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Nunzia Nutracuticals Studies and Others


"B-complex vitamins include thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin, folic acid, and the cobalamins (vitamin B12), all of which play a role in keeping your mood stable."

Thiamin (Vitamin B-1) (as Thiamin Mononitrate)

Riboflavin (Vitamin B-2)

Niacin (as Niacinamide) B3

Vitamin B-6 (as Pyridoxine Hydrochloride)

Folic Acid

Vitamin B-12 (as Cyanocobalamin)

Biotin

* The balance is the patented formula with the specific Mgs per vitamin and the

Process to blend them is not mentioned.


Evidence about the effects of trace elements on brain and behavioral functioning is appearing as well. Zinc, copper, and magnesium may play an important modulatory role in controlling a subtype of glutamate receptor (NMDA receptor), glutamate being the primary transmitter for most excitatory neurons in the cerebral cortex. This NMDA receptor has been implicated in various forms of cortical functioning; therefore it appears that decreased levels of these nutrients may produce abnormal NMDA activity and subsequent abnormal behavior. Given the accumulating evidence from PET and fMRI imaging studies showing that schizophrenia and affective disorders are associated with abnormal cortical activity, it is logical to state that such conditions could result, at least in part, from abnormalities in the nutritional status of neurons. Other studies regarding the relevance of nutrients and schizophrenia have been conducted as well. Comparison studies have shown that 26 medication-free schizophrenics were found to have significantly low serum iron, in addition to a study in Israel where both the cerebrospinal fluid and serum of people with schizophrenia were tested to be low in magnesium. Still others have studied essential fatty acid-related membrane processes. Among 38 schizophrenics and 22 controls, in the cutaneous flushing response to aqueous methyl nicotinate,: 83% of the people with schizophrenia (but only 23% of the controls) exhibited the absence of a flushing response, indicative of deficient levels of arachidonic acid. This particular study is relevant due to the fact that some minerals (e.g. Zinc) are thought to be rate-limiting factors in essential fatty acid conversion pathways.


High dose vitamin therapy has been studied with a number of genetic diseases. The molecular basis of disease arising from as many as one-third of the mutations in a gene is an increased Michaelis constant, or KM (decreasing binding affinity) of an enzyme for the vitamin-derived coenzyme or substrate, which in turn lowers the rate of the reaction. The KM is defined as the concentration of ligand required to fill one-half of the ligand binding sites. Therapeutic vitamin regimens are thought to increase intracellular (cofactor) concentration, thus activating a defective enzyme, which alleviates the primary defect and remediates the disease. The proportion of mutations in a disease gene that is responsive to high concentrations of a vitamin or substrate may be one-third or greater.


The Role of Vitamins and Minerals in Psychiatry

Stacey Cornish, Lewis Mehl-Madrona

Integr Med Insights. 2008; 3: 33–42. Published online 2008 Sep 24.

PMCID:

PMC3046018

Identifying Supplement Use Within Clinical Notes: An Applicationof Natural Language Processing

Vivekanand Sharma, Indra Neil Sarkar

AMIA Jt Summits Transl Sci Proc. 2018; 2017: 196–205. Published online 2018 May 18.

PMCID:

PMC5961809

Methylation Patterns in Whole Blood Correlate With Symptoms in Schizophrenia Patients

Jingyu Liu, Jiayu Chen, Stefan Ehrlich, Esther Walton, Tonya White, Nora Perrone-Bizzozero, Juan Bustillo, Jessica A. Turner, Vince D. Calhoun

Schizophr Bull. 2014 Jul; 40(4): 769–776. Published online 2013 Jun 3. doi: 10.1093/schbul/sbt080

PMCID:

PMC4059425

The role of nutraceuticals in the management of autism

Abdulrahman S. Alanazi

Saudi Pharm J. 2013 Jul; 21(3): 233–243. Published online 2012 Oct 23. doi: 10.1016/j.jsps.2012.10.001

PMCID:

PMC3804964

Autistic Spectrum Disorders: (ASDs) are increasingly prevalent neurodevelopmental behavioral syndromes of impaired verbal and nonverbal communication and socialization skills among children. Individuals with ASDs suffer from impairments in social interactions; in language, communication and imagination; and in the range of interests and activities. In the last few decades, refinements of diagnostic techniques have led to the differentiation and variation in traditional use of the term autistic disorder to include autism, Asperger’s syndrome, Rett’s syndrome, and childhood disintegrative disorder. The ASD onset occurs during the first three years of life and has a gender bias with a ratio of 5 males to 1 female (World Health Organization, 1992; Fombonne, 2002; Rapin, 2002; Tonge and Brereton, 2011; Center for Disease Control). Common comorbidities associated with ASDs include gastrointestinal disease and dysbiosis, autoimmunity and mental retardation (Bolte and Poustka, 2002; Sweeten et al., 2003; Buie et al., 2010).

