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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. One line of evidence suggests that MDMA produces these effects by releasing oxytocin, a peptide involved in social bonding. In the current study, we investigated the acute effects of MDMA and oxytocin on social and emotional processing in healthy human volunteers. The primary outcomes included measures of emotion recognition and sociability desire to be with others. Cardiovascular and subjective effects were also assessed. On measures of social function, MDMA impaired recognition of angry and fearful facial expressions, and the larger dose 1. Oxytocin produced small but significant increases in feelings of sociability and enhanced recognition of sad facial expressions. Additionally, responses to oxytocin were related to responses to MDMA with subjects on two subjective measures of sociability. Thus, MDMA increased euphoria and feelings of sociability, perhaps by reducing sensitivity to subtle signs of negative emotions in others. The present findings provide only limited support for the idea that oxytocin produces the prosocial effects of MDMA. In light of these effects, it is also being tested as an adjunct to psychotherapy for post traumatic stress disorder Mithoefer et al, Yet, the mechanisms by which MDMA produces its apparently unique empathogenic effects are not known. One line of evidence suggests that MDMA produces these effects by releasing oxytocin, a peptide involved in social bonding Bos et al, Oxytocin has also been linked to drug abuse in other contexts: Burkett and Young point to striking resemblances between addiction and social bonding and attachment, noting substantial overlap between the endogenous oxytocin and drug reward systems, and McGregor and Bowen have proposed that oxytocin may be a safe and effective treatment for drug addiction. Together, these links suggest that there may be commonalities in the prosocial subjective, cognitive, and behavioral effects of MDMA and oxytocin. In the human laboratory, MDMA enhances subjective, cognitive, and emotional measures of social processing. It increases positive mood states, as well as feelings of friendliness and feeling close to others Bedi et al, ; Harris et al, ; Hysek and Liechti, ; Kirkpatrick et al, ; Tancer and Johanson, On objective measures of social function, it alters the ability to recognize the emotions of others: it improves correct categorization of positive mental states, such as friendliness in others Hysek et al, while impairing categorization of negative states such as expressions of hostility or fear Bedi et al, ; Hysek et al, Thus, MDMA may facilitate social behavior by producing positive and prosocial subjective states, as well as by enhancing the sensitivity to positive emotions and reducing sensitivity to negative emotions in others. MDMA may produce these effects in part by increasing release of oxytocin. In addition to its effects on dopamine, serotonin, and norepinephrine in the brain Han and Gu, ; Rothman et al, ; Verrico et al, , MDMA also appears to release oxytocin. In humans, MDMA increases plasma levels of oxytocin Dumont et al, ; Hysek et al, , and these increases are correlated with feelings of sociability Dumont et al, Single doses of intranasal oxytocin can also produce prosocial, anxiolytic, and affiliative effects in healthy adults Bos et al, ; Lim and Young, For example, oxytocin has been shown to increase trust and generosity Kosfeld et al, ; Zak et al, , reduce responses to social stressors Heinrichs et al, , increase positive communication Ditzen et al, , and, like MDMA, enhance recognition of positive emotional states and dampen responses to negative emotions in others Di Simplicio et al, ; Domes et al, a , b ; Marsh et al, ; Shahrestani et al, On the other hand, other studies have failed to detect prosocial effects of oxytocin, and indeed, found that it can produce antisocial effects such as feelings of envy and mistrust Bartz et al, a ; Declerck et al, ; Shamay-Tsoory et al, The conditions under which oxytocin enhances, or impairs, social interaction remain to be determined. Nevertheless, similar patterns of prosocial effects produced by MDMA and intranasal oxytocin would be consistent with the possibility that central oxytocin contributes to the prosocial effects of MDMA. To examine this possibility, we examined the prosocial effects of both MDMA and oxytocin in the same individuals. In this study, we tested the subjective, cardiovascular, and behavioral effects of oral MDMA 0. We hypothesized that both MDMA and oxytocin would dose-dependently 1 increase self-report measures of sociability and desire to socialize and 2 enhance objective indicators of social function. Previous data from our laboratory and others indicate that MDMA dose-dependently increases both cardiovascular measures and feelings of euphoria, whereas intranasal oxytocin does not Bedi et al, , ; de Oliveira et al, ; Norman et al, ; MacDonald and MacDonald, Potential participants completed an initial telephone and an in-person psychiatric evaluation and medical examination, including an electrocardiogram and a physical examination. Inclusion criteria were age between 18 and 35 years, at least a high school education, fluency in English, and BMI between 18 and All participants were Caucasian because this was part of a larger genetic study. Participants were told that the purpose of the study was to evaluate individual differences in drug response. They were told they could receive a stimulant such as