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Psychoneuroendocrinology (2011) xxx, xxx—xxx

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p s y n e u e n

REVIEW

A review of safety, side-effects and subjective
reactions to intranasal oxytocin in human research
Elayne MacDonald a, Mark R. Dadds a,*, John L. Brennan b,
Katrina Williams c, Florence Levy d, Avril J. Cauchi aaSchool of Psychology, University of New South Wales, Kensington, Sydney, NSW 2052, Australia
School of Psychiatry, University of New South Wales, Child and Adolescent Mental Health, Sydney Children’s Hospital,
Randwick, NSW 2031, AustraliacUniversity of Melbourne, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria 3052, AustraliadSchool of Psychiatry, University of New South Wales, Head, Child and Family East, Prince of Wales Hospital, Randwick, NSW 2031,
Australiab

Received 6 December 2010; received in revised form 6 February 2011; accepted 26 February 2011

KEYWORDS
Intranasal;
Oxytocin;
Safety;Side-effects;
Drug awareness;
Social behaviour

Summary
Background: Human research investigating the impact of intranasal oxytocin on psychologicalprocesses 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 and2010 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% wereparticipants 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 toscreen and exclude participants, monitor side effects and subject reactions. Side effects are notdifferent between oxytocin and placebo and participants are unable to accurately report onwhether they have received oxytocin and placebo. Three case reports of adverse reactions due tomisuse 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, andapplication with younger age groups, vulnerable populations, and with females.
# 2011 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: +61 2 9385 3538; fax: +61 2 9385 3641.
E-mail address: m.dadds@unsw.edu.au (M.R. Dadds).
0306-4530/$ — see front matter # 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.psyneuen.2011.02.015

Please cite this article in press as: MacDonald, E., et al., A review of safety, side-effects and subjective reactions to intranasal oxytocin inhuman research. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.02.015

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E. MacDonald et al.

Contents
1.

2.

3.

Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2. Data collection and analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Side-effects reported . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Strategies for monitoring, recording and reporting of side-effects/adverse reactions . . . . . . . . . . . . . . . . .
2.3. Exclusion criteria and concurrent use of medication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4. Pre-study instructions, administration procedures and subjective awareness of drug allocation . . . . . . . . .
2.5. Case reports of adverse reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dating back to the 1950s, oxytocin was the first peptide
hormone to be purified, synthesised, and made available
for pharmacologically defined studies (Du Vigneaud et al.,1953a,b). Synthetic oxytocin, also known as ‘pitocin’ and‘syntocinon’, is widely used for inducing labour, postpartum
care and for enhancing lactation (Gimpl, 2008). The administration of oxytocin in neonatal settings has been predominately via intravenous infusion, although nasal delivery isused in many countries for enhancing lactation. It is also
becoming increasingly accessible via the internet and is
produced regularly by research pharmacies for use withinclinical trials.
Comprehensive product information describing the pharmacology and possible side effects of intravenous infusion ofsynthetic oxytocin is accessible from Novartis pharmaceuticals (Novartis, 2011). Moreover, safety information regarding
adverse reactions is reported on regulatory databases worldwide, for example the Foods and Drugs Association in the
United States (Foods and Drugs Association, 2011) or the
Therapeutic Goods Association in Australia (Australian Government Department of Health and Aging Therapeutic Goods
Association, 2011). The European Medicines Agency lists all
individual European National regulatory authorities (European Medicines Agency, 2011). Specifically, Novartis reportsthat cardiovascular changes including tachycardia and bradycardia can be common. Nausea, vomiting and headaches
have also been reported to occur with intravenous infusion.
Less frequent reactions from intravenous infusion include
water intoxication and associated neonatal hyponatraemia,
skin rashes and anaphylactoid reactions (Novartis, 2011).
Safety information regarding the use of intranasal oxytocin is available from European countries such as the Netherlands where it is marketed for improving lactation (CBG
Medicines Evaluation Board, 2011). Product information fromthe Netherlands lists headaches, nausea and allergic dermatitis occurring rarely (>1/10,000, <1/1000) and abnormal
uterine contractions known to occur sometimes (1/1000,<1/100). Previous research studies investigating the role ofoxytocin in enhancing lactation have reported no safetyconcerns (Newton and Egli, 1958; Huntingford, 1961; Fewtrell et al., 2006). There are, however, special warnings forprolonged use of excessive doses together with large volumesof fluid as this has been known to cause water intoxication
with hyponatraemia (Hubner-Mayer, 1996).