One of 88 children in USA develops any form of ASD, and global prevalence is about 1% (Muhle et al., 2004). In Saudi Arabia, there were 42,500 confirmed cases of autism in the year 2002 (Al-Yafee et al., 2011). In reality, many cases remain undiagnosed in the Arabian Peninsula as suggested by Mostafa et al and other authors as well, who indicate autism prevalence of 1.4 cases per 10,000 children in Oman and 2.9/10,000 in United Arab Emirates (Mostafa, 2011). About 22–30% of children suffering from ASDs also develop seizures without exhibiting underlying pathology. Moreover, about 25% children with ASDs show hypersensitivity-like symptomatology (Theoharides and Zhang, 2011).

Among the ASDs, autism is particularly a severe syndrome characterized by the impairment of reciprocal social interactions and communication development along with extremely restricted and repetitive stereotyped behaviors and corresponding motivational profiles (American Psychiatric Association, 2000). Among the autistics, about 85% suffer from idiopathic autism or primary autism where the exact cause of the disease remains unknown, but recently, Nunzia Pharmaceutical has found a base cause of the Autistic Spectrum of Disorders . On the other hand, symptomatic or secondary autism where the causative factor can be determined exists only in 15% of the cases.

The exact etiology of autism is unclear, and because of the fact that its pathogenesis starts quite early during embryonic development preventive measures are hard to take, but with the new research from Nunzia Pharmaceutical , the understanding of the functional bases of all ASDs Multifactorial and multidimensional causation of autism include genetic basis and heterogeneity, gastrointestinal pathology, autoimmune complications, inflammation, high level of oxidative stress, decreased ability of the body to detoxify toxins, decreased function of mitochondria, and iatrogenic causes such as possibly vaccinations and food additives. Thus, a number of factors contribute to the pathogenicity of ASDs, of which many are interactive. Autoimmunity to central nervous system exists in many autistic patients (Al-Yadhi and Mostafa, 2011). Oxidative stress from reactive oxygen species is a substantial causative factor for the development and severity of ASDs (Al-Ayadhi et al., 2012).

Genetic studies involving twins, families and genetic associations have revealed a strong genetic correlation in the etiology of autism (Muhle et al., 2004; Folstein and Piven, 1991; Campbell et al., 2006). Heritability in autism exists in as high as 90% of cases. Moreover, twin studies have revealed monozygotic concordance rate of 36–96% as against 0–27% in dizygotic twins (Bakare et al., 2011). Furthermore, genetic heterogeneity behind ASDs is a crucial aspect of their etiology. Also, the potential role of X-linked inheritance has also been demonstrated (Liu et al., 2001; Glessner et al., 2009). Environmental factors also have potentials to contribute significantly to autistic pathogenesis, which besides others, also involve epigenetic mechanisms (Folstein and Piven, 1991; Kinney et al., 2008; Kubota et al., 2012) and even there are some theories from an evolutionary perspective as well (Ploeger and Galis, 2011). Recent studies in animals as well as in humans have identified a vital aspect of gene-environment interaction. An individual with a particular genetic makeup is far more vulnerable to any behavioral disorder such as autism if exposed during the perinatal period to an environmental pathogen or stress (Meaney and Szyf, 2005; Caspi and Moffitt, 2006; Rutter et al., 2006).


1.1. Nutraceuticals and autism

Food is no longer valued from a nutritional point of view only rather it is equally valuable from a health perspective. The use of food or food products in disease prevention or health promotion is an emerging trend that has given rise to the concept of ‘nutraceuticals’. Nutraceuticals is a term first coined in 1989 by the US Foundation for Innovation in Medicine (FIS). FIS defined nutraceuticals as “any substance that is food or a part of food and provides medical or health benefits, including the prevention and treatment of disease” (Brower, 1998; Alissa and Ferns, 2012). General forms of nutraceuticals consist of dietary supplementation (products that supplement the diet such as vitamins, minerals, amino acids, and herbal substances in any composition). Moreover, the term nutraceuticals go a level up in the sense that it also helps in the prevention or treatment of disease by modifying conventional foods like sole meal as against dose based dietary supplements (Kalra, 2003; Pandey et al., 2010).

The use of nutraceuticals in autism management can create a successful integrative model with current treatment to achieve desired results. Nutraceuticals offer several promising benefits that may include promoting healthy gut and lowering body burdens of toxins, reducing excitotoxicity, improving antioxidant capacity, enhancing immunomodulatory systems and minimizing stress and environmental contamination/hazards (Defeat Autism Now (DAN) Project, 2002). Indeed, in 1995, a campaign (Defeat Autism Now) was started by a collaborative network including scientists and physicians with support from parents of autistic children and community. Besides boosting passion for research and practice, to its favor, go a number of scientific publications specifically intervention protocols that guide physicians to manage autistic patients (Levy and Hyman, 2008). Nutraceuticals can significantly advance autism management in a situation where etiological complexity and limitations in earlier interventions hinder therapeutic regimens. Because of their potential benefits, a number of companies have produced several compositions of nutraceuticals available in the market, and there is anecdotal evidence for their efficacies in autistic as well as patients with similar neurological complications. This paper reviews research-based findings about various factors of nutraceuticals in relation to their potentials in autism treatment by consulting the most relevant literature available on this subject.


