Table 4.

Studies of cobalamin injections for autism spectrum disorder with clinical outcomes. Childhood autism rating scale (CARS); clinical global impression scale (CGI); subcutaneous (SC); years old (yo).

Study	Participants	Treatment	Outcomes	Adverse Effects
Subcutaneous Methylcobalamin Injections: Prospective Double-Blind Placebo Controlled Studies
Bertoglio et al., 2010 [55] Crossover	30	64.5 µg/kg SC every 3 days	No change in overall behavior	Hyperactivity; mouthing objects
Hendren et al., 2016 [35] Parallel	57	75 µg/kg SC every 3 days	Significant improvement in CGI	No significant difference between groups
Subcutaneous Methylcobalamin Injections: Prospective Uncontrolled Study
Frye et al., 2013 [53]	40	75 µg/kg 2x/wk for 3 months with folinic acid	Overall improvement in development. Clinical improvement associated with biochemical improvements	Hyperactivity (10%), reduced sleep (6%), impulsiveness (3%)
Intramuscular Cobalamin Injections with Type of B12 not specified: Retrospective Case Series/Reports
Pineles et al., 2010 [46]	3	B12 IM	Improvement in vision	None reported
Duvall et al., 2013 [47]	1	B12 IM with oral MVI	Improvements in pulmonary hypertension and musculoskeletal problems	None reported
Malhotra et al., 2013 [32]	1	B12 IM with oral MVI	Improvements in eye contact, licking fingers, hyperactivity, pacing, echolalia, and repetitive behaviors and in CARS score	None reported
Oral Multivitamin, which Included Cobalamin: Prospective Double-Blind Placebo-Controlled Studies
Adams and Holloway 2004 [48] Parallel	30	1200–1600 mcg Daily Orally	Improved gastrointestinal problems and sleep	No adverse events in those adhering to the protocol
Adams et al., 2011 [49] Parallel	141	500 mcg Daily Orally	Improved hyperactivity, tantrums and receptive language	Mild behavioral problems, diarrhea, constipation
Oral Multivitamin, which Included Cobalamin: Prospective Controlled Study
Adams et al., 2018 [50]	37	500 mcg Daily Orally	Improved non-verbal IQ, daily living skills and social skills	Worsened behaviors, gastrointestinal disturbance, facial rash, aggression, stereotypy
Oral Methylcobalamin: Retrospective Case Report
Corejova et al., 2015 [54]	1	mB12 500 µg orally per day	Nocturnal enuresis resolved; reappeared when treatment was stopped	Increased stereotypy and hyperactivity
Oral Hydroxycobalamin: Retrospective Case Report
Nashabat, et al., 2017 [51]	3	hB12 10 mg orally pr day	Improved developmental milestones	None
Methylcobalamin with Route of Administration Not Specified: Prospective Uncontrolled Study
Nakano et al., 2005 [52]	13	25–30 µg/kg/day (up to 1500 µg) mB12 for 6–25 months	Improvements in IQ, developmental quotient and CARS score	No significant events