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NCT Number: NCT07778511

How Does the Opioid System Shape Stress and Social Behaviour in Men and Women and What Role Does Childhood Unpredictability Play?

The study aims to investigate sex differences in the effect of mu-opioid receptor (MOR) activation on stress response and social behaviour modulated by early life stress.

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Key information

Conditions

Stress Behavior Behavioral Symptoms Chemically-Induced Disorders Early Life Stress Mental Disorders Narcotic-Related Disorders Opioid Opioid-Related Disorders Sex Differences Social Behavior Stress, Psychological Substance-Related Disorders

Age range

18 year–40 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

About this study

While opioid use disorder presents a rising public health concern, the underlying neurobiological mechanisms of substance use are not well understood. In animal studies, activation of the Mu Opioid Receptor (MOR) system has been shown to have stress-buffering effects and to decrease affiliative behaviour, which is in line with addiction models postulating impaired stress response and poor social interactions to be risk indicators for addiction pathogenesis. In humans however, this has not been consistently found. Importantly, behavioural pharmacology studies have often been restricted to male test subjects or have been underpowered. Therefore, a significant knowledge gap remains regarding sex-specific differences in MOR activation. The additional impact of chronic stress in the form of early life stress significantly affects brain development, in turn shaping stress reactivity and affiliative behaviour in later life. This forms the basis of the research question of the present study, whether sex and childhood unpredictability modulate the effects of MOR activation on stress response and social interaction behaviour.

The prototypical opioid morphine will be used to activate the MOR. Participants will receive the study medication on two separate visits in a randomised, counterbalanced order. Afterwards, participants will conduct computer-based stress and social interaction tasks.

Learning more about individual differences in MOR activation and its effects on stress and social behaviour can help to uncover vulnerability and risk factors for opioid use disorder and improve personalised treatment opportunities.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age 18-40 years
  • Ability to read, understand, and provide written informed consent in German
  • Proficiency in German
  • Able to give blood samples (no blood- or needle-related phobia)
  • Good health as determined by medical history, ECG, and clinical assessment of lab tests. Lab tests will include potassium, creatinine, hemoglobin, glucose, calcium, BUN, complete blood count, total bilirubin, AST, ALT, and GGT. The final decision will be according to the judgment of the study physician.
  • Females must have a negative urine pregnancy test (hCG) at inclusion and at the start of each study session. Females of childbearing potential who are sexually active and have not been surgically sterilized must agree to use an adequate method of birth control during the study.
  • Prior experience with medical opioids (at least one experience with prescription opioids such as oxycodone, morphine, hydromorphone, fentanyl, hydrocodone, codeine, or dihydrocodeine) and paracetamol.
  • Body mass index (BMI) between 19 and 30 kg/m2

Exclusion criteria

  • Any current instable medical or neurological condition
  • Any clinically significant psychiatric disorder (i.e., psychotic and stress-related disorders) including a diagnosis of substance use disorder (defined in DSM-5 terms as Moderate or Severe). Participants will be screened using the Structured Clinical Interview - SCID for DSM-5). If indication is obtained that a clinically significant psychiatric disorder may be present, a full SCID will be carried out by appropriately trained staff.
  • Significant adverse reaction to prior opioid or paracetamol exposure
  • Reporting any illegal drug use >15 life-time occasions and regular drug use during the last three months incl. the test period (except for nicotine and alcohol)
  • Any current use of CNS-active medications.
  • Current use of opioid analgesics, opioid use for > 6 weeks (lifetime), or within the three months prior to study enrollment.
  • Fagerström Test of Nicotine Dependence (FTND) Score > 5 (strong nicotine dependence)
  • Heavy alcohol use based on the Alcohol Use Disorder Identification Test (AUDIT)
  • Lifetime diagnosis of cardiac disease.
  • Clinically significant laboratory or ECG abnormality that could be a safety issue in the study
  • Acute or chronic respiratory issues (e.g., cold, flu, asthma, etc.)
  • Lifetime diagnosis of liver or kidney disease including moderate or severe renal impairment (creatinine clearance < 50 ml/min)
  • Lifetime diagnosis of schizophrenia, bipolar disorder, obsessive-compulsive disorder, or autism spectrum disorder according to DSM-5
  • Diagnosis of a current episode of depression based on DSM-5 criteria
  • Current diagnosis of a moderate or severe substance use disorder according to DSM-5
  • Daily cannabis consumption in the past three months
  • Use of psychotropic medication within the last 7 days
  • Participation in other pharmacological studies within the last 2 months
  • Alcohol use within the last 24 hours controlled by breathalyzer
  • Unable to provide a negative urine drug screen (cannabinoids, amphetamines, opiates and opioids, benzodiazepines, and cocaine).
  • Positive pregnancy test or nursing (self-report)
  • For women: irregular menstrual cycle or menopause

Treatment and study plan

Morphine

Drug

Sevredol 10mg, oral single-dose administration

Placebo

Drug

identical in appearance to active drug, containing no active substance (mannitol), oral one-time administration

Primary outcomes

  1. Self-report of subjective stress during stress exposure

    Time frame: During the experimental stress task

    Sex-specific differences in the stress relieving effects of morphine compared to placebo. Subjective stress response will be measured by differences between self- and other condition in ratings using a 1-7 Visual Analogue Scale (VAS) with the anchors "not at all" (1) to "very much" (7) for the items "How secure do you feel?" and "How stressed do you feel?" throughout the stress task.

