**2. Effectiveness of intranasally administered OT on social cognition and prosocial behaviors in healthy adults**

We consider that reciprocal interaction with others would go through the processes of selfconsciousness as a construct deeply embedded in human society, social cognition, and prosocial behavior. Self-consciousness (i.e., self-representation or self-reference) may be a key concept in considering the psychopathology of ASD [20]. Can individuals with attenuated self-consciousness distinguish self from others in a social context? Children and adolescents with ASD made fewer statements classified as the social not but physical, active and psychological category compared to non-ASD subjects [21]. Typical interaction with others may be realized only under the conditions of typical self-consciousness. While biological investigations of self-consciousness have been performed using functional magnetic resonance imaging in ASD and healthy individuals [22, 23], the effects of OT on self-consciousness in humans remain unclear.

Social cognition implies important factors underlying not just face-to-face exchanges with others but also even circumstances alone in a crowd. People may wonder "Who is he?" "What has my daughter been thinking?" or "That person is watching me". All of this corresponds to social cognition. Prosocial behavior implies the favorable or unfavorable impressions that a person has toward others, and the following actions based on these impressions. People are impressed by others' behaviors and may bring these impressions into actions: "He looks trustworthy. I will consult with him about which course to take after graduation," "I hate people who discriminate against the weak. So, I will not talk to him." These are prosocial behaviors.

There have been many studies regarding the effects of OT on social cognition and prosocial behavior in healthy adults since the pioneering study by Kosfeld et al. [24] Interest in OT has increased due to the positive results obtained: e.g., strengthening of memory for faces [25] and increased emotional empathy [26] in social cognition, increased generosity [27] and trust [28] in prosociality. However, the results are inconsistent on closer inspection (for details, see [29]). For example, 259 healthy students participated in a study regarding the effects of OT on cooperative behavior in a randomized, double-blind, placebo-controlled design [30]. Participants played two economic games, which were a Coordination Game with strong incentives to cooperate and a Prisoner's Dilemma game with weak cooperative incentives, after one-half of them talked together and the other half spoke to no-one. The former group receiving OT showed more cooperation only in the Coordination Game than participants receiving placebo. However, the latter group receiving OT showed less cooperation only in the Cooperation Game than participants receiving placebo. Prosocial behaviors on receiving OT proceeded in the opposite directions according to whether social information was presented previously.

Based on the review of Bartz et al. [29], of 14 studies investigating social cognition, nine (69.2%) showed that OT exerted a significant main effect on the outcome compared to placebo (Table 1). Eight of these nine studies suggested that the effect of OT was significantly modulated by situational differences or individual factors. However, there was a marginal trend between the distributions of two categorical variables of OT effect and modulated OT effect (Fisher's exact test, *P* = 0.095).


Modulated oxytocin effect Fisher's exact test

Is Intranasal Administration of Oxytocin Effective for Social Impairments in Autism Spectrum Disorder? 99

Of 32 studies investigating prosocial behavior, 17 (53.1%) showed that OT exerted a significant main effect on the outcome compared to placebo. Five of these 17 studies suggested that the effect of OT was significantly modulated by situational differences or individual factors. On the other hand, 12 of 15 studies without a significant main effect of OT were significantly modulated by situational differences or individual factors. The distribution of two categorical variables was significantly different (*P* = 0.006). The more these factors affect study participants, the less the effects of OT emerge in them. That is, the effects of OT on sociality, especially prosocial behavior, may be affected by external factors in addition to the function of OT itself and, moreover, external factors may show paradoxical effects. For example, 66 healthy adults participated in a money game, in which they rated their emotions (envy and gloating) toward their opponents when they gained more or less money, in double-blind, placebo-controlled, with-in subject design [31]. Interestingly, OT increased the envy ratings when the participant gained less money and the

While early research that suggested effectiveness of OT in psychiatric diseases such as social anxiety disorder and ASD generated considerable enthusiasm, the reasons for the inconsistent and paradoxical results of OT on sociality in healthy humans remain unresolved. However, the pathophysiology of ASD has not yet been elucidated and no effective treatments for social impairments in ASD exist. It would be useful to investigate

**3. Effectiveness of intranasally or intravenously administered OT in ASD** 

Four randomized, double-blind, placebo-controlled trials of short-term OT administration in subjects with high-functioning ASD have been published since 2003 (Table 2) [32-35].

