Clinical trial NCT01573273
Conditions: Cocaine Dependence
Keywords: cocaine substance abuse drug abuse cocaine dependence drug addiction
Sponsor: Medical University of South Carolina
Start date: 2012-10-01; Completion date: 2017-12-19
Enrollment: 112 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Stress is likely involved in relapse to cocaine use. This project will investigate the role oxytocin may play in the stress response in cocaine-dependent men and women and examine how oxytocin may impact brain activity in individuals exposed to cocaine-related cues.

Detailed description:
Stress is an important predictor of relapse, and targeting stress-activated pathways may lead to therapeutic advancements in the treatment of substance use disorders. Oxytocin has been shown to promote trust, social bonding, and calmness; however, its potential effects have not been explored in cocaine-dependent individuals. Oxytocin receptors have been localized to brain regions that are activated by drug-paired cues and preclinical studies have shown that oxytocin attenuates the acute and long-term behavioral effects of psychostimulants. However, little is known about the role of oxytocin in mediating the affective response to cocaine-paired cues and associated neural activity in cocaine-dependent men and women. This project is a direct evolution from our previous SCOR-supported research. Our work has progressed from characterizing sex/gender differences in response to social stressors and cocaine cues in cocaine-dependent men and women, to our on-going work evaluating whether stress potentiates cue-induced craving and the impact of hormones on this response. The proposed study will investigate the role of oxytocin in the sex/gender differences in stress response and craving in cocaine-dependent individuals and preliminarily explore its therapeutic potential.

Arms: arm 1: Cocaine-dependent women received 40 IUs of intranasal oxytocin prior to completing a Social Stress Task. arm 2: Cocaine-dependent women received intranasal saline prior to completing a Social Stress Task. arm 3: Cocaine-dependent women received 40 IUs of intranasal oxytocin prior to completing the first of two fMRI cue-exposure tasks. arm 4: Cocaine-dependent women received intranasal saline prior to completing the first of two fMRI cue-exposure tasks. arm 5: Cocaine-dependent women received 40 IUs of intranasal oxytocin prior to completing the second of two fMRI cue-exposure tasks. arm 6: Cocaine-dependent women received intranasal saline prior to completing the second of two fMRI cue-exposure tasks. arm 7: Cocaine-dependent men received 40 IUs of intranasal oxytocin prior to completing a Social Stress Task. arm 8: Cocaine-dependent men received intranasal saline prior to completing a Social Stress Task. arm 9: Cocaine-dependent men received 40 IUs of intranasal oxytocin prior to completing the first of two fMRI cue-exposure tasks. arm 10: Cocaine-dependent men received intranasal saline prior to completing the first of two fMRI cue-exposure tasks. arm 11: Cocaine-dependent men received 40 IUs of intranasal oxytocin prior to completing the second of two fMRI cue-exposure tasks. arm 12: Cocaine-dependent men received intranasal saline prior to completing the second of two fMRI cue-exposure tasks.
Interventions: intervention 1: Oxytocin intervention 2: Saline
Intervention descriptions: intervention 1: intranasal administration, 40 IUs intervention 2: intranasal administration, 40 IUs

Protocol documents:
Prot_SAP_000.pdf: 
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Title: Oxytocin in Cocaine Dependence 
NCT: 01573273 
Date of Document: 8/1/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Oxytocin in Cocaine Dependence 
SPECIFIC AIMS 
Previous work conducted by the MUSC SCOR identified sex/gender differences in preclinical and clinical 
models of cocaine cue and stress reactivity that may contribute to gender differences in relapse. The proposed 
project will build on this work by exploring potential mechanisms for these sex/gender differences. Specifically, 
several studies have indicated that hypothalamic neuropeptides mediate behavioral responding to stress as 
well as play a role in neuroadaptations that occur as a consequence of long-term cocaine use. The 
hypothalamic neuropeptide oxytocin promotes trust, social bonding, and calmness. Given these effects, 
oxytocin may have a therapeutic role in ameliorating the negative affect commonly observed prior to relapse in 
cocaine-dependent individuals. As estrogen appears to enhance oxytocin’s effects, women may have an 
enhanced response to oxytocin. The specific aims of the proposed project are:  
 
Specific Aim 1: Using a human laboratory paradigm, determine the impact of oxytocin on stress-
induced craving in cocaine-dependent women and men. 
Preclinical and clinical investigations have found that the neuropeptide oxytocin exerts anxiolytic effects in 
stress paradigms. However, little is known about the potential anxiolytic effects of oxytocin in cocaine-
dependent individuals, or if a gender differential in response exists.  
Hypothesis 1a: Intranasal administration of oxytocin will attenuate drug craving response and stress reactivity 
to a psychosocial stress task in cocaine-dependent individuals compared to placebo administration.   
Hypothesis 1b: The ameliorative effects of oxytocin on drug craving response and stress reactivity will be 
more pronounced in cocaine-dependent women as compared to cocaine-dependent men. 
Exploratory Hypothesis 1c:  The stress and craving reduction induced by oxytocin in women will be related 
to estrogen and progesterone levels.  
Specific Aim 2: Using a neuroimaging cue paradigm, explore the impact of oxytocin on neural 
correlates and subjective responses of cocaine cue reactivity in cocaine-dependent men and women.  
Presentation of cocaine-paired cues elicits a stress response in cocaine-dependent individuals. Neuroimaging 
studies indicate substantial overlap in the corticostriatal limbic circuitry responsible for cue and stress-primed 
drug craving. Oxytocin receptors have been localized to these same regions and preclinical studies have 
shown that oxytocin attenuates the acute reinforcing properties of psychostimulants. Despite these findings, 
little is known about the role of oxytocin in modulating the affective response to cocaine-paired cues and 
associated neural activity in cocaine-dependent men and women and whether there are gender differences in 
this modulation.   
Hypothesis 2a: Intranasal administration of oxytocin will decrease subjective ratings of cue-induced cocaine 
craving in cocaine-dependent men and women compared to placebo administration.  
Hypothesis 2b: Intranasal administration of oxytocin will decrease functional activity in the anterior cingulate 
cortex, amygdala, striatum, and prefrontal cortex compared to placebo administration.   
Exploratory Hypothesis 2c: The attenuation of functional activity in the anterior cingulate cortex, amygdala, 
striatum and prefrontal cortex following oxytocin administration will be greater in cocaine-dependent women as 
compared to cocaine-dependent men. 
Exploratory Hypothesis 2d: Oxytocin will modulate resting-state and task-related functional connectivity 
among sub-networks implicated in reward and motivation (nucleus accumbens, and orbitofrontal cortex), 


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memory and learning (amygdala and hippocampus), and cognitive control (prefrontal cortex and anterior 
cingulate cortex). Oxytocin may increase connectivity between reward/motivation and cognitive control sub-
networks in craving states as an index of top-down regulation. 
In summary, the proposed project will provide important data on the effect of oxytocin on stress and craving in 
cocaine-dependent individuals, explore the neural circuitry involved in response to oxytocin administration, and 
investigate whether sex/gender differences in response exist. 
 
RESEARCH STRATEGY 
A. Significance 
Gender differences in cocaine use disorders. A growing body of literature indicates important gender 
differences in the symptomatology, course, and treatment of addictive disorders, including cocaine 
dependence. Approximately 38% of the 5.3 million individuals in the United States who reported cocaine use in 
2008 were women (SAMSHA, 2009); despite this lower prevalence of use, there is evidence that women may 
actually have an increased vulnerability to the development and deleterious consequences of cocaine 
dependence. Women meet criteria for drug dependence more quickly and enter treatment programs earlier as 
compared to men (Brecht et al., 2004; Cotto et al., 2010; Hernandez-Avila et al., 2004; McCance-Katz, 1999; 
Ridenour et al., 2005; Westermeyer & Boedicker, 2000). Cocaine-dependent women also have greater 
psychiatric, medical, social/family, and employment problems (Brady & Randall, 1999; Elman et al., 2001; 
Najavits & Lester, 2008; Wong et al., 2002) and are more likely to attribute relapse to negative emotional states 
and interpersonal conflict than men (Connors et al., 1998; Terry-McElrath et al., 2009). These findings suggest 
gender differences in cocaine use and dependence which may have important treatment implications.  
 
Stress and substance use. Multiple theories of addiction postulate that stress plays an important role in 
vulnerability and motivation to use and abuse substances (Brady & Sinha, 2005; Higgins & Marlatt, 1975; Koob 
& Le Moal, 2001; Russell & Mehrabian, 1975). Generally, these models suggest that drug use may begin as an 
attempt to modulate tension or distress in some cases. Over time, dependence can develop, and motivation for 
drug use may include treatment of withdrawal symptoms and response to conditioned cues as well as stress 
relief and mood enhancement. Thus, vulnerability to drug dependence and relapse may be a result of negative 
reinforcement/relief from stress or positive reinforcement/mood enhancement. Consistent with this model, 
clinical studies have shown drug or alcohol consumption to be positively associated with subjective reports of 
stress, lack of support, and avoidance coping (Cronkite & Moos, 1984; Hall, Havassy, & Wasserman, 1991; 
McMahon, 2001; Pohorecky, 1991). Data from our previous SCOR work also suggests that cocaine use can be 
related to stress and negative life events (Waldrop et al., 2007a; Waldrop et al., 2007b).  
 
Stress and craving. Considerable empirical literature exists demonstrating that internal mood states related to 
stress and negative emotion can elicit craving in a laboratory setting, even in the absence of drug cues 
(Childress et al., 1994; Cooney et al., 1997; McRae-Clark et al., 2011; Sinha et al., 1999). In cocaine-
dependent individuals, studies show that personalized imagery of stress situations as well as exposure to drug-
related cues produce significant increases in cocaine craving, heart rate, cortisol, and subjective anxiety (Fox 
et al., 2008; Sinha et al., 1999; Sinha et al., 2000). Of note, our SCOR data suggests that there may be 
important gender differences in subjective ratings of stress and craving in response to cocaine cues and 
interpersonal stressors. Following presentation of cocaine-related cues, peak subjective ratings of stress and 
craving were correlated in both cocaine-dependent men and women. In response to a social stressor, 
subjective ratings of peak stress and craving were correlated in cocaine-dependent women; however, a 
significant correlation was not present in cocaine-dependent men (Waldrop et al., 2010). These findings 
suggest that stress related to interpersonal triggers is more highly associated with drug craving in women as 
compared to men. Importantly, several studies have found stress/mood-elicited craving predicted relapse to 
substance use (Cooney et al., 1997; Killen & Fortmann, 1997; Sinha et al., 2006). We have also recently 
reported that subjective stress and craving response to a pharmacological stressor (corticotrophin releasing 
hormone) predicts relapse to cocaine use (Back et al., 2010). Thus, it appears that provocation of subjective 


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stress not only elicits craving, but it may also independently predict relapse, supporting the targeting of stress-
activated pathways for relapse medication development (Winhusen & Somoza, 2001).  
 
