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Cited by 124Neuroendocrine regulation and behaviorCannabis and Cannabinoid ResearchStress Responses and Cortisol

Effect of oxytocin on craving and stress response in marijuana-dependent individuals: A pilot study

Open access
McRae-Clark, Aimee L., Baker, Nathaniel L., Maria, Megan Moran-Santa, Brady, Kathleen T.·2013·Psychopharmacology
DOI 10.1007/s00213-013-3062-4PMC PMC3729589
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Abstract

Stress has been shown to be a significant factor in the maintenance of marijuana use. Oxytocin is a hypothalamic neuropeptide that has been shown to moderate behavioral responding to stress as well as play a role in the neuroadaptations that occur as a consequence of long-term drug use. The current study evaluated the impact of oxytocin pretreatment on craving, stress, and anxiety responses following a psychosocial stress task in marijuana-dependent individuals. In a laboratory setting, baseline measurements of craving (assessed using the Marijuana Craving Questionnaire; MCQ), salivary cortisol and dehydroepiandrosterone (DHEA), stress, and anxiety were collected in 16 participants (age 19–40) meeting DSM-IV criteria for marijuana dependence. Participants were then administered either oxytocin 40 IU (n = 8) or placebo (n = 8) nasal spray prior to completion of the Trier Social Stress Task (TSST). Measurements were repeated pre-TSST, immediately post-TSST, and 5-, 35-, and 60-min post-TSST. Oxytocin reduced both MCQ total score and DHEA levels from before to after the TSST. It also decreased anxiety, but not subjective stress ratings. Although preliminary, these results suggest that oxytocin may play a role in the amelioration of stress-induced reactivity and craving in marijuana-dependent individuals.

AI snapshot

Written from the paper’s full text.

TL;DR

In a pilot randomized, double-blind laboratory study, intranasal oxytocin (40 IU) before the Trier Social Stress Test reduced marijuana craving, DHEA, and anxiety in marijuana-dependent individuals compared with placebo. Subjective stress and cortisol did not differ significantly.

Key findings

  • Following the TSST, oxytocin-treated participants had lower Marijuana Craving Questionnaire total scores than placebo: 43.1 (33.2, 53.0) vs. 57.5 (47.6, 67.4); Cohen’s d=1.20, driven mainly by expectancy (d=1.22) and emotionality (d=1.15) subscales.
  • Oxytocin was associated with lower post-TSST DHEA [log transformed: −0.2 (−0.4, 0.1) vs. 0.2 (0.0, 0.5); d=1.08] and lower anxiety [3.3 (1.8, 4.7) vs. 5.5 (4.0, 6.9); d=1.02].
  • Subjective stress ratings did not differ significantly between groups [3.0 (0.8, 5.2) vs. 3.7 (1.5, 5.9); d=0.34], and cortisol showed a similar pattern but did not reach significance (d=0.69).
  • Before the stressor, oxytocin did not significantly reduce craving, anxiety, stress, or neuroendocrine measures, though the authors note a trend for reduced craving and DHEA prior to the TSST.

Methods

  • Pilot randomized, double-blind, placebo-controlled study: 16 participants meeting DSM-IV criteria for marijuana dependence were randomized to oxytocin 40 IU (n=8) or placebo (n=8) nasal spray 40 minutes before the TSST.
  • Craving (Marijuana Craving Questionnaire), subjective stress and anxiety (0–10 Likert), and salivary cortisol and DHEA were measured at baseline, pre-TSST, immediately post-TSST, and 5, 35, and 60 minutes post-TSST.
  • Linear mixed effects models assessed group, time, interaction, and baseline effects, adjusted for baseline outcome levels and self-reported number of marijuana use sessions per using day in the prior 90 days; cortisol and DHEA were natural log transformed, and Cohen’s d effect sizes were reported.

