Wikipedia

Oxytocin deficiency

Oxytocin deficiency is a rare medical condition in which oxytocin secretion and/or levels are deficient.[1][2][4][8] Symptoms may include social deficits, anxiety, and depression, among others.[1][2][3] It is associated with conditions like hypopituitarism, arginine vasopressin deficiency (central diabetes insipidus), and craniopharyngioma, among others.[1][2][4][5]

Oxytocin deficiency
Other namesOT deficiency; OXT deficiency
Chemical structure of oxytocin
SpecialtyEndocrinology
SymptomsSocial deficits, anxiety, depression, others[1][2][3]
CausesHypopituitarism, arginine vasopressin deficiency, craniopharyngioma, others[1][2][4][5]
Diagnostic methodNot currently available (but oxytocin-elevating provocation tests such as MDMA in research settings)[1][2][4][6]
TreatmentNot currently available
MedicationNot currently available (but oxytocin receptor agonists like oxytocin under research)[1][2][7]

There is currently no diagnostic test for oxytocin deficiency in routine clinical settings.[1][2][4] However, it can be diagnosed via provocation tests in research settings, for instance with the oxytocin-elevating drug MDMA.[2][1][4][6] Efforts are underway towards developing diagnostic tests for oxytocin deficiency with alternative approaches, for instance acute estrogen challenge.[1][2][4][9]

No treatment for oxytocin deficiency is currently available.[1] However, clinical trials of exogenous intranasal oxytocin substitution therapy for the condition are underway.[1][2][7] Oxytocin itself suffers from major pharmacokinetic drawbacks that may limit its usefulness.[4][10][11] In addition, tolerance or tachyphylaxis may occur with continuous therapy.[12][13][14][15] Other potential options for oxytocin therapy under investigation include small-molecule oxytocin receptor agonists like LIT-001[10][11][16][17] and drugs that increase oxytocin production and hence indirectly exert oxytocin-like effects like KNX-100.[18][19][20][21]

Oxytocin deficiency was first formally identified and documented in 2023.[1][22][8][23][6] It was found in people with arginine vasopressin deficiency using MDMA provocation.[1][6] Since then, efforts are being made towards diagnosis and treatment of the condition.[1][2][4]

Symptoms

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Oxytocin deficiency has been associated with symptoms including impaired social cognition, reduced empathy, insecure attachment, social anxiety, reduced trust, alexithymia, depression, and reduced psychosocial resilience, among others.[1][2][3]

The entactogen MDMA is used both recreationally and in MDMA-assisted psychotherapy for treatment of conditions like post-traumatic stress disorder (PTSD).[24][25][26][27] It robustly increases oxytocin levels, and this effect is thought to be involved in its entactogenic effects.[24][28][29][1] In people with oxytocin deficiency due to arginine vasopressin deficiency, MDMA fails to elevate oxytocin levels and shows markedly blunted entactogenic effects, including diminished effects like euphoria, enhanced empathy, and reduced anxiety.[30][1][31][6]

Knockout mice for oxytocin or the oxytocin receptor show characteristics including lactation impairment, greater anxiety-like behavior, social deficits, increased aggression, repetitive behaviors, obesity, and reduced bone formation and osteoporosis, among others.[4] Similar behavioral changes have been found in socially isolated rodents, which show decreased oxytocin receptor levels and can be rescued by oxytocin receptor agonists.[32][33][34] In addition, administration of oxytocin receptor antagonists can produce behavioral changes similar to those of social isolation.[32][35][36]

Causes

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Oxytocin deficiency is known to occur in conditions of hypopituitarism such as arginine vasopressin deficiency (central diabetes insipidus), craniopharyngiomas, and others.[1][2][4][5] It may also occur in congenital diseases such as Prader–Willi syndrome and Schaaf–Yang syndrome.[37][38][39][40] There has been interest in whether oxytocin deficiency may occur and cause symptoms in autism as well.[41][42][4]

Diagnosis

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No clinical test currently exists for diagnosis of oxytocin deficiency in routine practice.[1][2][4] In addition, single-point oxytocin measurements are unreliable due to limitations such as poor specificity, high variability, and poor association with central oxytocin levels.[1][2] Relatedly, oxytocin levels in the brain are 100- to 1,000-fold higher than those in the bloodstream.[1][2][4]

Oxytocin-elevating interventions may be useful as a diagnostic provocation test for unmasking oxytocin deficiency.[2][1][4] Certain drugs can robustly elevate oxytocin levels with a single dose under normal circumstances, for instance the entactogen MDMA (+500–800%) and estrogens like estradiol and ethinylestradiol (e.g., +100–400%).[1][6][4][43] Controlled ovarian hyperstimulation can increase estradiol levels by around 90-fold and oxytocin levels by about 6.5-fold.[44] MDMA fails to elevate oxytocin levels in people with arginine vasopressin deficiency in research settings.[1][6] As such, it can be used to reliably diagnose oxytocin deficiency in people with this condition.[1][6] However, routine clinical use of MDMA for oxytocin deficiency is limited by its psychoactive effects and controlled status, though lower doses or safer alternatives may be more feasible.[1][4] Estrogens are being studied for potential diagnosis of oxytocin deficiency.[4][9] Fenfluramine has been found in the past to more than double oxytocin levels.[45][46] Serotonergic psychedelics like LSD, psilocybin, and mescaline also increase oxytocin levels, though of course are precluded by their hallucinogenic effects.[47][48][49][50][51][52][53] In addition, they produce much smaller increases in oxytocin levels compared to MDMA.[50][54][55][56]

