Table 2: Nutraceuticals in ASD.

Author Year Type and duration of study Sample size Type of intervention ComparatorsDose Outcome measureFindings Comments

Omega 3

Amminger et al. [22]2007Randomized, double blind, placebo controlled, parallel group  
Duration: 6 weeks
(M 13)  
Age: 5–17 years
Omega 3  
Placebo  

One drop-out from this group
0.84 g/day EPA and 0.7 g/day DHAABCNo significant difference between the two groups No details about blinding  
Small sample size  
Power analysis not reported

Bent et al. [23]2011Randomized, double blind, placebo controlled, parallel group  
Duration: 12 weeks
(M 24; F 3)  
Age: 3–8 years
Omega 3  

Drop-out
Placebo  

Drop-out  
0.7 g/day EPA and 0.46 g/day DHAABC, PPVT-III, EVT, SRS, BASC, CGI-Improvement No statistically significant differenceOnly per-protocol analysis  
Small sample size  
Short study duration

Bent et al. [24]2014Randomized, double blind, placebo controlled, parallel group  
Duration: 6 weeks
(M 50; F 7)  
Age: 5–8 years
Omega 3 Placebo  
1.3 g/daily of omega 3 (1.1 g/day of EPA plus DHA) ABC, CGI, SRSNo statistically significant differenceSmall sample size  
Short study duration

Meguid et al. [25]2008Open label  
Duration: 3 months
(M 18; F 12)  
Age: 3–11 years
Omega 3None240 mg/day DHA; 52 mg/day EPA; 68 mg/day Omega-6 fatty acidsCARSImprovement in 20 childrenStatistical analysis incorrect (conducted only on children which showed a reduction in symptoms)  
Open label design  
Small sample size  
Multicomponent intervention (also omega 6)

Politi et al. [26]2008Open label  
Duration: 6 weeks
(M 50; F 7)  
Age: 18–40 years
Omega 3 None0.93 g/day EPA plus DHA, 5 mg/day vitamin ERossago behavioral checklistNo significant change from baselineSmall sample size  
Short study duration  
Open label design  
No standardized outcome measure

Voigt et al. [27]2014Randomized, double blind, placebo controlled, parallel group  
Duration: 6 months
(M 40; F 8)  
Age: 3–10 years
Omega 3 Placebo  
200 mg/day DHACGI-Improvement scale, CDI, ABC, BASC No significant difference between active group and placeboSmall sample size  
Low dosage

Vitamins

Findling et al. [28]1997Randomized, double blind placebo controlled, crossover  
Duration: 8 weeks
(M 11; F 1)  
Drop-out
Age: 3–12.9 years
Vitamin B6-magnesiumPlaceboB6: 30 mg/kg/day (max = 1 g/day); Mg: 10 mg/kg/day (max = 350 mg/day)CARS, CGI, CPRS, OCS No difference between the two groupsSmall sample size  
Short study duration  
Multicomponent intervention  
Per protocol analysis

Kuriyama et al. [29]2002Randomized double blinded placebo controlled parallel group  
Duration: 4 weeks

Entered the study only
(M 4; F 4)  
Drop-out
Age: 3–12.9 years
Vitamin B6 Placebo   
B6: 200 mg/dayIQ (WISC-III) and SQ (SM)No difference between active group and placeboSmall sample size  
High attrition rate  
Unclear characterization of patients “children with PDDs who exhibit clinical features similar to those of pyridoxine dependent epilepsy but do not have a history of seizures”  
Clinical characterization unclear (only PDD)

Tolbert et al. [30]1993Randomized double blind placebo controlled, asymmetric crossover with 10 week treatment blocks (B6/Mg 20 w-placebo 10 w; or B6/Mg 10 w-placebo 10 w-B6/Mg 10 w)  
Duration: 30 weeks

