts were all normalized to contain 185 mg total withanolides, based on the commercial product specifications. In this way the bioequivalence between the extracts could be evaluated.

• Product A -Shoden®, 185 mg total withanolides (35%), total product weight = 480 mg
• Product B – Brand S, 185 mg total withanolides (10%), total product weight = 1,850 mg
• Product C – Brand K, 185 mg total withanolides (5%), total product weight = 3,700 mg
• Product D – Generic, 185 mg total withanolides (2.5%), total product weight = 7,400 mg

Design: A randomized, placebo controlled, double blind, cross-over, single dose bioavailability and bioequivalence clinical study

Measurements: withanolide content in the blood

Strengths: researchers normalized for withanolide content (185 mg)

Results: Products B, C, and D showed similar with respect to bioavailability and would be considered bioequivalent based on the normalization of their total withanolide content. Product A, Shoden®, showed significantly greater bioavailability and retention for 24+ hours in the circulating blood.

Potential language: Shoden®, shown in an unpublished pharmacokinetic bioavailability and bioequivalence study, remains circulating in the blood for over 24 hours while the comparison materials disappeared after 6-9 hours. This makes Shoden® perfect for a lower, once per day, efficacious dose.

Limitations: small sample size, unpublished, lack of details related to the subjects, study location, methods. Future comparison studies with larger sample sizes are warranted.

Disclosures:

• Unpublished study
• Mfg. supplied study

Note: The branded Ashwagandha’s in the study are confidential (for context, Brand S is Sensoril®, Brand K is KSM-66®). If claims are made related to this study, refer to the brands as S & K or discuss the generic ashwagandha data (Product D, 2.5% withanolides).

This data was used to help justify Shoden’s® use in the finished formula. This study has not been published. Future comparison studies with larger sample sizes are warranted.

Preclinical (mechanistic) research

Murthy et al, 2022. Hydroalcoholic extract of ashwagandha improves sleep by modulating GABA/Histamine receptors and EEG Slow-Wave pattern in vitro – in vivo experimental models

Purpose: To investigate the effect of ashwagandha extract (AE) on GABA expression and histamine receptors in treated rat cells when compared to controlled cells, in a dose dependent manner. In vivo rat model was used to further investigate the in vitro efficacy.

Design: In vitro and in vivo experimental (rat) models

Dosage:

• The treatment groups for the pentobarbital sleep-induction study received AE dissolved in 0.5% CMC at the dose levels of 5, 25, and 50 mg/kg body weight.
• For the EEG study after the acclimatization, 18 animals were randomly divided into 3 groups comprising of six animals in each group. The animals were fasted overnight and were treated with 10 mg/kg of AE for groups I, II, and III with a dose mg/bodyweight of 10, 25, and 50, respectively.

Measurements: rat glioblastoma (C6) cell lines were studied using semiquantitative reverse transcriptase-polymerase chain reactions. The effects of AE on sleep onset and duration were studied in Swiss albino mice using the pentobarbital-induced sleep model. EEG was used to measure nonrapid eye movement (NREM) and rapid eye movement sleep patterns in wistar rats

Results:

• Significant increase in gene expression levels of GABA receptor and histamine H3 receptors compared to controls induced by AE at doses of 15 and 30 ug/ml.
• AE at doses of 10, 25, and 50 mg/kg body weight showed a significant decrease in time to sleep onset and increased total sleep duration in the pentobarbital-induced sleep model
• At 50 mg/kg body weight dosage level, a significant decrease of 34% in sleep onset time and 47% increase in sleep duration was observed
• The EEG study showed significant improvement in alpha, beta, theta, delta, and gamma bands at doses of 10, 25, and 50 mg/kg body weight with delta waves showing increases of 30%, 46%, and 34%, respectively.

Potential language: In vitro and in vivo animal models suggest ashwagandha’s calming properties work by interacting with the brain's GABA receptors which control your circadian rhythm and regulate your sleep-wake cycle.