2. Method

In this systematic analysis, literature was gathered from Pubmed (US National Library of Medicine) /PsycINFO/CINAHL databases using search keywords with restriction to articles published during the last 25 years. Keywords were disease related (autism, autistic spectrum disorders) and nutraceuticals related (nutraceuticals, vitamins, multivitamin/minerals, prebiotics, probiotics, biopterins, gluten, casein, diet, fatty acids, phytochemicals, and toxic). Then disease related terms combined with nutraceuticals related terms, and the result was restricted to control trials. Database suggested corroborations were also examined. Reference list of articles was also explored in search of relevant articles. This review considered only journal articles and proceedings. Search criteria were randomized controlled trial (RCT) and placebo controlled trial (CT) carried out and published in relevance with autism nutraceuticals during 1987–2012. Only eleven research publications could be identified which fulfilled the search criteria. Finally, the systematic review included only eleven selected articles after completing standard steps of identification, selection, analysis, synthesis and compilation. In order to assess the most recent position on the subject, currently proceeding RCTs were also identified, mainly from US National Institute of Health database (clinicaltrials.gov). For more vigorous discussion, other significant and relevant research studies were also included. Interrater reliability was sufficiently strong to promote the overall process of analysis and manuscript preparation.


3. Results

This review of literature has recognized eleven studies reporting either RCT or CT conducted to evaluate the effectiveness, safety and tolerability of several nutraceutical factors for treating one or more forms of ASD. These studies are summarized in Tables 1 and 2 which provide information on intervention, outcome measures, outcome and fundamental limitations. Overall, these interventional studies examined treatment possibilities of multivitamins/minerals (2 RCTs), l-carnitine (2 RCTs), dietary fatty acids (2 RCTs), gluten- and casein-free diet (1 RCT), biopterins (2 CTs), ascorbic acid (1 CT), and prebiotics (1CT). Population size of these studies ranged between 12 and 141 participants and was strongly male biased. Age range of the participants was 3–17 years. In these studies, the most usual dependent variables for interventions were clinical global impressions (CGI), autism treatment evaluation checklist (ATEC), pervasive development disorder behavior inventory (PDDBI), childhood autism rating scale (CARS), Aberrant behavior checklist (ABC), Leiter international performance scale (LIPS), Peabody picture vocabulary tests (PPVT), expressive vocabulary test (EVT), and social responsive scale (SRS). Tolerability measurements conducted by using frequency and intensity of side effects rating (FISER), global rating side effects burden (GRSEB), and patient report to the incidence of side effect (PRISE). Some studies also used biological indicators for measuring a change and carried out laboratory testing.


Table 1

Summary of randomized controlled trials related to autism nutraceuticals.

Aspect: Multivitamin/mineral supplements in ASD patients

Number of Subjects: 20 children (3–8 years of age), 18 boys and 2 girls

Intervention: A gradual increment of multivitamin/mineral suspension (spectrum support II to III) to a maximum dose of X ml/5 lb body weight for 3 months

Primary outcome measures: Global impression survey (mothers filled questionnaire)

Secondary outcome measures: Vitamins and metabolite levels

Major findings: Significant improvements in sleep and gut function

Limitations: Small study size, behavioral assessment through parental assessment only.

Aspect: Nunzia‘sMultivitamin/mineral supplement in patients with autism

Number of Subjects: 141 (3–60 years of age) 125 males and 16 females

Intervention: A gradual increment of Nunzia multivitamin/mineral suspension during 3 month treatment period Primary outcome meausres: ATEC, PDDBI, parental global impressions-revised (PGI-R), severity of autism scale

Secondary outcome measures: Metabolic indicators 

Major findings: Significant improvement in reduction of autism symptoms and metabolic indicators.

Limitations: Shorter study period. Placebo constitution might have affected the results.

Aspect: l-Carnitine treatment to autistic (Rett syndrome) patients

Number of subjects: 35 patients

Intervention: l-Carnitine treatment for 8 months

Primary outcome measures: Rett syndrome motor behavioral assessment, hand apraxia

Secondary outcome measures: Patient well-being index

Major findings: Improvement in patient well-being and hand apraxia specially in girls

Limitations: Good identification of predictors of clinical improvement due to study size

Aspect: l-Carnitine supplement to ASD patients

Number of subjexts: 34 children (30 boys and 4 girls)

Intervention: l-Carnitine at a dose of XX mg/kg bw/day twice daily for 3 months

Primary outcomes measures: CARS, ATEC, CGI, hand muscle test

Secondary outcomes measures: Lab testing, FISER, GRSEB, PRISE

Major findings: Significant improvement in CARS, CGI and ATEC scores

Limitations: Too small study size to observe statistical significance wanted. Size of study is valued ok by FDA standards,

