Attenuating trauma- and cocaine-related intrusions by blocking memory reconsolidation with minocycline: protocol for a transdiagnostic randomized controlled trial

ABSTRACT

Background: Post-traumatic stress disorder (PTSD) and substance use disorders frequently co-occur, with their comorbidity linked to poorer treatment outcomes. Beyond this epidemiological overlap, PTSD and, in particular, cocaine use disorder (CUD) have also been conceptually linked, as maladaptive memory processes are thought to play a central role in both of their etiopathogeneses. PTSD and CUD are each characterized by intrusive memories – either trauma or cocaine related – that sustain distress and craving, respectively. These parallels have motivated transdiagnostic mechanistic research targeting memory reconsolidation. Matrix metalloproteinase-9 (MMP-9) is critically involved in synaptic plasticity and memory updating, and has been suggested as a pharmacological entry point for modulating reconsolidation-related processes.

Objective: This study examines whether pharmacological interference with reconsolidation via MMP-9 inhibition by minocycline modulates trauma- and cocaine-related intrusive memories and their neurobiological correlates in PTSD and CUD.

Method: In this monocentric, randomized, double-blind, placebo-controlled trial (NCT05902819), individuals with PTSD (n = 60) or CUD (n = 60) receive a single dose of minocycline – a tetracycline inhibiting MMP-9 – or placebo prior to an individualized, imagery-based reactivation of their most salient intrusive memory. Intrusive memories in day-to-day life are assessed using event-based ecological momentary assessment and pre–post intrusion questionnaires. Neurobiological correlates of maladaptive memory processing are indexed through functional magnetic resonance imaging and magnetic resonance spectroscopy, and peripheral biomarkers are obtained from blood, urine, and hair samples. Diagnostic status and comorbid symptoms are characterized using clinical interviews and standardized self-report measures.

Conclusions: This trial adopts a mechanistic framework to investigate whether minocycline-augmented memory reactivation modulates intrusions and associated neurobiological markers in PTSD and CUD. By directly targeting candidate memory mechanisms shared by both disorders, it evaluates a transdiagnostic reconsolidation-based approach and is expected to inform models of intrusive memory persistence and updating. The findings may guide future development of memory-focused interventions in trauma- and addiction-related disorders.

HIGHLIGHTS

• This randomized controlled trial evaluates a transdiagnostic, mechanism-focused intervention targeting maladaptive memory processes in PTSD and cocaine use disorder.

• Minocycline is used as an MMP-9 inhibitor to modulate intrusive trauma- and cocaine-related memories following brief imagery-based memory reactivation.

• The study integrates multimodal neurobiological assessments (fMRI, MRS, peripheral biomarkers) with ecological momentary intrusion measures to characterize changes in memory-related mechanisms.

1. Introduction

Within clinical populations, post-traumatic stress disorder (PTSD) and substance use disorders (SUDs) frequently co-occur, with approximately 40–50% of individuals meeting criteria for both conditions (Brady et al., 2004; Pietrzak et al., 2011). This high rate of comorbidity has prompted increasing interest in whether shared underlying mechanisms contribute to their persistence and mutual maintenance. Beyond overlapping risk factors and shared symptom clusters, including sleep disturbances, hyperarousal, and emotion dysregulation (Enman et al., 2015; Gisquet-Verrier & Le Dorze, 2019; Hinckley & Danielson, 2022), both conditions are characterized by maladaptive memory processes. In PTSD and SUDs, emotionally charged experiences – traumatic experiences or episodes of substance use – can be encoded and retrieved in ways that strengthen rather than resolve distressing associations. As a result, underlying memory representations and their dynamics may play a central role in the persistence of both disorders.

