Abstract
Rationale
Cocaine use disorder (CUD) is associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which plays a critical role in the human stress response. Men and women with CUD differ in reactivity to social stressors. The hypothalamic neuropeptide oxytocin is involved in anxiolytic and natural reward processes, and has shown therapeutic potential for addictive disorders and stress reduction.
Objectives
To examine the impact of oxytocin (oxytocin (OXY) vs. placebo (PBO)) and gender (female (F) vs. male (M)) on response to a social stress task in individuals with CUD. To explore whether ovarian hormones moderate this stress response.
Methods
One hundred twelve adults with CUD were randomized to receive 40 IU intranasal oxytocin (n = 56) or matching placebo (n = 56). Forty minutes after drug administration, participants were exposed to a social stressor. Generalized linear mixed models were used to examine neuroendocrine (cortisol) and subjective (craving, stress) response at pre-stressor, stressor + 0, + 10, + 30, + 60 min.
Results
Gender moderated the effect of oxytocin on neuroendocrine response (p = 0.048); women receiving oxytocin (F + OXY) showed blunted cortisol response compared to the other three groups (F + PBO; M + OXY; M + PBO). There was a main effect of gender on subjective stress response; women reported greater stress following the stressor compared to men (p = 0.016). Oxytocin had no significant effect on craving or stress, and gender did not moderate the effect of oxytocin on either measure. Higher endogenous progesterone was associated with lower craving response in women (p = 0.033).
Conclusions
Oxytocin may have differential effects in men and women with CUD. Women may be at greater risk for relapse in response to social stressors, but ovarian hormones may attenuate this effect.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Anker JJ, Carroll ME (2010a) Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats. Psychopharmacology 208(2):211–222. https://doi.org/10.1007/s00213-009-1721-2
Anker JJ, Carroll ME (2010b) The role of progestins in the behavioral effects of cocaine and other drugs of abuse: human and animal research. Neurosci Biobehav Rev 35(2):315–333. https://doi.org/10.1016/j.neubiorev.2010.04.003
Anker JJ, Carroll ME (2011) Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones. Curr Top Behav Neurosci 8:73–96. https://doi.org/10.1007/7854_2010_93
Back SE, Hartwell K, DeSantis SM, Saladin M, McRae-Clark AL, Price KL, Moran-Santa Maria MM, Baker NL, Spratt E, Kreek MJ, Brady KT (2010) Reactivity to laboratory stress provocation predicts relapse to cocaine. Drug Alcohol Depend 106(1):21–27. https://doi.org/10.1016/j.drugalcdep.2009.07.016
Baker TB, Piper ME, McCarthy DE, Majeskie MR, Fiore MC (2004) Addiction motivation reformulated: an affective processing model of negative reinforcement. Psychol Rev 111(1):33–51. https://doi.org/10.1037/0033-295X.111.1.33
Bernstein DP, Fink L (1998) Childhood Trauma Questionnaire: a retrospective self-report manual. The Psychological Corporation, San Antonio
Borrow AP, Handa RJ (2017) Estrogen receptors modulation of anxiety-like behavior. Vitam Horm 103:27–52. https://doi.org/10.1016/bs.vh.2016.08.004
Bozdogan H (1987) Model selection and Akaike's Information Criterion (AIC): The general theory and its analytical extensions. Psychometrika 52:345–370. https://doi.org/10.1007/BF02294361
Brady KT, Sinha R (2005) Co-occurring mental and substance use disorders: the neurobiological effects of chronic stress. Am J Psychiatry 162(8):1483–1493. https://doi.org/10.1176/appi.ajp.162.8.1483
