not-yet-known not-yet-known not-yet-known unknown Exploring the therapeutic potential of Bacopa monnieri in autism spectrum disorder: A comprehensive review

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Data may be preliminary. 26 March 2025 V1 Latest version Share on not-yet-known not-yet-known not-yet-known unknown Exploring the therapeutic potential of Bacopa monnieri in autism spectrum disorder: A comprehensive review Authors : Neluwa-Liyanage Indika 0000-0001-7963-234X [email protected] , Udara Senarathne , Subani Anandavadivel , Bhashika Senevirathne , Shanaka Karunathilaka , Walallawita Dushman , Piumi De Abeysundarab , and Sagarika Ekanayake Authors Info & Affiliations https://doi.org/10.22541/au.174301930.06099958/v1 922 views 454 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract The plant Bacopa monnieri is a traditional medicinal herb renowned for its nootropic properties. The plant extracts have been evaluated for its efficacy in addressing many neurological conditions. However, the efficacy of B. monnieri is yet to be evaluated for autism spectrum disorder (ASD). This review explores and aligns the underlying pathogenic mechanisms in ASD with the molecular and functional characteristics of B. monnieri to evaluate its potential as a therapy in ASD. Additionally, the review addresses strategies for overcoming its drawbacks due to heavy metal accumulation and bitter taste. A comprehensive literature search was conducted in PubMed and Google Scholar using specific keywords related to B. monnieri (” Bacopa monniera,” ” B. monnieri,” ” Herpestis monniera,” ” Moniera cuneifolia”) and those related to ASD, its co-occurring symptoms, and pathogenic mechanisms. Papers were chosen based on an initial screening process, and the evidence was narrated under identified key themes to provide a structured analysis of the therapeutic potential and mechanisms of action of B. monnieri in ASD. Evidence indicated that oxidative stress, neuroinflammation, heavy metal toxicity, mitochondrial dysfunction, neurotransmitter imbalance, and altered cell signalling in ASD could be targeted by the molecular and functional characteristics of B. monnieri, corroborating the potential of B. monnieri to improve symptoms and co-occurring conditions in ASD. To validate these effects, clinical trials should assess primary outcomes related to the core symptoms of ASD, as well as secondary outcomes that focus on improvements in co-occurring conditions and metabolic alterations. not-yet-known not-yet-known not-yet-known unknown Exploring the therapeutic potential of Bacopa monnieri in autism spectrum disorder: A comprehensive review Neluwa-Liyanage Ruwan Indikaa,b, Udara Dilrukshi Senarathnea,c, Subani Anandavadiveld, Bhashika Sithijanee Senevirathned, Shanaka Karunathilakae, Walallawita Kankanamge Tharindu Dushmanthaf, Piumi De Abrew Abeysundarabb,d, Sagarika Ekanayakea,b a Department of Biochemistry, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka. b Centre for Food Quality Testing & Analysis, University of Sri Jayewardenepura, Nugegoda, Sri Lanka. b Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Victoria, Australia. d Department of Food Science and Technology, Faculty of Applied Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka. e Department of Botany, Faculty of Science, University of Ruhuna, Matara, Sri Lanka. f Department of Ayurveda Medicine and Indigenous Medicine, Faculty of Indigenous Medicine, University of Colombo. *Corresponding author Neluwa-Liyanage Ruwan Indika Address: Department of Biochemistry, Faculty of Medicine, University of Sri Jayewardenepura, Nugegoda, Sri Lanka. E-mail: [email protected] Tel. +94 70 333 1636 Details of Authors not-yet-known not-yet-known not-yet-known unknown Full name Name with initials ORCID Institutional email Neluwa-Liyanage Ruwan Indika N-L.R. Indika 0000-0001-7963-234X [email protected] Udara Dilrukshi Senarathne U.D. Senarathne 0000-0003-2329-6871 [email protected] Subani Anandavadivel S. Anandavadivel 0009-0003-8722-230X [email protected] Bhashika Sithijanee Senevirathne B.S. Senevirathne 0000-0002-8300-8870 [email protected] Shanaka Karunathilaka S. Karunathilaka 0000-0003-0016-5641 [email protected] Walallawita Kankanamge Tharindu Dushmantha W.K.T. Dushmantha 0000-0002-7365-6313 [email protected] Piumi De Abrew Abeysundara P.De.A. Abeysundara 0000-0003-3656-2462 [email protected] Sagarika Ekanayake S. Ekanayake 0000-0002-0383-9923 [email protected] not-yet-known not-yet-known not-yet-known unknown 1 1 Abstract The plant Bacopa monnieri is a traditional medicinal herb renowned for its nootropic properties. The plant extracts have been evaluated for its efficacy in addressing many neurological conditions. However, the efficacy of B. monnieri is yet to be evaluated for autism spectrum disorder (ASD). This review explores and aligns the underlying pathogenic mechanisms in ASD with the molecular and functional characteristics of B. monnieri to evaluate its potential as a therapy in ASD. Additionally, the review addresses strategies for overcoming its drawbacks due to heavy metal accumulation and bitter taste. A comprehensive literature search was conducted in PubMed and Google Scholar using specific keywords related to B. monnieri (” Bacopa monniera ,” ” B. monnieri ,” ” Herpestis monniera ,” ” Moniera cuneifolia ”) and those related to ASD, its co-occurring symptoms, and pathogenic mechanisms. Papers were chosen based on an initial screening process, and the evidence was narrated under identified key themes to provide a structured analysis of the therapeutic potential and mechanisms of action of B. monnieri in ASD. Evidence indicated that oxidative stress, neuroinflammation, heavy metal toxicity, mitochondrial dysfunction, neurotransmitter imbalance, and altered cell signalling in ASD could be targeted by the molecular and functional characteristics of B. monnieri , corroborating the potential of B. monnieri to improve symptoms and co-occurring conditions in ASD. To validate these effects, clinical trials should assess primary outcomes related to the core symptoms of ASD, as well as secondary outcomes that focus on improvements in co-occurring conditions and metabolic alterations. Keywords Autism , Bacopa monnieri , mitochondrial dysfunction, nootropic, oxidative stress Abbreviations not-yet-known not-yet-known not-yet-known unknown ADADDMADHDASDCDICNSCOMTCREBERKFDAFOXO3HMGB1IL-6KAMAONREMNrf2PDROSSAHSAMTNF-αWHO Alzheimer’s diseaseAutism and Developmental Disabilities MonitoringAttention-deficit/hyperactivity disorderAutism Spectrum DisorderChildren’s Depression InventoryCentral nervous systemCatechol-O-methyl transferasecAMP Response Element-Binding ProteinExtracellular signal-regulated kinaseFood and Drug AdministrationForkhead box O3High-mobility group box 1Interleukin 6Kainic acidMonoamine oxidaseNon-Rapid Eye MovementNuclear factor erythroid 2-related factor 2Parkinson’s diseaseReactive Oxygen SpeciesS-AdenosylhomocysteineS-AdenosylmethionineTumor necrosis factor - alphaWorld Health Organization Table of contents 1. Introduction 2. Method 3. B. monnieri plant, medicinal uses and bioactive compounds 4. Potential of Bacopa in treating ASD 5. Cognitive effects 6. Improvements in hyperactivity 7. Improvements in sleep-related problems 8. Improvements in gastrointestinal symptoms and intestinal dysbiosis 9. Anti-epileptic effects 10. Anti-depressant and anti-anxiolytic effects 1. Mechanisms of action 2. Antioxidants and anti-inflammatory activity 3. Epigenetic effects 4. Protection against heavy metal toxicity 5. Improving mitochondria dysfunction 6. Modulation of neurotransmitter systems 7. Modulation of cell signaling 8. Metabolic effects 9. Improvement of cerebral blood flow 10. B. monnieri for food and pharmaceutical processing 11. Adverse effects 12. Conclusions Introduction Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by challenges in social interaction, communication, and associated with restricted and repetitive patterns of behavior, interests, or activities. The worldwide prevalence of autism is nearly 1% with a rapid increase in the prevalence over time [1,2]. The Autism and Developmental Disabilities Monitoring (ADDM) Network estimated an increase in the prevalence of ASD in children aged 8 years in the United States, from 0.67% in 2000 to 2.78% in 2020. The prevalence of ASD in boys was four times higher than that in girls [3]. The prevalence of attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorder (ASD) ranges from 2.6% to 95.5%. Furthermore, individuals with