Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine

This Review examines how oxytocin (OXT) and arginine vasopressin (AVP) contribute to human social cognition and behaviour and assesses their translational potential for mental disorders marked by social dysfunction. It contextualizes the importance of these evolutionarily conserved neuropeptides in attachment, social exploration, recognition, aggression, anxiety, fear conditioning and extinction. The purpose is to integrate behavioural, genetic, neuroendocrine and neuroimaging evidence in humans, highlight gaps and unresolved mechanisms, and evaluate whether neuropeptide-based interventions, particularly intranasal delivery combined with psychotherapy, can advance treatment for conditions such as autism spectrum disorders (ASD), social anxiety disorder (SAD), borderline personality disorder (BPD) and schizophrenia.

Behavioural studies: Correlational work links peripheral OXT to trust, affectionate contact, reduced stress responses and lower anxiety in depression, with reduced peripheral OXT reported in depression, schizophrenia and ASD; however, the relationship between peripheral measures and CNS function is controversial. Intranasal administration studies show AVP may enhance certain cognitive processes and event-related potentials; OXT and AVP can have opposing cognitive effects. OXT buffers social stress responses (lower cortisol during TSST with social support), increases positive communication during couple conflict, and modulates attention to eyes and emotion recognition with mixed valence-specific effects. OXT selectively affects social memory (e.g., recognition of faces; familiarity for social stimuli), and AVP enhances familiarity for emotional faces and recognition of sexual cues in men. OXT increases trust in economic games, generosity, and in-group cooperation, modulates responses to betrayal, and increases perceived trustworthiness/attractiveness; but can also enhance envy/gloating and does not necessarily buffer explicit social rejection. AVP studies suggest sex-dimorphic effects on social perception and potentially opposite effects to OXT in social stress. Overall, OXT tends to promote social approach and decoding of emotional cues; AVP may increase stress responsiveness and negative affective responses. Human genetics: Common variants in OXTR (notably rs53576 and rs2254298) associate with ASD risk, social skills in ASD, empathy, reward dependence, and affect, with gene-by-environment interactions (e.g., early adversity). CD38 variants (affecting OXT secretion) associate with autism; CD38 expression is reduced in ASD lymphoblastoid lines, spurring translational efforts (e.g., ATRA to upregulate CD38). AVPR1A microsatellite repeats (RS1, RS3) show transmission disequilibrium in ASD and associate with social behaviours (altruism in Dictator Game, musical ability, pair bonding, age of first intercourse, personality traits) and prepulse inhibition. Imaging genetics links OXTR and AVPR1A variants to structural and functional differences in hypothalamus, amygdala and cingulate, implicating a limbic regulatory circuit. Interactions with other systems: OXT/AVP interact with gonadal hormones (oestrogen upregulates OXTR and OXT release), serotonin (OXT effects mediated via serotonergic neurons; SLC6A4 variants interact with OXTR to influence parenting and negative emotionality), and dopamine (convergent pathways in prefrontal cortex and striatum relevant to reward and pair bonding). Neuroimaging: Intranasal OXT generally attenuates amygdala responses to threatening and social stimuli and reduces amygdala–brainstem coupling; effects can be subregion-specific and context-dependent, with evidence of increased eye fixation accompanied by specific amygdala subregion activation. Female-specific studies suggest OXT may increase activation in social cognition networks, indicating sexual dimorphism. Intranasal AVP alters cingulate regulation of amygdala and modulates temporoparietal junction activity during social recognition, indicating cortical effects. Evidence converges on an amygdala–cingulate–hypothalamus circuit as a key locus of neuropeptide action. Treatment implications: Intranasal OXT shows promise in ASD (improved emotion recognition, increased social gaze/interaction), SAD (attenuated amygdala hyperreactivity to fear; improved speech performance with exposure therapy), BPD (stress buffering; mixed effects on cooperation), and schizophrenia (reduced positive/negative symptoms; dose-dependent effects on affect discrimination). AVP antagonists (V1a/V1b) are potential treatments for stress-related disorders and depression.

This article is a narrative Review synthesizing human behavioural experiments, neuroendocrine correlational studies, genetic association and imaging genetics findings, and neuroimaging challenge studies using intranasal administration of OXT and AVP. It summarizes paradigms such as the Trier Social Stress Test (TSST), event-related brain potentials, emotion recognition tasks (e.g., Reading the Mind in the Eyes), visual attention and gaze tracking, social economic games (trust game, Dictator Game), fear conditioning/extinction, and fMRI tasks (emotional face matching, social recognition matching). It integrates evidence from genetic polymorphisms (OXTR SNPs; AVPR1A microsatellites), gene–environment interactions, and pharmacological manipulations, and references supplementary tables of human intranasal studies.

