A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research
Abstract
Background Human research investigating the impact of intranasal oxytocin on psychological processes has accelerated over the last two decades. No review of side effects, subjective reactions and safety is available. Method A systematic review of 38 randomised controlled trials conducted between 1990 and 2010 that investigated the central effects of intranasal oxytocin was undertaken. A systematic search for reports of adverse reactions involving intranasal oxytocin was also completed. Results Since 1990, research trials have reported on N=1529 (79% male) of which 8% were participants with developmental or mental health difficulties. Dosages ranged from 18 to 40 IU, mainly in single doses but ranged up to 182 administrations. Diverse methods have been used to screen and exclude participants, monitor side effects and subject reactions. Side effects are not different between oxytocin and placebo and participants are unable to accurately report on whether they have received oxytocin and placebo. Three case reports of adverse reactions due to misuse and longer-term use of intranasal oxytocin were reported. Conclusions The evidence shows that intranasal oxytocin: (1) produces no detectable subjective changes in recipients, (2) produces no reliable side-effects, and (3) is not associated with adverse outcomes when delivered in doses of 18-40 IU for short term use in controlled research settings. Future research directions should include a focus on the dosage and duration of use, and application with younger age groups, vulnerable populations, and with females.
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The oxytocin dose (24 IU) and timing (40 min before fMRI) are the most commonly used in oxytocin administration studies to date.
“This timing and dosage are by far the most commonly used in oxytocin administration studies to date.25”
From Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women (2017) · cites this paper as [25]
Intranasal oxytocin produces no detectable subjective changes in recipients and no reliable side effects, and is not associated with adverse outcomes when delivered in doses of 18-40 IU for short-term use in controlled research settings.
“These authors reported that intranasal OT produces no detectable subjective changes in recipients and no reliable side effects, and that it is not associated with adverse outcomes when delivered in doses of 18–40 IU for short-term use in controlled research settings.”
From Oxytocin under opioid antagonism leads to supralinear enhancement of social attention (2017) · cites this paper as [68]
Acute oxytocin administration reveals few safety concerns.
“Acute OT administration reveals few safety concerns (17).”
From Chronic intranasal oxytocin causes long-term impairments in partner preference formation in male prairie voles (2013) · cites this paper as [17]
Acute intranasal OXT seems to produce no negative side effects in both healthy volunteers and subjects with developmental or mental health difficulties when delivered in doses of 18-40 IU.
“Acute intranasal OXT seems to produce no negative side effects in both healthy volunteers and subjects with developmental or mental health difficulties when delivered in doses of 18-40 IU (MacDonald et al, 2011).”
From Chronic and acute intranasal oxytocin produce divergent social effects in mice (2014) · cites this paper as MacDonald et al, 2011
The overall safety of single doses of intranasal oxytocin is well established.
“While the overall safety of single doses of intranasal oxytocin are well established (MacDonald et al., 2011)”
From Augmenting Prolonged Exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial (2018) · cites this paper as MacDonald et al., 2011
The dose and timing of medication administration is based on past research in our group and others.
“The dose and timing of medication administration is based on past research in our group and others (Cardoso et al., 2013; Flanagan et al., 2015; MacDonald et al., 2011).”
From Augmenting Prolonged Exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial (2018) · cites this paper as MacDonald et al., 2011
Oxytocin could enter the central nervous system through intracellular junctions of the olfactory epithelia to mimic endogenous oxytocin release.
“could enter the central nervous system through intracellular junctions of the olfactory epithelia 76 to mimic endogenous oxytocin release 77”
From Beyond the hype and hope: critical considerations for intranasal oxytocin research in autism spectrum disorder (2017) · cites this paper as [76]
The efficacy of oxytocin administration depends on dosage.
“it has been proposed that the efficacy of oxytocin administration depends on dosage.10, 12, 13”
From Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial (2016) · cites this paper as [13]
A dose of 40 IU oxytocin twice a day is comparable to the doses previously used in human studies investigating effects of multiple treatments of oxytocin and does not produce significant side effects or adverse outcomes.
“A dose of 40 IU twice a day is comparable to the doses previously used in human studies investigating effects of multiple treatments of oxytocin [61,62] and does not produce significant side effects or adverse outcomes [63].”
From Efficacy of oxytocin administration early after psychotrauma in preventing the development of PTSD: study protocol of a randomized controlled trial (2014) · cites this paper as [63]
Intranasal oxytocin administration reliably modulates neuropsychological functions in humans in the absence of relevant side effects.