000
000
000
000
000
000
000
000
000
000
000
000

Although detailed information is available regarding theoxytocin system (see Gimpl and Fahrenholz, 2001; Holmes
et al., 2003, 2004) the underlying mechanisms of reported
side-effects are not always clear. It is widely accepted thatthe rare adverse reaction of water intoxication following
oxytocin administration is thought to be related to the close
similarity in chemical structure between oxytocin and theantidiuretic hormone, vasopressin (Potter, 1964; Legros,
2001; Brunton et al., 2006). The pharmacokinetics of intranasal oxytocin are also not fully understood. It is known thatthe half-life when administered IV is about 3 min (Brunton
et al., 2006) and current evidence has found reliable central
effects when administering vasopressin nasal spray (Bornet al., 2002). In relation to general intranasal drug delivery
it has been suggested that pathways of action involve thevasculature, cerebrospinal fluid, and lymphatic system (Hanson and Frey, 2008).
In addition to peripheral affects, oxytocin also acts as aneurotransmitter in the brain influencing many aspects ofsocial behaviour (Landgraf and Neumann, 2004; Lee et al.,2009). The last two decades have witnessed a surge in
research investigating the application of oxytocin as amethod of enhancing psychological function in humans.
Research involving healthy adults has linked oxytocin witha range of effects such as reducing levels of anxiety (Heinrichs et al., 2003), and increasing levels of trust (Kosfeld
et al., 2005), gaze to the eyes (Guastella et al., 2008a), andaccurate emotion processing (Di Simplicio et al., 2009;
Fischer-Shofty et al., 2010). The vast majority of studies
investigating oxytocin and social behaviour in humans has
utilised nasal delivery as the administration method (MacDonald and MacDonald, 2010).
As noted above, current safety information regarding
the use of intranasal oxytocin with humans is largely
derived from usage by mothers to promote lactation. Thereis now an increased application of intranasal oxytocin inclinical trials for psychological problems, extending to use
with children and young people. However despite recommendations (Loke et al., 2007), there is no available review
into side effects and safety when used in these contexts.
Evidence from intravenous infusion of oxytocin suggests
possible cardiovascular effects and as previously reported
there have been cases of water intoxication from intranasal
oxytocin. Thus, it is essential to assess risk factors when

Please cite this article in press as: MacDonald, E., et al., A review of safety, side-effects and subjective reactions to intranasal oxytocin inhuman research. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.02.015

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A review of safety, side-effects and subjective reactions to intranasal oxytocin in human researchadministering to wider populations of differing participant
profiles.
This article provides a systematic review from researchstudies investigating the central effects of intranasal
oxytocin conducted between 1990 and 2010. Lactation
studies were excluded to enable a clear focus on research
investigating the central effects of intranasal oxytocin.
A systematic review of case reports documenting
adverse reactions following intranasal oxytocin was also
undertaken.

1. Method
1.1. Selection criteria
The search, retrieval and screening of studies were undertaken by the first author. Data sources included regulatory
websites, such as the Therapeutic Goods Association (TGA)and The Foods and Drugs Administration (FDA), Medline, theCochrane Library, Google scholar and a general internet
search. Key works used in this search included oxytocin,
pitocin, syntocinon, intranasal oxytocin, nasal spray oxytocin, adverse reactions oxytocin, and side-effects oxytocin.
A recent systematic review of intranasal oxytocin and its
prosocial effects in humans (MacDonald and MacDonald,2010) was included as a data source. Inclusion of studies
was restricted to clinical trials conducted between 1990
and 2010. There was no restriction on study design, suchthat we included randomised, crossover designs, double
blind and single blind. The rationale for the date restriction
was based on information provided from Fehm-Wolfsdorf
and Born’s (1991) review which examined 30 studies published from 1980 to 1990 where intranasal or intravenous
oxytocin and vasopressin was administered to humans. This
review noted that sample sizes in all 30 studies were small
and that there were some severe methodological shortcomings in the experiments. All case reports documenting
adverse reactions in humans following intranasal oxytocin
were included. No date restriction was imposed regarding
adverse reactions from intranasal oxytocin to enable comprehensive reporting of such events. Two studies involving
intravenous infusion of oxytocin with participants diagnosed with Autism Spectrum Disorders (ASD) were included
to enable a review of all safety data available when administering to this clinical population. There were 38 studies
identified for this review, all of which were peer-reviewed
and three case reports. There are no adverse reactions fromintranasal oxytocin listed on any of the regulatory databases. There were no prospective or retrospective observational studies found.

1.2. Data collection and analysis
A questionnaire was designed to gather specific information
regarding occurrence of side effects, subjective awareness,methods for monitoring, recording and reporting sideeffects, and general research methodology (available fromfirst author by request). This questionnaire was designed
based on recommendations from the 2007 Cochrane paper‘‘Systematic reviews of adverse effects: framework for astructured approach’’ (Loke et al., 2007).

3

One reviewer, the first author, read each journal article
and completed the questionnaire for each study from theavailable information. Each questionnaire was then sent tothe corresponding author of all 38 identified studies. The
authors were asked to check the questionnaire for accuracy,
add any additional information and return for inclusion in thisreview. Information was extracted from the questionnaires
and entered into an SPSS database and included; participantdetails; substance administration procedures; participant
perception of drug allocation; and monitoring, recording
and reporting of side-effect information. Of the three casestudies reporting adverse effects information was extracted
on the adverse reactions reported, participant details anddosage amounts.

2. Results
All studies collected data on side-effects for both oxytocin
and placebo; in the results below, the term ‘side effects’ isthus used with reference to both unless otherwise specified.
Questionnaires were returned from authors of 68% (26 out of38) of studies, no corrections where made although additional information was provided by 21 authors. This additional information included, a statement highlighting that noside-effects occurred (n = 13), details regarding side-effects
when they did occurred (n = 7); methods of monitoring anddetecting side-effects (n = 8); and participant subjective
effects (n = 14). The majority of studies reported no sideeffects resulting in positively skewed and leptokurtic data;thus, descriptive statistics and non-parametric tests wereconducted using SPSS 18 software to evaluate hypotheses.
There were 12 studies whereby authors did not confirm theaccuracy of the completed questionnaire or provide any
additional information. The following results, however,include analysis of all 38 studies.
Table 1 presents detailed information regarding each of
the 38 randomised controlled trials. In 76% of studies participants (N = 1345) were healthy adults aged between 20 and
30 years. In a total sample of 1529, 926 participants received
oxytocin of which 735 (79%) were male. There were ninestudies with a total of 182 participants that investigated theeffects of intranasal oxytocin on individuals with a developmental, medical or mental health disorder. Of these clinical
trials, 67% (N = 6) employed a within subject or crossover
research design. Only one study recruited young participants
under 20 years old, 16 participants diagnosed with ASD aged
12—19 years old (Guastella et al., 2010).

