Bacopa monnieri (50)

1. Tamboli et al. 2018. Comparative phytochemical evaluation of natural and micropropagated plants of Bacopa monnieri (L.)
2. Chaudhari et al. 2017. Neurocognitive Effects of Nootropic Drug Brahmi (Bacopa monnieri) in Alzheimer's Disease
3. Thakkar et al. 2017. Development and Optimization of Dispersible Tablet of Bacopa monnieri with Improved Functionality for Memory Enhancement
4. Mallick et al. 2017. Exploring the Cytotoxic Potential of Triterpenoids-enriched Fraction of Bacopa monnieri by Implementing In vitro, In vivo, and In silico Approaches
5. Jeena et al. 2017. Comparative transcriptome analysis of shoot and root tissue of Bacopa monnieri identifies potential genes related to triterpenoid saponin biosynthesis
6. Leung et al. 2017. The effect of Bacopa monnieri on gene expression levels in SH-SY5Y human neuroblastoma cells
7. Sharma et al. 2017a. Optimization of a Bacopa monnieri-based genetic transformation model for testing the expression efficiency of pathway gene constructs of medicinal crops
8. Khurshid et al. 2018. Effect of herb-drug interactions of Bacopa monnieri Linn. (Brahmi) formulation on the pharmacokinetics of amitriptyline in rats
9. Hosamani, Krishna & Muralidhara 2016. Standardized Bacopa monnieri extract ameliorates acute paraquat-induced oxidative stress, and neurotoxicity in prepubertal mice brain
10. Verma et al.2018. Development of Microbial Consortia for Growth Attributes and Protein Content in Micropropagated Bacopa monnieri (L.)
11. Bhatia et al. 2017. Bacopa monnieri extracts prevent hydrogen peroxide-induced oxidative damage in a cellular model of neuroblastoma IMR32 cells
12. Leonard et al. 2017. Statistical optimization for enhanced bacoside A production in plant cell cultures of Bacopa monnieri
13. Patel, Singh & Singh 2017. Standardized extract of Bacopa monnieri (CDRI-08): Effect on germ cell dynamics and possible mechanisms of its beneficial action on spermatogenesis and sperm quality in male mice
14. Piyabhan, Wannasiri & Naowaboot 2016. Bacopa monnieri (Brahmi) improved novel object recognition task and increased cerebral vesicular glutamate transporter type 3 in sub-chronic phencyclidine rat model of schizophrenia
15. Promsuban et al. 2017. Bacopa monnieri extract enhances learning-dependent hippocampal long-term synaptic potentiation
16. Mitra-Ganguli et al. 2017. A randomized, double-blind study assessing changes in cognitive function in Indian school children receiving a combination of Bacopa monnieri and micronutrient supplementation vs. placebo
17. Tanwar et al. 2016. Effect of Bacopa monnieri Extract on Storage and Microbial Quality of Vacuum Packaged Chicken Nuggets
18. Kishore, Kaur & Singh 2016. Renoprotective effect of Bacopa monnieri via inhibition of advanced glycation end products and oxidative stress in STZ-nicotinamide-induced diabetic nephropathy
19. Jain et al. 2017. Toxicity assessment of Bacopa monnieri L. grown in biochar amended extremely acidic coal mine spoils
20. Al-Hasawi 2017. A Comparative Study of the Polysialylation Inhibition in the Kelly Neuroblastoma Cell Line by Withania somnifera and Bacopa monnieri Extracts
21. Ullah et al. 2017. Action of Bacopa monnieri to antagonize cisplatin-induced emesis in Suncus murinus (house musk shrew)
22. Mishra, Mishra & Jha 2018. Effect of traditional medicine brahmi vati and bacoside A-rich fraction of Bacopa monnieri on acute pentylenetetrzole-induced seizures, amphetamine-induced model of schizophrenia, and scopolamine-induced memory loss in laboratory animals
23. Srimachai et al. 2017. Bacopa monnieri extract increases rat coronary flow and protects against myocardial ischemia/reperfusion injury
24. Kishore, Kaur & Singh 2017. Bacosine isolated from aerial parts of Bacopa monnieri improves the neuronal dysfunction in Streptozotocin-induced diabetic neuropathy
25. Muszyńska et al. 2016. In vitro cultures of Bacopa monnieri and an analysis of selected groups of biologically active metabolites in their biomass
26. Sarkar & Jha 2017. Morpho-histological characterization and direct shoot organogenesis in two types of explants from Bacopa monnieri on unsupplemented basal medium
27. Shahid et al. 2017. Neuroprotective effect of Bacopa monnieri against morphine-induced histopathological changes in the cerebellum of rats
28. Charoenphon et al. 2016. Brahmi (Bacopa monnieri): Up-to-date of memory boosting medicinal plant: A review
29. Singh et al. 2017. Role of ethanolic extract of Bacopa monnieri against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mice model via inhibition of apoptotic pathways of dopaminergic neurons
30. Saoji et al. 2017. The role of phospholipid as a solubility- and permeability-enhancing excipient for the improved delivery of the bioactive phytoconstituents of Bacopa monnieri
31. Chen & Yang 2017. Pharmaceutical composition and drug effect of synthetic Bacopa monnieri L. health promoting agent from the perspective of resistance fatigue
32. Kean, Downey & Stough 2017. Systematic Overview of Bacopa monnieri (L.) Wettst. Dominant Poly-Herbal Formulas in Children and Adolescents
33. Shahid et al. 2017. A bacosides containing Bacopa monnieri extract alleviates allodynia and hyperalgesia in the chronic constriction injury model of neuropathic pain in rats
34. P. Jain et al. 2017. Phytochemical analysis of Bacopa monnieri (L.) Wettst. and their anti-fungal activities
35. Gupta et al. 2017a. Microbial interference mitigates Meloidogyne incognita mediated oxidative stress and augments bacoside content in Bacopa monnieri L.
36. Patel et al. 2017. Effect of standardized extract of Bacopa monnieri (CDRI-08) on testicular functions in adult male mice
37. Christopher et al. 2017. Elite genotypes of Bacopa monnieri, with high contents of Bacoside A and Bacopaside I, from southern Western Ghats in India
38. Nemetchek et al. 2017. The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain
39. Mallick et al. 2015. Evaluation of anticancer potential of Bacopa monnieri L. against MCF-7 and MDA-MB 231 cell line
40. Rency et al. 2017. In vitro propagation and genetic fidelity analysis of alginate-encapsulated Bacopa monnieri shoot tips using Gracilaria salicornia extracts
41. Jasim et al. 2017. Bacopaside N1 biosynthetic potential of endophytic Aspergillus sp. BmF 16 isolated from Bacopa monnieri
42. McPhee et al. 2016. Cognitive training and Bacopa monnieri: Evidence for a combined intervention to alleviate age associated cognitive decline
43. Hazra et al. 2017. Reversion of BDNF, Akt and CREB in Hippocampus of Chronic Unpredictable Stress Induced Rats: Effects of Phytochemical, Bacopa Monnieri
44. Phulara et al. 2015. Bacopa monnieri promotes longevity in Caenorhabditis elegans under stress conditions
45. Kean et al. 2015. A Randomized Controlled Trial Investigating the Effects of a Special Extract of Bacopa monnieri (CDRI 08) on Hyperactivity and Inattention in Male Children and Adolescents: BACHI Study Protocol (ANZCTRN12612000827831)
46. Tanwar, Kumar & Pankaj 2017. Effect of Bacopa monnieri extracts on storage quality of chicken nuggets at refrigeration temperature (4 ± 1°C)
47. Kean, Downey & Stough 2016. A systematic review of the Ayurvedic medicinal herb Bacopa monnieri in child and adolescent populations
48. Ramasamy et al. 2015. In Silico and In Vitro Analysis of Bacoside A Aglycones and Its Derivatives as the Constituents Responsible for the Cognitive Effects of Bacopa monnieri
49. Das et al. 2016. Bacopa monnieri-Induced Protective Autophagy Inhibits Benzo[a]pyrene-Mediated Apoptosis
50. Gupta et al. 2017b. Chitinolytic microbes confer Meloidogyne incognita resistance and augment secondary metabolites in Bacopa monnieri (L.) Pennell

• Bacopa monnieri (51-100)

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Tamboli, Firoj A.; Vinod D. Rangari, Suresh G. Killedar, Sagar U. Jadhav, Trupti S. Ghatage and Vishwajeet P. Kore 2018. Comparative phytochemical evaluation of natural and micropropagated plants of Bacopa monnieri (L.). Marama Pharmaceutical Journal 22(1): 66-73. DOI: 10.12991/mpj.2018.42

Bacopa monnieri is a highly valuable medicinal plant from the Scophulariaceae family has been proven its importance majorly in relation to botanical, commercial, ethnopharmacological, phytochemical, pharmacological and toxicological studies. It is distributed in the wet and marshy lands throughout India, Nepal, Sri Lanka, China, Taiwan, and Hawaii. It shows the presence of alkaloids (nicotine, brahmin, herpestine), saponins (hersaponin, betulic acid and bacosides) and other chemicals like stigmastanol, betasitosterol, and stigmasterol. It is found to be effective in several neurological disorders like anxiety and neurosis. It is also used in anti-inflammatory, antioxidant, analgesic and antipyretic activity, treat asthma, insanity, epilepsy, hoarseness, enlargement of spleen, snake bite, rheumatism, leprosy, eczema and ringworm, it is also used as a diuretic, appetitive and cardio tonic. (Tamboli et al. 2018: 66)

Does nootropic use qualify as ethnopharmacology? I ordered some online, but the packaging says it is used for hair care. I'm hoping that it's not mixed with anything and should work fine as a tea. "Hoarseness" is also mentioned somewhere online (found when searching for its use as a hair care product); defined as "(of a person's voice) sounding rough and harsh, typically as the result of a sore throat or of shouting." In Ayurvedic qualities: Svarya, Svarada - "improves quality of voice" (here).

Bacopa monnieri is a herb of medicinal importance which has many proven beneficial pharmacological activity. Due to the pharmacological importance and commercial value of the plant, over exploitation from natural resources is taking place and putting this herb at the edge of endangered species. (Tamboli et al. 2018: 66)

Below, "The original brahmi is an ancient Ayurvedic herb which has been extinct for centuries" - and this may happen again.

Chaudhari, Kaustubh S.; Nishant R. Tiwari, Rakesh R. Tiwari and Rohan S. Sharma 2017. Neurocognitive Effects of Nootropic Drug Brahmi (Bacopa monnieri) in Alzheimer's Disease. Annals of Neurosciences 24(2): 111-122. DOI: 10.1159/000475900

Ayurvedic herbal medications are increasingly researched due to their biosafety profile and usefulness in cognitive impairment. In this article, we critically reviewed one such Medhya Rasayana (nootropic drug) Brahmi - derived from extract of Bacopa monnieri (EBm). Studies have shown that EBm promotes free radical scavenger mechanisms and protects cells in prefrontal cortex, hippocampus, and striatum against cytotoxiity and DNA damage implicated in AD. It also reduces lipoxygenase activity reducing lipid peroxidation, increases glutathione peroxidase and chelates iron. (Chaudhari et al. 2017: 111)

Does "biosafety profile" mean "considerable protection against age-related neurodegeneration rather than progressive toxicity or tolerance formation" (Aguiar & Borowski 2013: 314)?

The neuroprotective effect of EBm is also due to nitric oxide-mediated cerebral vasodilation. EBm improved the total memory score and maximum improvement was seen in logical memory and paired associate learning in humans and reversed phenytoin-induced memory impairment in experimental model. (Chaudhari et al. 2017: 111)

Cerebral vasodilation may account for the subjective experience of half-meditative or half-conscious sleep when taken in a generous quantity before going to bed.

Ayurveda or the Indian system of Medicine viz. Sushruta Samhita, Charak Samhita and Atharva Veda describe plants which have a prabhava [|] (specific action) on the intellect and memory as Medhya Rasayana (Medhya - intellect or retention, Rasayana - procurement or preparation). (Chaudhari et al. 2017: 112-113)

Evidently there is a whole system of "pharmacodynamic" terminology. Interestingly, the source used here (Kulkarni, Girish & Kumar 2012) lead me to this online source which explains that "The original brahmi is an ancient Ayurvedic herb which has been extinct for centuries", and Kulkarni et al. call Bacopa monnieri... Aindri. It looks a bit like brahmi might be a myth. Aindri is one of the names of the Hindi god Indrani, queen of Indra, "the goddess of wrath and jealousy". Might this have something to do with "hoarseness" and the so-called "soul-calming properties" of bacopa?

This study [Kamkaew et al. 2013] showed that chronic administration of EBm and G. biloba increased the cerebral blood possibly contributing to their nootropic and neuroprotective action. (Chaudhari et al. 2017: 117)

Ginkgo and Bacopa "shar[e] similarities in their mechanism of action" and "administration of two extracts in combination may have a better efficacy im improving cognitive function in normal healthy subjects" (Nathan et al. 2001: 163)

Limited studies are available demonstrating the side effects of Brahmi in human beings as well as animals. The most commonly encountered side effects are nausea, gastrointestinal upset, intestinal hypermotility which can be explained on the basis of cholinergic action of EBm. (Chaudhari et al. 2017: 118)

The extracts with higher bacoside content are pretty much laxatives at higher doses. The untreated plant material sold for hair care (not extracted with acetone and methanol) do increase appetite and the frequency of bowel movements, but it doesn't call out a complete flush.

Although libido remained unaffected in Brahmi treated rats, fertility was markedly reduced. EBm had no effect on dopamine and serotonin balance in rat brain, so there was no constitutional change as it is seen with other antidepressants. (Chaudhari et al. 2017: 118)

Now this is important. Possibly why it's not habit inducing or tolerance forming. Needs to be examined further because various sources claim that "Bacopa monnieri interacts with the dopamine and serotonergic systems", leaving it as vague as that.

Thakkar, Vaishali Tejas; Amol Deshmukh, Lal Hingorani, Payal Juneja, Lalji aldaniya, Asha Patel, Tosha Pandya, and Mukesh Gohel 2017. Development and Optimization of Dispersible Tablet of Bacopa monnieri with Improved Functionality for Memory Enhancement. Journal of Pharmacy & Bioallied Sciences 9(3): 208-215. DOI: 10.4103/jpbs.JPBS_8_17

In the current years, focus is given to the needs of the patients while developing a formulation. Children shall be provided with medicines that are designed according to their needs. Children with the age of more than 12 years can swallow a solid oral dosage form (SODF) of reasonable size. A large percentage of the children within the age group of 6-12 years find it difficult to swallow SODF. The formulators are left with two options. A liquid dosage form can be developed for such patients. However, the issue of stability and large volume to be administered must be handled. The second option is to formulate dispersable tablets, which takes care of the two issues of stability and large volume to be administered. (Thakkar et al. 2017: 208)

Stability concerning the copious amount needed to achieve a palpable effect (the the merrier; 300-450 mg extract per day will do but is considered a low dose; best results - from online sources - stand at 750) and the length of time necessary (12 weeks of chronic administration shows improvement). Dispersion tablets are those water-soluble fizzy pills (e.g. C-vitamin for kids).

The Bacopa monnieri is traditional Ayurvedic medicine, and reported for memory-enhancing effects. The Bacoside is poorly soluble, bitter in taste and responsible for the memory enhancement action. Memory enhancer is commonly prescribed for children or elder people. (Thakkar et al. 2017: 208)

The poor solubility may be further looked into in terms of the organic interactions with drugs in the Ayurvedic system. The bitter taste I would describe as "salty". I once opened a Bacognize (tm) capsule and tipped my tongue in it, can't even describe the stingy and repulsive taste. Untreated plant material tea is less obnoxious (even as mild as Gotu kola extract, which has practically no taste) and reminds the extract only when hot water is poured on a higher quantity. Currently testing DIY solution, hot water + wine.

Brahmi is extensively used to for memory enhancement and to enhance learning by the students. It has ability to enhance cognitive function. Study on brahmi has been conducted in children and also in alzheimer's patient. B. monnieri contains various alkaloids such as brahmin, herpestine, saponins, monierin, and hersaponin. The key active herbal principle is reported to be Bacoside A, which is poorly water soluble and bitter in taste. (Thakkar et al. 2017: 208)

The "conducted in children" phrase cites Martis & Rao 1992. "Neuropharmacological activity of Herpestis menniera". This used to be a synonym of Bacopa monnieri. Also Lysimachia monnieri and Graticola monnieri. Likewise with "jalabrahmī" (जलब्रह्मी/जलब्राह्मी) - which means "water/borne", thus Estonian "säsi-vesikaak" makes more sense.

Mallick, Mohammad Nasar; Washim Khan, Rabea Parveen, Sayeed Ahmad, Sadaf, Mohammad Zeeshan Najm, Istaq Ahmad and Syed Akhtar Husain 2017. Exploring the Cytotoxic Potential of Triterpenoids-enriched Fraction of Bacopa monnieri by Implementing In vitro, In vivo, and In silico Approaches. Pharmacognosy Magazine 13: S595-606. DOI: 10.4103/pm.pm_397_16

Bacopa monnieri (BM) is a herbaceous plant traditionally used from time immemorial in Ayurvedic and folklore medicines. We hpothesized that the extract of the whole plant might contain numerous molecules with having antitumor activities that could be very effective in killing human cancer cells. (Mallick et al. 2017: 595)

Timeline still unclear. The year 1200 comes to mind, and yet some claim 3000 years of use, some only a few hundred years.

The plant Bacopa monnieri (BM) (L.), is a traditional Ayurvedic plant, used for centuries as a memory enhancing, anti-inflammatory, antipyretic, sedative, antiepileptic agent, nervine tonic, anti-tumor agent, anti-Parkinson's agent, cardiotonic agent, protective effect, anti-Alzheimer's drug, hepatoprotective agent, antimicrobial agent, and adaptogenic agent. It is found in wetlands throughout the Indian subcontinent and locally known as Brahmi or Jalanimba. Antioxidant properties of Bacopa may postulate protection from free radical damage in cardiovascular disorder and certain types of cancer. The plant is reported to have cytotoxic potentials due to the presence of triterpenoid saponins such as bacoside A, bacoside B, brahmine, and herpestine. (Mallick et al. 2017: 596)

As impressive and variable list as any other.

The reliable principles of arbitrating the healthier value of any anticancer drug are the loss of leukemia cells from the blood, reduction of solid tumor volume, and prolongation of life span. Tumor grafting includes a local inflammatory reaction, with increasing vascular penetrability resulting in an intense ascetic fluid accumulation. Our results showed a significant reversal of tumor regression parameters complemented by a reduction in WBC count in BDM treated mice. The DCM/enriched fraction also constrained the accumulation of ascetic fluid in the peritonal cavity of the tumor-bearing animals. Above results clearly revealed the antitumor effect of BM on EAC tumor cells. (Mallick et al. 2017: 601)

Good. Bacopa monnieri is an effective anticancer drug at least against some forms of cancer.

Jeena, Gajendra Singh; Shahnoor Fatima, Pragya Tripathi, Swati Upadhyay, and Rakesh Kumar Shukla 2017. Comparative transcriptome analysis of shoot and root tissue of Bacopa monnieri identifies potential genes related to triterpenoid saponin biosynthesis. BMC Genomics 18: 1-15. DOI: 10.1186/s12864-017-3865-5

Bacopa monnieri commonly known as Brahmi is utilized in Ayurveda to improve memory and many other human health benefits. Bacosides enriched standardized extract of Bacopa monnieri is being marketed as a memory enhancing agent. (Jeena et al. 2017: 1)

They keywords here are "enriched", referring to the processed extract, and "marketed", as in, it is "commonly known" as Brahmi instead of Aindri because it may not necessarily be the exact plant the monks used to memorize lengthy hymns.

In the conventional system of Indian medicine, Bacopa is well treated as a drug to augment intelligence and memory function and cobat the effects of mental stress. It is also used for gastrointenstinal infections, rejuvenation, skin disorders, epilepsy, pyrexia and analgesia. Apart from that Bacopa monnieri extract is familiar to possess potent antioxidant and anticancer propertes. Bacopa monnieri has many efficacious compounds in addition to alkaloids, flavonoids, betulic acid, stigmasterol, beta-sitosterol and saponins (bacoside A, bacoside B, bacopasaponin C, bacopaside I, bacopaside II, bacopaside X, bacopaside N2). (Jeena et al. 2017: 2)

Evidently they've discovered new compounds since my last readings.

Evaluation and extraction of bacosides from areal part of the plant using HPLC chromatographic technique have been performed and reported that highest concentration of bacoside A is present in stolon (9.54 mg/g dry wt) followed by leaves (4.73 mg/g dry wt) and roots. (Jeena et al. 2017: 2)

Significantly more exact than the online sources which say that all of the plant, including the roots, can be used. It may be true, but is inexact. Stolons are the "runners" or creeping horizontal plant stems. Latin for "branch".