Stress and cue reactivity. Cue-reactivity paradigms are commonly used in systematic investigations of 
craving (Drummond et al., 1990). The presentation of cocaine-related cues may also induce stress responses. 
Data from the previous funding period demonstrated increased subjective feelings of stress in cocaine-
dependent individuals following cue presentation (Waldrop et al., 2010). This is congruent with other reports of 
increased anxiety and negative emotion following cocaine-cue exposure (Fox et al., 2008; Sinha et al., 2000). 
Further, cocaine-cue videos produced significantly greater brain activity in cocaine-dependent individuals than 
healthy controls in regions that were activated in response to sad videos. Thus, drug-paired cues may recruit 
brain regions responsible for the processing of negative affective stimuli (Wexler et al., 2001).   
 
Oxytocin and stress. Oxytocin is a nine amino acid neuropeptide with peripheral endocrine and central neural 
actions that is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. Peripherally, 
oxytocin elicits physiologic events necessary for copulation, parturition, and lactation (Ludwig & Leng, 2006). 
Central release of oxytocin within limbic nuclei has been implicated in “pro-social” behaviors and may also 
have anxiolytic effects. For example, several preclinical studies have shown that oxytocin increases approach 
behavior in rats (Witt et al., 1992), and is essential for partner preferences and monogamous pair bonding in 
prairie voles (Williams et al., 1994). Central administration of oxytocin receptor antagonists prevents pair 
bonding in female prairie voles without any significant impact on mating. In fact, neonatal nurturing promotes 
long-term plasticity within the limbic circuitry, while childhood maltreatment has been associated with low 
urinary oxytocin levels (Francis et al., 2002; Fries et al., 2005). Intranasal administration of oxytocin attenuates 
anticipatory anxiety, subjective stress, and hypothalamic-pituitary-adrenal (HPA) axis activation to a 
psychosocial laboratory stress task and increases trust (de Oliveira et al., 2011; Heinrichs et al., 2003; Kosfeld 
et al., 2005). In addition, intranasal oxytocin attenuates circulating cortisol levels in men with a history of 
childhood maltreatment (Meinlschmidt & Heim, 2007). In agreement, neuroimaging studies demonstrate that 
intranasal administration of oxytocin attenuates amygdala activation following stressful and fearful stimuli 
(Baumgartner et al., 2008; Domes et al., 2007; Kirsch et al., 2005). Taken together, these studies demonstrate 
that oxytocin may play a potential therapeutic role in ameliorating stress and anxiety.  
 
Oxytocin and substance use disorders. Both preclinical and clinical studies suggest that oxytocin may 
attenuate the effects of both acute and long-term drug use. Molecular studies have localized oxytocin receptors 
to the mesolimbic dopamine reward circuit, including the amygdala, nucleus accumbens, and ventral tegmental 
area (VTA) (Vaccari et al., 1998). Similar to drugs of abuse, oxytocin infusion directly into the VTA promotes 
dopamine release in the nucleus accumbens (Melis et al., 2007). Systemic administration of oxytocin promotes 
conditioned place preference in rodents, indicating that oxytocin is rewarding (Liberzon et al., 1997). 
Behavioral studies utilizing animal models of drug reinforcement demonstrate that oxytocin dose-dependently 
decreases cocaine-induced hyperactivity and stereotypy (Sarnyai et al., 1991; Sarnyai et al., 1992).  
Interestingly, chronic administration of oxytocin reduces dopamine release in the nucleus accumbens, 
indicating that oxytocin may be involved in the plasticity that occurs within the reward circuit as a function of 
repeated drug use (Kovacs et al., 1998). In addition, oxytocin inhibits the development of tolerance to repeated 
cocaine administration (Sarnyai et al., 1992) and may also attenuate self-administration of cocaine (Sarnyai & 
Kovacs, 1994). Oxytocin administration has been shown to block methamphetamine-induced locomotor activity 
and reduce methamphetamine reinstatement (Carson et al., 2010). These preclinical findings implicate 
oxytocin in the acute effects of stimulants, as well as the long term behavioral consequences of repeated use. 
 
Limited clinical research has examined the effects of oxytocin in drug-dependent populations. 
Immunohistochemical analysis of post-mortem brains from alcoholics indicate a significant reduction in 
oxytocin immunoreactivity in the hypothalamus (Sivukhina et al., 2006).  Further, mothers using cocaine during 
pregnancy exhibit significantly lower plasma oxytocin levels, as well as greater hostility and depression as 
compared to control mothers (Light et al., 2004). Based on a positive preclinical study in which increasing 
oxytocin levels were hypothesized to moderate the effects of lithium-attenuated cannabinoid withdrawal in rats 


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(Cui et al., 2001), a trial of lithium on marijuana withdrawal symptoms demonstrated positive outcomes, 
including decreased anxiety, lending support to this hypothesis (Winstock et al., 2009). These clinical findings, 
coupled with preclinical reports, suggest that oxytocin may decrease some symptoms associated with drug 
dependence such as negative affect, withdrawal, and tolerance. Our group has recently completed a pilot 
investigation of oxytocin administration prior to a social stressor task in marijuana-dependent participants. 
Oxytocin-treated individuals, as compared to placebo, demonstrated a significant trend towards reduced 
craving and cortisol response (see Preliminary Data). The proposed study will be the first controlled 
examination of the effect of oxytocin on stress or cue-induced craving in cocaine-dependent individuals.  
 
Neural correlates of drug craving, sex differences, and potential role of oxytocin. Compulsive drug-
seeking in response to stress and drug cues may be a function of disruption in the circuitry responsible for 
maintaining executive control and response inhibition in response to emotional evocative stimuli (Baler & 
Volkow, 2006). In support, neuroimaging studies of cocaine-dependent individuals have implicated prefrontal, 
limbic and striatal regions in both cue and stress-primed drug craving. For example, cocaine cues (videos and 
guided imagery) increase activity in limbic regions including the amygdala and anterior cingulate cortex of 
cocaine-dependent individuals but not healthy controls (Childress et al., 1999; Wexler et al., 2001; Garavan et 
al., 2000). Kilts and colleagues found that activity in the ventral striatum of cocaine-dependent men was 
significantly greater during cocaine-cue exposure than during exposure to neutral cues (Kilts, et al., 2001). In 
contrast, stress attenuated activity in frontal, limbic/paralimbic regions and increased activity in the dorsal 
striatum of cocaine-dependent individuals (Sinha et al., 2005).   
 
Significant sexual dimorphism in frontal-limbic-striatal structure, function, and neurochemistry are well 
documented (Cahill, 2006). Therefore, it is not surprising that there are sex differences in the neural correlates 
of drug craving. For example, stressful imagery produced greater activity in the left anterior and right posterior 
cingulate, left insula, and inferior medial cortices of cocaine-dependent women as compared to cocaine-
dependent men (Li et al., 2005). On the other hand, cocaine-dependent women exposed to guided imagery of 
cocaine use exhibited significantly less activity in the amygdala, insula, orbitofrontal and ventral cingulate 
cortices as compared to cocaine-dependent men (Kilts et al., 2004).   
 
Interestingly, oxytocin receptors appear to be widely distributed within frontal-striatal-limbic regions.  In 
situ hybridization studies have localized oxytocin receptor mRNA in the hypothalamus, rostral regions of the 
frontal cortex, bed nucleus of the stria terminalis, anterior cingulate, dorsal striatum, and the amygdala 
(Yoshimura et al., 1996; Yoshimura et al., 1993). In addition, oxytocin administration attenuates amygdala 
activity to emotional evocative faces (Domes et al., 2007). Of note, the reduction in amygdala activity was 
observed in response to both aversive and happy faces, indicating that oxytocin may attenuate reactivity to 
both aversive and appetitive stimuli. 
 
Functional Connectivity in Cocaine Users. Measures of resting state functional connectivity have been 
employed in neuroimaging studies to evaluate the strength of communication within networks encoding 
functions ranging from vision and somatosensory perception to motivation and executive function (Fox & 
Raichle, 2007; Fox et al., 2005). Recently, measures of resting state functional connectivity have been applied 
to substance-dependent populations. The strength of connectivity within regions in the reward circuit was 
compared between healthy controls and cocaine users. Greater functional connectivity was found between the 
ventral striatum and orbitofrontal cortex of the cocaine group compared to healthy controls (Wilcox et al., 
2011). In contrast, Gu and colleagues found that the strength of connectivity between the ventral tegmental 
area, thalamus/lentiform nucleus/ventral striatum, medial prefrontal cortex, and amygdala was significantly 
lower in cocaine-dependent individuals as compared to controls (Gu et al., 2010). Tomasi and colleagues 
found that cocaine abusers exhibited significantly lower connectivity between the midbrain, thalamus, rostral 
cingulate cortex, and cerebellum (Tomasi et al., 2010). This disparity in findings indicates the need for 
additional studies assessing functional connectivity in cocaine-dependent individuals. Moreover, the strength of 
functional connectivity during exposure to cocaine cues has not been explored. 
 


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Impact of estrogen and progesterone on reward, craving, and response to oxytocin. Estrogen and 
progesterone levels fluctuate throughout the menstrual cycle. Progesterone levels peak seven to twelve days 
after ovulation marking the middle of the luteal phase; estrogen levels dominate throughout the cycle but peak 
six to ten days after the start of the menstrual cycle, marking the mid-follicular phase (Evans et al., 2002). In 
addition to sex differences in brain structure, function, and neurochemistry, circulating gonadal hormones play 
a critical role in mediating the subjective response to the drug itself, cues, and stress. Preclinical studies have 
localized estrogen and progesterone receptors to brain regions responsible for mediating the physiological and 
behavioral response to stress and cues (Alves et al., 1998; Cushing & Kramer, 2005; Laflamme et al., 1998). 
Preclinical studies conducted by MUSC SCOR investigators demonstrated that cocaine seeking is significantly 
attenuated during the proestrus phase of the estrous cycle when progesterone levels are highest (Feltenstein 
& See, 2007; Kippin et al., 2005). In a recent study of treatment-seeking cocaine-dependent women, subjective 
craving following exposure to a laboratory stressor was significantly lower in women with elevated 
progesterone compared to women with low progesterone (Sinha, et al., 2007). It has also been demonstrated 
that ovarian hormone levels can impact the response to smoked cocaine with the positive or “rewarding” 
effects of cocaine significantly lower during the luteal phase compared to the follicular phase (Evans et al., 
2002; Sofuoglu et al., 1999). Taken together, these studies indicate that during the follicular phase when 
estrogen levels are elevated, the positive and rewarding properties of stimulants peak, while increases in 
progesterone during the luteal phase may be decrease craving and/or drug effect.   
 