2.1. Side-effects reported
Overall, there were minimal side-effects reported from all 38
randomised controlled studies (a complete list is available
from the first author upon request). Table 2 presents information on side-effects reported by five or more participants.
Of 1529 participants, mild side-effects were reported by 18%(n = 279). A Spearman correlation showed that there wasalmost a one-to-one relationship between the frequency ofside-effects reported by oxytocin and placebo participants,
rs = .903, p < .001. Furthermore, a Wilcoxon signed rank test
indicated that there was no significant difference between
the frequency of side effects reported for oxytocin (Mdn = 0)

Please cite this article in press as: MacDonald, E., et al., A review of safety, side-effects and subjective reactions to intranasal oxytocin inhuman research. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.02.015

Study design andsubject status

Subjects (n)and gender
OT

Nasal spray

Total side
effects

AR Safety monitoring methods

Nasal spraysupplier

PL ingredients

OT

PL

Healthy: double blind with PL control
Bruins et al. (1992)
11 M

23 M

20 IU single

Not reported

0

0

0

Heinrichs et al. (2003)

19 M

37 M

24 IU single

0

0

19 M

38 M

24 IU single

0

0

0

Kosfeld et al. (2005)

89 M

178 M

24 IU single

0

0

0

Mood and physiological questionnaire;
Medical assessment; BP & HR
Mood questionnaire Medical
assessment
Mood questionnaire Medical
Assessment
Mood questionnaire

Zak et al. (2007)

34 M

68 M

40 IU single

All ingredients
minus OT
All ingredients
minus OT
All ingredients
minus OT
Normal saline0

Heinrichs et al. (2004)

0

0

0

Medical Assessment

Baumgartner et al. (2008)

25 M

48 M

24 IU single

0

0

35 M

69 M

24 IU single

13

12

0

Guastella et al. (2008a)

25 M

52 M

24 IU single

6

0

0

Petrovic et al. (2008)

15 M

27 M

32 IU single

0

0

0

Mood questionnaire; Medical
assessment
Mood questionnaire; Medical
assessment; self report; obs
Mood questionnaire; checklist;
Medical assessment
Checklist Medical Assessment

Unkelbach et al. (2008)

21 M

44 M

24 IU single

0

0

0

Mood questionnaire Medical Assessment

Rimmele et al. (2009)

22 M

41 M

24 IU single

0

0

0

Mood questionnaire

Singer et al. (2008)

10 M

20 M

32 IU single

All ingredients
minus OT
All ingredients
minus OT
All ingredients
minus OT.
All ingredients
minus OT
All ingredients
minus OT
All ingredients
minus OT
All ingredients
minus OT.

0

Guastella et al. (2008b)

Ingredients notreported
Syntocinon:
Novartis
Syntocinon
Novartis
Syntocinon
Novartis
Syntocinon
Novartis
Syntocinon
Novartis
Compounding
chemist
Syntocinon
Novartis
Syntocinon
Novartis
Compounding
chemist
Syntocinon
Novartis
Syntocinon
Novartis

000Ditzen et al. (2009)

24 M
24 F
14 M

47 M
47 F
29 M

40 IU single

Not reported

0

0

0

Not reported

6

6

0

36 M
17 F
23 M

71 M
33 F
46 M

0

0

13

18

0

48 M
48 F

All ingredients
minus OT
All ingredients
minus OT.
All ingredients
minus OT

0

25 M
26 F

Syntocinon
Novartis
Syntocinon
Novartis
Compounding
chemist
Syntocinon
Novartis
Syntocinon
Novartis

Mood and Physiological questionnaire;checklist; Medical Assessment;
self -report &obs
Physiological questionnaire;checklist Medical assessment; BP & HR
Mood questionnaire; checklist
Medical assessment
Mood questionnaire Medical assessment

41

31

0

Di Simplicio et al. (2009)
Guastella et al. (2009a)
Gamer et al. (2010)
Theodoridou et al. (2009)24 IU single
24 IU single
24 IU single
24 IU single

Mood questionnaire; Medical
assessment; BP & HR; self report; obs
Mood and physiological questionnaire;checklist; medical assessment; self
report & obs

E. MacDonald et al.

OT & PL Dosage
details+ Models

Safety data from 38 randomised controlled trials studying the effects of nasal delivery oxytocin in humans 1990—2010.