Some include the description of genes encoding enzyme catalized metabolic steps mediated in the biosynthetic pathway of artemisinian in Artemisia annua [sweet wormwood], withanolides in Withania somnifera [ashwagandha], cannabinoids in Cannabis sativa, ginsenosides in Panax ginseng, glycyrrhizin in Glycyrrhiza uralensis [Chinese liquorice], picrosides in Picrorhiza kurroa [Kutki], cardiac glycosides in Calotropis procera [Sodom apple], menthol content in Mentha species, medecinal diterpene in Andrographis paniculata and biosynthesis of steroidal saponins in Asparagus racemosus [Shatawari]. (Jeena et al. 2017: 2)

An interesting list of plants.

The present manuscript has studied the comparative de novo transcriptome analysis of shoot and root tissue of Bacopa monnieri. The identified transcript from shoot and root will further be useful to understand the biosynthetic pathway of pharmacologically useful secondary metabolite present in different tissues of B. monnieri. (Jeena et al. 2017: 10)

I am increasingly suspicious of the bacoside A enriched extracts, which exclude these secondary metabolites. I've been thinking about one of the above papers (Thakkar et al. 2017) in which a water-soluble tablet for children is made. Are the authors even aware of Brahmi Ghee traditionally mixed with honey and other spices to make it palatable for children?

The transcriptional regulatory responses of these transcripts after MeJA treatment and wounding would be useful further to identify transcripts responsive to elicitation. The above information can be utilized as an effective component through genetic engineering for enhancing the metabolite content. (Jeena et al. 2017: 12)

Whereas some express concern about the future status of the plant with regards to its commercial application, e.g. it becoming endangered (Tamboli et al. 2018), here the idea seems to be to create a version of the plant that has a higher bacoside yield. Though there could arise a between historical indigenous use and patents on plant-derived drugs by western pharmaceutical companies, or biopiracy, like has occurred with Catharanthus roseus.

Leung, How-Wing; Gabriel Foo, Gokulakrishna Banumurthy, Xiaoran Chai, Sujoy Ghosh, Tora Mitra-Ganguli and Antonius M. J. VanDongen 2017. The effect of Bacopa monnieri on gene expression levels in SH-SY5Y human neuroblastoma cells. PLoS ONE 12(8): 1-21. DOI: 10.1371/journal.pone.0182984

Bacopa monnieri is a plant used as a nootropic in Ayurveda, a 5000-year-old system of traditional Indian medicine. Although both animal and clinical studies supported its role as a memory enhancer, the molecular and cellular mechanism underlying Bacopa's nootropic action are not understood. (Leung et al. 2017: 1)

Wikipedia says that "Ayurveda therapies have varied and evolved over more than two millennia" and that "The central theoretical ideas of Ayurveda developed in the mid-first millennium BCE". So timeline is still uncertain.

Notwithstanding its wide availability, the mechanisms of action of Bacopa have yet to delineated. Several mechanisms have been proposed concerning the nootropic effects of Bacopa. These included alterations of the levels of several neurotransmitters, including serotonin (5-hydroxytryptamine, 5-HT), acetylcholine and dopamine. Elevation of the neurotransmitter 5-HT resulted in activation of cAMP response element-binding protein (CREB) and subsequent changes in transcription, protein phosporylation and histone modification. Other research groups have suggested that Bacopa regulate pre- and post-synaptic proteins and induce the formation of new dendrites. These proposed mechanisms are not mutually exclusive and the discrepanicies could be attributed to a selective bias in the targets that were investigated by each research group. (Leung et al. 2017: 2)

Hah, "no effect on dopamine and serotonin balance" (Chaudhari et al. 2017: 118), my ass.

Cells showed a differentiated neuronal phenotype (formation of extensive neurites) after 3-5 days. (Leung et al. 2017: 5)

Phraseology for what's going on here.

[...] listing [1] the biological processes, [2] cellular components and [3] molecular functions affected by Bacopa treatment. Many of the affected biological processes referred to functions that were of critical importance in the central nervous system. [Primarily: (1) Positive regulation of protein kinase activity; Regulation of nervous system development; Oxygen transport; Regulation of synaptic transmission; Cellular calcium ion homeostasis; (2) Extracellular vesicle; Cytoskeletal part; Ribonucleoprotein complex; Cell projection; Neuron projection; (3) RNA binding; Substrate-specific transporter activity; Oxidoreductase activity; Transcription factor binding; Heme binding] (Leung et al. 2017: 7)

Interestingly, statistically the most relevant aspects are pretty much in line with what I've already gathered from various studies, e.g. protein kinase activity; neuron projection; oxidoreductase activity.

The most striking finding was the Neuroplastin gene (NPTN), because a single nucleotide polymorphism (SNP) in the Neuroplastin locus associates with cortical thickness and intellectual ability in adolescents. Neuroplastin is a synaptic glycoprotein involved in long-term potentiation (LTP) in hippocampal CA1 synapses that modulates neuritogenesis and neuronal plasticity. (Leung et al. 2017: 7)

It certainly sounds like the mechanism between the adage that Bacopa doesn't make you learn more but makes you forget less.

Six Biological Functions were preducted to be inhibited by Bacopa treatment, including (1) organismal death, (2) damage of brain, (3) apoptosis and (4) synthesis of reactive oxygen species (ROS), and (5) growth failure. Note that the activation states of these disease-related categories were decreased by Bacopa treatment. Many of these Bacopa effects would therefore be expected to contribute to increased brain health and improved brain development. (Leung et al. 2017: 13)

Much more concrete than the regular listing of positive effects, some of which have a definite ring of being anecdotal.

A gene ontology analysis of the mRNA affected by Bacopa indicated effects on brain development, Ca²⁺ and K⁺ ion homeostasis, synaptic function and long-term potentiation, providing the first mechanistic support for the well-published nootropic effects of Bacopa on cognitive function and memory performance. (Leung et al. 2017: 14)

This study does indeed provide an array of possible mechanisms of action that could explain the published and anecdotal data on the effects of Bacopa monnieri.

Overexpression of superoxide dismutase in aged mice exhibited enhanced hippocampal LTP, better cerebellum-dependent motor learning and better hippocampus-dependent spatial learning. Similarly, rats exposed to another antioxidant, Curcumin, also had improved memory retention. Identification of the exact subset of genes of the oxidative stress response pathway that are controlled by Bacopa now enables more mechanistic studies of the neuroprotective effects of Bacopa. (Leung et al. 2017: 15)

The possible positive interaction of BM with Ginkgo biloba has been somewhat frequently reported, but this made me consider including Curcumin in my Bacopa+ regimen (I've heard about the positive anti-inflammatory effects of Curcumin with black pepper before, from "What I've Learned" on Youtube). Thus far (in this series) this was the best paper. Kiitos to the authors.

Sharma, Abhishek; Neha Verma, Priyanka Verma, Ram Kishor Verma, Archana Mathur and Ajay Kumar Mathur 2017a. Optimization of a Bacopa monnieri-based genetic transformation model for testing the expression efficiency of pathway gene constructs of medicinal crops. In Vitro Cellular & Developmental Biology - Plant 53(1): 22-32. DOI: 10.1007/s11627-017-9804-y

Synthetic biology and metabolic engineering of plants are providing new opportunities in agriculture and medicines (Gandhi et al. 2015). Controlled modulation of plant metabolic pathways in homogenous or heterologous systems is one such opportunity relevant for food, nutrition, and healthcare (Sainsbury and Lomonosssoff 2014; Farré et al. 2015). Methods for the introduction of foreign genes to modify or reconstitute a metabolic trait have now been validated in more than 150 higher plants species (Abiri et al. 2015). (Sharma et al. 2017a: 22)

This was only suggested in one paper above (cf. Jeena et al. 2017: 12) but apparently work is already underway.

Ideally, such model systems must possess a high level of morphogenic totipotency, a short in vitro regeneration cycl and competence for transgene uptake. (Sharma et al. 2017a: 23)

Now that is a lexical finding: the ability of a single cell to divide and produce all of the differentiated cells in an organism, e.g. spores and zygotes. When carried over into linguistic functionalism it could go well with a potiori.

The aims of the present study were to develop a protocol that would rapidly produce buds from leaf explants and to optimize an Agrobacterium tumefaciens-mediated transformation protocol in the medicinal herb Bacopa monnieri. Gene constructs contained the terpenoid indole alkaloid (TIA) pathway from Catharanthus roseus were tested for heterologous expression. B. monnieri is a nootropic herb that produces triterpenoid saponins called bacosides, which are reported effective for neutralizing mental stress, epileptic disorders, and improving memory functions (Sivaramakrishna et al. 2005; Mathew et al. 2010). (Sharma et al. 2017a: 23)

I highlighted only the mental stress effect but the three effects here listed are essentially (1) anxyolytic (elevation of serotonin, maybe the GABA mechanism); (2) the effect on cellular calcium ion homeostasis; and (3) regulating pre- and post-synaptic proteins.

The lack of transgenic research in B. monnieri is largely accounted for by two reasons. Firstly, almost the entire supply of raw herb to the pharma industry is met through collection from wild forests rather than the cultivation of this herb. Secondly, the biosynthetic pathways of the saponins and sapogenins (bacosides) in B. monnieri remain undefined such that deliberate engineering of their genes cannot be attempted. (Sharma et al. 2017a: 29)

So, actually there is some merit to the claim that "Due to the pharmacological importance and commercial value of the plant, over exploitation from natural resources is taking place and putting this herb at the edge of endangered species." (Tamboli et al. 2018: 66)

Khurshid, Fowad; Jeyabalan Govindasamy, Habibullah Khalilullah, Mohammad Shivli Nomani, Mudassar Shahid, Mohammad Ruhal Ain and Mohammad Sultan Alsultan 2018. Effect of herb-drug interactions of Bacopa monnieri Linn. (Brahmi) formulation on the pharmacokinetics of amitriptyline in rats. Brazilian Journal of Pharmaceutical Sciences 53(4): e17072. DOI: 10.1590/s2175-97902017000417072

Interactions between herbs and drugs may increase or decrease the pharmacological or toxicological effects of either component. Experimental data on the pharmacokinetic interactions between herbal products and drugs are limited [...] This study concluded that B. monnieri significantly enhanced the oral bioavailability of amitriptyline in rats. (Khurshid et al. 2018: 1)

Ah, finally I have a chance to forward an anecdotal personal experience: consumed a low dose of lysergic acid diethylamide alongside a copious amount of Bacopa and the resulting trip lasted nearly twice as long as a regular acid trip, was much more pleasant (experienced very mindful meditation), and it may be noteworthy to remark that the combination heightened the sense of hearing (I could discern the footsteps of resident Blattella germanica during the night and experimented with their Umwelten - turns out they're much less responsive to light and tapping vibrations than they are to breath blown their way).

Bacopa monnieri, a perennial herb, belongs to the family, Scrophulariceae and is commonly known as Brahmi in the Ayurvedic system of medicine. It has been widely employed as a brain stimulator, antidepressant, and memory enhancer (Stough et al. 2001). (Khurshid et al. 2018: 1)

At the end of this series I should do what I left undone after the first, namely write up a summary in my native Estonian. I've chosen to title it, tentatively, as "Säsi-vesikaak kui ajukasvataja" ('Waterhyssop as brain-grower').

The above-mentioned findings have been strengthened by several clinical studies (Stough et al. 2001; Roodenrys 2002; Calabrese et al. 2008) that ascribed the observed antidepressant effects to its phytochemical constituents, known as bacoside. (Khurshid et al. 2018: 2)

Phraseological findings: "observed" because the exact mechanisms of action still require much further research; and "phytochemical constituents" would go well with "biosafety profile" as headings.

Recently, a study conducted to evaluate the effects of a standardized extract of B. monnieri on the expression and activity of hepatic and intestinal cytochrome P450 3A and P-glycoprotein (Pgp) in rats revealed that administration of B. monnieri for 7 days modulated the expression of CYP3A and Pgp. Administration of B. monnieri led to a reduced expression of CYP3A and concomitant decrease in the CYP3A-dependent testosterone hydroxylase catalytic activity in liver and intestine (Singh et al. 2013). Another study reported similar findings that B. monnieri moderately inhibited CYP2C19, CYP2C9, CYP1A2, and CYP3A4 but weakly inhibited CYP2D6 (Ramasamy, Kiew, Chung 2014). These findings indicated towards the possible potential of B. monnieri to contribute to herb-drug interactions when orally co-administered with drugs metabolized by CYP1A2, CYP2A4, CYP2C9, and CYP2C19. Based on this hypothesis, the plasma levels of drug administered concomitantly could be elevated by inhibition of drug-metabolizing enzymes to prolong the pharmacological effects of the drug, thereby increasing the incidence of drug-induced toxicity (Hu et al. 2005). (Khurshid et al. 2018: 8)

This would explain my above-mentioned recreational drug experience. It also means that I'd better be careful with long-term use (12 weeks?), and perhaps institute the schedule practiced by Paul Stamets (heard on Joe Rogan podcast on Youtube), i.e. giving your body a break from micro-dosing and the like during the weekends.

Hosamani, Ravikumar; Gokul Krishna and Muralidhara 2016. Standardized Bacopa monnieri extract ameliorates acute paraquat-induced oxidative stress, and neurotoxicity in prepubertal mice brain. Nutritional Neuroscience 19(10): 434-446. DOI: 10.1179/1476830514Y.0000000149

Clinical trial data have reported Bacopa extract to be neurobeneficial in improving various neurocognitive aspects in children and to abrogate neurotoxic effects of metals such as aluminum. (Hosamani, Krishna & Muralidhara 2016: 434)

Lexical finding. Sounds like a synonym for "adaptogenic" and the like. Google search gives several results on the front page related to Bacopa (i.e. this and this), though this might have something to do with my searching for BM so frequently as of late.

At the end of experiments, the animals were decapitated. The brain was taken out, rinsed with saline to remove the blood and subsequently dissected on an ice-cold surface to obtain the cortex, cerebellum, hippocampus, and striatum. From each brain region, cytosol and mitochondrial moieties were prepared, subjected to the assessment of various biochemical parameters and DA levels. (Hosamani, Krishna & Muralidhara 2016: 436)

I'm recording this for a possible piece of fiction writing where giant mice exercise the same routine on humans.

As shown in Table 5, mice administered with BM showed slight increase in body weight as compared with the control group at week 4. However, no significant difference was observed in food intake between control and BM-fed mice (data not shown). Further, mice fed with BM did not show any observable pathological signs or behavioral abnormalities during the feeding period. (Hosamani, Krishna & Muralidhara 2016: 438)

Uh-oh, does this imply a weight gain even without a change in diet when chronically administered to human subjects? Concerned.jpg

Verma, Jay Prakash; Kavindra Nath Tiwari, Janardan Yadav and Awadesh Kumar Mishra 2018. Development of Microbial Consortia for Growth Attributes and Protein Content in Micropropagated Bacopa monnieri (L.). Proceedings of the National Academy of Sciences India Section B - Biological Sciences 88(1): 143-151. DOI: 10.1007/s40011-016-0743-x

Bacopa monnieri (L.) used as medicinal plant since 5000 BC in the Ayurvedic system of medicine. (Verma et al. 2018: 143)

Oh lord. Just last year it was reported to be "a 5000-year-old system of traditional Indian medicine" (Leung et al. 2017: 1), now it jumped to 7000. There seems to be no consensus in these publications about the age of Ayurveda.

This is a nerve tonic to improve mental health, memory and intellect and to promote youthful vitality. (Verma et al. 2018: 143)

This is a first. There is a number of long lists of putative effects but 15 papers into this subject (total), I've never noticed anyone mention youthful vitality.

This belongs to the family Scrophulariaceae and commonly known as Pennell (Indian Pennywort). (Verma et al. 2018: 143)

I was wondering what Pennell means - thought it was a plant system designator, like Linnaeus (because it commonly occurs after L.").

Two saponins namely bacoside A and B are known as "memory chemicals" (Rastogi, Pal & Kulshreshtha 1994; Singh & Dhawan 1997). It has a great market demand and economy value due to its high medicinal properties such as analgesic, anticancer, [|] antioxidant, adaptogenic, antidepressant, antianxiety and anti-epileptic effects. (Verma et al. 2018: 143-144)

Sadly the two sources calling bacosides memory chemicals are not available online.

High biomass production of B. monnieri has an important use in preparation of herbal formulation by pharmaceutical industries as well as for isolated important phytoconstituents for the preparation of herbal medicine. Due to over exploitation and poor seed viability B. monnieri is listed in threatened category (Tiwaly, Tiwaly & Singh 2001). (Verma et al. 2018: 144)

Hard to believe that the stuff is marketed as a hair care product then. Thankfully this source is available.

Ahmad et al. reported that the mechanisms of PGPR and PGPF are the biological nitrogen fixation, solubilization of mineral phosphates and other macro and micronutrients, production of phytohormones, vitamins, enzymes, siderophore and biocontrol agents (antibiotics hydrogen cyanide and/or fungicidal compounds) to inhibit soil borne phytophatogen. Several reports have been discussed the use of bioinoculants such as PGPR for enhancing growth and biomass yield of different medicinal and aromatic crops. Rhizosphere bacteria and mycorrhiza have been reported to increase the secondary metabolite contents (triterpenoids) in the medicinal plants like Artemisia annua and Centella asiatica. Current studies highlight the role of PGPR and PGPF in enhancing protein as well as the secondary metabolite contents in micropropagated plants of B. monnieri. Certain positive and associative microbial activities can be suppressed as a low-input biotechnology to help sustainable and environmentally friendly practices for stability and productivity of both agricultural systems and natural ecosystems. Therefore, the present study is aimed to develop an efficient microbial consortium for the plant growth and protein content of B. monnieri, which can contribute to higher accumulation of secondary metabolite contents. (Verma et al. 2018: 144)

That's one solution to the problem of increasing the contents of bacosides in micropropagated crops. The "genetic engineering for enhancing the metabolite content" (Jeena et al. 2017: 12) may be hampered by the fact that "the biosynthetic pathways of the saponins and sapogenins (bacosides) in B. monnieri remain undefined such that deliberate engineering of their genes cannot be attempted" (Sharma et al. 2017: 29). Can't get into the plant? Then figure a way to surround it.

Bhatia, Gaurav; Vikram Dhuna, Kshitija Dhuna, Manpreet Kaur and Jatinder Singh 2017. Bacopa monnieri extracts prevent hydrogen peroxide-induced oxidative damage in a cellular model of neuroblastoma IMR32 cells. Chinese Journal of Natural Medicines 15(11): 834-846. DOI: 10.1016/S1875-5364(18)30017-7

The ratio of oxidants and antioxidants determines the cellular redox status. Any imbalance between these two defines the oxidative state of the cell, leading to apoptosis or necrosis. The brain cells are highly susceptible to oxidative insults, mainly due to reactive oxygen species (ROS). Oxygen itself is a comparatively unreactive compound but can be metabolized in vivo to form highly reactive free radicals, which include superoxide anions, hydroxyl radicals, and many other reactive species. These free radical species play an important role in the pathophysiology of many neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HT), ischemia, and aging. (Bhatia et al. 2017: 834)

Been seeing "free radical scavenger" and "ROS" so frequently here that it may be worth while to record this general overview.

Today, the conventional medicines, including antibiotics, are ineffective against many serious diseases and therefore herbal renaissance is emerging all over the world. In Ayurvedic medicinal system, Bacopa monnieri Linn. (Scrophulariaceae), commonly known as "Brahmi", has been used as a well-known nerve relaxant and cognition-enhancer. The bioactive components of Brahmi such as alkaloids, brahmine, herpestine, bacosides and bacosaponins are well known for their protective effects. The constituents responsible for Bacopa's cognitive effects are bacosides A and B. (Bhatia et al. 2017: 835)

Like "youthful vitality", "nerve relaxant" is somewhat too general, but nevertheless useful overall. Nerve relaxant combines "nerve tonic" with BM's anxiolytic (anti-anxiety) effect.

Earlier studies have also supported this protective potential of B. monnieri. Besides B. monnieri extracts, aqueous and alcoholic extracts of some other plants like Rosmarinus officinalis and Lonicera japonica have also been known to protect against H₂O₂ induced oxidative stress. (Bhatia et al. 2017: 842)

Good to know. Learning about one plant inevitably leads to notice of other plants.

