RPEP-00050 · 1987Rats drinking 2% salt solution showed progressive increases in three neuropeptide mRNAs in the hypothalamus (a brain region controlling hormones):
Vasopressin, oxytocin, and dynorphin mRNAs all increased in the magnocellular neurons of the supraoptic and paraventricular nuclei. These are the brain cells that make these peptide hormones.
Enkephalin mRNA was not detectable in these brain areas under normal conditions. It only appeared after 12 days of salt loading or after the acute stress of a salt injection into the abdomen.
Lactating mother rats (10 days postpartum) showed a very large increase in oxytocin mRNA, with smaller increases in vasopressin and dynorphin. No enkephalin or CRF (corticotrophin-releasing factor) changes were seen in lactating rats.
Lightman, S L; Young, W S · Animal Study
RPEP-00079 · 1988Endogenous opioid peptides inhibit the release of both vasopressin and oxytocin from the posterior pituitary. They also affect anterior pituitary hormones through the hypothalamic portal blood system.
Dynorphin mRNA co-exists in the same neurons as vasopressin. Stimuli that increase vasopressin secretion (like salt loading) also increase dynorphin mRNA accumulation. This parallel regulation strongly suggests dynorphin has a genuine role alongside vasopressin.
Pro-enkephalin A mRNA co-exists with CRF in a different group of hypothalamic cells. Stresses that increase CRF mRNA also increase pro-enkephalin mRNA in the same area.
The co-existence of opioid peptides with established hormones in the same cells, combined with their coordinated regulation, provides powerful evidence that opioids are genuine neuroendocrine regulators, not incidental bystanders.
Lightman, S L · Review
RPEP-00261 · 1993Naloxone significantly increased plasma oxytocin on days 15, 18, and 21 of pregnancy but not in non-pregnant, early pregnant, or post-partum rats.
Douglas, A J; Dye, S; Leng, G; Russell, J A; Bicknell, R J · Animal Study
RPEP-00287 · 1994Naloxone (5 micromolar) enhanced potassium-evoked oxytocin release from spinal cord synaptosomes, showing tonic opioid inhibition of spinal oxytocin.
Daddona, M M; Haldar, J · In Vitro
RPEP-01055 · 2005Intranasal oxytocin attenuated amygdala reactivity to threatening facial expressions measured by fMRI in healthy humans, providing the first neural imaging evidence for oxytocin's anxiolytic mechanism through direct fear-circuit modulation.
Kirsch, Peter; Esslinger, Christine; Chen, Qiang; Mier, Daniela; Lis, Stefanie; Siddhanti, Sarina; Gruppe, Harald; Mattay, Venkata S; Gallhofer, Bernd; Meyer-Lindenberg, Andreas · RCT
RPEP-01196 · 2006Only arginine vasopressin (not oxytocin or endogenous opioid peptides) in the paraventricular nucleus mediated electroacupuncture-induced analgesia — demonstrating pathway specificity where different brain nuclei use different peptide systems for the same analgesic effect.
Yang, Jun; Liu, Wen-yan; Song, Cao-you; Lin, Bao-cheng · Animal Study
RPEP-01197 · 2006MSG-induced hypothalamic analgesia was mediated through central AVP signaling exclusively, with oxytocin and opioid peptide antagonists having no effect — confirming vasopressin's dominance in hypothalamic pain modulation pathways.
Yang, Jun; Liu, Wen-Yan; Song, Cao-You; Lin, Bao-Cheng · Animal Study
RPEP-01221 · 2007Intranasal oxytocin significantly improved performance on the Reading the Mind in the Eyes test in healthy men, demonstrating enhanced social cognition and emotional theory of mind — a distinct cognitive effect beyond anxiety reduction.
Domes, Gregor; Heinrichs, Markus; Michel, Andre; Berger, Christoph; Herpertz, Sabine C · RCT
RPEP-01312 · 2008Intranasal oxytocin in healthy men increased trust behavior AND prevented trust adaptation (trust reduction) after betrayal in a social investment game, shaping the neural circuitry of both trust formation and trust resilience — with implications for social anxiety and autism.
