How Does the Opioid System Shape Stress and Social Behaviour in Men and Women and What Role Does Childhood Unpredictability Play? (MOR-SAFE)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Stress; Sex Differences; Early Life Stress; Opioid
• Intervention / Treatment: Drug: Morphine; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sara L Kroll, Dr. phil.; Phone Number: +41 (0)58 384 34 13; Email: saraliane.kroll@bli.uzh.ch
• Study Contact Backup: Name: Ella L Sommer; Phone Number: +41 (0)58 384 26 01; Email: ella.sommer@bli.uzh.ch

Study Locations

• Switzerland
  • Zurich, Switzerland, 8032
    • University Hospital of Psychiatry Zurich
    • Contact: Sara L Kroll, Dr. phil.; Phone Number: +41 (0)58 384 34 13; Email: saraliane.kroll@bli.uzh.ch
    • Contact: Ella L. Sommer; Phone Number: +41 (0)58 384 26 01; Email: ella.sommer@bli.uzh.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Morphine; Participants receive the active drug (morphine) on Visit 1or Visit 2.	Drug: Morphine; Sevredol 10mg, oral single-dose administration
Placebo Comparator: Placebo; Participants receive the non-active comparator (placebo) on Visit 1 or Visit 2.	Drug: Placebo; identical in appearance to active drug, containing no active substance (mannitol), oral one-time administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Self-report of subjective stress during stress exposure	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.	During the experimental stress task
Endocrinological markers of stress response	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).	Throughout the experiment sessions (baseline and approx. 10, 20, 30, 60 and 105 minutes after stress onset, 6 samples).
Psychophysiological stress response of heart rate measured by electrocardiogram	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).	During the experimental stress task
Psychophysiological stress response of heart rate variability measured by electrocardiogram	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.	During the experimental stress task
Psychophysiological measure of sympathetic activity	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).	During the experimental stress task
Changes in self-reported subjective stress over time	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"	Throughout the experimental sessions (from before stress induction to 10, 20, 30, 60 and 105 minutes after stress onset, 7 times).
Self-reported feeling of shame post-stress	Sex-differences in morphine effects on the Experiential Shame Scale (ESS) score, ranging from 25 -100, with higher values indicating stronger feelings of shame.	~10 minutes after stress onset
Changes in self-reported affect over time	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.	Throughout the experimental sessions (from before stress induction to 10, 30, 60 and 105 minutes after stress onset, 6 times).
Early life stress	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.	Prior to enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective differences in experiencing social interaction	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.	During the experimental tasks
Behavioural differences of social approach and avoidance	Sex-specific differences in morphine effects on behavioural measures (measured by number of button presses) during the social approach/avoidance task.	During the experimental task
Psychophysiological cardiac markers of social interaction measured by heart rate using electrocardiogram	Sex-specific differences in morphine effects on heart rate (beats per minute) during the social approach/avoidance task and the affective touch task.	During the experimental tasks
Psychophysiological cardiac markers of social interaction measured by heart rate variability using electrocardiogram	Sex-specific differences in morphine effects on heart rate variability during the social approach/avoidance task and the affective touch task.	During the experimental tasks
Psychophysiological measure of sympathetic activity during social interaction	Sex-specific differences in morphine effects on skin conductance response (SCR) during the social approach/avoidance task and the affective touch task.	During the experimental tasks.
State anxiety over time	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	Throughout the experimental sessions (from before stress induction to approx. 10, 30, 60, and 105 minutes after stress onset, 6 times).
Drug Effects Questionnaire (DEQ)	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".	Throughout the experimental sessions (immediately after drug administration until approx. 3 hours after study medication administration, 7 times).
Drug concentration	Differences in concentration of the study drug in blood between the two test sessions.	Throughout the experimental sessions (from 1 hour after drug administration until approx. 3 hours after study medication administration, 4 samples).
Changes in oxytocin over time	Sex-specific differences in morphine effects on oxytocin levels measured in saliva.	Throughout the experimental sessions (from before stress induction to approx. 10, 20, 30, 60 and 105 minutes after stress onset, 6 samples).
Early life stress	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.	Prior to enrollment
Hair concentrations of chronic stress markers	Modulation of tonic endocannabinoid (2-AG, AEA, OEA, PEA, SEA) and glucocorticoid (cortisol, cortisone, ACTH) concentrations in hair on primary and secondary outcomes.	At screening
Personality traits	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.	Single measure, during experimental session
Trait assessment of loneliness	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.	Single measure, during experimental session
Rosenberg Self Esteem Scale	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.	Single measure, during experimental session.
Brief Resilience Scale	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.	Single measure, during experimental session.
Becker Depression Inventory	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.	Single measure, during experimental session.
Trait anxiety level	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.	Single measure, during experimental session.
Snaith Hamilton Anhedonia Pleasure Scale	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.	Single measure, during experimental session.
Relationship Structures Questionnaire	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.	Single measure, during experimental session.
Socioeconomic status ladder	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.	Single measure, during experimental session.
Sex hormone concentration	Modulation of baseline concentrations of steroid sex hormones (testosterone, progesterone, estradiol) in plasma on primary and secondary outcomes.	Single measure at both experimental sessions.

Collaborators and Investigators

• Sponsor: Sara L. Kroll
• Investigators: Principal Investigator: Sara L Kroll, Dr., Psychiatric University Hospital, Zurich

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: August 5, 2026
• First Submitted That Met QC Criteria: August 19, 2026
• First Posted (Actual): August 21, 2026

Study Record Updates

• Last Update Posted (Actual): August 21, 2026
• Last Update Submitted That Met QC Criteria: August 19, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: sex differences; stress; morphine; opioid use disorder; endocannabinoid system; early life stress; social behaviour; mu opioid receptor; affiliative behaviour
• Additional Relevant MeSH Terms: Narcotic-Related Disorders; Mental Disorders; Behavioral Symptoms; Substance-Related Disorders; Chemically-Induced Disorders; Behavior; Opioid-Related Disorders; Stress, Psychological; Social Behavior; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Alkaloids; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Phenanthrenes; Morphine Derivatives; Morphine
• Other Study ID Numbers: 2026-00586; PZ00P1_208759 (Other Grant/Funding Number: Swiss National Science Foundation)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No