Other drugs that more modestly elevate oxytocin levels (+20%) include melatonin, glucagon, and kisspeptin, but the increases have been deemed insufficient for diagnostic purposes among other limitations.[1][57][58][59] Other relevant oxytocin-elevating provocation tests include insulin tolerance test (+100%), physical exercise or sexual self-stimulation (+50–200%), and psychosocial stress (+50–150%), but all have drawbacks such as side effects or potential variability and unreproducibility.[2][1] Neurophysin I (NP-I), a stable stable carrier protein co-released with oxytocin, is a surrogate biomarker of oxytocin production, and has been found to be a more reliable and robust indicator of oxytocin production than oxytocin levels themselves.[1][2][4][60][61] Oxytocin-elevating provocation and/or NP-1 surrogate tests may eventually lead to a routine clinical diagnostic test for oxytocin deficiency.[1][2]

Treatment

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There is currently no treatment for oxytocin deficiency.[1] However, there is interest in oxytocin substitution therapy in the treatment of the condition.[1] A clinical trial of oxytocin nasal spray (Syntocinon) for oxytocin deficiency in people with arginine vasopressin deficiency (central diabetes insipidus) is underway as of May 2026.[7] Other trials of oxytocin therapy for oxytocin deficiency are also underway.[1][2]

Although intranasal oxytocin can produce measurable brain changes and associated prosocial effects,[2] it has shown modest, mixed, and disappointing results in clinical trials for various indications such as treatment of autism among others.[4][62][63][64][65] Relatedly, the drug is limited by pharmacokinetic problems such as very poor blood–brain barrier permeability (e.g., 0.002–0.005% of total dose) and a very short elimination half-life (3–5 minutes in plasma, 28 minutes in cerebrospinal fluid) related to its peptide nature.[4][10][11][66] Another possible limitation of oxytocin receptor agonists is tolerance or tachyphylaxis, for instance due to oxytocin receptor desensitization or downregulation.[12][13][14][15]

In addition to peptide oxytocin receptor agonists like oxytocin, small-molecule oxytocin receptor agonists like LIT-001 and LIT-002, which show greatly improved pharmacokinetic properties like central permeability and duration in comparison, are a potential future approach for oxytocin therapy that is under development.[10][11][16][17] The same may be true of arachidonate 15-lipoxygenase (ALOX15) inhibitors such as KNX-100 (SOC-1), which increase central oxytocin production and have been found to indirectly produce robust oxytocin-like effects in animals.[18][19][20][21]

History

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Oxytocin deficiency was first formally identified and documented by Mirjam Christ-Crain and colleagues in Basel, Switzerland in 2023.[1][22][8][23][6] This was via an MDMA provocation test in people with arginine vasopressin deficiency (central diabetes insipidus), who failed to show the strong increases in circulating oxytocin levels and associated entactogenic effects that are seen following administration of MDMA in healthy volunteers.[1][6] However, a much earlier study in 1983 also reported blunted oxytocin secretion in response to estrogen provocation in two males with the condition.[67]