Gupta, 2019. Withania somnifera dunal ameliorates neurodegeneration and cognitive impairments associated with systemic inflammation

Purpose: To investigate the neuroprotective effects of ashwagandha (ASH-WEX) using in vivo rat model system by inducing systemic lipopolysaccharide (LPS) neuroinflammation

Design & dosage: in vivo rat model - young adult wistar strain male albino rats were randomized into 4 groups. Ashwagandha dose is equivalent to 140 mg/kg/day

• Control: orally administered with water as vehicle for 8 weeks
• LPS alone: orally administered with water as vehicle for 8 weeks and given a single dose of LPS intraperitoneally on last day of treatment regimen
• LPS + ASH-WEX: orally given ASH-WEX 4 ml/kg body weight for 8 weeks and injected with a single dose of LPS on last day
• ASH-WEX alone: orally given ASH-WEX 4 ml/kg body weight for 8 weeks and

Measurements: the rotarod, narrow beam walking and novel object recognition test to analyze their neuromuscular coordination, working memory and learning functions. After these tests have been completed, the rats brain regions and expression of proteins associated with synaptic plasticity and cell survival were isolated and studied using western blotting and quantitative real time PCR. Active fraction (FIV) was evaluated in vitro

Results:

• LPS + ASH-WEX & ASH-WEX alone treated rats exhibited normal grooming behavior with longer duration and frequency of grooming bouts compared to controls.
• Suppressed the cognitive and motor-coordination impairments associated with systemic neuroinflammation
• Regulated the expression of various proteins involved in synaptic plasticity and neuronal cell survival, restores neurite outgrowth and protects cells from apoptosis caused by LPS-induced neuroinflammation.

Potential language: In vivo and in vitro animal models suggest ashwagandha may have neuroprotective properties by supporting neuronal activity.

Bhatnagar, 2009. Neuroprotective effects of Withania somnifera Dunal: A possible mechanism

Purpose: To understand the possible effects of ashwagandha’s (WS) neuroprotective action during stress

Design & dosage: Adult Swiss albino mice of both sexes were divided into control and experimental groups and exposed to restraint stress for 30 days. A dose of 40 mg/kg BW was given to the mice

Measurements: Activity of NADPH diaphorase and factors that regulate NADPH-d such as acetylcholine, serotonin, and corticosterone were evaluated.

Results: WS treatment significantly reversed the stress induced NADPH-d activation. It is suggested that WS did not have a direct effect on NADPH-d but it inhibits by suppressing corticosterone release and activating choline acetyltransferase (the enzyme that synthesizes acetylcholine), in turn, increasing serotonin levels in the hippocampus to inhibit NADPH-d. Animal research suggests after exposure to stress, ashwagandha may be neuroprotective by reducing nitric oxide production, in turn, this lowers corticosterone release and improves neurotransmitter activity

Potential language: Animal research suggests after exposure to stress, ashwagandha may be neuroprotective by bringing bodily functions into balance.

Note: too much nitric oxide production can cause neuronal cell death. Cortisol is the primary endogenous adrenal steroid in humans; corticosterone is the primary adrenal corticosteroid in laboratory rodents.

Human studies

Deshpande et al, 2020. A randomized, double blind, placebo-controlled study in healthy subjects for 6 weeks.

Purpose: To evaluate the effect of daily supplementation of a standardized ashwagandha extract compared to placebo in healthy subjects with non-restorative sleep (NRS) after six weeks.

Population: Screening of 751 subjects were assessed with n=150 healthy subjects (mean age of 37.6 years) being randomized. A few were lost to follow up and 9 subjects had other medical conditions, with n=144 completing the study.

Treatment: 2 capsules contained 120 mg Shoden® Ashwagandha (total of 42 mg withanolides) or matching placebo (rice powder) for 42 days (6 weeks). Subjects were instructed to take 2 capsules daily with water in the evening, 2 hours prior to the evening meal.

Design: Randomized, double-blind, placebo-controlled parallel trial. 3 phase trial - 1) screening 2) pre treatment phase 3) treatment phase. The treatment phase had 42 days (6 weeks) where days 15, 22, 29, & 43 were interviews by telephone. During the screening phase, subject were given the STOP BANG, RSQ-W, and WHOQOL questionnaires and blood was obtained for safety analysis. Activewatch was given and data collected after 7 days.

• 1:1 block- randomization

Composition: 60 mg Shoden® Ashwagandha (total of 21 mg withanolides) per capsule.

Measurements:

• Primary outcomes: mean percent change in total score of restorative questionnaire-weekly (RSQ-W) at the end of 6 weeks between groups. 9 questions, with answers scaled from 1-5. The total RSQ-W score is based on an average from all 9 questions, and presented as a scale of 0-100.
• Secondary outcomes: mean percent change of qualify of life scores using WHOQOL-Bref scale at the end of 6 weeks between the two groups. Is a self-administered, 26-item, cross culturally validated questionnaire measuring the following broad domains: (scaled in a positive direction, higher the better based on a scale of 0-100)
• Physical health
• Social relationships
• Psychological health and environment
• An objective measure, the Activesleep® device was used to calculate the sleep parameters. It is worn on the wrist like a regular watch and was instructed to be worn at all times. Measured within group and between groups.
• Sleep Latency (SOL)
• Sleep Efficiency (SE): refers to the actual time spent for sleep in comparison to overall time spent in bed
• Total sleep time (TST): referred to as the actual sleep time in a sleep period
• Total bed time (TBT)
• Wake after sleep onset (WASO): is the duration a person remains awake after the defined onset of the sleep
• Average # of awakenings and average awakening time

Statistically significant results: (**further evaluation of sleep study parameters can be found in NSI Tech Paper, the results below were taken straight from the published study).