- Intranasal oxytocin (OXT) reduces amygdala reactivity to social and threatening stimuli and decouples amygdala from brainstem autonomic regions, supporting an anxiolytic mechanism underlying prosocial effects. - OXT enhances social cognition: improved emotion recognition (including masked faces), increased gaze to the eye region, selective modulation of social memory and familiarity for faces, and increased trust and generosity in social economic contexts; effects are context-dependent and can include parochial altruism and increased envy/gloating. - Arginine vasopressin (AVP) tends to increase stress endocrine responses (cortisol, heart rate) under socio-evaluative threat and modulate cortical circuits regulating emotion (cingulate) and social cognition (temporoparietal junction), with sex-dimorphic effects on social perception. - Genetic variation in OXTR (rs53576, rs2254298) and AVPR1A (RS1, RS3) associates with ASD risk and a range of social phenotypes (empathy, reward dependence, altruism, pair bonding), and impacts limbic circuitry structure and function (hypothalamus, amygdala, cingulate) in imaging genetics studies. - CD38, a regulator of OXT secretion, shows variants and reduced expression associated with ASD, inspiring translational strategies (e.g., ATRA) to enhance OXT release. - Interactions between neuropeptides and serotonin/dopamine systems converge on an amygdala–cingulate–hypothalamus–striatal circuit that mediates social-emotional processing and stress regulation. - Early clinical evidence: OXT improves aspects of social functioning in ASD and attenuates amygdala hyperreactivity in SAD; pilot data suggest stress buffering in BPD and symptom reduction in schizophrenia. AVP receptor antagonists (V1a/V1b) show anxiolytic/antidepressant-like effects in animals and are candidate therapeutics.

The compiled evidence supports the hypothesis that OXT and AVP modulate core neural circuits underpinning social cognition, affect regulation and stress responses, particularly the amygdala–cingulate–hypothalamus network. OXT’s attenuation of amygdala responsivity and enhancement of social cue processing align with improved social approach behaviours and stress buffering, addressing translational goals for disorders with social dysfunction. AVP’s facilitation of stress endocrine responses and modulation of cortical regulatory regions suggests complementary or opposing roles to OXT, with therapeutic potential via antagonism in stress-related psychopathology. Genetic associations and imaging genetics findings provide mechanistic links from receptor variation to circuit-level differences and behavioural phenotypes, strengthening a translational framework. Convergence with serotonin and dopamine systems indicates multi-system targets and potential combinatory interventions. The Review argues for ‘psychobiological therapy’ — pairing neuropeptide modulation (e.g., OXT agonists) with psychotherapy to enhance social engagement and treatment efficacy in ASD, SAD, BPD and schizophrenia.

OXT and AVP are key modulators of human social-emotional processing with demonstrable effects on limbic circuitry and behaviour. OXTR and AVPR1A genetic variation influences risk for ASD and social phenotypes via amygdala–cingulate–hypothalamus circuits. Intranasal OXT shows early promise as an adjunct to psychotherapy for social dysfunction across disorders; AVP receptor antagonists are potential treatments for stress-related psychopathology. Future research should develop selective, longer-acting OXTR agonists and non-peptidergic modulators, clarify brain penetration and pharmacodynamics of intranasal delivery, map receptor distributions (e.g., via PET), examine sex differences and gene–environment interactions, and expand task paradigms and connectivity analyses to refine circuit-level targets for tailored interventions.

- Peripheral measures of OXT/AVP are controversial and may not reflect central neuropeptide function; CSF measures are invasive and not feasible routinely. - Many pharmacological fMRI and behavioural studies predominantly include male participants; evidence of sexual dimorphism necessitates systematic studies in females and across hormonal states. - Heterogeneity of behavioural paradigms and stimuli limits comparability; task-specific activation may obscure broader neuropeptide effects. - Distribution of OXT/AVP receptors in the human brain is incompletely characterized; lack of specific PET ligands constrains receptor mapping. - Intranasal pharmacodynamics and brain penetration mechanisms remain unclear; intravenous routes have limited CNS delivery and peripheral side effects. - Limited number of randomized, controlled clinical trials; small samples and mixed findings (e.g., BPD cooperation, schizophrenia dose effects) constrain generalizability. - Genetic associations are not wholly consistent and may reflect linkage disequilibrium; functional consequences of many variants require clarification.