References

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  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Atila C, Refardt J, Christ-Crain M (March 2026). "Arginine Vasopressin Deficiency and Oxytocin Deficiency in the Endocrine Clinic". J Clin Endocrinol Metab. 111 (4): 922–937. doi:10.1210/clinem/dgaf651. PMC 13017940. PMID 41363127.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Leibnitz S, Christ-Crain M, Atila C (November 2025). "Oxytocin: a neglected hormone in pituitary disease - From function to the diagnosis of a deficiency, resulting clinical relevance, and potential treatment options in endocrinology". Arch Endocrinol Metab. 70 (special 1): e20250259. doi:10.20945/2359-4292-2025-0259. PMC 12668196. PMID 41313193.
  3. 1 2 3 Atila C, Beck J, Refardt J, Erlic Z, Drummond JB, Sailer CO, Liechti ME, Rocha BS, Beuschlein F, Winzeler B, Christ-Crain M (May 2024). "Psychopathological characteristics in patients with arginine vasopressin deficiency (central diabetes insipidus) and primary polydipsia compared to healthy controls". Eur J Endocrinol. 190 (5): 354–362. doi:10.1093/ejendo/lvae040. PMID 38551325.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Aulinas A, Lawson EA (July 2025). "The Oxytocin System and Implications for Oxytocin Deficiency in Hypothalamic-Pituitary Disease". Endocr Rev. 46 (4): 518–548. doi:10.1210/endrev/bnaf008. PMC 12259237. PMID 39985439.
  5. 1 2 3 Bhargava R, Daughters KL, Rees A (February 2019). "Oxytocin therapy in hypopituitarism: Challenges and opportunities". Clin Endocrinol (Oxf). 90 (2): 257–264. doi:10.1111/cen.13909. PMID 30506703.
  6. 1 2 3 4 5 6 7 8 9 10 Atila C, Holze F, Murugesu R, Rommers N, Hutter N, Varghese N, Sailer CO, Eckert A, Heinrichs M, Liechti ME, Christ-Crain M (July 2023). "Oxytocin in response to MDMA provocation test in patients with arginine vasopressin deficiency (central diabetes insipidus): a single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial". Lancet Diabetes Endocrinol. 11 (7): 454–464. doi:10.1016/S2213-8587(23)00120-1. PMID 37192642.
  7. 1 2 3 Atila C, Leibnitz S, Nikaj A, Liechti ME, De Quervain D, Christ-Crain M (May 2026). "Oxytocin substitution therapy in patients with AVP deficiency (central diabetes insipidus): study protocol of a double-blind, randomised placebo-controlled trial". BMJ Open. 16 (5) e109940. doi:10.1136/bmjopen-2025-109940. PMC 13141166. PMID 42082227.
  8. 1 2 3 Verbalis JG (September 2023). "Oxytocin deficiency - a 'new' human disorder?". Nat Rev Endocrinol. 19 (9): 505–506. doi:10.1038/s41574-023-00870-z. PMID 37430034.
  9. 1 2 "Plasma Oxytocin Response to Oral Estrogens in Healthy Controls and AVP-Deficiency (PHOENIX)". ClinicalTrials.gov. 22 January 2026. Retrieved 10 July 2026.
  10. 1 2 3 4 Gulliver D, Werry E, Reekie TA, Katte TA, Jorgensen W, Kassiou M (January 2019). "Targeting the Oxytocin System: New Pharmacotherapeutic Approaches". Trends Pharmacol Sci. 40 (1): 22–37. doi:10.1016/j.tips.2018.11.001. hdl:1959.4/unsworks_81554. PMID 30509888.
  11. 1 2 3 4 Nashar PE, Whitfield AA, Mikusek J, Reekie TA (2022). "The Current Status of Drug Discovery for the Oxytocin Receptor". Oxytocin. Methods Mol Biol. Vol. 2384. pp. 153–174. doi:10.1007/978-1-0716-1759-5_10. ISBN 978-1-0716-1758-8. PMID 34550574.
  12. 1 2 Macdonald K, Feifel D (2013). "Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders". Front Neurosci. 7: 35. doi:10.3389/fnins.2013.00035. PMC 3597931. PMID 23508240.
  13. 1 2 Daniels N, Moerkerke M, Steyaert J, Bamps A, Debbaut E, Prinsen J, Tang T, Van der Donck S, Boets B, Alaerts K (April 2023). "Effects of multiple-dose intranasal oxytocin administration on social responsiveness in children with autism: a randomized, placebo-controlled trial". Mol Autism. 14 (1) 16. doi:10.1186/s13229-023-00546-5. PMC 10117268. PMID 37081454. Furthermore, in terms of dosing scheme, recent work showed that intermittent (every other day) administration may be therapeutically more efficient than continual administration to obtain anxiolytic effects [43]. These observations were attributed to reflect a desensitization of the endogenous oxytocinergic system upon too high concentrations and/or too high frequencies of exogenous OT administration. The current observation that a single 4-week course yields similar immediate effects as a twice 4-week course therefore reinforces the notion that longer durations of nasal spray administration periods do not necessarily facilitate higher treatment responses. Similarly, in a recent large-scale trial administering OT over a 24-week period, it was noted that the long duration might have attenuated initial early responses to OT [19].