both ADHD and ASD experience more severe cognitive impairments and emotional/behavioral issues compared to those with either disorder [4,5]. While conventional medical approaches remain the cornerstone of the management of ASD, an increasing number of individuals and practitioners are exploring complementary and alternative therapies, including plant-derived bioactive compounds rooted in Ayurveda as remedies [6,7].The rationale for considering Ayurvedic therapies in the context of ASD lies in the foundational principles of Ayurveda, which prioritize an individualized and holistic approach to healthcare [8]. Medicinal herbs such as B. monnieri, Zingiber officinale, Camellia sinensis, Piper nigrum, Curcuma longa, Glycine max, Prunus dulcis, Ginkgo biloba, Arthrospira platensis, Chlorella vulgaris, Astragalus membranaceus, Centella asiatica, Withania Somnifera, Melissa Officinalis, and Acorus calamus have been purported to offer neuroprotective benefits, presenting a potential avenue for addressing concerns associated with neurodevelopmental disorders such as ADHD and ASD [9-12]. The objective of this review is to comprehensively analyze and synthesize the available evidence on the therapeutic potential of B. monnieri in the management of ASD. Specifically, this review aims to evaluate clinical outcomes associated with the use of B. monnieri in individuals with ASD, as well as to explore the underlying mechanisms of action that may contribute to its therapeutic effects. By integrating findings from clinical studies, preclinical research, and mechanistic investigations, this review seeks to provide a detailed understanding of the potential role of B. monnieri in improving core- and co-occurring symptoms of ASD and identify gaps in the current literature that warrant further investigations. Method A comprehensive literature search was conducted in PubMed and Google Scholar using specific keywords and search terms. The search strategy included keywords related to B. monnieri (” Bacopa monniera ,” ” B. monnieri ,” ” Herpestis monniera ,” ” Moniera cuneifolia ”) and terms related to autism spectrum disorder (ASD) (”autism,” ”ASD,” ”autistic”). Additionally, we included terms related to co-occurring symptoms commonly associated with ASD (”hyperactivity,” ”ADHD,” ”epilepsy,” ”seizures,” ”gastrointestinal,” ”constipation,” ”mood,” ”depression,” ”anxiety,” ”sleep,” ”cognitive,” ”intellectual”) and terms associated with pathogenic mechanisms in ASD (”oxidative stress,” ”redox,” ”inflammation,” ”heavy metals,” ”mercury,” ”lead,” ”methylation,” ”gut microbiome,” ”dysbiosis,” ”neurotransmitter,” ”melatonin,” ”dopamine,” ”glutamine,” ”serotonin”). Moreover, terms related to the molecular mechanisms of B. monnieri (”nootropic,” ”antioxidant,” ”anti-inflammatory,” ”antidepressant,” ”anxiolytic,” ”sedative,” ”laxative,” ”antimicrobial,” ”antiepileptic,” ”anticonvulsant,” ”chelate”) were utilized in the search. In PubMed, search filters were applied to titles and abstracts, while in Google Scholar, filters were applied only to titles. Additionally, some papers were retrieved manually by referring to the references cited in selected articles. Papers were chosen based on an initial screening process, and the evidence was narrated under identified key themes to provide a structured analysis of the therapeutic potential and mechanisms of action of B. monnieri in ASD. B. monnieri plant, medicinal uses and bioactive compounds B. monnieri (synonyms;, Bacopa monniera, Herpestis monniera, Moniera cuneifolia) belongs to the family Plantaginaceae (formerly Scrophulariaceae) [13]. It is identified with various synonyms and vernacular names across languages, including Brahmi, Aindri, Sarasvati , Jala Nimbha, & Lunabala in Sanskrit, Thyme-leaved Gratiola, Indian pennywort & water hyssop in English, Barami & Jal Neem in Hindi , Nirpirami Piramiyapundu in Tamil, and Lunuwila in Sinhala [14-17]. The herbal species which relates to genus Bacopa is dispersed throughout the tropical and subtropical regions such as Nepal, India, Sri Lanka, China, Taiwan, Hawaii, Vietnam, as well as Florida and other southern regions in the USA [16,18]. It is a perennial creeping herb with succulent, prostrate stems and small, oblong leaves arranged opposite decussate along the stems. The plant typically bears single, axillary, white color flowers with five petals slightly shaded with pale blue to violet. The habitat to B. monnieri is characterized by wetlands, marshes, and the edges of slow-moving water bodies. It thrives in damp, tropical environments, often submerged or partially submerged in water [14,17]. The entire plant is employed in the preparation of Ayurvedic medicine, for its diverse properties. B. monnieri leaves contain a rich array of compounds including many bioactive phytochemicals and essential nutrients [19,20]. In Ayurveda, traditional formulations, such as Brahmi Ghrita (incorporating Brahmi and Ghee), Brahmimuli Adi Kashaya (decoction of Brahmi roots, etc.), and Saraswatarishta (fermented liquid containing Brahmi ), have been developed and utilized to harness these therapeutic attributes [21-23]. B. monnieri is also available in various dosage forms including tablets [24-27], capsules[28-30], caplets [31], syrups [32], and powders[33,34]. Tablets and capsules are commonly used due to convenience and standardized dosages. Syrups provide an alternative for those who have difficulty in swallowing pills. Powders could be mixed with food or drinks, offering flexibility in administration [34]. Due to nootropic action, B. monnieri , is considered a ” Medhya Rasayana ”, a term used in Ayurveda to describe a group of medicinal plants which means intellect, and/or retention of memory (Medga) by regular use of the herbal preparation (Rasayana) [15,33,35,36]. The medicinal properties of B. monnieri are mainly attributed to triterpenoid saponins in the plant and its cognitive-enhancing properties are likely due to a group of saponins referred to as bacosides [37]. The main bacosides found in the plant include bacoside A (a mixture of bacoside A3, bacopaside II, bacopaside X and bacopasaponin C). These triterpenoid saponins contain three sugar units with either jujubogenin or pseudojujubogenin as their aglycone units. Bacoside B is a mixture of four minor diglycosidic saponins: bacopaside N1, bacopaside N2, bacopaside IV and bacopaside V. Other saponins include bacopaside I, bacopaside III, bacopasaponin E, and bacopasaponin F [38,39]. These compounds are known to increase the transmission of nerve impulses, repair neurons, increase kinase activity, promote neurogenesis, modulate neurotransmitter metabolism and improve synaptic plasticity, protect the brain against oxidative damage, reduce inflammation, and prevent Aß aggregation and formation of fibrils [16,20,39,40]. The other chemical constituents identified in B. monnieri include alkaloids (brahmine, nicotinine, herpestine), flavonoids (quercetin, luteolin, rutin, apigenin), phenolics (chlorogenic acid, neochlorogenic acid, caffeic acid), fatty acids (palmitic acid, linoleic acid, oleic acid myristoleic acid, cis-10-pentadecanoic acid, palmitoleic acid), sterols (β-sitosterol, stigmasterol), indole compounds (L-Tryptophan, serotonin), etc[41-46]. These compounds collectively contribute to the plant’s medicinal properties and efficacy in traditional Ayurvedic medicine. Potential of Bacopa in treating ASD The plant has gained much attention for its neuroprotective properties against conditions such as dementia, amnesia, memory dysfunction, Parkinson’s disease (PD), Alzheimer’s disease (AD), epileptic seizures, encephalomyelitis, schizophrenia, and ADHD and is reported to have sedative, anti-inflammatory, anticonvulsant, cognitive-enhancing, antinociceptive, anti-anxiolytic and antidepressant effects that are pertinent to mitigating various key pathophysiological and symptomatological aspects of ASD[47-49]. It is also used for controlling asthma, bronchitis, hoarseness, rheumatism, and fever, generalized weakness, lethargy, fatigue and exhaustion, water retention, diarrhea, piles, dysentery, dyspepsia, vomiting, giddiness, worms, burning of the skin, and cigarette smoking-associated diseases [17,49]. B. monnieri has a high therapeutic index with a low side effect profile, making it a relatively safe option for therapeutic indications [28,50,51]. Despite the extensive attention to the diverse mechanisms of action evident in in-vitro and animal studies, clinical evidence for the treatment of neurological and psychiatric disorders with