Elsevier

Psychoneuroendocrinology

Volume 74, December 2016, Pages 92-100
Psychoneuroendocrinology

Urinary and plasma oxytocin changes in response to MDMA or intranasal oxytocin administration

https://doi.org/10.1016/j.psyneuen.2016.08.011Get rights and content

Highlights

  • Urinary oxytocin levels increase after MDMA and intranasal oxytocin administration.

  • In healthy adults urine and plasma oxytocin levels are correlated after taking MDMA.

  • In ASD youths urine and plasma oxytocin levels are correlated after taking oxytocin.

Abstract

Background

The neuropeptide oxytocin (OT) has received increased experimental attention for its putative role in both normal social functioning and several psychiatric disorders that are partially characterized by social dysfunction (e.g., autism spectrum disorders: ASD). Many human experimental studies measure circulating plasma levels of OT in order to examine the relationship between the hormone and behavior. Urinary OT (uOT) assays offer a simple, easy, and non-invasive method to measure peripheral hormone levels, but the correspondence between uOT and plasma OT (pOT) levels is unclear. Here, we conducted two within-subjects, double-blind studies exploring changes in uOT and pOT levels following administration of two drugs: MDMA, an oxytocin-releasing drug (Study 1), and intranasal oxytocin (INOT: Study 1 and 2).

Methods

In Study 1, 14 adult participants (2 females) were each administered either oral 1.5 mg/kg MDMA or 40 IU INOT across two different study sessions. In Study 2, 10 male participants (adolescents and young adults) diagnosed with ASD received either 40 IU INOT or placebo across two different sessions. In both studies, blood and urine samples were collected before and after drug administration at each study session. For Study 1, 10 participants provided valid plasma and urine samples for the MDMA session, and 8 provided valid samples for the INOT session. For Study 2, all 10 participants provided valid samples for both INOT and placebo sessions. Pre- and post-administration levels of pOT and uOT were compared. Additionally, correlations between percent change from baseline uOT and pOT levels were examined.

Results

Study 1: Plasma OT and uOT levels significantly increased after administration of MDMA and INOT. Furthermore, uOT levels were positively correlated with pOT levels following administration of MDMA (r = 0.57, p = 0.042) but not INOT (r = 0.51, p=0.097). Study 2: There was a significant increase in uOT levels after administration of INOT, but not after administration of placebo. Under both conditions, INOT and placebo, significant increases in pOT levels were not observed. Additionally, change from baseline uOT and pOT levels were positively correlated (r = 0.57, p=0.021). There was no significant correlation between uOT and pOT levels following placebo administration.

Conclusion

Our results show a measurable and significant increase in pOT and uOT levels after the administration of MDMA (Study 1) and INOT (Study 1 and Study 2). Additionally, a positive correlation between uOT and pOT levels was observed in both samples (healthy adults and ASD patients) in at least one condition. However, uOT and pOT levels were not correlated under all conditions, suggesting that uOT levels do not fully correspond to pOT levels in the time windows we measured. Future studies should further examine the relationship between levels of pOT and uOT in healthy and clinical populations on measures of social behavior because uOT may serve as an additional non-invasive method to measure peripheral OT changes.

Introduction

Over the past 25 years, oxytocin (OT) − a neuropeptide synthesized in the paraventricular nucleus and supraoptic nucleus of the hypothalamus and released to both central and peripheral circulation − has received increased attention for its role in social functioning. Evidence from preclinical, clinical, and human laboratory studies indicate that OT is involved in social behavioral and cognitive domains, including attachment and pair bonding in laboratory animals, as well as social affiliation, parental care behaviors, socioemotional processing, social reward, and generosity in humans (Carter et al., 2008, Donaldson and Young, 2008, Feldman et al., 2010, Insel and Young, 2001, Macdonald and Macdonald, 2010). It is important to note that evidence concerning the role of OT in some social domains in humans remains mixed. While some studies show a relationship between OT and trust (Heinrichs et al., 2009), others do not (Christensen et al., 2014). Nevertheless, there is mounting evidence that OT functioning is involved in several psychiatric disorders that have social dysfunction including autism spectrum disorders (ASD), depression, anxiety, drug abuse, and schizophrenia (Burkett and Young, 2012, Francis et al., 2014, McGregor and Bowen, 2012, McQuaid et al., 2014, Souza et al., 2010a, Souza et al., 2010b, Teltsh et al., 2012, Weisman et al., 2013). Continued examination of OT will be required to understand its neurobiological role in modulating both typical and atypical social behaviors.