  14. 1 2 Kou J, Zhang Y, Zhou F, Sindermann C, Montag C, Becker B, Kendrick KM (July 2022). "A randomized trial shows dose-frequency and genotype may determine the therapeutic efficacy of intranasal oxytocin". Psychol Med. 52 (10): 1959–1968. arXiv:0912.1770v1. doi:10.1017/S0033291720003803. PMID 33272333. A single dose of oxytocin-reduced amygdala responses to all face emotions but for threatening (fear and anger) and happy faces, this effect was abolished after daily doses for 5 days but maintained by doses given every other day. [...] Infrequent chronic oxytocin administration may be therapeutically most efficient [...] Our findings are highly consistent with preclinical animal models demonstrating OXTR desensitization following repeated doses of OT in some brain regions (Terenzi & Ingram, 2005; Smith et al., 2006; Stoop, 2012) and that chronic administration can reduce brain OXTR expression (Du et al., 2017) and alter patterns of neurochemical release (Benner et al., 2018). Importantly, chronic doses of OT in rodents fail to produce anxiolytic effects normally seen with single doses (Du et al., 2017), which mirrors our present observations. The apparent long-lasting desensitization effects of daily OT administration on amygdala responses to threatening and happy faces may be contributed to by dose magnitude and so possibly lower daily doses might be less problematic.
  15. 1 2 Le J, Zhang L, Zhao W, Zhu S, Lan C, Kou J, Zhang Q, Zhang Y, Li Q, Chen Z, Fu M, Montag C, Zhang R, Yang W, Becker B, Kendrick KM (2022). "Infrequent Intranasal Oxytocin Followed by Positive Social Interaction Improves Symptoms in Autistic Children: A Pilot Randomized Clinical Trial". Psychother Psychosom. 91 (5): 335–347. doi:10.1159/000524543. PMID 35545057. Previous trials using chronic intranasal OXT administration have adopted a once- or twice-daily dosing frequency with the objective of raising basal concentrations. However, there is no empirical support for this treatment strategy and G protein-coupled receptors exhibit rapid desensitization and downregulation following exogenous treatment with agonist ligands [31, 32]. Chronic/ daily OXT treatment leads to extensive OXTR and vasopressin-1A receptor downregulation in the rat forebrain [33–36]. Additionally, when OXT binds to its receptor it can differentially recruit intracellular G protein-coupled pathways with increasing OXT bioavailability shifting coupling away from the excitatory Gq protein to the inhibitory Gi one [37–39]. This may explain inverted Ushaped dose-response curves reported for acute OXT treatment with higher doses having opposite effects to lower ones [8, 40]. Chronic relative to acute dosing with OXT can impair rather than enhance social behavior [41–43] and increase rather than decrease anxiety in rodents [44]. In humans, we have shown that once-daily treatment with intranasal OXT for 5 days reduces its effects on neural and anxiolytic responses to emotional stimuli, whereas they are maintained or enhanced by less frequent administration every other day [45, 46]. Thus, OXT given at too great a frequency and/or too high a concentration can reduce or even reverse its functional effects.
  16. 1 2 Frantz MC, Pellissier LP, Pflimlin E, Loison S, Gandía J, Marsol C, Durroux T, Mouillac B, Becker JA, Le Merrer J, Valencia C, Villa P, Bonnet D, Hibert M (October 2018). "LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism". J Med Chem. 61 (19): 8670–8692. doi:10.1021/acs.jmedchem.8b00697. PMID 30199637.
  17. 1 2 Hibert M, Zhao Q, Noel-Duchesneau L, Peron F, Brugoux A, Bolot F, Marsol C, Bonnet D, Verner E, Kos I, Iminov R, Kondratov I, Orcel H, Couvineau P, Cong X, Ben Boubaker R, Mouillac B, Valencia C, Gizzi P, Daubeuf F, Garnier D, Villa P, Poirier R, Mery S, Laboute T, Le Merrer J, Becker J (April 2026). "LIT-002, a highly potent and selective nonpeptide oxytocin receptor agonist that improves social interaction in mouse models of autism". SSRN Electronic Journal. doi:10.2139/ssrn.6624262.
  18. 1 2 Klein A (31 January 2018). "A Helping Hand / The Love Drug That Could Draw People Away From Any Addiction". New Scientist. doi:10.1016/S0262-4079(18)30221-5. [...] after they injected the third [oxytocin precursor fragment], they found the rats became more social, showing an increased preference for spending time with other rats rather than objects, and even cuddling up to rats they had never met before. "Bingo. That was when we thought it must be activating the oxytocin system," says Bowen. [...] they found the fragment was strongly activating the brain's two major oxytocin-producing factories. [...] Since then, the team has tested this small molecule – named synthetic oxytocin-like compound 1 (SOC-1) – in rats [...] how exactly does SOC-1 work? Their research so far suggests it stimulates a rush of oxytocin that recalibrates the brain's focus towards social engagement. [...]
  19. 1 2 "Combatting addiction with 'the love hormone'". sponsored.chronicle.com. 3 November 2021. Retrieved 13 January 2026. [(KNX-100)], which was discovered at the University of Sydney, mimics the anti-addictive and pro-social effects of oxytocin, as well as a number of its effects in the brain, but overcomes the limitations of administering oxytocin itself.
