The effect of intranasal oxytocin on social reward processing in humans: a systematic review

The paper investigates whether intranasal oxytocin modulates social reward processing in humans, distinguishing between the anticipatory (wanting) and consummatory (liking) phases of reward. The context highlights that while dopamine and opioids underlie nonsocial reward processing (e.g., food), social rewards may rely more strongly on oxytocinergic signaling. Evidence from animals and some human studies suggests oxytocin’s involvement in social attachment, trust, memory, fear reduction, and reward processing, but human findings are inconsistent. The authors hypothesize that such inconsistencies may be due to methodological differences, including reward phase examined, stimulus type (interactive vs. simple social cues), administration route and dose, sex/gender effects, onset timing after dosing, and clinical condition. The study’s purpose is to systematically review randomized, double-blind, placebo-controlled human studies using intranasal oxytocin and tasks that isolate social reward wanting or liking, assess study quality, and provide guidance for future research.

Background literature delineates reward processing into wanting (anticipation, motivation) primarily associated with dopaminergic systems, and liking (consumption, hedonic impact) involving opioidergic mechanisms. Oxytocin is synthesized in hypothalamic nuclei and projects to brain regions central to social behavior and reward (amygdala, striatum, ventral pallidum, prefrontal cortex). Animal studies indicate oxytocin’s modulation of social behavior and reward via interactions with dopamine (overlapping receptor distributions in striatum, pallidum, VTA) and opioids (nucleus accumbens, arcuate nucleus). Human findings have been mixed, with some well-powered studies reporting null or negative effects, suggesting that oxytocin’s role may be phase-, stimulus-, dose-, sex-, onset-, and population-dependent.

The systematic review followed PRISMA guidelines and was preregistered in PROSPERO (CRD42021278945). Searches were conducted in Web of Science, Scopus, PubMed, and preprint servers (BioRxiv, MedRxiv, PsyArXiv) from September 2021 to May 2022 using terms related to oxytocin, intranasal administration, social reward, wanting/liking, motivation, and hedonic processing. Inclusion criteria: randomized, double-blind, placebo-controlled human studies using intranasal oxytocin and tasks measuring social reward wanting (during anticipation) or liking (during consumption), with behavioral, subjective, or fMRI measures. Exclusion criteria: indistinguishable social vs. non-social rewards; absence of wanting/liking assessment (e.g., learning-only studies); no behavioral/fMRI measures; sexual stimuli (to avoid different neurochemical systems). The selection used a PRISMA flow: 385 records identified; 156 duplicates removed; 229 screened; 70 full texts assessed; 51 excluded (reasons: no social reward [33], learning aspect [4], not double-blind [1], sexual [5], monetary/social undifferentiated [8]); 19 studies included. Study quality (reporting, validity, power) was assessed using Downs and Black, by one reviewer and checked by a second. Results were synthesized narratively, summarizing general study info, tasks/paradigms, measures/outcomes, and classifying by reward phase, stimulus type, dosage, sex/gender, clinical status, and onset time.

• Nineteen studies (n=984; ages 13–43) were included; sample sizes ranged 16–104; conducted across China, USA, Germany, Netherlands, Norway, Australia, France. Overall risk of bias mainly low. • Reward anticipation: 11 studies measured anticipation; only one behavioral study (Bradley et al.) and two self-report studies (Alvares; Xu) detected significant oxytocin effects; among four fMRI studies, only one (Groppe et al.) found increased VTA activity during anticipation (female sample). • Reward consumption: 13 studies measured consumption; 9/13 reported significant IN-OXY effects enhancing consummatory social reward processing on at least one measurement level. fMRI effects were reported in 11/12 consumption studies, with modulation in PFC (including OFC, mPFC), insula, precuneus, ACC, amygdala, and striatum; several connectivity changes were observed (e.g., insula–amygdala; NAcc–prefrontal/precuneus; amygdala–OFC/precuneus/ACC/MTG). Some studies reported decreased neural responses in women (amygdala and other regions). • Stimulus type: Interactive tasks (7 studies) yielded oxytocin effects in 5 studies, with effects during consumption found in both consumption-measuring interactive studies. Simple stimuli (12 studies) showed oxytocin effects in 8 studies, mostly during consumption. • Dosage: 13 studies used ~24 IU (including 26 IU and age-dependent up to 24 IU); 6 studies used 40 IU. Significant effects were found across both dosing ranges; one 24 IU study reported no effects. Evidence did not permit determining superior dose due to methodological heterogeneity. • Sex/gender: Six male-only studies; four female-only; seven mixed-sex with sufficient female participation. Some sex-dependent effects: oxytocin increased social reward processing in men but decreased it in women in certain contexts (e.g., amygdala reactivity); one study found effects only in men (Xu). Other studies reported effects irrespective of sex or null effects for both. Oral contraceptive use was variably controlled or reported. • Onset: Task onset times ranged 30–50 min post-administration (often 45 min); significant findings commonly occurred at 45–50 min, but inconsistencies and lack of task duration reporting precluded firm conclusions. • Clinical condition: Effects observed in healthy participants (12/16 studies) and clinical groups (ASD, PTSD, schizophrenia). In PTSD, oxytocin increased responses to social reward (Nawijn), with opposite effects in healthy controls for certain ROIs; in ASD and schizophrenia, some studies reported significant effects, suggesting potential benefit in populations with social deficits.

The review indicates that intranasal oxytocin reliably modulates neural processing of social rewards, particularly during consumption (liking), and less so during anticipation (wanting). The regions repeatedly modulated—PFC/OFC, insula, precuneus, ACC, amygdala, and striatum—align with networks implicated in salience, valuation, hedonic processing, and social/self-referential cognition. Connectivity findings support oxytocin’s integration within reward and affective circuits. The dominance of neural over behavioral effects suggests oxytocin’s impact may be more detectable at the (neuro)physiological level under typical experimental timings. Effects appear sensitive to stimulus type, with interactive, socially valid contexts potentially yielding more robust oxytocin modulation. Sex-dependent patterns, including possible inverted U-shaped dose-response with higher baseline oxytocin in women, may underlie contrasting findings (e.g., amygdala decreases in women vs. increases in men). Onset timing and individual differences (e.g., social adaptivity, depressive symptoms, PTSD) further moderate outcomes, emphasizing the need for tailored designs measuring baseline traits and optimizing dose and timing.

Intranasal oxytocin can modulate social reward-related brain activity in humans, with more consistent effects during the consumption phase. Modulation likely involves PFC/OFC, insula, precuneus, ACC, amygdala, and striatum. Limited support was found for effects on anticipation. Future research should: • Prioritize interactive tasks with real or perceived real social partners to increase ecological validity. • Systematically examine sex differences and individual baseline characteristics (e.g., social proficiency, hormonal status), including careful consideration of oral contraceptive use. • Conduct dose–response and timing studies to identify optimal dosing and onset windows for behavioral and neural outcomes. • Include clinical populations characterized by social reward deficits and measure individual variability to maximize translational relevance.

Study-level limitations include low external validity of unimodal/non-interactive stimuli, predominant reliance on healthy male samples, and incomplete reporting (e.g., peak coordinates, exact p-values, female proportions, sampling methods), which may introduce bias and hinder cross-study comparisons. Many oxytocin studies are underpowered relative to typically small effect sizes. Review-level limitations include potential omission of relevant studies due to database/language constraints, deviations from preregistration to include infant stimuli, exclusion of studies lacking reported inclusion criteria details, lack of publication bias assessment, and reliance on narrative synthesis rather than meta-analysis. Only 19 of 385 screened records met inclusion criteria, underscoring limited cumulative evidence.