Surprisingly few studies have examined the impact of ovarian hormones on the neural correlates of 
drug craving; however; neuroimaging studies of healthy women tested at different phases of their menstrual 
cycle are intriguing. For example, Goldstein and colleagues compared brain activity of healthy women exposed 
to images depicting negative affective stimuli during both the early and late follicular/mid-cycle phase of their 
menstrual cycle. Activity within the limbic regions was significantly greater during early as compared to late 
follicular phase (Goldstein et al., 2005). In addition, during the late follicular phase, the magnitude of activity in 
the amygdala was correlated with arousal, a pattern not observed early in the cycle when both progesterone 
and estrogen are low. While these data suggest that estrogen may attenuate limbic reactivity to emotional 
evocative stimuli in healthy subjects, the role of progesterone is unclear since subjects were not tested during 
the luteal phase of their cycle. Dreher and colleagues measured the limbic response to uncertain anticipated 
monetary reward in healthy women during the mid-follicular and mid-luteal phases of their menstrual cycle.  
Anticipation of uncertain rewards produced significantly greater activity in the amygdala and orbitofrontal cortex 
during the follicular phase than the luteal phase of their cycle (Dreher et al., 2007), suggesting that estrogen 
may enhance limbic responding to predictors of reward. 
 
Studies have indicated that the ability of oxytocin to modulate social behaviors, such as attachment and 
aggression, is dependent upon gonadal hormone receptors localized the within limbic circuitry. Estrogen 
promotes oxytocin release and is required for the synthesis of oxytocin receptors in the amygdala (Lim & 
Young, 2006). Animal studies have also demonstrated greater oxytocin release in females compared to males 
in response to threat (De Kloet et al., 1986; McCarthy, 1995). In one clinical study, oxytocin or placebo spray 
was administered to couples engaged in a ten-minute conflict discussion of finances, education, or leisure time 
(Ditzen et al., 2009). While oxytocin significantly increased positive behaviors (eye contact and emotional self-
disclosure) relative to negative behavior (contempt and defensiveness) compared with the placebo, no 
significant gender differences were found. However, a trend towards an accelerated reduction in salivary 
cortisol levels following the task was observed in the oxytocin-treated women, but not in the men. As stated 
previously, cocaine-dependent women are more likely to report negative affect and stress prior to relapse as 
compared to men. Combined with the evidence that estrogen enhances the effects of oxytocin, a more robust 
anxiolytic/anticraving response to oxytocin in drug-dependent women as compared to men might be predicted. 
This hypothesis will be tested in the proposed project. 
Genetic Testing: The role of neuropeptides in mediating the affective and behavioral responses to stress and 
cues is well documented.  However, there is still significant individual variability in the OT system.  For 
example, exogenous OT increases trust and bonding others have found that OT reduces trust and social 
bonding in individuals with borderline personality disorder (Simeon, et al., 2011:Bartz, et al., 2011).  In addition, 
while one study found that low levels of plasma OT were associated with symptom severity in women with 


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major depression, another study found no correlation (Ozsoy, et al., 2009; Parker, et al., 2010).  Thus, 
understanding how individual variability in the OT system impacts the affective responses to stress particularly 
in cocaine-dependent individuals could have a significant impact on the development of effective treatment 
strategies targeted at specific neuropeptide systems.  An emerging literature suggests that genetic 
polymorphisms in neuropeptide receptors play an important role risk and resilience to psychopathology (Brune, 
2012). For example, polymorphic variation in the OT receptor gene (rs2254298) has been associated with an 
increased risk for depression and anxiety disorders.  Therefore we plan to examine genes associated with the 
neuropeptide system that regulate the corticolimbic brain activity. Blood will be collected from consenting 
participants for genetic testing. Our group has previously collaborated with Dr. Ananda Amstadter at Virginia 
Commonwealth University (VCU), whose research group has been actively investigating genetic variations 
associated with addiction. Briefly, whole blood will be collected in EDTA containing vacutainers and stored at -
70º at the Institution of Psychiatry Laboratory.  De-identified samples will be shipped on dry ice  to Dr. 
Amstadter’s Laboratory at VCU.  The DNA will be extracted and assayed using standardized commercially 
available kits.   
 
Summary. Stress is an important predictor of relapse, and targeting stress-activated pathways may lead to 
therapeutic advancements in the treatment of substance use disorders. Oxytocin has been shown to promote 
trust, social bonding, and calmness; however, its potential effects have not been explored in cocaine-
dependent individuals. Oxytocin receptors have been localized to brain regions that are activated by drug-
paired cues and preclinical studies have shown that oxytocin attenuates the acute and long-term behavioral 
effects of psychostimulants. However, little is known about the role of oxytocin in mediating the affective 
response to cocaine-paired cues and associated neural activity in cocaine-dependent men and women. This 
project is a direct evolution from our previous SCOR-supported research. Our work has progressed from 
characterizing sex/gender differences in response to social stressors and cocaine cues in cocaine-
dependent men and women, to our on-going work evaluating whether stress potentiates cue-induced 
craving and the impact of hormones on this response. The proposed study will investigate the role of 
oxytocin in the sex/gender differences in stress response and craving in cocaine-dependent 
individuals and preliminarily explore its therapeutic potential.  
 
B. Innovation 
The proposed project will be the first clinical investigation of oxytocin in cocaine-dependent individuals. 
It has been suggested that oxytocin may be useful therapeutically in addiction treatment (Carson et al., 2010); 
however, limited clinical research with oxytocin in addicted populations has been conducted. Further, although 
a strong preclinical literature supports the role of ovarian hormones in cocaine craving and relapse, little is 
known about the impact of ovarian hormones on the neural correlates of drug craving. The methodology 
proposed also incorporates novel technologies and analytical techniques. The use of neuroimaging will 
allow identification of the neural circuitry involved in oxytocin-mediated affective response to cocaine-
paired cues, and exploration of sex/gender differences in activation. Inclusion of functional connectivity 
analyses will allow further elucidation of the sub-networks involved in cocaine-related reward and motivation. 
Further, the proposed project is innovative as it is extends an animal model of a potential therapeutic 
intervention (oxytocin) to a human laboratory setting. Therefore, this project will further the ability to 
directly translate findings from an animal model to an ecologically valid test of stress and relapse in cocaine-
dependent humans, and explore the impact of hormonal status on response in this model. 
 
C. Approach 
C.1. Preliminary Studies. Below, a brief overview of some of the major findings from our previous funding 
periods is provided. Additionally, preliminary data of direct relevance to the proposed project is presented.  
 


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C.1.a. Progress report. In our initial SCOR project, we explored sex/gender differences in response to a 
social stressor and drug cues in cocaine-dependent individuals. As discussed above, we found gender 
differences in the relationships between subjective ratings of craving across the tasks suggesting that social 
stressors may be more closely associated with relapse for cocaine-dependent women as compared to men 
(Waldrop et al., 2010). Further, greater dysregulation in the HPA-axis response to corticotropin-releasing 
hormone (CRH) was observed in cocaine-dependent women as compared to cocaine-dependent men or 
healthy men and women (Brady et al., 2009). Subjective response to CRH and drug cues in the laboratory 
setting correlated with relapse to cocaine use (Back et al., 2010). We additionally investigated the impact of 
early life trauma and current life stressors, and how these factors may contribute to stress response, craving, 
and cocaine use (Back et al., 2008; DeSantis et al., 2011; Moran-Santa Maria et al., 2010; Waldrop et al., 
2007). A complete listing of publications resulting from our previous work can be found in Appendix 4. Taken 
together, our findings suggest that the HPA axis in women may be more sensitive to the toxic effects of 
cocaine or early life trauma as compared to men. Cocaine-dependent women have a greater physiologic and 
subjective response to stress and the magnitude of this response may be related to the potential for relapse. 
This suggests that the stress response is particularly important in understanding sex/gender differences in drug 
dependence and other psychiatric disorders and is also an important target in developing both 
psychotherapeutic and pharmacotherapeutic interventions for cocaine-dependent women.   
C.1.b. Oxytocin Administration. In a paradigm similar 
to what will be used in the proposed project, we 
administered oxytocin or placebo nasal spray to 16 
marijuana-dependent individuals. As shown in Figure 
1, oxytocin treatment prior to completion of the Trier 
Social Stress Task (TSST) resulted in an attenuated 
cortisol response as compared to placebo (p=0.066). A 
decrease in craving with oxytocin administration 
compared to placebo was also observed (p=0.025). 
These pilot results suggest that oxytocin may be useful 
for reducing stress response and craving in drug-
dependent populations. An open-label pilot study 
involving oxytocin administration in cocaine-dependent 
participants is ongoing. To date, we have administered 
oxytocin to five cocaine dependent individuals, and the 
drug has been well-tolerated. 
 
C.1.c. Examination of neural correlates of cocaine craving. We are currently conducting a neuroimaging 
study (R01DA023188-S2; PI: Brady) in which we have examined response to cocaine cues in 39 cocaine-
dependent participants using fMRI. In this sample, the presentation of cocaine cues, relative to neutral objects, 
was associated with a widespread pattern of 
activation including left occipital cortex, left 
superior 
frontal 
gyrus, 
right 
dorsolateral 
prefrontal cortex, anterior cingulate, bilateral 
hippocampus, right amygdala, posterior cingulate 
cortex, and left orbitofrontal cortex (see Figure 
2). Subjective craving was significantly higher 
following cocaine images blocks (M = 1.66, SD = 
0.89) versus neutral object blocks (M = 0.58, SD 
= 0.61; p < 0.001), demonstrating our ability to 
elicit craving with our scanning paradigm. 
C.1.d. Functional Connectivity in Cocaine Users. We recently completed a preliminary study using a graph 
theory-based approach to functional connectivity with the Brain Connectivity Toolbox (BCT; Rubinov & Sporns, 
2011) to examine changes in functional network structure when cocaine-users (n=37) were viewing cocaine-
Figure 1. Change in cortisol following oxytocin 
administration and TSST completion. 
 
Figure 2. SPM map of blood oxygen level dependent 
(BOLD) response to cocaine cues minus neutral objects 
using a voxelwise threshold of z = 3.09 and a corrected 
cluster threshold of p < 0.05. 
 