Leonard, J.; Bishwanath Seth, Binod B. Sahu, V. R. Singh and Nivedita Patra 2017. Statistical optimization for enhanced bacoside A production in plant cell cultures of Bacopa monnieri. Plant Cell, Tissue and Organ Culture. In press. DOI: 10.1007/s11240-017-1373-6

As a result of its commercial applications, the natural habitat of this plant has depleted significantly and it as been enlisted as a highly endangered species by National Medicinal Plant Board, Government of India in 2004 and has been listed in the prioritized list of medicinal plants for cultivation (http://www.nmpb.nic.in./content/prioritised-list-medicinal-plants-cultivation). (Leonard et al. 2017: 1)

Finally a source. Bacopa is listed in the file "Species for 30% subsidy". The cost per acre for 2016-17 says very little to be, but the number is on par with Aloe vera and Centella asatica.

Plant tissue culture can be an important technology to salvage useful plants from being endangered as a result of the destructive extraction process. The tissue culture technique can be further utilized for the genetic modification of the germline followed by micropropagation to obtain several new plants with desired properties (Bagherieh-Najjar and Nezamdoost 2016). Furthermore, genetic transformation of callus cultures using Agrobacterium rhizogenes have been reported to produce enhanced Bacopa saponins by B. Monnieri (Majumdar et al. 2011) and enhanced anthaquinone production by Rubia cordifolia (Bulgakov et al. 2002). (Leonard et al. 2017: 1)

Destructive extraction process due to manufacturers considering the whole plant useful, despite the aerial portion of the plant containing more, and stolons specifically most.

The chemical drugs obtained from plants can be classified according to their chemical structures, among which the most common classes are alkaloids, terpenoids and polyphenols. These secondary metabolites are not directly related to the physiological growth of plants but help in the plant's longevity. (Leonard et al. 2017: 2)

Crush plants, extract their secondary metabolites that aid in their longevity, process and consume them ourselves for our own longevity. We're literally stealing longevity from plants.

Toxicity of bacoside A was predicted and the results showed that LD50 value was 1500 mg/Kg. On the basis of this study bacoside A can be classified with group 4 toxicity compounds which are not termed as harmful. (Leonard et al. 2017: 6)

Good to know. LD₅₀ is the median lethal dose.

Patel, Shishir Kumar; Shilpi Singh and Shio Kumar Singh 2017. Standardized extract of Bacopa monnieri (CDRI-08): Effect on germ cell dynamics and possible mechanisms of its beneficial action on spermatogenesis and sperm quality in male mice. Biochemical and Biophysical Research Communications, 494(1-2): 34-41. DOI: 10.1016/j.bbrc.2017.10.089

Bacopa monnieri (L.) Wettst. (common name, Brahmi; family, Plantaginaceae) is a medicinal plant that has been used in Indian traditional medical system of Ayurveda as medhya-rasayana (memory enhancing and rejuvenating). It is a perennial, creeping herb native to wetlands in India, especially the north-east and the southern regions. Bacopa has many pharmacological properties such as memory boosting, antiparkinsonian, antianxiety, hepatoprotective, antioxidant and anticonvulsant. (Patel, Singh & Singh 2017: 34)

Slightly different than "Medhya Rasayana (Medhya - intellect or retention [memory enhancing], Rasayana - procurement or preparation [rejuvenating])" (Chaudhari et al. 2017: 113).

It is believed that the fertility and the sexual life of men have declined due to several factors such as altered lifestyle, pathological complications, nutritional deficiency and exposure to environmental pollutants. There is, therefore, a need to find out a suitable remedy which could proe as dietary supplement or as medicine to vitalize the male reproductive functions. Our recent study with CDRI-08 (p.o., 40 and 80 mg/kg body weight (BM)/day for 28 days) in Parkes (P) mice has shown that the treatment caused an improvement in epididymal sperm quality by increasing viability and decreasing morphological abnormalities, and in steroidogenic indices in the testis by increasing the expressions of proteins and enzymes involved in testosterone biosynthesis; further, the treatment also increased germ cell proliferation and decreased lipid peroxidation level in the testis. (Patel, Singh & Singh 2017: 34)

The well-known phenomenon of lower testosterone and fertility in modern human males. Some studies in this series have already referred to these findings.

Oxidative stress (OS) is a condition when the production of [|] reactive oxygen species (ROS) overcomes the antioxidant defence mechanism, and this has been identified as one of the major causes of male infertility. Spermatogenesis and Leydig cell steroidogenesis are known to be vulnerable to OS-mediated damage. Further, spermatozoa are more susceptible to ROS-mediated damage and to lipid peroxidation because of the high content of polyunsaturated fatty acids in their cell membrane. (Patel, Singh & Singh 2017: 36-37)

Is ROS really behind all the commonly listed diseases (Alzheimers, Parkinsons, Huntingtons, etc.) as well as male infertility? Seems like a lot to put on one factor.

It is believed that the curative or the supplementary effects of medicinal plants are because of the presence of phytochemicals that strengthen the cellular defence system to fight against various kinds of insults, causing reproductive disorders. Several animal and in vitro studies have shown antioxidant properties of CDRI-08 [BM]. (Patel, Singh & Singh 2017: 39)

Leung et al. (2017) said something about the effects on cellular membrane (or the substrate surround it) but I can't find it. Hopefully there are studies which shed more light on the cellular mechanisms modified by BM.

Piyabhan, Pritsana; Supaporn Wannasiri and Jarinyaporn Naowaboot 2016. Bacopa monnieri (Brahmi) improved novel object recognition task and increased cerebral vesicular glutamate transporter type 3 in sub-chronic phencyclidine rat model of schizophrenia. Clinical & Experimental Pharmacology & Physiology 43(12): 1234-1242. DOI: 10.1111/1440-1681.12658

Schizophrenia is one of the most debilitating psychotic illnesses affecting approximately 1% of the world population. Individuals with schizophrenia experience array of symptoms ranging from positive symptoms (e.g. hallucination, delusions, thought disorder, perceptual disturbances, and increased motor function), negative symptoms (e.g. alogia, anhedonia, flat affect, avolition, and social withdrawal), and cognitive impairment. (Piyabhan, Wannasiri & Naowaboot 2016: 1234)

Lexical finding: "the decrease in the motivation to initiate and perform self-directed purposeful activities". Reminds me of the lay observation that schizophrenics can be noticed by their poor hygiene.

Recently, the glutamate hypothesis, another explanation of schizophrenic mechanisms, has received high attention. Earlier studies demonstrated that administration of drugs that inhibit NMDA glutamate receptors, such as ketamine and phencyclidine (PCP), can produce symptoms resemble to schizophrenia. (Piyabhan, Wannasiri & Naowaboot 2016: 1235)

Drugs that induce schizophrenia. Wikipedia says that glutamate is a neurotransmitter and one of the most abundant molecules in the brain.

The reduction of VGLUT1 and VGLUT2, leading to glutamatergic hypofunction, is known to be related with cognitive dysfunction in schizophrenia; however, there is limited data of VGLUT3 in schizophrenia. As VGLUT3 expression appears on various types of neurons (e.g. glutamatergic, cholinergic, serotonergic and GABAnergic neurons) in the brain, it is likely that VGLUT3 is not specific to only glutamatergic neurotransmission. (Piyabhan, Wannasiri & Naowaboot 2016: 1235)

These do appear to be some of the systems most frequently mentioned in the neuropharmacological studies of BM.

Our previous studies revealed that Brahmi can improve cognitive function and prevent deficit in cognition in rat model of schizophrenia-like psychosis by increasing VGLUT1 and VGLUT2 in the brain. However, the cognitive enhancement and neuroprotective effects of Brahmi and its mechanisms of action especially via VGLUT3 have not been investigated. (Piyabhan, Wannasiri & Naowaboot 2016: 1235)

How many mechanisms of action can one plant extract have?

All of these previous studies indicate that abnormalities of glutamate, acetylcholine, GABA and serotonin are associated with schizophrenia. As VGLUT3 is a transporter found in neurons producing these neurotransmitters, it is possible that VGLUT3 may have a role in the schizophrenia pathogenesis. Indeed, our present study demonstrated that VGLUT3 was decreased in cortical and subcortical glutamatergic, GABAergic, cholinergic and serotonergic innervation in schizophrenia. [...] We also investigated VGLUT3 expression in all areas of brain in rats receiving Brahmi before PCP administration. Interestingly, these rats show little cognitive deficit despite receiving PCP administration, and VGLUT3 expression was significantly increased in all brain areas compared to rats receiving only PCP. Overall, our study demonstrated that Brahmi possesses both cognitive enhancement- and neuroprotective effects, and its mechanism of action may be mediated by the up-regulation of VGLUT3. (Piyabhan, Wannasiri & Naowaboot 2016: 1238)

In other words, Bacopa is an effective prophylactic. Anecdotal personal experience attests to a heavy dose of Bacopa diminishing to the point of complete ineffectiveness the recreational use of Cannabis sativa.

Brahmi could be a novel therapeutic agent for the treatment and prevention of cognitive deficit in schizophrenic patients. By giving in combination with antipsychotic drugs, it may help improving both positive and negative symptoms and cognitive impairment in people with schizophrenia. (Piyabhan, Wannasiri & Naowaboot 2016: 1239)

Be very careful! Prescribing Bacopa with synthetic antipsychotic drugs can be dangerous. Though not itself toxic and "can be classified with group 4 toxicity compounds which are not termed as harmful" (Leonard et al. 2017: 6), it can inhibit "drug-metabolizing enzymes to prolong the pharmacological effects of the drug, thereby increasing the incidence of drug-induced toxicity" (Khurshid et al. 2018: 8).

Promsuban, Charkriya; Suveerawan Limsuvan, Pravit Akarasereenont, Kanokwan Tilokskulchai, Sompol Tapechum and Narawut Pakaprot 2017. Bacopa monnieri extract enhances learning-dependent hippocampal long-term synaptic potentiation. NeuroReport 28(16): 1031-1035. DOI: 10.1097/WNR.0000000000000862

Bacopa monnieri has been used in Ayurvedic medicine as a memory enhancer for a long time; however, its direct effect on synaptic plasticity has not been investigated. To the best of our knowledge, this study is the first to report the effect of B. monnieri on long-term synaptic potentiation in acute hippocampal slices. (Promsuban et al. 2017: 1031)

Above, a study published in 2018 said likewise that "to the best of our knowledge" it was the first of its kind. Something similar was published in 2017. The 2018 paper may have been submitted in 2016.

Long-term potentiation (LTP) is the long-lasting facilitation of synaptic strength that involves the increase of synaptic efficacy by formation of the excitatory post-synaptic potential levels above baseline. A previous study found that LTP played important roles in hippocampal-dependent spatial learning and memory processes. (Promsuban et al. 2017: 1031)

Getting the baseline terminology down.

The rats were deeply anesthetized with isoflurane until they were unconscious, and they were quickly decapitated by a guillotine. Then, the brain was removed rapidly and immediately, and transferred into 4°C oxygenated artificial cerebrospinal fluid (ACSF) with sucrose solution. Then, the brain was cut to remove unused portions, which were the cerebellum and the frontal pole. (Prohemsuban et al. 2017: 1032)

Recording this, too, for a possible short story where giant lab rats decapitate humans, perhaps anesthetizing them with some recreational drug that wouldn't actually do the job.

The memory-enhancing and cognition-enhancing effects of Brahmi are considered to be mediated by bacoside A. In 2013, Roshin et al. worked on the Brahmi whole-plant extract and bacoside A. Both of their neuroprotective effects at the molecular leels were almost the same. These findings suggest that Brahmi and bacoside A most likely exerted the same neuroprotective effect on the brain and these molecular changes might also have occurred again in the present electrophysiological study. Brahmi extract altered many key protein-downstream signaling molecules involving in LTP processes. Various studies with varying doses and durations of Brahmi extract administration have shown its effects on the molecular mechanisms underlying enhanced learning and memory performance in healthy animals. (Promsuban et al. 2017: 1034)

Meaning that the unprocessed plant material sold as hair care products might do the same trick as a bacoside content enhanced extract?

The inverted 'U-shaped' LTP effect might be explained by other effects of Brahmi extract such as serotonin activation. Brahmin extract treatment has shown to significantly upregulate the levels of serotonin receptor expression and serotonin neurotransmitter in the hippocampus and it may exert an inhibitory effect through GABAnergic neurons (Rajan et al. 2011; Turner, Mokler & Luebke 2004). Therefore, this inhibitory effect might be more prominent at the high dose, possibly reducing the LTP augmentation effect of Brahmi extract in this study. (Promsuban et al. 2017: 1034)

I'll have to look into these (cited) studies because the role of serotonin and related neurotransmitters in the effects of BM is still unclear (to me).

Mitra-Ganguli, Tora; Soumik Kalita, Sakshi Bhushan, Con Stough, James Kean, Nan Wang, Vidhu Sethi and Anuradha Khadilkar 2017. A randomized, double-blind study assessing changes in cognitive function in Indian school children receiving a combination of Bacopa monnieri and micronutrient supplementation vs. placebo. Frontiers in Pharmacology 8: Article 678. DOI: 10.3389/fphar.2017.00678

Bacopa has been used in the Ayurvedic medicinal system for ~3,000 years and is classed as a medhyarasayana, a drug used to improve memory and intellect (medhya) (Russo and Borelli, 2005). The memory and learning enhancing effects of Bacopa have been studied in healthy adult populations with mostly positive results in terms of cognition (Stough et al. 2001, 2008; Nathan et al. 2004; Pase et al. 2012). A recent systematic review indicated that of nine clinical double blind placebo controlled B. monnieri trials in humans, eight demonstrated improvements in memory, attention, cognition, and mood (Pase et al. 2012). These nootropic effects are attributed to the key constituents of Bacopa known as bacosides A and B. (Mitra-Ganguli et al. 2017: 3)

3000 years is a low bar. The timeline is still murky.

The mechanisms of action appear to act on the central nervous system and are seen to modulate cholinergic densities (Uabundit et al. 2010), acetylcholine levels (Bhattacharya et al. 1999), have β-amyloid scavenging properties (Holcomb et al. 2006), and demonstrated compelling evidence for its anxiolytic capabilities (Bhattacharya et al. 2000; Russo et al. 2003; Dhanasekaran et al. 2007; Kapoor et al. 2009). (Mitra-Ganguli et al. 2017: 3)

Found all but two, one an article in a book (Bhattacharya et al. 1999) and another with a crazy-long DOI, "10.1002/(SICI)1099-1573(200005)14:33.0.CO;2-O".

The effects of BM on memory, attention, and cognitive function has been less well studied in controlled trials in children. In a non-double-blinded study conducted in 40 children aged 6-8 years from rural India, those receiving Bacopa syrup (350 mg) three times daily for 3 months showed increased exploratory drive, improved perceptual images of patterns and increased perceptual organization and reasoning ability, compared with children who received placebo (Sharma et al. 1987). A randomized, double-blind, placebo-controlled trial evaluating BM in 36 children with diagnosed attention deficit/hyperactivity disorder was conducted over a 16-week period (Negi et al. 2000). In the 19 children who received Bacopa (50 mg twice daily for 12 weeks, followed by 4 weeks' placebo), significantly greater improvements in sentence repetition, logical memory and paired associate learning tasks were observed at 12 weeks compared with the 17 children who receive placebo. (Mitra-Ganguli et al. 2017: 3)

These are significantly different from the usual suspect list of effects, though I predict explicitly cognitive studies will yield a crop of similar observations, which I'll have to compare at some point. (Thus far I've read relatively few neurocognitive studies in this cycle.)

It is possible that the dosage of EBM used in this study might have been too low to effects these central nervous system actions that could ultimately have a positive impact on attention and memory. (Mitra-Ganguli et al. 2017: 11)

This may certainly be the case. In animal studies, for example, 40 mg/Kg does nil, while 80 mg/Kg shows demonstrable improvement. The more the merrier, eh. Oh yeah, "The dose of BM extract used in our study (250 mg/day)" (ibid, 11) of course does next to nothing. The case of Ginkgo biloba is a good illustration - one can take low doses regularly for years and not notice anything besides not getting as sleepy, and then find out that clinically evident effects appear only after double the dose advised on the packaging.

There is also a possibility that the bioavailability of Bacopa may have been reduced in a food supplement matrix or in a beverage powder rather than a capsule. Previous studies have used Bacopa extract in the form of a capsule (Negi et al. 2000) or syrup (Ramarao et al. 2011), and it would be of interest to compare whether the efficacy of Bacopa differs according to method of administration as this may affect bioavailability. (Mitra-Ganguli et al. 2017: 11)

It certainly would. Bacosides are notoriously non-water-soluble. The best results could probably found with Ghee (fat-soluble?) or with alcoholic tincture. Even though this research did not yield positive results, the authors should be thanked for their admirable compendium of references and for publishing negative results, which are very much needed unless the barrage of positive results give the false impression that it works no matter what.

Tanwar, Tanuj; Arvind Kumar, Fahim Raja, Saniya B. Kamal and Sourab Dua 2016. Effect of Bacopa monnieri Extract on Storage and Microbial Quality of Vacuum Packaged Chicken Nuggets. Journal of Pure & Applied Microbiology 10(3): 1977-1986.

Today, consumers demand for organic, safe, natural and high quality foods. The preference of consumer towards natural food compels the food industry to work upon and include natural antioxidant in meat products to impart oxidative stability (Camo et al. 2007). The herbal extract can act as a potent natural antioxidant which can be used in different meat products. This antioxidant has potency to act against lipolysis and proteolysis thereby imparting protein and lipid stability. The addition of these alcoholic aqueous extracts of herbs not only improves the sensory characteristic but also enhance shelf-life of the meat products (Wojdylo et al. 2007). (Tanwar et al. 2016: 1977)

Is that really the best use for an endancered medicinal plant? Are chicken nuggets here really considered "natural food"?

The pH of Bacopa monnieri L. extract fortified vacuum packaged chicken nuggets was recorded to be significantly (p<0.05) lower as compared to vacuum packaged control. The pH was increased significantly on successive storage days irrespective of levels of fortification of Bacopa monnieri L. extract in vacuum packaged chicken nuggets including vacuum packaged control chicken nuggets. However, the inclination in pH level was significantly (p<0.05) lower in treated product as compared to vacuum packaged control. It may be due to the fact that Bacopa monnieri L. extract contains bacoside and other phenols and flavonoids which are proton donors and acidic in nature. This was supported by the finding of Velasco and Williams (2011), and their work was also suggestive of decline of pH in meat product with increase in successive increase level of Bacopa monnieri L. extract incorporation in vacuum packaged chicken nuggets. (Tanwar et al. 2016: 1979)

Not sure what to do with this information, but will record it nonetheless.

The TBA value indicated that control vacuum packaged chicken nugget was not suitable for consumption on 45^th day of refrigeration storage whereas all levels of Bacopa monnieri L. extract incorporated vacuum packaged chicken nugget was found to [|] be suitable for consumption even on 45^th day. This was an indicative of the fact that Bacopa monnieri L. extract had preventive effect on lipid peroxidation and hence enhanced its shelf-life. (Tanwar et al. 2016: 1981-1982)

Damn you. We're stealing the secondary metabolites of plants responsible for their longevity for our own longevity, not that of processed meat products!

The terbal extract had affected microbial cell by various antimicrobial mechanisms. It may disrupt enzyme system, disrupt genetic material of bacteria attacking on phospholipidbilayer cellular membrane and forming fatty acid hydroperoxidase (Arques et al. 2008; Burt et al. 2007). The herbal extract had antimicrobial activity and when incorporated in meat product could elongate its shelf life during refrigeration storage. The bacoside has antimicrobial effect against both Gram positive and Gram negative bacteria (Proestos et al. 2008). The present finding was also supported by Ceylan and Fung (2004) who reported significantly decline in microbial load with incorporation of herbal extract in various meat product. (Tanwar et al. 2016: 1942)

This is actually disconcerting. The effects of BM on various enzymes in general, I mean, not the antimicrobial effect itself, though it does raise some concern over its effects upon gut microbiota when plant material tea is consumed chronically.

It may be due the fact that the principle component bacoside present in Bacopa monnieri extract had significant antimicrobial effect at refrigeration temperature. The bacoside interact with phospholipid bilayer of microbial cell wall and cell membrane and disrupt it. The present result was also supported by findings of Rota et al. (2008) who suggested Psychotropic antimicrobial affect of essential oils and extracts of herbal plants. It also defunct electron transport system, ion gradient and other enzyme ddependent cellular mechanisms of psychotropic bacteria (Burt 2004). (Tanwar et al. 2016: 1983)

While I lack compassion for psychotropic bacteria, who's to say that this mechanism of action could not be operative in humans as well? Concerned.jpg

Kishore, Lalit; Navpreet Kaur and Randhir Singh 2016. Renoprotective effect of Bacopa monnieri via inhibition of advanced glycation end products and oxidative stress in STZ-nicotinamide-induced diabetic nephropathy. Renal Failure 38(9): 1528-1544. DOI: 10.1080/0886022X.2016.1227920

Oxidative stress also plays a key role in the pathogenesis of diabetes and diabetic complications. The excessive free radicals generation occurs in diabetes due to glucose oxidation, nonenzymatic glycation of proteins etc. These high levels of free radicals can lead to lipid peroxidation, damage of enzyme system, and cellular organelles. It can also lead to insulin resistance. These consequences of oxidative stress can uphold the development of complications of diabetes metillus. (Kishore, Kaur & Singh 2016: 1528)

It would appear that the synthesis of reactive oxygen species plays a key role in everything, up to and including male infertility and the spoiling of refrigerated meat products.