  20. 1 2 Iain McGregor (October 2017). Serendipity and the Hard Slog: An Insiders Account of the Discovery and Development of a Novel Therapeutic for Treating Addiction and Social Deficits (PDF). Biological Psychiatry Australia 7th Annual Scientific Meeting, Wollongong Sunday 29 — Tuesday 31 October 2017, Abstract Book. Early studies in laboratory animals showed the capacity of oxytocin to increase prosocial behaviours and to reduce methamphetamine, cocaine and alcohol self-administration and withdrawal symptoms. However, oxytocin itself is unlikely to ever become a mainstream therapeutic due to its poor brain penetration and lack of oral bioavailability. Investigation of non-peptide small molecule oxytocin-like compounds by our group lead to the serendipitous discovery of Synthetic Oxytocin-Like-Compound 1 (SOC-1), a novel compound that stimulates brain oxytocin circuitry and has dramatic prosocial and anti-addiction effects in animal models. [...] SOC-1 shows favourable pharmacokinetics and a very promising toxicity profile, [...] The mode of action of SOC-I remains something of a mystery: it stimulates magnocellular oxytocin-containing neurons in the hypothalamus but does not show affinity for more than 100 different receptors and transporters that have been screened, including the oxytocin receptor. [...]
  21. 1 2 Michael Bowen, Kinoxis Therapeutics (11 January 2026). Developing Novel ALOX15 Inhibitors for Dementia and Pain, High-Need CNS Indications. Sachs Associates 9th Annual Neuroscience Innovation Forum for Business Development, Licensing & Investment, 11th January 2026, Marines' Memorial Club, San Francisco, USA.
  22. 1 2 Lawson EA (August 2024). "Understanding oxytocin in human physiology and pathophysiology: A path towards therapeutics". Compr Psychoneuroendocrinol. 19 100242. doi:10.1016/j.cpnec.2024.100242. PMC 11225698. PMID 38974962.
  23. 1 2 Ilie MD, Raverot G (July 2023). "Oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus)". Lancet Diabetes Endocrinol. 11 (7): 442–443. doi:10.1016/S2213-8587(23)00126-2. PMID 37192643.
  24. 1 2 Dunlap LE, Andrews AM, Olson DE (October 2018). "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine". ACS Chem Neurosci. 9 (10): 2408–2427. doi:10.1021/acschemneuro.8b00155. PMC 6197894. PMID 30001118.
  25. ↑ Morland LA, Rothbaum BO, Sippel LM, Maples-Keller J, Schnurr PP (April 2026). "State of the Science: MDMA-assisted psychotherapy for the treatment of posttraumatic stress disorder". J Trauma Stress. 39 (2): 173–187. doi:10.1002/jts.70060. PMID 41820235.
  26. ↑ O'Brien S, Nutt D (January 2025). "MDMA-assisted therapy: challenges, clinical trials, and the future of MDMA in treating behavioral disorders". CNS Spectr. 30 (1) e15. doi:10.1017/S1092852925000057. PMC 13064729. PMID 39882724.
  27. ↑ Wolfgang AS, Fonzo GA, Gray JC, Krystal JH, Grzenda A, Widge AS, Kraguljac NV, McDonald WM, Rodriguez CI, Nemeroff CB (January 2025). "MDMA and MDMA-Assisted Therapy". Am J Psychiatry. 182 (1): 79–103. doi:10.1176/appi.ajp.20230681. PMID 39741438.
  28. ↑ Vaslavski A, Gross AH, Israel S, Peled-Avron L (October 2025). "The effect of MDMA administration on oxytocin concentration levels: systematic review and a multilevel meta-analysis in humans". Neurosci Biobehav Rev. 177 106324. doi:10.1016/j.neubiorev.2025.106324. PMID 40812728. These foundational mechanistic insights were soon validated in human studies around 2009–2012, showing acute MDMA administration (~1.5 mg/kg) raises plasma oxytocin several-fold—typically from ~20 pg/mL to over 80 pg/mL—and correlates with enhanced sociability, emotional openness, and reduced fear recognition (Dumont et al., 2009; Hysek, Domes, et al., 2012a). [...] The administration of MDMA can elevate oxytocin levels substantially, often reported as a fourfold increase in some contexts (Dumont et al., 2009).
  29. ↑ Kamilar-Britt P, Bedi G (October 2015). "The prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA): Controlled studies in humans and laboratory animals". Neurosci Biobehav Rev. 57: 433–446. doi:10.1016/j.neubiorev.2015.08.016. PMC 4678620. PMID 26408071.
  30. ↑ Vogt SB, Liechti ME (2025). "Clinical Pharmacology". In Nutt DJ, Thurgur H (eds.). Psychedelics in Psychiatry. International Review of Neurobiology. Vol. 181. London: Academic Press. pp. 99–148. doi:10.1016/bs.irn.2025.02.003. ISBN 978-0-443-34386-5. PMID 40541320. The MDMA-induced release of oxytocin also contributes to acute positive emotional effects of MDMA, including enhancing trust and emotional empathy and reducing fear perception (Atila et al., 2023; Dumont et al., 2009; Francis et al., 2016; Hysek et al., 2014; Kirkpatrick et al., 2014). For example, the importance of oxytocin in mediating MDMA's effects was demonstrated in a study of patients with arginine vasopressin deficiency (also known as central diabetes insipidus) who also had been shown to have a deficit in oxytocin (Atila et al., 2023). In these patients, MDMA failed to elevate oxytocin levels, and it also markedly reduced empathetic and anxiolytic effects compared with healthy controls.