FIG 1 & TABLE 2 DATA

• Significantly reduced overall non-restorative sleep based on questionnaire data (RSQ-W)
• Significantly improved energy level scores, mood scores, rested/refreshed state scores, mental alertness based on individual WHOOQOL-Bref scale
• 72% mean increase in the self-reported quality of sleep in ashwagandha group as compared with 29% in the placebo group
• Improved the quantity of sleep
• Decreased wake time after sleep onset (WASO)
• Significantly improved QOL parameters – physical, psychological, and environmental

Conclusion: Supplementation with the Shoden® extract for 6 weeks improved overall quality of sleep by significantly improving the NRS condition in healthy subjects

Limitations: Further analysis was conducted post publication and was not peer-reviewed. The NSI Tech Paper goes in to more detail. No limitations were mentioned by the researchers

Strengths: healthy subjects, large sample size, safety was evaluated, no other medications were allowed (including supplements) without approval, ashwagandha was authenticated by a qualified botanist. No significant differences between baseline of active vs placebo group on all parameters measured including baseline demographic data.

Adverse events: No major AEs were reported. 4 mild AEs in the placebo and six in the active group, which was non-significant

Safety evaluation: good standing

Potential disclosures:

• Study location: India
• Mfg supplied material

Notes: Nonrestorative sleep (NRS) has been recently developed identified and validated as a clinical endpoint for inadequate sleep. NRS may increase fatigue, lower cognitive function and reduce quality of life (QOL)

Lopresti et al, 2019. A randomized, double-blind, placebo-controlled, cross over study examining the hormonal and vitality effects of Ashwagandha (Withania somnifera) in aging, overweight males

Purpose: To evaluate the effect of ashwagandha extract (Shoden®) on salivary hormones and symptoms of fatigue and vitality in healthy, overweight men

Population: 82 healthy male subjects, aged 40-70 years (mean age of 51) reporting mild-to-moderate symptoms of fatigue or reduced vitality were screened and n= 50 completing phase 1 (first 8 weeks) and n=43 completing all 16 weeks. There were 14 dropouts (no significant difference between groups). No participant withdrew from the study due to self-reported adverse effects from tablet intake.

• Medication free for at least 3 months, BMI between 25-35.

Treatment: The total daily intake of withanolide glycoside during the treatment condition was 21 mg (two tablets) or identical placebo for 8 weeks. Participants were instructed to take two tablets once daily, 2 hours away from food (preferably after dinner).

Design: A 16 week randomized, double-blind, placebo-controlled, crossover trial. No washout period was included in this crossover trial as the aim in the second period of the trial was to investigate the durability of changes after discontinuation of the active treatment.

• The randomization structure comprised seven randomly permuted blocks
• Based on previous studies that have focused on stress & anxiety, the total number of participants to find an effect was calculated as 57

Composition: 60 mg Shoden® Ashwagandha (total of 21 mg withanolides) per 2 tablets

Measurements:

• Aging Males’ Symptoms (AMS) self-report measure: The AMS is a 17-item, self-report questionnaire measuring psychological, somatic, and sexual symptoms. Items are rated on a 5-point Likert scale from 1 (none) to 5 (extremely severe). The AMS is a commonly used and reliable/valid measure of aging symptoms in men and their impact on quality of life.
• Profile of Mood States, Short Form (POMS-SF); Fatigue-Inertia and Vigor-Activity subscale scores: The POMS-SF is a 35-item, self-report questionnaire with subscales including Anger-Hostility, Confusion-Bewilderment, Depression-Dejection, Fatigue-Inertia, Tension-Anxiety, Vigor-Activity, and Friendliness. Items are rated on a 5-point Likert scale from 0 (not at all) to 4 (extremely).
• Hormonal changes: salivary testosterone, cortisol, DHEA-S, estradiol (collected at baseline, week 8, and week 16)

Statistically significant results:

• 18% greater increase in DHEA-S, and 14.7% greater increase in testosterone compared to placebo. Lower levels of these hormones have been associated with reduced longevity and lower quality of life.

