Synapsa® 

(Bacopa monnieri extract)

Overview

• Synapsa®, Bacopa monnieri, also known as Brahmi, is an Ayurvedic herb traditionally used for its anxiolytic, antidepressant, sedative, and adaptogenic actions. Modern research supports its use for cognitive function.
• Synapsa® holds 8 human clinical studies, clinically shown to have positive acute and long-term cognitive outcomes. Synapsa® has the potential to cover a wide range of consumer benefits relating to learning, memory, and mental performance.
• Country of origin: India
• Proposed shelf life of 2 years
• Pre-DSHEA Status
• Synapsa® is non-GMO, gluten free, free of allergens, and contains no artificial or synthetic ingredients

(PIDS_Synapsa)

Composition & Dosing

Synapsa® (Bacopa monnieri) (whole plant) (std. to 55% bacosides)

Synapsa® is a registered trademark of Soho Flordis International Pty Ltd.

Clinical dose: ranges from 250-640 mg per day. Synapsa® Product standard grade has been clinically evaluated at 320 mg per day. Formulations containing the standard grade of Product must include dose recommendations of at least 320 mg per day (daily serving size).

Note: "CDRI08 is marketed and sold as KeenMind through the Healthcare Professional (Practitioner) channel by Soho Floridis International (SFI), and in the USA by SFI's subsidiary Prothera. It is a finished product sold exclusively to healthcare professionals. Synapsa® and Keenmind® are identical extracts manufactured by Laila Nutraceuticals, but marketed in different channels."

What is special about Synapsa®?

Seed-to-shelf-quality – is the key to reproducible clinical trial results. Synapsa® is made via a proprietary patented process. It is a unique extract with a wide range of active constituents that contribute to its therapeutic properties.

A complex mix of saponins, namely bacoside A and bacoside B, are responsible for most of the neuromodulatory and neuroprotective activities exerted by the standardized CDRI-08™ Bacopa monnieri extract. The active constituents of Bacopa monnieri extract are well absorbed following oral ingestion as evidenced by beneficial effects on information processing and decision times at one- and two-hours following ingestion.

Bacosides present in Synapsa® are non-polar glycosides, which possibly cross the blood brain barrier, and its biodistribution in the brain has been confirmed.

(Pardridge, 1999), (De et al, 2008), (Nimisha, 2019), (Jager, 2011)

Confidential: “A patented extraction process for making Synapsa® as well as a standard clinical dose that is used in human studies was developed by the Central Drug Research Institute in Lucknow, India. The extraction process follows a controlled and exacting farming and manufacturing process to ensure a standardized level of quality, since each step of the process can influence the final product’s complex phytochemical profile and therapeutic action. These processes yield a level of product consistency that allows Synapsa® to be used reliably in clinical studies and as an efficacious dietary supplement.”

(Confidential PLT360 Synapsa Claims Dossier March 2019 with pubs)

Natural Medicines Database Safety, Effectiveness & Interaction Analysis

• POSSIBLY SAFE ...when used orally and appropriately, short-term. Bacopa has been used safely in clinical trials at a dose of up to 600 mg daily for up to 12 weeks
• CHILDREN: POSSIBLY SAFE ...when used orally and appropriately, short-term. Clinical research suggests bacopa extract might be safe to use at a dose of 225 mg daily for up to 6 months or 320 mg daily for up to 14 weeks in children aged 6-14 years
• PREGNANCY AND LACTATION: Insufficient reliable information available; avoid using.
• When used orally, bacopa is well tolerated.
• No major drug interactions; theoretically, bacopa may decrease or increase the effectiveness of certain drugs this data is loosely based on in vitro data and one case report.
• No nutrient interactions found

Toxicology data

• Acute oral toxicity of Bacopa monnieri extract was studied in female rats by giving a single orally administered dose at a level of 5,000 mg/kg. Rats were monitored for toxic signs for 14 days. In the chronic toxicity test, groups of both female and male rats were given daily oral doses of B. monnieri extract at dose levels of either 30, 60, 300 or 1,500 mg/kg for 270 days.
• Results:
• The acute toxicity test found no significant differences between the experimental and the control group rats.
• In the chronic toxicity test, animal behavior and health of the experimental groups were normal, just as in the control rats.
• All values of other parameters assessed remained within the normal range. (Sireeratawong, 2016)

Research summary:

Preclinical research:

• Jyoti, 2006. Neuroprotective role of Bacopa monniera extract against aluminium-induced oxidative stress in the hippocampus of rat brain
• Sheikh, 2007. Effect of Bacopa monniera on stress induced changes in plasma corticosterone and brain monoamines in rats
• Kamkaew, 2012. Bacopa monnieri Increases Cerebral Blood Flow in Rat Independent of Blood Pressure
• This study did not use CDRI08
• Preethi, 2016. Possible involvement of standardized Bacopa monniera extract (CDRI-08) in epigenetic regulation of reelin and brain-derived neurotrophic factor to enhance memory

Human Studies

• Nathan, 2001. (acute) The acute effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy normal subjects
• No statistically significant results found
• Downey, 2012 (acute) An acute, double-blind, placebo-controlled crossover study of 320 mg and 640 mg doses of a special extract of Bacopa monnieri (CDRI 08) on sustained cognitive performance
• Benson, 2013 (acute) An acute, double-blind, placebo-controlled crossover study of 320 mg and 640 mg doses of Bacopa monnieri (CDRI 08) on multitasking stress reactivity and mood
• Stough, 2001 (chronic) The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects
• Roodenrys, 2002. (chronic) Chronic Effects of Brahmi (Bacopa monnieri) on Human Memory
• Raghav, 2006. (chronic) Randomized controlled trial of standardized Bacopa monniera extract in age-associated memory impairment
• Stough, 2008 (chronic) Examining the Nootropic Effects of a special extract of Bacopa monniera on Human Cognitive Functioning: 90-day Double-Blind Placebo-Controlled Randomized Trial
• Kean, 2021. (chronic) Effects of Bacopa monnieri (CDRI 08®) in a population of males exhibiting inattention and hyperactivity aged 6 to 14 years: A randomized, double-blind, placebo-controlled trial

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)

• Bacopa monnieri = 410 results with no filters or specified search criteria
• Bacopa monnieri + cognitive= 107 results with no filters
• Bacopa monnieri + cognitive = 10 results with an RCT filter

Preclinical research

Jyoti, 2006. Neuroprotective role of Bacopa monniera extract against aluminum-induced oxidative stress in the hippocampus of rat brain

Purpose: To investigate the neuroprotective effect of Bacopa extract against aluminum-induced changes in peroxidative products, such as thio-barbituric acid-reactive substance (TBA-RS) and protein carbonyl contents and superoxide dismutase (SOD) activity

Design: Forty male wistar rats of 6 months of age, weighing 350– 400 g were used for this 5-week study.

Dosage: Animals were divided into 4 groups

• Group 1: control; water only
• Group 2: AlCl3; treated control, at an oral dose of 50 mg/kg/day in drinking water for 5 weeks
• Group 3: AlCl3 + Bacopa extract treated group, AlCl3 at an oral dose of 50 mg/kg/day and Bacopa extract in 10% gum acacia at a dose of 40 mg/kg/day for 5 weeks
• Group 4: AlCl3 + L-deprenyl treated group, L-deprenyl administered simultaneously with AlCl3. L-Deprenyl, dissolved in saline solution, was administered by intraperitoneal injection at a dose of 1 mg/kg/day

Composition: Bacopa extract contained 55–60% bacosides estimated as bacoside A.

Measurements & Methods:

• Preparation of tissue homogenates: Six rats of each group were killed by cervical dislocation after the treatment period. Hippocampi were rapidly dissected out on ice plate, according to the stereotaxic atlas of Paxinos and Watson.
• TBA-RS levels, protein oxidation, protein carbonyl content, and SOD activity was measured

Results:

• Data obtained in the present experiments would show that lipid peroxidation and protein oxidation significantly increased in the hippocampus of aluminum treated rats in comparison with controls, whereas the superoxide dismutase activity, significantly decreased.
• In animals co-administered with Bacopa extract during AlCl3 treatment, the lipid peroxides and the protein oxidation levels significantly decreased whereas SOD activity elevated in comparison to aluminum treated rats.
• In summary, aluminum treatment results in the elevation of lipid peroxides and protein oxidation, and depression of SOD activity in the hippocampus. These aluminum-induced neurotoxic effects are prevented by Bacopa extract.

Potential language: Animal research suggests Bacopa monnieri is neuroprotective by mitigating aluminum-induced oxidative stress in the hippocampus of the brain.

Sheikh, 2007. Effect of Bacopa monniera (BM) on stress induced changes in plasma corticosterone and brain monoamines in rats

Purpose: To evaluate the effect of BM on acute stress (AS) and chronic unpredictable stress (CUS) induced changes in plasma corticosterone and monoamines-noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in cortex and hippocampus regions of brain in rats. Panax quinquefolium (PQ) was used as a standard.