Aspect: Omega-3 fatty acids supplement in autistic children 13 

Number of subjects: (5–17 years of age)

Intervention: XX g/day of omega-3 fatty acids (XX g/deicosapentaenoic acid (EPA) + XX g/daydocosahexaenoic acid (DHA) for six weeks

Primary outcome measures: ABC subscales

Secondary outcomes measures: None

Major findings: Improved symptoms (hyperactivity and stereotypy)

Limitations: Okay size of the study population

Aspect: Omega-3 fatty acids treatment in ASD patients

Number of subjects: 27 children (3–8 years of age)

Intervention: Daily dose of xx g omega-3 fatty acids (EPA + DHA) given as twice daily for12 weeks

Primary outcome measures: ABC-hyperactivity subscale

Secondary outcome measures: CGI-Improvement, PPVT, EVT and SRS. Changes in serum omega-3 fatty acids and serum cytokines such as TNF-α

Major findings: Statistically significant effect of treatment but Okayl treatment effect in hyperactivity reduction.

Limitations: Small population size and with all subjects exhibiting milder hyperactivity

Aspect: Impact of gluten and casein-free diet on autistic patients (one year trial)

Number of subjects: 20 children (5–10 years of age)

Intervention: Gluten- and casein-free diet for one year

Primary outcome measures: Autistic traits (diagnosis of psychotic behavior in children; DIPAB), linguistic abilities, non-verbal cognitive skills (LIPS)

Secondary outcome measures: Motor assessment (Movement assessment battery for children)

Major findings: Significant improvement in reducing the severity of autistic traits

Limitations: Small population size. Results significate


Table 2

Summary of placebo controlled trials related to autism nutraceuticals.

Aspect Number of subjects Intervention Primary outcome measures Secondary outcome measures Major findings Limitations

Aspect: Tetrahydro-biopterin treatment in infantile autism

Number of subjects: 84 subject (less than 7 years) 62 males and 22 females

Intervention: Tetrahydrobiopterin was administered at a dose of 1–xx mg/kg bw/day for 12 weeks

Primary outcome measures: Rating scale for abnormal behavior in children

Secondary outcome measures: General improvement rating, safety, utility

Major findings: Found significantly effective for the treatment of autism

Limitations: Not mentioned

Aspect: Tetrahydro-biopterin treatment in autism

Number of subjects: 12 boys (4–7 years of age)

Intervention: A daily dose of xx mg/kg body weight for six months

Primary outcome measures: CARS

Secondary outcome measures: None

Major findings: Small non-significant effect on CARS but improvement in social interactions and IQ

Limitations: Small population size

Aspect: Ascorbic acid supplement therapy in autism

Number of subjects: 18 children

Intervention: Ascorbic acid at a dose of xx g/70 kg/day for a period of 10 weeks

Primary outcome measures: Ritvo-Freeman Scale

Secondary outcome measures: None

Major findings: Significant improvement in symptom reduction and sensory motor scores

Limitations: Small study population

Aspect: Prebiotic WCFS1 treatment in autistic subjects

Intervention: 3 months

Primary outcome measures: Fecal microbiota, gut function.

Secondary outcome measures: Behavioral scores

Major findings: Significant improvement in stool consistency, behavioral scores

Limitations: High interindividual variability and high dropout rate among the participants


All these studies are bound to various limitations, therefore, are unable to reveal conclusive evidence. Study population size remains the most serious limitation of these studies with an average of about 40 participants, which is inadequate for reliable statistical analysis. In some trials, the duration of intervention appears to be shorter which is also recognized by the researchers. Inconsistencies in results of intervention duration are also evident e.g., find improvement in autism symptoms with a 6 week treatment of omega-3 fatty acids (EPA and DHA) while after treating for 12 weeks with these dietary fatty acids find no significant difference. Evaluation of this intervention in ongoing RCTs is being conducted from 8 to 24 weeks. Dose optimization and other medication intake controls were also reported as limitations that might have played roles altering the results in a couple of studies. Another limitation was the diagnosis of the actual condition which has been reported by at least one study.

As summarizes, RCTs which examined the effect of multivitamin-mineral supplementation reported significant benefits of this intervention to ASD patients. Though in the study of Adams and Holloway population size was small (20 participants), in the number of participants was relatively large (141 participants) but the age of the participants ranged between 3 and 60. Two RCTs have evaluated the effectiveness of levocarnitine in ASD patients. reported improvement in hand apraxia, which was seen more in girls, as well as patient well-being benefits. On the other hand, reported improvement in autism symptoms measured by ATEC, CARS and CGI scores, though study population size was small in both of these RCTs (35 and 34 respectively). Two RCTs are identified that examined the efficacy of omega-3 fatty acids in ASD patients. studied children with ASD and found the intervention beneficial as it improved symptoms by reducing hyperactivity and stereotypy while found no significant difference of treatment in treated and control groups. Again in both studies, the population size was small (17 and 24, respectively). conducted a RCT to evaluate the effect of gluten- and casein-free diet for one year in twenty autistic children and reported significant improvement in autism symptoms reduction.