PNEC-1942; No. of Pages 13

4

Please cite this article in press as: MacDonald, E., et al., A review of safety, side-effects and subjective reactions to intranasal oxytocin inhuman research. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.02.015

Table 1

24 IU single dose Syntocinon:
Novartis a

Kirsch et al. (2005)

15 M

15 M

27 IU single

Meinlschmidt and Heim (2007) 19 M

19 M

24 IU single

Burri et al. (2008)

10 M

10 M

24 IU single

Keri and Benedek (2009)

10 F

10 F

24 IU single

Fischer-Shofty et al. (2010)

27 M

27 M

24 IU single

Domes et al. (2010)

16 F

16 F

24 IU single

Healthy: single blind PL control
Savaskan et al. (2008)
9M
9F
Domes et al. (2007b)
30 M

18 M
18 F
30 M

20 IU single

Domes et al. (2007a)

13 M

13 M

24 IU single

Shamay-Tsoory et al. (2009)

26 M
33 F
26 M

26 M
33 F
26 M

24 IU single

Buchheim et al. (2009)

Severe constipation: double blind PL control
Ohlsson et al. (2005)
29 F
59 F

24 IU single

24 IU single

40 IU 182
doses (twice
daily for13 weeks

Post traumatic stress disorder: double blind PL control
Pitman et al. (1993)
15 M
30 M
20 IU
ASD: crossover, double blind with placebo control
14 M
Hollander et al. (2003)
14 M
1F
1F
Hollander et al. (2007)
14 M
14 M
1F
1F
Guastella et al. (2010)
16 M
16 M
ASD: within sub double blind with PL control
Andari et al. (2010)
11 M
11 M
2F
2F

10 U/ml
10 U/ml
24 IU single

24 IU single

All ingredients in 13
nasal spray minus
active OT.
All ingredients0minus OT
Not reported
12

15

0

Checklist medical assessment

0

0

7

0

Mood questionnaire;
BP & HR self report; obs
Physiological questionnaire

All ingredients
minus OT
All ingredients
minus OT
Saline solution

0

0

0

Medical Assessment BP & HR

2

3

0

1

0

0

All ingredients
minus OT00

0

Checklist; Medical assessment
BP & HR; self report
Mood questionnaire Medical
assessment; obs
Mood questionnaire
Medical assessment

Syntocinon
Novartis
Syntocinon
Novartis
Syntocinon
Novartis
Syntocinon
Novartis
Syntocinon
Novartis

Isotonic
natriumchlorid
All ingredients
minus OT.
All ingredients
minus OT
Not reported

0

0

0

0

0

0

0

0

0

2

1

0

All ingredients
minus OT

00

0

Syntocinon
Novartis

All ingredients
minus OT

20

23

0

Physiological questionnaire
Medical Assessment; BP/HR;
self report; obs

Single dose:
pitocin

Saline000Medical Assessment; BP/HR,
self report; obs

Infusionover 4 hInfusionover 4 hCompounding
chemist

Not reported

8

3

0

Not reported

Not
Not
0
known Known530Medical Assessment;
BP & HR; self report; obs
Medical Assessment;
BP & HR; self report; obs
Side-effect checklist;
Medical Assessment

Syntocinon:
Novartis
Syntocinon
Novartis
Syntocinon
Novartis
Syntocinon
Novartis
Syntocinon
Novartis
Syntocinon
Novartis

Syntocinon:
Novartis

All ingredients
minus OT
Not reported

0

0

0

Medical Assessment BP &HR; self report & obs
Mood questionnaire
Medication assessment
Mood questionnaire
Medication assessment
Mood questionnaire Medical
Assessment; obs
Mood questionnaire; Medical
Assessment; Self report; obs

Mood questionnaire
Medical Assessment+ Models

35 M
39 F

PNEC-1942; No. of Pages 13

17 M
18 F

A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research

Please cite this article in press as: MacDonald, E., et al., A review of safety, side-effects and subjective reactions to intranasal oxytocin inhuman research. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.02.015

Alvares et al. (2010)5

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PNEC-1942; No. of Pages 13

ASD = autism spectrum disorder; SAD = social anxiety disorder; OCD = obsessive compulsive disorder.
a
Oxytocin spray ingredients syntocinon: oxytocin, sodium phosphate, citric acid, sodium chloride, sorbitol, glycerol and preservatives; PL = placebo; OT = oxytocin; AR = adverse reactions;
HR = heart rate; BP = blood pressure; Obs = observation.

Mood questionnaire Medical
Assessment067
All ingredients
minus OT
Syntocinon:
Novartis
25 M
12 M
SAD double blind PL
Guastella et al. (2009b)

24 IU(1 dose weekly
for 4 wks)

0
Not
Not
known known
Not reported
Syntocinon
Novartis
40 IU 28 doses:
4 daily over
7 days
4M
3F
OCD crossover, double blind PL
Epperson et al. (1996a)
4M
3F

2
0
SalineSyntocinon
Novartis
40 IU 28
doses:4 daily
over 7 days
Trichotillomania: crossover, double blind PL control
Epperson et al. (1996b)
2F
2F

OT

OT & PL Dosage
details

Nasal spraysupplier

PL ingredients

OT

PL

0

AR Safety monitoring methods
Total side
effects
Nasal spray
Subjects (n)and gender
Study design andsubject status

Table 1 (Continued )Mood questionnaire medical
assessment; HR/BP, self report

E. MacDonald et al.

Mood questionnaire BP & HR

6or placebo participants (Mdn = 0), z = .980, p = .327,
r = 0.16. The main categories of reported side-effects
included, increased calmness/euphoria, feeling more comfortable or having more energy reported by 5% (n = 78); lightheadedness, drowsiness and/or headache reported by 6%(n = 88) and nasal irritation, dry mouth/throat reported by
3% (n = 40). Three female participants in a study that investigated the long term effects of oxytocin in treating chronic
constipation (Ohlsson et al., 2005) reported severe vertigo on
the first day of treatment, one of which had received placebo. All three participants withdrew on the first day, noother information was available. Five participants in thisstudy also reported menstrual disturbances, four of those
had received placebo.