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related pictures compared to rest. Figure 3 shows the modular structure based on the group-averaged 
correlation matrix. In the rest condition, 4 modules emerged (color coded in Figure 3), but in the cocaine 
condition, there was significant reorganization of the modules relative to rest. The blur condition was identical 
to rest whereas the object condition was different from both the rest and cocaine conditions. Notably, in the 
cocaine condition there was greater integration across brain regions as evidenced by the emergence of only 3 
modules. In addition, the diversity coefficient (which is a measure of functional integration) was greater in the 
cocaine than the rest condition for all regions that changed module membership in the cocaine condition 
(Figure 3-cocaine; all p’s < .05) except for the right middle occipital gyrus (region 52). Regions that became 
more integrated with the fronto-parietal module (green) included the insula, posterior cingulate, auditory cortex, 
and dorsal visual regions. We speculate that this reorganization reflects heightened attention to and salience of 
the cocaine stimuli given the characterization of fronto-parietal cortex as a dorsal attention network (Fox et al., 
2006) and insula-cingulate connections 
as part of a salience network (Menon & 
Uddin, 2010). There was also increased 
connectivity/integration of ventral visual 
regions with temporal and ventro-
medial prefrontal regions which may 
reflect strong engagement of memory 
systems related to the cocaine images 
(Childress et al., 1999). Although some 
typical reward-related regions (caudate, 
putamen; 
blue 
module) 
were 
dissociated from the other modules in 
the 
cocaine 
condition, 
this 
also 
occurred 
when 
participants 
were 
viewing objects. The other changes in 
module membership in Figure 4 were 
specific 
to 
the 
cocaine 
condition. 
Although this is a preliminary analysis, it 
demonstrates 
the 
feasibility 
of 
conducting 
graph 
theory-based 
functional connectivity analysis for the 
proposed project. In addition, regions that changed module membership in the cocaine condition included 
some of the same regions that have oxytocin receptors (e.g., amygdala, anterior/posterior cingulate, and 
striatum). Finally, Olaf Sporns, a major developer of the BCT, has agreed to be consultant on this project (see 
Letter of Support). He is currently integrating network-based statistics (Zalesky et al., 2010) into the BCT to 
allow for group comparisons of functional networks.  
 
C.1.e. Summary. As demonstrated by the work above, the research team has experience with stress-induction 
studies (Brady, McRae-Clark, Moran-Santa Maria), cue-reactivity research (Brady, McRae-Clark), 
administration of oxytocin (McRae-Clark), neuroimaging (Brady, Joseph, Moran-Santa Maria), functional 
connectivity analyses (Sporns, Joseph), and recruitment and retention of cocaine-dependent individuals for 
participation in laboratory-based studies (Brady, McRae-Clark). Hence, the study team has the necessary skills 
to ensure the successful completion of the proposed study. 
 
C.2. Research Design and Methods. In this project, the impact of acute pre-treatment with oxytocin (40 IU) or 
placebo on the subjective and physiologic response to the Trier Social Stress Task (TSST) in men and women 
with cocaine-dependence will be investigated. Additionally, participants will complete two functional magnetic 
resonance imaging (fMRI) scans in the presence of cocaine-related cues. Prior to each scan, participants will 
receive either oxytocin (OXY) or placebo (PBO) in a counter-balanced, double-blind fashion. A schematic of 
study procedures is shown below. 


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C.2.a. Participants. A total of 152 participants (76 cocaine-dependent women and 76 cocaine-dependent 
men), aged 18 or older, will be recruited over a 51-month period. Additional inclusion criteria include consent to 
random assignment and ability to read and provide informed consent. Exclusion criteria include women who 
are pregnant, nursing, or plan to become pregnant during the course of the study; women who have had a 
complete hysterectomy, are post-menopausal, are receiving hormone replacement or hormonal contraceptive 
therapy,; having a history of or current major psychiatric or medical disorder; requiring concomitant medication 
that could affect neuroendocrine measures; and being currently dependent on other substances, with the 
exception of nicotine, alcohol and marijuana. A detailed list of inclusion/exclusion criteria can be found in 
Human Subjects. 
 
C.2.b. Recruitment. Participants will be recruited primarily through media advertisements, as we have had 
good results using this method in previous studies. We are using a similar recruitment strategy for our ongoing 
SCOR protocol. In addition to recruiting through advertisements, our research group also has established 
relationships with clinical programs that screen individuals for research or treatment program participation.  In 
particular primary clinical sources which could be used for recruitment include individuals presenting to the 
Charleston Center for inpatient or outpatient treatment and individuals from the Ralph H. Johnson VA Medical 
Center. For patients involved in clinical programs, participation in this protocol will be arranged so as not to 
interfere with treatment participation. Chart review may also be conducted to identify potential subjects, 
although only subjects who have agreed to be contacted about research will be contacted. During the previous 
SCOR funding period, we consented over 700 cocaine-dependent research participants.  Respondent-Driven 
Sampling” (RDS), will be used to enhance recruitment of the sample (Heckathorn, 1997). The RDS sampling 
methodology is based on recruiting the eligible friends and acquaintances of each participant so that the 
sample “snowballs”. Each eligible participant who completes an interview will be given coupons to pass on to 
other potential participants. The coupons will have a unique code linked to the person who passes them out. A 
referral will be instructed to call the site offices for screening and, if eligible, an appointment for further 
evaluation. If a referral completes the screening process and is eligible for the study, the participant who 
referred the person can redeem the coupon for $20 and 5 fishbowl picks . 
C.2.c. Procedures. 
C.2.c.1. Screening/Assessment. Individuals will be screened for eligibility over the telephone by a trained 
research assistant. Major inclusion/exclusion criteria will be assessed during the telephone interview; if an 
individual seems potentially eligible, (s)he will be invited for an in-person interview with the research team. 
Prior to any study procedures, the individual will sign an IRB-approved informed consent form. Following 
consent, a battery of standardized assessments will be delivered (described below). At the time of this 
interview, a general medical history and physical exam will be performed to insure that the subject is eligible to 
participate. If a patient is ineligible to participate, (s)he will be given a referral for medical care and/or an 
appropriate treatment program. 
 
a. Screening and Diagnostic Instruments. Quick Screen: This assessment will quickly determine whether 
an individual meets study inclusion or exclusion criteria. The instrument is designed to assess for substance 
dependence and obvious psychiatric, medical, and logistic exclusions. Mini-International Neuropsychiatric 
Interview (M.I.N.I.): The M.I.N.I. is a brief structured interview that was designed to assess DSM-IV diagnoses 
using a series of questions in dichotomous format (yes/no). Earlier studies have found that the M.I.N.I. is 
similar in sensitivity, specificity, and inter-rater reliability to other more lengthy diagnostic interviews, such as 
Assessment
Day 1
• Abstinence assessed
• OXY or PBO
• TSST completed  
Day 2
• Abstinence assessed
• OXY or PBO
• fMRI session 1 completed
Day 3
• Abstinence assessed
• OXY or PBO
• fMRI session 2 completed
Follow-up


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the SCID-I/P (Sheehan & Lecrubier, 2003; Sheehan et al., 1998). Structured Clinical Interview for DSM-IV 
(SCID-I/P): The SCID-P is a structured diagnostic interview that assesses each of the criteria for DSM-IV 
diagnoses. The alcohol and drug use disorder modules will be to thoroughly assess both current and lifetime 
diagnostic status for abuse and dependence. It has excellent inter-rater and test-retest reliability (First et al., 
2002). Menstrual History Diary: Participants will be asked to estimate the timing of their cycle for the 90-days 
prior to study entry and to track their cycle during study participation. Daily Hassles Scale: The Daily Hassles 
Scale consists of a list of 117 irritating, frustrating, or distressing events that characterize everyday interactions 
with the environment. Participants rate both frequency and intensity for the past month. The Daily Hassles 
Scale is positively correlated with adaptational ability and is a good predictor of psychological symptoms 
(Kanner et al., 1981). Adverse Childhood Experiences (ACE) Questionnaire: The modified ACE 
questionnaire assesses childhood maltreatment and exposure to household dysfunction. It has been utilized to 
examine the relationship between adverse childhood experiences and health risk behavior in adulthood (Felitti 
et al., 1998). In addition to providing data to assess the impact of early childhood trauma on cocaine use, 
utilization of the ACE will allow for potential cross-SCOR collaborations as it also being employed by the 
UCLA, Yale and Harvard SCORs. Childhood Trauma Questionnaire (CTQ):  The CTQ is a 25-item self-
report questionnaire used to assess the extent to which individuals have experienced five domains of 
childhood abuse and neglect (sexual abuse, physical abuse, emotional abuse, emotional neglect and physical 
neglect). Subjects answer each question using a 5-point Likert scale ranging from (1) never true to 5 (very 
often true). Severity scores for each domain can range from 5 (no history of abuse/neglect) to 25 (severe 
abuse/neglect). The questionnaire also includes a minimization/denial scale. The reliability and validity of the 
CTQ are excellent (D. P. Bernstein, et al., 1997; D. P. Bernstein, Fink, L.A., 1998). The Pittsburg Sleep 
Quality Index will be used to assess sleep patterns (Buysse, et al., 1989). The Quick Inventory of 
Depressive Symptoms (Rush, et al., 2003) will be used to measure depression and a short form anxiety scale 
from the PROMIS© item bank will be used to measure anxiety.  The Life Events Occurrence Scale 
(Maciejewski,, et al.) will be used to inventory adult trauma. A brief survey from the National Health and 
Nutrition Examination Survey (CDC, 2000) will be used to rate quality of life, and a body map will be used to 
rate areas of pain. A brief smoking history will also be obtained. 
 
b. Substance-Related Instruments. Form 90: The Form 90 (Miller, 1996), an assessment instrument 
commonly used in substance use studies, is similar in concept to the Time Line Follow-back (Sobell & Sobell, 
1992). This is a calendar-based instrument designed to assess daily substance consumption. Study 
participants will be asked to estimate the amount of substance consumed with the aid of visual cues designed 
to accurately quantify consumption. Cocaine will be recorded in dollar value, as well as quantity, in order to 
standardize for different types of cocaine use (crack, IV, nasal, etc.). Alcohol, nicotine, and other drug use will 
also be tracked. For cocaine use, the data will be summarized in three ways: a) percent of abstinent days (i.e., 
no use), b) amount of use per day, and c) amount used per using day Inventory of Drug-Taking Situations 
(IDTS) (Annis et al., 1997): This instrument measures typical drug using situations based on Marlatt and 
Gordon’s (1985) eight category taxonomy. This instrument contains eight subscales mapping frequency of use 
in eight distinct types of situations including use during negative situations (unpleasant emotions) and positive 
situations (social situations).  Although initially calculated to assess alcohol use, this scale has been modified 
for use with drug abusers and has demonstrated sensitivity to gender differences (Ross et al., 1994). 
Participants will also be asked to provide a urine sample to be tested for drugs of abuse. 
 
c. Progesterone and Estrogen Tracking. We will explore the impact of progesterone and estrogen levels on 
cocaine craving, stress, and oxytocin effects. Because our hypotheses are related to ovarian hormone levels 
rather than menstrual cycle phase, direct measurement of hormone levels at the time of testing is the most 
appropriate measure to address our hypotheses (Becker et al., 2005). As there is significant individual 
variability in progesterone and estrogen levels across the menstrual cycle, we will measure progesterone and 
estrogen at the initial assessment and each of the three study visits. We expect that these four samples will 
provide a profile of hormone levels for each study participant. Since we are interested in having a range of 
hormone levels for comparison, we will test 50% of participants during the luteal phase when progesterone 


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levels are high, and 50% of participants during the follicular phase when progesterone levels are low. Cocaine-
dependent women have normal 28-day ovulatory cycles (Evans et al., 2002, Evans & Foltin, 2006; Fox et al., 
2008); therefore, we will be able to approximate the menstrual cycle phase by taking a menstrual cycle history 
during the initial assessment and will schedule the study visits accordingly. Direct ovarian hormone 
measurement will allow us to utilize all participants’ data with absolute progesterone and estrogen levels as 
continuous measures.  
 