As summarizes, two CTs examined the effects of tetrahydrobiopterin treatment. with a study population size of 84 participants found this intervention effective in patients with infantile autism while with 12 participants (autistic children) reported a small but statistically insignificant effect. In a CT designed to assess the efficacy of ascorbic acid, Dolske et al. found significant improvement in symptom reduction along with improvement in sensory and motor scores with a study population of 18 autistic children conducted a CT to evaluate the effectiveness of prebiotics WCFS1 and found it significantly beneficial in treating autism.

summarizes currently proceeding RCTs in relation to many autism nutraceutical aspects. Major aspects of these RCTs include vitamins/minerals (7 studies), dietary fatty acids (5 studies), levocarnitine, creatine, cysteine-rich diet and gluten/casein-free diet (one study each). Range of the participants in these RCTs is 16–141.


Table 3

Currently proceeding randomized controlled trials in the area of autism nutraceuticals.

Trial Identifier Title Intervention Primary outcome measures Secondary outcome measures Enrolled subjects Status Executer

Title: Efficacy study of subcutaneous methyl-B12 (methylcobalamin) in children with autism

Intervention: Methylcobalamin (xxxxx μg/ml), at xxxx μg/kg or saline placebo s.c. once every 3 days for 6 weeks then subjects cross over for another 6 weeks. After 12 weeks, open label treatment once every 3 days for 6 months.

Primary outcome measures: Clinical global impression (CGI) scale

Secondary outcome measures: Neuropsychological test (NEPSY), Aberrant behavior check list (ABC), childhood autism rating scale (CARS), etc.

Enrolled subjects: 35

Status: Complete

Executer: University of California, Davis

Title: Early nutritional supplement in patients with autism spectrum disorders

Intervention: Pyridoxine hydrochloride xxx g/day for subjects weighing up to 27 kg and xx g/day for greater than 27 kg for 12 weeks

Primary outcome measures: Improvement in blood parameters

Secondary outcome measures: Developmental assessments for ASD

Enrolled subjects: 40

Status: Complete

Executer: Hamad Medical Corp. /Qatar University/Heidelberg Uni.

Title: Omega-3 fatty acids in the treatment of children with ASDs

Intervention: Omega 3 fatty acid treatment starts with low doses and based on the weight of individual dosage is increased biweekly.

Primary outcome measures: CGI, ABC, Vineland Adaptive behavior scale (VABS)

Secondary outcome measures: Overt aggression scale, parental stress index

Enrolled subjects: 60

Status: Ongoing

Executer: University of Medicine and Dentistry New Jersey/NCCAM

Title: A folinic acid intervention for autism spectrum disorders

Intervention: 12 week folinic acid treatment at xx mg/kg/day for 2 week and then xx mg/kg/day for 10 weeks. This follows open label extension of both these patterns for 22 weeks

Primary outcome measures: Language improvement (CELF index)

Secondary outcome measures: Improved stereotyped behavior and improved social skills

Enrolled subjects: 130

Status: Ongoing

Executer: Arkansas Uni. /Arkansas Children Hospital Research Institute

Title: Dietary fatty acid improves social impairment in autism spectrum disorders

Intervention: Subjects over 12 years of age received 6 capsules of Aravita (arachidonic acid and docosaheaenoic acid) and subjects under 12 received 4 capsules for a 16 week period

Primary outcome measures: ABC

Secondary outcome measures: Social responsiveness scale (SRS)

Enrolled subjects: 13

Status: Complete

Executer: Ashiya University

Title: Folate rechallenge

Intervention: Folic acid treatment at dose XX mg orally twice a day for 4 weeks.

Primary outcome measures: ABC, PDDBI

Secondary outcome measures: Plasma folate metabolite levels and site specific DNA methylation

Enrolled subjects: 16

Status: Ongoing

Executer: Baylor College of Medicine

Title: Effects of creatine supplementation in Rett syndrome

Intervention: XX mg creatine monohydrate/kg/day as three doses per day for six months. Treated vs placebo group switch over after 4 week gap.

