Safety and tolerability of temporal interference stimulation in humans: a systematic review and meta-analysis of an emerging deep neuromodulation technology.

BACKGROUND: Temporal interference stimulation (TIS) uses kilohertz-frequency currents to generate a low-frequency amplitude-modulated envelope within brain tissue, enabling deeper targeting while minimizing superficial stimulation. As human applications expand, a systematic evaluation of safety and tolerability is needed. METHODS: Following PRISMA guidelines (PROSPERO: CRD420251081135), we searched Ovid MEDLINE, Embase, and APA PsycINFO (May 2, 2025) for peer-reviewed human TIS studies reporting safety or tolerability outcomes. Methodological quality and risk of bias were assessed using design-appropriate RoB 2, ROBINS-I, and Johanna Briggs Institute tools. Random-effects meta-analyses were conducted in R. Parallel-arm randomized controlled trials (RCTs) were synthesized using risk ratios (RRs), with sensitivity analyses using risk differences (RDs), alternative continuity corrections, and pooling models. Within-subject studies were summarized descriptively using pooled adverse event (AE) proportions, with additional sensitivity analyses by transformation, study quality, and AE-elicitation method. RESULTS: Twenty-four studies (N = 853 participants; 21 RCTs, 3 non-randomized) were included. No serious AEs (SAEs) were reported. In parallel-arm RCTs (k = 5 arms; N = 192 participants), most AEs showed effects near null. Tingling was more frequent with active TIS (RR = 2.95; 95% CI, 1.25-7.00; RD = 0.18; 95% CI, 0.01-0.34). In within-subject studies (k = 20 arms; N = 531 participants), descriptive pooled AE proportions varied across outcomes, with the highest estimates observed for fatigue, sleepiness, and tingling. DISCUSSION: TIS was generally well-tolerated in humans, with predominantly mild, transient AEs and no SAEs reported. Evidence is limited to conservative parameters (~2kHz; ≤2mA/channel), small sample sizes, and short-term TIS applications.