 
C.2.c.2. Session Procedures.  
a. Session Preparation. Participants will be informed that they will be expected to remain abstinent from 
cocaine and other drugs for the three-day period prior to the test sessions in order to minimize the impact of 
recent drug/alcohol use on stress and cue reactivity. Participants will be asked to come into the office to 
provide a urine sample once during the three days prior to test sessions to encourage abstinence and session 
completion. Participants will be instructed to arrive at the Addiction Sciences Division (ASD) on each test day, 
and to avoid caffeinated beverages on the test day since caffeine can introduce variability to the heart rate 
response. If the individual is nicotine-dependent, (s)he will be provided with nicotine patches throughout their 
clinic stay. Upon arriving at the ASD, the participant will be breathalyzed and will provide a urine sample, which 
will be tested for the presence of amphetamines, d-methamphetamine, cocaine, opioids, THC and 
benzodiazepines; if female, a urine pregnancy test will also be administered. If the pregnancy and urine drug 
tests are negative, with the possible exception of THC, the session will proceed. In the event a participant tests 
positive, the laboratory visit will be rescheduled. A blood pressure cuff will be placed on the subject’s arm, and  
baseline subjective measures, physiologic measures (blood pressure and heart rate), and salivary 
progesterone, estradiol, and cortisol will be collected.   
b. TSST. On Day 1, participants will be served lunch and be seated in the ASD testing room where they will be 
allowed to read or watch television until the TSST testing procedures begin. Forty minutes prior to the TSST, 
participants will be randomly assigned to receive study medication (intranasal oxytocin or placebo; see 
Medication Administration). Two more baseline assessments of subjective, hormonal (cortisol), and physiologic 
measures (blood pressure and heart rate) will be collected, one 20 minutes pre-task and the second5 minutes 
pre-task.  
 
1. Medication Administration. Participants will be administered 40 IUs of oxytocin nasal spray or matching 
placebo at 40 minutes prior to study tasks. This dose was selected based on previous studies that have used 
similar doses of oxytocin (Ditzen et al., 2009; Heinrichs et al., 2003; Kubazansky et al., 2009), as well as our 
own previous pilot work (see Preliminary Data). Timing of administration is also based on our pilot work and 
previous studies showing central activity of oxytocin 40 minutes after intranasal administration (Heinrichs et al., 
2009). Intranasal oxytocin and matching placebo will be compounded by a MUSC Investigational Drug Service. 
Randomization will be done by the MUSC Investigational Drug Service, who will keep a record of the blind and 
be available should unblinding be required. To achieve balance in sample size with respect to gender, a block 
randomized design with randomly varying block sizes will be used.  
 
2. TSST. The TSST is a standardized psychological stress challenge which has been used extensively in 
research studies. A meta-analysis supports its utility for evoking a HPA axis stress response in a laboratory 
setting (Dickerson & Kemeny, 2004). It has induced a robust and reliable physiological stress response in 
cocaine, marijuana, and alcohol-dependent individuals in our previous studies (McRae et al., 2006; McRae-
Clark et al., 2011; Waldrop et al., 2010). When the TSST begins, The participant will be told that (s)he will give 
a speech and perform an arithmetic task. The topic of the speech will be why (s)he should be hired for a 
particular job (the individual’s “dream job”). The participant will deliver the speech as though speaking to a 
group of potential employers. The experimenter then tells the participant that (s)he has 5 minutes to prepare 
the speech, and starts the countdown clock (placed in view of the individual). The experimenter leaves the 
room to allow the participant to prepare. After 5 minutes, three individuals unfamiliar to the participant (the 
audience) enter the room and are seated; the individual will be instructed by one audience member to stand 


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and begin his/her prepared speech (without notes). The speech will be delivered for 5 minutes. If the individual 
pauses, (s)he will be instructed to continue. At the end of the speech task, the individual will be instructed to 
serially subtract 13 from 1,022 as quickly and accurately as possible. The mental math recitation will continue 
for 5 minutes, at the end of which time, the spokesperson will instruct the individual to stop and be seated, and 
the audience leaves the room . Immediately following the task, a salivary sample will be collected to assay 
cortisol and physiological (blood pressure and heart rate) and subjective measures (CCQ-Brief, Within Session 
Rating Scale, obtained. Measurements will also be obtained 10- (CCQ-Brief, Within Session Rating Scale, 
STAI cortisol, physiological), 30-(CCQ-Brief, Within Session Rating Scale, cortisol, physiological), and 60-
minute post-task(CCQ-Brief, Within Session Rating Scale, STAI cortisol, physiological). 
 
3. Assessments. All baseline and within-session measurements have been previously used by our research 
group. Wherever possible, the same assessment instruments will be used in Project IV to foster cross-study 
analysis and comparison (i.e., psychiatric assessment, trauma history). . Urine Drug Screening: Drug screens 
will be performed using the iCup DX Drug Screen Cup, an in vitro diagnostic test for the qualitative detection 
of drug or drug metabolite in the urine. The test profile consists of amphetamines,  d-methamphetamine, 
cocaine, opioids, , THC and benzodiazepines.  Results will be used to ascertain abstinence prior to initiation of 
test sessions and to substantiate self-reports. Breathalyzer: Participants will have their breath sampled for the 
presence of alcohol (Alco-Sensor III, Intoximeters Inc., St. Louis, MO).  Self Report Measures. Within Session 
Rating Scale:  A modification of the Within Session Rating Scale (Childress, McLellan, & O'Brien, 1986a) will 
be used to assess craving and mood during the procedure. This 100 mm visual analogue scale is anchored 
with the adjectival modifiers (“not at all, mildly, moderately, and extremely”). The scale includes items 
assessing anxiety, stress, anger, irritability, and depressed mood. State-Trait Inventory (STAI): The STAI is a 
20-item self-report scale (Spielberger, 1983) employing a Likert-scale format with four responses per item (1-
4). Ten of the STAI items measure feelings of stress and anxiety, while the remaining ten items measure 
feelings of relaxation. The STAI has good psychometric properties. Cocaine Craving Questionnaire-Brief 
(CCQ-Brief): The CCQ-Brief is a 10-item scale derived from the Cocaine Craving Questionnaire (Tiffany et al., 
1993) and demonstrated to be a valid and reliable measurement of current cocaine craving (Sussner et al., 
2006). Physiological Measures. Heart rate and blood pressure will be measured using an intermittently 
inflatable cuff as indices of physiological arousal during the test session. Hormonal Measures. Cortisol: Cortisol 
will also be measured in unstimulated passive saliva using the Salimetrics expanded range, high sensitivity 
salivary cortisol enzyme immunoassay kit. This kit has a lower sensitivity level of <0.003 µg/dL. The correlation 
between salivary and serum cortisol has been shown to be high (r=0.91, p<0.0001). Cortisol is commonly 
measured as an indication of stress response in human laboratory studies. Progesterone: Progesterone will be 
measured from a salivary sample tested using the Salimetrics salivary progesterone enzyme immunoassay kit. 
The lower limit of sensitivity is 5 pg/ml, and the correlation between serum and saliva is highly significant 
(r=0.80, p<0.0001). Estradiol: Estradiol will be measured from a salivary sample tested using the Salimetrics 
17β-estradiol enzyme immunoassay kit collected in EDTA-tubes and processed using a chemiluminescent 
immunoassay. The lower limit of sensitivity is 0.1 pg/ml, and correlation with serum is high (r=0.80, p<0.001).   
4. Discharge. Following the 60-minute assessment, participants will be given instruction regarding scanning 
appointments on days 2 and 3. A member of the research staff will be available to discuss management of any 
craving urges if craving remains elevated at the end of study procedures. 
 
c. fMRI Sessions. On Days 2 and 3, participants will be asked to arrive at the ASD. Upon arrival, the 
participant will be breathalyzed and will provide a urine sample, which will be tested for substances and 
pregnancy (if applicable). If the pregnancy and urine drug tests are negative, with the possible exception of 
THC, the session will proceed. In the event that a participant tests positive, the scanning session will be 
rescheduled. Baseline subjective measures, physiologic measures (blood pressure and heart rate), and 


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salivary progesterone, estradiol, and cortisol will be collected.  Individuals will then be escorted to the Center 
for Advanced Imaging Research (CAIR; see letter of support) by approved study personnel where MRI scans 
will be performed.  
 
1. Medication Administration. At the beginning of the session, participants will be screened for metal using a 
handheld metal detector, and oxytocin (40IU) or placebo will be intranasally administered 40 minutes prior to 
cue exposure procedures. Although the pharmacokinetics of intranasal oxytocin are not fully understood 
(MacDonald et al., 2011), given the relatively short half-life of systemically administered oxytocin 
(approximately six minutes), we would not anticipate carry-over effects from repeated once daily dosing. 
Further, the order of administration will counterbalanced to obviate order effect; half of the participants will 
receive oxytocin prior to the first fMRI session and half will receive placebo.  
 
2. Image Acquisition Parameters. A 3 Tesla Siemens Trio magnetic resonance imaging scanner equipped with 
a 12-channel head coil for whole-brain imaging will be used for data acquisition. Participants’ heads will be 
stabilized using foam padding between the head and the head coil. T2*-weighted gradient echo EPI images 
will be acquired with the following parameters: TR = 2500 ms, TE = 27 ms, flip angle = 77º, 40 axial slices 
(FOV = 224 x 224 mm, thickness = 3.5 mm voxels with 0.5 mm gap, in interleaved order. A high resolution T1-
weighted MPRAGE anatomical scan (TR = 8.1 ms, TE = 3.7 ms, flip angle = 8°, field of view = 256 mm, 1.0 
mm) covering the entire brain and positioned using a saggital scout image will be acquired for co-registration 
and normalization of functional images. The scanning planes will be oriented parallel to the anterior 
commissure–posterior commissure line.  
 