Baumgartner, Thomas; Heinrichs, Markus; Vonlanthen, Aline; Fischbacher, Urs; Fehr, Ernst · RCT
RPEP-01357 · 2008AVPR1a and OXTR genetic polymorphisms are associated with human social behavior variation: autism spectrum features, pair-bonding patterns, empathy levels, and social anxiety — establishing the genetic basis for neuropeptide-mediated social behavior.
Israel, Salomon; Lerer, Elad; Shalev, Idan; Uzefovsky, Florina; Reibold, Mathias; Bachner-Melman, Rachel; Granot, Roni; Bornstein, Gary; Knafo, Ariel; Yirmiya, Nurit; Ebstein, Richard P · Review
RPEP-01386 · 2008Intranasal oxytocin and vasopressin modulate human social brain circuits (amygdala fear, insula empathy, prefrontal evaluation) as demonstrated by fMRI — neuropeptide modulation of social cognition with therapeutic implications for autism and social anxiety.
Meyer-Lindenberg, Andreas · Review
RPEP-02617 · 2015Intranasal oxytocin (24 IU) administered after Pavlovian fear conditioning facilitated fear extinction in healthy men. Using fMRI, researchers showed that oxytocin simultaneously dampened amygdala activity (the brain's fear center) while boosting prefrontal cortex signaling (the region responsible for rational control over fear). This dual action matches exactly what neuroscience models predict would be needed to overcome conditioned fear responses.
Specifically, in the early phase of extinction, oxytocin increased skin conductance responses and prefrontal cortex activation to conditioned fear stimuli. In the late phase, oxytocin enhanced the decline of fear responses. The amygdala suppression was present in both phases, suggesting a sustained calming effect on the brain's alarm system.
Eckstein, Monika; Becker, Benjamin; Scheele, Dirk; Scholz, Claudia; Preckel, Katrin; Schlaepfer, Thomas E; Grinevich, Valery; Kendrick, Keith M; Maier, Wolfgang; Hurlemann, René · Randomized Controlled Trial
RPEP-03169 · 2016Single-dose oxytocin administration has consistently shown significant positive effects on experimental measures related to core autism spectrum disorder (ASD) symptoms in clinical trials. However, randomized clinical trials of continuous (multi-dose) oxytocin treatment have failed to show significant improvements in clinically meaningful endpoints — such as how individuals with ASD actually interact with other people in real-world situations.
The review identifies critical unresolved issues: optimal dose and duration remain unknown, the intranasal delivery system needs optimization, individual response variability is not well understood, and there is a lack of objective, reliable measurement tools for the core social symptoms of ASD.
Yamasue, Hidenori · Review
RPEP-04859 · 2020Two different autism spectrum disorder (ASD) mouse models were used. One was created by prenatal valproic acid exposure (environmental cause), the other by the Nl3R451C genetic mutation (genetic cause). Both had impaired social memory, the ability to distinguish familiar from novel mice.
Selectively expressing hM3Dq (an activating DREADD receptor) in oxytocin receptor-positive (OXTR+) neurons in the lateral septum (LS) allowed researchers to activate these specific neurons with a chemical trigger.
In the valproic acid model, activation restored social memory in the three-chamber social test. In the Nl3R451C model, social memory was restored in a single-field test. Both represent core ASD symptoms.
The OXTR+ neurons in the LS project to the CA1 region of the hippocampus, suggesting social memory depends on an oxytocin-responsive circuit from the lateral septum to the hippocampus. This identifies a specific neural pathway that could explain how intranasal oxytocin therapy improves social symptoms in ASD patients.
Horiai, Machi; Otsuka, Ayano; Hidema, Shizu; Hiraoka, Yuichi; Hayashi, Ryotaro; Miyazaki, Shinji; Furuse, Tamio; Mizukami, Hiroaki; Teruyama, Ryoichi; Tamura, Masaru; Bito, Haruhiko; Maejima, Yuko; Shimomura, Kenju; Nishimori, Katsuhiko · Animal Study (Mice, Neuroscience)
RPEP-04881 · 2020The review synthesizes evidence for multiple cardioprotective mechanisms of oxytocin:
Direct cardiac protection: oxytocin reduces infarct size and improves functional recovery in ischemia-reperfusion models. When given at the onset of reperfusion, it enhances cardiomyocyte viability by activating PI3K and Akt phosphorylation.