B. monnieri is sparse. Majority of clinical trials are conducted with healthy adults of varying age groups (Table 1) with a few studies in healthy children or children with ADHD (Table 2) or patients with Parkinson’s disease, anhedonia, memory impairment, and mild cognitive impairment, self-reported poor sleep and Alzheimer’s disease (Table 3) [52-56]. On the other hand, clinical trials assessing the efficacy of a multi-ingredient herbal supplement or compound herbal preparations containing B. monnieri do not conclusively establish that the therapeutic benefits observed are solely attributable to B. monnieri [9,57-62]. The ensuing sections of this review paper discusses the potential for using Bacopa monnier in managing ASD by examining the therapeutic potential of its activity in modulating various biochemical, immunological, digestive, neurological, and behavioral factors specifically increased oxidative stress, inflammation, neurotransmitter imbalance, gut microbiome, cognitive functions, core-symptoms and co-occurring symptoms associated with the condition. The potential therapeutic effects and the underlying biochemical mechanisms of its action are summarized in Figure 1 and 2. Cognitive effects Individuals with ASD exhibit variable impairment in cognitive functions. The findings of meta-analyses indicated that individuals with ASD exhibit significant impairment in executive functioning [63], processing speed [64], working memory[65,66], episodic memory [67], and prospective memory [68], when compared to neurotypical individuals. A meta-analysis of randomized controlled trials indicates that B. monnieri extracts have a positive impact on cognitive function improvement [69]. Clinical trials have demonstrated that B. monnieri has positive cognitive effects across all age groups. Double-blind, placebo-controlled clinical trials demonstrated positive cognitive effects in healthy adult participants (Table 1), and patients with mild cognitive impairment [24] and memory impairment [50,70] (Table 3), on long term administration of B. monnieri. Subjects who were treated with B. monnieri demonstrated significant improvements in delayed recall memory, Stroop task reaction times, information processing, verbal learning, working memory, and memory consolidation compared to the placebo group [25,27,71-73]. The effect of B. monnieri on attention and cognitive processing evaluated via event-related potentials over a 3-month consumption period, indicated a reduction in the latency of the N100 and P300 components [27]. A randomized placebo-controlled trial, where medical students were treated with a standardized extract of B. monnieri for six weeks indicated statistically significant improvements in cognitive functions, particularly in the digit span backward and logical memory tests [26]. A Double-blind, placebo-controlled trials found that B. monnieri caplets and extracts significantly improved memory and learning ability in healthy adults without any adverse effects or biochemical changes [31]. A Double-blind, placebo-controlled trials in children with inattention and hyperactivity demonstrated no significant behavioral differences but decreased error-making and improvements in cognitive flexibility and executive functioning [55]. Furthermore, 50 mg twice daily dose of Bacopa showed significant improvements in logical memory, sentence repetition, and paired associate learning tasks in children with ADHD compared to placebo [74]. An open-label clinical trial with healthy participants aged 4 to 18 years with Intelligent Quotient (IQ) between 70-90, showed significant improvements in working memory, short-term verbal memory, logical memory, personal life-related memory, and both visual and auditory memory from baseline [75]. Clinical trials on healthy adults have demonstrated long term positive effects on memory speed [76]. Moreover, some studies examined the short-term cognitive effects of B. monnieri in healthy adults. For instance, a double-blind, placebo-controlled crossover study demonstrated positive cognitive effects, particularly at both 1 hour and 2 hours post B. monnieri consumption, suggesting an early nootropic effect [77]. A double-blind, placebo-controlled clinical trial, involving cognitively demanding tasks administered over a 60-minute period demonstrated that B. monnieri led to improved cognitive performance, two hours post-consumption [78]. These results thus strongly indicate that B. monnieri has the potential to address impairments in executive functioning, processing speed, working memory, episodic memory, and prospective memory in individuals with ASD. However, despite these possible positive effects, no clinical trials have been conducted to date. Improvements in hyperactivity Hyperactivity and ADHD are common co-occurring conditions in children with ASD [4]. Some studies that found hyperactivity-reducing effects of B. monnieri may be aligned with hyperactivity in ASD. Systematic review by Dutta et al., provides a strong indication of the efficacy and safety of several herbal remedies including B. monnieri in ADHD [9,10,53]. An open-label study indicated that B. monnieri extracts significantly reduced ADHD symptom subtest scores, except for social problems. Specifically, improvement in self-control (89%), reductions in restlessness scores (93%), attention-deficit symptoms (85%), learning problems (78%), impulsivity (67%), and psychiatric problems (52%) were observed in children. Overall, 74% of children exhibited up to a 20% reduction in total subtest scores, while 26% of children showed a reduction between 21- 50%. However, the small sample size (n=31) is a concern for generalizing the findings. Furthermore, the open-label design introduces the potential for bias, which could influence the outcomes [53]. Moreover, a randomized, double-blind, placebo-controlled trial reported that B. monnieri has cognitive, mood, and sleep benefits in male children aged 6 to 14 years exhibiting inattention and hyperactivity. However, the lack of significant behavioral improvements and the unexpected placebo group findings warrants further investigation [55]. Given that hyperactivity and ADHD are common co-occurring conditions in ASD, and B. monnieri has demonstrated positive effects in children with hyperactivity and inattention, future clinical trials on therapeutic effects of B. monnieri in children with ASD should incorporate these relevant outcomes as secondary outcome measures in the design. Improvements in sleep-related problems In individuals with ASD, deficiency and irregularity in the levels of melatonin contribute to abnormal circadian rhythm [79]. Consequently, research efforts have been directed towards elucidating the role of melatonin in reducing sleep-related problems in this population. A systematic review and meta-analysis of interventional studies indicated positive effects of melatonin on total sleep time, sleep latency, and sleep efficiency, though no significant impact on wake after sleep onset and night awakenings was observed [80,81]. The efficacy of B. monnieri in improving sleep has not been studied in subjects with ASD, highlighting a major area that requires further research. However, randomized, double-blind, placebo-controlled clinical trials have demonstrated no significant behavioral differences but improved sleep routine in children (age 6-14 years) [55] and reduced self-reported sleep disturbances, improved sleep quality with no significant improvement in sleep patterns in physically healthy adults, when given B. monnieri extracts [56]. However, ingestion of B. monnieri tablets for 8 weeks did not increase the score of subjective sleep quality, sleep latency, sleep duration, sleep efficiency, and sleep disturbances in patients with mild cognitive impairment [24]. Administration of nano-encapsulated Bacoside A and Bacopaside I decreased sleep latency, and increased Non-Rapid Eye Movement (NREM) sleep duration in KA-induced rat seizure model [82]. Sedative effects appear to be mediated by triterpenoid saponins in B. monnieri . Furthermore, B. monnieri contain indolyl compounds such as L-tryptophan which are involved in the regulation of circadian rhythm [43]. Further research will be mandatory to conclude the effect of B. monnieri on sleep related problems in ASD. Improvements in gastrointestinal symptoms and Intestinal dysbiosis Gastrointestinal symptoms such as abdominal pain, constipation, bloating, and diarrhea are frequently experienced by children with ASD [83-85]. A plethora of evidence points toward the