(M 10; F 5)  
Age: 6–18 years
Vitamin B6-magnesiumPlaceboB6: 200 mg/70 kg; Mg: 100 mg/70 kgRLRSNo differenceNo information on placebo  
Presence of a control group, but not randomized  
Small sample size  
Low dosage of B6/Mg  
Asymmetric study design

Bertoglio et al. [31] 2010Randomized, double blind, placebo controlled, crossover  
Duration: 12 weeks
(M 28; F 2)  
Age: 3–8 years
Methyl B12Placebo64.5 mcg/kg every three daysCGI-I, PIA-CV, CARS, PPVT-III, ABC, CBC, Stanford Binet Fifth Edition Routing Subsets, MCDINo significant difference between active treatment and placeboSmall sample size  
Short study duration  
Improvement only in post hoc analysis

Frye et al. [32]2013Open label trial  
Duration: 3 months
(gender not explicitly reported)  
Drop-out
Age: 4–6 years
Methyl B12 vitamin plus folinic acidNone75 g/Kg methylcobalamin every three  
Folinic acid (400 g) twice daily
VinelandImprovement in all Vineland subscalesOnly patients with abnormal redox metabolism were included  
High attrition rate  
Statistical analysis only performed on completers  
Small sample size

Dolske et al. [33]1993Randomized double blinded placebo controlled, crossover with asymmetric design with 10 w block (randomly assigned to vitC-vitC-placebo or vitC-placebo-vitC)  
Duration: 30 weeks

Age: 3–8 years
Vitamin CPlacebo8 g/70 kg/dayRLRSSignificant improvement in vitC treatedSmall sample size  
Short study duration  

Adams et al. [34]2011Randomized double blinded placebo controlled trial  
Duration: 3 months
(M 125; F 16)  
Age: 5–16 years
Multivitaminic supplement
Drop-out
Placebo
Drop-out  
Each supplement was titrated to be over the recommended daily allowance but under the tolerable upper limitPDD-BI, ATEC, SAS, parent-rated behaviorsImprovement of parent-rated irritability in the active groupNo power calculation  
High attrition rate  
Only per-protocol analysis

Danfors et al. [35]2005Randomized, double blind, placebo controlled, crossover  
Duration: 6 months
(M 12)  
Age: 4–7 years
Tetrahydrobiopterin (BH4)Placebo3 mg/kg/dayCARS (baseline, 3 and 6 month)Small changes in CARS total scoreSmall sample size  
Only post-hoc analysis reveals significant changes in CARS subdomain

Frye et al. [36]2013Open label  
Duration: 16 weeks
(M 9; F 1)  
Age: 2–6 years  
Children must have low cerebrospinal fluid level of BH4
Tetrahydrobiopterin (BH4)  
Drop-out
None20 mg/kg/dayPLS, SRS, CARS, ASQ, VinelandSignificant improvement in PLS, CARS, ASQ, and VinelandOpen label  
Small sample size  
High attrition rate (20%)  
High tetrahydrobiopterin dose (usually 1–6 mg/kg/day)

Klaiman et al. [37]2013Randomized, double blind, placebo controlled, parallel group  
Duration: 16 weeks

Age: 3–7 years
Tetrahydrobiopterin (BH4)Placebo20 mg/kg/dayCGI, PLS, ABC, SRS, VinelandNo significant difference between the two groupsImprovement only in post hoc analysis on secondary measures  
High tetrahydrobiopterin dose (usually 1–6 mg/kg/day)

L-carnosine

Chez et al. [38]2002Randomized double blinded placebo controlled  
Duration: 8 weeks
(M 21; F 10)  
Age: 3–12 years
L-Carnosine Placebo 
800 mg/dayCARS, GARS, CGI  
Expressive and Receptive One-Word Picture Vocabulary tests,
Significant improvement in the active group in GARS and in the Receptive One-Word Picture Vocabulary testSmall sample size  
No power calculation  
Half of the subjects were on stable dosage of valproic acid