These memories are dynamic, emotionally charged representations that can intrude involuntarily into consciousness and disrupt cognitive and emotional functioning (Brewin et al., 2010; Gisquet-Verrier & Le Dorze, 2019; Kavanagh et al., 2009; Zacher, Dietiker, Häffner, et al., 2025). In PTSD, intrusive re-experiencing constitutes a hallmark symptom and is a key driver of disorder persistence (Brewin, 2014; Brewin & Holmes, 2003; Ehlers & Clark, 2000). In SUDs, analogous intrusive phenomena, such as vividly re-experienced substance-related memories or images, are assumed to elicit craving and compulsive substance use and relapse (Kavanagh et al., 2009; Milton & Everitt, 2012; Zacher, Dietiker, Janousch, et al., 2025). These processes appear particularly pronounced in cocaine use disorder (CUD), where strong cue reactivity and psychological reinforcement render cocaine-related memories especially salient (Gawin, 1991). Recent phenomenological work from our group directly comparing trauma-related and substance-related intrusions in daily life also suggests overlap in their vividness and sensory qualities across PTSD and CUD (Zacher, Dietiker, Häffner, et al., 2025). Such parallels raise the question of whether intrusive phenomena in PTSD and CUD may, at least in part, draw on overlapping pathological memory mechanisms that reinforce maladaptive associative networks (Iyadurai et al., 2019; Kalivas et al., 2023). In this view, both conditions have been conceptualized as ‘disorders of memory’, in which aberrant retrieval and reconsolidation processes contribute to the persistence of maladaptive memories and associated responses (Gisquet-Verrier & Le Dorze, 2019; María-Ríos & Morrow, 2020).

The hypothesis of shared maladaptive memory processes is further supported by converging evidence at the neurofunctional level. Similar alterations in neural activation have been observed in PTSD and SUD within regions implicated in emotional memory processing, such as the amygdala, anterior cingulate cortex, thalamus, and ventromedial prefrontal cortex (Koob & Volkow, 2016; Lanius et al., 2006; Michaels et al., 2021; Thome et al., 2020), as well as in reward-related structures, including the nucleus accumbens (NAcc) and ventral tegmental area (Peters et al., 2009). The overlap of these alterations in neural circuits across PTSD and CUD supports the existence of converging underlying mechanisms affecting salience attribution and memory–emotion coupling (Kalivas et al., 2023). Moreover, both acute stress and cocaine use can induce long-lasting neuroplastic changes within these circuits, disrupting glutamatergic homeostasis and synaptic plasticity, particularly in the NAcc and amygdala (Averill et al., 2017; Engeli et al., 2021; Fang et al., 2018; Schmidt & Pierce, 2010; Wright & Dong, 2020). Such alterations are thought to increase cue reactivity and bias salience processing, thereby potentially impeding the adaptive updating of trauma- or substance-related memories. Conversely, changes towards more adaptive memory processing should be accompanied by corresponding alterations in observable neurofunctional markers and glutamate levels within the NAcc and amygdala. To date, however, it remains unclear whether similar neurochemical and functional mechanisms underlie intrusive memories in PTSD and CUD.

Contemporary cognitive–neurobiological models propose that, in both disorders, the original (index) memory of the traumatic or substance-related experience may become consolidated into a dysfunctional memory trace that remains highly reactive to environmental cues (Gisquet-Verrier & Le Dorze, 2019). Such memories are easily reactivated and can perpetuate symptoms through recurrent intrusions. In PTSD, several established therapies explicitly engage the trauma memory to promote more adaptive updating of its emotional and cognitive meaning, indicating that targeting memory traces can be clinically relevant (Cusack et al., 2016; Dewar et al., 2019). In CUD, by contrast, interventions have largely focused on craving management and relapse prevention, rather than directly modifying memory representations (Kampman, 2019). From a mechanistic perspective, this contrast highlights the need to experimentally probe whether maladaptive memory processes can be modulated across PTSD and CUD, and whether such modulation engages similar underlying mechanisms in both disorders.