Bacopa monnieri (L.) Wettst. (Scrophulariaceae), commonly known as "Brahmi" is a medicinal herb, found throughout the Indian subcontinent in wet and marshy places. It has been used for centuries in Ayurvedic system of medicine as a brain tonic, memory enhancer, revitalizer of sensory organs, antianxiety, cardio-tonic, diuretic, antidepressant, and anticonvulsant agent. (Kishore, Kaur & Singh 2016: 1528)

The other extreme of the confusing timeline. Which is it then, centuries or millena?

Previously, B. monnieri and its isolate, Stigmasterol, have been reported as antihyperglycemic agents in alloxanized diabetir rat. The present study aims to evaluate chronic complication of diabetes i.e., DN using STz-NAD model for type 2 diabetes. (Kishore, Kaur & Singh 2016: 1535)

In other wors, Stimgasterol lowers blood sugar levels.

Induction of diabetes with STZ is associated with the characteristic loss of body weight, which is due to increased muscle wasting and due to the loss of tissue proteins. Oral administration of BA, BHA, and ST improved the body weight in diabetic rats. (Kishore, Kaur & Singh 2016: 1537)

Muscles are of course the first to go even with extreme fasting. Note that "mice administered with BM showed slight increase in body weight" (Hosamani, Krishna & Muralidhara 2016: 438) even without induced diabetes.

Saponins isolated from medicinal plants are found to be renoprotective as they reduce fasting blood glucose and abluminuria, reverses the glomerular hyperfilteration state and ameliorates proliferative glomerular pathological changes during the early stages of DN in rat models. Saponins produce a significant reduction in blood glucose and lipid profile. This hypoglemic action is due to the nature of saponins to stimulate β-cells to produce insulin. (Kishore, Kaur & Singh 2016: 1538)

Interesting. "Renoprotective" is typically missing from the listings of positive effects. Would this also mean that people with blood sugar issues should avoid using BM as a nootropic?

Jain, Shilpi; Arjun Singh, Puja Khare, D. Chanda, Disha Mishra, Karuna Shanker and Tanmoy Karak 2017. Toxicity assessment of Bacopa monnieri L. grown in biochar amended extremely acidic coal mine spoils. Ecological Engineering 108A: 211-219. DOI: 10.1016/j.ecoleng.2017.08.039

Here, we examined the response of biochar for reducing the phytotoxicity of Al, Cd, Cr, Cu, Fe and Pb in Bacopa monnier L. cultivated in contaminated mine soil. The [|] hypotheses for the study are 1. What is the effect of BC on the metal accumulation on the plant? 2. Whether the Bacopa monnier L. grown in the area of mine spoil could have any toxic effects on human health after consumption? [↩] To achieve these aims, bacopa plants were selected for this study firstly, it could be easily grown in the marshy land and good phytoremediator (Mirsha et al. 2016; Singh et al. 2006). Secondly, it is wildly cultivated and one of the most important plants in Ayurveda (Mishra et al. 2016). (Jain et al. 2017: 211-212)

From centuries to millenia, again. I'm worried about the heavy metal content in Bacopa because Ayurvedic plants cultivated in India have a 21% chance of being contaminated (Wikipedia).

For this study, 18 mice (9 males and 9 females) were taken and divided into three groups (control, treated and untreated) comprising 3 male and 3 female mice in each group. The animals were maintained at 22 ± 5 °C with humidity control and also on an automatic dark and light cycle of 12 h. The animals were fed with the standard rat feed and provided libitum drinking water. Mice of grou 1 were kept as a control and animals of groups 2, and 3 were kept as an experimental. The animals were acclimatized for 7 days in the experimental environment prior to the actual experimentation. (Jain et al. 2017: 216)

Instead of giant rats, I think the short story should revolve around very advance alien scientists who similarly acquire 18 humans (capture them from the streets at night, for example), and divide them into experiment groups. They'll have 7 days to "acclimatize" with their situation before some weird experimentation begins, which is concluded by them being decapitated. The "standard human feed" could be chicken nuggets.

Biomass yields in T3 and T6 were slightly, but significantly less (3%) than control; however, bacoside content was slighly higher than the control soil (T1). Biochar treatment showed significant (P < 0.05) enhancement in plant biomass yield as compared to overburden treatments without biochar, the enhancement in the yield of bacopa grown in biochar treatment was 32%. PLants grown it the overburden treatment without biochar (T3 and T6) had lower chlorophyll content as compared to (T1). Similar pattern was also observed for the protein content. (Jain et al. 2017: 217)

The researchers testing bacteria and nutrients to increase the secondary metabolite yield should be reading this.

No metal was detected in the alcoholic extract due to insolubility of metals in organic solvent. Hence, this portion was not considered for the toxicity study. However, the toxicity of aqueous extract was assessed by in vivo acute oral toxicity in Swiss-albino mice. (Jain et al. 2017: 217)

A definite reason to prefer the processed (bacoside content enhanced) extract: it's a guarantee of no heavy metal pollutants.

As the Bacopa is as an alternative medicine and extensively consumed by the local people in India. Hence, it could contribute to the intake of heavy metals. Risk assessment index (HQ and THQ) evaluation indicates that adverse health effects are not likely to occur after consuming the Bacopa grown on overburden. [...] Whereas, the HQ values calculated for the present study are in the range of 0.01-0.24. Also, all THQ values for all estimated metals were lower than 1.0. Our results suggested that serious risk of adverse health effects through the ingestion of contaminated Bacopa to local inhabitants is low. (Jain et al. 2017: 218)

Well, that's a relief: "no metal toxicity was observed" in the mice.

Al-Hasawi, Nada Ahmad 2017. A Comparative Study of the Polysialylation Inhibition in the Kelly Neuroblastoma Cell Line by Withania somnifera and Bacopa monnieri Extracts. International Journal of Applied Research in Natural Products 10(1): 32-41.

In mammals, PSA [polysialic acid] is mainly attached to the neural cell adhesion molecule (NCAM), which expressed on cell membranes, and plays a role in neural development and recognition. Highly polysialylated NCAM is abundant in the embryonic tissues. After birth, most NCAM molecules lose PSA, and in the adult brain, polysialylated NCAM is continually expressed in areas where neural plasticity persists, including the hippocampus and olfactory bulb. (Al-Hasawi 2017: 32)

I knew that the hippocampus remains active in producing new neural cells (per the neurogenesis hypothesis) but that the olfactory bulb does, too, is new to me. Does this imply that it is easier to learn new smells in later life?

In spite of the possibility of inhibiting PSA synthesis by unnatural precursors or CMP molecules, these inhibitors are highly hydrophilic and unable to pass through cell membranes, and increasing cell permeability is necessary to ensure their potency. Thus, PSA suppression by inhibitors with more "drug-like" qualities is necessary for inhibiting polysialyltransferases in the Golgi, with good pharmacokinetic parameters. (Al-Hasawi 2017: 33)

Terminology for bioavailability and substrate-specific transporter activities.

Scientific studies have demonstrated the multi-pharmaceutical utilization of W. somnifera for its neuroprotective, neuro-regenerative, anti-oxidant, anti-inflammatory, anti-stress, and immune-modulatory properties, as well as its anti-cancer potential. (Al-Hasawi 2017: 33)

Phraseology for the long list of positive effects common to general descriptions of B. monnieri.

Taken together, it was shown that treating Kelly cells with the water and hexane extracts of W. somnifera significantly reduced PSA level without significantly affecting cell survival, whereas treating these cells with the same extracts of B. monnieri has no significant potential of reducing PSA level despite the significant reducing effect on cell survival. (Al-Hasawi 2017: 40)

Noted. Though the author did not discuss possibilites of what went wrong. Could the extraction method have been faulty? I couldn't make out the chemical portion, but I noticed that in this study the leaves of B. monnieri. It is reported that the "highest concentration of bacoside A is present in stolon (9.54 mg/g dry wt) followed by leaves (4.73 mg/g dry wt) and roots" (Jeena et al. 2017: 2), meaning a portion of the plant with less bacoside content was used.

Ullah, Ihsan; Fazal Subhan; Zengbing Lu; Sze Wa Chan and John A. Rudd 2017. Action of Bacopa monnieri to antagonize cisplatin-induced emesis in Suncus murinus (house musk shrew). Journal of Pharmacological Sciences 133(4): 232-239. DOI: 10.1016/j.jphs.2017.03.001

BM has a long history of clinical use in the Ayurvedic system of medicine since ancient times. Attempts have been made to identify its active constituents, and to determine its mechanism of action in anxiety and depression. Indeed, a variety of herbal formulations containing BM extract are available and are described as neurotonics. Studies investigating its mechanism of action have focused on its calcium channel blocking and anti-oxidant activity. Recent studies indicate that BM extracts are more effective than metoclopramide to reduce cisplatin-induced emesis in pigeons, via a mechanism that prevents increases in dopamine in the brainstem and increases in 5-HT [serotonin] in the intestine. (Ullah et al. 2017: 232)

That's a tactful way to circumnavigate the issue of the age of Ayurveda. The effects on serotonin and dopamine are getting more specific.

BM was collected in the month of November (2010) from Rumalee stream near Quaid-e-Azam University, Islamabad Pakistan, and was authenticated by Prof. Dr. Muhammad Ibrar, Department of Botany, University of Peshawar. A specimen was submitted to the herbarium for future reference (voucher No 7421). (Ullah et al. 2017: 234)

Thus far I've read it being gathered from botanical gardens, bought from the local market, from accredited distributors, etc. but this is the first DIY collecting I've noticed.

Episodes of emesis were characterized by rhythmic abdominal contractions that were associated with either oral expulsion of solid or liquid materials from the gastrointestinal tract (i.e. vomiting) or without the passage of materials (i.e. retching movements). Two consecutive episodes of retching and/or vomiting were considered separate when an animal changed its location in the observation chamber or when the interval between retches and/or vomits exceeded 2 s (Lau et al. 2005). (Ullah et al. 2017: 235)

Hesus Kristos. This is how aliens would describe humans vomiting spoiled "standard human feed" (chicken nuggets, mcburgers, etc.).

However, the anti-emetic profile of MPG in our studies is different from both the BM extracts and palonosetron which may infer that BM anti emetic mechanism is not through its purported action to reduce oxidative stress, and/or the oxidative stress induced by aluminium is different from cisplatin; certainly cisplatin is highly emetic, whereas aluminium formulations have beneficial actions against dyspepsia. (Ullah et al. 2017: 238)

For once the oxidative stress reduction mechanism is not seen as the primary effect.

The anti-dopaminergic and anti-serotonergic effect of BM fractions and subsequent suppression of cisplatin-induced emesis has been observed in the pigeon against cisplatin. Conceivably, a reduction of dopamine and 5-HT in the brain and periphery may also contribute to the anti-emetic activity of BM fractions. However, BM is also reported to have voltage and receptor-operated calcium channel blocking activity. (Ullah et al. 2017: 238)

The effects no-one lists in those lengthy iterations (anxiolytic, etc.).

Mishra, Amrita; Arun K. Mishra and Shivesh Jha 2018. Effect of traditional medicine brahmi vati and bacoside A-rich fraction of Bacopa monnieri on acute pentylenetetrzole-induced seizures, amphetamine-induced model of schizophrenia, and scopolamine-induced memory loss in laboratory animals. Epilepsy & Behavior 80: 144-151. DOI: 10.1016/j.yebeh.2017.12.040

Conventional treatment of epilepsy consists primarily of anticonvulsant medications. Although these drugs often control or reduce the frequency of seizures, some patients show little or no improvement. These medications only control the seizure but do not cure other symptoms like memory loss. In complcated cases where epileptic seizures are associated with schizophrenia and memory loss, the medication becomes complex, and patients have to take many medicines together. These medications cause side effects, dizziness, and toxicity. The use of traditional medication has increased dramatically in recent times. A significant numbers of these medicines are used for treating patients with neurological and psychiatric disorders. (Mishra, Mishra & Jha 2018: 144)

How much potential is there for BM to actually cure memory loss? Would regulating pre- and post-synaptic proteins and inducing the formation of new dendrites do the trick?

A number of medicinal plants have been reported to have significant anticonvulsant, memory-enhancing, and antischizophrenia activities. However, most of the studies carried out on these plants are on extracts or chemical fractions. In Ayurvedic therapeutics, the plants are normally processed in combination with other plants or with mineral- or animal-derived substances. Thus, majority of the pharmacological studies are not in conformity with indications mentioned in Ayurvedic classics. Keeping this fact into consideration, the present study was designed to evaluate anticonvulsant, memory-enhancing, and antischizophrenia activities of BV [Brahmi vati], which is a traditional Ayurvedic formulation used for centuries with claimed efficacy in treatment of convulsions, mental disorders, heart weakness, and fever. (Mishra, Mishra & Jha 2018: 145)

Some 20 articles into this cycle it actually gets interesting. With all the lipservice to Ayurveda in these studies - mostly limited to emphasizing its age, which varies from a few centuries up to seven thousand apparently - none have given very detailed information about its original use.

It contains abhraka bhasma (mica), sangeyasaba bhasma (jadite), akik bhasma (agate), manikya bhasma (ruby), candrodaya (sulfur and mercury), pravala bhasma (red coral), kaharuba pisti (amber), svarna bhasma (gold foil), mukta bhasma (pearl), brahmi (Bacopa monnieri), nisotha (Operculina turpethum), aguru (Aquilaria agallocha), kumkuma (Crocus sativus) as its main ingredients and twenti-four other plant drugs. (Mishra, Mishra & Jha 2018: 145)

Okay. The Wikipedia pages for these plants are somewhat uninformative. I may have to look into whether any of them are acquireable. The full table, ibid.:

Local name	Botanical name/source	Part used	Qty
Abhraka bhasma	Calcinated biotite mica	-	6 g
Aguru	Aquilaria agallocha Roxb	Heart wood	18 g
Akarkara	Anacyclus pyrethrum DC.	Root	4 g
Akik bhasma	Calcined agate	-	6 g
Amber	Ambergris	Substance produced from digestive system of sperm whales	18 g
Anisuna	Pimpinella anisum Linn.	Fruit	4 g
Ashwagandha	Withania somnifera Dunal.	Root	4 g
Brahmi	Bacopa monnieri Linn.	Aerial part	18 g
Candrodaya	Calcined suphur and mercury	-	6 g
Chitraka	Plumbago zeylanica Linn.	Root	4 g
Dhanyaka	Coriandrum sativum Linn.	Fruit	4 g
Ela	Elettaria cardamomum Linn.	Seed	4 g
Jatipatri	Myristica fragrans Houtt	Aril/mace, Seed	4 g
Kaharuba pisti	Processed amber	-	6 g
Kasturi/Lata kasturi	Hibiscus abelmoschus Linn.	Seed	18 g
Krsnajiraka	Carum carvi Linn.	Fruit	4 g
Kulinjana	Alpinia galanga Willd.	Rhizome	4 g
Kumkuma	Crocus sativus Linn.	Stigma	18 g
Kustha	Saussurea lappa C.B. Clarke	Root	4 g
Lavanga	Eugenia caryophyllata Thunb.	Flower bud	4 g
Manikya pisti	Processed ruby	-	6 g
Mukta bhasma	Calcined pearl	-	6 g
Nagakesara	Mesua ferrea Linn.	Androcium	4 g
Nisotha	Operculina turpetha Linn.	Root	18 g
Patra	Cinnamomum tamala Buch. Ham.	Leaf	4 g
Pippali(mula)	Piper longum Linn.	Fruit, Root	4 g
Pravala bhasma	Calcined Red Coral	-	6 g
Rumimastagi	Pistacia lentiscus Linn.	Exudates	4 g
Sangeyasaba pisti	Processed jadite	-	6 g
Sankhapuspi	Convolvulus pluricaulis Choisy	Plant	4 g
Surpha	Foeniculum vulgare Mill	Fruit	4 g
Svarna bhasma	Calcined gold foil	-	6 g
Sveta Chandana	Santalum album Linn.	Heart wood	4 g
Tvak	Cinnamomum zeylanicum Blume.	Stem bark	4 g
Vansalochana	Bambusa arundinacea Retz. Willd	Silicious concretion	4 g

I'll have to look into these in due time.

This mixture was ted [sic] with Bacopa monnieri Linn. juice and by the hand rolling process prepared pills of about 250 mg. (Mishra, Mishra & Jha 2018: 146)

Dose too low.

Ingredients of brahmi vati namely Crocus sativus stigmas, Convolvulus pluricaulis, Aquilaria agallocha, Plumbago zeylanica, Piper longum have been previously reported to possess anticonvulsant potential. Bacopa monnieri (ethanolic extract at 50 mg/g) has also been reported to have anticonvulsant activity; but in the present study, the BM-treated group did not show a significant response. (Mishra, Mishra & Jha 2018: 149)

Administer an insignificant dose, receive insignificant results.

Other ingredients like Piper longum, Convolvulus pluricaulis and Crocus sativus have also been previously reported to possess memory-enhancing activity. (Mishra, Mishra & Jha 2018: 150)

"Curcumin, also had improved memory retention" (Leung et al. 2017: 15), but turns out to be a waste of time, and the animal experiments for memory and learning (Morris water navigation task) are not very convincing overall.

Brahmi vati, which is a combination of herbs and mineral products, has shown significant effects in comparison with a single plant bacoside A-rich extract of Bacopa monnieri at the same dose. [...] Brahmi vati was found to possess significant anticonvulsant, antischizophrenia, and memory-enhancing activities. The polyherbomineral traditional formulation brahmi vati was found to be more effective in comparison with bacoside A-rich extract of Bacopa monnieri plant at the same dose. (Mishra, Mishra & Jha 2018: 150)

The traditional formula was interesting in itself but several of those plants grow only high up in Indian mountains. I'll have to check the availability in stores, but some can be rather easily acquired.

High MDA [malondialdehyde, a marker for oxidative stress] and diminished GSH [glutathione, an important antioxidant] status been linked with normal aging, as well as with neurodegenerative diseases. Brahmi vati administration decreased brain MDA levels and increased GSH levels. In the BV-treated groups, brain AChE [acetylcholinesterase, an neurotransmitter enzyme] activity significantly decreased. The involvement of the cholinergic system in learning/memory has long been established. It is expected that decreased AChE activity may enhance cholinergic activity by raising AChE level (inhibition of metabolism), thereby maintaining/improving cognitive functions. (Mishra, Mishra & Jha 2018: 150)

Okay. Decrease in activity may raise its level. I think I need to acquire the basics of neurochemistry for this.

Srimachai, Sirintorn; Sylvie Devaux, Celine Demougeot, Sarawut Kumphune, Nina D. Ullrich, Ernst Niggli, Kornkanok Ingkaninan, Natakorn Kamkaew, C. Norman Scholfield, Sompol Tapechum and Krongkarn Chootip 2017. Bacopa monnieri extract increases rat coronary flow and protects against myocardial ischemia/reperfusion injury. BMC Complementary And Alternative Medicine 17(1): Article 117. DOI: 10.1186/s12906-017-1637-z

It is unlikely that any classical single substance or drug could perform in this manner, but several multifunctional herbals have the potential to fulfill such a role. [↩] They include, the medicinal Ayurvedic herb, which is thought to improve cardiovascular function. Thus, oral B. monnieri given to rats for three weeks reduced biochemical and histopathological perturbations caused by ischemia/reperfusion (I/R), while increasing myocardial antioxidant enzymes and reducing myocardial apoptotic signaling proteins. (Srimachai et al. 2017: 2)

BM is frequently described as "cardiotonic", though I haven't seen anything very specific.

There is also some evidence that B. monnieri improves systemic vascular function. It relaxes a wide range of arteries, ppartly through endothelial NO release and in vascular smooth muscle by inhibiting Ca²⁺ influx and Ca²⁺ release from the sarcoplasmic reticulum. Nevertheless, chronic oral administration of B. monnieri to rats for 12 weeks increased cerebral blood flow without changing blood pressure. This is particularly important because B. monnieri has been traditionally used to enhance memory and several clinical trials suggest that it does have nootropic actions. (Srimachai et al. 2017: 2)

Does this imply calcification?

B. monnieri increased coronary flow in normal hearts. In normalyl perfused isolated rat hearts, during stabilization, all hemodynamic parameters including coronary flow, LVDP and HR remained constant and similar in all treatment groups. Application of 30 or 100 μg/ml B. monnieri for 30 min produced a concentration-dependent increase in coronary flow. (Srimachai et al. 2017: 5)

An explicitly cardiotonic effect.