3. Scanning Procedures. Prior to entering the scanner, subjective measures, physiologic measures (heart rate 
and blood pressure) and salivary cortisol will be collected. Participants will be given earplugs/headphones to 
protect their hearing and an optical hand pad rating device to allow them to respond to study tasks. Their ability 
to view a nearby projection screen (via a back-projected mirror mounted to their head coil) and correctly make 
ratings with the hand pad will be assessed prior to scanning. During initial scanner tuning, localizing, and 
structural scanning, participants will be shown relaxation images (i.e., 20 scenic pictures, each displayed for 30 
seconds). Next participants will be asked to look at a cross-hair for 6-minutes while resting state connectivity 
data are collected.  Next, the cocaine cue exposure paradigm will be administered. The paradigm to be used 
was adapted from a well-studied alcohol-cue exposure paradigm (George et al., 2001; Myrick et al., 2008), and 
is currently being utilized in an ongoing imaging study being conducted by the research team (R01DA023188-
S1; PI: Brady; see Preliminary Data). The paradigm consists of pictures of cocaine and related objects (e.g., 
crack pipe), neutral objects (e.g., furniture), and visual control images that match the cocaine pictures in color 
and hue, but lack object recognition. Stimulus presentation occurs over six 90-second epochs. Each epoch 
contains three 24-second blocks (cocaine images, neutral objects, control images), containing five pictures 
displayed for 4.8 seconds each, and one 24 second rest block (i.e., cross-hair). Blocks, and stimuli within 
blocks, are presented in pseudorandom order. During the task, participants will be asked to rate their stress 
and craving after each block using their hand pad; ratings range from zero (“none”) to four (“severe”). Salivary 
cortisol and subjective measures will be collected immediately following the task, and 30 and 60 minutes post 
task.  
 
4. Discharge. Following data collection, the participants will be debriefed, and scheduled for follow-up 
appointments. As on Day 1, a member of the research staff will be available to discuss management of any 
craving urges if craving remains elevated at the end of study procedures.  
C.2.c.3. Follow-Up Procedures. Participants will return to the research clinic once weekly for the two weeks 
following completion of scanning procedures. At each visit, a urine drug screen will be obtained and TLFB data 
on cocaine and other drug use will be obtained. Participants will have had a brief period of monitored 
abstinence during testing procedures (3 days prior to testing, 3 days during testing); measurement of relapse 
to cocaine use after early abstinence in a clinical population provides homology and integration with Project III, 
which is assessing similar outcomes in a preclinical model. At each follow-up visit, measures of daily stress will 
be obtained using the 10-item Perceived Stress Scale (PSS; Cohen et al., 1983), and subjects will be asked to 


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specifically assess possible precipitants of use when cocaine use is reported. The PSS has been used 
previously in cocaine dependent adults (Fox et al., 2009; Hyman et al., 2007), and has demonstrated test-
retest reliability. The menstrual history diary will be updated at each visit. Following study completion, referrals 
to treatment programs will be provided to all participants. At the first follow-up visit, blood will be collected from 
consenting participants for genetic testing.  
 
C.2.c.4. Subject Compensation. Participants will receive $25 for completing screening assessments and 
procedures ($10 for the history and physical and $15 for the interview/paperwork), and $25 if they present 
once during the three days prior to testing. Participants will receive $75 for completing the TSST, $100 for the 
first scanning session, and $125 for the second scanning session. Patients will receive study session payment 
at the end of Day 3. Additionally, “fishbowl” contingency management will be used to encourage abstinence 
and study retention (Petry et al., 2001; Petry et al., 2002). Participants who present to the clinic and provide a 
clean urine drug screen will receive chances to draw from a bowl containing 250 chips that are assigned a 
certain value (230 chips denote $1, 18 chips denote $10, one chip denotes $50, and one chip denotes $100). 
Participants will be allowed three draws on day one, five draws on day two, and seven draws on day three. We 
have used this procedure successfully in previous trials requiring similar periods of abstinence in cocaine-
dependent outpatients (i.e., presenting to the initial laboratory session with a negative UDS and maintaining 
abstinence for three days during study procedures), and have had a completion rate of approximately 80%. 
Participants will also be compensated $20 for completing each follow-up visit (two visits total). The fishbowl 
method will also be used to encourage attendance at follow-up visits; participants will be allowed nine draws at 
the first follow-up appointment and 13 draws at the final visit. Participants may be paid in gift cards, cash, or 
money orders. To facilitate female participation, financial assistance for childcare may be provided if 
necessary. 
 
C.2.c.5. Data Management. The REDCap Study Database Version 4, supported by the MUSC CTSA, will be 
used to capture data directly into an online database (Harris et al., 2009). Auditing will occur quarterly by 
comparing a random sample of 10% of participant’s original datasheets to the values entered for those 
individuals in all data files. fMRI data are automatically transferred to servers managed by CAIR. Task data will 
be stored on CAIR computers which receive daily data backups. 
 
C.2.d. Statistical Methods. The hypotheses associated with Aim 1 are interested in the effect of oxytocin on 
cocaine craving and stress in response to the TSST. It is hypothesized that cocaine-dependent participants 
receiving oxytocin will demonstrate greater attenuation of stress and craving response to TSST as compared 
to those receiving matched placebo. A linear mixed effects model containing all serially measured time points 
will be used to assess the effects of oxytocin versus placebo on each dependent variable. Restricted maximum 
likelihood (REML; Patterson and Thompson, 1971) methods will be used to estimate the fixed effects and 
variance components, and baseline values will be used as covariates in the regression models. To test the 
hypothesis that women will experience greater ameliorative effects of oxytocin on stress and craving response 
following the TSST as compared to males, similar models will examine the differential (interaction) in the 
scores reported between men and women by treatment group (oxytocin vs. placebo). Additionally, as an 
exploratory analysis, the strength of the effects of oxytocin in women will be assessed with differences in 
estrogen and menstrual cycle phase as independent variables. In a subgroup analysis of women entered into 
the study, linear mixed effects models will be developed to assess the association of estrogen and menstrual 
phase (independently) on the stress and craving response to the TSST. Non-linear associations will also be 
explored using cubic spline models (Marrie et al., 2009). Within each family of dependent measures, the Type I 
error rate will be controlled using a post-hoc Bonferroni correction. 
 
The hypotheses associated with Aim 2 are concerned with the impact of oxytocin on cocaine cue 
reactivity. It is hypothesized that oxytocin will decrease cue-induced cocaine craving in cocaine-dependent 
men and women compared with placebo administration. Post-acquisition preprocessing and statistical analysis 
will be performed using Matlab 7.8 (Mathworks, Sherborn, MA0 with Statistical Parametric Mapping software 8 


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(SPM 8, The Wellcome Department of Cognitive Neurology, London). All volumes within a task run will be 
realigned to the first volume. After realignment (including adjustment for sampling errors), scans with greater 
than one mm in three axes or one degree in three orientations will be excluded from group analyses. Following 
realignment, images will be stereotactically normalized into a standard space with a resolution of 2x2x2 mm 
voxels using the Montreal Neurological Institute (MNI) EPI template in SPM8. Subsequently, the data will be 
smoothed with a 8x8x8 mm Gaussian kernel and will be high-pass filtered (cue exposure paradigm cut-off 
period = 288s). Following preprocessing, within-task data from individual participants will be analyzed with a 
fixed-effects general linear model (GLM), with cocaine cue exposure activity modeled as a box-car function 
convolved with the standard canonical hemodynamic response function. The GLM procedure is repeated for 
each voxel with six movement parameters (3 rotation values in radian and 3 translation values in millimeter) 
included as covariates to control for the influence of head motion on the data. First-level analysis will be 
conducted and contrast maps will be generated. For the cue exposure paradigm, the main contrast of interest 
is the cocaine pictures vs. neutral objects contrast. Following first-level analysis, subject-specific contrasts will 
be entered into second-level, random-effects analyses. Areas of brain associated with group (oxytocin vs. 
placebo) and sex (women vs. men) differences on these contrasts will be identified using independent samples 
t-tests within a GLM framework. The combined group parameter maps will be threshold using a significance 
level of p<0.05, corrected for multiple comparisons.  
 
For Exploratory Hypothesis 2d, a graph-theory approach to functional connectivity will be used. The 
BCT (Rubinov & Sporns, 2011) includes metrics specifically designed for functional brain networks, which are 
fully connected with weighted and signed connections. The metrics combine both positive and negative 
weights, but weight the positive connections more heavily. Within each of 116 anatomical regions of the AAL 
atlas, the average intensity value at each time point will be extracted for each subject. The time series (shifted 
by one TR) will be segmented into four separate time series, one for each condition (cocaine images, blur, 
objects, rest) (Fair et al., 2007; Just et al., 2004). Correlation matrices will then be computed for each subject 
and each condition and submitted to the BCT. For each subject and each condition, several BCT metrics will 
be computed (see Rubinov & Sporns, 2011 for more details). Network measures include modularity and 
number of modules. Node-specific measures include diversity coefficient, within-module weights, within-
module clustering coefficient, and strength. We will also compute 20 random networks for each subject that 
preserve the weight and strength properties of the cocaine network (following Rubinov & Sporns, 2011), since 
that is the network of most interest. The same metrics that are computed for the cocaine, object, blur, and rest 
networks will be computed for the 20 random networks, then averaged to provide a single metric for the 
random network. In addition, a group-average correlation matrix will be computed (Pearson r-values from 
individual participants are Fisher z-transformed prior to averaging) for each of the four conditions and subject 
groups to obtain a modularity partition for the group, which will be visualized using Gephi software (Bastian, 
Heymann, & Jacomy, 2009), as in Figure 4. Network and node-based metrics will be submitted to mixed 
ANOVAs (one ANOVA for each metric and each node in the case of node-based metrics) with gender and 
treatment as between-subjects variables and condition (cocaine, object, blur, rest, random) as the repeated 
factor. Most metrics allow for comparison with the random networks except for strength and weight metrics 
because those are preserved in random networks and will be identical to the cocaine condition. 
 