“intranasal oxytocin administration has been shown to reliably modulate neuropsychological functions in a series of studies (2–5) in the absence of relevant side effects (16).”
From Oxytocin Reduces Reward-Driven Food Intake in Humans (2013) · cites this paper as [16]
Oxytocin administered intranasally has central actions with minimal side effects.
“Oxytocin administered intranasally has central actions with minimal side effects, and is appealing as a potential targeted therapy for obesity(15).”
From Oxytocin reduces caloric intake in men (2015) · cites this paper as [15]
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Kinetics and dose dependency of intranasal oxytocin effects on amygdala reactivity
Spengler, F. B., Schultz, J., Scheele, D., Essel, M., Maier, W., Heinrichs, M., & Hurlemann, R. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.04.015 · Cited by 229 · see citing works
Hollenstein, T., & Lougheed, J. P. (2013) · American Psychologist · doi:10.1037/a0033586 · Cited by 226 · see citing works
Oxytocin Reduces Reward-Driven Food Intake in Humans
Ott, V., Finlayson, G., Lehnert, H., Heitmann, B., Heinrichs, M., Born, J., & Hallschmid, M. (2013) · Diabetes · doi:10.2337/db13-0663 · Cited by 226 · see citing works
“This approach has been validated, among others, for vasopressin, a close homolog of oxytocin (14), and intranasal oxytocin administration has been shown to reliably modulate neuropsychological functions in a series of studies (2–5) in the absence of relevant side effects (16).”
BackgroundOxytocin reduces caloric intake in men
Lawson, E. A., Marengi, D. A., DeSanti, R. L., Holmes, T. M., Schoenfeld, D. A., & Tolley, C. J. (2015) · Obesity · doi:10.1002/oby.21069 · Cited by 208 · see citing works
“Oxytocin administered intranasally has central actions with minimal side effects and is appealing as a potential targeted therapy for obesity (15).”
BackgroundPaloyelis, Y., Doyle, O. M., Zelaya, F. O., Maltezos, S., Williams, S. C., Fotopoulou, A., & Howard, M. A. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.10.005 · Cited by 187 · see citing works
“, in 14% of studies until 2011 (66) and still being used (15)] to maximize power.”
Chronic and acute intranasal oxytocin produce divergent social effects in mice
Huang, H., Michetti, C., Busnelli, M., Managò, F., Sannino, S., Scheggia, D., Giancardo, L., Sona, D., Murino, V., Chini, B., et al. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2013.310 · Cited by 199 · see citing works
“Acute intranasal OXT seems to produce no negative side effects in both healthy volunteers and subjects with developmental or mental health difficulties when delivered in doses of 18–40 IU (MacDonald et al, 2011).”
BackgroundThe effects of oxytocin on eating behaviour and metabolism in humans
Lawson, E. A. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.115 · Cited by 196 · see citing works
Brain oxytocin: how puzzle stones from animal studies translate into psychiatry
Grinevich, V., & Neumann, I. D. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0802-9 · Cited by 189 · see citing works
“So far, neither reliable side effects nor adverse consequences have been reported in males or females, adults or children after acute IN application of OXT (versus placebo) at doses between 18 and 40 IU [160, 161].”
BackgroundSocial attention: a possible early indicator of efficacy in autism clinical trials
Dawson, G., Bernier, R., & Ring, R. H. (2012) · Journal of Neurodevelopmental Disorders · doi:10.1186/1866-1955-4-11 · Cited by 181 · see citing works
“These studies have largely involved the experimental use of intranasally administered OT, a synthetic preparation of the peptide previously developed and approved for use with non-CNS indications (for example lactation support) [73].”
BackgroundMacDonald, K., & Feifel, D. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00035 · Cited by 181 · see citing works
Advances in human oxytocin measurement: challenges and proposed solutions
Tabak, B. A., Leng, G., Szeto, A., Parker, K. J., Verbalis, J. G., Ziegler, T. E., Lee, M. R., Neumann, I. D., & Mendez, A. J. (2023) · Molecular Psychiatry · doi:10.1038/s41380-022-01719-z · Cited by 170 · see citing works
“OTHER METHODS OF STUDYING OXYTOCIN IN HUMAN SOCIAL PROCESSES Intranasal administration studies The potential use of oxytocin as a treatment for neuropsychiatric disorders, and the lack of reported side-effects [63], has led to numerous human studies involving intranasal oxytocin administration [1].”