Design: Adult male Sprague–Dawley rats weighing 180–200 g was employed in the study

• The extract was administered daily for 3 days prior to exposure to acute stress (AS) whereas in chronic unpredictable stress (CUS) regimen, extract was administered 45 min prior to exposure to stress daily for 7 days. Drugs were prepared fresh daily before administration.

Dosage: Both BM and PQ extracts were administered daily by oral gavage using a ball ended feeding needle as a suspension prepared in 0.5% gum acacia.

• Different groups of animals were fed with extracts of BM at 40 and 80 mg/kg and PQ at 100 mg/kg body weight p.o. daily for 3 days

Composition: BM contained 55–60% bacosides estimated as bacoside A

Measurements & Methods:

• Subjecting animals to acute stress (AS) (immobilization for 150 min once only) and chronic unpredictable stress (CUS) (different stressors for 7 days)

Results:

• Acute stress exposure significantly increased the levels of serotonin and decreased monoamines-noradrenaline content in both the brain regions while dopamine content was significantly increased in cortex and decreased in hippocampus regions.
• In the chronic unpredictable stress regimen, levels of monoamines-noradrenaline, dopamine and serotonin were significantly depleted in cortex and hippocampus regions of brain.
• Supplementation with BM, attenuated the stress induced changes in levels of serotonin and dopamine in cortex and hippocampus regions, but was not effective in normalizing monoamines-noradrenaline in the acute stress model.
• Pretreatment with BM significantly increased monoamines-noradrenaline, dopamine, and serotonin levels in the cortex and levels of monoamines-noradrenaline and serotonin in the hippocampus region.
• Bacopa monnieri is a supportive adaptogenic herb by normalizing the stress induced alterations of corticosterone and levels of monoamines-noradrenaline (NA), dopamine (DA) and serotonin (5-HT) of the brain.

Potential language: Animal research suggests Bacopa monnieri has a neurotransmitter effect, namely normalizing dopamine and serotonin levels in the brain after exposure to stress.

Kamkaew, 2012. Bacopa monnieri Increases Cerebral Blood Flow (CBF) in Rat Independent of Blood Pressure

Purpose: To investigate the chronic and acute effects on CBF compared with Ginkgo biloba and donepezil

Design & dosage: Wistar rats were divided into 4 groups and, for 8 weeks, fed daily by gastric lavage 0.3mL of water containing either the following: 1) control group: water only 2) B. monnieri (40 mg/kg) extract suspension in water 3) G. biloba (60 mg/kg) triturated with water or 4) Donepezil (1 mg/kg) triturated with water

• For the acute experiment, non-operated rats were urethane anaesthetized and the femoral artery and femoral vein cannulated to measure arterial BP and to inject drugs, respectively.

Composition:

• B. monnieri extract std. to 6.25% total saponins (Bacoside A, Bacoside I, Bacoside X, bacopa saponin C)
• Ginkgo biloba extract std. to 24% flavone glycosides and 6% terpenoids
• Donepezizl hydrochloride
• Control: water only

Measurements & Methods:

• CBF measured by laser doppler from rat cerebral cortex
• Systolic blood pressure by using the tail cuff method or via arterial cannulation

Results:

• B. monnieri produced a 25% increase in cerebral blood blow compared with controls
• Ginkgo biloba produced a similar effect, 29% increase in cerebral blood flow compared with controls
• There was no increase with donepezil
• Blood pressure and heart rate was unchanged between and within groups over the 8 weeks
• The acute experiment, injection of the drugs, reduced BP in all animals with concomitant decreases in CBF
• In conclusion, chronic oral B. monnieri extract increased CBF independent of BP, and this effect
• explains its nootropic and possibly neuroprotective actions.

Potential language: Animal research suggests B. monnieri has a nootropic effect by increasing cerebral blood flow

Preethi, 2016. Possible involvement of standardized Bacopa monniera extract (CDRI-08) in epigenetic regulation of reelin and brain-derived neurotrophic factor to enhance memory

Purpose: To investigate if BME alters the methylation status of reelin and brain-derived neurotropic factor (BDNF) to enhance the memory through the interaction of N-methyl-d-aspartate receptor (NMDAR) with synaptic proteins

Design: Rats were subjected to an object recognition test following daily oral administration of BME (80 mg/kg) in 0.5% gum acacia plus 5-azaC

Dosage: Std. B. monnieri extract (55% bacosides) and The DNA methyl transferase (DNMT) inhibitor, 5-azacytidine

Measurements & Methods:

• object recognition test (behavior test): In novel object recognition test, rodents’ innate habit of exploring novel object in their environment has been utilized to evaluate their memory. Exploration time was scored as when the rat nose was touching the object or orienting its head towards the object with in a distance of 1cm.
• After the behavioral test, methylation status of reelin, BDNF and activation of NMDAR, and its interactions with synaptic proteins were tested

Results:

• Rats showed higher discrimination towards novel objects than old objects during testing.
• Elevated levels of unmethylated DNA in reelin and BDNF were found in promotor region.
• These results suggest that BME regulates reelin epigenetically, which might enhance NMDAR interactions with synaptic proteins and induce BDNF. These changes may be linked to improved novel object recognition memory

Potential language: Animal research suggests B.monnieri may improve recognition memory by modulating memory formation pathways

Notes: Several studies have reported that DNA methylation/demethylation in a specific promoter region of reelin and brain-derived neurotrophic Factor (BDNF)dictates the transcriptional activity thereby critically regulating synaptic plasticity, learning, and memory. Reelin is a large secreted glycoprotein richly expressed at hippocampus by a subset of GABA-ergic interneurons. Epigenetics is the study of how your behaviors and environment can cause changes that affect the way your genes work.

Human studies

Nathan, 2001. (acute) The acute effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy normal subjects

Purpose: To examine the acute effects of an extract of Bacopa monniera on cognitive function in normal healthy human subjects

Population: 38 healthy subjects, aged between 18 and 60 years

Treatment: B. monniera (300 mg) or placebo; subjects were reassessed on the same battery of neuropsychological tests 2 hours post drug administration.

Design: Double-blind, placebo-controlled independent group design

Composition: B. monniera (std. to 55% bacosides)

Measurements: see study for details

Results: No statistically significant results found in tests examining attention, working and short-term memory, verbal learning, memory consolidation, executive processes, planning and problem solving, information processing speed, motor responsiveness and decision-making.

Conclusion: No significant changes were found on any of the tests. The findings suggest B. monniera, at least for the dose administered, has no acute effects on cognitive functioning in normal healthy subjects Limitations: small sample size

Notes: Acute effects may be observed in individuals with a lower baseline level of cognitive functioning. Age may have also played a factor. No biological assessments were collected from the participants, and no assessment of mood prior to, or after completing the cognitive assessments were completed, possibly limiting the study’s ability to assess whether B. Monnieri produces an anxiolytic or nootropic effect

Downey, 2012 (acute) An acute, double-blind, placebo-controlled crossover study of 320 mg and 640 mg doses of a special extract of Bacopa monnieri (CDRI 08) on sustained cognitive performance

Purpose: To assess the acute effects of a specific extract of BM (KeenMind®-CDRI 08) on cognitive function in normal healthy participants

Population: 24 healthy subjects (4 males and 20 females), aged 18-56 years (average age of 25) with a BMI from 15.4-32.74 kg/m2

• Subjects were excluded if they smoke, had a history of illness or taking any medications or herbal extracts

Treatment: On each testing day, subjects received 4 capsules containing a total of 320 mg of KeenMind®, 640 mg of KeenMind®, or placebo

Design: Double-blind, placebo-controlled, crossover study

• On test day, subjects were instructed to eat a light breakfast while abstaining from alcohol and coffee
• Each subject was required to attend 4 sessions (one practice and 3 study visits) that were conducted 1 week apart to ensure washout
• Practice data was not included in the analysis

Composition: B. monnieri extract (std. to 55% bacosides)

Measurements:

• Cognitive Demand Battery: comprised of a ‘stress and mental fatigue’ visual analogue scale (VAS), two Serial subtraction tasks (Serial Threes and Serial Sevens), and the Bakan Rapid Visual Information Processing task (total duration 10 minutes, 6 repetitions)
• Stress and mental fatigue VAS: subjective feelings of stress and mental fatigue rated as ‘not at all’ to ‘very much so’
• Serial 3s subtraction task: Participants were required to mentally count backwards in threes from a given number as accurately and as quickly as possible, for duration of 2 min
• Serial 7s subtractions task: same as the serial 3s; however, the only noticeable distinction was the subtraction of sevens replacing the subtraction of threes.
• Rapid visual information processing task (RVIP): Participants were required to monitor a randomized continuous series of digits for targets of three consecutive odd or even numbers and respond as quickly as possible
• Blood pressure, arterial stiffness, cerebral blood flow
• The above was conducted pre dose and then immediately followed by ingestion of the active. After 2 hours, the above tests and measurements were conducted again, a cycle that lasted approximately 60 minutes. The same testing sequence was carried out in all three study visits.