  2. Endocrinological markers of stress response

    Time frame: Throughout the experiment sessions (baseline and approx. 10, 20, 30, 60 and 105 minutes after stress onset, 6 samples).

    Sex-specific differences in the stress relieving effects of morphine compared to placebo measured by changes in plasma concentrations of cortisol and endocannabinoids (2-AG, AEA, PEA, SEA, OEA).

  3. Psychophysiological stress response of heart rate measured by electrocardiogram

    Time frame: During the experimental stress task

    Sex-specific differences in the stress relieving effects of morphine compared to placebo measured by differences between self and other condition in heart rate (beats per minute).

  4. Psychophysiological stress response of heart rate variability measured by electrocardiogram

    Time frame: During the experimental stress task

    Sex-specific differences in the stress relieving effects of morphine compared to placebo measured by differences between self and other condition in heart rate variability.

  5. Psychophysiological measure of sympathetic activity

    Time frame: During the experimental stress task

    Sex-specific differences in the stress relieving effects of morphine compared to placebo measured by differences between self and other condition in skin conductance response (SCR).

  6. Changes in self-reported subjective stress over time

    Time frame: Throughout the experimental sessions (from before stress induction to 10, 20, 30, 60 and 105 minutes after stress onset, 7 times).

    Sex-specific differences in morphine-mediated stress relief measured by changes in Visual Analogue Scales (VAS), ranging from 0-100 with the anchors " not at all " (0) and "extremely" (100) for the items:

    "I feel stressed", "I feel safe", "I feel relaxed", "I have a dry mouth", "I feel nauseous", "I feel confident", "I feel ashamed", "I feel vulnerable"

  7. Self-reported feeling of shame post-stress

    Time frame: ~10 minutes after stress onset

    Sex-differences in morphine effects on the Experiential Shame Scale (ESS) score, ranging from 25 -100, with higher values indicating stronger feelings of shame.

  8. Changes in self-reported affect over time

    Time frame: Throughout the experimental sessions (from before stress induction to 10, 30, 60 and 105 minutes after stress onset, 6 times).

    Sex-specific differences in morphine effects on changes of positive and negative affect measured using the Positive and Negative Affect Schedule (PANAS) scores. Scores for both subscales range from 10 to 50 with higher scores indicating stronger positive or negative affect, respectively.

  9. Early life stress

    Time frame: Prior to enrollment

    Modulation of the Questionnaire of Unpredictability in Childhood (QUIC) sum score on differences in primary outcomes. Scores range from 0-38 with higher scores indicating greater exposure to instability and unpredictability during childhood.

Secondary outcomes

  1. Subjective differences in experiencing social interaction

    Time frame: During the experimental tasks

    Sex-specific differences in morphine effects on subjective pleasantness ratings measured by VAS scales (1-100) during the social approach/avoidance task and affective touch task with higher ratings indicating more pleasantness.

  2. Behavioural differences of social approach and avoidance

    Time frame: During the experimental task

    Sex-specific differences in morphine effects on behavioural measures (measured by number of button presses) during the social approach/avoidance task.

  3. Psychophysiological cardiac markers of social interaction measured by heart rate using electrocardiogram

    Time frame: During the experimental tasks

    Sex-specific differences in morphine effects on heart rate (beats per minute) during the social approach/avoidance task and the affective touch task.

  4. Psychophysiological cardiac markers of social interaction measured by heart rate variability using electrocardiogram

    Time frame: During the experimental tasks

    Sex-specific differences in morphine effects on heart rate variability during the social approach/avoidance task and the affective touch task.

  5. Psychophysiological measure of sympathetic activity during social interaction

    Time frame: During the experimental tasks.

    Sex-specific differences in morphine effects on skin conductance response (SCR) during the social approach/avoidance task and the affective touch task.

  6. State anxiety over time

    Time frame: Throughout the experimental sessions (from before stress induction to approx. 10, 30, 60, and 105 minutes after stress onset, 6 times).

    Sex-specific differences in morphine effects on changes in state anxiety measured by the State-Trait Anxiety Inventory (STAI) score. Scores can range from 20 -80 with higher scores indicating greater anxiety

  7. Drug Effects Questionnaire (DEQ)

    Time frame: Throughout the experimental sessions (immediately after drug administration until approx. 3 hours after study medication administration, 7 times).

    Sex-specific differences in drug effects will be measured using the Drug Effects Questionnaire (DEQ; subjective experiences are reported of "feeling the drug", "feeling high", "drug liking" and "disliking", and "desire to take the drug again") measured on an electronic 0-100 VAS, anchors "not at all" and "extremely".