Brady KT, Back SE, Waldrop AE, McRae AL, Anton RF, Upadhyaya HP, Saladin ME, Randall PK (2006) Cold pressor task reactivity: predictors of alcohol use among alcohol-dependent individuals with and without comorbid posttraumatic stress disorder. Alcohol Clin Exp Res 30(6):938–946. https://doi.org/10.1111/j.1530-0277.2006.00097.x
Buffalari DM, Baldwin CK, Feltenstein MW, See RE (2012) Corticotrophin releasing factor (CRF) induced reinstatement of cocaine seeking in male and female rats. Physiol Behav 105(2):209–214. https://doi.org/10.1016/j.physbeh.2011.08.020
CBHSQ (2017) Key substance use and mental health indicators in the United States: results from the 2016 National Survey on Drug Use and Health (HHS Publication No. SMA 17-5044, NSDUH Series H-52). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/
Childress AR, McLellan AT, O'Brien CP (1986) Abstinent opiate abusers exhibit conditioned craving, conditioned withdrawal and reductions in both through extinction. Br J Addict 81(5):655–660 Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/3466632
Cotto JH, Davis E, Dowling GJ, Elcano JC, Staton AB, Weiss SR (2010) Gender effects on drug use, abuse, and dependence: a special analysis of results from the National Survey on Drug Use and Health. Gend Med 7(5):402–413. https://doi.org/10.1016/j.genm.2010.09.004
de Oliveira DC, Zuardi AW, Graeff FG, Queiroz RH, Crippa JA (2012) Anxiolytic-like effect of oxytocin in the simulated public speaking test. J Psychopharmacol 26(4):497–504. https://doi.org/10.1177/0269881111400642
DeSantis SM, Baker NL, Back SE, Spratt E, Ciolino JD, Moran-Santa Maria M, Dipankar B, Brady KT (2011) Gender differences in the effect of early life trauma on hypothalamic-pituitary-adrenal axis functioning. Depress Anxiety 28(5):383–392. https://doi.org/10.1002/da.20795
Dickerson SS, Kemeny ME (2004) Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull 130(3):355–391. https://doi.org/10.1037/0033-2909.130.3.355
Ditzen B, Schaer M, Gabriel B, Bodenmann G, Ehlert U, Heinrichs M (2009) Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict. Biol Psychiatry 65(9):728–731. https://doi.org/10.1016/j.biopsych.2008.10.011
Dorn LD, Lucke JF, Loucks TL, Berga SL (2007) Salivary cortisol reflects serum cortisol: analysis of circadian profiles. Ann Clin Biochem 44(Pt 3):281–284. https://doi.org/10.1258/000456307780480954
Dumais KM, Bredewold R, Mayer TE, Veenema AH (2013) Sex differences in oxytocin receptor binding in forebrain regions: correlations with social interest in brain region- and sex-specific ways. Horm Behav 64(4):693–701. https://doi.org/10.1016/j.yhbeh.2013.08.012
Eckstein M, Scheele D, Weber K, Stoffel-Wagner B, Maier W, Hurlemann R (2014) Oxytocin facilitates the sensation of social stress. Hum Brain Mapp 35(9):4741–4750. https://doi.org/10.1002/hbm.22508
Feltenstein MW, Henderson AR, See RE (2011) Enhancement of cue-induced reinstatement of cocaine-seeking in rats by yohimbine: sex differences and the role of the estrous cycle. Psychopharmacology 216(1):53–62. https://doi.org/10.1007/s00213-011-2187-6
First MB, Spitzer RL, Gibbon M., Williams JB (2002) Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition. Retrieved from
Flanagan JC, Baker NL, McRae-Clark AL, Brady KT, Moran-Santa Maria MM (2015) Effects of adverse childhood experiences on the association between intranasal oxytocin and social stress reactivity among individuals with cocaine dependence. Psychiatry Res 229(1–2):94–100. https://doi.org/10.1016/j.psychres.2015.07.064