2.2. Strategies for monitoring, recording andreporting of side-effects/adverse reactions
All studies included in this review (N = 38) reported methods
for monitoring side-effects either in the review questionnaire
or in the published article. Monitoring methods were categorised under seven headings. Table 1 presents monitoring
methods used in each individual study. The most frequent
methods included medical assessment reported in 84% ofstudies (n = 32) and mood questionnaires, such as theMulti-dimensional Mood Questionnaire (Steyer et al., 1997)
and the positive and negative affect schedule (PANAS) (Watson et al., 1988), reported in 61% of studies (n = 23). Other
methods used were non-standardised questionnaires aimed
at gathering specific physiological/side-effect data (16%,n = 5), self-report and interviews (40%, n = 15), side-effectchecklists (24%, n = 9) and observation (29%, n = 11). Monitoring of blood pressure and heart rate was reported in 37%
of studies (n = 14).
The combination of monitoring methods varied between
studies. Of the 21 studies that found no side-effects, 48%(N = 10) reported using only standardised mood questionnaires combined with a medical assessment to monitor participants’ reactions. The remaining 52% of studies used aleast one monitored method specifically targeted at recording information on side-effects, such as self-report, observation, physical symptoms questionnaire and monitoring ofheart rate/blood pressure. Of the 16 studies that reported
the occurrence of side-effects, 94% monitored participants’reactions through a least one targeted method. A Mann—
Whitney-U test indicated there was a significantly higher
frequency of side-effects reported in studies that used targeted methods (Mdn = 0.50) compared to those that usedmood questionnaires and medical assessment (Mdn = 0),
U = 60.5, p = 0.002, r = 0.50. Consistent with analyses above
for the entire sample, however, there was no significant
difference between the mean number of side-effects
reported by participants who were administered oxytocin(Mdn = 0) or placebo (Mdn = 0), within studies using targeted
methods, z = 0.980, p = 0.327, r = 0.16.
There were a small number of studies (n = 6; 16%) thatused a medical practitioner to complete the medical assessment and 8% (n = 3) of studies reported having a medical
practitioner present throughout the trial. Four of the former
and one of the latter studies reported side effects, with nodifferences between oxytocin and placebo. These numbers of

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Total # oftimes
symptomreported

Onset

Duration

Total PL OT Unknown Immediate Within Unknown <4 hN
1st 2 hLight headedness/vertigo
Drowsiness/sleepy
Dry throat/mouth
Nasal irritation
Runny nose
Abdominal/stomach pain
Anxious/worried/uncomfortable
Euphoric/energised/uplifted
Calm, relaxed, comfortable
Headache

21
38
12
14
13
8
18
14
59

10
22
6
8
6
3
11
5
27
29

11
16
6
6
7
5
7
9
32
14

100%
53%
60%
100%
100%
100%
100%
15

47%
100%
40%
100%

100%
50%
60%
100%
67%
64%
93%

100%

42%
100%
40%
100%

Severity<24 h Mild8%

16% 16%76%
7%45%

Final outcome Participant status

Moderate Severe Symptoms
cleared

86%
100%
100%
100%
100%
100%
100%
100%
39% 100%

14%

100%
100%
100%
100%
100%
100%
100%
100%
100%
100%

Healthy ASD Othera
76%
95%
100%
40%
100%
13%
56%
100%
78%
52%

24%
5%
60%
13%
33%

74%
11%

13%
10%

21%
38%

PL = placebo; OT = oxytocin.
aOther category included: obsessive compulsive disorder; social anxiety disorder; Trichotillomania; severe constipation and post traumatic stress disorder. ASD = autism spectrum disorders+ Models

Symptom

PNEC-1942; No. of Pages 13

List of side-effects reported by 5 participants or more from all 38 randomised controlled studies.

A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research

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Table 2

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PNEC-1942; No. of Pages 138

E. MacDonald et al.

studies were too small to use for statistical comparisons,however they did not appear to differ from the other studies
in terms of the occurrence of side-effects for either oxytocinor placebo.
Reporting methods on side-effect information within the
published article for each of the 38 studies was also collated.
Of the 21 studies where side-effects did not occur methods ofreporting included; no information reported (n = 5; 13%);
generic summaries providing a brief statement outlining thatno side-effects occurred (n = 9; 24%) and generic summary
combined with a table or statistical analysis (n = 7; 18%). Of
the 16 studies where side-effects did occur reporting methods included; a detailed list specifying the type of sideeffects (n = 7; 18%), a generic summary which stated thatside-effects were minimal (n = 2; 5%), generic summary
combined with a table or statistical analysis (n = 6; 16%)
and no information (n = 1; 3%).