Results:

• Subjects improved performance from baseline for the Cognitive Demand Battery (Serial 3s) at the 1st, 2nd, and 4th repetition, treatment had no effect on cardiovascular markers or lessening task-induced rating of stress and fatigue
• Subjected improved performance compared to placebo for the Cognitive Demand Battery at the 1st and 4th repetition, trending towards the same effect during the second. A significant main effect for time was also observed, with more correct responses occurring across the repeated assessments.
• No significant difference was found for the Serial 7s, RVIP
• Consumption of the clinically standard dose of BM (320 mg; CDRI 08) improved Serial 3s performance in three of the first four repetitions of the CDB

Conclusion: BM may provide acute enhancing effects upon cognitive functioning (reasoning and cognitive speed) even in healthy young individuals

Limitations: small sample size, uneven distribution of male: female subjects, this relative improvement raises the possibility that further cognitive enhancement may have been observed earlier if the CDB repetitions had commenced closer to dosing

Strengths: significant washout period between test days

Adverse events: No adverse effects were reported throughout the study for any of the three treatments

Safety evaluation: Blood pressure, arterial stiffness, cerebral blood flow

Potential disclosures:

• Mfg supplied material
• Mfg funded
• Study location: Australia

Benson, 2013 (acute) An acute, double-blind, placebo-controlled crossover study of 320 mg and 640 mg doses of Bacopa monnieri (CDRI 08) on multitasking stress reactivity and mood

Purpose: To assess the acute effects of BM in normal healthy subjects

Population: 17 healthy subjects between the ages of 18-44 years (average age of 25)

• Subjects were excluded if a smoker, history of disease, chronic illness, infections, pregnant or lactating
• Subjects were excluded if taking medications or other herbal extracts

Treatment: On each testing day, subjects received 4 capsules containing a total of 320 mg of KeenMind®, 640 mg of KeenMind®, or placebo taken after breakfast

Design: Double-blind, placebo-controlled cross over study

• On the day of testing, participants were required to consume only a light breakfast while abstaining from alcohol and caffeine
• Each subject was required to attend 4 sessions (one practice and 3 study visits) that were conducted 1 week apart to ensure washout

Composition: B. monnieri extract (std. to 55% bacosides)

Measurements:

• MTF: this test requires attention to be given to 4 tasks presented simultaneously, each on one of 4 quadrants on a computer screen, whilst monitoring the central counter displaying the score, which is dictated by the accuracy and speed of the response. The test was ‘medium’ difficulty and performed over 20 minutes. The test included
• Mental Arithmetic: subjects add a series of numbers, by clicking the numbers to add up to the desired answer. 10 points given for correct responses or deduction of 10 points for in correct answer
• Stroop: A series of color names (red, blue, yellow, and green) were presented in differing font colors (red, blue, yellow, and green), and the subjects were required to respond to the color of the font by using their computer mouse to click on one of the four available answers. 10 points given for correct responses or deduction of 10 points for in correct answer
• Letter search: Four letters were presented during the initial four seconds of testing. The letters then disappeared, but could be reviewed at any time by clicking on a ‘retrieve list’ button. At 10-s intervals, a single target letter appeared and the subject indicated whether or not the letter belonged to the original four letters by clicking on a ‘yes’ or a ‘no’ button. 10 points given for correct responses or deduction of 10 points for in correct answer
• Visual Tracking: A dot progressively moved outwards from the center of the task through five concentric circles. Subjects were asked to allow the dot to travel as far from the center as possible without letting it touch the edge of the outermost circle before clicking on a ‘reset’ button. Two points were awarded per circle that the dot had passed through, with a maximum of 10 points. Subjects were deducted 10 points per half second that the dot touched the outer edge before resetting the task
• Mood measures:
• Bond-Lader VAS: consists of 16 visual analogue scales with the end points anchored by antonyms reflecting three key mood factors: ‘alert’ (alert–drowsy, attentive–dreamy, lethargic–energetic, muzzy–clearheaded, coordinated–clumsy, mentally slow–quick witted, strong–feeble, interested–bored, incompetent– proficient), ‘calm’ (calm–excited, tense–relaxed), and ‘content’ (contented–discontented, troubled–tranquil, happy–sad, antagonistic–friendly, withdrawn–sociable). On a scale of 0-100, a pen and paper version was used, and subjects were asked to mark each line between the antonyms indicating how they felt at the present time.
• State Trait Anxiety Inventory: was used to measure anxiety before and after the testing. Consisted of 20 items measured on a 4-point Likert scale with 1= ‘not at all’ and 4= ‘very much so’. A subscale was also included that consists of 20 items on a 4-point Likert scale with 1 = ‘almost never’ and 4 = ‘almost always’, with higher scores reflecting greater levels of trait anxiety.
• Salivary cortisol