Memory reconsolidation refers to the brief time window after memory reactivation during which the memory trace becomes temporarily labile and open to modification before it is restabilized (Lee et al., 2017; Nader et al., 2000). This window can be experimentally harnessed to attenuate the affective charge or motivational impact of trauma- or substance-related memories while preserving their core declarative content (Kindt & Elsey, 2023). Attempts to interfere with memory reconsolidation have employed either behavioural competition tasks, such as visuospatial interference, or pharmacological interventions disrupting molecular pathways, such as β-adrenergic or N-methyl-D-aspartate-dependent signalling (Brunet et al., 2018; Kindt et al., 2009; Saladin et al., 2013). More recently, research has focused on extracellular mechanisms that regulate synaptic plasticity. The extracellular matrix (ECM) provides structural and molecular scaffolding for synaptic connections and undergoes transient remodelling following memory reactivation. Matrix metalloproteinase-9 (MMP-9), an enzyme that degrades ECM components and enables the brain-derived neurotrophic factor (BDNF)-dependent plasticity necessary for late-phase long-term potentiation, is involved in this remodelling process (Beroun et al., 2019; Nagy et al., 2006). Inhibition of MMP-9 is thought to interfere with reconsolidation by preventing the restabilization of reactivated memory traces (Bach, Brown, et al., 2019; Brown et al., 2009), thereby providing a mechanistic handle on memory modulation processes.

While the broad-spectrum tetracycline doxycycline has shown partial success in modulating reconsolidation-related processes in humans by reducing fear-memory retention (Bach et al., 2018; Bach, Näf, et al., 2019), subsequent findings have been inconsistent (Meister et al., 2023; Wehrli et al., 2024). The structurally related antibiotic minocycline offers several advantages, including superior blood–brain-barrier penetration, greater potency for MMP-9 inhibition, and pronounced anti-inflammatory effects through modulation of microglial activity (Modheji et al., 2015). Preclinical and human studies further indicate that minocycline can modulate fear learning, neural plasticity, and affective processing, and has been explored as an adjunctive agent across several psychiatric conditions, including PTSD, depression, schizophrenia, and SUDs (Panizzutti et al., 2023; Romero-Miguel et al., 2021; Xia et al., 2024). Taken together, these findings suggest that minocycline may serve as a useful pharmacological probe to experimentally modulate reconsolidation-related mechanisms in humans.

Based on this evidence, the present study investigates from a mechanistic perspective whether administering minocycline during brief guided imagery-based reactivation of intrusive trauma- or cocaine-related memories modulates reconsolidation-related processes in PTSD and CUD. While high rates of comorbidity motivate the investigation of potentially shared mechanisms, the intervention is conducted in diagnostically distinct PTSD and CUD groups to isolate disorder-specific and transdiagnostic effects. Using a monocentric, randomized, double-blind, placebo-controlled design, individuals with PTSD or CUD undergo guided memory reactivation sessions under either a single dose of minocycline (200 mg) or placebo. We will examine whether minocycline, compared to placebo, is associated with pre-to-post-intervention changes in: (1) the frequency and phenomenological characteristics of intrusive memories, as assessed both retrospectively via intrusion questionnaires and in daily life via ecological momentary assessment (EMA); (2) glutamate concentrations in the amygdala and NAcc; and (3) neural activation within salience- and emotion-processing circuits during script-driven imagery (SDI) of the index memory. The inclusion of EMA enables the capture of dynamic within-person fluctuations in intrusive memories and thereby provides ecologically valid data that complement laboratory-based and neurobiological measures. By comparing these behavioural, neurochemical, and neurofunctional indices across PTSD and CUD, the study aims to test whether intrusive memories in both disorders show similar susceptibility to pharmacological modulation of reconsolidation-related mechanisms, thereby providing experimental insight into potential transdiagnostic memory processes.