2.3. Exclusion criteria and concurrent use of
medication
The process and content of exclusion criteria was highly variable across studies. The most frequently reported exclusion
criteria was significant medical and mental illness (n = 34; 90%and n = 33; 87% consecutively); use of medication (n = 28;72%); drug and alcohol abuse (n = 25; 66%); neurological disorders, including seizure activity, (n = 21; 55) and pregnancy/
breastfeeding (37% — all studies with females participants).
Other less frequently reported exclusion criteria included;
endocrinological disorders (n = 11; 29%); heart disease andcardiovascular disorders (n = 7; 18%); kidney disease (n = 6;16%); and allergy to preservatives (n = 4; 10%).
Considering that safety data available from intravenous
infusion of oxytocin (TGA, 2010) points to the importance ofheart disease, cardiovascular problems, and neurologicalconditions such as epilepsy in reactions to oxytocin, we
tested the benefits of excluding participants with these
conditions. A Mann—Whitney-U test indicated that studies
that excluded participants with heart disease, cardiovascularor neurological disorders (Mdn = 0) did not report lower side
effects than studies who did not exclude these conditions(Mdn = 0), U = 149.0, p = 0.696, r = 0.06, and again, there
was no difference in side effects between oxytocin andplacebo in these exclusion groups.
Two (22%) of the nine studies that investigated the effects
of intranasal oxytocin on individuals with a developmental,
medical or mental health disorders accepted participants
who were regularly taking other medications. The first study
which investigated the impact of oxytocin with youth diagnosed with ASD (Guastella et al., 2010) included 2 participants who were stabilised for over 8 weeks on psychotropic
medications, including a 15 years old administering ecitalopram and paliperidone and a 17 years old stabilised on
fluoxetine, risperidone and desmopressin. Frequency ofside-effects reported by participants diagnosed with ASD(Mdn = 1.5) did not differ significantly from all other participants (Mdn = 0), U = 61.00, p = 0.840, r = 0.04. The second study examined intranasal oxytocin as an adjunct toexposure therapy for individuals with social anxiety andincluded four participants stabilised on anti-depressantsand three participants taking cardiovascular medications(Guastella et al., 2009b). Individual participant information
was not available. There was no difference in reporting ofside-effects, however, when participants received oxytocin
compared to placebo in both of these studies.

2.4. Pre-study instructions, administration
procedures and subjective awareness of drug
allocation
Information regarding pre-study instructions was available
for 63% (n = 24) of studies. These used similar instructions
prior to administering intranasal oxytocin: asking participants to abstain from caffeine, alcohol and nicotine 24 hprior (N = 9; 23%); 12 h prior (N = 5; 13%); or 2 h prior (N = 10;26%). In addition 39% (N = 15) of studies recommended
abstaining from food and drink, other than water, for 2 hprior the experiment. A Kruskal—Wallis test was conducted toevaluate differences among the three time points of abstaining from caffeine, alcohol and nicotine on the median changeof the frequency of side-effects reported in each study(N = 24). There were no significant differences in the frequency of side effects for the three types of pre-study
instructions, H(2) = 1.090, p = 0.602.
Table 3 presents information regarding administration
procedures for intranasal oxytocin from 36 studies, excluding
those that used intravenous infusion. The dosage amounts
range from 18 IU to 40 IU, with 78% of studies administering
20—24 IU. There were four studies that administered oxytocin over an extended time period, with 66% of participants
being female (Epperson et al., 1996a,b; Ohlsson et al., 2005;
Guastella et al., 2009b). Three of these studies included
clinical populations, with participants diagnosed with obsessive compulsive disorder (OCD) (N = 1) (Epperson et al.,1996a); social anxiety (N = 1) (Guastella et al., 2009b) andTrichotillomania (N = 1) (Epperson et al., 1996b). Of thesestudies, nine adults received four doses of 40 IU per day for
one week (Epperson et al., 1996a,b) and 12 adult males
received 24 IU once per week for four weeks (Guastella
et al., 2009b). The longest intranasal oxytocin administration
period was 13 weeks, with 40 IU administered twice daily to
29 female participants (30 received placebo) (Ohlsson et al.,2005). Participants in this study were questioned regarding
side-effects on a weekly basis. At the end of the 13 weeks atotal of 39 side-effects had been reported and were equallydistributed between oxytocin and placebo participants. The
total frequency of side-effects in this study was similar tostudies involving the short-term use of intranasal oxytocin.
Subjective perceptions of drug allocation was provided by
74% of studies (n = 28). Of the 28 studies, 93% reported thatparticipants (n = 1115) were unable to distinguish between
oxytocin and placebo, x2 (2, N = 28) = 44.64, p < 0.001. Twostudies (7%) reported that some participants were able toreliably detect when there had received oxytocin or placebo.
This included a study with n = 20 males who received a single
dose of either 24 IU oxytocin or placebo; 80—100% correctly
guessed drug allocation reportedly on the basis of degree of
sexual arousal after administration (Burri et al., 2008). The
second study involved 27 male participants, two of whomwere excluded from analysis because they reported during
debriefing that they were certain of what substance they hadreceived (Fischer-Shofty et al., 2010).

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A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research
Table 39Intranasal oxytocin: dosage and time between administration and experimental tasks.