  31. ↑ Atila C, Refardt J, Christ-Crain M (August 2024). "Arginine vasopressin deficiency: diagnosis, management and the relevance of oxytocin deficiency". Nat Rev Endocrinol. 20 (8): 487–500. doi:10.1038/s41574-024-00985-x. PMID 38693275. To this purpose, MDMA (also known as the recreational drug 'ecstasy') was assessed in a 2023 study as a stimulus for oxytocin9 (Fig. 4). MDMA increases peripheral oxytocin levels and central oxytocin-mediated behavioural effects, which are associated with its empathic and prosocial profile. These effects include increased closeness and openness to others, enhanced trust, elevated happiness and an overall sense of well-being102–105. In the 2023 study, patients with AVP deficiency showed no difference in basal plasma oxytocin levels compared with matched healthy control individuals. In response to MDMA administration, control individuals showed an eight-fold increase in plasma levels of oxytocin, whereas no response was seen in patients9. In patients, psychoactive effects induced by MDMA (for example, 'good effect', 'liking effect' or 'feeling high') were either blunted or absent compared with control individuals (Fig. 4). [...] Thus, in contrast to the predicted effects in control individuals, nearly all of the psychoactive effects of MDMA were either blunted or absent in patients9.
  32. 1 2 Krimberg JS, Lumertz FS, Orso R, Viola TW, de Almeida RM (March 2022). "Impact of social isolation on the oxytocinergic system: A systematic review and meta-analysis of rodent data". Neurosci Biobehav Rev. 134 104549. doi:10.1016/j.neubiorev.2022.104549. hdl:10923/25707. PMID 35074312.
  33. ↑ Tan O, Musullulu H, Raymond JS, Wilson B, Langguth M, Bowen MT (September 2019). "Oxytocin and vasopressin inhibit hyper-aggressive behaviour in socially isolated mice". Neuropharmacology. 156 107573. doi:10.1016/j.neuropharm.2019.03.016. PMID 30885607.
  34. ↑ Li J, Wu C, Li Y, Chai K, Yao D, Chen K, Xia Y (February 2026). "Oxytocin attenuates isolation-evoked emotional and social behavioral dysregulation through neural, immune, and microbiota mechanisms". Transl Psychiatry. 16 (1) 159. doi:10.1038/s41398-026-03888-9. PMC 13004923. PMID 41667420.
  35. ↑ Johnston MP, Wanat MJ (2022). "Mitigating the impact of adolescence isolation on the development of social anxiety: A potential role for oxytocin". Front Behav Neurosci. 16 1038236. doi:10.3389/fnbeh.2022.1038236. PMC 9608628. PMID 36311867. Rats separated from their mothers experience deficits in social behavior which are associated with decreased oxytocin receptor binding and lower immunoreactive oxytocin levels (Lukas et al., 2010; Oreland et al., 2010). Additionally, antagonizing oxytocin receptors in juvenile rodents mimics the behavioral effects of isolation (Huang et al., 2021). [...] Pre-clinical studies have shown that isolation can lead to social deficits and decreased functioning of the oxytocin system (Lukas et al., 2010; Oreland et al., 2010; Makinodan et al., 2012; Oliveira et al., 2019; Huang et al., 2021; Baracz et al., 2022; Krimberg et al., 2022). Additionally, antagonizing oxytocin receptors can recapitulate the effects of isolation on behavior (Huang et al., 2021).
  36. ↑ Huang L, Duan C, Xia X, Wang H, Wang Y, Zhong Z, Wang B, Ding W, Yang Y (January 2021). "Commensal microbe-derived propionic acid mediates juvenile social isolation-induced social deficits and anxiety-like behaviors". Brain Res Bull. 166: 161–171. doi:10.1016/j.brainresbull.2020.12.001. PMID 33279588.
  37. ↑ Althammer F, Muscatelli F, Grinevich V, Schaaf CP (August 2022). "Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies". Transl Psychiatry. 12 (1) 318. doi:10.1038/s41398-022-02054-1. PMC 9360032. PMID 35941105.
  38. ↑ Paparella R, Bei A, Bernabei I, Fiorentini C, Iafrate N, Lucibello R, Marchetti L, Pastore F, Maglione V, Niceta M, Fiore M, Caronti B, Vitali M, Pucarelli I, Tarani L (November 2025). "Oxytocin Deficiency in Childhood and Adolescence: Clinical Features, Diagnostic Challenges and Therapeutic Perspectives". Curr Issues Mol Biol. 47 (12): 982. doi:10.3390/cimb47120982. PMC 12731813. PMID 41614746.
  39. ↑ Oztan O, Zyga O, Stafford DE, Parker KJ (November 2022). "Linking oxytocin and arginine vasopressin signaling abnormalities to social behavior impairments in Prader-Willi syndrome". Neurosci Biobehav Rev. 142 104870. doi:10.1016/j.neubiorev.2022.104870. PMC 11024898. PMID 36113782.
  40. ↑ Petersson M, Höybye C (August 2024). "Is Oxytocin a Contributor to Behavioral and Metabolic Features in Prader-Willi Syndrome?". Curr Issues Mol Biol. 46 (8): 8767–8779. doi:10.3390/cimb46080518. PMC 11353121. PMID 39194735.
  41. ↑ Boulton KA, Guastella AJ (August 2026). "Oxytocin and autism - A precision medicine framework to unpack mechanisms and evidence". Neurosci Biobehav Rev. 187 106746. doi:10.1016/j.neubiorev.2026.106746. PMID 42144048.