2. Method

2.1. Study setting

This randomized controlled trial (RCT) forms the central component of a larger project that also includes screening and baseline assessments in a healthy control group and a group with comorbid PTSD and SUD. The present protocol focuses on the RCT, which comprises the intervention arms of the study. The first five visits are conducted on site at the University Hospital of Psychiatry, Zurich (PUK), followed by a remote follow-up via telephone and an online survey. Figure 1 illustrates the four study arms (n = 30 participants per arm) and the overall sequence of study visits. More detailed measures are listed in Table 1. This study was approved by the Ethics Committee of Zurich on 26/08/2022 (BASEC ID: 2022-01177), with all protocol amendments reapproved according to local regulations, and complies with the Declaration of Helsinki of 1975, as revised in 2013.

Figure 1.

Overview of the study design and structure of the intervention sessions. Following screening on day 0 (T1), participants are randomized (1:1) to receive minocycline or placebo within post-traumatic stress disorder (PTSD) and cocaine use disorder (CUD) groups, i.e. PTSD minocycline, PTSD placebo, CUD minocycline, and CUD placebo groups. Baseline and short-term follow-up include multimodal assessments [magnetic resonance spectroscopy (MRS), functional magnetic resonance imaging (fMRI), biological sampling, and psychological questionnaires, including the Intrusion Questionnaire]. Baseline assessment (T2, day 3) includes fMRI scanning, biological samples, and questionnaires. Two intervention sessions (T3, day 6; and T4, day 9) involve guided memory reactivation under study medication. Short-term follow-up (T5, day 12) repeats baseline assessments, and long-term follow-up (T6, day 102) includes online psychiatric interviews and questionnaires. Ecological momentary assessment (EMA) and fitness tracking are conducted from T2 to 3 days after T5. The lower panel illustrates the detailed structure of each intervention session: urine screening, medication intake, a 120 min waiting period, questionnaires, guided imagery of the index memory, and post-imagery questionnaires with debriefing.

Table 1.

Participant timeline.

	Screening  (T1)	Baseline (T2)	Intervention sessions (T3 & T4)	Follow-up (T5)	Long-term follow-up (T6)
Patient information and informed consent	x
Inclusion/exclusion criteria	x
Medical examination	x
Routine laboratory tests	x
Urine pregnancy test (women only)	x	x	x	x
Structured Clinical Interview for DSM-5 – Clinical Version	x
Scale for Suicidal Experience and Behaviour	x
Random allocation to intervention arm (verum vs placebo)	x
Hair toxicology	x
Drug urine quick test	x	x	x	x
Demographics	x
Blood markers for inflammation/MMP-9		x		x
Concomitant medication interview	x	x	x	x	x
Global Assessment of Functioning Scale	x			x	x
Clinician-Administered PTSD Scale for DSM-5 (PTSD only)	x			x
Life Events Checklist (PTSD only)	x
PTSD Checklist DSM-5 (PTSD only)		x
Dissociative Experiences Scale – Taxon (PTSD only)		x
Interview for psychotropic drug consumption	x				x
Cocaine use pattern (CUD only)		x		x
Cocaine Craving Questionnaire Brief (CUD only)		x	x	x	x
Obsessive Compulsive Cocaine Use Scale (CUD only)		x		x	x
Script generation for SDI	x
Check for changes in health condition (including substance use and sleep quality)		x	x	x	x
Intrusion Questionnaire	x			x	x
Childhood Trauma Questionnaire – Short Form		x
ADHD – Self-Report Scale		x
Beck Depression Inventory-II		x		x
Pittsburgh Sleep Quality Index		x		x
Functional magnetic resonance imaging		x		x
Magnetic resonance spectroscopy		x		x
Ecological momentary assessment			from T2 to 3 days after T5
Fitbit			from T2 to T5
Reflective Functioning Questionnaire			x
Personality Inventory for DSM-5			x
Intervention: medication administration and guided imagery			x
VAS distress pre- and post-memory reactivation		x	x	x
Response to Script-Driven Imagery		x	x	x
Emotion Inventory for Distressing Events			x
Serious adverse events	x	x	x	x	x

Note: More specific information on measures can be found in Supplement A.

DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; MMP-9 = matrix metalloproteinase-9; PTSD =  post-traumatic stress disorder; CUD = cocaine use disorder; SDI = script-driven imagery; ADHD = attention deficit hyperactivity disorder; VAS =  visual analogue scale.

2.2. Eligibility criteria

General inclusion criteria encompass:

• sufficient German language proficiency

• age between 18 and 60 years

• ability to provide informed consent and follow the study procedures.

Participants in the PTSD group must:

• meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for current PTSD (full or subthreshold PTSD diagnosis, as defined by Blanchard et al. 1996).

Participants in the CUD group must:

• meet DSM-5 criteria for current mild, moderate, or severe CUD,

• report regular cocaine use within the past 12 months and a minimum of one use occasion in the past 6 months.

General exclusion criteria encompass:

• current or past severe neurological disorders, head injuries, or systemic/rheumatic diseases

• clinically significant concomitant disease states, such as renal failure (estimated glomerular filtration rate < 60 mL/min/1.73 m²), hepatic dysfunction (alanine aminotransferase > 90 IU/L for women or 110 IU/L for men; aspartate aminotransferase > 74 IU/L; γ-glutamyltransferase > 70 IU/L for women or > 120 IU/L for men), or cardiovascular disease

• diagnosis of schizophrenia, bipolar disorder, or autism spectrum disorder (DSM-5)

• history of three or more suicide attempts, any suicide attempt within the past 12 months, or acute suicidality

• contraindication for MRI (e.g. pregnancy, metal implants, claustrophobia)

• participation in another study with investigational drugs within 30 days preceding and during the present study

• any known circumstance potentially contraindicating minocycline intake, including known allergy to minocycline, current use of medications interacting with minocycline, and breast feeding or intention to become pregnant during study participation or within 3 months afterwards.

Participants in the PTSD group are excluded if DSM-5 criteria are met for:

• severe nicotine use disorder

• moderate or severe alcohol or cannabis use disorder

• any other SUD

• current or past diagnosis of CUD.

Participants in the CUD group are excluded if DSM-5 criteria are met for:

• severe alcohol or cannabis use disorder

• any other SUD

• a current or past PTSD diagnosis.

2.3. Power analysis

A priori power calculations were conducted using G*Power based on effect sizes reported in previous pharmacological reconsolidation interference studies. Moderate-to-large effects (Cohen’s d = 0.51–2.19) were reported for propranolol-based reconsolidation blockade in PTSD (Brunet et al., 2018). We used an effect size of Cohen’s d = 0.5 (f = 0.25). Assuming a 2 × 2 mixed between-subjects design (intervention group: PTSD vs CUD × condition: minocycline vs placebo) with two repeated measures (pre, post), a test–retest correlation of r = 0.5, α = 0.01, and power = 0.90, the required total sample size was estimated at n = 84 (i.e. 42 per group). To accommodate an anticipated ∼20% dropout rate, the recruitment target was set to N = 120 participants (60 per group), ensuring maintained statistical power despite attrition. Participants discontinuing before completing the intervention phase will be replaced to preserve the target sample size.

A supplementary sensitivity analysis was performed using less conservative yet empirically supported parameters for the primary outcome measure (test–retest reliability r = 0.7, as reported for the Intrusion Questionnaire by FDA, 2017; Hackmann et al., 2004) and a conventional α = 0.05, keeping all other parameters identical. This analysis yielded a required total sample size of n = 66 (33 per group). Hence, the planned recruitment target of N = 120 remains conservative across both sets of assumptions.

2.4. Recruitment

Recruitment is carried out through digital and community outreach strategies, including social media online marketplaces, distribution of flyers at social venues and on public transport, and study presentations at healthcare institutions specializing in PTSD and SUD. Individuals interested in participating can register through a dedicated study website. Registered candidates are subsequently contacted by an investigator for an initial telephone screening checking eligibility to attend the on-site screening visit (T1).

