Table 3.

Study efficacy outcomes for studies examining the use of SAMe in CNS signs.

First Author (Year)	Efficacy
Alpert (2004) [14]	SAMe: Intent-to-treat analyses based on the HAM-D Response rate of 50% Remission rate of 43% Other improvements with SAMe: Significant decrease in Clinical Global Impressions Severity scores (4.0 ± 0.7 to 2.7 ± 1.2, df = 29; p < 0.0001) Significant improvement SQ-depression (13.2 ± 4.9 vs. 7.5 ± 5.3, respectively, t-test; df = 29; p = 0.001) and anxiety scores (12.2 ± 4.9, vs. 8.0 ± 5.6, respectively; df = 29; p = 0.012)
Anderson (2016) [15]	Anxiety levels improved Patient’s dose was titrated and continual improvement was shown
Arnold (2005) [16]	1600 mg more effective on CNS than 400 mg Both superior to placebo
Bambling (2015) [17]	1600 mg and 800 mg SAMe were effective: 35% achieved significant symptom improvement at the end of 15 weeks No significant difference between doses (p > 0.05) Non-responders saw improvements with adding 1600 mg of magnesium orotate BDI change: significant reduction in symptom scores [df = 18; p < 0.001] OQ45 change: significant reduction in functional distress scores [df = 18; p < 0.001] QOL change: significant increase in scores [df = 18; p < 0.001]
Carpenter (2011) [18]	Positive Results in Mild-to-Moderate (n = 9 studies): 5 studies reported significant positive results with SAMe in mild-moderate depression 2 studies reported positive results but not significant Mean treatment effect size = 1.0 (range 0.33–1.6) Positive Results in Moderate-to-Severe (n = 5 studies): 4 studies reported positive results but not significant Mean treatment effect size = 0.87 (median 0.79)
Cuomo 2020 [7]	SAMe (monotherapy) versus placebo: 3 out of 5 studies showed improvement SAMe (monotherapy) versus antidepressants (imipramine, escitalopram): 4 studies, no differences SAMe + SSRI vs. SSRI + placebo: 1 study, improvement
De Berardis (2013) [20]	Significant decrease in HAM-D score Response achieved by 60% (50% reduction in HAM-D score and CGI-I score of 1 or 2) Remission achieved by 36% (HAM-D score of ≤7) Significant reduction in SHAPS and SDS
Di Pierro (2015) [21]	No improvement for either group at 3 months Effectiveness demonstrated at 6 and 12 months for both groups SAMe vs. amitriptyline: SAMe had better results in terms of score, number of individuals in remission Amitriptyline at 6 and 12 months: score reduction was about 22% and 17% for the amitriptyline group SAMe at 6 and 12 months: score reduction was about 34% and 37%
Djokic (2017) [22]	Significant differences between SAMe and placebo in HAM-D and CGI-S scores at 3 months (p < 0.001) In SAMe: HAM-D improved from 20.17 ± 3.89 at baseline to 10.73 ± 3.4 with no influence of age or gender CGI-S improved from 4.1 ± 0.71 to 2.67 ± 0.76 CGI-I improved to 2.50 ± 0.68 (baseline not given)
Dolcetta (2013) [23]	4 patients tolerated the full dose and demonstrated efficacy: Behavioral improvements at 1 month and 12 months (n = 1) Improvement in sleep quality (n = 1) Improvement in self-injurious behavior and able to attend high school (n = 1) Improvement in anxiety and speech (n = 1)
Galizia (2016) [24]	No significant difference in depressive symptoms between SAMe and: escitalopram (n = 1), placebo (n = 2) Similar improvements in depressive symptoms, but no difference between SAMe and imipramine (n = 4) Significant improvement of SAMe vs. placebo when added on to an SSRI (p = 0.01; 73 participants; 1 study)
Green (2012) [25]	No treatment effect was found on ADHD symptoms (ADHD-RS) (p = 0.6) CGI-I improved in (28.6% SAMe vs. 14.3% placebo) Depressive disorder: SAMe group had a larger improvement on clinical scales than the placebo group