  8. Drug concentration

    Time frame: Throughout the experimental sessions (from 1 hour after drug administration until approx. 3 hours after study medication administration, 4 samples).

    Differences in concentration of the study drug in blood between the two test sessions.

  9. Changes in oxytocin over time

    Time frame: Throughout the experimental sessions (from before stress induction to approx. 10, 20, 30, 60 and 105 minutes after stress onset, 6 samples).

    Sex-specific differences in morphine effects on oxytocin levels measured in saliva.

  10. Early life stress

    Time frame: Prior to enrollment

    Modulation of the Questionnaire of Unpredictability in Childhood (QUIC) sum score on differences in secondary outcomes. Scores range from 0-38 with higher scores indicating greater exposure to instability and unpredictability during childhood.

  11. Hair concentrations of chronic stress markers

    Time frame: At screening

    Modulation of tonic endocannabinoid (2-AG, AEA, OEA, PEA, SEA) and glucocorticoid (cortisol, cortisone, ACTH) concentrations in hair on primary and secondary outcomes.

  12. Personality traits

    Time frame: Single measure, during experimental session

    Modulation of personality traits measured by the Neuroticism-Extraversion-Openness Five-Factor Inventory (NEO-FFI) on primary and secondary outcomes. Scores range from 0-48 per subscale. Higher scores indicate higher expression of the trait.

  13. Trait assessment of loneliness

    Time frame: Single measure, during experimental session

    Modulation of loneliness measured by the German version of the UCLA loneliness scale on primary and secondary outcomes. Scores can range from 20-80 with higher scores indicating greater feelings of loneliness.

  14. Rosenberg Self Esteem Scale

    Time frame: Single measure, during experimental session.

    Modulation of self-esteem measured by the Rosenberg Self Esteem Scale (RSES) on primary and secondary outcomes. Scores range from 0 -30 with scores below 15 suggesting low self-esteem, 15 to 25 reflecting a normal or average range, and 26 to 30 indicating high self-esteem.

  15. Brief Resilience Scale

    Time frame: Single measure, during experimental session.

    Modulation of resilience measured by the Brief Resilience Scale (BRS) on primary and secondary outcomes. Scores range from 1-5 with a higher score indicating a better ability to bounce back after stress.

  16. Becker Depression Inventory

    Time frame: Single measure, during experimental session.

    Modulation of depression measured by the Becker Depression Inventory (BDI-II) on primary and secondary outcomes. Scores range from 0-63 with higher scores indicating more severe depressive symptoms.

  17. Trait anxiety level

    Time frame: Single measure, during experimental session.

    Modulation of anxiety measured by the State Trait Anxiety Inventory (STAI) on primary and secondary outcomes. Scores range from 20-80 per subscale, with higher scores indicating higher levels of trait anxiety.

  18. Snaith Hamilton Anhedonia Pleasure Scale

    Time frame: Single measure, during experimental session.

    Modulation of anhedonia measured by the Snaith Hamilton Anhedonia Pleasure Scale (SHAPS) on primary and secondary outcomes. Scores range from 0-14 with higher scores indicating less ability to feel pleasure.

  19. Relationship Structures Questionnaire

    Time frame: Single measure, during experimental session.

    Modulation of attachment style measured by the Experiences in Close Relationship Structures Questionnaire (ECR-RS) on primary and secondary outcomes. Two scores, one for attachment-related avoidance and the other for attachment-related anxiety, are computed for different interpersonal targets. The avoidance score can be computed by averaging items 1 - 6 and the anxiety score by averaging items 7 - 9, respectively.

  20. Socioeconomic status ladder

    Time frame: Single measure, during experimental session.

    Modulation of socioeconomic status (SES) measured by the MacArthur SES ladder on primary and secondary outcomes. Participants rate their perceived socioeconomic status and social standing using two ladder scales ranging from 1-10: one relative to people in Switzerland and one relative to people in their community. Higher scores indicate higher perceived socioeconomic status or social standing.

  21. Sex hormone concentration

    Time frame: Single measure at both experimental sessions.

    Modulation of baseline concentrations of steroid sex hormones (testosterone, progesterone, estradiol) in plasma on primary and secondary outcomes.

Study contacts

Contact information is provided by the study sponsor or research team.

Ella L Sommer

CONTACT

[email protected]

+41 (0)58 384 26 01

Sara L Kroll, Dr. phil.

CONTACT

[email protected]

+41 (0)58 384 34 13

Sponsors and collaborators

Lead sponsor

Sara L. Kroll

Other

Registry information

Official study title

Randomized, Double-blind, Placebo-controlled, Crossover Study Investigating Sex-specific Effects of Mu-opioid Receptor Activation on Stress and Social Interaction and Its Modulation by Early Life Stress

Acronym: MOR-SAFE

Important dates

Study start
2026
Primary completion
2026
Study completion
2028
First posted
Aug 21, 2026
Registry last updated
Aug 21, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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