Flanagan JC, Sippel LM, Santa Maria MMM, Hartwell KJ, Brady KT, Joseph JE (2019) Impact of oxytocin on the neural correlates of fearful face processing in PTSD related to childhood trauma. Eur J Psychotraumatol 10(1):1606626. https://doi.org/10.1080/20008198.2019.1606626
Fox HC, Hong KI, Siedlarz K, Sinha R (2008) Enhanced sensitivity to stress and drug/alcohol craving in abstinent cocaine-dependent individuals compared to social drinkers. Neuropsychopharmacology 33(4):796–805. https://doi.org/10.1038/sj.npp.1301470
Fox HC, Sofuoglu M, Morgan PT, Tuit KL, Sinha R (2013) The effects of exogenous progesterone on drug craving and stress arousal in cocaine dependence: impact of gender and cue type. Psychoneuroendocrinology 38(9):1532–1544. https://doi.org/10.1016/j.psyneuen.2012.12.022
Gossen A, Hahn A, Westphal L, Prinz S, Schultz RT, Grunder G, Spreckelmeyer KN (2012) Oxytocin plasma concentrations after single intranasal oxytocin administration—a study in healthy men. Neuropeptides 46(5):211–215. https://doi.org/10.1016/j.npep.2012.07.001
Guastella AJ, Hickie IB, McGuinness MM, Otis M, Woods EA, Disinger HM, Chan HK, Chen TF, Banati RB (2013) Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research. Psychoneuroendocrinology 38(5):612–625. https://doi.org/10.1016/j.psyneuen.2012.11.019
Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R et al (2000) Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 284(5):592–597
Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U (2003) Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 54(12):1389–1398 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/14675803
Heinrichs M, von Dawans B, Domes G (2009) Oxytocin, vasopressin, and human social behavior. Front Neuroendocrinol 30(4):548–557. https://doi.org/10.1016/j.yfrne.2009.05.005
Hernandez-Avila CA, Rounsaville BJ, Kranzler HR (2004) Opioid-, cannabis- and alcohol-dependent women show more rapid progression to substance abuse treatment. Drug Alcohol Depend 74(3):265–272. https://doi.org/10.1016/j.drugalcdep.2004.02.001
Higgins RL, Marlatt GA (1975) Fear of interpersonal evaluation as a determinant of alcohol consumption in male social drinkers. J Abnorm Psychol 84(6):644–651. https://doi.org/10.1037//0021-843x.84.6.644
Joseph JE, McRae-Clark A, Sherman BJ, Baker NL, Moran-Santa Maria M, Brady KT (2019) Neural correlates of oxytocin and cue reactivity in cocaine-dependent men and women with and without childhood trauma. Psychopharmacology. https://doi.org/10.1007/s00213-019-05360-7
Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162(8):1403–1413. https://doi.org/10.1176/appi.ajp.162.8.1403
Kay A, Taylor TE, Barthwell AG, Wichelecki J, Leopold V (2010) Substance use and women's health. J Addict Dis 29(2):139–163. https://doi.org/10.1080/10550881003684640
Koch SB, van Zuiden M, Nawijn L, Frijling JL, Veltman DJ, Olff M (2016) Intranasal oxytocin administration dampens amygdala reactivity towards emotional faces in male and female PTSD patients. Neuropsychopharmacology 41(6):1495–1504. https://doi.org/10.1038/npp.2015.299
Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278(5335):52–58. https://doi.org/10.1126/science.278.5335.52
Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24(2):97–129. https://doi.org/10.1016/S0893-133X(00)00195-0
Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E (2005) Oxytocin increases trust in humans. Nature 435(7042):673–676. https://doi.org/10.1038/nature03701
Kubzansky LD, Mendes WB, Appleton A, Block J, Adler GK (2009) Protocol for an experimental investigation of the roles of oxytocin and social support in neuroendocrine, cardiovascular, and subjective responses to stress across age and gender. BMC Public Health 9:481. https://doi.org/10.1186/1471-2458-9-481