2.5. Informed consent

Prospective participants receive detailed study information and the informed-consent document several days prior to their first visit (T1). At the start of this visit, a delegated investigator obtains written informed consent before any study procedures are initiated, or data are collected. Each participant receives a signed copy of the consent form. A separate consent document is provided for the optional secondary use of data.

2.6. Intervention

2.6.1. Study medication, randomization, and blinding

Following inclusion at screening (T1), participants are randomly assigned (1:1) to receive either 200 mg minocycline (verum) or 120 mg mannitol (placebo). The selected minocycline dose corresponds to the standard U.S. Food and Drug Administration (FDA)-approved individual antibiotic dose (FDA, 2017). To minimize the risk of adverse effects, participants undergo thorough medical screening prior to inclusion and are monitored during and after medication administration. The study medication is administered as a single oral dose at each intervention session. Allocation is generated via a computer-based random number sequence and independently managed by the hospital pharmacy at PUK. Both participants and study personnel remain blinded to allocation. Study medication is prepared and dispensed by the hospital pharmacy in identical-appearing capsules to preserve double-blinding. To assess blinding integrity, participants are asked at short-term follow-up to indicate their perceived treatment allocation. Unblinding is permitted only in the event of a serious adverse event (SAE) with suspected medication involvement, with full documentation of the date, event, and personnel involved. Complete unblinding occurs only after study completion. Based on pharmacokinetic data, minocycline reaches peak plasma concentration approximately 120 min post-ingestion (Agwuh & MacGowan, 2006), at which point the memory reactivation task begins.

2.6.2. Memory reactivation protocol

The reactivation procedure follows established principles of mental imagery (Blackwell, 2021) and imaginal re-experiencing (phase 1a of imagery rescripting and reprocessing therapy) (Hackmann, 2011; Schmucker & Köster, 2025), and is further referred to as guided imagery-based reactivation. The index memory is a personalized trauma-related (PTSD group) or cocaine-related (CUD group) narrative identified during screening.

To standardize engagement with sensory imagery, the procedure starts with a brief imagination warm-up, which participants have also practised during screening. Participants are then guided to engage with the index memory through its sensory modalities (i.e. visual, auditory, olfactory, gustatory, affective, and bodily) in a structured sequence, spending approximately 2 min re-experiencing each modality.

Evidence suggests that memory reactivation engages reconsolidation only under certain boundary conditions, including moderate emotional arousal and the presence of a prediction error (Elsey & Kindt, 2017). Emotional arousal is maintained within the individual’s ‘window of tolerance’ (Corrigan et al., 2011; Noël, 2023) by pausing the guided imagery if distress or craving ratings after a sensory segment exceed 8 (on a scale of 0–10), and repeating the segment if ratings fall below 5. In the CUD group, acute craving ratings serve as an index of successful engagement with the cocaine-related memory during reactivation, analogous to distress ratings in the PTSD group. A prediction error is introduced by violating participants’ expectations: PTSD participants are exposed to trauma cues in a safe, controlled context, while CUD participants are interrupted before imagining cocaine use and instructed to remain abstinent 24 h after the intervention sessions. These steps are intended to maximize the likelihood that memory retrieval engages reconsolidation processes. Adherence to the 24 h abstinence instruction is assessed at the subsequent visit via self-report of cocaine use since the last intervention session. Non-adherence does not lead to study discontinuation, but is documented.