Given the challenges, risk, and invasiveness of measuring OT in cerebrospinal fluid (csfOT), many experimental and observational studies measure peripheral levels of the hormone as a proxy for central hypothalamic release. The relationship between central and peripheral OT levels is complex. Studies comparing basal csfOT and plasma OT (pOT) levels have yielded mixed results: i.e., both positive correlations (Carson et al., 2015) and no correlation (Kagerbauer et al., 2013). Studies utilizing exogenous OT administration have shown increases in both central and peripheral OT levels, in animals and humans (i.e. intranasal OT or intravenous OT; Dal Monte et al., 2014, Freeman et al., 2016, Striepens et al., 2013), with some correspondence observed between central and peripheral OT levels in non-human primates and rats (Dal Monte et al., 2014, Freeman et al., 2016, Neumann et al., 2013), but no correlation between pOT and csfOT levels in humans (Striepens et al., 2013). Nevertheless, pOT levels have been found to be positively associated with several behavioral outcomes, including less anxiety in children (Carson et al., 2015), and parents’ positive communication and social engagement with their children (Feldman et al., 2011), suggesting that this peripheral measure may be an indicator of OT functioning in the brain.

Another method to determine peripheral levels of OT is to measure urine OT (uOT). This is a simple method and can be calibrated for fluid intake/excretion variability. Urine OT may not replace measuring OT levels in CSF or plasma, but it is a non-invasive approach for studying OT and its relationship with behaviors. Researchers have reported associations between social outcomes and uOT (Feldman et al., 2011, Saito et al., 2014, Seltzer et al., 2010). However, while there are associations between social outcomes and pOT and uOT levels (Carter et al., 2007, Feldman et al., 2011, Parker et al., 2014, Seltzer et al., 2010), there is ongoing controversy about the relative value of each method. Although some researchers suggest that pOT sampling remains the method of choice for measuring peripheral OT levels (Hoffman et al., 2012), there remains limited data directly comparing pOT with uOT levels. Some correlational evidence suggests correspondence between pOT and uOT (Hoffman et al., 2012), while other studies have reported a lack of correspondence between the two measures (Feldman et al., 2011). Some of these discrepancies may be related to differences in time course and steady-state in different body fluids, which have varying volume distributions and clearance processes. Behavioral effects of OT and other neuropeptides often correlate with CSF changes measured 10–120 min after intranasal administration (Born et al., 2002, Striepens et al., 2013). OT changes in blood and plasma occur on the time course of minutes whereas changes in urine occur over hours (Fig. 1).

Non-invasive methods of measuring peripheral OT levels − such as urine assay − will move the field forward, as research into the role of OT in social behavior continues to increase. This is especially important in studies with children or in disorders where repeated blood draws for non-essential measures are challenging. Therefore, to further understand the relationship between pOT (invasive) and uOT (non-invasive) levels we analyzed data from two studies where we collected both urine and plasma before and after administration of MDMA (±3,4-methylenedioxymethamphetamine), INOT (intranasal oxytocin), and/or placebo. Our laboratory and others have demonstrated that MDMA dose-dependently increases acute pOT levels (Dumont et al., 2009, Hysek et al., 2012, Hysek et al., 2014, Kirkpatrick et al., 2014a, Schmid et al., 2014), and pOT levels increase following INOT to a lesser degree (Gossen et al., 2012, Striepens et al., 2013). Here, Study 1 extends upon our previously published study, which examined MDMA- and INOT-induced changes in both pOT levels and self-reported feelings of sociability (Kirkpatrick et al., 2014a). Study 2 introduces data collected from individuals with ASD during an INOT single-dose versus placebo challenge.