Labuschagne I, Phan KL, Wood A, Angstadt M, Chua P, Heinrichs M, Stout JC, Nathan PJ (2010) Oxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorder. Neuropsychopharmacology 35(12):2403–2413. https://doi.org/10.1038/npp.2010.123
Lee MR, Rohn MC, Tanda G, Leggio L (2016) Targeting the oxytocin system to treat addictive disorders: rationale and progress to date. CNS Drugs 30(2):109–123. https://doi.org/10.1007/s40263-016-0313-z
Love TM (2018). The impact of oxytocin on stress: the role of sex. Current opinion in behavioral sciences 23:136–142. https://doi.org/10.1016/j.cobeha.2018.06.018
Lynch WJ, Roth ME, Carroll ME (2002) Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology 164(2):121–137. https://doi.org/10.1007/s00213-002-1183-2
McClure EA, Baker NL, Gray KM, Hood CO, Tomko RL, Carpenter MJ, Ramakrishnan VR, Buchanan CJ, Saladin ME (2019) The influence of gender and oxytocin on stress reactivity, cigarette craving, and smoking in a randomized, placebo-controlled laboratory relapse paradigm. Psychopharmacology 237:543–555. https://doi.org/10.1007/s00213-019-05392-z
McRae AL, Brady KT, Carter RE (2006) Buspirone for treatment of marijuana dependence: a pilot study. Am J Addict 15(5):404. https://doi.org/10.1080/10550490600860635
McRae-Clark AL, Carter RE, Price KL, Baker NL, Thomas S, Saladin ME, Giarla K, Nicholas K, Brady KT (2011) Stress- and cue-elicited craving and reactivity in marijuana-dependent individuals. Psychopharmacology 218(1):49–58. https://doi.org/10.1007/s00213-011-2376-3
McRae-Clark AL, Baker NL, Maria MM, Brady KT (2013) Effect of oxytocin on craving and stress response in marijuana-dependent individuals: a pilot study. Psychopharmacology 228(4):623–631. https://doi.org/10.1007/s00213-013-3062-4
Miller MA, Bershad A, King AC, Lee R, de Wit H (2016) Intranasal oxytocin dampens cue-elicited cigarette craving in daily smokers: a pilot study. Behav Pharmacol 27(8):697–703. https://doi.org/10.1097/FBP.0000000000000260
Moeini M, Omidi A, Sehat M, Banafshe HR (2019) The effects of oxytocin on withdrawal, craving and stress response in heroin-dependent patients: a randomized, double-blind clinical trial. Eur Addict Res 25(1):41–47. https://doi.org/10.1159/000496194
Paliwal P, Hyman SM, Sinha R (2008) Craving predicts time to cocaine relapse: further validation of the Now and Brief versions of the cocaine craving questionnaire. Drug Alcohol Depend 93(3):252–259. https://doi.org/10.1016/j.drugalcdep.2007.10.002
Potenza MN, Hong KI, Lacadie CM, Fulbright RK, Tuit KL, Sinha R (2012) Neural correlates of stress-induced and cue-induced drug craving: influences of sex and cocaine dependence. Am J Psychiatry 169(4):406–414. https://doi.org/10.1176/appi.ajp.2011.11020289
Reed SC, Haney M, Manubay J, Campagna BR, Reed B, Foltin RW, Evans SM (2019) Sex differences in stress reactivity after intranasal oxytocin in recreational cannabis users. Pharmacol Biochem Behav 176:72–82. https://doi.org/10.1016/j.pbb.2018.11.008
Ridenour TA, Maldonado-Molina M, Compton WM, Spitznagel EL, Cottler LB (2005) Factors associated with the transition from abuse to dependence among substance abusers: implications for a measure of addictive liability. Drug Alcohol Depend 80(1):1–14. https://doi.org/10.1016/j.drugalcdep.2005.02.005
Robinson TE, Berridge KC (2003) Addiction. Annu Rev Psychol 54:25–53. https://doi.org/10.1146/annurev.psych.54.101601.145237
Roy A (2002) Urinary free cortisol and childhood trauma in cocaine dependent adults. J Psychiatr Res 36(3):173–177. https://doi.org/10.1016/s0022-3956(02)00002-x