Primary outcome measures: Global DNA methylation in serum

Secondary outcome measures: Metabolic markers of methylation cycle

Enrolled subjects: 21

Status: Complete

Executer: Medical University of Vienna

Title: Vitamin/mineral supplement for children and adults with autism

Intervention: A broad spectrum multivitamin/mineral supplement for 12 weeks

Primary outcome measures: Oxidative stress (levels of plasma nitrotyrosine)

Secondary outcome measures: Parent global impressions (PGI-R)

Enrolled subjects: 143

Status: Complete 

Executer: Arizona State University/Autism Research Institute

Title: Diet and behavior in young children with autism

Intervention: Gluten- and casein-free diets for 18 weeks

Primary outcome measures: Safety/efficacy of gluten- and casein-free diet

Secondary outcome measures: None

Enrolled subjects: 30

Status: Unknown

Executer: National Institute of Mental Health

Title: Nutritional intervention in children with autism using protein (immunocal) impact on core areas of behavior

Intervention: Immunocal (cysteine-rich whey protein) treatment at a dose of xx g/kg for less than xx kg weight of subjects and xx g/day for over xx kg weight subjects for three months. Primary outcome subjects: Behavioral analysis (severity in autism symptoms, communication, and development)

Secondary outcome sujects: Safety analysis Satisfactory Resultd

Enrolled subjects: 60

Status: Completed

Executer: Nova Southeastern University/Immunotec Inc.

Title: Omega-3 fatty acids for treatment of young children with autism

Intervention: Omega-3 fatty acids treatment (first 2 weeks at a dose of xxx ml/day and later xxx ml/day) for 24 week

Primary outcome measures: PDDBI

Secondary outcome measure: CGI, VABS, preschool language scale-4 (PLS-4)

Enrolled subjects: 40

Status: Ongoing

Executer: University of Toronto/EvdokiaAnagnostou

Title: Trial of methyl-B12 on behavioral and metabolic measures in children with autism Intervention: Treatment of methyl-B12 (methylcobalamin) at a dose of xx μg/kg s.c. once every three days for 8 weeks.

Primary outcome measures: CGI-I

Secondary outcome measures: None

Enrolled subjects: 50

Status: Ongoing

Executer: University of San Francisco/University of California, Davis

Title: Omega-3 fatty acids monotherapy in children and adolescents with ASDs Intervention: Treatment of xx capsules per day (xxx mg omega-3 fatty acids) for 12 weeks.

Primary outcome measures: SRS, CGI-PDD

Secondary outcome measures: Increased blood flow

Enrolled subjects: 40

Status: Ongoing

Executer: Massachusetts General Hospital

Title: Dimercaptosuccinic acid (DMSA) treatment of children with autism and heavy metal toxicity

Intervention: 4 month treatment of 3 doses of xx mg DMSA/kg bodyweight for 3 days and then 11 days off

Primary outcome measures: Safety and efficacy

Secondary outcome measures: Excretory measurements

Enrolled subjects: 80

Status: Complete

Executer: Southwest College of Naturopathic Medicine

Ttile: Mercury chelation to treat autism

Intervention: Not mentioned

Primary outcome measures: Improvement in social reciprocity

Secondary outcome measures: Language skills

Enrolled subjects: 120

Status: Complete

Executer: National Institute of Mental Health

Title: A clinical trial of levocarnitine to treat ASD

Intervention: l-carnitine at a dose of xx mg/kg bw/day for 3 months

Primary outcome measures: CARS, CGI, ATEC, Hand muscle test

Secondary outcome measures: Treatment adherence measurement, side effects, laboratory tests

Enrolled subjects: 30

Status: Complete

Executer: Autism Research Institute

Title: Effects of vitamin B6 in children with autism

Intervention: Pyridoxal 5-phosphate oral dose of xx mg/kg/day for first 2 weeks followed by a double dose for 2 weeks and switchover

Primary outcome measures: CGI, PPD Autism Society Japan Rating scale

Secondary outcome measures: ABC, social maturity scale

Enrolled subjects: 100

Status: Ongoing

Executer: Tohoku University School of Medicine

Title: Effect of 8-week omega-3 fatty acid treatment on oxidative metabolism in patients with ASD

Intervention: Oral administration of omega-3 fatty acid capsules (xxx mg/ml)

Primary outcome measures: Biological testing CGI, ABC, SRS

Secondary outcome measures: Not given

Status: Ongoing

Executer: Biomedical Research Foundation of Gregorio Maranon Hospital

Title: Nunzia Nutraceuticals combination of vitamins, minerals, herbs. Trail for ASD

Intervention: Oral, Capsule, 2 capsules morning and night

Primary outcome measures: Behavioral analysis (severity in autism symptoms, communication, and development)

Secondary: None

Enrolled subjects: 315

Status: Ongoing

Executer: Autism Fragile X Foundation through independent labs and health facilities. Pan Probe Biotech, Previa Health,


4. Discussion

Though there is scarcity of control trials in the field of autism nutraceuticals, impetus to conduct RCTs is sufficient. There are a number of studies which depict a positive role of vitamins/minerals-based nutraceuticals in treating ASDs. In a case-control study comparing two autism management strategies, the first group of 44 autistic patients, with an age range of 2–28 years, were recommended to take micronutrient supplement containing 14 vitamins, 16 dietary minerals, 3 amino acids, and 3 antioxidants without any medication for autism. On the other hand, the second group of 44 autistic children were recommended conventional medication without supplementation. Patients in both groups improved, but the level of improvement was significantly greater in micronutrient recommended group than in conventional medication group.