Results:

• Consumption of the clinically standard dose of BM (320 mg; CDRI 08) improved Letter Search and Stroop task performance (1 and 2 h post-dosing) and Alertness ratings (2 h) prior to completion of the MTF.
• In the 320 mg condition, there was a significant change from baseline to 2 hr compared to placebo for mood and anxiety ratings

Conclusion: Based on the Stroop task performance test, supplementation with 320 mg BM, shows a same day effect that is consistent with faster information processing and decision-making time, and improves aspects of attention/freedom of distractibility. Based on the letter search task, supplementation with 320 mg BM, shows a same day effect that is consistent with memory-enhancement qualities. BM may also improve alertness and contentedness when undergoing cognitive demanding tasks. These results suggest an earlier nootropic effect of BM than previously investigated.

Limitations: small sample size, uneven distribution of male: female subjects, it was not instructed for the subjects to abstain from any kind of exercise, exact time of day subjects took the active was not provided. Further research is needed in a larger sample size to confirm these results.

Strengths: limiting confounding factors such as caffeine, coffee, varied breakfast intake, significant washout period

Adverse events: none reported

Safety evaluation: no safety parameters were used

Potential disclosures:

• Mfg supplied material
• Mfg funded
• Study location: Australia

Notes: The MTF has been shown to increase negative mood and anxiety and induce a stress related physiological response, therefore mood measures were included in this study

Stough, 2001 (chronic) The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects

Purpose: To validate neuropsychological tests to examine the chronic effects of an extract B. monniera on cognition in healthy human subjects

Population: 46 healthy volunteers (11 males and 35 females) aged between 18 and 60 years, weighing between 48 and 94 kg (106-207 pounds)

• Inclusion criteria: no pre-existing physical or psychiatric conditions and were free of medication

Treatment: Participants were randomly allocated to one of two treatment conditions: Keenmind B. monniera extract (Keenmind) group (n=23; 2×150 mg) or placebo group. Subjects were instructed to take 2 capsules a day for 12 weeks.

Design: A double-blind placebo-controlled study

• Following baseline testing, each participant was then given a bottle of capsules (B. monniera extract or placebo) for 12 weeks.
• Participants received weekly phone calls over the 12-week treatment period to monitor any treatment effects and to enhance compliance.

Composition: B. monnieri extract (std. to 55% bacosides) (CDRI, Keenmind)

Measurements: neuropsychological testing at baseline, 5 weeks, 12 weeks (see table 1)

• A battery of well-validated neuropsychological tests were employed to assess a wide range of cognitive variables including attention, short-term memory, verbal learning, memory consolidation, executive processes, planning and problem solving, information processing speed, motor responsiveness, and decision making.
• This battery comprised Cognometer tests of working memory, Digit Symbol Substitution Test, Speed of Comprehension Test, Digit Span, Trail Making Test, Rey Auditory Verbal Learning Test, and Inspection Time.
• Changes in state anxiety were examined using the State-Trait Anxiety Inventory

Results:

• BM significantly improved speed of visual information processing measured by the IT task and learning rate, and memory consideration, and decrease forgetting rate measured by the AVLT compared to placebo with maximal effects at 12 weeks.
• BM produced a significant decrease in the state anxiety compared to placebo

Conclusion: BM, given chronically, improves processing speed, verbal learning rate, and memory consolidation (Transition of information from short-term to long-term memory)

Limitations: small sample size, uneven distribution of male: female subjects, lack of control for diet and exercise, lack of study details – were subjects instructed to take with food? Morning, evening?

Strengths: long term study to evaluate the chronic consumption of BM

Adverse events: mild AEs were reported see table 2, most common was nausea, dry mouth, and fatigue

Safety evaluation:

Potential disclosures:

• Mfg supplied material
• Mfg funded
• Study location: Australia

Roodenrys, 2002. (chronic) Chronic Effects of Brahmi (Bacopa monnieri) on Human Memory

Purpose: To report the effects of BM on human memory

Population: 76 adults aged between 40 and 65 years (mean age of 49) who were not taking any medication or other herbal preparation, and reported no head injuries, completed the study.