Conclusion: The intake of Shoden® for 8 weeks was associated with increased levels of DHEA-S and testosterone. Although improvements were seen, no significant differences between groups were found in fatigue, vigor, or sexual well-being. Further studies with larger sample sizes are required to substantiate the current findings.

Limitations: small sample size despite the researchers calculating statistical power to find an effect, the small sample size with the dropouts, self-reported levels of fatigue, vigor, and sexual well-being were mild which may have affected the overall significance of the data. Further studies with larger sample sizes are required to substantiate the current findings. In addition, volunteers were recruited via social media, and these likely included individuals motivated to improve their general well-being. Monitoring of these changes are difficult and were not undertaken in this study.

Strengths: exclusion criteria, crossover design, efficacy of participant treatment blinding was examined by asking participants to predict group allocation (placebo, ashwagandha, or uncertain) at the completion of each phase of the study.

Adverse events: Ashwagandha supplementation was well tolerated with no reported adverse events or participant withdrawal associated with its intake.

Safety evaluation: not measured as its safety profile is supported by previously conducted studies

Potential disclosures:

• Study location: Western Australia
• Mfg supplied material

Notes: In addition to the mentioned limitations, previous studies were conducted on Indian populations which may have had a cultural impact on the results. The study results suggest that ongoing supplementation with ashwagandha is required to sustain changes or longer intake is required.

Confidential. Unpublished (paper is in peer review status). Shoden Manuscript.

Shoden® promotes relief from stress and anxiety: A randomized, double-blind, placebo-controlled Study in Healthy Subjects with High Stress Levels

Purpose: To examine the effects of Shoden® 60 mg & 120 mg in physically healthy subjects with higher stress and anxiety

Population: n=60 healthy subjects with higher stress and anxiety were recruited

• Subjects who fulfilled the DSM –IV Criteria for generalized anxiety disorder (GAD) with a HAMA score > 20, and morning serum cortisol > 25 mcg/dl were included in the study.
• Subjects with a high depression rating were excluded

Treatment: 60 mg Shoden®, 120 mg Shoden® or matching placebo for 60 days

Design: Randomized, placebo-controlled study

• 1:1:1 allocation ratio

Composition: Shoden® containing 35% withanolide glycosides

Measurements:

• Primary: Hamilton Rating Anxiety Scale (HAM-A)
• Secondary: morning serum cortisol, testosterone, perceived stress scale (PSS), clinical global impressions scale (CGI), and patient’s global impression of change scale (PGIC)

Statistically significant results: *results should be expressed as mean/average

• 60 mg and 120 mg of Shoden® significantly decreased HAM-A scores by 59%
• 60 mg and 120 mg of Shoden® significantly decreased morning serum cortisol by 66% and 67%, respectively.
• 60 mg and 120 mg of Shoden® significantly increased testosterone by 22% and 33%, respectively.
• 60 mg and 120 mg of Shoden® significantly decreased PSS scores by 53% and 62%, CGI-severity by 72% and 68%, and PGIC by 60% respectively.

Conclusion: Based on preliminary data, Shoden® may support occasional anxiety and stress at a low dose of 60 or 120 mg per day.

Limitations: Cannot draw conclusions until paper has been published

Strengths: Cannot draw conclusions until paper has been published

Adverse events: Cannot draw conclusions until paper has been published

Potential disclosures: Cannot draw conclusions until paper has been published

Notes: Researcher’s suspect that a low dose extract with higher withanolide glycosides would decrease cortisol and increase testosterone thereby reducing stress & anxiety

Additional references:

This study is summarized below for additional support. It was conducted using double the dose that is in the Kwik Brain Formula. Therefore, if results from this study are referenced, the dosing discrepancy is a mandatory disclosure.

Lopresti et al, 2019. A randomized, double-blind, placebo-controlled study in healthy subjects for 60 days

(240 mg/d dose)

Study details: healthy subjects with mild anxiety received 240 mg/d of Shoden® or matching placebo in this prospective, randomized, double-blind, placebo-controlled study for 60 days

Results summary:

• Increased plasma free testosterone in males by 11% versus placebo, no change in females
• Cortisol levels significantly reduced by 23%, no change in placebo
• Lowered plasma DHEA-S levels of 8% compared to placebo
• Reduced symptoms of occasional mood, anxiety, and stress (DASS-21) by 30% compared to a 10% reduction in placebo
• Reduced anxiety (HAM-A) by 30% compared to placebo