presence of intestinal dysbiosis in individuals with ASD [86,87]. Modulating the gut microbiome using prebiotics, probiotics and fecal microbiota transplantation has been employed as a strategy to reduce behavioral and gastrointestinal symptoms associated with ASD [83,88-90]. A clinical trial involving children with ASD, after one month of intervention with polyherbal compounds of Ayurveda without Bacopa (Rajanyadi Churna, Vilwadi Guilka), alongside lifestyle guidelines and conventional therapies produced statistically significant improvement in the relative abundance of Bifidobacterium , indicating a reduction in dysbiosis, compared to the control group [91]. However, no trial to date has investigated the effects of Bacopa on reduction in intestinal dysbiosis in ASD. Phenolic compounds, glycosides, alkaloids, tannins, and flavonoids in the extracts of B. monnieri have shown broad-spectrum anti-bacterial and antifungal effects [19,42,44,92-94]. A multi-ingredient herbal supplement containing B. monnieri , and several other herbals altered bacterial species in the gut microbiome. Interestingly, the reduction of Sutterella in the gut was shown to be associated with improved bowel movements of participants [95]. Moreover, Bacopaside I, has demonstrated the ability to mitigate stress-induced gut-brain axis damage and modulate gut microbiota in mice, by increasing the abundance of probiotic bacteria and short-chain fatty acids such as acetic acid [96]. In addition to modulation of gut microbiota, the antispasmodic [97] and antinociceptive effects [98] of B. monnieri may also help relieve gastrointestinal symptoms in children with ASD. Anti-epileptic effects Epilepsy is another co-occurring condition in individuals with ASD [99]. The median overall period prevalence of epilepsy in people with ASD is 12.1%, while the prevalence of ASD in individuals with epilepsy is 9.0%. Notably, the prevalence of ASD in epilepsy is higher in males, whereas epilepsy in ASD is more common in females [100]. Shared genetic factors, inherited metabolic disorders, mitochondrial dysfunction, and immune dysregulation might explain the co-occurrence of these conditions [101]. The anti-epileptic or anti-convulsive potential of B. monnieri has been discussed in several review papers [47,48]. To date no clinical trial has been conducted to demonstrate the efficacy and safety of B. monnieri as an anti-epileptic. Therefore, evidence is limited to pre-clinical studies. B. monnieri treatment of epileptic rats significantly reversed the epilepsy-associated alterations in brain tissues such as increased glutamate receptor binding, and increased gene expression of NMDA R1, and increased activity of glutamate dehydrogenase, decreased GABA receptors levels to near-control levels [102,103]. It has been demonstrated in kainic acid (KA) induced rat seizure model that nano-encapsulated Bacoside A and Bacopaside I reduces epileptic spikes and this anticonvulsant action is mediated in a similar manner to benzodiazepines, which is a GABA agonist [82,104]. Additionally, nano-encapsulation of these compounds has been shown to lower cytotoxicity, decrease expression of epileptic markers such as fractalkine, high-mobility group box 1 (HMGB1), Forkhead box O3 (FOXO3), and pro-inflammatory cytokines, protect neurons from apoptosis, and restore mitochondrial membrane potential in mouse neuronal stem cells (mNSC) and neuroblastoma cells [82]. Furthermore, a transcriptomic study demonstrated upregulation of SLC12A5 in human neuroblastoma cell line following Bacopa treatment [105]. This transporter mediates electroneutral potassium-chloride cotransport in mature neurons, and its pathogenic variants are linked epilepsy and ASD [106]. Together, these findings support the potential of nano-encapsulated Bacosides as therapeutic agents with anticonvulsant and neuroprotective properties. Anti-depressant and anti-anxiolytic effects Mood problems are common in individuals with ASD and include symptoms such as anxiety and depression [107]. These mood disturbances significantly impact daily functioning and quality of life, often exacerbating the challenges associated with ASD. Serotonin (5-hydroxytryptamine) and its precursor L-Tryptophan, both indole compounds are found in B. monnieri [43,46]. Serotonin is a neurotransmitter which regulates a variety of functions including sleep and moods. The antidepressant activities of these compounds are well documented. L-Tryptophan is a constituent in some dietary supplements used in the treatment of depression and stress disorders. The active constituents of B. monnieri leaf have the ability to increase serotonin levels in the brain, which relieves anxiety, nervousness, and depression and allows the mind to relax. Mannan et al. stated that the methanolic extract of B. monnieri at doses of 100 and 200 mg/kg was found to have potential antidepressant effects and increased locomotion, and at lower doses (80 mg/kg) B. monnieri leaf extract produced a significant response of anxiolytic effects [47]. A randomized, double-blind, placebo-controlled clinical trials have demonstrated significant decrease in depression and combined state and trait anxiety scores in healthy elderly participants [25]. Positive mood effects and a reduction in salivary or brain cortisol levels have been demonstrated in healthy individuals and patients with anhidonia, indicating a physiological mechanism for stress reduction associated with B. monnieri consumption [77,108]. The effect on mood was assessed in children aged 6 to 14 years who exhibited inattention and hyperactivity, using the Children’s Depression Inventory (CDI). Significant improvements were observed in the ’interpersonal problems’ subscale, while trends toward significance were noted in the ’feelings of ineffectiveness’ subscale and in total CDI scores when comparing baseline to week 8 in children consuming B. monnieri extracts versus placebo [55]. Based on these findings, it can be concluded that B. monnieri demonstrates significant potential as a therapeutic agent for mood enhancement and stress reduction across different age groups. Mechanisms of action Chelation of metal ions [109,110], enhancement in activities of antioxidative defense enzymes [58,111], scavenging reactive oxygen species [112], inhibition of inflammatory cytokines [58,113], and improving cerebral blood floor [114] are the mechanisms of action of B. monnieri , particularly pertinent to ASD. Other properties of this plant that may not be directly relevant to ASD include, anti-hypercholesterolemic, anti-diabetic, antiemetic, antiulcer, anti-aging, bronchodilatory, vasodilatory, hepatoprotective, anti-allergic, and anticancer effects [47,115]. Antioxidants and anti-inflammatory activity Oxidative stress and neuroinflammation have received much attention as significant factors in the pathophysiology of ASD with numerous studies consistently reporting differences in oxidative stress and inflammation observed in ASD compared to neurotypical controls [116]. While the blood concentrations of oxidized glutathione, malondialdehyde, and nitric oxide were higher, reduced glutathione, total glutathione, and cysteine concentrations were significantly lower (p<0.05) in subjects with ASD compared to neurotypical controls, suggesting a dysregulation in redox homeostasis [117]. Increased concentrations of pro-inflammatory cytokines have also been reported in individuals with ASD [118]. Furthermore, increased oxidative stress and neuroinflammation have been demonstrated in postmortem brain tissues of individuals diagnosed with ASD [119]. In this context, B. monnieri demonstrates multiple mechanisms that protect the brain from oxidative damage [120]. The nuclear factor erythroid 2-related factor 2 (Nrf2) is the master regulator of cellular responses against oxidative stress. It is a transcription factor that binds to antioxidant response elements located at the promoters of many cytoprotective antioxidant and phase II drug-metabolizing genes [121]. Using phytochemicals to activate the Nrf2 pathway to alleviate the oxidative stress, inflammation, and mitochondrial dysfunction associated with ASD is a potential therapeutic avenue [122]. In vitro studies have demonstrated that B. monnieri extracts and Bacoside-A affect the Keap1/Nrf2 pathway, helping to restore Nrf2, which is an important regulator of antioxidant genes [123,124] as mentioned above. In-vitro studies have also demonstrated that bioactive compounds in B monnieri scavenge reactive oxygen species, inhibit lipoxygenase activity