This implies that contractility was not solely a direct consequence of better blood flow. One explanation for this disconnect could invlove Ca²⁺ influx, which we show was inhibited in isolated myocytes. On the other hand, inhibition of vascular smooth muscle L-type Ca²⁺ maximises the vasodilation through the lingering action of B. monnieri, thus providing metabolic resources to re-establish the extra- and intracellular milieu. (Srimachai et al. 2017: 8)

As with the modification in the AChE mechanism, it would appear that Bacopa is a resource reallocator.

These anti-inflammatory effects of B. monnieri may be mediated through one of its constituents, betulic acid (Viji et al. 2010; Zhao et al. 2013). (Srimachai et al. 2017: 8)

One by one BM's phytoconstituents become clearer.

B. monnieri protected against I/R injury in rat heart as judged by its ability to recover coronary flow, contractile force and function, and reduced infarct volume. As such, [|] it could form the basis of a promising cardioprotectant (and cerebroprotectant) for patients at risk from infarcts. In pursuing this, the protectant and cytotoxic components need to be identified and plant strains or exrtaction protocols showing more efficacious chemical profiles selected. (Srimachai et al. 2017: 8-9)

It seems probable that the various phytoconstituents will be isolated for treatments of epilepsy, diabetes, and cardial/coronary issues.

Kishore, Lalit; Navpreet Kaur and Randhir Singh 2017. Bacosine isolated from aerial parts of Bacopa monnieri improves the neuronal dysfunction in Streptozotocin-induced diabetic neuropathy. Journal of Functional Foods 34: 237-247. DOI: 10.1016/j.jff.2017.04.044

Diabetic peripheral neuropathy (DPN) is one of the major complications caused by long-standing hyperglycemia and frequently results in clinically significant morbidity (Balakumar, Arora, Ganti, Reddy, & Singh 2009). [...] One mechanism that has been recognized to play a significant role in the pathogenesis of sensory neuron damage, is the process of reactive diacarbonyls forming AGEs due to hyperglycemia (Jack & Wright 2012). Collectively these pathways cause an imbalance in the mitochondrial redox state of the cell and lead to excessive formation of reactive oxygen species (ROS). (Kishore, Kaur & Singh 2017: 237)

The exact stuff Paul Stamets claims Lion's mane can remedy (by stimulating nerve growth factor, apparently).

A study conducted by Ghost, Maity, & Singh 2011 proved that Bacosine, a triterpene from B. monnieri, increase in peripheral glucose consumption as well as protection against oxidative damage in alloxanized diabetes. (Kishore, Kaur & Singh 2017: 238)

Another phytoconstituent with an interesting function.

Muszyńska, Bożena; Maciej Łojewski, Katarzyna Sułkowska-Ziaja, Agnieszka Szewczyk, Joanna Gdula-Argasińska and Patrycja Hałaszuk 2016. In vitro cultures of Bacopa monnieri and an analysis of selected groups of biologically active metabolites in their biomass. Pharmaceutical Biology 54(11): 2443-2453. DOI: 10.3109/13880209.2016.1158843

Bacopa monnieri (L.) Pennell Scrophulariceae (Water hyssop), known locally in India as Brahmi or Jalanimba, is one of the most important plants in the system of Indian medicine called Ayurveda. Bacopa monnieri has been used in India for 5000 years to treat epilepsy and insomnia, and as a sedative and anxiety reducing herb. (Muszyńska et al. 2016: 2443)

Back to a generous estimation.

Based on previous studies, these effects are due to the ability of the plant extracts to modulate the cholinergic system (Peth-nui et al. 2012). Compounds which are attributed to the above activities are bacosides and triterpenoids belonging to the saponins (Rastogi et al. 2012). This plant is also used in the treatment of neurodegenerative diseases (e.g., Alzheimer's disease or Parkinson's). It also exhibits antioxidant, anti-inflammatory, antipyretic, antiulcer, cardioprotective, cooling, laxative and adsorbing effects (Biswas et al. 2012). It is used in cases of dermatitis, anemia, diabetes, cough, swelling, fever, arthritis, anorexia and dyspepsia. Hydro-alcoholic and alcoholic extracts activate detoxification processes, support processes of the renewal and regeneration of tissues, intensify the processes of protein synthesis, stabilize the structure of cell membranes and prevent the overgrowth of the prostate. (Muszyńska et al. 2016: 2443)

I swear these lists are getting longer and longer.

In the bloodstream, this herb functions as a metal chelating agent able to remove any excess of toxic metals. It is also used in phytoremediation for the disposal of heavy metals such as damium and chromium. (Muszyńska et al. 2016: 2443)

Useful, should you buy plant material from India that's contaminated with toxic metals. One study (above) on BM's phytoremediation (Jain et al. 2017) explicitly excluded chromium. What's up with that?

Information about the presence of compounds from other groups, for example, indole and phenolic compounds, fatty acids and sterols, in this plant, is limited, but the content of these compounds might participate in the physiological activity of B. monnieri. Indole compounds are involved in the regulation of sleep, mood; it coordinates the work of the biological clock controlling circadian rhythm, exhibits anti-cancer properties, and plays a neuroprotective role. Indole derivatives are also compounds with anti-inflammatory and analgesic properties. (Muszyńska et al. 2016: 2444)

Only previous mention in this post: "Gene constructs contained the terpenoid indole alkaloid (TIA) pathway from Catharanthus roseus were tested for heterologous expression." (Sharma et al. 2017: 23)

In the current study, we did not find any free sterols in biomass from in vitro cultures of B. monnieri. These results are in contrast to those from Chatterji et al. (1963) who observed stigmasterol, stigmastanol and β-sitosterol. The difference between these and the current analysis was as follows: plant material used (naturally grown versus in vitro culture) and method of determination (melting point vs HPLC). (Muszyńska et al. 2016: 2447)

Turns out that wild specimens may be preferable for some phytoconstituents.

Serotonin has a wide spectrum of pharmacological activity and it acts as a neurotransmitter in the central nervous system and, together with melatonin, is a regulator of the daily rhythm. Moreover, it is produced not only in the brain bt mainly by enterochromaffin-like cells in the duodenum and it is involved in the contraction of smooth muscles, regulates gastrointestinal motility, affects blood pressure, participates in blood clotting and acts as an antioxidant (Turner et al. 2006; Kaneez & Arshad 2007; Keszthelyi et al. 2009). Serotonin produced endogenously in the brain is involved in the regulation of sleep, anxiety, aggression, body temperature, mood, maturation process, regeneration and reduction of cell-aging processes which lead to a general improvement of the immunological system of the body. (Muszyńska et al. 2016: 2449)

General description of what serotonin does. The interaction between BM and 5-HT are still not clear (to me), but we're slowly working towards more clarity.

In the case of L-tryptophan addition to the medium, its influence was only observed on L-tryptophan level in the biomass (an almost 10-fold increase). This suggests that the added compound passed to the cultured explants. However, the mere fact of the prevalence of indole compounds in the plant might suggest that these secondary metabolites can support the antidepressant effect of bacosides. Zinc and magnesium are activators of enzymes which may explain the increase of the metabolites. It should be noted that the levels of L-tryptophan and serotonin are high when compared with garlic (approx. 0.1 mg/g DW L-tryptophan) and Hypercium perforatum from in vitro cultures (Muszyńska et al. 2014) or an edible mushroom Leccinum scabrum (approx. 0.27 mg/g DW L-tryptophan and 0.2 mg/g DW serotonin) (Muszyńska et al. 2013). (Muszyńska et al. 2016: 2449)

Interesting stuff.

Phenolic compounds were examined during the process of phytochemical screening by Subashri and Koilpillai (2012) and Shah et al. (2012) who only reported that these kinds of secondary metabolites are found in B. monnieri. Both assign the [|] antioxidant properties of this plant to flavonoids and phenolic compounds. We found three phenolic compounds in B. monnieri. The highest concentration of chlorogenic acid (0.70 mg/g DW) and neochlorogenic acid (0.40 mg/g DW) were found in material supplemented with 0.5 g/L serine, and caffeic acid (0.04 mg/g DW) in biomass supplemented with 0.1 g/L L-tryptophan. [...] The content of the examined phenols in B monnieri is high for plants [...] (Muszyńska et al. 2016: 2450-2451)

Does the bacoside extraction process exclude these secondary metabolites?

The third most common unsaturated fatty acid is myristoleic acid (12.6%. Unlike the previous two, this is rare in nature. One of the major sources of this fatty acid is the seed oil from plants of the Myristicaceae, comprising up to 30% of the oil in some species. (Muszyńska et al. 2016: 2452)

Notice that the traditional Brahmi vati formula prescribes the aril/mace as well as the seeds of "Jahipatri" or Myristica fragrans Houtt (Mishra, Mishra & Jha 2018: 145). Could it be that the traditional formulae complements (that is, increases the dosage of) the rare phytoconstituents already present in BM?

A significant repression of COX-2 and cPGES proteins was noted both in the cells treated with B. monnieri extracts alone and in the cells activated with LPS which may be due to synergistic anti-inflammatory effects of indolic, phenolic, fatty acids, bacoside A and other compounds in B. monnieri extract. Cyclooxygenase-2 is a key enzyme in the inflammatory response, decreasing the expression of this protein by some compounds may be regarded as an anti-inflammatory characteristic. (Muszyńska et al. 2016: 1452)

Building a case against the bacoside A increased extract that excises other compounds. This was a better paper than most.

Sarkar, Sayantika and Sumita Jha 2017. Morpho-histological characterization and direct shoot organogenesis in two types of explants from Bacopa monnieri on unsupplemented basal medium. Plant Cell, Tissue and Organ Culture 130(2): 435-441. DOI: 10.1007/s11240-017-1231-6

Bacopa monnieri (Linn.) Wettst. belongs to Scrophulariaceae family and is valued as a powerful memory enhancing and brain rejuvenating herb (Mukherjee and Dey 1966). The therapeutic property of this plant is attributed due to the presence of different dammarine type triterpenoid bacopa saponins or bacosides (Majumdar et al. 2013). (Sarkar & Jha 2017: 435)

Powerful?

Ever since Skoog and Miller (1957) postulated that plant hormones are centrally involved in organogenic processes, it has been amply demonstrated in literature that the fate of meristemoids can be manipulated by exogenous supply of hormones (Thorpe 1980; Tran Than Van 1980; Hicks 1994) or by insertion of T-DNA genes specifying the synthesis of axins or cytokinins (Owens et al. 1998; Wabiko and Minemura 1996). (Sarkar & Jha 2017: 440)

Phytohormones make micropropagation of plants more efficient.

Shahid, Muhammad; Fazal Subhan, Gowhar Ali, Ihsan Ullah, Javaid Alam, Sami Ullah and Khalid Rauf 2017. Neuroprotective effect of Bacopa monnieri against morphine-induced histopathological changes in the cerebellum of rats. Pakistan Journal of Pharmaceutical Sciences 30(6): 2067-2074.

Bacopa monnieri (Linn.) Pennell [Syn. Bacopa monniera (L.) Wettst., Herpestis monniera, Gratiola monniera] (family - Scrophulariceae) known as "Brahmi" in India and "Jas Neem Booti" in Pakistan, is a perennial herb, which is found in marshy places around the world including Pakistan (Qureshi and raza Bhatti 2008). It is used in traditional medicine for the management of anxiety, poor cognition and lack of concentration (Russo and Borrelli 2005). The major chemical constituents isolated from B. monnieri are dammarane type triterpenoid saponins with jujubogenin and pseudojujubogenin as the aglycones including bacosides A₁-A₃, bacopasaponins A-G and bacopasides I-V (Murthy et al. 2006; Deepak et al. 2005). (Shahid et al. 2017: 2067)

The synonym case (Bacopa monniera) is so bad that if you search EBSCO with the ending -a instead of -i you'll get a completely different set of results. It's possible that whole realms of research live a distinct life unmet by each other because of one letter.

Purkinje cells are GABAergic neurons, which serve as the sole output of the cerebellar cortex (Voogd and Glickstein 1998). Morphine is especially associated with apoptosis of GABAergic neurons (Mao et al. 2002). (Shahid et al. 2017: 2072)

Possibly why severe alcoholics likewise need GABAmimetic substances to function.

In this study, daily pretreatment with mBME at a dose of 40 mg/kg for 14 and 21 days provided protection against morphine-induced histopathological changes in the cerebellum. The tested dose of B. monnieri is considered as safe and is based on its toxicity profile, as previously reported (Abbas et al. 20110. B. monnieri has been shown to alleviate methyl mercury induced oxidative stress (Sumathi et al. 2012) and thus protects the cerebellum against neurochemical and histopathological changes (Christinal and Sumathi 2013). The neuroprotective effect of B. monnieri is due to its strong antioxidant activity that decreases nitrite, nitrate and lipid peroxidation and improves catalase activity (Saraf et al. 2010). (Shahid et al. 2017: 2072)

Will there ever be consensus on the neuroprotective effects of BM and further animal experiments with only this aspect as research objective decease?

Charoenphon, Natthawut; Nanthida Anandsongvit, Piya Kosai, Kanjana Sirisidthi, Niwat Kangwanrangsan and Wannee Jiraungkoorskul 2016. Brahmi (Bacopa monnieri): Up-to-date of memory boosting medicinal plant: A review. Indian Journal of Agricultural Research 50(1): 1-7. DOI: 10.18805/ijare.v50i1.8582

According to the National Medicinal Plants Board report, the annual marked demand for Brahmi, Bacopa monnieri is around 1,000 tones [sic] in year 2000, which increased many fold due to its potential uses in Ayurvedic medicine to treat variety of diseases (Tripathy et al. 2012). In recent years, B. monnieri has receivd much attention worldwide due to its wide spectrum of pharmacological activities. (Charoenphon et al. 2016: 1)

No doubt the market demand has increased exponentiall since the beginning of the century. This wide spectrum is evident from common lists of positive effects.

Taxonomic classification: The taxonomy of B. monnieri is in the Kingdom (Plantae); Subkingdom (Viridiplantae); Infrakingdom (Streptophyta); Superdivision (Embryophyta); Division (Tracheophyta); Subdivision (Spermatophytina); CLass (Magnoliopsida); Subclass (Asteridae); Superorder (Asteranae); Order (Lamiales); Family (Plantaginaceae); Genus (Bacopa); Species (B. monnieri) (ITIS 2015). (Charoenphon et al. 2016: 1)

What is "Scrophulariceae", then?

Neuroprotective activity: The active constituents responsible for B. monnieri's cognitive effects are bacosides A and B, moreover, triterpenoid saponins are responsible to enhance nerve impulse transmission (Mahatoe et al. 2000; Hou et al. 2002; Chakravarty et al. 2001; 2003). The bacosides also aid in repair of damaged neurons by enhancing kinase activity, neuronal synthesis, restoration of synaptic activity, and nerve impulse transmission (Singh & Dhawan 1997). Peth-Nui et al. (2012) demonstrated that B. monnieri suppresses acetylcholinesterase activity resulting in enhanced [|] cholinergic function, which in turn enhances attention and memory processing and increases working memory in elderly people. (Charoenphon et al. 2016: 2-3)

Haven't seen all that much about improving nerve impulse transmission in recent literature. Likewise with protein kinase activity. Maybe upcoming papers will shed more light.

The patients involved in this trial also reported improvement in their quality of life, and decrease in the irritability and insomnia. (Charoenphon et al. 2016: 3)

Hoarseness.

Singh, Babita; Shivani Pandey, Satyndra Kumar Yadav, Rajesh Verma, Surya Pratap Singh and Abbas Ali Mahdi 2017. Role of ethanolic extract of Bacopa monnieri against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mice model via inhibition of apoptotic pathways of dopaminergic neurons. Brain Research Bulletin 135: 120-128. DOI: 10.1016/j.brainresbull.2017.10.007

Parkinson's disease (PD) is a second most common progressive neurodegenerative disease occurring in the old age population with the pathological manifestations of loss of dopaminergic neurons in the substantia nigra (SN). The severity of the disease has been shown to be correlated with dopamine (DA) neuronal cell loss in the SN, which is consistent with the view that the neurodegenerative process progresses over many years before any symptoms appear (Sawle & Myers 1993). (Singh et al. 2017: 120)

By the looks of it (abstract) this paper could give valuable information about the interaction of BM and the dopaminergic system.

Cells have several mechanisms by which they can decide their own individual fate, in response to unfavorable intracellular or extracellular conditions. This regulatory homeostatic function is genetically programmed and is therefore termed programmed cell death (PCD) or apoptosis. (Singh et al. 2017: 120)

This is how one learns the necessary terminology.

Importantly, BM is a potent neuronal tonic and has been used in the treatment of many neurological deficits. The medicinal potential of Bacopa monnieri is extensively reported in Indian system of medicine such as Athar-Ved, Carak Samhita, Susrutu Samhita for treatment of epilepsy, insomnia, anxiety, mild sedative and memory enhancer (Pandey et al. 2013). BM exhibits anti-stress action, repoiring the injured neurons in PD (Jadiya et al. 2011; Hosamani et al. 2016) though the molecular mechanism of this ability of BM remains unknown. (Singh et al. 2017: 121)

Note that Brahmi vati is actually a mixture of herbs and minerals in which BM is merely prominent. But there does appear to be hope that BM can not only ameliorate but cure neurodegenerative diseases.

However, BM treatment significantly protected against dopaminergic damage, compared to MTPT treated group (p < 0.05) whereas only BM treated group showed no change on comparison to control group. (Singh et al. 2017: 124)

All the experiments result in pretty much this: BM is neuroprotective against damaging substances but produces no observable difference against the control group. Hopefully this does no translate exactly to human trials, and benefit to healthy adults can be observed when proper tests are administered (these animal tests are mostly physical in nature, and don't test memery very reliably). I wonder if long-term studies are already going on.

Although the anti-Parkinsonian property of BM, a medicinal plant (Jadiya et al. 2011; Hosamani et al. 2016) is known, the mechanism of BM mediated neuroprotection is elusive. Therefore it is worthwhile to investigate the neuroprotective efficacy of BM. In the present study, MPTP induced Parkinsonism model was used as it imposes a slow and progressive neurodegeneration, which accurately depicts PD development. In this study, it was demonstrated that BM has potent anti-apoptotic activity in the MPTP model of the Parkinsonian mouse, which may contribute to the behavioural improvements correlated with its treatment. (Singh et al. 2017: 125)

Elusive indeed. Though I'm not sure if even an endless array of substance induced damage and proximate evidence of neuroprotection will take us any further in elucidating the relevant mechanisms of action. What else can we do besides decapitating mice en masse?

Neurotransmitter, Dopamine controls motor activity and movement. In the brain, dopamine is metabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) into its metabolites, DOPAC and HVA, respectively (Jinsmaa et al. 2009; Marchitti et al. 2007) [...] This study demonstrates that BM potently up regulates the level of not only dopamine, but DOPAC and HVA also. Our results suggest that the ethanolic extract of BM exhibits a strong antioxidant property, which helps in curing the oxidative damage occurring in DAergic neurons in the Parkinsonian mouse brain. (Singh et al. 2017: 126)

Does BM upregulate dopamine and its metabolites in healthy adult human brains? Even with animal models, where are the experiments with long-term administration?

Saoji, Suprit D.; Vivek s. Dave, Pradip W. Dhore, Yamini S. Bobde, Connor Mack, Deepak Gupta and Nishikant A. Raut 2017. The role of phospholipid as a solubility- and permeability-enhancing excipient for the improved delivery of the bioactive phytoconstituents of Bacopa monnieri. European Journal of Pharmaceutical Sciences 108: 23-35. DOI: 10.1016/j.ejps.2016.08.056

Recent years have seen a dramatic increase in the popularity of natural products in the management of several ailments (Sikarwar et al. 2008). Among other challenges, the poor bioavailability of the bioactive phytoconstituents is accepted as a major limitation to the use of natural products in mainstream pharmacotherapy. Attributes such as high molecular size, poor aqueous solubility, and lower plasma membrane permeability of pharmacologically active phytoconstituents are known to result in overall poor bioavailability of these compounds, thus limiting their pharmaceutical applications (Husch et al. 2013; Manach et al. 2004). (Saoji et al. 2017: 23)

I wonder if the minerals (ambergris, amber, ruby, pearl, red coral, jadite, and gold foil) in Brahmi vati serve the purpose of enhancing bioavailability.