amphetamine or ecstasy , a sedative such as Valium , a cannabinoid, a hormone such as oxytocin , or a placebo. Women who used hormonal contraceptives were tested regardless of menstrual cycle phase, but women not using hormonal contraceptives were tested only during the follicular phase days 2β14; White et al, Participants provided written informed consent before participation and after completing all sessions they were debriefed to explain the study. The study used a within-and-between-subjects, double-dummy design in which subjects received two doses of MDMA 0. After an initial orientation session, participants completed four outpatient sessions separated by at least 5 days as a washout period Abraham et al, Dosing order was randomized. On each session, participants ingested a capsule placebo or MDMA and received a nasal spray placebo or oxytocin. Sessions were rescheduled if the participant tested positive for drugs. During times when no measures were scheduled the participants were allowed to relax and watch movies or read. Participants completed subjective-effect questionnaires before and at regular intervals after capsule and nasal spray administration. At the end of the sessions, participants completed the ESQ on which they rated how much they would like to take the drug again VAS: 0β Participants completed two computerized measures of social and emotional processing, between and am during the anticipated time of peak drug effects. The order of task presentation was randomized. The version of the task includes four basic emotions ie, anger, fear, happiness, and sadness. The outcome measure was accuracy defined as the proportion of correct identifications minus the proportion of false alarms. Participants also completed the Social Evaluation Task SET during which they rated the perceived attractiveness, friendliness, and trustworthiness of facial pictures. Stimuli consisted of 80 full color faces; 20 different faces were presented each session 10 male and 10 female aged 18β25 years; Jones et al, Outcome measures were mean attractiveness, friendliness, and trustworthiness ratings, analyzed separately based on the gender of the participant and the facial image. At noon 2. Participants were instructed that their ratings, combined with an element of chance, would determine which activity was selected. In fact, the outcome of this task was randomized and determined before study participation. Subjects then engaged in the selected activity; for the social activity, they interacted with a trained confederate. Drug conditions were administered in randomized order, under double-blind conditions. Capsules and nasal sprays were prepared by The University of Chicago Hospitals investigational pharmacy. MDMA powder 0. Placebo capsules contained only lactose. These MDMA doses were selected based on our previous studies indicating that the drug reliably increases positive mood and alters emotional processing at these doses Bedi et al, , During the administration, participants sat comfortably in reclined position, with their heads tilted back to maximize absorption. Independent fixed effects were drug placebo, 0. For cardiovascular and subjective-effects measures, time of assessment was included as an independent factor. MLMs provided the error terms needed to calculate the following within-subjects planned comparisons: 1 placebo vs both active MDMA doses and 2 0. Data from the placebo and active oxytocin sessions were analyzed using MLMs. We conducted secondary partial correlational analyses to investigate the relationship between subjective responses to MDMA and oxytocin. They were They had used MDMA a mean of The participants did not differ on any demographic measure. MDMA dose-dependently increased cardiovascular measures across the session Figure 1. Error bars represent SEM. Overlapping error bars were omitted for clarity. PowerPoint slide. MDMA produced robust increases in self-reported ratings of feeling the drug. The drug increased ratings of both liking and disliking and it increased both positive mood states such as elated and friendly and negative states such as anxious and lonely Table 3 ; Figure 2 , top panels. Top panels: Selected mean scores on subjective ratings following administration of MDMA or placebo as a function of dose and time. Bottom panels: Selected scores on subjective ratings following administration of oxytocin or placebo as a function of dose and time. Error bars represent one SEM. Mean proportion of accurate identification of emotional facial expressions as a function of MDMA dose. Mean ratings of desire to engage in social and solitary activities as a function of MDMA dose. Oxytocin increased several self-report measures, compared with placebo, but these effects were small compared with the effects of MDMA. Mean ratings over the course of the entire session for all self-report measures are provided in Supplementary Table 1. Neither dose of oxytocin affected identification of other emotions, or performance on the SET. Subjective response to the lower oxytocin dose was significantly correlated with MDMA subjective response on some prosocial measures. The current results confirm and extend previous reports on the prosocial effects of MDMA and intranasal oxytocin. MDMA dose-dependently increased subjective feelings of friendliness and sociability and the larger dose 1. Overall, these data are consistent with previous reports of the prosocial effects of MDMA Bedi et al, , ; Hysek et al, ; Hysek and Liechti, ; Kirkpatrick et al, ; Tancer and Johanson, and extend these