BackgroundRoles of Oxytocin in Stress Responses, Allostasis and Resilience
Takayanagi, Y., & Onaka, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010150 · Cited by 164 · see citing works
Tachibana, M., Kagitani-Shimono, K., Mohri, I., Yamamoto, T., Sanefuji, W., Nakamura, A., Oishi, M., Kimura, T., Onaka, T., Ozono, K., et al. (2013) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2012.0048 · Cited by 151 · see citing works
“The vast majority of these previous studies almost exclusively involved single-dose administration, with the outcome measured in terms of improvements in social cognitive tasks (Green and Hollander 2010; MacDonald et al. 2011).”
Quintana, D. S., Alvares, G. A., Hickie, I. B., & Guastella, A. J. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.12.011 · Cited by 149 · see citing works
Oxytocin׳s role in anxiety: A critical appraisal
MacDonald, K., & Feifel, D. (2014) · Brain Research · doi:10.1016/j.brainres.2014.01.025 · Cited by 139 · see citing works
Effects of MDMA and intranasal oxytocin on social and emotional processing
Kirkpatrick, M. G., Lee, R., Wardle, M. C., Jacob, S., & de Wit, H. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.12 · Cited by 143 · see citing works
Elevated salivary levels of oxytocin persist more than 7 h after intranasal administration
van IJzendoorn, M. H., Bhandari, R., van der Veen, R., Grewen, K. M., & Bakermans-Kranenburg, M. J. (2012) · Frontiers in Neuroscience · doi:10.3389/fnins.2012.00174 · Cited by 137 · see citing works
MacDonald, K., MacDonald, T. M., Brüne, M., Lamb, K., Wilson, M. P., Golshan, S., & Feifel, D. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.05.014 · Cited by 140 · see citing works
“Another group of single-dose trials — the majority, in fact — describe no recognizable effects on subjective state (MacDonald et al., 2011).”
BackgroundMcCormack, S. E., Blevins, J. E., & Lawson, E. A. (2019) · Endocrine Reviews · doi:10.1210/endrev/bnz012 · Cited by 140 · see citing works
Oxytocin’s inhibitory effect on food intake is stronger in obese than normal-weight men
Thienel, M., Fritsche, A., Heinrichs, M., Peter, A., Ewers, M., Lehnert, H., Jan Born, A., & Hallschmid, M. (2016) · International Journal of Obesity · doi:10.1038/ijo.2016.149 · Cited by 139 · see citing works
Blevins, J. E., & Baskin, D. G. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.05.023 · Cited by 132 · see citing works
A double-blind randomized controlled trial of oxytocin nasal spray in Prader Willi syndrome
Einfeld, S. L., Smith, E., McGregor, I. S., Steinbeck, K., Taffe, J., Rice, L. J., Horstead, S. K., Rogers, N., Hodge, M. A., & Guastella, A. J. (2014) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.36653 · Cited by 131 · see citing works
Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques
Lee, M. R., Shnitko, T. A., Blue, S. W., Kaucher, A. V., Winchell, A. J., Erikson, D. W., Grant, K. A., & Leggio, L. (2020) · Nature Communications · doi:10.1038/s41467-020-15942-1 · Cited by 132 · see citing works
Martins, D., Mazibuko, N., Zelaya, F. O., Vasilakopoulou, S., Loveridge, J., Oates, A. E., Maltezos, S., Mehta, M. A., Wastling, S. J., Howard, M. A., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14845-5 · Cited by 130 · see citing works
Effects of single dose intranasal oxytocin on social cognition in schizophrenia
Davis, M. C., Lee, J., Horan, W. P., Clarke, A. D., McGee, M. R., Green, M. F., & Marder, S. R. (2013) · Schizophrenia Research · doi:10.1016/j.schres.2013.04.023 · Cited by 124 · see citing works
“In fact, no reliable side effects were noted in a review of 38 randomized controlled trials (MacDonald et al., 2011).”
Koch, S. B. J., van Zuiden, M., Nawijn, L., Frijling, J. L., Veltman, D. J., & Olff, M. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.11.018 · Cited by 123 · see citing works
“Besides its easy application, a recent review showed that short-term use of intranasal OT up to doses of 40 IU results in minimal side effects and is equally safe to use in psychiatric patients as in healthy individuals (MacDonald et al., 2011).”
BackgroundIntranasal oxytocin administration is reflected in human saliva
Weisman, O., Zagoory-Sharon, O., & Feldman, R. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.02.014 · Cited by 120 · see citing works
“The rare adverse reaction is thought to be related to the close similarity in chemical structure between OT and the hormone vasopressin (for a review of safety issues related to human OT administration research, see MacDonald et al., 2011).”