Several pharmaceutical and nutraceutical products containing extracts of Bacopa monnieri are commercially available (Pravina et al. 2007). However, current literature lacks studies on the issue of the low aqueous solubility of its extract, and any approaches to improve the solibility. In a recent study, the authors have demonstrated success in improving the solubility and permeability of a standardized extract of Centella asiatica via preparation of its complex with a hydrogenated soy phosphatidylcholine (Phospholipon® 90H) (Saoji et al. 2015a). In the present study, this approach was used to assess the feasibility of improving the aqueous solibility of Standardized Bacopa Extract (SBE). (Saoji et al. 2017: 24)

Good, but how can a lay user improve the bioavailability of the extract? Mixing the powdered extract with hot water and then wine does not appear to be the best course. E.g. how to achieve greater bioavailability without the use of difficult-to-come-by chemicals and reagents? (Gut feeling says that Ghee might be the way to go.)

The antidepressant-like activity of Bacopa extract is reported to be due to its adaptogenic effects via normalization of various stress parameters and monoaminergic levels, resulting in the restoration of normal monoaminergic neurotransmitters (Rai et al. 2003). Bacopasides, which are the major constituents of Bacopa, are also reported to exhibit antidepressant effects by improving the vital neurotransmitter activities (Chatterjee et al. 2010). (Saoji et al. 2017: 34)

Already well-established stuff.

Chen, Zhidan and Yanqin Yang 2017. Pharmaceutical composition and drug effect of synthetic Bacopa monnieri L. health promoting agent from the perspective of resistance fatigue. Pakistan Journal of Pharmaceutical Sciences 30(5): 1867-1874.

Recent studies showed that Bacopa monnieri had good tonic effect on the nervous system, digestive system, blood circulatory system, can protect the brain mitochondrial enzyme and improve the concentration of thyroid hormone, anti tumor, liver protection, smooth muscle relaxation and so on. (Chen & Yang 2017: 1867)

Not necessarily a good thing. Reddit nootropics wiki entry for Ashwagandha, for example, marks hyperthyroidism as a possible side effect.

Withania sonmnifera is the main active ingredient of Withanolide Withanolide compounds, [sic] such compounds can be transformed into physiological hormone the body needs, its biological activities including antibacterial, anti-inflammatory, cytotoxicity, cell immunity and anti-tumor aspects. (Chen & Yang 2017: 1868)

What? The authors should employ a native speaker to look over their grammar because much of this paper comes across as near-nonsense, e.g. from the conclusion, "can reduce cell damage caused by sports, improve the function of the way" (ibid, 1873).

Kean, James D.; Luke A. Downey and Con Stough 2017. Systematic Overview of Bacopa monnieri (L.) Wettst. Dominant Poly-Herbal Formulas in Children and Adolescents. Medicines 4(4): Article 86. DOI: 10.3390/medicines4040086

Complementary and alternative medicines (CAM) have been widely used throughout history. One common CAM treatment from the Ayurveda medicinal system is Bacopa monnieri (L.) Wettst. (B. monnieri), or "Brahmi", from the family Scrophulariceae. B. monnieri, is a perennial creeping herb that thrives in damp soils and marshes throughout the subcontinent and is classified as a nootropic (i.e., a cognitive enhancer). The ancient system of medicine, Ayurveda (Sanscrit for "science of life") embraces a holistic approach to healing; a comprehensive treatment system rather than the more commonly accepted single target, single treatment management. In Ayurveda, efficacious CAM treatments are used in combination, rather than individually, to provide a comprehensive synergistic effect. (Kean, Downey & Stough 2017: 1)

Neatly bypassing the question of the age of Ayurveda. As to the synergistic effect, looking at the ingredients of Brahmi vati, the traditional formula, I cannot help but think that perhaps BM is only the "delivery mechanism" substance that improves cerebral blood flow for other substances to hit their targets. The fact that BM shuts off some metabolic enzymes and prolongs the effects of other substances, could play into this.

Ingredients within [...] poly-herbal formula[e abstracted from Table 1]: Bacopa monnieri, Centella asiatica, Withania somnifera, Evolvulus alsinodes, Nardostachys jatamansi, Valeriana wallichii, Embelia ribes, Prunus amygdalus, Tinospora cordifolia, Terminalia chebula, Emblica officinalis, Oroxylum indicum, Celastrus paniculatus, Mucuna pruriens, Elettaria cardamomum [Ela, seed], Terminalia arjuna, Foeniculum vulgare [Surpha, fruit], Ipomoena digitata, Orchis mascula, Zingiber officinale [ginger], Myristica fragrans [Jatipatri, aril/mace, seed], Syzygium aromaticum, Convolvulus pluricaulis [Sankhapuspi, plant], Acorus calamus, Glycyrrhiza glabra, Plumbago zeylanica [Chitraka, root], Piper longum [Pippali, fruit; Pippalimula, root], Paeoniae alba, Spirulina platensis, Melissa officinalis. (Kean, Downey & Stough 2017: 5)

Some of these (noted) are included in the Brahmi vati formula. Some three are even available at a local esoteric shop (Loitsu Keller).

In the current review, this framework, along with the behavioural ADHD framework, highlighted the benefits of poly-herbal formulas on the distinct domains of visual perception, impulsivity, and attention. These domains play vital roles in children's academic abilities, allowing them greater concentration and understanding as well as reduced error-making. With the reporting of overall data, Memomet demonstrated improvement in the reasoning, language behaviour, number facility, mental speed, free recall memory, associative memory, and auditory memory domains, while it was reported that Mentat demonstrated overall benefits in reasoning, hyperactivity, peer relations, and aggression. (Kean, Downey & Stough 2017: 11)

These results should of course be interpreted with caution, and I hope to gain more exact insight once I reach the cognitive tests myself (I suspect they are further down the line in EBSCO search results).

The extent to which the additional herbal extracts may be working in synergism to aid these improvements is beyond the scope of this review. (Kean, Downey & Stough 2017: 11)

Since the interactions of phytochemicals in listed plants are unknown, I'd stick to the combinations advised in the traditional Brahmi vati formula.

In terms of the most common extracts included in the poly-herbal formulas, all of them included the Ayurvedic herb Centella asiatica (gotu kola), renowned for its cognitive [|] enhancing abilities and cardiovascular health. Three formulas included Withania somnifera (ashwagandha) a herb known for its anti-anxiety and anti-stress effects. Two formulas included Convolvulus pluricaulis (shankhpushpi), an Ayurvedic herb also known for its cognitive enhancing abilities. Two formulas included Nardostachys jatamansi (Jatamansi), utilised for its calming effects, as well as its anticonvulsive and antiepileptic activities. Two formulas included Embelia ribes (false black pepper), which has reported benefits in neuroprotection, as well as having antibiotic properties. (Kean, Downey & Stough 2017: 11-12)

As to interactions, BM and Centalla asiatica has the most certain synergy, especially with regards to the GABAnergic mechanism.

A weakness of this review is that only studies published in English were included. B. monnieri is native to India and, following 3000 years of its use in the Ayurvedic medicinal system, studies in languages other than English must exist. (Kean, Downey & Stough 2017: 12)

Citation needed.

Emblica officinalis (E. officinalis), otherwise known as the Indian Gooseberry, is derived from a tree of the Phyllanthaceae species. Recent studies have demonstrated E. officinalis has excellent antioxidant activity in single extract form and in polyherbal formulas, and has also demonstrated anti-inflammatory properties. (Kean, Downey & Stough 2017: 13)

One of the substances available in the mixture named "Triphala". The effects seem not that impressive, considering they're also ascribed to BM, but perhaps a combination would enhance these effects.

Mucuna pruriens (M. pruriens) produces a seed that contains L-DOPA, the precursor to dopamine neurotransmitters leading to investigations of its use in treating Parkinsons Diseas. The ethanolic extract of M. pruriens leaves has also demonstrated an antiepileptic and anticataleptic effect in animal models. Unfortunately retrieving the seeds from the tree is quite tricky with each seed pod covered in spicules that contain serotonin causing severe itching, which is where its name feijões malucos the "mad beans" comes from. (Kean, Downey & Stough 2017: 14)

The description and effects sounds suspiciously like the mega seeds in Rick and Morty: they also "sport small bristles and tiny bumps all over", and cause Morty to have a seizure after consumption.

Asparagus racemosus (A. racemosus), a root extract from the asparagus species, has potential as an anti-dandruff ingredient. Further high performance thin layer chromatography (HPTLC) analysis has demonstrated that A. racemosus had high levels of flavonoids, has demonstrated immunomodulatory capabilities, and has shown protection against xanthine oxidase, an enzyme that generates reaction oxygen species. (Kean, Downey & Stough 2017: 15)

Also locally available, though not all that impressive.

Convolvulous pluricaulis (C. pluricaulis) is a herb that is more commonly known as Shankhapushpi. The terb, much like Bacopa, is known as a Medhya, a drug used to improve memory and intellect. It has demonstrated cognitive enhancing capabilities with respect to learning and memory enhancement. When compared to E. alsinoides, C. pluricaulis displayed increased nootropic effects, but to a lesser extent than E. alsinoides. (Kean, Downey & Stough 2017: 15)

Now this is impressive, though not locally available. Good paper, this.

Shahid, Muhammad; Fazal Subhan, Nisar Ahmad and Ihsan Ullah 2017. A bacosides containing Bacopa monnieri extract alleviates allodynia and hyperalgesia in the chronic constriction injury model of neuropathic pain in rats. BMC Complementary and Alternative Medicine 17: Article 293. DOI: 10.1186/s12906-017-1807-z

Neuropathic pain refers to pain that originates from pathology of the nervous system. Its symptoms include spontaneous and stimulus evoked painful sensations manifested as paraesthesia, paroxysmal pain, hyperalgesia (pain sensation is significantly enhanced) or allodynia (non-noxious stimuli cause pain). Neuropathic pain is a disease of global burden. (Shahid et al. 2017b: 1)

Could have guessed as much, but good to have it on record.

The per se treatment with Bacopa monnieri and gabapentin treated animals showed a robust antihyperalgesic effect (P < 0.001) throughout the experimental duration as compared to CCI controls. (Shahid et al. 2017b: 6)

Results definitely worth the animal torture.

However, in this study, the tested doses of methanolic Bacopa monnieri extract have demonstrated no effect on the latency time in the sham-operated control rats. (Shahid et al. 2017b: 8)

Even better. /s

Jain, Paras; H. P. Sharma, Fauziya Basri, Kumari Priya and Pallavi Singh 2017. Phytochemical analysis of Bacopa monnieri (L.) Wettst. and their anti-fungal activities. Indian Journal of Traditional Knowledge 16(2): 310-318. DOI: 10.13140/RG.2.2.17307.46882

Medicinal plants are the one of the most important source of bio-fungicides. A large number of medicinal plants have been already investigated for their anti-fungal activity as well as antioxidant properties by several researches. Natural compounds are perceived as efficient, safe, cost effective and affordable in comparison with synthetic fungicides and synthetic anti-oxidants that might serve as leads for the development of novel drugs and in food industry to prolong the shelf life of foods, especially those rich in polyunsaturated fats. (P. Jain et al. 2017: 310)

"Our finding was supported [by researchers] who reported that ethanolic exctract of Bacopa monnieri and other herbs significantly reduces yeast and moulds count in various meat product. Moreover these extract possess natural fingucidal effect against food borne fungi." (Tanwar et al. 2016: 1983)

Historically, the use of Bacopa monnieri (Bm) dates back to approximately 6^th century AD. Today practitionares of Ayurveda recognize it as an adaptogen, a physiological agent that naturally increases the body's resistance to physical and emotional stress. (P. Jain et al. 2017: 311)

Probably the closest date, but citation still missing.

The residues of synthetic pesticides on plant product generate free radicals inside the body, damage cell components and are responsible for several diseases. Hence, by going back to the natural ways of life, and to avoid diseases, especially by avoiding synthetic pesticides, man finds hope in nature through its richness in plants like B. monnieri, which can pave the way to a new horizon in prevention of various diseases. (P. Jain et al. 2017: 317)

Not sure if this level of poeticity is merited.

Gupta, Rupali; Akanksha Singh, P. V. Ajayakumar and Rakesh Pandey 2017a. Microbial interference mitigates Meloidogyne incognita mediated oxidative stress and augments bacoside content in Bacopa monnieri L.. Microbiological Research 199: 67-78. DOI: 10.1016/j.micres.2017.03.005

Since time immemorial in the traditional medicine system, B. monnieri has been used as a remedy to improve intelligence as well as revitaliser of sensory organs, and other neurological function (Russo & Borrelli 2005; Sivaramakrishna et al. 2005). However, the increasing demand for herbal products has led to the overexploitation of the natural populations of B. monnieri landing it in the list of vulnerable species (Ceasar et al. 2010). (Gupta et al. 2017a: 67)

Is 6th century AD time immemorial?

Pathogen infection significantly suppressed the plant biomass compared to the yield in non pathogen infected pots. [...] Similarly, the total bacoside content of non infected bacopa plants was 2.1 fold higher owing to inoculation with microbial combination over the control. (Gupta et al. 2017a: 69)

Healthy plants have more biomass and secondary metabolites. Some researchers found that when L-tryptophan was added to the medium, "the added compound passed to the cultured explants" (Muszyńska et al. 2016: 2449). What would happen if bacosides were added to the medium? Would it help the plants combat ROS?

Patel, Shishir Kumar; Shilpi Singh, Hemant Kumar Singhand Shio Kumar Singh 2017. Effect of standardized extract of Bacopa monnieri (CDRI-08) on testicular functions in adult male mice. Journal Of Ethnopharmacology 197: 101-109. DOI: 10.1016/j.jep.2016.07.026

Procreation is an important moral and religious duty in human civilization. However, a large number of human population is still suffering from infertility and it is reported that 50% of infertile couples have male factors-related abnormalities (Shefi & Turek 2006; cited in Abdillahi & Van Staden 2012). Further, sperm abnormalities such as lack of sperm, too little sperm, abnormal sperm morphology and insufficient sperm motility may contribute to infertility (Feng 2003; cited in Abdillah & Van STaden 2012). (Patel et al. 2017: 101)

Very odd way of putting it. Is this why Western countries are falling behind in procreation? Amorality and atheism?

No significant differences were found in the number and motility of spermatozoa in the cauda epididymidis of CDRI-08-treated mice compared to controls. However, a significant increase was recorded in viability of spermatozoa in mice treated with 80 mg dose of the extract compared to controls. Further, a significant reduction in the number of morphologically abnormal spermatozoa was noted in both dose groups of CDRI-08-treated mice compared to controls. (Patel et al. 2017: 104)

Will this be the final word on the matter? Bacosides improve mice sperm...

Lipids are the prime target of free radicals, implicating that cell membranes with high levels of unsaturated fatty acids are especially at risk. Thus, spermatozoa are most vulnerable to peroxidative damage because they contain high concentration of polyunsaturated fatty acids. Peroxidation of sperm lipids is reported to destroy the structure of lipid matrix in sperm membranes which causes rapid loss of intracellular ATP leading to axonemal damage, a decrease in sperm viability and an increase in morphological defects in spermatozoa (Turk et al. 2007; cited in Ceribasi et al. 2010). (Patel et al. 2017: 106)

Actually interesting, because many mention lipid peroxidation but don't add anything about its mechanism of action.

Christopher, Cinthya; Anil John Johnson, Paravanparampil Jacob Mathew and Sabulal Baby 2017. Elite genotypes of Bacopa monnieri, with high contents of Bacoside A and Bacopaside I, from southern Western Ghats in India. Industrial Crops and Products 98: 76-81. DOI: 10.1016/j.indcrop.2017.01.018

Bacopa monnieri (L.) Wettst. (Plantaginaceae), commonly known as 'Brahmi', is an annual creeping herb with many ascending branches and adventitious roots at almost every nodes. It is pantropical in distribution and grows in wet, damp and marshy areas and on the banks of lakes and slow flowing rivers, up to an altitude of 1320 m (Ved & Goraya 2007). In India, it is found in almost all States and in the Andaman and Nicobar Islands (Lansdown et al. 2013). It grows profusely in all districts of Kerala, the southernmost State of India, surpassing altitudinal differences (Sasidharan 2004). (Christopher et al. 2017: 76)

This is perhaps an unmerited parallel, but could the "adventitious roots" of the plant have something to do with inducing the formation of new dendrites?

Owing to its pharmaceutical applications, traditional uses and export of its extract/drugs, B. monnieri is being collected extensively from the wild in India, and this overexploitation leads to its gene erosion. It is estimated that about 10,000-12,000 tons of fresh herb is collected every year from its wild habitats mainly from Tamil Nadu and West Bengal (Mathur et al. 2003; Karthikeyan et al. 2011). Only few wild accessions of B. monnieri show 'elite' content, and most of its natural populations are with low contents of bioactive principles (Bacoside A, Bacopaside I), and this is a major limitation for industrial applications of the species. (Christopher et al. 2017: 77)

Worry and concern.

Out of the sixty B. monnieri accessions screened in this study, three showed total contents of Bacoside A and Bacopaside I above 5.50%, dr. wt. (Acc. No. Bm 11 -6.55% [Pattaniyidukku, Alappuzha]; Acc. No. Bm. 50 -5.56% [Meppadi, Wayanad]; Acc. No. Bm. 52 - 6.58%% [Kumbla, Kasaragode]). [...] These three high yielding accessions could be treated as elite chemotypes/genotypes of B. monnieri. (Christopher et al. 2017: 80)

Pretty sad state of affairs with the average strain containing 1-2%.

Nemetchek, Michelle D.; Andrea A. Stierle, Donald B. Stierle and Diana I. Lurie 2017. The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain. Journal of Ethnopharmacology 197: 92-100. DOI: 10.1016/j.jep.2016.07.073

Bacopa monniera (L.) Wettst, also known as water hyssop, Brahmi, Bramabhi, and nirabarhmi, is a creeping plant found in warm, marshy wetland areas, including those of the Indian subcontinent, East Asia, Australia, and the United States. Bacopa has white to light purple flowers and small leaves, and the genus Bacopa contains over 100 species of the plant. (Nemetchek et al. 2017: 92)

These are apparently alternative transliterations from Sanskrit. Both are mentioned only a handful of times online.

Bacopa has been used medicinally for thousands of years by Ayurvedic physicians, the practitioners of the traditional system of medicine of India. Bacopa was first chronicled in several ancient Ayurvedic texts including the Caraka Samhita (2500 B.C.) and the Sushruta Samhita (2300 B.C.) where clear reference was made to its action on the central nervous system (CNS) (Sharma 2011; Ray et al. 2003). (Nemetchek et al. 2017: 92)

Finally a detailed chronology and citations! Sharma's translation of Caraka Samhita is actually available in the archive!

Neuroinflammation is mediated by microglial cells, which are the resident macrophages in the CNS. When pathogens or other inflammatory signals threaten the CNS, microglia migrate to the site of injury or disease and assume an active phenotype. Activated microglia can either transform into their neurotoxic phenotype (called M1) or a neuroprotective phenotype (called M2). Microglia exist in two distinct functional states; the M1 phenotype that produces proinflammatory cytokines such as Tumor Necrosis Factor alpha (TNF-α) and Interleukin 6 (IL-6), and the M2 phenotype that produces the anti-inflammatory cytokine IL-10 and downregulates the M1 response. (Nemetchek et al. 2017: 93)

Just 2 days ago the following piece appeared: "Researchers capture first ever images of microglia eating brain synapses. Findings suggest that microglia are nibbling synapses as a way to make them stronger, rather than weaker." (Nature)

Chronic inflammation can result from an imbalance between the M1 and M2 subsets, and under certain circumstances such as major injury or disease, microglia remain in the M1 phenotype and perpetuate the inflammatory response. This leads to upregulation of proinflammatory cytokines, and ultimately neuronal cell death. This activation and upregulation is not only siin in neurodegenerative diseases; recent studies have also shown the involvement of neuroinflammation in psychiatric diseases such as anxiety, depression, and schizophrenia. For both neurodegenerative and psychiatric diseases, the regulation of microglial activation is a potential therapeutic agent (Nakagawa & Chiba 2015). (Nemetchek et al. 2017: 93)

A mechanism of action much more interesting than the regularly touted antioxidant one.

These results show that the infusion and alkaloid bacopa fractions reduce the release of both TNF-α and IL-6 by approximately 20% from activated microglia compared to LPS alone. [↩] Thus, bacopa can significantly suppress the release of pro-inflammatory cytokines from activated microglia. It is interesting that in our hands, Bacoside A does not significantly reduce the release of these inflammatory cytokines. Bacoside A is generally considered to be one of the active constituents of bacopa and is thought to be responsible, at least in part, for its biological activity. (Nemetchek et al. 2017: 96)

Thus, BM is anti-inflammatory. I like that the authors may consider the role of other phytoconstituents of BM in further studies, since other phenols and flavonoids, e.g. stigmasterol and myristoleic acid, could be active in its lost list of positive effects.