Limitations

  • The paper states that this was a pilot study with a small sample size, that replication is needed, and that the sample was nontreatment seeking and predominantly male, which may limit generalizability.
  • The paper states it was underpowered to explore pre- and post-TSST time point interactions and that no pre-trial power calculation was performed.
  • The paper notes the subjective stress measure relied on a single question; the text also makes evident that no correction for multiple testing was applied and that group sizes were very small (n=8 per arm).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00213-013-3062-4

Cites

53 of 53 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 26 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Cigarette smoking status was significantly associated with reported MCQ scores during the study.

    “cigarette smoking status was significantly associated with reported MCQ scores during the study (MCQ Total Score and subscales: emotionality and expectancy).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Treatment group differences in models including smoking status as a covariate were similar to those from models adjusting for marijuana use.

    “The resulting estimated treatment group differences were similar to those reported for models adjusting for marijuana use (Table 2) but with slightly lower variance estimates.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Oxytocin attenuated marijuana craving (MCQ total score) following the TSST compared to placebo in marijuana-dependent individuals.

    “Oxytocin reduced both MCQ total score and DHEA levels from before to after the TSST.”
    • Also stated in: § Effects of Oxytocin Administration · plain
      “Following the stressor, the study group receiving oxytocin showed an attenuated craving response as measured by the MCQ total score [Table 2; 43.1 (33.2, 53.0) vs. 57.5 (47.6, 67.4); Cohen’s d=1.20; see Figure 1a]”
    • Also stated in: § DISCUSSION · plain
      “oxytocin administered prior to a psychosocial stress task resulted in decreased marijuana craving in response to the stressor”
    Quote in the paperSubstantial claim
  • Findingown data

    There was a possible association between cigarette smoking and the number of marijuana smoking sessions per day.

    “Evaluation of inclusion of smoking status with the adjusted model revealed a possible association between those that smoked cigarettes and the number of marijuana smoking sessions per day (smokers 2.5 ± 0.7 vs. non-smokers 1.9 ± 0.3; Wilcoxon p=0.06)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Prior to the stressor, oxytocin did not significantly reduce craving, anxiety, stress, or neuroendocrine measures.

    “Prior to the stressor, administration of oxytocin did not significantly reduce craving, anxiety, stress, or neuroendocrine measures (Table 2).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 15
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 20

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Cortisol had a similar response pattern to DHEA following the TSST but did not reach statistical significance.

    “The cortisol measure had a similar response pattern, but failed to reach a level of statistical significance (d=0.69; Figure 1c).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Cigarette smokers reported numerically higher craving scores than non-smokers at the pre-medication measure, but the difference was not statistically significant.

    “Results show that cigarette smokers (n=11) reported numerically (not statistically) higher craving scores than non-smokers (n=5) at the pre medication measure (mean ± SD: 48.0 ± 15.8 vs. 40.6 ± 12.9, respectively, p=0.63).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A sensitivity analysis was performed to examine the effects of smoking status on the relationship between oxytocin treatment and response to the TSST.

    “A sensitivity analysis was performed to examine the effects of smoking status on the relationship between oxytocin treatment and response to the TSST.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    All stated comparisons and statistical analyses were adjusted for baseline outcome levels and self-reported number of marijuana use sessions per using day.

    “All stated comparisons and statistical analysis are adjusted for baseline outcome levels as well as the self-reported number of marijuana use sessions per using day for the 90 days prior to study entry.”
    • Also stated in: § Baseline Clinical Characteristics · plain
      “Thus, adjustments were made for the amount of daily marijuana use episodes in all statistical models.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Spaghetti plots of individual response patterns were examined to assure that stated effects were not due to outlying observations.

    “Spaghetti plots so of individual response patterns over time were examined to assure that effects stated are not due to the influence of individual outlying observations.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Participants were randomly assigned to treatment condition and the assignment was double-blinded.

    “Participants were randomly assigned to the treatment condition and assignment was double-blinded.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    No pre-trial power calculation was performed because the primary aim was to estimate treatment effect and variability for design of a larger trial.

    “Since the primary aim of the pilot trial was to estimate treatment effect and variability of oxytocin on marijuana craving and neuroendocrine response for design of a larger trial, a pre-trial power calculation was not performed.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Results presented are from an intent-to-treat analysis.