Each session concludes with a brief guided imagery-based reactivation of a neutral autobiographical ‘anchor’ memory, identified prior to imagery, to support emotional regulation. To ensure procedural consistency, the same researcher conducts both intervention sessions for each participant. Mental strain associated with the guided imagery-based reactivation is assessed immediately before and after the mental imagery. This includes current distress ratings on a visual analogue scale (VAS; 0–10) and craving ratings in the CUD group using the Cocaine Craving Questionnaire – Brief (CCQ-Brief) (Tiffany, 1993). After the mental imagery, quality and intensity of emotions during reactivation are measured with the Emotion Inventory for Distressing Events (EIBE) (Schmucker & Köster, 2025). The success of imagery application is evaluated with the Response to Script-Driven Imagery Scale (RSDI) (Hopper et al., 2007). Figure 1 illustrates the timeline of procedures during intervention visits.

2.7. Endpoints

The study investigates two primary endpoint domains, namely, intrusion-related and neuroimaging outcomes, and a range of secondary endpoints assessing broader clinical and physiological changes. A complete overview of measures and their assessment time-points is provided in Table 1 and in Supplementary Section A.

2.7.1. Primary endpoints

Intrusion-related endpoints assess whether guided imagery under minocycline is associated with changes in the frequency and phenomenological characteristics of trauma- and cocaine-related intrusive memories, compared to placebo.

• Retrospective intrusion features are measured with the adapted Intrusion Questionnaire at T2 and T5. Primary retrospective intrusion endpoints include change in intrusion frequency, as well as changes in ratings of vividness, intrusiveness, nowness, and associated distress, fear, and loss of control from T2 to T5.

• Real-time intrusion features are captured via the Smartphone Ecological Momentary Assessment application (SEMA³) (O’Brien et al., 2024) using event-based completions of the adapted Intrusion Questionnaire (FDA, 2017; in Supplementary Section B) between T2 and T5 + 3 days (Figure 2). The primary EMA endpoints include change over time in the rate of intrusion-related entries and in phenomenological ratings (vividness, intrusiveness, nowness, distress, fear, loss of control) across recorded intrusions. Participants additionally receive a daily evening reminder prompting them to report any intrusion events that may not yet have been entered.

Figure 2.

Ecological momentary assessment (EMA) protocol and assessment window. The EMA period spans from baseline (T2, day 3) to 3 days after short-term follow-up assessment (day 15). The timeline includes intervention session 1 (T3, day 6), intervention session 2 (T4, day 9), and short-term follow-up (T5, day 12). Participants complete event-based entries whenever intrusive memories occur (indicated by cloud icons), using the adapted Intrusion Questionnaire with the SEMA³ smartphone application, which assesses vividness, intrusiveness, nowness, distress, fear, and loss of control. Bell icons indicate daily evening reminders prompting participants to report any intrusion events that may not yet have been entered.

Neuroimaging endpoints assess whether guided imagery under minocycline modulates neural and neurochemical indices of memory-related processing. For technical detail on acquisition and processing, see Supplementary Section D.

• Changes in glutamate concentrations are quantified at T2 and T5 using single-voxel ¹H-magnetic resonance spectroscopy (MRS) in the left amygdala (PTSD group) and the left NAcc (CUD group). The primary MRS endpoint is the change in glutamate concentration from T2 to T5 in the respective target region.

• Task-based functional magnetic resonance imaging (fMRI) using an SDI paradigm established for investigating memory-related neural activation in PTSD and CUD (Figure 3) measures blood-oxygenation-level-dependent (BOLD) responses during individualized audio scripts of three personal memories (conditions for PTSD group: trauma-related, trauma-unrelated stressful, neutral; conditions for CUD group: cocaine-related, cocaine-unrelated rewarding, neutral). Whole brain analyses assess within-subject changes from T2 to T5 in BOLD responses in contrasts between index-memory and stressful/rewarding or neutral conditions. For further details on the SDI paradigm, see Supplementary Section C.

Figure 3.

