Table 4.

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

First Author (Year)	Safety
Abeysundera (2018) [13]	Conclusion was that the patient experienced substance-/medication-induced mood disorder (when adding SAMe to the SSRI)
Alpert (2004) [14]	GI and headache side effects were most common No significant changes in weight, folate, B12, or homocysteine levels
Arnold (2005) [16]	Good tolerability
Bambling (2015) [17]	10 subjects dropped out
Carpenter (2011) [18]	Few instances of behavioral-related adverse events (AEs) No evidence for the occurrence of treatment-emergent suicidality detected AEs of mania/hypomania or psychomotor excitation following SAMe administration (n = 4) Increased anxiety-related AEs for SAMe than for placebo (n = 2)
Chitiva (2012) [19]	Patient attempted suicide after taking SAMe for 4 days
Cuomo 2020 [7]	Mild, transient, non-relevant side effects
De Berardis (2013) [20]	SAMe was well tolerated Most common adverse events: constipation (24%) nausea with decreased appetite (12%)
Di Pierro (2015) [21]	SAMe group had fewer side effects
Dolcetta (2013) [23]	Excess of excitement experienced at lower dosage, which led to discontinuations Increase in anxiety (n = 7)
Green (2012) [25]	No manic or psychotic symptoms No significant differences in side effects between groups Most common side effects were GI symptoms
Jaggumantri (2015) [26]	Patient 1: Discontinued 50 mg/kg/day at 3 months because of sleep disruptions and behavior issues 17 mg/kg/day was well-tolerated Patient 2: Discontinued 50 mg/kg/day because of behavioral issues
Kalman (2015) [27]	No significant adverse events
Limveeraprajak (2024) [5]	Generally well-tolerated
Mischoulon (2014) [30]	No significant differences in side effects between groups (p > 0.05) SAMe: GI, stomach discomfort, diarrhea
Murphy (2014) [31]	Discontinued after the 800 mg/day SAMe dosage due to brief episode of auditory hallucinations (n = 1) No other issues, including mania
Olsufka (2017) [32]	Treatment-emergent hypomania due to use of SAMe Admitted to the psych ER after “nervous breakdown” signs, racing thoughts, pressured speech Spouse described him as hyperactive, impulsive, loquacious, and irrational with side-to-side ocular movements
Papakostas (2010) [33]	No serious adverse events
Peng (2024) [34]	No significant difference between dropouts due to adverse effects (RR: 0.92, 95% CI: 0.49 to 1.73)
Saccarello (2020) [35]	Limited adverse events, which researchers believed were not related to products
Sakurai (2020) [36]	3200 mg/day SAMe: 31.3% experienced stomach or abdominal discomfort, significantly higher (p = 0.026) 25% experienced fluid retention or swelling (25.0%)
Sarris (2014) [40]	Well-tolerated No significant adverse events
Sarris (2018) [37]	5 SAMe group withdrawals possibly related to treatment: nausea, heightened anxiety, sleep issues
Sarris (2019) [38]	No significant differences between groups in adverse events More early termination in nutraceutical (n = 9) vs. placebo (n = 3); not significant
Sarris (2020) [39]	No significant differences in adverse events between groups (p = 0.53)
Shippy (2004) [42]	No dropouts due to side effects
Strous (2009) [43]	3 patients were discontinued from the study due to potential adverse effects of the study medication No significant differences between SAMe and placebo for all adverse events (all p > 0.05)
Targum (2018) [44]	High completion rate with 113 SAMe-assigned subjects (95.8%) Predominant adverse events were mild and primarily related to GI tract (<2% of patients)
Targum (2020) [45]	SAMe well-tolerated Predominant adverse events were mild and primarily related to GI tract