These studies not only provide an opportunity to further evaluate the association between pOT and uOT levels, but also provide a chance to examine the relationship between pOT and uOT levels in both healthy (Study 1) and clinical (Study 2) populations. Overall, this could provide information to a growing set of researchers interested in the influence of OT on normal social behavior and behavioral disruptions associated with a number of disorders. While there have been studies comparing baseline pOT and uOT levels (Feldman et al., 2011, Hoffman et al., 2012), to our knowledge there have been no published reports comparing the two assays following administration of either MDMA or INOT. We predicted that uOT and pOT levels would increase after the administration of MDMA (Study 1) and INOT (Studies 1 and 2). We further predicted that levels of uOT would be positively correlated with pOT levels under the drug conditions.

Section snippets

Participants

Healthy adults with past MDMA experience were recruited via community billboard advertisement and then completed an in-person psychiatric evaluation and medical examination, including an electrocardiogram and physical examination. Exclusion criteria included any significant cardiovascular, neurological, or major psychiatric illness including all Axis I disorders that might increase risk for an MDMA-related adverse event (Kirkpatrick et al., 2014b), or if they smoked more than 10 tobacco

MDMA-related effects on urinary oxytocin levels and correlations with plasma oxytocin levels

Overall, MDMA (1.5 mg/kg) produced a significant increase in uOT (Main effect of Time; F(1,9) = 80.5; p < 0.001; ηp2 = 0.90) and pOT levels (Main effect of Time: F(1,9) = 67.6; p < 0.001; ηp2 = 0.88); the mean difference between pre- and post-drug administration uOT levels was 86.0 ± 9.6 pg/mg creatinine and the difference for pOT levels was 11.2 ± 1.4 pg/mL. Supplementary Fig. 1a and Fig. 2a show that MDMA increases both pOT and uOT levels for each individual. Fig. 3a shows that the percent change from baseline

Discussion

Several of our results were consistent with our hypotheses − we observed significant increases in uOT levels after administration of MDMA (Study 1) and INOT (Study 1 and 2); and we noted significant increases in pOT levels post administration of MDMA (Study 1) and INOT (Study 1). In agreement with the second part of our hypothesis, percent change from baseline levels of uOT and pOT were positively significantly correlated in two different study populations: healthy adults (post-MDMA

Conclusion

In conclusion, our present data demonstrate that administration of two drugs (MDMA and INOT) acutely increases peripheral OT. Furthermore, these increases in uOT levels measured as changes from baseline were positively correlated with changes in pOT levels after MDMA administration in healthy adults and INOT administration in adolescent and young adults with ASD, although uOT and pOT measure did not fully overlap. INOT results in a lower magnitude of measurable, peripheral OT and may be

Role of funding sources

NIMH K23MH082121 (SJ) − supported conduct of the research (study design, data collection, and analysis).

3K23MH082121-03S1 (SMF) − supported conduct of the research (study design, data collection, and analysis).

Leadership Education in Neurodevelopmental and Related Disorders Training Program T73MC12835 (SMF) − supported analysis and manuscript preparation.

NIDA R01 DA02812, R21 DA026579 and the Institute for Translational Medicine (University of Chicago Medical Center) UL1TR000430 (MGK and HdW) −

Authors’ contributions

HdW (Study 1) and SJ (Study 2) were the principal investigators for the studies and coordinated the projects and SJ contributed to OT sample collection and methods for both studies. MGK and HdW contributed to Study 1 design, and SJ designed Study 2 with contributions from SMF. Data collection was performed by MGK (Study 1) and SMF (Study 2). Analyses were performed by SMF, MGK, and SJ. All authors contributed to manuscript preparation, read and approved of the final manuscript.

Conflicts of interest

There are no conflicts of interest for all authors.

Acknowledgements

This work was supported by NIMH K23MH082121 (SJ), 3K23MH082121-03S1 and Leadership Education in Neurodevelopmental and Related Disorders Training Program T73MC12835 (SMF), and NIDA R01 DA02812, R21 DA026579 and the Institute for Translational Medicine (University of Chicago Medical Center) UL1TR000430 (MGK and HdW). The authors would like to acknowledge: Dr. Toni E. Ziegler of the Wisconsin National Primate Research Center for her assistance with oxytocin measurement. The authors would also

References (67)

  • M. Heinrichs et al.