earlier findings by demonstrating modest correlations between the effects of MDMA and oxytocin in the same individuals. The drug increased ratings of drug liking as well as feelings of friendliness, insightful, and sociable. This mixed profile of both positive and negative subjective effects is consistent with the purportedly low abuse potential of MDMA relative to other amphetamines Kirkpatrick et al, It is possible that some of the negative subjective effects eg, increased loneliness were related to the socially isolated testing conditions, and these effects might not be evident in a social context Doty and de Wit, ; Kirkpatrick and de Wit, Interestingly, in our study MDMA also increased a behavioral measure of preference for social activities. When subjects were asked to rate their desire to engage in social and non-social activities, they reported increased desire for the social activity after MDMA 1. While similar effects have been shown for amphetamine Higgins and Stitzer, , this is the first time that MDMA has been found to affect preference for social activity. Overall, these data suggest that MDMA-related subjective effects may be enhanced if the drug was administered in the presence of other individuals. Future studies might directly compare acute MDMA-related effects in a social vs an isolated context. MDMA 1. This is consistent with some findings Bedi et al, , although in other studies MDMA also improved identification of positive emotions using a different task Reading the Eyes in the Mind Task, which shows only the area around the eyes: Hysek et al, The current study also differs from past findings by measuring accuracy in a way that controls for false alarms. Nonetheless, the extent to which MDMA increases social behavior by decreasing sensitivity to negative expressions or increasing sensitivity to positive expressions remains to be resolved. However, the nature of the MDMA effect remains unclear. In the present study, MDMA did not alter performance on the other measure of social and emotional processing ie, perception of attractiveness and trustworthiness. The exact behavioral and psychological processes involved in the prosocial effects of this drug remain to be determined, perhaps by testing subjects under more naturalistic social conditions, or using more sensitive probes, including psychophysiological measures Wardle and de Wit, Intranasal oxytocin also increased subjective feelings of sociability and some measures of positive mood. The current subjective-effects findings are novel, as most previous studies have not reported detectable subjective effects following intranasal oxytocin administration MacDonald et al, Several features of the design, including the within-subject placebo comparison condition and repeated measures across the time course of the effect may have increased the sensitivity of our procedure, relative to previous studies. Interestingly, the finding that the lower oxytocin dose produced greater effects on subjective feelings of sociability is consistent with previous studies indicating that the effects of oxytocin are non-linear. It has been suggested that higher doses of oxytocin may block some if its effects because of increased binding with vasopressin receptors for a review, see MacDonald and Feifel, A previous study reported that oxytocin improves recognition of a range of emotions Shahrestani et al, and another study found that the effects of oxytocin on emotional stimuli may differ in women and men Domes et al, The full profile of subjective and behavioral effects of oxytocin remains to be determined. Other studies have used further measures of prosocial behaviors, showing that oxytocin increases measures of trust, generosity, and interpersonal communication Kosfeld et al, ; Zak et al, ; Ditzen et al, ; for review, see MacDonald and MacDonald, , while other researchers have shown that oxytocin can produce antisocial behaviors, such as feelings of envy and mistrust Bartz et al, a ; Declerck et al, ; Shamay-Tsoory et al, ; for review, see Bartz et al, b. The reasons for the differences are not known, but may include characteristics of the subject samples eg, age, gender, and hormonal state or testing environment eg, outcome measures used, social and physical context of testing. The present findings show that exogenous administration of oxytocin can produce positive mood changes that could facilitate psychosocial function. At the doses tested here, MDMA and oxytocin did not produce similar effects. For example, for the majority of prosocial subjective-effect items, responses to MDMA were not correlated with responses to intranasal oxytocin, suggesting that the social effects of MDMA are not fully mediated by oxytocin. Clearly, MDMA at these doses produced substantially greater effects than intranasal oxytocin. However, it is likely that the drugs produced different levels of oxytocin in plasma and the brain. Although, both MDMA Hysek et al, and intranasal oxytocin Domes et al, increase plasma levels of oxytocin, the relative levels are difficult to compare across studies. We have suggestive preliminary data from a separate study that MDMA increased plasma levels of oxytocin to higher levels than intranasal oxytocin, at the doses tested here. Brain levels of the peptide, however, are not known. It is also possible that the effects of oxytocin are more subtle than MDMA effects, and may be influenced by environmental context and individual differences such as sex, behavioral history, and psychiatric conditions Bartz et al, b. These differences may