Flavonoids

Taliou et al. [39]2013Open label  
Duration: 26 weeks
(M 42; F 8)  
Drop-out
Age: 4–10 years
Flavonoid  
1 capsule/10 Kg/day
NoneLuteolin (100 mg/capsule), quercetin (70 mg/capsule), and the rutin (30 mg/capsule) Vineland, ABC, ATEC, CGI-improvementImprovement in Vineland and ABC scoresOpen label design  
Small sample size  
High attrition rate

Probiotics

Kałuzna-  
Czaplińska  
and Błaszczyk [40]
2012Open label  
Duration: 2 months
(M 20; F 2)  
Age: 4–10 years
Probiotic  
1 capsule twice daily
NoneLactobacillus acidophilus (strain Rosell-11, containing 5 × 109 CFU/g)Observer rated autism core symptomsImprovementOpen label design  
All children have gastrointestinal problems  
Other CAM treatments were used concomitantly  
Small sample size  
No standardized outcome measure

Enzyme supplementation

Munasinghe et al. [41]2010Randomized double blinded placebo controlled crossover  Duration: 6 months (M 36; F 7)  
Drop-out
Age: 3–8 years
Digestive enzyme supplementPlaceboPeptizyde  
(Peptidase, Protease 4.5 and Papain)  
two capsules with each meal
GBRS, ARS of gastrointestinal symptoms, and the Rescorla LDSNo differenceHigh drop-out rate  
Not clear if intention-to-treat or per-protocol analysis  
Not all outcome measures were standardized

Herbal remedies

Hasanzadeh et al. [42]2012Randomized double blinded placebo controlled  
parallel group  
Duration: 10 weeks
(M 39; F 8)  
Age: 4–12 years  
All children were on risperidone 2-3 mg/day according to weight
Ginkgo biloba (M 19; F 4) Placebo  
(M 20; F 4)
80 mg/day if weight <30 kg; otherwise 120 mg/day ABCNo differenceSmall sample size  
Short study duration  
Only one outcome measure

Miyaoka et al. [43]2012Open label  
Duration: 12 weeks
(M 22; F 18)  
Age: 8–40 years
YokusanNone5.0–7.5 g/dayCGI-Severity, ABCImprovement in CGI and the irritability subscale of ABCOpen label design  
Small sample size

Chan et al. [44]2014Open label  
Duration: 6 months
(M 26; F 4)  
Age: 7–17 years
Bornel and Borax nasal drops None  
10 mL/dayBRIEF, Tower of California, CCTT, CPRS, event-related EEG assessmentImprovementNot placebo controlled  
Open label design  
Small sample size  
Statistical analysis not optimal

ABC, Aberrant Behavior Checklist; ARS, Additional Rating scale; ATEC, Autism Treatment Evaluation Checklist; ASD, autism spectrum disorder; ASQ, Autism Symptoms Questionnaire; BASC, Behavioral Assessment System for Children; BRIEF, Behavior Rating Inventory of Executive Function; CARS, Childhood Autism Rating Scale; CCTT, Children’s Color Trails Test; CDI, Child Development Inventory; CGI-I, Clinical Global Impression Scale of Improvement; CPRS, Children's Psychiatric Rating Scale; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; EVT, Expressive Vocabulary Test; GARS, Gilliam Autism Rating Scale; GBRS, Global Behaviour Rating Scale; IQ, Intelligence Quotient; LDS, Language Development Survey; OCS, Obsessive Compulsive Scale; PDD-BI, Pervasive Development Disorder Behavior Inventory; PLS, Preschool Language Scale; PPVT-III, Peabody Picture Vocabulary Test-Third Edition; RLRS, Ritvo-Freeman Real Life Rating Scale for Autism; SAS, Severity of Autism Scale SM; Social Maturity; SQ, Social Quotient; SRS, Social Responsiveness Scale; VABS, Vineland Adaptive Behavior Scale; WISC-III, Wechsler Intelligence Scales for Children-III.