Nitric oxide pathway: oxytocin stimulates local release of atrial natriuretic peptide (ANP) in the heart, which generates cGMP and nitric oxide synthesis. This vasodilatory and cytoprotective cascade is a key mechanism.
Anti-inflammatory: oxytocin reduces expression of pro-inflammatory cytokines and decreases immune cell infiltration into damaged heart tissue.
Regeneration: oxytocin stimulates differentiation of stem cells into cardiomyocyte lineages and promotes generation of endothelial and smooth muscle cells, supporting angiogenesis (new blood vessel growth).
Metabolic protection: oxytocin increases glucose uptake by cardiomyocytes, reduces hypertrophy, decreases oxidative stress, and protects mitochondria.
Signaling pathways: RISK (reperfusion injury salvage kinase) and STAT (signal transducer and activator of transcription) cardioprotective pathways are both involved.
Jankowski, Marek; Broderick, Tom L; Gutkowska, Jolanta · Review
RPEP-04913 · 2020This is a protocol for a two-stage pilot randomized controlled trial. In stage one (weeks 0-12), 60 ASD patients receive either oral L. reuteri probiotics or placebo. In stage two (weeks 13-24), all participants also receive intranasal oxytocin spray.
Primary outcomes include serum oxytocin levels, social behavior scores (Autism Behavior Checklist, Social Responsiveness Scale), an emotional facial matching test, and eye-tracking. Secondary outcomes include GI function, gut microbiome composition, and short-chain fatty acid levels.
The rationale is based on animal studies showing L. reuteri increases oxytocin levels and improves social behavior in ASD mouse models. Intranasal oxytocin has shown some promise in improving social functioning in ASD patients.
Kong, Xue-Jun; Liu, Jun; Li, Jing; Kwong, Kenneth; Koh, Madelyn; Sukijthamapan, Piyawat; Guo, Jason J; Sun, Zhenyu Jim; Song, Yiqing · Trial Protocol
RPEP-04927 · 2020Intranasal oxytocin (24 IU) enhanced emotional empathy responses to both positive and negative emotional stimuli in the Multifaceted Empathy Task, replicating previous findings across multiple cultures.
Eye-tracking revealed the mechanism: oxytocin increased the proportion of time participants spent viewing the faces of people in the pictures and decreased time spent viewing body posture and background context.
This suggests oxytocin does not directly amplify emotional processing. Instead, it redirects visual attention toward the most informative social cue (the face), which naturally leads to stronger empathic responses.
Le, Jiao; Kou, Juan; Zhao, Weihua; Fu, Meina; Zhang, Yingying; Becker, Benjamin; Kendrick, Keith M · Randomized Controlled Trial
RPEP-04990 · 20205-ALA and intranasal OXT both rescued ASD-like behaviors, but only 5-ALA corrected hippocampal oxidative stress and mitochondrial dysfunction; both restored parvalbumin interneuron numbers.
Matsuo, Kazuya; Yabuki, Yasushi; Fukunaga, Kohji · Animal
RPEP-05029 · 2020The amygdala contains a rich neuropeptide network where CGRP, CRF, oxytocin, vasopressin, opioids, neuropeptide S, and somatostatin interact to modulate pain processing and emotional-affective pain behaviors.
Neugebauer, Volker; Mazzitelli, Mariacristina; Cragg, Bryce; Ji, Guangchen; Navratilova, Edita; Porreca, Frank · Review
RPEP-05046 · 2020Acute intranasal oxytocin focally enhanced limbic connectivity, while repeated 7-day dosing caused widespread brain connectivity reconfiguration with paradoxical reduction in social behavior.
Pagani, Marco; De Felice, Alessia; Montani, Caterina; Galbusera, Alberto; Papaleo, Francesco; Gozzi, Alessandro · Animal Study
RPEP-05147 · 2020SOARS-B enrolled 290 participants across seven sites for a 24-week randomized trial of intranasal oxytocin in ASD, making it the best-powered study to date.