C.2.e. Power and Sample Size. Aim 1. It is hypothesized that oxytocin will decrease ratings of subjective 
stress and cocaine craving following the TSST relative to placebo. Pilot data suggests an expected between 
group mean differences in total cocaine craving (CCQ) following the TSST of Δ=8.24 with a RMSE=11.03 
(d=0.75) (Cohen, 1988) and a stress rating (VAS) difference of Δ=1.07 with a RMSE=2.20 (d=0.49). As in the 
oxytocin pilot study, participants will be assessed at four post TSST time points (m), with an anticipated 
intraclass correlation coefficient of 0.78 for both craving and stress outcomes (ICC=0.78 & 0.79, respectively). 
The design effect, which accounts for the multiple correlated observation within each subject, is estimated to 
be 3.35 (DE= [1+(4-1)0.78]) (Donner and Klar, 2000). Assuming independent observations and an effect 
similar to the pilot data for the stress response (d=0.48), the total effective sample size would be 140 subjects 
(35 men and 35 women per treatment arm) to provide 80% power with a type I error rate of 0.05. In a clustered 
setting, the sample size is Neffective = nm/DE where n is the number of participants required when m replications 
within participants are performed after accounting for the design effect (DE). For the study at hand, the total 


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number of participants required is therefore estimated to be n=118 (=140*3.35/4), which will be rounded to 120 
to provide balance with respect to gender. Given an expected retention rate of approximately 80%, we will 
recruit 152 participants to obtain a final sample size of 120. This sample size will provide adequate power 
(80%) to detect the planned stress response, and more than adequate (98%) to detect the planned craving 
response to the TSST. In addition, the sample size of 120 participants will also provide 80% power to detect a 
1 standard deviation differential in treatment effect between cocaine-dependent men and women for the 
craving response to the TSST. Aim 2. Existing fMRI studies involving cocaine cue exposure have included 
between 6 (Maas et al., 1998) and 17 (Garavan et al., 2000) participants per group, and have reliably found 
activation in brain regions associated with cocaine craving (e.g., anterior cingulate, amygdala). However, 
Mumford & Nichols (2008) simulation study suggested that 23 participants per group may be necessary to 
obtain 80% power for a generic fMRI task design featuring 10, 15-second task block and 10, 15-second rest 
blocks. As such, our proposed 60 completer participants per group should provide adequate statistical power. 
 
c.2.f. Design Considerations. Choice of experimental groups. Inclusion of control participants was 
considered; however, craving is a main outcome measure of the proposed study, and it would not be expected 
that control participants would have a craving response to either the TSST or cocaine cues. Therefore, it was 
agreed that resources in this project would be best spent on including sufficient numbers of participants with 
cocaine dependence, as a demonstrated reduction in craving with oxytocin in this population may have 
important clinical implications. Potential modifiers of cerebral blood flow. Sex differences in hematocrit levels 
and baseline cerebral blood flow may impact the BOLD signal (Kastrup et al., 1997; Levin, et al., 2001). 
However, the present group comparisons will be based on changes in activation relative to control conditions 
(e.g., cocaine versus object activation differences for oxytocin versus placebo); therefore, even if baseline 
levels of blood flow are different across groups, the present analyses rely on fractional changes in fMRI signal 
relative to control and baseline conditions. Abstinence from cocaine has been shown to alter regional cerebral 
blood flow (Kosten et al., 1998; Volkow et al., 1988). If any statistical group differences are found, abstinence 
(days since last use) will be included as a covariate in the analysis. 
 
c.2.g. Operational Plan and Research Timetable. The first three months of the grant period will be used to 
obtain regulatory approvals and database creation. Fortunately, because we have ongoing trials involving 
cocaine-dependent populations, we have trained personnel and an active recruitment network. We also have 
an active IND for use of oxytocin in cocaine-dependent individuals. We anticipate no issues with study 
recruitment beginning by the fourth month of the first year, and for a total of 51 months. At a recruitment rate of 
approximately three participants per month, we should have no difficulty in completing the study in this 
timeframe. Data analysis and manuscript preparation will take place during the last six months of the fifth year. 
 
c.2.h. Use of Core Unit Services. This project will utilize multiple services coordinated through the 
Administrative Core (AC), such as biostatistical support (database creation, regular data audits, and statistical 
analyses), physician assistant services, and financial management. The use of shared personnel to perform 
these services across research components allows for significant overall cost-savings.  
 
 
 
 
 
 
 
 
 
 
 
 


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PROTECTION OF HUMAN SUBJECTS 
1. RISKS TO THE SUBJECTS 
a. Human Subjects Involvement and Characteristics 
Admission into the study is open to men and women and to all racial and ethnic groups, age 18-65. 152 
participants (76 cocaine-dependent women and 76 cocaine dependent men) will be recruited primarily through 
internet and newspaper advertisements. Inclusion/exclusion criteria that apply to all subjects are listed below: 
 
1) General Inclusion / Exclusion Criteria 
 
Inclusion Criteria 
1. Subjects must be able to provide informed consent and function at an intellectual level sufficient  to 
allow accurate completion of all assessment instruments. 
2. Subjects must meet DSM-IV criteria for current cocaine dependence (within the past three months). 
While individuals may also meet criteria for abuse of other substances, they must not meet criteria for 
dependence on any other substance (except nicotine) within the last 60 days. Alcohol has been known 
to affect HPA function (Adinoff et al., 1991), however to enhance recruitment efforts individuals with 
alcohol dependence or abuse will be included in the study if they do not require medically supervised 
detoxification.  Also, due to the high comorbidity of cocaine and marijuana dependence, and limited 
evidence that marijuana use affects HPA function, subjects with marijuana dependence will be 
included. 
3. Subjects must consent to remain abstinent from all drugs of abuse (except nicotine) for a three-day 
 
period immediately prior to the throughout study procedures. 
4. Subjects must consent to random assignment. 
5. Subjects must consent to participating in study procedures at the ASD and completion of two fMRI 
scans. 
 
 
Exclusion Criteria 
1. Women who are pregnant, nursing or of childbearing potential and not practicing an effective means of 
 
birth control (not including hormonal contraceptives). 
2. Women who are currently taking, or have taken in the past month, oral or other types of hormonal 
contraceptives or hormone replacement therapies. 
3. Women with premenstrual dysphoric disorder who are outside of the follicular phase.  
4. Women who have had a complete hysterectomy or are over 50 over one year post-menopausal, as 
ovarian hormones will be measured in the study. 
5. Subjects with evidence of or a history of significant hematological, endocrine, cardiovascular, 
pulmonary, renal, gastrointestinal, or neurological disease including diabetes, as these conditions may 
affect physiological/subjective responses.    Neurological exclusions include history of stroke, seizure 
disorders, multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. 
6. Subjects with Addison’s disease, Cushing’s disease or other diseases of the adrenal cortex likely to 
affect hormonal/neuroendocrine status. 
7. Subjects with a history of or current psychotic disorder or bipolar affective disorder as these may 
interfere with subjective measurements. 
8. Subjects with current major depressive disorder or post-traumatic stress disorder as these disorders 
are associated with characteristic changes in stress response. 
9. Subjects receiving synthetic glucocorticoid therapy, any exogenous steroid therapy, or treatment with 
other agents that interfere with hormonal measurements within one month of test session. 
10. Subjects taking any mood stabilizers, antipsychotics, benzodiazepines, opiates or opiate antagonists 
because these may affect test response. Subjects taking SSRI’s will be included. 
11. Subjects with any acute illness or fever. Individuals who otherwise meet study criteria will be 
rescheduled for evaluation for participation. 
12. Subjects whose height to weight ratio would preclude them from fitting comfortably in the MRI scanner. 


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13. Subjects who are unwilling or unable to maintain abstinence from alcohol and other drugs of abuse 
(except nicotine) for three days prior to the stress task procedure. 
14. Persons with ferrous metal implants or pacemaker since fMRI will be used. 
15. Subjects who are claustrophobic. 
16. Subjects with significant psychiatric or medical problems that would impair participation or limit ability to 
participate in scan.  
17. Subjects who require maintenance or acute treatment with any psychoactive medication including anti-
seizure medications which could potentially interfere with fMRI.  
18. Subjects meeting DSM-IV criteria for substance dependence (other than nicotine, cocaine, alcohol or 
marijuana) within the past 60 days. 
 
b. Sources of Materials 
Research material obtained from individual subjects includes questionnaires and interviews with study 
personnel, saliva and urine samples, as well as structural and functional MRI scans. To ensure confidentiality, 
all subject data will be letter/number coded, and only the investigators will have access to the master lists of 
codes. The research material will be obtained specifically for research purposes.  Written research material 
obtained will be stored in the Addiction Sciences Division, in an office that is locked when not in use. Saliva 
and urine samples will be stored in the Research Nexus and the Clinical Neurobiology Laboratory. 
Neuroimaging data will be stored on a secure password protected server maintained by MUSC’s Center for 
Advanced Imaging Research. 
 
c. Potential Risks 
Adverse effects associated with systemic oxytocin use in pregnancy may include seizures, mental 
disturbances, unexpected bleeding or contraction of the uterus. However, several studies have been 
conducted in humans with intranasal doses between 20 and 60 IU, and no side effects have been reported 
(Bruins, Hijman, & Van Ree, 1992; Fehm-Wolfsdorf, Bachholz, Born, Voigt, & Fehm, 1988; Pitman, Orr, & 
Lasko, 1993). A recent review by MacDonald and colleagues (2011) also found no adverse outcomes 
associated with oxytocin dosages of 18-40 IU for short term use in controlled research settings. Exposure to 
cocaine and negative emotional cues may produce some craving for cocaine or other discomfort. However, 
this discomfort is usually brief and subjects will be in the cocaine-free safety of a clinic environment. Since the 
scanner requires subjects to be motionless in an enclosed environment, there is the possibility of a 
claustrophobic reaction or anxiety or discomfort secondary to being stationary for 45-60 minutes per scan. 
Ferrous objects in the body that are undetected could move during scans. This could lead to tissue damage 
and hemorrhage. For patients who consent to genetic testing, there is the possibility of complications from 
venipuncture such as mild pain and possible bruising at the needle site. 
2. ADEQUACY OF PROTECTION AGAINSTS RISKS  
 
a. Recruitment and Informed Consent 
Patients will primarily be recruited through the use of advertisements (internet, newspaper).  The study PI, a 
Co-I, or other qualified study staff will obtain informed consent. The informed consent form includes a detailed 
description of the study procedures, along with statements regarding participants’ rights to withdraw from the 
procedure at any time without consequences. The informed consent form will be explained to subjects in easy-
to-understand language, and subjects will be instructed to read the form carefully prior to signing it.  Consent 
will be documented by the signature of the participant on the informed consent agreement, accompanied by 
the signature of the individual obtaining the consent. 
 