be attributable to their differing mechanisms of action. MDMA-related effects in the brain are widespread; it potently releases the monoamine neurotransmitters dopamine, serotonin, and norepinephrine in part by inducing carrier-mediated release through their respective transporters Han and Gu, ; Verrico et al, ; Rothman et al, , which likely contributes to its wide range of physiological, subjective, and behavioral effects. In rodents, endogenous and exogenous oxytocin binds in brain regions associated with mood, arousal, and reward Gimpl and Fahrenholz, and also increases levels of dopamine, serotonin, and norepinephrine Shahrokh et al, ; Vincent and Etgen, ; Yoshida et al, However, in contrast to MDMA, oxytocin modulates release of monoamines via activation of oxytocin receptors Gimpl and Fahrenholz, , and may have relatively specific and focused neuromodulatory effects on improved information processing in the brain Owen et al, Of course, the extent to which intranasal oxytocin acts on specific brain circuits and facilitates neurotransmitter release in humans has yet to be determined. The present study had several limitations. First, the behavioral measures may not have been obtained at optimal times to detect oxytocin effects. Further, in our study the placebo and oxytocin nasal spray formulations differed slightly, raising the possibility that differing sensations may have influenced subject expectations. This seems unlikely to be a major concern, since at the end of the session, participants identified both formulations as placebo equally often Other potential limitations are the selection of participants young adult MDMA users, in this case , or the doses of the drugs administered. In conclusion, MDMA produced a range of prosocial effects: It increased feelings of sociability, increased choice to engage in a social activity, and decreased recognition of anger and sadness in others. By contrast, intranasal oxytocin produced small increases in selected ratings of sociability and enhanced negative emotion recognition. Although comparisons between intranasally administered oxytocin and orally administered MDMA are difficult because of differences in dose and route, the present findings suggest that oxytocin is not likely to be the sole mechanism of the prosocial effects of MDMA. It was recently reported sub-threshold doses of either oxytocin or vasopressin and MDMA administered together increased prosocial behavior in rats Ramos et al, , suggesting an interesting future direction for this research in humans. Dr Kirkpatrick received salary compensation from The University of Chicago. Dr Wardle received salary compensation from The University of Chicago. Dr Lee received salary compensation from The University of Chicago and support from Azevan Pharmaceuticals for travel and data presentation for a research project unrelated to this manuscript. Dr de Wit received salary compensation from The University of Chicago and support from Unilever for a research project unrelated to this manuscript. 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We gratefully acknowledge Jon Solamillo, Celina Joos, Michael Helzer and Charles Frye for technical assistance, Emmanuel Semmes for pharmaceutical support, Gillinder Bedi for contributing to the study design and Matthew Baggott for providing valuable advice on the manuscript. You can also search for this author in PubMed Google Scholar. Correspondence to Harriet de Wit. Supplementary Information accompanies the paper on the Neuropsychopharmacology website. Reprints and permissions. Kirkpatrick, M. Neuropsychopharmacol 39 , β Download citation. Received : 03 July Revised : 11 January Accepted : 15 January Published : 22 January Issue Date : June Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content Thank you for visiting nature. Download PDF. Subjects Emotion Pharmacology Social behaviour. Kinetics of oxytocin effects on amygdala and striatal reactivity vary between women and men Article 30 November Oxytocin enhances neural approach towards social and non-social stimuli of high personal relevance Article Open access 08 December Drug-induced social connection: both MDMA and methamphetamine increase feelings of connectedness during controlled dyadic conversations Article Open access 22 September Design The study used a within-and-between-subjects, double-dummy design in which subjects received two doses of MDMA 0. Table 1 Study Design Full size table. Figure 1. Full size image. Figure 2. Figure 3. Figure 4. Article Google Scholar Download references. Acknowledgements We gratefully acknowledge Jon Solamillo, Celina Joos, Michael Helzer and Charles Frye for technical assistance, Emmanuel Semmes for pharmaceutical support, Gillinder Bedi for contributing to the study design and Matthew Baggott for providing valuable advice on the manuscript. View author publications. Additional information Supplementary Information accompanies the paper on the Neuropsychopharmacology website. Supplementary information. Supplementary Figure JPG kb. Supplementary Tables DOC kb. PowerPoint slides PowerPoint slide for Fig. PowerPoint slide for Fig. Rights and permissions Reprints and permissions. About this article Cite this article Kirkpatrick, M. Copy to clipboard. Joseph G. Wolfgang Charles W. Liechti Neuropsychopharmacology Search Search articles by subject, keyword or author. Show results from All journals This journal. Advanced search.
Effects of MDMA and Intranasal Oxytocin on Social and Emotional Processing
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