    Oxytocin, vasopressin, and human social behavior

    Front. Neuroendocrinol.

    (2009)
  • E.R. Hoffman et al.

    Plasma, salivary, and urinary oxytocin in anorexia nervosa: a pilot study

    Eat. Behav.

    (2012)
  • M.G. Kirkpatrick et al.

    Plasma oxytocin concentrations following MDMA or intranasal oxytocin in humans

    Psychoneuroendocrinology

    (2014)
  • E. MacDonald et al.

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

    Psychoneuroendocrinology

    (2011)
  • I.S. McGregor et al.

    Breaking the loop: oxytocin as a potential treatment for drug addiction

    Horm. Behav.

    (2012)
  • R.J. McQuaid et al.

    Making room for oxytocin in understanding depression

    Neurosci. Biobehav. Rev.

    (2014)
  • C. Modahl et al.

    Plasma oxytocin levels in autistic children

    Biol. Psychiatry

    (1998)
  • I.D. Neumann et al.

    Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice

    Psychoneuroendocrinology

    (2013)
  • S. Risi et al.

    Combining information from multiple sources in the diagnosis of autism spectrum disorders

    J. Am. Acad. Child Adolesc. Psychiatry

    (2006)
  • L.J. Seltzer et al.

    Non-invasive measurement of small peptides in the common marmoset (Callithrix jacchus): a radiolabeled clearance study and endogenous excretion under varying social conditions

    Horm. Behav.

    (2007)
  • C.T. Snowdon et al.

    Variation in oxytocin is related to variation in affiliative behavior in monogamous, pairbonded tamarins

    Horm. Behav.

    (2010)
  • R.P. Souza et al.

    Variants in the oxytocin gene and risk for schizophrenia

    Schizophr. Res.

    (2010)
  • O. Weisman et al.

    Plasma oxytocin distributions in a large cohort of women and men and their gender-specific associations with anxiety

    Psychoneuroendocrinology

    (2013)
  • T.L. White et al.

    Differential subjective effects of D-amphetamine by gender, hormone levels and menstrual cycle phase

    Pharmacol. Biochem. Behav.

    (2002)
  • K.W. Yuen et al.

    Plasma oxytocin concentrations are lower in depressed vs healthy control women and are independent of cortisol

    J. Psychiatr. Res.

    (2014)
  • T.E. Ziegler et al.

    The relationship of cortisol levels to social environment and reproductive functioning in female cotton-top tamarins, Saguinus oedipus

    Horm. Behav.

    (1995)
  • American Psychiatric Association, 2000. Diagnostic and statistical manual of mental disorders, fourth ed text rev....
  • E. Andari et al.

    Promoting social behavior with oxytocin in high-functioning autism spectrum disorders

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • S.F. Anestis

    Hormones and social behavior in primates

    Evol. Anthropol. Issues News Rev.

    (2010)
  • J.A. Bartz et al.

    Effects of oxytocin on recollections of maternal care and closeness

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • G. Bedi et al.

    Effects of MDMA on sociability and neural response to social threat and social reward

    Psychopharmacology (Berl.)

    (2009)
  • G. Bedi et al.

    Ecstasy (MDMA) and high prevalence psychiatric symptomatology: somatic anxiety symptoms are associated with polydrug, not ecstasy, use

    J. Psychopharmacol.

    (2010)
  • J. Bick et al.

    Mothers' and children's concentrations of oxytocin following close, physical interactions with biological and non-biological children

    Dev. Psychobiol.

    (2010)
  • Cited by (0)

    1

    Both authors contributed equally.

    2

    Current address: Department of Psychiatry, University of Minnesota, 717 Delaware Street SE, Room 516, Minneapolis, MN 55414, USA.

    3

    Current address: Department of Preventive Medicine, University of Southern California, 2001 North Soto Street, Los Angeles, CA 90032, USA.

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