and prevent hydrogen peroxide induced lipid peroxidation [112,125]. Cell cultures exposed to B. monnieri extracts inhibited the release of inflammatory cytokines such as TNF-α and IL-6 from microglial cells and inhibited caspases 1 and 3, and matrix metalloproteinase-3, the enzymes associated with inflammation in the brain [113]. Pretreatment of male Wistar rat with B. monnieri extract ameliorated several free radical-mediated neurotoxic effects induced by intracerebroventricular injection of streptozotocin including a decrease in reduced glutathione, reduced antioxidant enzyme activity, and reduced expression of superoxide dismutase (Cu/Zn type) expression in the hippocampus hippocampus [126]. In animal studies, B. monnieri increased superoxide dismutase, catalase, and glutathione peroxidase activities in the frontal cortex, striatum, hippocampus [111], and catalase and glutathione peroxidase activity in lymphocytes [127], indicating significant antioxidant effects. Furthermore, B. monnieri increased reduced glutathione and decreased malondialdehyde, total nitrite levels and proinflammatory cytokines in pups born to valproic acid-exposed mother Wistar rats [128,129]. The extracts exert protective effects against neurotoxin-induced neurological dysfunction and glutathione depletion [130,131]. The protective effect against the neurotoxin-induced oxidative stress has been shown to be mediated through restoration of antioxidant enzymes such as superoxide dismutase, and catalase [130]. Glutathione S-transferases (GSTs) are Phase II detoxification enzymes that catalyze the conjugation of glutathione to a wide variety of endogenous and exogenous electrophilic compounds. Variants of the genes encoding glutathione S-transferases are associated with blood lead (Pb) concentrations and symptoms of ASD [132-134]. Lead is a heavy metal which cause cellular oxidative stress by producing ROS such as hydroperoxides, singlet oxygen and hydrogen peroxide which may cause damage to genes and deplete antioxidant reserves (Flora, 2002) such as glutathione. The association between over-transmission of certain haplotypes in mothers and autistic disorder in their children also suggests potential gene-environment interaction occurring during pregnancy [135]. Animal studies have consistently reported that B. monnieri induces glutathione-S-transferase [127,130]. Regular consumption of B. monnieri leaves may help with the treatment of neurological disorders related to free radical damage [47]. Phenolics, flavonoids (luteolin, rutin, apigenin), triterpenoid saponins and sulfhydryl compounds in B. monnieri possess antioxidant potential [42,49,125,136]. The antioxidant compounds in B. monnieri plants increase with the growth of the plants and, peaks when the plants are fully mature and flowered, resulting in the highest antioxidant activity, and decrease with senescence [137]. Further, triterpenoids and bacosides of B. monnieri extracts exert anti-inflammatory effects by inhibiting the activities of lipoxygenases and cyclooxygenase-2 [47,138]. Epigenetic effects One of the notable metabolic abnormalities associated with autism is disrupted sulfur amino acid metabolism. This is strongly supported by evidence of irregularities across multiple markers related to this metabolic pathway. Meta-analyses reveal that individuals with ASD exhibit elevated levels of homocysteine, S-adenosylhomocysteine (SAH), and reduced glutathione, alongside decreased levels of methionine, S-adenosylmethionine (SAM), the SAM/SAH ratio, and cysteine [117]. Particularly the reduced SAM/SAH ratio indicates reduced methylation capacity in ASD [139]. These findings point to a redox imbalance linked to disruptions in the three key pathways of sulfur amino acid metabolism: remethylation, transmethylation, and transsulfuration. Moreover, another meta-analysis that focused on metabolites of transsulfuration and redox metabolism demonstrated significant improvements with methylcobalamin supplementation. The methylcobalamin supplementation decreased the levels of oxidized glutathione and increased the methylation capacity, cysteine, total glutathione, and total glutathione/oxidized glutathione ratio. The resultant improvements in redox ratio were significantly associated with clinical improvements [140]. These improvements in the redox metabolism by methylcobalamin could be mediated by scavenging reactive oxygen species, modulating cytokine and growth factor production against oxidative stress caused by the immune response and reducing oxidative stress induced by homocysteine [141]. The “redox-methylation hypothesis of autism” coined by Deth et al, proposes that abnormalities in redox metabolism and methylation processes may contribute to the development of ASD [142] which could be due to the effect on glutathione synthesis. In line with the hypothesis, children with ASD exhibit reduced methylation capacity [139] and altered DNA methylation in peripheral tissues [143]. Impaired methylation capacity may affect epigenetics by interfering with DNA and histone methylation. Dysregulation of epigenetic mechanisms has been identified as a significant causative factor in the pathogenesis of ASD. Therefore, identifying drugs that inhibit or reverse these epigenetic changes is of great clinical interest [144]. The ”SAM depletion hypothesis” is built upon the earlier hypothesis, proposing that a deficiency in SAM not only reduces methylation capacity but also impairs the activity of ”radical SAM” enzymes, a superfamily of enzymes that reductively cleave SAM to generate a radical intermediate in certain catalytic steps of endogenous lipoic acid and molybdenum cofactor synthesis. Additionally, depletion of SAM may also result in decreased, and disturbances in the mTOR signaling pathway [145]. Interestingly, B. monnieri has been studied for its potential effects on gene expression by modulating level of histone methylation and DNA methylation [146]. Thus B. monnieri appears to have beneficial epigenetic effects and warrants further study in relation to ASD. Furthermore, metabolomic analysis has identified choline and methionine as major constituents of Bacopa juice that could contribute to its neuroprotective effects [46]. Choline and methionine, through their respective metabolites betaine and S-adenosylmethionine (SAM), could help restore impaired methylation capacity and address SAM depletion in ASD (Figure 2). Protection against heavy metal toxicity Low levels of toxic metal exposure in infancy negatively impact neurodevelopment. Babies could be exposed to heavy metals through breast milk or formula, with varying levels of metals found in breast milk based on the exposure of mother to such hazards. During weaning, contaminated water and food continue to be sources of exposure [147]. Children with ASD were found to have higher concentrations of several heavy metals, including cadmium (Cd), lead (Pb), and mercury (Hg), in hair, blood and urine samples compared to healthy controls, suggesting a greater toxic metal exposure. However, there is significant heterogeneity among the studies [148,149]. Medicinal plants and natural products significantly help alleviate the harmful effects of mercury toxicity [150]. Naturally occurring organic compounds in B. monnieri bind to divalent metals demonstrating chelation properties [110,125]. Therefore B. monnieri may offer a relatively safe potential alternative to chelating agents like DMSA, which are known to have severe adverse effects [151]. B. monnieri was found to absorb, translocate, and concentrate heavy metals in the plant tissues [152-154]. Bacopa plant grown in co-contaminated soil have been shown to accumulate metals such as Chromium (Cr) [153,155], Cd [155-157], Arsenate (As) [158], Manganese (Mn) [155], Copper (Cu) [155], and Pb [155,159]. Heavy metals that enter the plant cells of Bacopa can be scavenged by many compounds such as the amino acids, organic acids, reduced glutathione and phytochelatins [160]. Phytochelatins are peptides that act as metal binding ligands, and their synthesis from reduced glutathione is induced by exposure to various metals such as and As and Cd [158,160]. Heavy metals trigger oxidative stress by producing reactive oxygen species (ROS) through various mechanisms, including the inhibition of antioxidant enzymes, depletion of glutathione, mitochondrial dysfunction, and lipid peroxidation [161]. Bacopa decrease Pb-induced oxidative stress in tissues by both chelation and antioxidant activities. The metal chelation ability of this plant