Jaggumantri (2015) [26]	Patient 1: SAMe was started at 50 mg/kg/day simultaneously with creatine, glycine, and L-arginine supplements Initial improved speech and ability to interact Stopped treatment at 3 months Restarted at 200 mg three times daily, which was reduced to 200 mg twice daily due to symptoms Patient 2: On SAMe 50 mg/kg/day, quality of speech and communication improved Discontinued after a few weeks
Kalman (2015) [27]	SAMe significantly: Reduced BDI-II scores at weeks four and eight, respectively (p = 0.001 and p = 0.002). Affected the BAI at week eight (p = 0.026). Changed the SOS-10 score at week eight (p = 0.038)
Levkovitz (2012) [28]	SAMe: Significantly improved ability to recall information (p = 0.04) Trend toward improved word-finding ability; p = 0.09
Limveeraprajak (2024) [5]	SAMe superior to placebo (SMD = −0.58, 95% CI = −0.93 to −0.23, I2 = 68%), even when two trials with a high risk of bias were excluded (SMD = −0.61, 91% CI = −1.05 to −0.17, I2 = 74%) IV route worse than IM or oral Moderate-certainty evidence suggests that SAMe may offer a moderate treatment effect SAMe + antidepressant vs. placebo + antidepressant: No significant difference between groups Very low-certainty evidence suggests that SAMe may not provide greater reduction in symptoms SAMe vs. antidepressant: No significant difference between groups (SMD = −0.22, 95% CI = −0.63 to 0.19, I2 = 76%) Low-certainty evidence suggests that SAMe may be as effective as antidepressants
Mischoulon (2012) [29]	SAMe: Plasma SAMe (p = 0.002) and SAH (p < 0.0001) levels significantly increased No change in HAM-D scores
Mischoulon (2014) [30]	SAMe vs. escitalopram vs. placebo: All treatment arms had significant reduction in HAM-D scores (p < 0.001) No significant difference between groups (p > 0.05) Response (50% decrease in HAM-D): not significant SAMe: 35% Escitalopram: 34% Placebo: 30% Remission (HAM-D score of ≤7): not significant SAMe: 28% Escitalopram: 28% Placebo: 17%
Murphy (2014) [31]	SAMe vs. placebo: No statistically significant differences in MADRS (p = 1.0), HAM-D (p = 1.0), or YMRS (p = 0.32) Model-estimated mean ratings at end point were 0.2 points higher for MADRS (corrected 95% CI = −11.1 to 11.5), 2.5 points lower for HAM-D (corrected 95% CI = −8.7 to 13.7), and 2.1 points higher for YMRS (95% CI = −2.3 to 6.5) for SAMe than for placebo
Papakostas (2010) [33]	SAMe + antidepressant vs. placebo + antidepressant: Nearly significant difference (p = 0.1) for lower endpoint HAM–D scores among SAMe-treated patients (mean: 11.1 [SD = 6.1]) relative to placebo-treated patients (mean: 15.8 [SD = 6.2]) Both outcome measures statistically significant in favor of adjunctive SAMe versus placebo (p = 0.01 and p = 0.02, respectively) Remission (HAM-D ≤7 or CGI-S = 1): significant (p = 0.03) SAMe = 10/39 Placebo = 2/34 Response (HAM-D 50% reduction or CGI-S < 3): significant (p = 0.02) SAMe = 20/39 Placebo = 7/34
Peng (2024) [34]	SAMe vs. placebo: No significant difference as monotherapy (SMD = –0.31, 95% CI = −0.65 to 0.03, p = 0.08; I2 = 66%) No significant difference in superiority as monotherapy (RR = 1.0, 95% CI = 0.79 to 1.26, p = 0.98; I2 = 0%) SAMe vs. imipramine or escitalopram No significant difference as monotherapy (SMD = 0.04, 95% CI = −0.09 to 0.16, p =0.56; I2 = 4%) No significant difference in superiority as monotherapy (RR = 1.08, 95% CI = 0.95 to 1.24, p = 0.24; I2 = 9%) SAMe vs. placebo as adjunctive therapy No significant difference (SMD = 0.02, 95% CI = −1.44 to 1.48, p = 0.98; I2 = 92%)