Dosage andwaiting time

Total number ofstudies (N = 36)

Individual dose
18 IU
20—24 IU
27—32 IU
40 IU

1 (3%) a
28 (78%)3 (8%)
5 (14%)

Total number of administrations1
32 (89%)4
1 (3%)28
2 (5%)182
1 (3%)
Waiting time before exp. Tasks
0—30 min
7 (20%)
45—60 min26 (72%)
Unknown
1 (3%)
Not applicable
2 (5%)

Duration of
study (no. of weeks)

Administration
procedure

Total no. of participantsreceiving OT

1 dose on 1 day
1 dose per week
4 doses per day
2 doses per day

874
12
9
29

4 (N = 1)
1 (N = 3)
13 (N = 1)
1 day (N = 32)
4 (N = 1)
1 (N = 2)
13 (N = 1)

N = number of studies (2 studies administered oxytocin via intravenous infusion not included in table).
a
One study administered 18 IU to 11 participants aged 11—15 years old.

2.5. Case reports of adverse reactions
A literature search located three case reports of adverse
reactions (Seifer et al., 1985; Ansseau et al., 1987; HubnerMayer, 1996). Two of these reports were published in 1980s
and one in 1990s. One involved a 55 years old man participating in the first trial of intranasal oxytocin as a treatment forOCD (Ansseau et al., 1987). Intranasal oxytocin was administered three times per day for four weeks, with the daily dose
between 8.4 IU and 16.8 IU. The patient was reported todevelop psychotic symptoms (hallucinations and delusions)and significant memory loss assessed through the visual motor
gestalt test (Bender, 1938) and visual retention test (Benton,1976). Although the explanation for the adverse reaction was
unclear, there was a decrease in the patient’s plasma sodium
and osmolality levels, possibly an antidiuretic effect of longterm oxytocin administration.
The other case reports involved long-term use of intranasal oxytocin to facilitate lactation (Seifer et al., 1985;
Hubner-Mayer, 1996). In both cases the adverse reaction was
the development of severe water intoxication due to excessive water intake in combination with intranasal oxytocin.
One female was hospitalized for a viral illness and given alarge quantity of intravenous fluid, in combination withexcessive self-administration of intranasal oxytocin. The
second female was 33 years old and was administering oxytocin eight times or more a day (exact dose unknown) anddrinking 5 l of herbal tea daily. Following a reduction in thepatient’s fluid intake she fully recovered back to normal.

3. Discussion
This paper reviewed side effects and safety data on the use of
intranasal oxytocin in 38 controlled trials conducted over thelast 20 years. To date, 1529 participants have received intranasal oxytocin or placebo, of which only 279 reported mildside-effects. The main categories included: (1) increased
calmness/euphoria or more energy; (2) light headedness,
drowsiness and/or headache and (3) nasal irritation, drymouth/throat. No difference in the type, frequency andseverity of side effects reported by placebo versus oxytocin
recipients was found. Further, evidence from these trials
shows that the short-term use of intranasal oxytocin administered to humans, both males and females, in dosage
amounts up to 40 IU (per dose) has resulted in no adverse
reactions.
It was clear from these data that people are unable todifferentiate whether they have received placebo or oxytocin. This indicates that psychological and behavioural effects
of intranasal oxytocin are unlikely to be due to subjects’
awareness of physical sensations, relaxation levels, and othersensations cueing them to receipt of the hormone. It also
indicates that the subjective-awareness effects of oxytocin
are subtle if not non-existent, far from the hyped ‘love drug’intervention of web-based fame.
Preliminary evidence shows that the short-term use of
intranasal oxytocin is equally safe to use with clinical populations, such as individuals with ASD as with healthy adults.
There has only been one study, however, with children andyoung people and there continues to be a predominate
recruitment of male participants (Guastella et al., 2010).
Future research should direct attention to clinical populations, including female participants and younger populations.
To examine in more depth factors contributing to participant safety this review analysed both research exclusion
criteria and pre-study instructions. Firstly, there is no evidence supporting the requirement for participants to abstain
from substances such as caffeine and nicotine longer than 2 hprior to receiving intranasal oxytocin. This is, however, safety
orientated and does not consider factors such as the effectsof nicotine on oxytocin levels. Research, for example, has
shown that nicotine stimulates the production of adrenaline

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10which inhibits oxytocin release (Cross, 1955), this may
require consideration in terms of impact on experimental
outcomes.
The relationship between exclusion criteria and side
effects was more complex. Studies that excluded participants with conditions such as neurological disease, heartdisease and cardiovascular disorders did not significantly
enhance or decrease participant safety. Indeed, there was
no evidence to suggest that any particular exclusion criteriaenhanced safety or that certain participants were more at
risk than others. Furthermore, we found no effects associated with the clinical status of the screener or evidence tosupport the need for a medical practitioner during administration of intranasal oxytocin and experimental tasks.
These results speak to the overall safety of short-term useof intranasal oxytocin. Minimal side effects have beenreported and no difference has been found in side effects
reported by placebo versus oxytocin recipients. The conclusion could be drawn that there are no participant risk factors
associated with short-term use of intranasal oxytocin. The
data, however, do not provide details on the presence orabsence of specific exclusion criteria does not quantify how
many participants met those criteria, remained in or were
removed from the study, and reported side effects. Moreover,
it is highly likely that authors of the original studies not only
controlled for exclusion criteria based on possible interactions with oxytocin, but mainly with regard to their outcome
criteria. Thus, we would benefit from specific detailed
review of exclusion and inclusion criteria from future studies.
This will be particularly important when studies use longer
term administration of intranasal oxytocin.
Given that oxytocin can modify heart rate and cause
cardiovascular effects (Petersson, 2002; Rasmussen et al.,2004), suggesting that people with heart and cardiovascularconditions may be more vulnerable to the effects of oxytocin.
Moreover, the case reports of adverse reactions all related tolonger term use of intranasal oxytocin and excessive fluid
intake; an antidiuretic effect that could be associated withseizures (Ansseau et al., 1987; Seifer et al., 1985; HubnerMayer, 1996). Thus neurological disorders may be an extra
risk factor. In addition, allergies are always an importantconsideration and screening for allergies to preservatives
within the nasal spray is recommended. Overall, futurestudies should be explicit regarding their exclusion criteria
and expertise of the screener. We recommend a standard
general screening for allergies, significant heart disease,cardiovascular and neurological disorders.
The use of medication was an exclusion criteria applied
across the majority of studies. Only two studies in this review
recruited participants who were regularly taking other medication (Guastella et al., 2009b, 2010). No adverse effects
were reported from these studies and interestingly threeparticipants were taking cardiovascular medication. The
current data provide no evidence to suggest that participants
taking medication are at risk of adverse reactions to shortterm use of intranasal oxytocins; however, the range of
medications included in the current data was quite limited.
Future research including participants on a broader range of
medications is essential to clarify safety.
Processes of monitoring and reporting side-effect information hold the foundation for accurately assessing participant safety regarding pharmacological substances (Loke and