Treatment: Participants were randomly allocated to one of two treatment conditions: Keenmind B. monniera extract (Keenmind) group, 300 mg for persons under 90 kg, and 450 mg for persons over 90 kg or placebo

Design: A double-blind, randomized placebo-controlled study

• Participants were tested on three separate occasions for approximately one hour.
• A second testing session was conducted approximately three months later (3-month test), at which participants were instructed not to take any remaining capsules
• A post-trial testing session occurred approximately six weeks after the end of trial session.

Composition: B. monnieri extract (Keenmind)

Measurements: baseline, 3 months, and a post-trial testing session approximately 6 weeks after the end of the trial

• At each testing session a battery of tasks was administered to assess attention, a range of memory abilities, and psychological state.
• A questionnaire about everyday memory performance
• Immediate recall of a short story; Digit span — forward and backward; A speeded coding task involving either directly copying each letter presented, writing the next letter in the alphabet or the previous letter
• Delayed recall of the short story read earlier; Three trials of learning six unrelated word pairs; A visual span task requiring tapping a sequence of blocks in correct order – forward and backward; A general knowledge test of 20 questions; Delayed recall of the word pairs; The Depression, Anxiety and Stress Scale

Results:

• The only measure to show significant effect was the delayed recall of word pairs task

Conclusion: Taking BM over a longer period of time may help subjects retain more information

Limitations: researchers do not provide the average weight of subjects or how many fell in the 300 mg or 450 mg dose, uneven distribution of male: female subjects, lack of control for diet and exercise, lack of study details – were subjects instructed to take with food? Morning, evening? The results may reflect a type 1 error.

Strengths: none, overall, this was a poorly designed study

Adverse events: one subject dropped out due GI related reaction

Safety evaluation: none

Potential disclosures:

• Mfg supplied material
• Mfg funded
• Study location: Australia

Notes: A type I error (false-positive) occurs if an investigator rejects a null hypothesis that is actually true in the population

Raghav, 2006. (chronic) Randomized controlled trial of standardized Bacopa monniera extract in age-associated memory impairment

Purpose: To investigate the efficacy of BM in subjects with age-associated memory impairment (AAMI) without any evidence of dementia or psychiatric disorder

Population: A total of 86 subjects were screened, with 40 Subjects over 55 years of age enrolled the study (37 men and 3 women), 5 dropouts, 35 subjects completed the study

• These subjects had memory loss in everyday activities—difficulty in remembering names of individuals following introduction, misplacing objects and difficulty in remembering telephone numbers.
• Subjects with a logical subset score < 6 (Wechsler Memory Scale) were included; those scoring > 24 on Mini Mental State Examination were excluded

Treatment: Subjects received either std. BM extract (125 mg), or placebo in a twice a day schedule for 12 weeks, followed by the placebo for another 4 weeks to both groups, making 16 weeks as the total duration of the study.

Design: Double-blind, placebo-controlled, parallel randomized trial

Composition: B. monnieri extract (std. to 55% bacosides)

Measurements:

• Wechsler Memory Scale, revised, Mini Mental State Examination and for side effects on Dosage Record Treatment Emergent Symptom Scale (DOTES). The subtests of Wechsler Memory Scale were used to include general information, orientation, mental control, logical memory, digit forward, digit backward, visual reproduction and paired associated learning, which required an administration period of 30 minutes.
• Each subject was evaluated at 0, 4, 8, 12, and 16 weeks of the trial

Results:

• BM supplementation improved mental control, logical memory, and digital forward compared to placebo at 12 weeks (table 2). Mental, logical, and digital forward was maintained after 4 weeks post treatment.
• BM and the placebo group showed statistically significant results for paired associate learning and total memory score (table 2)
• Digit backward and visual reproduction was non-significant. (table 2)
• Overall results for age-associated memory impairment, in the BM group, 10 subjects (55%) improved by 21% and above and 8 subjects (44.3%) improved up to 20%, whereas in the placebo group none of the subjects improved beyond 20%. This was statistically significant.

Conclusion: BM supplementation results in improved age-associated memory loss as evidenced by mental control, logical memory, and digital forward scores in an older population

Limitations: small sample size, uneven distribution of male: female subjects, no mention of limiting confounding factors such as taking other supplements, diet, or exercise. Time of day of the active taken or details about taking with or without food was not provided.

Strengths: sociodemographic and clinical variables were provided of the subjects

Adverse events: rash was reported in one subject in the BM group.

Safety evaluation: the detailed pre and post drug monitoring of clinical, hematological, and biochemical laboratory parameter did not reveal drug-related abnormality.

Potential disclosures:

• Study location: India
• Mfg supplied material; no mention of funding

Notes: Study does not document that the BM material is Keenmind (CDRI); supplier confirmed all studies provided are using the std. CDRI material.