Spanos, Marina; Chandrasekhar, Tara; Kim, Soo-Jeong; Hamer, Robert M; King, Bryan H; McDougle, Christopher J; Sanders, Kevin B; Gregory, Simon G; Kolevzon, Alexander; Veenstra-VanderWeele, Jeremy; Sikich, Linmarie · Clinical Trial Design
RPEP-05211 · 2020No between-group difference on the primary endpoint (ADOS reciprocity, effect size -0.08, P=.69), but oxytocin significantly reduced repetitive behavior (effect size 0.44, P=.026) and increased gaze fixation on social regions (effect size 0.55, P=.018).
Yamasue, Hidenori; Okada, Takashi; Munesue, Toshio; Kuroda, Miho; Fujioka, Toru; Uno, Yota; Matsumoto, Kaori; Kuwabara, Hitoshi; Mori, Daisuke; Okamoto, Yuko; Yoshimura, Yuko; Kawakubo, Yuki; Arioka, Yuko; Kojima, Masaki; Yuhi, Teruko; Owada, Keiho; Yassin, Walid; Kushima, Itaru; Benner, Seico; Ogawa, Nanayo; Eriguchi, Yosuke; Kawano, Naoko; Uemura, Yukari; Yamamoto, Maeri; Kano, Yukiko; Kasai, Kiyoto; Higashida, Haruhiro; Ozaki, Norio; Kosaka, Hirotaka · Human
RPEP-05224 · 2020Oxytocin exerts anxiolytic effects through modulation of social cognition, fear learning/extinction, HPA axis regulation, and interactions with serotonergic and GABAergic systems, with clinical evidence supporting potential therapeutic use in social anxiety and separation anxiety disorders.
Yoon, Seoyoung; Kim, Yong-Ku · Review
RPEP-05258 · 2021Daily intranasal OT for 4 weeks increased endogenous salivary OT levels that persisted at 4-week follow-up. Increases were most pronounced in individuals with larger improvements in ASD social symptoms, suggesting a positive spiral of OT release.
Alaerts, Kaat; Steyaert, Jean; Vanaudenaerde, Bart; Wenderoth, Nicole; Bernaerts, Sylvie · Human
RPEP-05333 · 2021Intranasal oxytocin (16-40 IU/day for 3 months) improved social behavior and stabilized eating behavior in boys with PWS and in children with the deletion genotype, with no overall group effects.
Damen, Layla; Grootjen, Lionne N; Juriaans, Alicia F; Donze, Stephany H; Huisman, T Martin; Visser, Jenny A; Delhanty, Patric J D; Hokken-Koelega, Anita C S · Rct
RPEP-05395 · 2021CAPS2 knockout mice had reduced plasma but increased hypothalamic/pituitary oxytocin levels (release failure). OXT neuron-specific CAPS2 deletion impaired social interaction and recognition, which was rescued by intranasal oxytocin administration.
Fujima, Shuhei; Yamaga, Ryosuke; Minami, Haruka; Mizuno, Shota; Shinoda, Yo; Sadakata, Tetsushi; Abe, Manabu; Sakimura, Kenji; Sano, Yoshitake; Furuichi, Teiichi · Animal
RPEP-05435 · 2021Intranasal oxytocin was anxiolytic for VPA males but anxiogenic for VPA females. In both sexes, oxytocin impaired social interactions in the sociability test and failed to improve sociosexual deficits. Prenatal VPA produced sex-specific behavioral deficits.
Harding, Shannon M; Masters, Ellen C; D'Agata, Christina M; Agudelo Rivera, Aura C; Smith, Emma C · Preclinical Animal Study
RPEP-05454 · 2021Meta-analysis of 28 studies (N=726 ASD patients) found oxytocin had beneficial effects on social functioning but no strong evidence for improvement in non-social domains. Multilevel meta-analytic model used.
Huang, Yi; Huang, Xin; Ebstein, Richard P; Yu, Rongjun · Meta Analysis
RPEP-05470 · 2021Oxytocin modulated 54 effective connectivity links among 15 brain regions, increasing both within- and between-network interactions in emotion, reward, salience, attention, and social cognition networks, with sex-dependent effects favoring males.