is confirmed by the reduction in tissue metal content, and reactive oxygen species and lipid peroxidation products. In addition, it increased the activity of endogenous antioxidant enzymes such as superoxide dismutase and catalase [109]. Neuroprotective ability against oxidative damage caused by Aluminum is another proven benefit of Bacopa. This could be due to its ability to lessen the inhibition of the action of certain enzymes, such as glutathione peroxidase and superoxide dismutase [162]. When compared to those that were simply given AlCl 3 , rats treated with B. Monnieri granules showed improved learning and memory retention [163]. As individuals with ASD have consistently high levels of aluminum in their brain tissue which is predominantly found inside microglia-like cells and other inflammatory non-neuronal cells [164], Bacopa may prove beneficial in reducing the effects due to Aluminum. Another benefit associated with B. monnieri is the ability to counteract methyl mercury toxicity. The ability for it to significantly prevent the reduction of activities of enzymes like glutathione peroxidase, catalase and superoxide dismutase, and to chelate metal ions could be the mechanisms by which mercury toxicity is counteracted [136,165]. As an antioxidant mechanism, cysteine and non-protein thiols in B. monnieri are involved in detoxifying the oxygen species and free radicals. This is evident by the increased levels of cysteine and non-protein thiols in the plant when exposed to heavy metals such as As, Hg and Cd [156,158,166]. However, cysteine content decreases at higher concentrations of Cd, due to stress induced in the plant [156]. Such a significant increase in cysteine level may play a stimulatory role for synthesizing peptides such as reduced glutathione and phytochelatin [156,158,160,166]. The recent identification of plant-derived phytochelatins in human urine paves the way for new research opportunities in nutrition and indicates potential benefits for addressing heavy metal toxicity [167]. Improving mitochondria dysfunction According to a meta-analysis (2012), the incidence of mitochondrial dysfunction among individuals with ASD was 5.0%, markedly exceeding the approximate incidence of 0.01% observed in the general population [168]. Elevated levels of biomarkers associated with mitochondrial dysfunction, including lactate, pyruvate, alanine, and creatine kinase, are present in significant proportions in individuals with ASD [169]. Dietary phytochemicals that activate Nrf2 have been proposed as a potential therapeutic avenue for mitochondrial dysfunction associated with ASD [122]. The evidence supporting this was discussed in the section on oxidative stress. Moreover, there is ample evidence supporting B. monnieri’ s capability to offer protection against mitochondrial dysfunction caused by various neurotoxins and oxidative stress [170]. For instance, B. monnieri suppresses mitochondrial crest damage, decreases matrix dilution, and boosts the presence of both healthy and total mitochondria within cells, offering protection against chemically-induced neurotoxicity [171]. Furthermore, B. monnieri offers cytoprotective activity in Benzo[a]pyrene-induced apoptosis, through the promotion of mitophagy and autophagy [172,173]. Given that mitochondrial dysfunction is a pivotal pathogenic mechanism proposed in ASD, addressing this abnormality using B. monnieri represents a promising strategy. Modulation of neurotransmitter systems Disturbances in the glutamatergic [174], dopaminergic [175], serotonergic [176,177], GABAergic [178], and cholinergic [179] neurotransmitter systems have been documented as emerging targets of treatment in ASD. Both in vitro and in vivo studies have demonstrated that bioactive compounds in B. monnieri could modulate these neurotransmitter systems to bring about desirable effects in ASD [20,115]. Methanolic extracts of B. Monnieri increased GABA, dopamine, and serotonin in IMR 32 neuroblastoma cells [180] and decreased hippocampal serotonin levels of valproate-exposed rats [129]. Furthermore, a gene expression study demonstrated upregulation glutamine transporters (SLC38A1) in human neuroblastoma cell line following Bacopa treatment (Leung et al., 2017). SLC38A1 facilitates glutamine transport from astroglia to GABAergic interneurons for GABA synthesis [181]. Correspondingly, the anticonvulsant effect of Bacoside A and Bacopaside I is supposed to be achieved through a mechanism comparable to benzodiazepines, acting as a GABA agonist [82,104]. Studies suggest that acetylcholine levels are possibly modulated by down-regulating acetylcholineesterase and up-regulating expression of brain-derived neurotrophic factor and M1 subtype of muscarinic acetylcholine receptor, and activation of choline acetyltransferase [182]. B. monnieri has been shown to reduce acetylcholineesterase activity and upregulate GluN2B (ionotropic glutamate receptors) subunit expression in prefrontal cortex and hippocampus [183]. The suppression of acetylcholinesterase may underlie the observed cognitive improvements, providing a potential mechanistic explanation for the memory-enhancing properties of B. monnieri [27]. However, the multifaceted nature of ASD and the intricacies of cognitive processes warrant continued investigation to elucidate the precise molecular mechanisms involved in these observed effects. Additionally, in vitro studies have demonstrated that B. monnieri antagonizes the action of serotonin (5-HT6 and 5-HT2A) receptors, inhibit acetylcholinesterase and catechol-O-methyl transferase (COMT), the enzyme responsible for catecholamine degradation [184]. However, the effect of B. monnieri on monoamine oxidase (MAO) activity was a statistically non-significant reduction compared to the placebo group [27]. In vitro studies have identified bacopaside I as the major constituent of B. monnieri , that selectively inhibits MAO-A enzyme [185]. Taken together, the modulation of neurotransmitter systems appears to offer a plausible mechanism supporting the benefits of B. monnieri in treating ASD. Modulation of cell signaling Animal studies have demonstrated that B. monnieri modulates the expressions of genes encoding proteins involved in intracellular signaling pathways; protein kinase B/Akt signaling pathway, cAMP Response Element-Binding Protein (CREB) pathway, extracellular signal-regulated kinase (ERK) pathway. Ingenuity Pathway Analysis of data from gene expression studies in human neuroblastoma cell lines identified FOXO3, Nrf2 and ATF4 (CREB-2) as transcription factors implicated in the changes in gene expression seen following Bacopa treatment [105]. The upstream regulatory genetic network that modulates these signaling pathways during early human neurogenesis has been shown to be disrupted in ASD [186-188]. Additionally, altered intracellular Ca²⁺ signaling can be identified as a potential target for pharmacological interventions [189]. Several lines of evidence indicate that alterations in the function of calcium channels are implicated in polygenic disorders affecting the central nervous system (CNS), and aberrations in intracellular Ca²⁺ signaling may also underlie ASD. In this context, the findings on Bacopa provide valuable insights [190]. Its spasmolytic effect, primarily through the inhibition of calcium influx via voltage and receptor-operated calcium channels, suggests that it may help regulate calcium homeostasis, potentially correcting dysregulated calcium signaling in the CNS [97]. Furthermore, as observed in a randomized double-blind controlled clinical trial, increase in serum calcium levels after 6-week administration of standardized extract of Bacopa to healthy medical students, while remaining within normal range, indicates a systemic effect on calcium metabolism [26]. These properties of Bacopa may be particularly relevant for disorders like ASD, where calcium channel function and intracellular Ca²⁺ signaling are disrupted. By modulating calcium influx at the cellular level and maintaining healthy systemic calcium levels, Bacopa might offer a therapeutic potential for addressing the underlying calcium signaling abnormalities in ASD and other CNS-related polygenic disorders. Metabolic effects not-yet-known not-yet-known not-yet-known unknown Although the metabolic effects of B. monnieri in ASD remain relatively underexplored, emerging evidence suggests its potential role in modulating biochemical pathways in ASD individuals. Further investigation into these metabolic impacts could not only offer novel insights into