Article

Intranasal Oxytocin Blocks Alcohol Withdrawal in Human Subjects

Department of Psychiatry , The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Alcoholism Clinical and Experimental Research (Impact Factor: 3.31). 10/2012; 37(3). DOI: 10.1111/j.1530-0277.2012.01958.x
Source: PubMed

ABSTRACT BACKGROUND: The neuropeptide, oxytocin (OT), has been reported to block tolerance formation to alcohol and decrease withdrawal symptoms in alcohol-dependent rodents. Numerous recent studies in human subjects indicate that OT administered by the intranasal route penetrates into and exerts effects within the brain. METHODS: In a randomized, double-blind clinical trial, intranasal OT (24 IU/dose, N = 7) or placebo (N = 4) was given twice daily for 3 days in alcohol-dependent subjects admitted to a research unit for medical detoxification using Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score-driven PRN administration of lorazepam. Subjects rated themselves on the Alcohol Withdrawal Symptom Checklist (AWSC) each time CIWA scores were obtained. Subjects also completed the Penn Alcohol Craving Scale, an Alcohol Craving Visual Analog Scale (ACVAS) and the Profile of Mood States (POMS) on inpatient days 2 and 3. RESULTS: All subjects had drunk heavily each day for at least 2 weeks prior to study and had previously experienced withdrawal upon stopping/decreasing alcohol consumption. OT was superior to placebo in reducing alcohol withdrawal as evidenced by: less total lorazepam required to complete detoxification (3.4 mg [4.7, SD] vs. 16.5 [4.4], p = 0.0015), lower mean CIWA scores on admission day 1 (4.3 [2.3] vs. 11.8 [0.4], p < 0.0001) and day 2 (3.4 [2.2] vs. 11.1 [3.6], p < 0.002), lower AWSC scores on days 1 and 2 (p < 0.02; p = 0.07), and lower ACVAS ratings (p = 0.01) and lower POMS Tension/Anxiety subscale scores on day 2 (p < 0.01). CONCLUSIONS: This is the first demonstration that OT treatment may block alcohol withdrawal in human subjects. Our results are consistent with previous findings in rodents that OT inhibits neuroadaptation to and withdrawal from alcohol. OT could have advantages over benzodiazepines in managing alcohol withdrawal because it may reverse rather than maintain sedative-hypnotic tolerance. It will be important to test whether OT treatment is effective in reducing drinking in alcohol-dependent outpatients.

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    • "For example, compared with placebo, intranasal oxytocin produced significantly lower symptoms of alcohol withdrawal and anxiety in alcohol-dependent subjects (Pedersen et al., 2013). Others have found that intranasal oxytocin produces significantly less craving and anxiety to a social stress task than placebo in marijuana-dependent subjects (Carson et al., 2013; McRae-Clark et al., 2013; Pedersen et al., 2013). Intranasal oxytocin is also known to enhance prosocial and affiliative behaviors in rodents (Ferguson et al., 2001; Witt et al., 1992) and non-human primates (Chang and Platt, 2013). "
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    ABSTRACT: Drug dependence and adverse childhood experiences (ACE) are commonly reflected by dysregulation of the hypothalamic-pituitary-adrenal axis (HPA). Accumulating research indicates that the neuropeptide oxytocin may regulate HPA function, resulting in reductions in neuroendocrine reactivity to social stress among individuals with drug dependence. However, emerging literature suggests that individual differences may differentially impact intranasal oxytocin's effects on human social behaviors. This study employed a double-blind, placebo-controlled design to examine the extent to which ACE influenced the effects of intranasal oxytocin (40IU) on neuroendocrine reactivity to a laboratory social stress paradigm in a sample of 31 cocaine-dependent individuals. ACE scores modified the relationship between intranasal oxytocin and cortisol reactivity. While ACE modified the relationship between intranasal oxytocin and DHEA response in a similar direction to what was seen in cortisol, it did not reach statistical significance. Findings are congruent with the emerging hypothesis that intranasal oxytocin may differentially attenuate social stress reactivity among individuals with specific vulnerabilities. Future research examining the nuances of intranasal oxytocin's therapeutic potential is necessary. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    07/2015; DOI:10.1016/j.psychres.2015.07.064
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    • "Based on this promising preclinical data, OT has been proposed as a therapeutic target for drug addiction (McGregor and Bowen, 2012). Although preliminary data from clinical studies are still limited, acute OT blocked alcohol withdrawal symptoms in humans (Pedersen et al., 2013) and ameliorated stress-induced reactivity and craving in marijuana-dependent individuals (McRae-Clark et al., 2013). Although OT can decrease drug reward-related behavior, the potential cellular mechanisms of OT's actions on motivated drug seeking remain unknown. "
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    ABSTRACT: Oxytocin, a neurohypophyseal neuropeptide, is a potential mediator and regulator of drug addiction. However, the cellular mechanisms of oxytocin in drug seeking remain unknown. In the present study, we used a self-administration/reinstatement model to study the effects of oxytocin on cocaine seeking and its potential interaction with glutamate function at the receptor level. Systemic oxytocin dose-dependently reduced cocaine self-administration during various schedules of reinforcement, including fixed ratio 1, fixed ratio 5, and progressive ratio. Oxytocin also attenuated reinstatement to cocaine seeking induced by cocaine prime or conditioned cues. Western-blot analysis indicated that oxytocin increased phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunit at the Ser 845 site with or without accompanying increases in phosphorylation of extracellular signal-regulated kinase, in several brain regions, including the prefrontal cortex, bed nucleus of the stria terminalis, amygdala, and dorsal hippocampus. Immunoprecipitation of oxytocin receptor and GluA1 subunit receptors further demonstrated a physical interaction between these 2 receptors, although the interaction was not influenced by chronic cocaine or oxytocin treatment. Oxytocin also attenuated sucrose seeking in a GluA1- or extracellular-signal-regulated kinase-independent manner. These findings suggest that oxytocin mediates cocaine seeking through interacting with glutamate receptor systems via second messenger cascades in mesocorticolimbic regions. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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    • "Oxytocin has also been implicated in modulating the reactivity of the hypothalamicpituitary-adrenal axis (Buisman-Pijlman et al., 2014b), thus in part determining the extent of psychological and physiological response to stress (Feldman, 2012). This expanding knowledge base has underpinned adult human and animal studies administrating intranasal oxytocin as a modulator of behaviors, for example, those associated with substance abuse (McGregor and Bowen, 2012; Pedersen et al., 2013). "
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