BackgroundOxytocin and postpartum depression: Delivering on what's known and what's not
Kim, S., Soeken, T. A., CROMER, S. J., Martinez, S. R., Hardy, L. R., & Strathearn, L. (2013) · Brain Research · doi:10.1016/j.brainres.2013.11.009 · Cited by 116 · see citing works
Cagna, F. D., Fusar‐Poli, L., Damiani, S., Rocchetti, M., Giovanna, G., Mori, A., Politi, P., & Brondino, N. (2019) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2019.17.1.1 · Cited by 118 · see citing works
Kosaka, H., Okamoto, Y., Munesue, T., Yamasue, H., Inohara, K., Fujioka, T., Anme, T., Orisaka, M., Ishitobi, M., Jung, M., et al. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.152 · Cited by 117 · see citing works
Flanagan, J. C., Sippel, L. M., Wahlquist, A., Moran-Santa Maria, M. M., & Back, S. E. (2018) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2017.12.014 · Cited by 117 · see citing works
“The dose and timing of medication administration is based on past research in our group and others (Cardoso et al., 2013; Flanagan et al., 2015; MacDonald et al., 2011).”
Oxytocin and Autism: A Systematic Review of Randomized Controlled Trials
Preti, A., Melis, M., Siddi, S., Vellante, M., Doneddu, G., & Fadda, R. (2014) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2013.0040 · Cited by 114 · see citing works
“In studies based on intravenous infusion of oxytocin in women to induce labor, for postpartum care, or to enhance lactation, cardiovascular changes (tachycardia or bradycardia), nausea, vomiting, and headaches, and, sometimes, water intoxication were reported to be common (MacDonald et al. 2011).”
InfluentialOxytocin in schizophrenia: a review of evidence for its therapeutic effects
MacDonald, K. S., & Feifel, D. (2011) · Acta Neuropsychiatrica · doi:10.1111/j.1601-5215.2011.00634.x · Cited by 111 · see citing works
“On the positive side, the extant research around the safety and tolerability of OT indicates that both short term [see (190) for recent review] and chronic use are both safe and tolerable in the populations and doses studied to date.”
BackgroundOxytocin in metabolic homeostasis: implications for obesity and diabetes management
Ding, C., Leow, M., & Magkos, F. (2018) · Obesity Reviews · doi:10.1111/obr.12757 · Cited by 101 · see citing works
“In addition, oxytocin administered intranasally has so far demonstrated significant central effects accompanied with an excellent safety profile with minimal side effects and adverse reactions (141).”
BackgroundThe interaction between the oxytocin and pain modulation in headache patients
Wang, Y.-L., Yuan, Y., Yang, J., Wang, C.-H., Pan, Y.-J., Lu, L., Wu, Y.-Q., Wang, D.-X., Lv, L.-X., Li, R.-R., et al. (2013) · Neuropeptides · doi:10.1016/j.npep.2012.12.003 · Cited by 107 · see citing works
Role of oxytocin signaling in the regulation of body weight
Blevins, J. E., & Ho, J. M. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9260-x · Cited by 108 · see citing works
Plasma oxytocin concentrations following MDMA or intranasal oxytocin in humans
Kirkpatrick, M. G., Francis, S. M., Lee, R., de Wit, H., & Jacob, S. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.04.006 · Cited by 106 · see citing works
“The doses of 20 and 40 IU IN-OT were chosen based on previous studies utilizing intranasally administered OT and the structurally similar neuropeptide, vasopressin (Bos et al., 2012; MacDonald et al., 2011).”
MethodOxytocin for the treatment of drug and alcohol use disorders
Lee, M. R., & Weerts, E. M. (2016) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000258 · Cited by 105 · see citing works
“In most human studies, participants could not discriminate between placebo and active drug (OT) (MacDonald et al., 2011).”
BackgroundMethodInfluentialA brief history of oxytocin and its role in modulating psychostimulant effects
Carson, D. S., Guastella, A. J., Taylor, E. R., & McGregor, I. S. (2013) · Journal of Psychopharmacology · doi:10.1177/0269881112473788 · Cited by 105 · see citing works
“For an overview of the safety, side-effects, and subjective reactions to intranasal OT see a recent review by MacDonald et al. (2011).”
BackgroundIntranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women
Bethlehem, R. A. I., Lombardo, M. V., Lai, M.-C., Auyeung, B., Crockford, S. K., Deakin, J., Soubramanian, S., Sule, A., Kundu, P., Voon, V, et al. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.72 · Cited by 96 · see citing works
Quintana, D. S., Westlye, L. T., Rustan, Ø. G., Tesli, N., Poppy, C. L., Smevik, H., Tesli, M., Røine, M., Mahmoud, R. A., Smerud, K. T., et al. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.93 · Cited by 103 · see citing works
Ellis, B. J., Horn, A. J., Carter, C. S., van IJzendoorn, M. H., & Bakermans‐Kranenburg, M. J. (2021) · Clinical Psychology Review · doi:10.1016/j.cpr.2021.101985 · Cited by 103 · see citing works
Intranasal oxytocin effects on social cognition: A critique
Evans, S. L., Dal Monte, O., Noble, P., & Averbeck, B. B. (2014) · Brain Research · doi:10.1016/j.brainres.2013.11.008 · Cited by 97 · see citing works
“This is confirmed by a systematic review of 38 randomised controlled trials of intranasal OT, which concluded that OT produces no detectable subjective changes in recipients (MacDonald et al., 2011).”
Oxytocin and stress-related disorders: neurobiological mechanisms and treatment opportunities
Sippel, L. M., Allington, C. E., Pietrzak, R. H., Harpaz-Rotem, I., Mayes, L. C., & Olff, M. (2017) · Chronic Stress · doi:10.1177/2470547016687996 · Cited by 99 · see citing works
“To date, most experimental research on OT has utilized intranasal administration (IN OT) given its convenience, noninvasiveness, and safety.(44) IN OT pharmacokinetics are not fully understood, and definitive evidence for how much OT, a large peptide, reaches target brain areas via IN delivery is lacking;(23) however,…”
BackgroundCD38 and its role in oxytocin secretion and social behavior
Higashida, H., Yokoyama, S., Kikuchi, M., & Munesue, T. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.12.011 · Cited by 98 · see citing works
“(Yamasue et al., 2009; Ebstein et al., 2009: Munesue et al., 2010; MacDonald et al., 2011; Bartz et al., 2011).”
Targeting the Oxytocin System to Treat Addictive Disorders: Rationale and Progress to Date
Lee, M. R., Rohn, M. C. H., Tanda, G., & Leggio, L. (2016) · CNS Drugs · doi:10.1007/s40263-016-0313-z · Cited by 97 · see citing works
“Doses that are associated with CPP are much higher than that used in humans [97], and in most human studies, subjects cannot discern that they have received the drug [98].”
Rault, J.-L., Carter, C. S., Garner, J. P., Marchant, J. N., Richert, B. T., & Lay, D. C. (2013) · Physiology & Behavior · doi:10.1016/j.physbeh.2013.02.007 · Cited by 94 · see citing works
“A recent review suggested that intranasal OT produces no side-effects for short term use [67].”
Calcagnoli, F., Kreutzmann, J. C., de Boer, S. F., Althaus, M., & Koolhaas, J. M. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.09.019 · Cited by 92 · see citing works
Alvares, G. A., Quintana, D. S., & Whitehouse, A. J. O. (2017) · Autism Research · doi:10.1002/aur.1692 · Cited by 91 · see citing works
“Safety outcomes have been recently reported from a modified maximum-tolerated-dose study in ASD [Anagnostou et al., 2014], confirming the mild to moderate side effects reported in adult studies [MacDonald et al., 2011], however, the open-label design limits interpretations about these reports.”
Oxytocin and the modulation of pain experience: Implications for chronic pain management
Tracy, L. M., Georgiou‐Karistianis, N., Gibson, S. J., & Giummarra, M. J. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.04.013 · Cited by 89 · see citing works
Mitchell, J. M., Arcuni, P. A., Weinstein, D., & Woolley, J. D. (2016) · Journal of Addiction Medicine · doi:10.1097/adm.0000000000000213 · Cited by 82 · see citing works
“Additionally, to assess for potential subjective side effects of oxytocin, subjects were asked whether they thought they received oxytocin or placebo at the end of each experimental session (MacDonald et al., 2011).”
BackgroundResultHart, L. A. (2014) · Anthrozoös · doi:10.2752/089279314x14117221853976 · Cited by 87 · see citing works
“This naturalistic therapy bears merit more than administering oxytocin from the pharmacy, an approach that is also being tried (review: MacDonald et al. 2011).”