    “All analyses were performed using standard randomized control trial methodology and results presented are from intent to treat analysis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The Trier Social Stress Test (TSST) is a standardized psychological stress challenge that has shown utility for evoking an HPA axis stress response in a laboratory setting.

    “The TSST is a standardized psychological stress challenge which has shown utility for evoking an HPA axis stress response in a laboratory setting (Dickerson & Kemeny, 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dickerson & Kemeny, 2004 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Marijuana craving was assessed using the Marijuana Craving Questionnaire (MCQ), a 12-item instrument with four subscales.

    “baseline marijuana craving was assessed with the Marijuana Craving Questionnaire (MCQ) (Heishman et al., 2009), a 12-item instrument with four subscales (Expectancy, Purposefulness, Emotionality, and Compulsivity).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Heishman et al., 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Significance for all planned pair-wise comparisons was set at a 2-sided p-value of 0.05 and no correction for multiple testing was applied.

    “Significance for all planned pair-wise comparisons was set at a 2-sided p-value of 0.05 and no correction for multiple testing was applied to reported p-values.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The MINI International Neuropsychiatric Interview was used to assess psychiatric exclusions, and the substance use module of the Structured Clinical Interview for DSM-IV was used for substance use disorder diagnosis.

    “The MINI International Neuropsychiatric Interview (Sheehan and Lecrubier, 2006) was used to assess for psychiatric exclusions, and the substance use module of the Structured Clinical Interview for DSM-IV (First et al., 1994) was used for substance use disorder diagnosis.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sheehan and Lecrubier, 2006

      Not checked in the free run.

    • cites First et al., 1994

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Intranasal administration of oxytocin attenuates anticipatory anxiety, subjective stress, and HPA axis activation to a psychosocial laboratory stress task.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites de Oliveira et al., 2011

      Not checked in the free run.

    • cites Heinrichs et al., 2003 source

      Not checked in the free run.

    • cites Kosfeld et al., 2005 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The trial was registered with clinicaltrials.gov (NCT01335789).

    “The trial was registered with www.clinicaltrials.gov (NCT01335789).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Salivary cortisol and DHEA were measured using Salimetrics enzyme immunoassay kits with specified precision.

    “Samples were collected via passive drool, and hormone measurements were analyzed using Salimetrics enzyme immunoassay kits (Salimetrics LLC, State College, PA).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    There were no between-group differences for any demographic or clinical baseline characteristics measured, and the two treatment groups were similar in age, cigarette smoking status, and baseline levels of marijuana craving, stress and anxiety.

    “There were no between group differences for any of the demographic or clinical baseline characteristics measured.”
    • Also stated in: § Baseline Clinical Characteristics · plain
      “The two treatment groups were similar in age, cigarette smoking status, and baseline levels of marijuana craving, stress and anxiety.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The sample was nontreatment seeking and predominantly male, which may impact the generalizability of the results.

    “Further, our sample was nontreatment seeking and predominantly male, which may impact the generalizability of the results.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DHEA may promote an adaptive response to stress by antagonizing the effects of cortisol.

    “As such, it has been suggested that DHEA may promote an adaptive response to stress by antagonizing the effects of cortisol (Morgan et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Morgan et al., 2004 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    DHEA is secreted synchronously with cortisol in response to ACTH and is elevated in response to psychosocial stress.

    “DHEA is secreted synchronously with cortisol in response to ACTH, and has been shown to be elevated in response to psychosocial stress (Izawa et al., 2008; Lennartsson et al., 2012; Morgan et al., 2004).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Izawa et al., 2008 source

      Not checked in the free run.

    • cites Lennartsson et al., 2012 source

      Not checked in the free run.

    • cites Morgan et al., 2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DHEA has anabolic and antiglucocorticoid effects, as opposed to cortisol, a catabolic hormone.