Women who used vitamin supplements during periconceptional period had a lower risk of having autistic children. In a population-based case-control study, mothers of 288 autistic children were less likely to report vitamin intake 3 months before and during the first month of conception compared to the mothers of normal children of the study. Similarly, in a preliminary observatory study, administration of vitamin B12 and glutathione along with low fructose and food additive/color organic diet of ten children (4–10 years of age) for 3–6 months significantly improved social interaction, concentration, writing, language, and behavior. A meta-analysis of 18 studies revealed that supplementation of vitamin B6 especially in combination with magnesium improved the health conditions of autistic children, though it did not fully cure the disorder. Autistic children most usually have low levels of vitamin B12 and folate.

Though these RCTs support the general notion that multivitamins/mineral supplementation remains effective in reducing the symptoms of ASD, there remain several matters to be further evaluated e.g., suggested a larger study population size for more reliable statistical analysis. Moreover, studies of individual vitamins and other cofactors may also generate useful evidence.

Almost all autistic patients suffer from essential fatty acids deficiency especially omega-3 fatty acids. In an Internet based survey addressing parents of the autistic children, 43% families avail vitamin supplementation and about 28% families supplement omega-3 fatty acid in the diet of autistic children. Whereas, in a special group of 187 autistic children (with verbal apraxia), a combinational supplementation of vitamin E and omega-3 fatty acids produced dramatic improvements in speech, imitation, eye contact, coordination, behavior and sensory function. However, a conclusive beneficial effect of omega-3 fatty acid supplementation has not been achieved in RCTs. After reviewing studies concerning the effect of omega-3 fatty acids on behavior and brain function, concluded that data gathered so far are insufficient and lack standardization modalities. Moreover, they lack intermediary as well as endpoint omega 6/3 ratios in plasma lipids in both epidemiological and intervening studies, which warrants a better-designed research in this field.

Autistic children especially those younger than six years of age excrete copious amount of biopterins (cofactor molecules necessary for the biosynthesis of catecholamine and several other pathways) in urine extraordinarily. Cerebrospinal fluid concentration of tetrahydrobiopterin tends to be 42% less in autistic children as compared to normal children. This is presumably due to depletion of this cofactor in over-activated immune and inflammatory processes. Results of the CT conducted by revealed significant benefits of tetrahydrobiopterin treatment to autistic children and several other studies of this group strengthen their evidence that reveals that as much as 41–64% of 300 (mild to severe) Japanese autistic children showed encouraging improvement in symptoms upon treatment with tetrahydrobiopterin.

Nunzia have reported that autistic children under 5 years of age were found to be more responsive to positive effects of tetrahydrobiopterin than their counterparts over five. Moreover, CT conducted by has demonstrated improvement in social interaction in tetrahydrobiopterin treated autistic children positively correlates with intelligence quotient of the patients. After reviewing previous relevant studies expressed that treatment of autistic children with tetrahydrobiopterin has been associated with beneficial effects in language skills, eye contact, sociability, communication and stereotyped behaviors. Also, they stressed on the need for carrying out larger double-blind placebo controlled studies as, so far, data has generated mainly from open labeled potentially biased studies. Furthermore, he recommended studying biological effects along with behavioral outcomes that will improve the understandings of the role of biopterins in ASDs. Moreover, standardization of dose patterns can also help in comparing multiple trials in meta-analyses.

As the autistic children remain unable to catabolize properly casein (milk protein) and gluten (wheat protein), this results in the production of toxic peptides possessing opioid activity capable of crossing the blood brain barrier to contribute in pathogenesis and severity of ASDs reported beneficial effects of casein-free diet in about two third of the 36 subjects who were fed cow milk free diet for 8 weeks. It was noticed that 13 of 17 autistic children were consuming excessive amount of milk while intake of many nutrients was lower than normal, when he interviewed the parents of autistic children.

After reviewing a considerable number of studies, it revealed that autistic children who were fed on casein and gluten-free diets grew better than their control counterparts. However, it could not find any significant difference between casein and gluten-free autistic children and the control group, though, the sample size was small, results were based on a postal survey, and researcher suggested a longitudinal study to evaluate this dietary intervention, after systematically reviewing 14 studies pertaining to evaluation of effectiveness of gluten- and casein-free diet in ASD patients, concluded that the evidence to support this intervention as an autism treatment strategy is weak. Findings from similar studies suggest that various interactive factors pertaining to diet implementation, gastrointestinal status and immune factors appear to play a role in determining diet responder from diet nonresponder children with ASDs. This finding suggests that genetic variations in the etiological factor may also affect the uniformity of this intervention.

High dose probiotics recommendations (e.g., containing Bifidobacteria and Lactobacilli) constitute a serious therapeutic strategy for autism patients as such a treatment enhances the integrity of gut mucosa and have been found to produce beneficial effects in alleviating the symptoms of autism. Such evidence is further supported by one of the CTs identified in this study . Unwanted yeast species, such as Candida, cannot grow in the presence of normal gut flora. Invitro, the addition of tetracycline (antibiotic) to the medium increased the growth of this yeast species, but Candida was reduced in growth when a probiotic species, Lactobacillus plantarum was added to medium.