Saccarello (2020) [35]	SAMe + Lactobacillus plantarum vs. placebo: Significant improvement in depressive symptoms for treatment group (p = 0.0247) Significant improvement in absolute reduction in Zung score on day 14 for treatment (p = 0.0345) Significant improvement in cognitive and anxiety for treatment on day 14 (p = 0.0133)
Sakurai (2020) [36]	SAMe vs. escitalopram vs. placebo: No within-group and between-group differences were found in any of the efficacy measures for responders and non-responders
Sarris (2014) [40]	SAMe vs. escitalopram vs. placebo: All treatments had significant reduction in HAM-D score (F1,100 = 5.50, p = 0.021) Mean (SD) reduction: SAMe = 7.31 (5.96), escitalopram = 6.69 (5.70), placebo = 4.00 (5.64) Significant difference in improvement between groups (p = 0.039) SAMe vs. placebo: SAMe more effective Effect size for SAMe vs. placebo was moderate to large (d = 0.74) Significant effect between baseline and endpoint (F1,65 = 5.89, p = 0.018), with this effect occurring at every time point from week 1 (p = 0.04) to week 12 (p = 0.007) Higher remission rates (p = 0.003) SAMe vs. escitalopram: SAMe superior during weeks 2, 4, and 6 Remission rates (HAM-D < 7): Significantly different between groups (χ22,102 = 8.57; p = 0.014) SAMe = 34% for SAMe Escitalopram = 23% Placebo = 6%
Sarris (2015) [41]	SAMe vs. escitalopram vs. placebo in HAM-D: Significant reduction for males treated with SAMe (−8.9 points) vs. placebo (−4.6 points) (p = 0.034) No other differences
Sarris (2018) [37]	SAMe + antidepressant vs. placebo + antidepressant: All groups had a significant reduction in MADRS over time (p < 0.001) Response rates (MADRS decrease of −50%) at week 8 (54.3% SAMe, 50% placebo, p = 0.68 between groups) Remission rates (MADRS score < 10 at final assessment) (43.5% SAMe, 38.3% placebo, p = 0.61 between)
Sarris (2019) [38]	Nutraceutical product vs. placebo: Placebo had a greater reduction in MADRS score (−1.75 points lower) Both groups improved over time No other significant differences between groups
Sarris (2020) [39]	SAMe: Clinically significant reduction in MADRS (−3.76 points) at 8 weeks Not statistically significant reduction in MADRS score between groups (p = 0.13)
Shippy (2004) [42]	Significant reduction in HAM-D scores, df = 13, p < 0.001 Response rate (intent-to-treat, all 19 patients): 74% Remission rate: 93% (14/15 patients who completed)
Strous (2009) [43]	SAMe vs. placebo: Significant improvements in SAMe patients only: Decrease in OAS scores (F = 5.6, df = 14, p = 0.032) Reduction of CGI-S scores (p < 0.01) Improvement in QLS scores (p < 0.001) Both groups, but greater reduction in SAMe: Improvement in CGI-I scores (p < 0.01)
Targum (2018) [44]	SAMe + antidepressant or placebo + antidepressant: No statistically significant treatment differences Note: study did not achieve primary endpoint due to subject selection differences First half of the study participants: favored SAMe Non-significant trend for the MADRS improvement (1st half: 27.8 ± 5.70, 2nd: 28.9 ± 6.65; p = 0.19) Non-significant trend for the IDS-SR improvement (p = 0.08)
Targum (2020) [45]	MADRS and HAM-D: SAMe was significantly better than placebo (F = 6.39; df = 1; p = 0.012), effect size = 0.404
Ullah (2022) [46]	Subjects who received the treatment in the placebo–SAMe order had higher PHQ-9 score values compared to those who received the treatment in a SAMe–placebo sequence (p = 0.030) HAM-D score decreased significantly between t0 and t1 measurements (p < 0.001) for all patients

Acronyms: Standardized Mean Difference (SMD).