    “As opposed to cortisol, a catabolic hormone, DHEA has anabolic and antiglucocorticoid effects (Kalimi et al., 1994; Maninger et al., 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kalimi et al., 1994 source

      Not checked in the free run.

    • cites Maninger et al., 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In Cui's study, oxytocin was shown to block anxiety-associated withdrawal symptoms.

    “in Cui’s study oxytocin was shown to block anxiety-associated withdrawal symptoms (Cui et al, 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cui et al, 2001 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    As this was a pilot study, the sample size was small and replication of the results is needed.

    “As this was a pilot study, the sample size was small and replication of the results is needed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The expectancy and emotionality subscales measure anticipation of positive outcomes from smoking marijuana and may be reflective of the anxiolytic properties of oxytocin.

    “These subscales measure anticipation of positive outcomes from smoking marijuana such as a reduction in nervousness and feeling more content, and may therefore be reflective of the anxiolytic properties of oxytocin.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    de Oliveira and colleagues reported that oxytocin decreased anticipatory anxiety but did not affect public speaking fear in a non-dependent population.

    “Of note, de Oliveira and colleagues (2012) recently reported similar findings in a non-dependent population participating in a comparable stress task in which oxytocin was found to decrease anticipatory anxiety but did not affect public speaking fear.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites de Oliveira and colleagues (2012)

      Not checked in the free run.

24 of 24

  • The authors state this as an assumption.

    This is the first controlled trial of oxytocin administration in a drug-dependent population.

    “To our knowledge, this is the first controlled trial of oxytocin administration in a drug-dependent population.”

  • The paper relies on this without support.

    The Trier Social Stress Test induces stress-induced marijuana craving that is relevant to real-world stress-induced craving in marijuana-dependent individuals.

    “At 2:00 PM, the Trier Social Stress Test (TSST) began.”
    “Craving, subjective, and hormone measurements were collected immediately following completion of TSST, and 5-, 35-, and 60-minutes post task.”
2 of 2

Claims other papers make about this one

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Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Cohen J (1988) Statistical power analysis for the behavioral sciences, 2nd edn. Erlbaum, Hillsdale
  2. First MB, Spitzer RL, Gibbon M, Williams JBW (1994) Structured clinical interview for Axis 1 DSM-IV Disorder—patient edition (SCIP-I/P, version 2.0). Biometrics Research Department, New York
  3. SAMSHA (2010) Results from the 2009 National Survey on Drug Use and Health: Volume 1. Summary of National Findings. In: U.S. Department of Health and Human Services, S.A.M.H.S.A., Office of Applied Studies (Ed.)

Cited by

Sorted by citations

Authors
McRae-Clark, A. L., Baker, N. L., Maria, M. M.-S., & Brady, K. T.
Affiliations
Medical University of South Carolina (US)
ORCID
Venue
Psychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2013-04-06
Volume
228
Issue
4
Pages
623-631
ISSN
  • 0033-3158 (ISSN-L)
  • 1432-2072
DOI
10.1007/s00213-013-3062-4
PMC
PMC3729589
OpenAlex
W2043676928
Semantic Scholar
ae426bc7c6f7131c6e8818b8077caea941b7a0bd
Cited by
124
References
53
Citations by year
2026: 5 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 13 · 2020: 9 · 2019: 9 · 2018: 19 · 2017: 15 · 2016: 20 · 2015: 6 · 2014: 11 · 2013: 1
FWCI
19.01
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Psychopharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Medical University of South Carolina
  • National Institutes of Health
  • South Carolina Clinical and Translational Research Institute, Medical University of South Carolina
  • National Center for Research Resources (UL1RR029882)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
oxytocin, cannabis use disorder, craving, stress response, anxiety, Trier Social Stress Test, salivary cortisol, dehydroepiandrosterone, psychosocial stress
MeSH terms
Adult, Anxiety, Marijuana Abuse, Dehydroepiandrosterone, Double-Blind Method, Female, Humans, Hydrocortisone, Male, Oxytocin, Pilot Projects, Psychological Tests, Saliva, Stress, Psychological, Young Adult, Nasal Sprays

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