Urinary and plasma oxytocin changes in response to MDMA or intranasal oxytocin administration
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)
- et al.
Intranasal oxytocin in the treatment of autism spectrum disorders: a review of literature and early safety and efficacy data in youth
Brain Res.
(2014) - et al.
Social effects of oxytocin in humans: context and person matter
Trends Cogn. Sci.
(2011) - et al.
Acute effects of steroid hormones and neuropeptides on human social-emotional behavior: a review of single administration studies
Front. Neuroendocrinol.
(2012) - et al.
Oxytocin, vasopressin and sociality
Prog. Brain Res.
(2008) - et al.
Natural variations in maternal and paternal care are associated with systematic changes in oxytocin following parent-infant contact
Psychoneuroendocrinology
(2010) - et al.
Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders
Brain Res.
(2014) - et al.
Plasma and CSF oxytocin levels after intranasal and intravenous oxytocin in awake macaques
Psychoneuroendocrinology
(2016) - et al.
Oxytocin plasma concentrations after single intranasal oxytocin administration − a study in healthy men
Neuropeptides
(2012) - et al.
Hormonal correlates of human paternal interactions: a hospital-based investigation in urban Jamaica
Horm. Behav.
(2007) - et al.
Oxytocin and autistic disorder: alterations in peptide forms
Biol. Psychiatry
(2001)
Oxytocin, vasopressin, and human social behavior
Front. Neuroendocrinol.
Plasma, salivary, and urinary oxytocin in anorexia nervosa: a pilot study
Eat. Behav.
Plasma oxytocin concentrations following MDMA or intranasal oxytocin in humans
Psychoneuroendocrinology
A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research
Psychoneuroendocrinology
Breaking the loop: oxytocin as a potential treatment for drug addiction
Horm. Behav.
Making room for oxytocin in understanding depression
Neurosci. Biobehav. Rev.
Plasma oxytocin levels in autistic children
Biol. Psychiatry
Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice
Psychoneuroendocrinology
Combining information from multiple sources in the diagnosis of autism spectrum disorders
J. Am. Acad. Child Adolesc. Psychiatry
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.
Variation in oxytocin is related to variation in affiliative behavior in monogamous, pairbonded tamarins
Horm. Behav.
Variants in the oxytocin gene and risk for schizophrenia
Schizophr. Res.
Plasma oxytocin distributions in a large cohort of women and men and their gender-specific associations with anxiety
Psychoneuroendocrinology
Differential subjective effects of D-amphetamine by gender, hormone levels and menstrual cycle phase
Pharmacol. Biochem. Behav.
Plasma oxytocin concentrations are lower in depressed vs healthy control women and are independent of cortisol
J. Psychiatr. Res.
The relationship of cortisol levels to social environment and reproductive functioning in female cotton-top tamarins, Saguinus oedipus
Horm. Behav.
Promoting social behavior with oxytocin in high-functioning autism spectrum disorders
Proc. Natl. Acad. Sci. U. S. A.
Hormones and social behavior in primates
Evol. Anthropol. Issues News Rev.
Effects of oxytocin on recollections of maternal care and closeness
Proc. Natl. Acad. Sci. U. S. A.
Effects of MDMA on sociability and neural response to social threat and social reward
Psychopharmacology (Berl.)
Ecstasy (MDMA) and high prevalence psychiatric symptomatology: somatic anxiety symptoms are associated with polydrug, not ecstasy, use
J. Psychopharmacol.
Mothers' and children's concentrations of oxytocin following close, physical interactions with biological and non-biological children
Dev. Psychobiol.
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.