  42. ↑ Xing C, Yu X (June 2025). "Oxytocin and autism: Insights from clinical trials and animal models". Curr Opin Neurobiol. 92 103015. doi:10.1016/j.conb.2025.103015. PMID 40157057.
  43. ↑ Chiodera P, Volpi R, Capretti L, Marchesi C, d'Amato L, De Ferri A, Bianconi L, Coiro V (November 1991). "Effect of estrogen or insulin-induced hypoglycemia on plasma oxytocin levels in bulimia and anorexia nervosa". Metabolism. 40 (11): 1226–1230. doi:10.1016/0026-0495(91)90220-q. PMID 1943752. Plasma oxytocin (OT) levels were measured before and after stimulation with estrogens (1 mg ethynylestradiol orally) [...] Fig 1. OT secretion after oral administration of ethynylestradiol (1 mg, at time 0) [...]
  44. ↑ Tachibana A, Yamamoto Y, Noguchi H, Takeda A, Tamura K, Aoki H, Minato S, Uchishiba M, Yamamoto S, Kamada S, Yoshida A, Kinouchi R, Yoshida K, Iwasa T (December 2022). "Changes in Serum Oxytocin Levels under Physiological and Supraphysiological Gonadal Steroid Hormone Conditions in Women of Reproductive Age: A Preliminary Study". Nutrients. 14 (24): 5350. doi:10.3390/nu14245350. PMC 9787714. PMID 36558508.
  45. ↑ Siegel A, Bhatt S, Bhatt R, Zalcman SS (2007). "The neurobiological bases for development of pharmacological treatments of aggressive disorders". Curr Neuropharmacol. 5 (2): 135–147. doi:10.2174/157015907780866929. PMC 2435345. PMID 18615178.
  46. ↑ Lee R, Garcia F, van de Kar LD, Hauger RD, Coccaro EF (May 2003). "Plasma oxytocin in response to pharmaco-challenge to D-fenfluramine and placebo in healthy men". Psychiatry Res. 118 (2): 129–136. doi:10.1016/s0165-1781(03)00070-2. PMID 12798977.
  47. ↑ van Elk M, Yaden DB (September 2022). "Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review". Neurosci Biobehav Rev. 140 104793. doi:10.1016/j.neubiorev.2022.104793. hdl:1887/3515020. PMID 35878791.
  48. ↑ Carter CS (August 2025). "The psychedelic-peptide paradox: a hormetic hypothesis". Compr Psychoneuroendocrinol. 23 100303. doi:10.1016/j.cpnec.2025.100303. PMC 12205328. PMID 40584160.
  49. ↑ Constantino JL, van Dalfsen JH, Massetti S, Kamphuis J, Schoevers RA (January 2025). "Neurobiological mechanisms of antidepressant properties of psilocybin: A systematic review of blood biomarkers". Prog Neuropsychopharmacol Biol Psychiatry. 136 111251. doi:10.1016/j.pnpbp.2025.111251. hdl:11370/fcbc42ee-bb43-45cc-a93d-2cbc4faf3acc. PMID 39788410.
  50. 1 2 Thuery G, Crossen F, Mc Loone D, Hinds C, Duffy R, Jairaj C, Harkin A, Kelly JR (2026). "Psychedelic therapy and postpartum depression: priorities and prospects". Ther Adv Psychopharmacol. 16 20451253251408280. doi:10.1177/20451253251408280. PMC 12972557. PMID 41816502. Psychedelics and peptide hormones. DOI administration in rats acutely increases oxytocin and prolactin release in a 5-HT2AR-dependent manner.59 In healthy humans, circulating oxytocin and prolactin are acutely increased by LSD60 and psilocybin.61 Ley et al.62 additionally found that mescaline increased circulating oxytocin levels, although they found no effect of psilocybin. LSD-mediated increases in oxytocin were abrogated by co-administration of the 5-HT2AR antagonist ketanserin, providing human evidence that the effect is largely 5-HT2AR-mediated.60 Interestingly, Straumann et al.63 found that the increase in oxytocin induced by LSD, although statistically significant, was minimal compared with that induced by MDMA. Similarly, Holze et al.64 found that MDMA, but not LSD, significantly increased plasma oxytocin concentrations. These data may help explain why pro-social effects are particularly pronounced during MDMA experiences, whereas they are less intense, though still reliably observed, with LSD.
  51. ↑ Holze F, Avedisian I, Varghese N, Eckert A, Liechti ME (2021). "Role of the 5-HT2A Receptor in Acute Effects of LSD on Empathy and Circulating Oxytocin". Front Pharmacol. 12 711255. doi:10.3389/fphar.2021.711255. PMC 8313809. PMID 34326773.
  52. ↑ Ley L, Holze F, Arikci D, Becker AM, Straumann I, Klaiber A, Coviello F, Dierbach S, Thomann J, Duthaler U, Luethi D, Varghese N, Eckert A, Liechti ME (October 2023). "Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants". Neuropsychopharmacology. 48 (11): 1659–1667. doi:10.1038/s41386-023-01607-2. PMC 10517157. PMID 37231080. In the present study, both 500 mg mescaline and LSD, but not psilocybin, enhanced circulating oxytocin. Therefore, the present study was the first to document elevated plasma oxytocin levels in response to mescaline as it was previously shown for LSD [24, 27, 28] and psilocybin [24]. In fact, 500 mg mescaline was the strongest releaser of oxytocin among the psychedelics that were tested herein. [...] As for its limitations; we failed to achieve instant dose equivalence, leading to a subsequent increase in the mescaline dose from 300 to 500 mg. The study thus tested two doses of mescaline against LSD and psilocybin. [...] Figure S4. Effects on plasma levels of oxytocin and brain-derived neurotrophic factor (BDNF). Mescaline and LSD significantly increased plasma oxytocin levels compared with placebo. Oxytocin levels were significantly higher after mescaline (n = 32) compared with psilocybin.