Jiang, Xi; Ma, Xiaole; Geng, Yayuan; Zhao, Zhiying; Zhou, Feng; Zhao, Weihua; Yao, Shuxia; Yang, Shimin; Zhao, Zhongbo; Becker, Benjamin; Kendrick, Keith M · Neuroimaging Study (FMRI Meta Analysis)
RPEP-05484 · 2021Oxytocin increased N,N-dimethylglycine (FDR p=0.043, d=0.74; N=83). In high-responder subgroup: FDR p=0.004, d=1.13, N=60. DMG increase correlated with clinical improvement at 2 weeks (r=-0.485, p=0.006) and deterioration at 2-4 weeks (r=0.415, p=0.032).
Kato, Yasuhiko; Kuwabara, Hitoshi; Okada, Takashi; Munesue, Toshio; Benner, Seico; Kuroda, Miho; Kojima, Masaki; Yassin, Walid; Eriguchi, Yosuke; Kameno, Yosuke; Murayama, Chihiro; Nishimura, Tomoko; Tsuchiya, Kenji; Kasai, Kiyoto; Ozaki, Norio; Kosaka, Hirotaka; Yamasue, Hidenori · Rct
RPEP-05501 · 2021POGZWT/Q1038R mice showed social deficits and reduced OXTR expression. POGZ binds to the OXTR promoter region, regulating its transcription. OXT neuron numbers in PVN were unchanged. Intranasal oxytocin effectively restored social behavior in POGZ mutant mice.
Kitagawa, Kohei; Matsumura, Kensuke; Baba, Masayuki; Kondo, Momoka; Takemoto, Tomoya; Nagayasu, Kazuki; Ago, Yukio; Seiriki, Kaoru; Hayata-Takano, Atsuko; Kasai, Atsushi; Takuma, Kazuhiro; Hashimoto, Ryota; Hashimoto, Hitoshi; Nakazawa, Takanobu · Animal
RPEP-05506 · 2021Multiple neuropeptide systems (CRF, dynorphin, substance P, nociceptin, orexin, vasopressin, NPY, endocannabinoids, and others) are dysregulated in the extended amygdala/habenula during drug withdrawal, driving hyperkatifeia that motivates compulsive drug seeking across substances.
Koob, George F · Review
RPEP-05591 · 2021Randomized clinical trial showed no substantial modulation of empathy-related behavioral or neural responses by intranasal oxytocin administration compared to placebo.
Mayer, Annalina V; Wermter, Anne-Kathrin; Stroth, Sanna; Alter, Peter; Haberhausen, Michael; Stehr, Thomas; Paulus, Frieder M; Krach, Sören; Kamp-Becker, Inge · Clinical Trial
RPEP-09095 · 2024Among the novel agents studied in animal models, liraglutide showed neuroprotective and anti-inflammatory effects against vincristine-induced nerve damage. Oxytocin demonstrated analgesic properties. Other promising candidates included ulinastatin (enzyme inhibitor), aripiprazole (antipsychotic), anakinra (IL-1 receptor antagonist), and thioctic acid (antioxidant). All work through different mechanisms including reducing inflammation, protecting nerve integrity, and modulating pain pathways.
Pușcașu, Ciprian; Negreș, Simona; Zbârcea, Cristina Elena; Chiriță, Cornel · Review
RPEP-09122 · 2024Oxytocin shows dose-dependent effects on alcohol use behavior: low doses do not significantly affect drinking or tolerance, but higher doses given before alcohol exposure produce varying behavioral and physiological results. In preclinical (animal) studies, oxytocin reduced withdrawal symptoms and alcohol self-administration. In clinical (human) studies, oxytocin may decrease neural cue reactivity (how strongly the brain responds to alcohol-related cues) and withdrawal symptoms.
The timing and dose of oxytocin appear critical — the peptide seems to work by strengthening stress-coping mechanisms and reducing anxiety, which are key drivers of alcohol craving and relapse. However, results are inconsistent across studies, and the optimal dosing and treatment protocols remain unclear.
Rastogi, Kriti; Weerts, Elise M; Ellis, Jennifer D · Review
RPEP-09354 · 2024Daily intranasal oxytocin (0.8 IU/kg for 4 weeks): 2x more social interaction time from week 2. 50% reduced explorative behavior at 4 weeks. 30% reduction in repetitive behavior persisting 4 weeks post-treatment. Effects lasted 4 weeks after treatment ended. However, ~10% increase in social disinterest also observed.