the heterogeneity of ASD but also pave the way for the development of metabolic biomarkers to monitor therapeutic responses to B. monnieri in clinical settings. A recent double-blind, placebo-controlled clinical trial incorporated comprehensive metabolomic profiling of plasma, urine, and fecal samples, offering valuable insights into the metabolic changes associated with B. monnieri treatment in ASD. Metabolomics data analysis of this study revealed that tentatively identified differential metabolites are related to pathways such as aminoacyl-tRNA biosynthesis, aromatic amino acid metabolism (phenylalanine, tyrosine, tryptophan), and branched chain amino acid metabolism (valine, leucine, and isoleucine) [76]. In line with the aforementioned studies, a transcriptomic study demonstrated upregulation of aminoacylation of tRNAs, and amino acid transport in human neuroblastoma cell line following Bacopa treatment [105]. Additionally, a metabolomic study has identified essential amino acids such as branched chain amino acids (valine and isoleucine), phenylaniline, tryptophan and methionine as key compounds B. monnieri juice [46]. This is particularly interesting as abnormalities in metabolomic profiles, such as disruptions in branched-chain amino acid [191], phenylaniline [192], tryptophan [193], and t-RNA [194], and abnormal zinc status [195] have been observed in individuals with ASD. Improvement of cerebral blood flow Significant differences in global cerebral perfusion and the cerebral blood flow between the left and right hemispheres have been observed in children with ASD compared to typically developed controls, highlighting the role of lateralization of cerebral blood flow in neurodevelopmental conditions [196,197]. Such perfusion abnormalities appear to be associated with the cognitive dysfunction observed in ASD [198]. Daily oral dosing B. monnieri was found to increase cerebral blood flow by 25% in rats following chronic administration, similar to Ginkgo biloba. The enhancement of cerebral blood flow may support its documented cognitive-enhancing properties by optimizing the delivery of oxygen and essential nutrients to the brain [114]. Human clinical trials have not yet been conducted to determine whether B. monnieri can enhance cerebral blood flow in children. B. monnieri for food and pharmaceutical processing Despite the many benefits, B. monnieri, if harvested from heavy metal contaminated environments can lead to adverse outcomes without proper processing [158,159,199]. The According to a survey conducted in 2018, B. monnieri harvested from various contaminated sites across India, contained high concentrations of heavy metals including Mn, Cu, Pb, Ni and Zn accumulated above the maximum permissible levels approved by WHO [199]. Similarly, Bacopa stems and leaves collected from a natural habitat, had Cr above the maximum permissible levels designated by the WHO [200]. Similarly, the accumulation of metals in the roots is shown to be higher than in the shoots [155,158]. However, most heavy metals have been shown to be lower in B. monnieri leaves compared to stems and roots [200]. Thus, utilizing only, the leafy components for consumption and medicinal purposes would reduce the risk of the intake of heavy metals through Bacopa . A study conducted in 2008 revealed that the herbal medicines constituted with B. monnieri were within the tolerable limits as per the recommended dosage [201]. As above studies clearly demonstrate, bioaccumulation of heavy and inorganic metals could pose health hazards in plants grown in heavily contaminated soil which may exceed safe limits for medicinal use and consumption. Therefore, it is crucial to evaluate the trace metal content of B. monnieri before human consumption or preparation of herbal formulations [159]. The application of biochar to heavy metal contaminated soil has been proved to be one promising method of reducing heavy metal accumulation in plants. The bioaccumulation factor and translocation factor studied after addition of biochar demonstrated a reduction in the uptake of heavy metals by Bacopa . The reasons for this could be immobilization of heavy metals by forming insoluble metal complexes such as Cd(OH)2, Pb(OH)2, modification of bioavailability in soil, due to the exchangeable inorganic compounds and bases in or binding of heavy metals to the organic content in soil [154,202]. In addition, cultivation under greenhouse conditions, with minimal heavy metal contamination could ensure the quality and safety of the plants to be used for medicinal purposes. The bitter taste of B. monnieri is a challenge for the patient compliance [17]. Therefore, the formulations should aim to mask this bitterness to make them more palatable for children. The Indian market offers a wide range of food products that incorporate Bacopa as a functional food ingredient [203]. Value-added products like nutri balls mix, pittu mix, health drink mix, cookies, and soup mix have been prepared using Bacopa powder [204]. Adverse effects Pravina et al. evaluated the safety and tolerability of B. monnieri extract in healthy adults using a randomised, open-labelled, dose escalation design with the administration of B. monnieri capsules daily for 30 days. Pre and post parameter evaluation accompanied by detailed clinical examinations (body weight, pulse rate, blood pressure), haematological (haemoglobin, white cells), biochemical (fasting plasma glucose, creatinine, bilirubin, liver enzymes, total protein, albumin, and urinalysis), and electrocardiographic parameters following administration (300 mg and 450 mg for 15 days each respectively) yielded no statistically significant changes in any of the parameter except for mild gastrointestinal symptoms which subsided spontaneously [28]. Another randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and tolerability of B. monnieri reported no adverse events in elderly subjects throughout the study period [50]. In open-label clinical trials involving children, no major side effects were observed, except a few cases of minor adverse effects such as vomiting and gastrointestinal discomfort [53,75]. Although a number of human clinical studies have demonstrated positive impacts of B. monnieri on healthy and disease conditions with a favourable safety profile [52] the current FDA’s position states that B. monnieri products are not approved for any medical purposes [51]. Conclusions In conclusion, B. monnieri holds significant therapeutic potential for addressing various pathogenic mechanisms underlying ASD, including oxidative stress, neuroinflammation, heavy metal toxicity, mitochondrial dysfunction, neurotransmitter imbalance, altered cell signaling and impaired cerebral blood flow. Additionally, its potential to alleviate co-occurring conditions such as gastrointestinal symptoms, sleep problems, cognitive impairment, hyperactivity, epilepsy, and mood changes highlights its comprehensive benefits. However, despite these possible positive effects, research on therapeutic effects of B. monnieri on ASD is still in its early stage with no clinical trials conducted to date. Future directions To validate aforementioned effects several promising avenues could be explored. Preclinical studies such as animal models of autism could be used to investigate how main metabolic abnormalities pertaining to ASD could be improved. The potential biomarkers such as sulfur- amino acids, porphyrins, melatonin, methylation capacity and markers of mitochondria dysfunction shall be included in the metabolic studies. Rigorous clinical trials are needed to assess primary outcomes related to the core symptoms of ASD, as well as secondary outcomes that focus on improvements in co-occurring conditions and metabolic alterations. Such comprehensive evaluation will provide a clearer understanding of B. monnieri ’s efficacy and safety in treating ASD. Furthermore, assessing Bacopa’s efficacy compared to other natural cognitive enhances (e.g. Centella asiatica and Ginki biloba ) and potential synergistic effects when combined with them would be useful. Dietary modifications incorporating Bacopa and other nootropic vegetables in the diet may provide a holistic and non-invasive approach that existing behavioral and medical interventions. Table 1. Clinical effects of B. monnieri based on clinical trials on healthy adult human subjects Memory Executive functioning Language skills Attention Stroop effect Anxiety Impulsivity Mood 2021 Minale et al. [76] RCT: DB, PC Setting: Thailand 45 B: 21 P: 24 Healthy adults 55 – 80 Y 300 mg of standardized Bacopa extract twice daily (BC: 16%) 12 weeks √ - - - - - - - 2016 Kumar et al. [26] RCT: DB, PC Setting: India 60 B:28 P:14 Healthy adults (Medical students) 19-22 Y Bacognize 300 mg/d (BC: >11%) 6 weeks √ √ √ X - - - - 2014 Benson et al. [77] RTC: DB, PC, crossover Setting: Australia 17 Healthy adults 18-44 Y Keenmind 320 or 640 mg (BC: >55%) Single dose √ X - - √ √ - √ 2013 Sathyanarayanan et al. [205] RTC: DB, PC, crossover Setting: India 66 B:33 P:33 Healthy adults 35-60 Y BacoMind 450 mg/d (BC: 40-50%) For 12 weeks X X X X X √ - - 2013 Downey et al. [78] RTC: DB, PC, crossover Setting: Australia 24 Healthy adults 18-56 Y Keenmind 320 or 640 mg (BC: >55%) Single dose (1 week apart) √ √ - - - X - - 2012 Peth-Nui et al. [27] RCT: DB, PC Setting: Thailand 60 B:40 P:20 Healthy adults Phrompittayarat 001 300/ 600 mg (BC: 5% w/w) For 12 weeks √ √ - √ - √ - - 2011 Mandal et al. [31] RCT: DB, PC 84 B:41 P: 43 Healthy adults 30-42 Y 1 caplet daily for 12 weeks (Each caplet contains 100 mg of extract B. monnieri whole plant and 650 mg of powder Bacopa minnieri whole plant. √ - - - - - - - 2010 Morgan and Stevens [206] RCT: DB, PC Setting: Australia 81 B:36 P: 45 Healthy adults >55 Y BacoMind 300 mg/d (BC: 40-50%) For 12 weeks √ X √ - - - - - 2008 Stough et al.[71] RCT: DB, PC Setting: Australia 62 B:33 P: 29 Healthy adults 18-60y Keenmind 300 mg/d For 90 days √ √ - - - - - - 2008 Calabrese et al. [25] RCT: DB, PC Setting: Australia 48 I:24 C:24 Healthy adults >65y; mean: 73.5y MediHerb 300 mg/d for 12 weeks X √ - X √ √ - X 2002 Roodenrys et al. [29] RCT: DB, PC 76 B:37 P:39 Healthy adults 40-65 y Keenmind 300 mg/d for 90kg (BC: 55%) For 12 weeks X √ - X - X - - 2001 Nathan et al. [207] RCT: DB, PC Setting: Australia 38 B:18 P:20 Healthy adults 18-60 Y Keenmind 300 mg (BC: min 55%) Single dose X X X X X X X X 2001 Stough et al. [72] Erratum [73] RCT: DB, PC 46 B: 23 P:23 Healthy adults 18-60 Y (39.4±11.4 Y) Two capsules a day for 12 weeks. (Each capsule contained 160 mg B. monniera extract equivalent to 4 g dried herb) √ √ - - - √ - - B: Bacopa group, BC: bacoside content, CT: Clinical trial, DB: double-blind, P: placebo group, PC: placebo-controlled not-yet-known not-yet-known not-yet-known unknown Table 2: Clinical effects of B. monnieri based on clinical trials on healthy children and children with attention-deficit/hyperactivity disorder not-yet-known not-yet-known not-yet-known unknown Memory Executive functioning Language skills Attention Stroop effect Anxiety Impulsivity Mood 2022 Kean et al. [55]RCT: DB, PCSetting: 112 ADHD children(DSM-IV ADHD rating score >15)6-14 Y CDRI 08 Bacopa extract160 mg/d (35kg)(BC: 55%)14 weeks √ √ - √ √ √ √ √ 2014 Dave et al. [53]CT: Open labelledSetting: India 31 ADHD children with an IQ ≥806-12 Y BacoMind225 mg/d(BC: 5% w/w)For 6 months √ √ - √ - - √ √ 2008 Dave et al. [75]CT: Open labelledSetting: India 28 Healthy childrenwith an IQ of 70-904-18 Y BacoMind250 mg/d(BC: >5% w/w)For 4 months √ √ √ - - - - - 2000 Negi et al. [74]RCT: DB, PC 36I:18C:18 Children with ADHD Bacopa plant extract50 mg twice dailyfor 12 weeks √ √ - - - - - - not-yet-known not-yet-known not-yet-known unknown ADHD: attention-deficit hyperactivity disorder, B: Bacopa group, BC: bacoside content, C: control group, CT: Clinical trial, DB: double-blind, PC: placebo-controlled, not-yet-known not-yet-known not-yet-known unknown Table 3: Clinical effects of B. monnieri based on clinical trials on adults with Parkinson’s disease, anhedonia, memory impairment, and mild cognitive impairment Memory Executive functioning Language Attention Stroop effect Anxiety Sleep quality Mood 2024 Delfan et al. [24] RCT: TB, PC Setting: Iran 62 B: 31 P: 31 Adults with mild cognitive impairment One pill of 160 mg B. monnieri extract in 2 months X X √ √ - - X - 2023 Santos et at. [208] RCT: DB, PC Setting: Brazil 20 B: 11 P: 9 Adults with Parkinson’s disease 73.6±3.9Y Cognitus 225 and 450 mg/d (BC: 25 – 34%) 90 days - - - - - - - √ 2021 Lopresti et al. [56] RCT: DB, PC Setting: Australia 100 B: 49 P: 51 Physically healthy adults with self-reported sleep disturbances 18 - 70 Y 300 mg/d 27 days - - - - - X √ X 2020 Micheli et al. [108] Preclinical phase trial Setting: Italy 42 B: 19 C: 23 Adults with anhedonia (SHAPS score ≥3) B. monnieri 300 mg 4 weeks Control: citalopram 40 mg - - - - - - - √ 2008 Barbhaiya et al. [50] RCT: DB, PC Setting: India 44 B: 23 P: 21 Memory impaired adults (MMSE 24+) 50-75 Y BacoMind 450 mg/d (BC: >5% w/w) For 12 weeks √ - - √ - - - - 2006 Raghav et al. [70] RCT: DB, PC Setting: India 35 B:18 P:17 Memory impaired adults 55-70y Bacopa extract 250 mg/d (BC: min 55%) For 12 weeks √ √ - - - - - - B: Bacopa group, BC: bacoside content, CT: Clinical trial, DB: double-blind, P: placebo group, PC: placebo-controlled Author contribution not-yet-known not-yet-known not-yet-known unknown NLRI- conceptulaization, methodology, visualization, writing original draft, review & editing not-yet-known not-yet-known not-yet-known unknown UDS-writing - original draft, review & editing SA- writing original draft not-yet-known not-yet-known not-yet-known unknown BSS- writing original draft not-yet-known not-yet-known not-yet-known unknown SK-writing, review & editing, visualization not-yet-known not-yet-known not-yet-known unknown WKTD- writing original draft PDAA-writing, review & editing, supervision not-yet-known not-yet-known not-yet-known unknown SE-writing, review & editing, conceptualization, project administration, supervision not-yet-known not-yet-known not-yet-known unknown Funding not-yet-known not-yet-known not-yet-known unknown This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 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( CAT: Catalase, CREB: cAMP Response Element-Binding Protein, FOXO3: Forkhead box O3, GPX: Glutathione peroxidase, GST: Glutathione S-transferase, IL-6: Interleukin 6, Nrf2: Nuclear factor erythroid 2-related factor 2, ROS: Reactive Oxygen Species, SOD: Superoxide dismutase, TNF-α: Tumor necrosis factor - alpha) Figure 2: Metabolic abnormalities in autism spectrum disorder and the corrective mechanisms of Bacopa monnieri . Key disruptions, including oxidative stress, reduced methylation capacity, mitochondrial dysfunction, and disrupted tryptophan-serotonin-melatonin axis are addressed by Bacopa through multiple mechanisms. (ASD: Autism spectrum disorder, ASMT: Acetylserotonin O-methyltransferase, B12: Vitamin B12, BHMT: Betaine-homocysteine S-methyltransferase, BM: Bacopa monnieri , CAT: Catalase, CBS: Cystathionine β-synthase, D4HCY: Homocysteine residue of D4 dopamine receptor, D4MET: Methionine residue of D4 dopamine receptor, D4SAH: S-Adenosylmethionine residue of D4 dopamine receptor, D4SAM: S-Adenosylhomocysteine residue of D4 dopamine receptor, GPX: Glutathione peroxidase, GSH: Reduced glutathione, GSSG: Oxidized glutathione, MethylTHF: 5-Methyltetrahydrofolate, MS: Methionine synthase, mtROS: Mitochondrial reactive oxygen species, SAH: S-Adenosylhomocysteine, SAM: S-Adenosylmethionine, SOD: Superoxide dismutase, THF: Tetrahydrofolate) Information & Authors Information Version history V1 Version 1 26 March 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords autism bacopa monnieri mitochondrial dysfunction nootropic oxidative stress Authors Affiliations Neluwa-Liyanage Indika 0000-0001-7963-234X [email protected] University of Sri Jayewardenepura View all articles by this author Udara Senarathne University of Sri Jayewardenepura Faculty of Medical Sciences View all articles by this author Subani Anandavadivel University of Sri Jayewardenepura Faculty of Applied Sciences View all articles by this author Bhashika Senevirathne University of Sri Jayewardenepura Faculty of Applied Sciences View all articles by this author Shanaka Karunathilaka University of Ruhuna Faculty of Science View all articles by this author Walallawita Dushman University of Colombo Faculty of Indigenous Medicine View all articles by this author Piumi De Abeysundarab University of Sri Jayewardenepura View all articles by this author Sagarika Ekanayake University of Sri Jayewardenepura View all articles by this author Metrics & Citations Metrics Article Usage 922 views 454 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Neluwa-Liyanage Indika, Udara Senarathne, Subani Anandavadivel, et al. not-yet-known not-yet-known not-yet-known unknown Exploring the therapeutic potential of Bacopa monnieri in autism spectrum disorder: A comprehensive review. 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