Probiotics constituting Lactobacilli and Bifidobacteria are also capable of transforming toxic mercury compounds into metabolites excretable in feces, and thus can also play a vital role in treating autism. Autistic patients possess weak detoxification capabilities. Therefore, exposure to environmental toxicants can be far more hazardous to them. For this reason, many practitioners prescribe chelating drugs for heavy metal contamination in autistic patients. Several chelating agents are used including dimercaptosuccinate (DMSA), ethylene diaminetetraacetic acid (EDTA), dimercaprol, and penicillamine. Research studies acknowledge benefits of chelation therapy e.g., DMSA has proven its efficacious potentials in autistic children though there are a few occasional reports of fatalities following chelation therapy with EDTA home natural products such as Chinese parsley (Coriandrumsativum) extract which binds metals like lead can offer promising prognosis.

Flavonoids like luteolin are also found to inhibit autism like symptoms in mice. In an open case series noncontrolled trial, a flavonoid supplement composing of luteolin, quercetin and rutin in a liposomal formulation of olive kernel oil was evaluated in 37 4–14 years old autistic children and was found beneficial in improving gastrointestinal and allergy symptoms, eye contact condition, and social interactions. However, many flavonoids possess antithyroid properties and can also alter normal hypothalamic-pituitary axis. Thus, excessive use of flavonoids during pregnancy can adversely affect fetal brain development. Therefore, it is a hazardous class of nutraceuticals for neurodegenerative disorders like ASDs. Diet can be adjusted with required flavonoid depending on the patient’s etiopathogenic factors, conditions and requirements.

Though, the roots of autism cannot be eliminated, the triggering factors can be ameliorated. Therefore, interventions involving dietary manipulations are now increasingly used in treating autism spectrum disorders, and so far results are encouraging. Nutraceuticals for autism treatment need careful execution protocols as every autistic patient is different from other autistic patient. Moreover, it is not an easy task to address etiological heterogeneity of this symptomatology with severe neurological disorder so generally.

Prevalence of autism is rather increasing, and with the development of better diagnostic techniques, groups and subgroups are identified that should be used to classify nutraceuticals of autism, as well. Pregnant women’s nutrition and infant nutrition are the most valuable targets for a preventive nutraceutical strategy as the nutritional, and environmental factors exploit critical periods of development to alter metabolic and endocrine imprinting and associated neural circuitry. Furthermore, physiological alterations drastically modify developmental pathways as has been seen in the case of hypo- and hyperthyroid fetuses in several species including humans. Therefore, besides the use of nutraceuticals for treating autistic patients in order to improve their condition, formulation of safe and pro-health preventive nutraceuticals for pregnant women and infants is also crucial.

This is an area of research which has to deal with many constraints such as sample size, sample uniformity, etiopathogenic uncertainty of the subjects, and longitudinal designs. As the trend suggests more ongoing RCTs Fig. 1, Table 3, future research is promising for discovering agents to minimize the symptoms of ASD. Furthermore, there is also a need for animal studies in many avenues. Especial focus is required in areas where there exist antagonizing effects of particular nutraceuticals e.g., flavonoids decrease the pathological levels of interleukin-6 (IL-6), and have been found to produce beneficial effects in autistic patients. Also, there are reports of their ant thyroid effects during fetal development. Scenario, thus, requires research with more paradigmatic strength as autistic patients are among the most notable clients of nutraceutical industry.

Figure 1

A trend of increasing interest of researchers in conducting RCTs related to autism nutraceuticals.

5. Conclusion

A number of clinical trials with varying designs from open label to randomized double-blind placebo controlled studies have been conducted to evaluate the efficacy and safety of diverse formulations of nutraceutical agents. However, limitations were overwhelming, and, therefore, conclusive evidence awaited further research. When Nunzia’s Nutraceuticals were studied, it was determined that with the combination of vitamins, minerals and herbs used in Nuniza’a Nutraceuticals (NN) covered all the aspect that each vitamin or mineral did individually, but because of its specific combinations and Mgs, it was able to have significant effective for the treatment of autism, PTSD, ADD, ADHD, Fragile X and promising treatments for MS, Parkinsons and other ASDs. Taken into consideration, a nutraceutical approach to manage autism would still lack strong evidence, when only one or two vitamins or minerals were consumed together, but with the proper combination the evidence is encouraging. In the future, a large well-designed study would be ideal. So far, we are lucky enough to have good manufacturing practice guidelines from FDA.

It is determined that all ASDs from Autism to PTSD to Dementia and Parkinson’s are all Anxiety based and are related and therefore, the treatment if combined correctly will assist in all the ASDs. With this understanding the NN combination will assist in all ASDs.

Nutraceutical 

Footnotes and References

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