Sarnyai Z, Kovacs GL (2014) Oxytocin in learning and addiction: from early discoveries to the present. Pharmacol Biochem Behav 119:3–9. https://doi.org/10.1016/j.pbb.2013.11.019
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E et al (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33 quiz 34-57
Sherman BJ, Baker NL, McRae-Clark AL (2017) Effect of oxytocin pretreatment on cannabis outcomes in a brief motivational intervention. Psychiatry Res 249:318–320. https://doi.org/10.1016/j.psychres.2017.01.027
Sinha R, Fuse T, Aubin LR, O'Malley SS (2000) Psychological stress, drug-related cues and cocaine craving. Psychopharmacology 152(2):140–148. https://doi.org/10.1007/s002130000499
Sinha R, Garcia M, Paliwal P, Kreek MJ, Rounsaville BJ (2006) Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes. Arch Gen Psychiatry 63(3):324–331. https://doi.org/10.1001/archpsyc.63.3.324
Sobell LC, Sobell MB (1992) Timeline follow-back: a technique for assessing self-reported alcohol consumption. In: Litten RZ, Allen JP (eds) Measuring alcohol consumption: psychosocial and biomedical methods. Humana Press, Totawa, pp 41–72
Sofuoglu M, Dudish-Poulsen S, Nelson D, Pentel PR, Hatsukami DK (1999) Sex and menstrual cycle differences in the subjective effects from smoked cocaine in humans. Exp Clin Psychopharmacol 7(3):274–283
Sofuoglu M, Babb DA, Hatsukami DK (2001) Progesterone treatment during the early follicular phase of the menstrual cycle: effects on smoking behavior in women. Pharmacol Biochem Behav 69(1–2):299–304 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11420098
Sofuoglu M, Mouratidis M, Mooney M (2011) Progesterone improves cognitive performance and attenuates smoking urges in abstinent smokers. Psychoneuroendocrinology 36(1):123–132. https://doi.org/10.1016/j.psyneuen.2010.07.005
Valstad M, Alvares GA, Egknud M, Matziorinis AM, Andreassen OA, Westlye LT, Quintana DS (2017) The correlation between central and peripheral oxytocin concentrations: a systematic review and meta-analysis. Neurosci Biobehav Rev 78:117–124. https://doi.org/10.1016/j.neubiorev.2017.04.017
Van Hedger K, Bershad AK, Lee R, de Wit H (2020) Effects of intranasal oxytocin on stress-induced cigarette craving in daily smokers. Nicotine Tob Res 22(1):89–95. https://doi.org/10.1093/ntr/nty159
Waldrop AE, Price KL, Desantis SM, Simpson AN, Back SE, McRae AL, Brady KT (2010) Community-dwelling cocaine-dependent men and women respond differently to social stressors versus cocaine cues. Psychoneuroendocrinology 35(6):798–806. https://doi.org/10.1016/j.psyneuen.2009.11.005
Funding
This study was sponsored by a National Institute on Drug Abuse grants P50DA016511 (Brady), U54DA016511 (McRae-Clark), K23DA045099 (Sherman), and K24DA038240 (McRae-Clark), with additional support from the National Center for Advancing Translational Sciences grant UL1TR001450 (Brady).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Written informed consent was obtained prior to the baseline assessment. All procedures were conducted in accordance with Good Clinical Practice Guidelines and the Declaration of Helsinki and received Institutional Review Board (IRB) approval.
Conflict of interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Sherman, B.J., Baker, N.L., Brady, K.T. et al. The effect of oxytocin, gender, and ovarian hormones on stress reactivity in individuals with cocaine use disorder. Psychopharmacology 237, 2031–2042 (2020). https://doi.org/10.1007/s00213-020-05516-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-020-05516-w