32 15 14 19-56 74-110 Intravenously 10U Repetitive behavior

33 15 14 19-56 74-110 Intravenously 10U Comprehension of

34 13 11 17-39 unknown Intranasally 24 IU Social ball tossing

**Table 2.** Randomized, double-blind, placebo-controlled trials of short-term oxytocin administration in

The designs were naturally different between these studies in terms of age and gender of participants, medication methods, doses of OT and outcomes, so no conclusions could be drawn regarding the treatment of ASD patients based on a single-dose design. However, OT

Medication method

Oxytocin dose

IU

Outcomes

scale

affective speech

game

Reading the Mind in the Eyes-Revised

Intelligence quotient

35 16 16 12-19 unknown Intranasally 18 or 24

gloating ratings when they gained more money compared to placebo.

whether OT can improve the core symptoms of ASD.

Age (years)

subjects with high-functioning autism spectrum disorder

**subjects** 

Reference number

n Male gender

**Table 1.** Relationship between oxytocin effect and modulated oxytocin effect (designed according to [25])

Of 32 studies investigating prosocial behavior, 17 (53.1%) showed that OT exerted a significant main effect on the outcome compared to placebo. Five of these 17 studies suggested that the effect of OT was significantly modulated by situational differences or individual factors. On the other hand, 12 of 15 studies without a significant main effect of OT were significantly modulated by situational differences or individual factors. The distribution of two categorical variables was significantly different (*P* = 0.006). The more these factors affect study participants, the less the effects of OT emerge in them. That is, the effects of OT on sociality, especially prosocial behavior, may be affected by external factors in addition to the function of OT itself and, moreover, external factors may show paradoxical effects. For example, 66 healthy adults participated in a money game, in which they rated their emotions (envy and gloating) toward their opponents when they gained more or less money, in double-blind, placebo-controlled, with-in subject design [31]. Interestingly, OT increased the envy ratings when the participant gained less money and the gloating ratings when they gained more money compared to placebo.

98 Neuroendocrinology and Behavior

These are prosocial behaviors.

information was presented previously.

Social

to [25])

modulated OT effect (Fisher's exact test, *P* = 0.095).

Yes No

Social cognition implies important factors underlying not just face-to-face exchanges with others but also even circumstances alone in a crowd. People may wonder "Who is he?" "What has my daughter been thinking?" or "That person is watching me". All of this corresponds to social cognition. Prosocial behavior implies the favorable or unfavorable impressions that a person has toward others, and the following actions based on these impressions. People are impressed by others' behaviors and may bring these impressions into actions: "He looks trustworthy. I will consult with him about which course to take after graduation," "I hate people who discriminate against the weak. So, I will not talk to him."

There have been many studies regarding the effects of OT on social cognition and prosocial behavior in healthy adults since the pioneering study by Kosfeld et al. [24] Interest in OT has increased due to the positive results obtained: e.g., strengthening of memory for faces [25] and increased emotional empathy [26] in social cognition, increased generosity [27] and trust [28] in prosociality. However, the results are inconsistent on closer inspection (for details, see [29]). For example, 259 healthy students participated in a study regarding the effects of OT on cooperative behavior in a randomized, double-blind, placebo-controlled design [30]. Participants played two economic games, which were a Coordination Game with strong incentives to cooperate and a Prisoner's Dilemma game with weak cooperative incentives, after one-half of them talked together and the other half spoke to no-one. The former group receiving OT showed more cooperation only in the Coordination Game than participants receiving placebo. However, the latter group receiving OT showed less cooperation only in the Cooperation Game than participants receiving placebo. Prosocial behaviors on receiving OT proceeded in the opposite directions according to whether social

Based on the review of Bartz et al. [29], of 14 studies investigating social cognition, nine (69.2%) showed that OT exerted a significant main effect on the outcome compared to placebo (Table 1). Eight of these nine studies suggested that the effect of OT was significantly modulated by situational differences or individual factors. However, there was a marginal trend between the distributions of two categorical variables of OT effect and

cognition Oxytocin effect Significant 8 1 P = 0.095

Prosociality Oxytocin effect Significant 5 12 P = 0.006

**Table 1.** Relationship between oxytocin effect and modulated oxytocin effect (designed according

Null 2 3

Null 12 3

Modulated oxytocin effect Fisher's exact test

While early research that suggested effectiveness of OT in psychiatric diseases such as social anxiety disorder and ASD generated considerable enthusiasm, the reasons for the inconsistent and paradoxical results of OT on sociality in healthy humans remain unresolved. However, the pathophysiology of ASD has not yet been elucidated and no effective treatments for social impairments in ASD exist. It would be useful to investigate whether OT can improve the core symptoms of ASD.