E. MacDonald et al.
Derry, 2001; Ernst and Pittler, 2001; Loke et al., 2007).
Targeted monitoring tools previously recommended include
the use of standardised tools for assessing side-effects, using
open-ended questions, interviews, observations and reporting detailed information in the published article (Loke andDerry, 2001). We found that studies using more targeted
monitoring tools reported a higher frequency of side-effects;
however, there were no adverse reactions is any study, allstudies reported no difference in frequency of side-effects
between oxytocin and placebo participants and there were
29% of studies using targeting monitoring that still reported
no side-effects.
Given that research with oxytocin is likely to expand into
increasingly vulnerable clinical samples, there will be anincreasing need for appropriate monitoring tools, such as
specific side-effect checklists or interviews to enable a comprehensive assessment of all physiological reactions. Monitoring methods and outcome information should be clearlyreporting in the published article for transparent distributionof safety data. Details regarding onset, duration, severity
and final outcome are all important for inclusion in the
published article. To assist this process there are some very
useful guidelines currently available to assist with this monitoring and reporting process (Loke and Derry, 2001). It would
also be useful for studies to collate information regarding theease at which participants administer intranasal oxytocin.
Information could include, whether participant presented
with any nasal congestion, if sneezing occurred, and anyother general observed details. This information is valuable
as it is difficult to assess the exact quantity of substance eachparticipant receives when administering intranasally compared to intravenous infusion.
Advancements into the clinical application of intranasal
oxytocin will require higher-dose longer term use of thissubstance, the safety of which remains unknown (MacDonald
and MacDonald, 2010). This review included one study thatadministered intranasal oxytocin over a 13 week time periodwith daily administration of 40 IU placebo or oxytocin to 59
females (Ohlsson et al., 2005). There were limited sideeffects reported, equally distributed between placebo andoxytocin. Nevertheless, there are concerns regarding safetywith females and the potential to cause electrolyte imbalances with chronic use (MacDonald and MacDonald, 2010).
This review presented three case reports of adverse reactions
linked to antidiuretic effects of oxytocin, two involved theexcessive misuse of intranasal oxytocin and water intake andone involved long-term use (Seifer et al., 1985; Ansseau
et al., 1987; Hubner-Mayer, 1996). Recommendations forhigher-dose longer term use include the implementation of
screening and exclusion criteria outlined above, appropriatemonitoring of participants through targeting methods andclear advice/information regarding appropriate fluid intake.
In conclusion, this article conducted a systematic review
of safety and side effects data in research investigating thecentral effects of intranasal oxytocin in humans. Evidence
from 38 randomised controlled trials, nine studies in vulnerable groups, showed no side-effects specific to oxytocin
versus placebo, and no adverse reactions. The most frequently reported sensation was a feeling of calmness, but
again this did not differ between oxytocin and placebo. The
short-term use of intranasal oxytocin (1) produces minimalside-effects (2) produces no detectable differences in side-

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A review of safety, side-effects and subjective reactions to intranasal oxytocin in human researcheffects reported by either placebo or oxytocin participants,(3) produces no detectable subjective changes in recipients
and, (4) preliminary is equally safe to use with vulnerable
populations as with healthy adults. A systematic search foradverse reactions found only three reported incidents, twodue to misuse of the nasal spray oxytocin and one linked withlong term application.
In order to safeguard further clinical applications of oxytocin, research should direct attention to the impact of
intranasal oxytocin when applied in higher-dosage longerterm, when used with younger individuals, different clinicalpopulations and concurrently with additional medications.
Such research goals will advance the current understandingof the pharmacokinetics, pharmacodynamics and generalsafety of intranasal oxytocin when administered to humans.

Role of the funding source
The authors did not receive funding for this project and so
there is no role to report.

Conflict of interest
The authors have no conflict of interest in providing animpartial report. The authors report no biomedical financial
interest. The authors are conducting a clinical trial investigating the impact of intranasal oxytocin with youth within
the autism spectrum.

Acknowledgements
We would like to thank the researchers who kindly provided
additional information regarding the monitoring and reporting of side-effects from their studies.

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