Few alkaloids have been reported from bacopa, and no biological activity has been associated with these compounds (Murthy et al. 2006). The results of this study suggest that the alkaloid fraction warrants further investigation. [...] Our data suggests that the alkaloid and the infusion fraction contain the greatest anti-inflammatory activity at least in terms of microglial release of pro-inflammatory cytokines. (Nemetchek et al. 2017: 97)

Alkaloids in this case include Brahmine, herpestine and hydrocotyline (Table 1. Active constituents of EBm; in Chaudhari et al. 2017: 114). Other sources (even Wikipedia) also report minuscule amounts of nicotine.

Mallick, Mohammad Nasar; Mohammad Salman Akhtar, Mahammad Zeeshan Najm, E. T. Tamboli, Sayeed Ahmad and Syed Ahtar Husain 2015. Evaluation of anticancer potential of Bacopa monnieri L. against MCF-7 and MDA-MB 231 cell line. Journal of Pharmacy & Bioallied Sciences 7(4): 325-328. DOI: 10.4103/0975-7406.168038

Cancer is a genetic disease that arises from an accumulation of mutations in critical genes. This allows a cell to escape the normal growth control and proliferate until it becomes a clinically evident tumor. The six essential alterations in cell physiology have been identified, which collectively dictate malignant growth; (i) Self-sufficiency in growth signals; (ii) insensitivity to growth-inhibitory (antigrowth) signals; (iii) evasion of programmed cell death (apoptosis); (iv) limitless replicative potential; (v) sustained angiogenesis; and (vi) tissue invasion and metastasis. These properties give the cancer cells a growth advantage over the general cell population. (Mallick et al. 2015: 325)

Interesting general education portion of the paper.

It has been used in Ayurvedic and Unani systems of medicine for the treatment of various ailments and diseases. (Mallick et al. 2015: 325)

"Unani medicine "is the term for Perso-Arabic traditional medicine as practiced in Mughal India and in Muslim culture in South Asia and modern day Central Asia. The term Yūnānī means "Greek", as the Perso-Arabic system of medicine was based on the teachings of the Greek physicians Hippocrates and Galen."

It is used as a memory enhancer [...] for the presence of bacoside A and B, brahmin, different types cucurbitacins, and betulinic acid. Currently, cucurbitacins have also been reported for their [|] strong anti-tumorigenic and anti-proliferative activity [...] (Mallick et al. 2015: 325-326)

In a later paper (Mallick et al. 2017), cucurbitacin B and E are reported in Bacopa monnieri, otherwise papers read in this current cycle do not mention it.

The results showed good cytotoxic activity in DCM fraction in both the cell lines may be due to the presence of cucurbitacins and betulinic acid in DCM fraction. (Mallick et al. 2015: 327)

Both phytoconstituents are present in very low amounts, making it a pretty big if.

Rency, Arockiam Sagina; Lakkakula Satish, Subramani Pandian, Periyasamy Rathinapriya and Manikandan Ramesh 2017. In vitro propagation and genetic fidelity analysis of alginate-encapsulated Bacopa monnieri shoot tips using Gracilaria salicornia extracts. Journal of Applied Psychology 29(1): 481-494. DOI: 10.1007/s10811-016-0918-0

Seaweeds are macroscopic benthic marine algae which are the natural resources of several bioactive compounds. Seaweeds and their products have been used throughout the world for increasing plant growth and yield in the form of fertilizers or biostimulants (Craigie 2011). The chemical analysis profile of seaweed liquid extracts (SLEs) and shown that seaweeds contain several plant growth regulating substances such as cytokinins (Stirk et al. 2003), auxins (Stirk et al. 2004), betaines (Khan et al. 2009), gibberellins (Stirk et al. 2014), and abscisic acid (Vinoth et al. 2014). (Rency et al. 2017: 481)

Now imagine "elite" genotypes of Bacopa monnieri (Christopher et al. 2017) grown in a medium with exogenous supply of plant hormones (Sarkar & Jha 2017), seaweeds and biochar (Jain et al. 2017).

Synthetic seeds have great advantages in the field of plant conservation because they are very small in size, virus free germplasms, low cost of production, ready availability, easy for transporting and handling, and also produce viable and genetically identical plants even after long term storage (Ray & Bhattacharya 2008; Mishra et al. 2011). Previously, synthetic seeds for germplasm conservation wer eprepared from somatic embryos. However, recently synthetic seeds were mostly prepared from shoot tip explants since these are very effective for in vitro regeneration and having more mitotic activity when compared to other parts of the plants (Ballester et al. 1997). (Rency et al. 2017: 482)

Reading these papers is eye-opening with regard to new biotechnologies, if nothing else.

Jasim, B.; P. S. Daya, K. S. Sreelakshmi, P. Sachidanandan, R. Aswani, Mathew Jyothis and E. K. Radhakrishnan 2017. Bacopaside N1 biosynthetic potential of endophytic Aspergillus sp. BmF 16 isolated from Bacopa monnieri. 3 Biotech 7(3): Article 210. DOI: 10.1007/s13205-017-0788-4

Chemical ecology provided by the host plant is considered to have tremendous impact on biosynthetic potential af endophytic microorganisms. This has been proved by increasing reports on production of plant-specific metabolites by endophytes. (Jasim et al. 2017: 1)

Whoa. Endophytic microorganisms produce the primary bioactive secondary metabolites in Bacopa monnieri? Can they be isolated and grown ex vivo to produce bacosides?

Due to the presence of a large number of bioactive metabolites, B. monnieri is having significant applications in diverse clinical canditions (Aguiar and Borowski 2013). The array of metabolites also makes B. monnieri to be a potent source for investigating the presence of fungal endophytes capable of synthesizing host plant-specific metabolites. (Jasim et al. 2017: 1)

Primarily neurodegenerative diseases, epilepsy, and diabetes.

Current study has focused on the isolation and identification of endophytic fungi from B. monnieri. The isolation has resulted in the purification of 26 endophytic fungi which were further screened and analyzed for the biosynthesis of bacopaside using LC-MS and MS/MS analyses. Among various isolates, one was found to have bacopaside producing potential. [...] Based on distinct colony characteristics, 26 endophytic fungi have been purified from stem of B. monnieri and were named as BmF 1 to BmF 26. The purified isolates were sub-cultured periodically and stored for further screening and identification. (Jasim et al. 2017: 2)

Crazy stuff - 26 fungi in one plant stem!

When the extract of BmF 16 was subjected to LC-MS/MS-based fragmentation analysis, it showed the presence of both molecular ion mass and the fragmentation masses specific to bacopaside N1. [...] The presence of specific mass spectrum is confirmatory to the presence of bacopaside N1. (Jasim et al. 2017: 3)

"Sivaramakrishna et al. (2005) indicated that Bacopaside B is also a mixture of four saponins namely Bacopaside N1, Bacopaside N2, Bacopaside IV and Bacopaside V. However, identity of Bacopaside B appears ambiguous as it may be formed huring the extraction of the plant via hydrolysis of saponins of Bacopaside A (Deepak & Amit 2013)." (Christopher et al. 2017: 77) - even in the best case scenario you'll only have one component of an ambiguous phytoconstituent. Interesting stuff nevertheless.

Endophytic organisms reside in a metabolite rich environment which can have significant impact on their biosynthetic potential. There are a large number of studies which suggest the role of endophytic microbes in plant growth regulation, phyto-protection and also in the production of plant-specific metabolites. (Jasim et al. 2017: 3)

It would appear that this particular strain of Aspergillus sp. might have "learned" to produce the host plant-specific metabolite from residing in the plant organism. Could we, in the future, engineer such microorganism to produce these metabolites in higher concentrations? Will even the ongoing century see the commercial availability of mold-produced bacopaside instead of plant material?

McPhee, Grace M.; Luke A. Downey, Anthony Noble and Con Stough 2016. Cognitive training and Bacopa monnieri: Evidence for a combined intervention to alleviate age associated cognitive decline. Medical Hypotheses 95: 71-76. DOI: 10.1016/j.mehy.2016.09.002

Neuroimaging data further supports the occurrence of age associated cognitive decline, with structural and functional changes occurring in the brains of older adults. Specifically, research has shown that with age, there is a reduction in the activation of previously used neuronal pathways, leading to inefficient neuronal firing during cognition. Consequently, this change from efficient to inefficient neural activity may in part explain the underlying cause of age associated cognitive decline, and the subsequent negative outcomes, such as reduced quality of life, problems with daily living and increased risk of dementia in older adults. (McPhee et al. 2016: 71)

This calls to mind the effect of Bacopa monnieri on sleep: with a generous amount of bacoside enhanced extract, sleep becomes quasi-lucid (one may have the experience of being "wide awake" during sleep, wondering when you're going to fall asleep, etc. while actually sleeping). One thing I've noticed recently with whole-plant extract is that sleep becomes pretty solid but dreams become very active, so that each morning I wake up with a completely new set of old experiences re-hashed, often from childhood or from long ago; stuff I don't think about during the day come back more easily in dreams.

Nutraceutical interventions have also demonstrated an ability to improve cognitive performance by targeting brain health on a molecular level and subsequently encouraging synaptogenesis and modulating neuroplasticity in the brain. One nutraceutical that has demonstrated a range of cognitive enhancing properties is Bacopa monnieri (BM). A number of animal studies have detailed how BM upregulates protein kinases and neurotrophins crucial for the production and strengthening of neuronal pathways. Furthermore, BM has also displayed cognitive enhancing effects in humans in a number of randomised controlled trials. (McPhee et al. 2016: 72)

This is pretty much the general impression I received from my previous cycle of reading about BM.

One explanation for these training dependent improvements is that cognitive training may encourage neuronal firing and therefore increase synaptogenesis in the brain of older adults; with current theories on synaptogenesis postulating that it occurs in an activity dependent manner. Specifically, a cognitive task induces the activation of particular neural networks; and repeated activation of this network encourages increased connectivity between neurons, which is enacted by events occurring in the synapse. Importantly, the formation and/or reorganisation of these networks are reliant on the creation (long term potentiation: LTP) and deduction (long term depression: LTD) of synapses, a processed termed synaptic plasticity. (McPhee et al. 2016: 73)

This may account for the casual observation that people pushing over 60 are much more lucid in an academic context where every semester barrages them with a bunch of new faces and a lot of new information. The activity-dependent nature of synaptogenesis basically amounts to the dictum use it or lose it.

Glutamate has been shown to be an important mediator for synaptic formation, as it aidhs in the initiation of action potentials. Specifically, glutamate binds to AMPA receptors on the post-synaptic cell, causing the movement of sodium ions (NA⁺) into and potassium ions (K⁺) out of the post-synaptic cell, initiating depolarisation. Once the cell is depolarised, NMDA receptors and voltage gated calcium channels (VGCC) on the post-synaptic membrane allows the inflow of calcium ions (Ca²⁺) into the intracellular space. (McPhee et al. 2016: 73)

This must be the famous cellular calcium ion homeostasis (Leung et al. 2017: 7) or calcium channel blocking activity (Ullah et al. 2017: 232).

Calcium dependent protein kinases, such as calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA) and protein kinase C (PKC) initiate short-term and long-term synaptogenesis through a number of mechanisms. For example, the sudden increase in Ca²⁺ can instigate the activation of CaMKII, which has been shown to modulate the creation and dissipation of synaptic connections, increase the formations of new dendritic spines and filopodia (initial projections or 'budding' of dendrites) and increase the expression of AMPA receptors on the post-synaptic membrane, increasing the likelihood of glutamate activated depolarisation. (McPhee et al. 2016: 73)

Phraseological finding. This is what could be metaphorically compared to the actual description of the BM plant: "an annual creeping herb with many ascending branches and adventitious roots at almost every node" (Christopher et al. 2017: 76).

Evidently, there are a number of activity dependent molecular mechanisms which initiate short and long-term synaptic changes. Importantly, these changes are instigated by increased neuronal activity, which may explain the re-writing of neuronal networks and improved cognitive outcomes observed after cognitive training. Interestingly, these synaptogenesis inducing mechanisms have also been shown to occur after consumption of the nootropic, Bacopa monnieri (BM). (McPhee et al. 2016: 74)

That's the neurological way of putting the, by now commonplace, adage that every act of remembering is simultaneously an act of re-writing the memory.

Specifically, improvements were observed in a number of memory domains in cognition, including; free recall, associative memory, memory span, and visual memory. Measures of delayed recall in particular showed significant effects after BM supplementation. (McPhee et al. 2016: 74)

Personal anecdotal evidence attests to this as well. During this current regimen I've noticed that sometimes I can hold some overheard item of information in memory, finish my ongoing task, and respond to the item after a period during which I otherwise might have forgotten the item. In other words, things "stick" more.

The researchers note that although BM supplementation has been observed to improve memory, there are less studies assessing another aspects of cognition. Despite this, a small amount of studies have observed improvements in processing speed as measured by the Stroop test and Inspection time after 12 weeks of supplementation; as well as improvements in sustained attention with fewer errors made in the rapid visual information processing task after 90 days of supplementation. (McPhee et al. 2016: 74)

Also verified by personal experience: less procrastination and cognitive activity fatigue. I've read over 40 papers in this cycle already. During my first bout of experimentation with Bacopa in 2014 I read 64 papers in a month, which was then a personal record. In other cognitive studies this probably aligns most closely with "increased exploratory drive" (cf. Mitra-Ganguli et al. 2017: 3).

Hazra, Somoday; Sourav Kumar, Goutam Kumar Saha and Amal Chandra Mondal 2017. Reversion of BDNF, Akt and CREB in Hippocampus of Chronic Unpredictable Stress Induced Rats: Effects of Phytochemical, Bacopa Monnieri. Psychiatric Investigation 14(1): 74-80. DOI: 10.4306/pi.2017.14.1.74

Previous studies from our laboratory and others have shown various neuropharmacological effects of Bacopa monnieri extract (BME). BME may be an effective alternative for the treatment of neuropsychiatric diseases such as depression, anxiety disorders, clinical mental disorders, obsessive compulsive disorders, hysteria, epilepsy and insomnia. (Hazra et al. 2017: 74)

We're slowly inching towards neurological and neuropathological studies that revolve around depression and anxiet, though progress is slow because the next umpteen papers at least are mostly botanical.

Neurotrophins the key molecules in specific brain regions is responsible for neuronal growth, maintenance, cellular differentiation and survival of neurons in the central nervous system. Neurotrophins include brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophins 3 (NT-3) and 4 (NT-4). BDNF is the best characterized among all neurotrophins because of its role in synaptic plasticity and its potential role in the disease pathology or treatment of many psychiatric diseases. (Hazra et al. 2017: 75)

Mentioned by McPhee et al. (2016). General education.

Unpredictable stressors like (1 mA, 15s duration, average 1 foot shock/min) for 60 min, 5 min cold water swim (at 4°C), 1 min tail pinch, 60 min restrain, 48 h food deprivation, 24 h water deprivation, and overnight illumination) was applied in random order to maximize the unpredictable nature of the stressors. (Hazra et al. 2017: 75)

Things to consider as plot points in that alien experimentation short story I'm probably never going to write.

Chronic treatment with BME (80 mg/kg b.w) had significantly increased BDNF level in the hippocampus than CUS group rats (p<0.001), suggesting that BME had a reversing effect on BDNF level in hippocampus. (Hazra et al. 2017: 77)

At this point this is well expected. Those rats were probably tortured with unpredictable stressors and decapitated for nothing. Also, how can you say "significant increase" when "p<0.05 were considered as statistically significant" (ibid., 76)? There should be another word for this.

Hippocampus is a part of key limbic region of brain that [is] structurally and functionally affected by stress. Several experiments revealed certain relations between MDD [Major depressive disorder] and neuronal atrophy in the hippocampus. Hippocampus is critically involved in the regulation of mood and memory. Stress causes reduction in hippocampal volume in depressed patients. (Hazra et al. 2017: 78)

It is probably not a coincidence that BM affects both mood and memory, though I'm not sure how sacrificing so many rats can lead us to discover its mechanism of action.

Phulara, Suresh C.; Virendra Shukla, Sudeep Tiwari and Rakesh Pandey 2015. Bacopa monnieri promotes longevity in Caenorhabditis elegans under stress conditions. Pharmacognosy Magazine 11(42): 410-416. DOI: 10.4103/0973-1296.153097

B. monnieri (L.) Pennell, (Plantagenaceae) commonly known as Brahmi is an important medicinal plant having a major role in traditional and modern systems of Indian medicine. This plant is used in the treatment of mental disorders such as epilepsy and mental retardation, in asthma and as a cardiotonic and diuretic. B. monnieri extract is also known to possess anticancer and antioxidant properties. [...] Keeping in view the vivid pharmacological properties of B. monnieri, the present investigation was undertaken to assess the efficacy of different pharmacological doses [...] (Phulara et al. 2015: 410)

The plant family has been updated. The authors commendably notice that it is extensively used and researched in modern Indian medicine.

Since the systematic evaluation of efficacy, safety, and mode of action of plant extracts in mammalian model is time consuming and costly, so there was a need of such a model organism in which results could be obtained easily, in less time and more efficiently. Caenorhabditis elegans, a free-living nematode is such a promising model organism in which aging and ROS associated manipulation can be done more efficiently and accurately in short course of time. Besides its short lifespan, the ease of genetic and dietary manipulation has also led C. elegans to become established at the forefront of aging studies. (Phulara et al. 2015: 410)

Evidently keywords like "longevity" and "rejuvenation" among the lists of vivid pharmacological properties has caught the attention of aging researchers.

Survival of the worms was scored daily till the death of last worm. (Phulara et al. 2015: 411)

Straight savage.

Our results revealed that there was no significant increase in mean lifespan of C. elegans in any of the treatment [...] Only 4-6% mean lifespan was increased in different test concentrations of BMW. (Phulara et al. 2015: 412)

Not that surprising. There are probably more powerful antioxidants available among herbal remedies to test out.

The lethality of stress and associated aging is directly linked to the damage caused by ROS, resulting in the decline of cells and tissues. [...] All the BMW concentrations reduced the ROS level inside the worm significantly as compared to untreated-control. (Phulara et al. 2015: 412)

It is still somewhat surprising how much importance is attributed to ROS in current researches. It's probably the easiest thing to study; at least easier than protein kinase, dendritic growth, and the like.

The phytomolecules and plant extracts efficiently improve the health and has been widely used for treatment of various ailments caused by different stressors due to their metal chelating and free radical scavenging properties. (Phulara et al. 2015: 414)

Reminds me of the studies of testicular functions in adult male mice (Patel, Singh & Singh 2017; Patel et al. 2017), in which they noted the reduction in various abnormalities in the spermatozoa but not much else. Here, "BMW protected age-associated behavioral declination such as pharyngeal pumping" (ibid., 413).

Kean, James D.; Jordy Kaufman, Justine Lomas, Antionette Goh, David White, David Simpson, Andrew Scholey, Hemant Singh, Jerome Sarris, Andrea Zangara and Con Stough 2015. A Randomized Controlled Trial Investigating the Effects of a Special Extract of Bacopa monnieri (CDRI 08) on Hyperactivity and Inattention in Male Children and Adolescents: BACHI Study Protocol (ANZCTRN12612000827831). Nutrients 7(12): 9931-9945. DOI: 10.3390/nu7125507

In 1937, stimulant medication was developed to treat the disease, officially making ADHD one of the first psychiatric disorders to be recognized, diagnosed and treated in children. [...] Recent debate regarding over diagnosis of ADHD has shown an increase in negativity from parent groups, mainstream media, and the research community. Most issues surround what is publicized as the unnecessary pharmacological intervention in a vulnerable population. Stimulant medication regulates neurochemical deficiencies via increasing the catecholamines dopamine (DA) and norepinephrine/noradrenaline (NE/NA), specifically within the prefrontal cortex (PFC). The PFC is largely responsible for specific cognitive functions, including executive function, attention and elements of impulsivity and hyperactivity. [...] Complementary, alternative and integrative medicines (CAIM) are a common treatment option for parents with children finding it difficult to focus at school, that exhibit behavioural issues, or that present with mild to moderate learning difficulties. (Kean et al. 2015: 9932)

Going by this general profile, BM does seem like a viable alternative, particularly due to its mild upregulation of dopamine and serotonin (cf. Leung et al. 2017). Or, in the authors' own words, "some studies have also documented an anxiolytic or improved mood effect. Both mood and cognitive processes are central to inattention and hyperactivity" (ibid., 9934)

Prior studies have found that half of all parents with children diagnosed with ADHD give their child CAIM without the proper consultation with their child's physician. This highlights the necessity for randomized controlled trials to examine the potential benefits and risks of prospective complementary medicines in the treatment of ADHD symptoms and facilitate evidence based recommendations of specific CAIM in clinical and subclinical populations. (Kean et al. 2015: 9932)

That's a good point. If they're already trying alternative medicine, why not give them evidence-based recommendations. For future research, though, I'd advise polyherbal remedies, i.e. BM alongside other Ayurvedic (and non-) herbs, though it might take some time before various combinations are clinically tested.