BackgroundKim, Y., Eom, J.-S., Yang, J., Kang, J., & Treasure, J. L. (2015) · PLoS ONE · doi:10.1371/journal.pone.0137514 · Cited by 85 · see citing works
Nose-to-Brain Delivery of Therapeutic Peptides as Nasal Aerosols
Alabsi, W., Eedara, B. B., Encinas-Basurto, D., Polt, R. L., & Mansour, H. M. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14091870 · Cited by 84 · see citing works
van IJzendoorn, M. H., Huffmeijer, R., Alink, L. R. A., Bakermans-Kranenburg, M. J., & Tops, M. (2011) · Frontiers in Psychology · doi:10.3389/fpsyg.2011.00258 · Cited by 83 · see citing works
“…our study involved females and thus contributes to filling a remarkable and unfortunate gap, given that the majority of research trials with oxytocin administration involve males (79%, MacDonald et al., 2011) and that results for males may not be generalizable to females (Bos et al., in press).”
ResultFrijling, J. L. (2017) · European Journal of Psychotraumatology · doi:10.1080/20008198.2017.1302652 · Cited by 84 · see citing works
Kim, Y., Kim, C., Cardi, V., Eom, J., Seong, Y., & Treasure, J. L. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.02.019 · Cited by 82 · see citing works
“It was designed that each oxytocin spray would deliver 40 IU of oxytocin, based on a recent review which reported that the short-term use of intranasal OTof up to 40 IU (per dose) in humans, both males and females, resulted in no detectable subjective changes in controlled research settings (MacDonald et al., 2011).”
MethodIntrapartum Synthetic Oxytocin and Its Effects on Maternal Well‐Being at 2 Months Postpartum
Gu, V., Feeley, N., Gold, I., Hayton, B. C., Robins, S., MacKinnon, A., Samuel, S., Carter, C. S., & Zelkowitz, P. (2015) · Birth · doi:10.1111/birt.12198 · Cited by 81 · see citing works
Oliva, J. L., Rault, J., Appleton, B., & Lill, A. (2015) · Animal Cognition · doi:10.1007/s10071-015-0843-7 · Cited by 80 · see citing works
Muttenthaler, M., Andersson, Å., Vetter, I., Menon, R., Busnelli, M., Ragnarsson, L. K. N., Bergmayr, C., Arrowsmith, S., Deuis, J. R., Chiu, H. S., et al. (2017) · Science Signaling · doi:10.1126/scisignal.aan3398 · Cited by 79 · see citing works
Russell, J. D., Maguire, S., Hunt, G. E., Kesby, A., Suraev, A. S., Stuart, J. M., Booth, J., & McGregor, I. S. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2017.10.014 · Cited by 75 · see citing works
Higashida, H., Yokoyama, S., Huang, J., Liu, L., Ma, W., Akther, S., Higashida, C., Kikuchi, M., Minabe, Y., & Munesue, T. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.01.030 · Cited by 74 · see citing works
“Nasal administration of OXT can increase social contact without severe aversive effects (Yamasue et al., 2009; Ebstein et al., 2009; Munesue et al., 2010; MacDonald et al., 2012).”
Oxytocin administration alters HPA reactivity in the context of parent–infant interaction
Weisman, O., Zagoory-Sharon, O., & Feldman, R. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.06.006 · Cited by 70 · see citing works
“…children’s stressrelated physiology and behavior within the parental context, future studies should examine OT effects in a dose-dependent manner (MacDonald et al., 2011; Goldman et al., 2011); test the effects of single versus multiple administration (MacDonald and Feifel, 2013); include both…”
Striepens, N., Matusch, A., Kendrick, K. M., Mihov, Y., Elmenhorst, D., Becker, B., Lang, M., Coenen, H. H., Maier, W., Hurlemann, R., et al. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.09.026 · Cited by 71 · see citing works
“Most of the human studies showing behavioral and brain effects of OXT have applied a single 24 IU OXT dose followed by measurements starting 45 min later (MacDonald et al., 2011; Striepens et al., 2011; Yamasue et al., 2012).”
BackgroundHormones, Stress, and Cognition: The Effects of Glucocorticoids and Oxytocin on Memory
Wirth, M. M. (2014) · Adaptive Human Behavior and Physiology · doi:10.1007/s40750-014-0010-4 · Cited by 72 · see citing works
“This work has been facilitated by the availability of oxytocin nasal spray, a safe and noninvasive way to elevate oxytocin levels in the human brain (MacDonald et al., 2011)3.”
