Table 4.
Outcome measures represented in effect size in key studies which have used d,l-leucovorin. Cohen’s d’ was calculated for studies which provided enough information to make such calculations. For controlled studies, the effect size represented the difference between the treatment and the control group, whereas for uncontrolled studies, the effect size was calculated only for the treatment. Effect sizes were considered small if Cohen’s d’ was 0.2; medium for Cohen’s d’ of 0.5, and large if Cohen’s d’ was 0.8. Effects in bold are statistically significant.
| Core ASD Symptoms | Communication | Behaviors | Other Symptoms |
|---|---|---|---|
| d,l-leucovorin Only Studies | |||
| Frye et al., 2013 [37] (Non-Treated Wait List Controlled) | |||
| Stereotypy d’ = 1.02 |
Verbal Comm d’ = 0.91
Expressive Lang d’ = 0.81 Receptive Lang d’ = 0.76 |
Attention d’ = 1.01 Hyperactivity d’ = 0.25 |
|
| Frye et al., 2018 [72] (Double Blind Placebo Controlled) | |||
|
ABC Social Withdrawal d’ = 0.27
ABC Stereotypy d’ = 0.60 |
Verbal Comm (All) d’ = 0.70
Verbal Comm (FRAA+) d’ = 0.91 |
Hyperactivity d’ = 0.05
|
|
| Renard et al., 2020 [74] (Single Blind Placebo Controlled) | |||
|
ADOS total score d’ = 1.16
Social interaction d’ = 1.11 SRS Total d’ = 0.03 |
Communication d’ = 0.66 | ||
| d,l-leucovorin Combined with Other Supplements | |||
| Adams et al., 2011 [73] ( Double Blind Placebo Controlled ; PGI-R Outcome) | |||
| Play d’ = 0.23 Sociability d’ = 0.15 |
Expressive Language d’ = 0.37 Receptive Language d’ = 0.44 |
Hyperactivity d’ = 0.60
Tantrums d’ = 0.53 |
Cognition d’ = 0.34 Gastrointestinal d’ = 0.30 Sleep d’ = 0.18 |
| Adams et al., 2018 [76] (Prospective Non-Treatment Controlled; PGI-2 Outcome) | |||
|
Play d’ = 1.50
Sociability d’ = 1.44 Eye Contact d’ = 1.41 Perseveration d’ = 1.33 Sound Sensitivity d’ = 1.14 |
Expressive Language d’ = 1.60
Receptive Language d’ = 1.99 |
Attention d’ = 1.19 Hyperactivity d’ = 1.46 Tantrums d’ = 1.00 Aggression d’ = 0.96 Self-Injury d’ = 0.69 |
Cognition d’ = 1.49
Gastrointestinal d’ = 2.09 Sleep d’ = 0.92 Mood d’ = 1.58 Anxiety d’ = 0.95 |
| Ramaekers et al., 2019 [44] (Baseline Controlled) | |||
| CARS d’ = 1.01–1.32 | |||
| Frye et al., 2013 [79] (Baseline Controlled) | |||
|
Interpersonal d’ = 0.43
Play d’ = 0.59 Coping d’ = 0.66 |
Expressive Language d’ = 0.59
Receptive Language d’ = 0.97 Written Language d’ = 0.56 |
Personal d’ = 0.65
Domestic d’ = 0.37 Community d’ = 0.52 |
|