The name brahmi derives from the word "Brahma", the mythical "creator" in the Hindu pantheon. Bacopa has been used in the Ayurvedic medicinal system for approximately 3000 years and is classified as a medhyarasayana, a drug used to improve memory and intellect (medhya). (Kean et al. 2015: 9933)

The only fault to be found in this is its staple nature. This very passage appears in numerous papers with very little variation, indicating that the authors of said papers are not doing original research but copy-paste'ing suitable aspects. I'm still considering what to make the subject of my semiotic analysis of the neuropharmacology of BM, but this very aspect, the lack of variation, might be the thing since it's basically a modern scientific "mythology" (the original "Brahmi" plant is extinct, Bacopa monnieri is actually "Aindri", etc.).

A standardized extract of Bacopa was formerly [formally?] launched by the Indian Prime Minister Narsimha Rao and made available in 1996 (then known as Memory Plus™). This was followed by its commercialization through Lumen Marketing (Chennai, India) in 2002 (then called ProMind™). In 2009, the Australian company Flordis (subsidiary company of Soho Flordis International Pty Ltd) launched a CDRI Bacopa extract derived from the most successful formulation ethanol extraction method, CDRI 08. (Kean et al. 2015: 9934)

Interesting stuff. The Memory Plus variety has made it to Estonian pharmaceutical markets, too, though it's a bit costly and for some unknown reason marketed towards male reproductive health. With recent findings of "elite" genotypes and other advances, I suspect the market will be shaken up pretty soon. This was a good paper, though it would have been interesting to get the results in within the same publication.

Tanwar, Tanuj K.; Arvind Kumar and Nrip K. Pankaj 2017. Effect of Bacopa monnieri extracts on storage quality of chicken nuggets at refrigeration temperature (4 ± 1°C). Nutrition & Food Science 47(1): 78-88. DOI: 10.1108/NFS-04-2016-0040

[Today,] consumers demand for [organic,] safe, natural and high-quality food [products]. The preference of consumer toward[s] natural [or organic] food compels the food industry to [work upon and] include natural antioxidant in meat products to impart oxidative stability (Camo et al. 2008). The herbal extract - Bacopa monnieri - can act as a potent natural antioxidant, which can be used in different meat products. [...] The addition of [these alcoholic aqueous] extract[s of herbs] not only improves the sensory characteristic, but also enhance /its/ shelf-life [of the meat products] (Tanwar, Kumar & Pankaj 2017: 78)

You again! And I see that you re-cycled your text (I square bracketed the differences). Not only is using an endangered plant for processed food preservatives unethical, this is self-plagiarism and should get the authors canned (from the Faculty of Veterinary Sciences and Animal Husbandry).

Most of the diseases that we encounter today are lifestyle diseases, which also include the degenerative disease. (Tanwar, Kumar & Pankaj 2017: 79)

Seems dubious. Citation needed.

The herbal extract could act as a very good flavoring agent. (Tanwar, Kumar & Pankaj 2017: 86)

The taste of BM is bitter and it's a natural laxative. What does ethanol taste like? Fuck off.

Kean, James D.; Luke A. Downey and Con Stough 2016. A systematic review of the Ayurvedic medicinal herb Bacopa monnieri in child and adolescent populations. Complementary Therapies in Medicine 29: 56-62. DOI: 10.1016/j.ctim.2016.09.002

The isolated active constituents of Bacopa are denoted bacoside A and bacoside B, and have demonstrated safety and tolerability in human adult volunteers. Hypothesized mechanisms of action on the central nervous system (CNS) are the modulation of cholinergic densities, acetylcholine levels, and β-amyloid scavenging properties. This has directed research to investigate the possible benefits of Bacopa on age-related cognitive decline and as a possible treatment of Alzheimer's dementia. (Kean, Downey & Stough 2016: 57)

"Administration of EBm was seen to protect the cholinergic neurons and reduced anticholinesterase activity comparable to donepezil, rivastimine, and galantamine." (Chaudhari et al. 2017: 111) and "The inhibition of enzymes in the cholinergic pathway like acetyl cholinesterase (AChE) and butryl cholinesterase (BuChE), prevents the degradation of cholinergic neurotransmitters and improves the cholinergic transmission in the brain, helping to improve long-term memory processes." (Dethe, Deepak & Agarwal 2016: 483)

"Deposition of Aβ protein in the brain parenchyma causing neuronal degeneration is the most important mechanism of pathogenesis in AD. A study done [|] by Mathew et al. on anti-amyloidogenic potentials of various herbs revealed that methanolic EBm decreased the formation of amyloid fibrils almost entirely and segregated the pre-formed amyloid fibrils up to a considerable extent." (Chaudhari et al. 2017: 117-118)

One of the current review authors (JDK) analysed the raw data from one study [Asthana, O. P.; J. S. Strivastava, R. C. Gupta et al. 2001. Clinical Evaluations of Bacopa Monniera Extract on Behavioural and Cognitive Functions in Children Suffering from Attention Deficit Hyperactivity Disorder. Central Drug Research Institute (CDRI). Unpublished] to determine the level of improvement, if any, at each time-point against placebo. This study employed a Mann-Whitney U test for treatment group comparisons at baseline and study end. At week 4 there were significant improvements in the language behaviour (p<0.05), mental speed (p<0.05), and associate memory (p<0.05) cognitive domains. At week 8 there were significant improvements in language behaviour (p<0.01), mental speed (p<0.01), memory span (p<0.01), and free recall memory (p<0.05) against placebo. Only one group recorded behavioural outcomes at multiple time points and reported significant improvements in hyperactivity (p<0.05 at four weeks; p<0.01 at eight weeks), and inattention (p<0.01 at four weeks) against placebo. There were no improvements in impulsivity at any stage of this study. (Kean, Downey & Stough 2016: 58)

Categories I'll have to keep in mind when I reach clinical studies, somewhere down the line.

Safety and tolerability data was well reported for 80% of studies with only 2.3% of all participants reporting side-effects involving stomach upset that subsided within days. (Kean, Downey & Stough 2016: 58)

Yuup.

Participant dropout rate was low overall (13%) with only one study [Sharma, R.; C. Chaturvedi and P. V. Tewari 1987. Efficacy of Bacopa Monnieri in revitalizing intellectual functions in children. Not available online] having zero dropouts. This study utilised powdered Bacopa in pineapple [|] flavoured syrup, whereas subsequent trials used capsules of Bacopa or Bacopa extract. The added pineabble flavouring might account for the lack of dropouts in the trial as the taste of the supplement may have appealed to the children, encouraging compliance. This syrup equated to 1050 mg of active treatment per day; an amount significantly higher than any subnequent studies have used, with the exception of a poly-herbal study by Ramarao et al. (Kean, Downey & Stough 2016: 59-60)

I was wondering, when this number was first presented, how they managed to feed such a generous dose to children. Syrup makes sense.

Ramasamy, Seetha; Sek Peng Chin, Sri Devi Sukumaran, Michael James Christopher Buckle, Lik Voon Kiew and Lip Yong Chung 2015. In Silico and In Vitro Analysis of Bacoside A Aglycones and Its Derivatives as the Constituents Responsible for the Cognitive Effects of Bacopa monnieri. PLoS ONE 10(5): 1-19. DOI: 10.1371/journal.pone.0126565

Various mechanisms of action for its cognitive effects have been proposed including acetylcholinesterase (AChE) inhibition β-amyloid reduction, antioxidant neuroprotection, neurotransmitter modulation (acetylcholine [ACh], 5-hydroxytryptamine [5-HT], dopamine [DA]), choline acetyltransferase activation and increased cerebral blood flow. (Ramasamy et al. 2015: 2)

By and by these mechanisms of action are largely "hypothetical", it seems (cf. Kean, Downey & Stough 2016: 57).

Saponins are susceptible to glycosidic cleavage at various sites to form secondary metabolites and finally the aglycone. Triterpenoid saponins from other neuropharmacologically active plants such as ginsenoside and jujuboside have shown that instead of the parent saponins, the metabolites transformed in vivo give better biological activity and pharmacokinetic characteristics. (Ramasamy et al. 2015: 2)

Perhaps one reason why the original Brahmi vati formula has such an extensive list of ingredients. Note that Ayurvedic medicine has a special terminology for metabolic processes.

[...] the docking of the parent compounds, bacopasaponin C, bacopaside X, bacopaside II and bacoside A3 in the CNS receptors and AChE gave a very low number of conformations in a cluster and were not able to fit into the othosteric site of the CNS receptors and AChE. In contrast, the aglycones (jujubogenin, pseudojujubogenin, ebelin lactone and bacogenin A1) with higher number of conformations in a cluster, docked better than the parent compound in the CNS receptor and AChE. These results indicate that the binding pockets of the CNS receptors and AChE were not able to accommodate the large glycoside groups on the bacosides. Among these compounds, ebelin lactone showed the strongest binding towards all the CNS receptors, with the lowest estimated free energy of binding. (Ramasamy et al. 2015: 7)

This ebelin lactone was identified from bacoside A nearly half a century ago (Kulshreshtha & Rastolgy 1973) but the papers in this cycle say nothing about it.

Since B. monnieri is taken orally and has neuropharmacological activities, the active constituents that give the pharmacological activity are necessarily orally and CNS active, i.e., the compound must be absorbed through the intestine and penetrate the BBB [blood brain barrier]. [...] the parent bacosides (bacopasaponin C, bacopaside X, bacopaside II, bacoside A3) fail te mett all but one (Log P < 5) criteria of oral CNS drug candidates. In particular, they fail to meet the criteria for molecular weight (> 899 Da), hydrogen-bonding capacity (hydrogen bond acceptors, 17 to 18; hydrogen bond donors 9 to 10) and molecular flexibility (number of rotatable bonds, 9 to 9). These unfavorable physiochemical traits of the parent bacosides most likely result in poor membrane permeability through the intestine and BBB. (Ramasamy et al. 2015: 7)

Harsh. Bacoside A, which is commonly held as the primary bioactive phytoconstituent of the plant, may not be so active after all, at least not directly.

Overall, the in silico studies demonstrated that the parent bacosides with glycones attached were not able to dock into CNS receptors and AChE, and had poor molecular and ADMET properties as CNS drugs. On the other hand, the aglycones and their acid hydrolysis derivatives showed better binding affinity towards the CNS receptors and AChE enzyme and conform to the required criteria for intestinal absorption and penetration of the BBB. (Ramasamy et al. 2015: 8)

Will future formulations of "Brahmi" consist of these derivatives?

Contrary to the in silico result, the aglycone jujubogenin did not show binding affinity towards all the receptors tested here. However, its derivative ebelin lactone showed affinity towards M₁ (K_i = 0.45 μM) and 5-HT_2A (K_i = 4.21 μM) receptors, which are implicated in memory and learning processes (Fisher 2008; Harvey 2003). (Ramasamy et al. 2015: 9)

These sources (cited, linked) look intriguing.

This study shows that bacoside A is unlikely to be absorbed through the intestine or to penetrate the BBB, using in silico models. Therefore, the bacosides are likely to undergo transformations in vivo to remove the sugar units as well as other biotransformations, that result in metabolites that may mediate the memory enhancing and cognitive activities. This is consistent with other neuropharmacologically active plants such as gingseng, Ginkgo biloba and jujube (red date), where their respective active constituents are formed via the metabolism of the parent compounds in vivo. (Ramasamy et al. 2015: 10)

Possibly why both Bacopa and Ginkgo require quite a large dose to be effective.

Although until now there are no pharmacokinetic studies on bacosides, similar studies on other saponin glycosides such as ginsenoside and flavonoid glycosides such as quercetin glucoside have been reported. In these studies, the parent glycosides were not found in the plasma after oral administration, while their metabolites were detected. This poor intestinal absorption of the glycosides is most likely due to their low membrane permeability. Therefore, prior to intestinal absorption into the systemic circulation, these glycosides undergo deglycosylation in the intestinal tract. IN the case of ginsenoside RB1, deglycosylation of the glycosides is by gastric acid, which remove the sugar units. (Ramasamy et al. 2015: 12)

Very interesting findings indeed. What is the role of betulic acid in this? Note that according to one source "bacoside and other phenols and flavonoids which are proton donors and acidic in nature" (Tanwar et al. 2016: 1979). Also, ultimately, this may be the reason why some (forgot who) report that plant material is just as effective as the bacoside increased extract, since the raw plant material already contains jujubogenin and pseudojujubogenin.

Besides this, glycosides that are not substrates for LPH, CBG and SGLT-1, will be transported towards the colon where they may be hydrolyzed by colon bacteria to release the aglycones, which can then be absorbed into the systemic circulation via passive uptake. (Ramasamy et al. 2015: 13)

At the end of the day it's still down to gut microbiota.

Flavonoids in the form of aglycones and conjugated forms are able to cross the BBB. During passage of the BBB, the conjugates may be metabolized back to the parent aglycone, which then enters the central nervous system (Jäger & Saaby 2011). Therefore, similar to glycosides from other CNS active plants and our in silico results here a similar pharmacokinetics behavior is expected for the bacosides. (Ramasamy et al. 2015: 13)

Extra reading on flavonoids.

There is evidence that the mechanisms of action of B. monnieri could be attributed to a combination of cholinergic modulation especially through the muscarinic cholinergic receptor. B. monnieri extract has been reported to alleviate the amnesic effects of scopolamine, a muscarinic receptor antagonist, suggesting a crucial role of muscarinic receptors in the action of B. monnieri. Furthermore, the administration of B. monnieri for two weeks reversed the depletion of acetylcholine, reduced choline acetylase activity and decreased muscarinic cholinergic receptor binding in the frontal cortex and hippocampus of rats with AD, induced by the neurotoxin colchicine. (Ramasamy et al. 2015: 14)

Whaddayaknow, animal experimentation can help zero in on the mechanism of action.

In addition to this, B. monnieri extract was found to induce neurite and neuronal dendritic growth (Bhattacharya, Kumar & Ghosal 1999; Sharma, Chaphalkar & Dikshit 2012), and studies have shown that muscarinic receptor activation plays a key role in neurite outgrowth (De Jaco, Augusti-Tocco & Biagioni 2002; Anelli et al. 2007). (Ramasamy et al. 2015: 14)

This is the strongest selling point, IMO, of B. monnieri - It'll make your brain cells grow dendrites!

Previous work has demonstrated that treatment with B. monnieri extract caused an increase in 5-HT levels in the hippocampus, hypothalamus and cerebral cortex of rats (Singh & Dhawan 1997; Sheikh et al. 2007). Charles et al. (2011) also found that B. monnieri extract caused a significant up-regulation in the synthesis of 5-HT and altered the ACh level, and proposed that the elevated 5-HT level may activate their receptor to facilitate the release of ACh and thus enhance learning ability and memory. (Ramasamy et al. 2015: 14)

At this point I'm just tracing the sources to read them myself because this definitely merits closer attention. Good paper.

Das, Durgesh Nandini; Prajna Paramita Naik, Aditi Nayak, Prashanta Kumar Panda, Subhadip Mukhopadhyay, Niharika Sinha and Sujit K. Bhutia 2016. Bacopa monnieri-Induced Protective Autophagy Inhibits Benzo[a]pyrene-Mediated Apoptosis. Phytotherapy Research 30(11): 1794-1801. DOI: 10.1002/ptr.5682

Benzo[a]pyrene (B[a]P), a five-ring polycyclic aromatic hydrocarbon (PAH), is a well-recognized environmental pollutant. The compound is generated during incomplete combustion of organic materials like fossil fuels, coal, oil and cigarettes and also from industrial waste, diesel exhaust and charcoal-broiled food (Bansal & Kim 2015). The B[a]P has been the source of increasinc concern in the human health due to widespread dispersion in the environment and the adverse health effect sincluding carcinogenesis associated with PAH exposure (Das et al. 2014). (Das et al. 2016: 1794)

General education portion. Off the bat: does BM protect against carcinogens in cigarettes? Common knowlede is that is chelates iron (Chaudhari et al. 2017: 111) and maybe zinc.

In addition, B[a]P is oxidized by many cytochrome P450 enzymes to several intermediates that have the ability to bind to the nuclear DNA covalently, and this binding results in the mutation, replication error and apoptosis-mediated cell death (Arlt et al. 2008; Stolpmann et al. 2012). (Das et al. 2016: 1794)

Welp, it has been proven that BM "modulated the expression of CYP3A and Pgp", as well as other cytochrome P450 enzymes (cf. Khurshid et al. 2018: 8).

The present study examined the role of BM in the protection of B[a]P-induced apoptosis through induction of autophagy. Our data showed that BM treatment rescues the cell viability decreased by B[a]P. Further, we investigated the mechanism of cytoprotection by BM against B[a]P, and it clearly indicated that BM found to inhibit the apoptosis induced by B[a]P. (Das et al. 2016: 1795)

Another fancy word to add to those long lists of positive effects (perhaps next to cardio- and neuroprotective effects).

BM dried in shade and then powdered; plant material was extracted thrice with 50% ethanol at room temperature. The obtained extract filtrates were pooled and then evaporated to dryness using a rotary evaporator under reduced pressure. The BM extract contained 55% bacoside. The quantification method comprises acid hydrolysis of bacosides, which yields quantitatively a transformed aglycone - ebelin lactone - conjugated triene system, and was estimated by UV spectrophotometry at 278 nm (Mathew et al. 2010). (Das et al. 2016: 1795)

The only other mention of ebelin lactone in current selection of papers.

Moreover, the active constituent of BM responsible for its pharmacological effects is bacoside A, a mixture of dammarane-type triterpenoid saponins containing sugar chains linked to a steroid aglycone skeleton. Distinctive saponins called 'bacosides', especially bacoside A, have been considered to be the foremost bioactive constituents responsible for the cognitive effects of BM (Kalachaveedu et al. 2015). (Das et al. 2016: 1700)

Cf. Ramasamy et al. (2015), above.

These bacosides are dammarane types of triterpenoid saponins with jujubogenin or pseudojujubogenin moieties as the aglycone units. Thus, it is conceivable that the bacoside constituent present in BM extracts may be metabolized to active forms before exerting their pharmacological activities. (Das et al. 2016: 1799)

Define:moiety - "each of two parts into which a thing is or can be divided". The conclusion is the same as Ramasamy et al.'s but I don't see how it follows from the premise given here.

Gupta, Rupali; Akanksha Singh, P. V. Ajayakumar and Rakesh Pandey 2017. Chitinolytic microbes confer Meloidogyne incognita resistance and augment secondary metabolites in Bacopa monnieri (L.) Pennell. Archives of Phytopathology & Plant Protection 50(3-4): 178-196. DOI: 10.1080/03235408.2017.1285522

Exploitation of beneficial microorganisms against Meloidogyne spp., or of bioactive compounds secreted by these microbes, could offer bonus opportunities for controlling disease. Several researches in this area have resulted in discovery of various biocontrol agents reported to perform against plant parasitic nematodes (Terefe et al. 2009). However, continued research is needed to identify potential organisms that can reduce nematode populations significantly in sick soil. (Gupta et al. 2017b: 179)

Biosemiotic interactions.

Bacopa monnieri (L.) Pennell (Brahmi), an important therapeutically essential perennial herb, is well known for its bioactive molecule (bacoside) reported for analgesic, anticancer, antioxidant, adaptogenic, antidepressant, antianxiety and anti-epileptic activities (Bammidi et al. 2011). the successful cultivation of B. monnieri faces a sterm threat owing to the disease of root-knot nematode, M. incognita (Pandey et al. 2003). (Gupta et al. 2017b: 179)

What makes it essential?

Some of bacteria and fungus have been found to produce antagonistic substances, which hinder the hatching of M. incognita significantly (Sikore et al. 2007). In the present investigation, it might be possible that chitinolytic microbes produced enough chitinases that damaged the egg shell or the juveniles within the eggs. Adam et al. (2014) reported pure metabolites of antagonistic microbes reduced egg hatching and juvenile mobility of root-knot nematodes. However, the nematicidal activity of M. arabinogalactanolyticum and Chitiniphilus sp. is reported for the first time herein which was validated by testing the efficacy of the selected strains in sterile as well as natural soil. (Gupta et al. 2017b: 192)

Microbial warfare.

It can also be hypothesised that the exploitation of chitinolytic microbes might have performed as an antagonistic agent for the stimulation of defence mechanism against plant parasitic nematodes (Tian et al. 2007). The total bacoside content was also enhanced in the plants treated with antagonistic microbes which were directly proportional to the biomasse of B. monnieri. The observations recorded are in agreement with the earlier studies where exploitation of antagonistic microbes improved the secondary metabolites content of medicinal and aromatic plants. (Gupta et al. 2017b: 193)

This raises the question: what is the original function of bacosides within Bacopa monnieri?