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b. Protections Against Risks 
All study participants will be closely monitored for psychiatric and medical stability. Patients in acute distress, 
including those endorsing suicidal ideation, will be seen by one of the psychiatrists in our division prior to being 
discharged. If the psychiatrist determines that the subject is in immediate danger, arrangements will be made 
for inpatient hospitalization at the Center for Drug and Alcohol Programs. Subjects who do not pose an 
immediate threat to self or others will be referred for services at the Center for Drug and Alcohol Programs, or 
a community mental health department if appropriate. The instrumentation used for physiological recordings 
meets all safety standards for non-invasive recordings, and participants are located out of reach of any AC-
powered devices in the laboratory.  All sessions will be conducted under the supervision of experienced 
personnel. If crisis intervention is necessary, senior staff will be available to evaluate the subject and provide 
an intervention or referral. If hospitalization is indicated, the patient will be hospitalized through the Center for 
Drug and Alcohol Programs at MUSC or an appropriate referral will be made. All subjects will be fully informed 
that they may withdraw from the experiment at any time without penalty. All subject records will be kept in a 
locked filing cabinet, and confidentiality of all materials will be maintained.  Offices also will be locked at times 
when not in use. Neuroimaging data are coded and maintained on a password protected server.   
 
To ensure confidentiality, all subject data will be coded by letters and/or numbers, and only the investigators 
will have access to the master lists of codes.  All patient records will be kept in an office that will be locked at 
times when not in use. The research staff understands the importance of maintaining confidentiality. This 
method of maintaining confidentiality has been used for several years by our research group and has been 
effective. All co-investigators and study personnel have completed (or will complete upon hiring) training in 
Good Research Practices as mandated by the MUSC IRB. 
Subjects will be taught about potential side effects of oxytocin, and will be closely followed by psychiatrists, a 
PharmD, and other members of the research team. Pregnancy tests will be performed on the day of oxytocin 
administration.  Oxytocin administration will occur in a fully staffed clinical environment with emergency 
medications (i.e., IM diphenhydramine, alprazolam) and equipment available as needed. Adverse events will 
be monitored throughout the study. If abnormalities in the brain images are found, the subjects will be 
immediately referred to an appropriate clinical care provider. A careful metal screening history will be taken 
from each subject to assess the possibility of metal devices and individuals will be screened with a metal 
detector for the possibility of implanted metal objects since magnetic movement of a metal device or metal 
object could well result in injury or risk to life. Prior exposure to pictures of the scanner, getting into the 
scanner, and seeing others in the scanner often reduces psychological discomfort or identifies people for 
whom scanning is not appropriate.  
 
3. POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECT AND OTHERS 
Possible risks to study participants include adverse reactions to oxytocin administration. Benefits include 
detailed assessment of substance use and referral for treatment. While the benefits to the individual patient are 
minimal, the minimal risks are reasonable in relation to the benefits to be gained from the investigation. An 
investigation of oxytocin’s effects on stress- and cue-induced craving may provide important information that 
can guide treatment for future patients with cocaine dependence.  
 
4. IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
This study may provide important information that can improve treatment for future patients with cocaine and 
other drug dependence. The minimal risks of the investigation are considered reasonable in relation to the 
expected knowledge to be gained.   
 


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5. DATA AND SAFETY MONITORING PLAN 
This section is based on the recommendations in NIDA’s “Guidelines for Developing a Data and Safety 
Monitoring Plan” (www.drugabuse.gov/funding/dsmbsop.html). A detailed DSMP will be developed and 
approved by NIH program staff prior to study initiation.  
 
5.1 Summary of the Protocol.   
This application proposes to investigate the effects of oxytocin on stress and cue induced reactivity in cocaine-
dependent individuals, and whether gender differences in response exist.  The primary outcome of interest is 
craving and stress response to the interventions. Inclusion/exclusion criteria are outlined above.  Power 
calculations and sample sizes are in the Data Analysis Plan section above.  
 
5.2 Trial Management.   
The study will be managed from the Addiction Sciences Division within the Department of Psychiatry and 
Behavioral Sciences at the Medical University of South Carolina.  The target population is described above in 
the inclusion/exclusion criteria. 
 
5.3 Data Management and Analysis. 
Data will be entered by research assistants directly into a computer using standard database software using 
REDCap.  The data analysis plan is outlined in the Data Analysis Plan section.  
 
5.4 Quality Assurance. 
Quarterly data audits, overseen by the Administrative Core, will be conducted.  Confidentiality protections are 
outlined above. 
5.5 Regulatory Issues. 
We currently have an active IND from the Food and Drug Administration for the use of oxytocin in cocaine-
dependent individuals (IND 109,726). Potential conflicts of interest will be reported using the upcoming NIH 
rules for disclosure.  Adverse Events (AEs)/Serious Adverse Events (SAEs) occurring during the course of the 
project will be collected, documented, and reported in accordance with protocol and IRB reporting 
requirements.  All research staff involved with adverse event reporting will receive general and protocol specific 
AE/SAE training including identification, assessment and evaluation, and documentation and reporting.  A 
research assistant will identify any potential adverse events during the course of the study from participant self-
report and administration of the visit assessments and procedures. The research assistant will provide 
information to a study physician, who will be responsible for AE/SAE assessment and evaluation including a 
determination of seriousness and study relatedness. Any significant actions taken by the local IRB and protocol 
changes will be relayed to NIDA.   
 
5.6 Definition of AE and SAE. 
An Adverse Event (AE) is defined as any untoward medical occurrence in a study subject administered a 
pharmaceutical product that does not necessarily have a causal relationship with this treatment (ICH GCP).  
Any unwanted change, physically, psychologically or behaviorally, that occurs in a study participant during the 
course of the trial is an adverse event.  A Serious Adverse Event (SAE) is defined as an adverse event that 
has one of the following outcomes: 
• 
Results in death, 
• 
Is life-threatening, 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
Results in persistent or significant disability/incapacity, 
• 
Is a congenital anomaly/birth defect OR 


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• 
Requires intervention to prevent one of the above outcomes. 
 
5.7 Documentation and Reporting. 
AEs/SAEs are documented and reported as per protocol and IRB requirements.  Research staff will identify 
adverse events and obtain all available information to assess severity, seriousness, study relatedness, 
expectedness, outcome and the need for change or discontinuation in the study intervention.  Adverse events 
are generally documented on AE Logs and AE Case Report Forms (CRFs).  Additional relevant AE information 
if available should be documented in a progress note in the research record as appropriate to allow monitoring 
and evaluating of the AE.  If the AE meets the definition for serious, appropriate SAE protocol specific reporting 
forms are completed and disseminated to the appropriate persons and within the designated timeframes as 
indicated above.  For each AE/SAE recorded, the research staff will follow the AE/SAE until resolution, 
stabilization or until the participant is no longer in the study as stated in the protocol. When a reportable SAE is 
identified, the research staff will notify the MUSC Institutional Review Board (IRB) within 24 hours and 
complete the AE report form in conjunction with the PI.  The MUSC IRB meets monthly and is located at 165 
Cannon Street, Rm. 501, Charleston, SC  29425.  Communication with the IRB is through email, memos, 
official IRB forms, and online reporting. A report will also be sent to the NIH program officer assigned to the 
project. 
 
If complete information is not available when the initial 24-hour SAE report is disseminated, follow-up 
information will be gathered to enable a complete assessment and outcome of the event.  This information may 
include hospital discharge records, autopsy reports, clinic records, etc.  The research staff will attach copies of 
source documents to the SAE report for review by the PI and for forwarding to the NIH program officer as 
appropriate within 2 weeks of the initial SAE report.  In addition, the PI will provide a signed, dated SAE 
summary report, which will be sent to the NIDA Medical Safety Officer within two weeks of the initial SAE 
report. 
 
We will report adverse events to the Medical University of South Carolina (MUSC) Institutional Review Board 
(IRB) online as soon as possible, but no later than 10 working days after the investigator first learns of the 
event.  The MUSC IRB AE reporting requirements are as follows:  All deaths that occur during the study or 30 
days post termination from the study are required to be reported as adverse events even if they are expected 
or unrelated.  Other adverse events are reportable to the MUSC IRB if the AE is unexpected AND related or 
possibly related AND serious or more prevalent than expected.  All three criteria must be met for an AE to be 
reported to the MUSC IRB.  The IRB definition of unexpected is that the AE is not identified in nature, severity 
or frequency in the current protocol, informed consent, investigator brochure or with other current risk 
information.  The definition of related is that there is a reasonable possibility that the adverse event may have 
been caused by the drug, device or intervention.  Reportable AEs are reviewed by the IRB Chair and reported 
to the IRB Board at the next meeting. 
 
5.8 Trial Safety. 
The potential risks and benefits and methods to minimize these risks are outlined above. The research staff will 
report any unexpected AEs or any scores of “severe” on the side-effect symptom rating form or any FDA-
defined serious AEs to the PI within 24 hrs so that the PI can decide on the appropriate action.  All unexpected 
AEs will be monitored while they are active to determine if treatment is needed.  Study procedures will follow 
the FDA’s Good Clinical Practice Guidelines (www.fda.gov/oc/gcp). Any outside requests for information or any 
breaches in confidentiality will be reported to Drs. Brady or McRae-Clark. All requests by participant’s 
physicians and other medical providers will be referred directly to Dr. Brady. 
 
5.9 Trial Efficacy. 


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This is not an intervention trial.  An interim analysis is not planned at the time. 
 
 
5.10 DSM Plan Administration. 
Drs. Brady and McRae-Clark will be responsible for monitoring the study. They will examine (monthly) the 
outcomes database and CAIR server for missing data, unexpected distributions or responses, and outliers.  A 
DSM report will be filed with the IRB and NIDA on a yearly basis, unless greater than expected problems 
occur.  The report will include participant characteristics, retention and disposition of study participants, quality 
assurance issues and reports of AEs, significant/unexpected AEs and serious AEs.  We will report outcomes at 
the end of the trial. 
 
5.11 DSM Board.   
If directed by NIDA program staff, we will create a Data Safety and Monitoring Board to monitor both the rate 
and severity of adverse events.  This panel will include 3 clinicians with expertise in substance dependence 
and a statistician.   
 
5.12  Risk Benefit Ratio. 
The assessments and questionnaires are non-invasive and have inherently minimal risks.  Potential risks of 
concern are loss of confidentiality, and adverse events to oxytocin. The potential risks of fMRI are minimal and 
include claustrophobia. As discussed above, our research team will attempt to minimize these risks.  
Knowledge gained by the proposed study would help fill an important void in research on gender differences in 
cocaine dependence. 
 
6. CLINICALTRIALS.GOV REQUIREMENTS 
In accordance with Public Law 110-85, this project will be registered at the ClinicalTrials.gov Protocol 
Registration System Information Website prior to study initiation. 
 
 
 
 
 
 
 
 
 
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