Szabó, Jakub; Mlynár, Matúš; Feješ, Andrej; Renczés, Emese; Borbélyová, Veronika; Ostatníková, Daniela; Celec, Peter · Animal Study
RPEP-09393 · 2024Social functioning traits predicted how intranasal oxytocin changed brain network dynamics — higher social function increased visual network microstates while lower social function increased salience network microstates.
Tomescu, Miralena I; Van der Donck, Stephanie; Perisanu, Emanuela M; Berceanu, Alexandru I; Alaerts, Kaat; Boets, Bart; Carcea, Ioana · RCT
RPEP-09533 · 2024PLR enhanced insulin transcytosis across RPMI 2650 human nasal epithelial cells by 7.8-fold at 2:1 insulin/PLR molar ratio (p<0.05), with each PLR domain (membrane docking, uptake, endosomal escape) contributing to the enhancement.
Wong, Sara; Brown, Alexander D; Abrahams, Abigail B; Nurzak, An Nisaa; Eltaher, Hoda M; Sykes, David A; Veprintsev, Dmitry B; Fone, Kevin C F; Dixon, James E; King, Madeleine V · In Vitro
RPEP-09577 · 2024Single-dose oxytocin trials consistently show efficacy for autism core symptoms, but repeated administration yields mixed results. Diminishing efficacy at higher/repeated doses may involve oxytocin-vasopressin receptor cross-talk and receptor desensitization.
Yamasue, Hidenori · Review
RPEP-09660 · 2024Semaglutide reduced amyloid plaques, p-Tau, and neuroinflammatory markers (GFAP, Iba1) while restoring oxytocin levels in both APP/PS1 mice (with improved cognition) and human AD brain organoids.
Zhang, Yinbing; Tang, Cheng; He, Yao; Zhang, Yingqian; Li, Qinxi; Zhang, Ting; Zhao, Bangcheng; Tong, Aiping; Zhong, Qixing; Zhong, Zhihui · Animal Study
RPEP-09661 · 2024Intranasal oxytocin at ≥48 IU/day showed significant improvement in social impairments (SRS) and repetitive behaviors (RBS) in ASD, while lower doses and overall pooled analysis showed no significant effects.
Zhang, Yingying; Zhang, Xiaolu; Huang, Linghong · Meta Analysis
RPEP-11206 · 2025Women with PCOS had significantly lower fasting oxytocin levels (1294 vs 1580 pg/mL, p=0.024) and reduced baseline and postprandial GLP-1 and GIP levels compared to matched controls. Oxytocin and GLP-1 were correlated at all time points, and in healthy controls, early oxytocin changes correlated with hunger and satiety — a relationship absent in women with PCOS. Food cravings were also significantly higher in the PCOS group.
Gunesli, Irmak; Ulug, Elif; Pinar, Aylin Acikgoz; Portakal, Oytun; Yildiz, Bulent O · Cross Sectional
RPEP-12034 · 2025Maternal behavior is orchestrated by a network of neuropeptides — primarily oxytocin, prolactin, and placental lactogens — that physically reshape the mother's brain during pregnancy and the postpartum period. These peptides rewire neural circuits connecting the hypothalamus to reward centers (nucleus accumbens, ventral tegmental area), making infant cues intrinsically motivating and rewarding.
Prolactin's role extends far beyond milk production: it drives adult neurogenesis, neuroprotection, and neuroplasticity in the maternal brain. Other peptides including galanin, spexin, PACAP, CRH, and TIP-39 also contribute. Dysregulation of these neuropeptide systems is linked to postpartum psychiatric disorders.
Leff-Gelman, Philippe; Pellón-Díaz, Gabriela; Camacho-Arroyo, Ignacio; Palomera-Garfias, Nadia; Flores-Ramos, Mónica · Review
RPEP-13017 · 2025Single and repeated binge ethanol withdrawal in adolescent rats produced sex-dependent effects on social anxiety-like behavior and neuropeptide gene expression.
Penta, Peter T; Villarreal, Susanna; Rameas, Caitlin I; Collins, Ella C; Towner, Trevor T; Varlinskaya, Elena I; Werner, David F · Animal Study
RPEP-13112 · 2025Intranasal oxytocin modulated social motor mirroring in context- and person-dependent ways in autistic and non-autistic men.
Prinsen, Jellina; Alaerts, Kaat · Rct