BackgroundDeMayo, M. M., Song, Y. J. C., Hickie, I. B., & Guastella, A. J. (2017) · Pediatric Drugs · doi:10.1007/s40272-017-0248-y · Cited by 71 · see citing works
Oxytocin and Vasopressin Receptor Gene Polymorphisms: Role in Social and Psychiatric Traits
Aspé-Sánchez, M., Moreno, M., Rivera, M. I., Rossi, A., & Ewer, J. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00510 · Cited by 68 · see citing works
Oxytocin Improves β-Cell Responsivity and Glucose Tolerance in Healthy Men
Klement, J., Ott, V., Rapp, K., Brede, S., Piccinini, F., Cobelli, C., Lehnert, H., & Hallschmid, M. (2016) · Diabetes · doi:10.2337/db16-0569 · Cited by 68 · see citing works
“In conjunction with the promising oxytocin-induced improvements of obesityrelated diabetic phenotypes observed in other studies (14–16) and the favorable side effect profile of this neuropeptide (43), our findings support the idea of testing oxytocin in a clinical context.”
ResultSex- and context-dependent effects of oxytocin on social sharing
Ma, X., Zhao, W., Luo, R., Zhou, F., Geng, Y., Xu, L., Gao, Z., Zheng, X., Becker, B., & Kendrick, K. M. (2018) · NeuroImage · doi:10.1016/j.neuroimage.2018.08.004 · Cited by 64 · see citing works
Pharmacological enhancement of exposure-based treatment in PTSD: a qualitative review
de Kleine, R. A., ROTHBAUM, B. O., & van Minnen, A. (2013) · European Journal of Psychotraumatology · doi:10.3402/ejpt.v4i0.21626 · Cited by 67 · see citing works
“The alternative of oxytocin enhancement may have better clinical utility, considering that it is easily administered e.g., as a nasal spray and produces little adverse effects (MacDonald et al., 2011).”
Oxytocin - A Multifunctional Analgesic for Chronic Deep Tissue Pain
Goodin, B. R., Ness, T. J., & Robbins, M. T. (2014) · Current Pharmaceutical Design · doi:10.2174/1381612820666141027111843 · Cited by 66 · see citing works
“Extensive clinical use in experimental studies has identified few toxicities of OXY treatment [41] apart from those associated with accidental overdose [42, 43] or use with co-morbidities such as gastroparesis [44].”
BackgroundBuemann, B., & Uvnäs-Moberg, K. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.109597 · Cited by 66 · see citing works
The Roles of Oxytocin and CD38 in Social or Parental Behaviors
Lopatina, O. L., Ивановна, И. А., Salmina, A. B., & Higashida, H. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2012.00182 · Cited by 64 · see citing works
“…in humans showed that nasal infusion of OXT increases trust (Kosfeld et al., 2005; Baumgartner et al., 2008), mindreading (Domes et al., 2007), and generosity (Zak et al., 2007), indicating an important role of OXT in human social behavior (MacDonald and MacDonald, 2010; MacDonald et al., 2011).”
BackgroundHorta, M., Kaylor, K., Feifel, D., & Ebner, N. C. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.10.012 · Cited by 62 · see citing works
“The promise of OT administration as an investigative and therapeutic tool has also been supported by the minimal and inconsistent side effects observed in humans, primarily when administered intranasally and in single doses (MacDonald et al., 2011).”
BackgroundInfluentialPaloyelis, Y., Krahé, C., Maltezos, S., Williams, S. C., Howard, M. A., & Fotopoulou, A. (2016) · Journal of Neuroendocrinology · doi:10.1111/jne.12347 · Cited by 61 · see citing works
Effects of a 10-day oxytocin trial in older adults on health and well-being
Barraza, J. A., Grewal, N. S., Ropacki, S., Perez, P., Gonzalez, A., & Zak, P. J. (2013) · Experimental and Clinical Psychopharmacology · doi:10.1037/a0031581 · Cited by 61 · see citing works
“Experimental studies of the effects of intranasal OT have been conducted in adults with doses between 20 and 264 IU, producing no significant adverse side effects in clinical and healthy populations (MacDonald et al., 2011).”
BackgroundOxytocin as Treatment for Social Cognition, Not There Yet
Erdozain, A. M., & Peñagarikano, O. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00930 · Cited by 61 · see citing works
“OXT and the results support OXT as well tolerated and safe, side-effects not differing between OXT and placebo (69, 70).”
ResultRash, J. A., & Campbell, T. S. (2014) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000068 · Cited by 58 · see citing works
“(36) reviewed safety, adverse effects, and subjective reactions to intranasal OT reported in 38 random controlled trials reporting on 1529 participants (78% male).”
BackgroundMethodZhao, Z., Ma, X., Geng, Y., Zhao, W., Zhou, F., Wang, J., Markett, S. A., Biswal, B. B., Ma, Y., Kendrick, K. M., et al. (2018) · NeuroImage · doi:10.1016/j.neuroimage.2018.09.067 · Cited by 55 · see citing works
“However, the basal ganglia networks don't exhibit a strong sensitivity to sleep (Tagliazucchi and Laufs, 2014), and meta-analytic data argues against effects of OXT on drowsiness (MacDonald et al., 2011).”