  53. ↑ Holze F, Ley L, Müller F, Becker AM, Straumann I, Vizeli P, Kuehne SS, Roder MA, Duthaler U, Kolaczynska KE, Varghese N, Eckert A, Liechti ME (May 2022). "Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects". Neuropsychopharmacology. 47 (6): 1180–1187. doi:10.1038/s41386-022-01297-2. PMC 9018810. PMID 35217796. Furthermore, the present study was the first to document increases in circulating oxytocin after psilocybin administration as previously shown for LSD [21, 22] and MDMA [28, 50].
  54. ↑ Arikci D, Borgulya J, Straumann I, Vizeli P, Luethi D, Thomann J, Rudin D, Vukalovic I, Eckert A, Liechti ME, Holze F (July 2026). "Acute dose-dependent effects of 4-bromo-2,5-dimethoxyphenethylamine (2C-B) compared with 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin in a double-blind, placebo-controlled study in healthy participants". Neuropsychopharmacology. 51 (8): 1511–1518. doi:10.1038/s41386-026-02428-9. PMC 13291353. PMID 42049943.
  55. ↑ Holze F, Vizeli P, Müller F, Ley L, Duerig R, Varghese N, Eckert A, Borgwardt S, Liechti ME (February 2020). "Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects". Neuropsychopharmacology. 45 (3): 462–471. doi:10.1038/s41386-019-0569-3. PMC 6969135. PMID 31733631.
  56. ↑ Straumann I, Ley L, Holze F, Becker AM, Klaiber A, Wey K, Duthaler U, Varghese N, Eckert A, Liechti ME (December 2023). "Acute effects of MDMA and LSD co-administration in a double-blind placebo-controlled study in healthy participants". Neuropsychopharmacology. 48 (13): 1840–1848. doi:10.1038/s41386-023-01609-0. PMC 10584820. PMID 37258715.
  57. ↑ Asla Q, Garrido M, Urgell E, Terzan S, Santos A, Varghese N, Atila C, Biagetti B, Plessow F, Christ-Crain M, Eckert A, Webb SM, Lawson EA, Aulinas A (November 2025). "Melatonin as a Possible Stimulus to Unmask an Oxytocin-Deficient State in Hypopituitarism and Hypothalamic Damage". J Clin Endocrinol Metab. 110 (12): e4205–e4214. doi:10.1210/clinem/dgaf201. PMC 12623053. PMID 40166823.
  58. ↑ Galbiati F, Plessow F, Plummer L, Campbell MB, Nazarloo S, Carter CS, Carroll RS, Kim HK, Pereira SA, Paulis D, Davis JM, Miller KK, Kaiser UB, Seminara SB, Aulinas A, Lawson EA (March 2025). "Sex-dependent increases in oxytocin levels in response to intravenous kisspeptin in humans". Eur J Endocrinol. 192 (3): K24–K29. doi:10.1093/ejendo/lvaf001. PMC 11886556. PMID 39965102.
  59. ↑ Atila C, Mekkattu S, Murugesu R, Gaisl O, Varghese N, Eckert A, Christ-Crain M (November 2024). "Plasma oxytocin levels in response to glucagon in patients with arginine vasopressin deficiency (central diabetes insipidus) and healthy controls". Endocrine. 86 (2): 774–781. doi:10.1007/s12020-024-03920-2. PMC 11489228. PMID 38935296.
  60. ↑ Atila C, Nikaj A, Leibnitz S, Liechti ME, Christ-Crain M (March 2025). "Neurophysin I: a reliable, novel, and robust biomarker for oxytocin". Eur J Endocrinol. 192 (4): 502–510. doi:10.1093/ejendo/lvaf078. PMID 40209095.
  61. ↑ Atila C, Murugesu R, Rudin D, Luethi D, Liechti ME, Christ-Crain M (March 2026). "Absence of detectable circadian rhythmicity of neurophysin I, a surrogate marker for oxytocin". Pituitary. 29 (2) 62. doi:10.1007/s11102-026-01670-0. PMID 41879918.
  62. ↑ Bonnieux J, Gumuchian ST, Harboun A, Trespalacios F, Bélisle KA, Haddad A, Quintus-Bosz O, McLellan A, Chester-Trudel L, Garred D, Resendes T, Hazel L, Wong SF, Ellenbogen MA (August 2026). "Does intranasal oxytocin reduce symptoms of mental disorders? A meta-analysis of clinical trials". Neurosci Biobehav Rev. 187 106749. doi:10.1016/j.neubiorev.2026.106749. PMID 42134427.
  63. ↑ Yao S, Kendrick KM (April 2025). "How does oxytocin modulate human behavior?". Mol Psychiatry. 30 (4): 1639–1651. doi:10.1038/s41380-025-02898-1. PMID 39827220.
  64. ↑ Erdozain AM, Peñagarikano O (2019). "Oxytocin as Treatment for Social Cognition, Not There Yet". Front Psychiatry. 10 930. doi:10.3389/fpsyt.2019.00930. PMC 6962227. PMID 31998152.
  65. ↑ Yamasue H (January 2024). "Is the efficacy of oxytocin for autism diminished at higher dosages or repeated doses?: Potential mechanisms and candidate solutions". Peptides. 171 171133. doi:10.1016/j.peptides.2023.171133. PMID 38072084.
  66. ↑ Boutaud AS (9 January 2022). "Oxytocin, from love potion to medicine". CNRS News. Retrieved 15 October 2025.
  67. ↑ Blackett PR, Seif SM, Altmiller DH, Robinson AG (1983). "Familial central diabetes insipidus: vasopressin and nicotine stimulated neurophysin deficiency with subnormal oxytocin and estrogen stimulated neurophysin". Am J Med Sci. 286 (3): 42–46. doi:10.1097/00000441-198311000-00007. PMID 6638059.
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