Stough, 2008 (chronic) Examining the Nootropic Effects of a special extract of Bacopa monniera on Human Cognitive Functioning: 90-day Double-Blind Placebo-Controlled Randomized Trial

Purpose: To assess the nootropic effect of BM long term in healthy subjects

Population: 117 healthy subjects aged between 18 and 60 years (mean age of 44.3 years) were screened, 62 completed the study with 80% treatment compliance.

• Participants were deemed suitable for the study if they had no history of the following: dementia or psychiatric disorders; neurological diseases; endocrine, gastrointestinal or bleeding disorders; no history of chronic illness or infection; not pregnant or lactating; not taking the following medications: anticoagulants, antidepressants, antipsychotics, anxiolytics, ACE inhibitors, anti-Parkinson’s medication or other cognitive enhancing drugs; and a non-smoker

Treatment: Bacopa monniera (2 × 150 mg KeenMind) or placebo for 90 days

Design: A double-blind, randomized, placebo-controlled study

Composition: B. monnieri extract (std. to 55% bacosides)

Measurements:

• During baseline testing, participants completed a battery of cognitive tests from the Cognitive Drug Research (CDR) computerized assessment system.
• This took 30 min to complete, with the primary outcome measures being five cognitive factors (‘Secondary memory’, ‘Working memory’, ‘Speed of memory’, ‘Speed of attention’, and ‘Accuracy of attention’) that can be derived from the complete CDR computerized assessment battery.
• A rapid visual information-processing task (RVIP) was also included.
• Participants were instructed to take two capsules a day for 90 days. Participants were re-tested after completing 90 days of treatment administration
• Tests included: word presentation, picture presentation, immediate word cognition, simple reaction time, digit vigilance, choice reaction time, spatial working memory, numeric working memory, delayed word recognition, delayed picture recognition, and rapid visual information processing.

Results:

• Of the 5 repeated measures ANOVAs conducted on the cognitive factor scores, only the ‘Working Memory’ factor reaching significance, with the BM group performance significantly improving over the treatment period. With reference to the single tasks that make up the ‘Working Memory’ factor, performance of the Spatial working memory (Accuracy) task was also improved.
• Rapid visual information processing was statistically significant in the BM group, with a significant reduction in the number of false alarms produced during this task.

Conclusion: Chronic consumption of BM over 90 days, showed improvements in ‘Working Memory’ performance, a specific improvement was noted on the accuracy scores of the Spatial Working Memory task. BM improves accuracy or ‘quality’ of performance long term.

Limitations: uneven distribution of male: female subjects (which was worse in the active group compared to placebo), no mention of limiting confounding factors such as taking other supplements, diet, or exercise. Time of day of the active taken or details about taking with or without food was not provided. Researchers note, a much larger sample size may result in more statistically significant results.

Strengths: larger sample size compared to previous studies

Adverse events: Negative symptoms reported included tiredness, fatigue, nausea, malaise, vomiting. The incidence of the other 52 positive and negative symptoms did not significantly differ between the two groups, suggesting the two treatments were reasonably well tolerated by both groups.

Safety evaluation: A nurse monitored positive and negative symptoms on a weekly basis; positive effects noted were feelings of increased energy, arousal, and cognitive clarity

Potential disclosures:

• Study location: India
• Mfg supplied material; no mention of funding

Notes: Although there were several tasks that were not significantly improved by the Bacopa monniera treatment, many of the statistical analyses trended towards an improvement in cognitive functioning in areas of attention, working memory and psychomotor tasks.

Additional reference (younger population group)

Kean, 2021. (chronic) Effects of Bacopa monnieri (CDRI 08®) in a population of males exhibiting inattention and hyperactivity aged 6 to 14 years: A randomized, double-blind, placebo-controlled trial

Claim summary:

• Over 30 years of scientific study
• Clinically demonstrated same-day effect
• Faster information processing and decision-making time
• Improves aspects of attention/freedom of distractibility
• Improves alertness and contentedness
• Provides an earlier nootropic effect than previously investigated
• Supports reasoning and cognitive speed even in healthy young individuals
• Long term use improves working memory performance
• Long term use improves accuracy or ‘quality’ of performance
• Improves age-associated memory loss as evidenced by mental control, logical memory, and digital forward scores in an older population
• Long term use decreases forgetting rate
• Long term use improves processing speed, verbal learning rate, and memory consolidation
• Long term use supports the transition of short-term memory to long term memory (memory consolidation)

Additional claims by the supplier can be found here: (Confidential PLT360 Synapsa Claims Dossier March 2019 with pubs)