BackgroundFrijling, J. L., van Zuiden, M., Koch, S. B., Nawijn, L., Goslings, J. C., Luitse, J. S., Biesheuvel, T. H., Honig, A., Bakker, F. C., Denys, D., et al. (2014) · BMC Psychiatry · doi:10.1186/1471-244x-14-92 · Cited by 59 · see citing works
“A dose of 40 IU twice a day is comparable to the doses previously used in human studies investigating effects of multiple treatments of oxytocin [61,62] and does not produce significant side effects or adverse outcomes [63].”
MethodKrüeger, F., Parasuraman, R., Moody, L. N., Twieg, P., de Visser, E. J., McCabe, K., O’Hara, M., & Lee, M. R. (2012) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nss026 · Cited by 58 · see citing works
Current findings on the role of oxytocin in the regulation of food intake
Spetter, M. S., & Hallschmid, M. (2017) · Physiology & Behavior · doi:10.1016/j.physbeh.2017.03.007 · Cited by 58 · see citing works
Rupp, H. A., James, T. W., Ketterson, E. D., Sengelaub, D. R., Ditzen, B., & Heiman, J. R. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2012.10.007 · Cited by 57 · see citing works
“Participants received an absolute dose of 24 IU, based on previous studies (Ditzen et al., 2009; Heinrichs et al., 2001; Kirsch et al., 2005; MacDonald et al., 2011).”
Oxytocin under opioid antagonism leads to supralinear enhancement of social attention
Dal Monte, O., Piva, M., Anderson, K. M., Tringides, M., Holmes, A. J., & Chang, S. W. C. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1702725114 · Cited by 55 · see citing works
Olszewski, P. K., Klockars, A., & Levine, A. S. (2016) · Journal of Neuroendocrinology · doi:10.1111/jne.12376 · Cited by 56 · see citing works
Sack, M., Spieler, D., Wizelman, L., Epple, G., Stich, J., Zaba, M., & Schmidt, U. (2017) · BMC Medicine · doi:10.1186/s12916-017-0801-0 · Cited by 57 · see citing works
“1115) in response to oxytocin treatment [31].”
Bartholomeusz, C. F., Ganella, E. P., Labuschagne, I., Bousman, C., & Pantelis, C. (2015) · Schizophrenia Research · doi:10.1016/j.schres.2015.06.007 · Cited by 54 · see citing works
“Given that short-term OXT treatment is well-tolerated, has no real side-effects when delivered in doses of 18–40 IU (MacDonald et al., 2011), and has repeatedly been shown to influence brain and behaviour in healthy individuals, it would appear that OXT research in psychosis is set to grow.”
Oxytocin and opioid addiction revisited: old drug, new applications
Zanos, P., Georgiou, P., Weber, C. D., Robinson, F., Kouimtsidis, C., Niforooshan, R., & Bailey, A. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13757 · Cited by 54 · see citing works
Oxytocin, Tolerance, and the Dark Side of Addiction
Pedersen, C. A. (2017) · International review of neurobiology · doi:10.1016/bs.irn.2017.08.003 · Cited by 58 · see citing works
Frantz, M., Pellissier, L. P., Pflimlin, E., Loison, S., Gandía, J., MARSOL, C., Durroux, T., Mouillac, B., Becker, J. A. J., Merrer, J. L., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00697 · Cited by 57 · see citing works
- Authors
- MacDonald, E., Dadds, M. R., Brennan, J. L., Williams, K., Levy, F., & Cauchi, A. J.
- Affiliations
- UNSW Sydney (AU)
- Royal Children's Hospital (AU)
- Corresponding author
- Dadds, Mark R.
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 36
- Issue
- 8
- Pages
- 1114-1126
- ISSN
- 0306-4530 (ISSN-L)
- OpenAlex
- W2057967199
- Cited by
- 352
- References
- 73
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 13 · 2023: 19 · 2022: 22 · 2021: 22 · 2020: 32 · 2019: 27 · 2018: 24 · 2017: 32 · 2016: 26 · 2015: 22 · 2014: 34 · 2013: 33 · 2012: 16
- FWCI
- 37.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- intranasal oxytocin, drug safety, adverse effects, subjective reactions, placebo effect, vulnerable populations, research ethics
- MeSH terms
- Administration, Intranasal, Female, Humans, Human Experimentation, Male, Mental Processes
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