Graphic representation of the script-driven imagery paradigm during functional magnetic resonance imaging (fMRI) acquisition. Each condition (neutral, stressful/rewarding, and trauma/cocaine) consists of three script repetitions. For each repetition, participants first listen to an individualized, standardized audio script (30 s; imagery), followed by a short recovery period (30 s; recovery) and self-report ratings (40 s; self-report scales). The full paradigm is completed separately for three conditions (neutral, stressful/rewarding, and trauma/cocaine), each lasting for approximately 6 min, resulting in a total task duration of 18 min. The order of the neutral and stressful/rewarding conditions is counterbalanced, while the trauma/cocaine condition is always presented last. At the end of the final block, participants complete the Response to Script-Driven Imagery Scale (RSDI). For further details see Supplementary Section C.

2.7.2. Secondary endpoints

Secondary outcomes explore broader clinical, behavioural, neurobiological, and psychophysiological changes that may accompany potential modulations of intrusions, including:

• Symptom severity measures: Changes in self-reported PTSD symptom severity [PTSD Checklist for DSM-5 (PCL-5)], or in cocaine use and craving severity and cocaine-related cognitive patterns (Interview for Psychotropic Drug Consumption, CCQ-Brief, Obsessive Compulsive Cocaine Use Scale] from T2 to T5.

• Experimental task ratings: Changes in subjective ratings of distress (VAS) and, in the CUD group, craving (CCQ-Brief) before and after the SDI-based memory reactivation paradigm from T2 to T5; changes in ratings of arousal and valence and of intensity of experienced intrusions and either dissociation (PTSD group) or craving (CUD group) after each narrative presentation during SDI from T2 to T5.

• Neuropathological biomarkers: Changes in cytoskeletal (neurofilament light chain, glial acidic fibrillary protein), inflammatory (sphingolipids and cytokines), and extracellular-matrix related markers (MMP-9 protein levels and gene expression) from T2 to T5, derived from blood plasma, serum, and gene-expression assays.

• Psychophysiological indices: Changes in autonomic activity (heart rate variability, respiratory rate) during SDI-based memory reactivation from T2 to T5, as well as heart rate and sleep parameters recorded continuously via wearable devices between T2 and T5.

• Exploratory clinical and computational measures: Self-report questionnaires assessing depressive symptoms, attention deficit hyperactivity disorder, sleep quality, trauma history, personality traits, reflective functioning, and global functioning are used for sample characterization and exploratory moderation analyses. Voice- and text-based language features of reported autobiographical memories recorded during T1 are explored as computational predictors of intrusion features.

Diagnostic interviews and toxicological screenings (hair and urine samples across time-points) are used primarily for eligibility verification and sample characterization, and are not considered study endpoints. Memory reactivation success is assessed via the RSDI (Hopper et al., 2007) following both guided imagery-based and SDI-based memory reactivation. Adverse events are documented at each contact, and SAEs are reported immediately to the sponsor–investigator and, if applicable, to the ethics committee, in accordance with Swiss regulatory requirements.

2.8. Data analysis

All analyses will be conducted according to the intention-to-treat principle, with additional per-protocol sensitivity analyses including only participants who complete the intervention and post-assessment. Differences between completers and non-completers will be explored and, where appropriate, additional adjustment strategies (e.g. propensity score approaches) may be considered.

The primary hypothesis is that pharmacological interference with memory reconsolidation using minocycline during guided memory reactivation will reduce the frequency and phenomenological salience of intrusive memories compared with placebo from pre- to post-intervention. In addition, we hypothesize that this behavioural change will be accompanied by neurobiological changes, including alterations in glutamate concentrations in the amygdala and NAcc and changes in neural activation during script-driven imagery of the index memory. We will further examine whether these effects differ between participants with PTSD and those with CUD.

Retrospective intrusion outcomes assessed at pre- and post-intervention will be analysed using linear or generalized linear mixed-effects models, depending on outcome distributions. Models will include condition (minocycline vs placebo) and group (PTSD vs CUD) as between-subject factors and time (pre- vs post-intervention) as a within-subject factor. Random intercepts for participants will account for within-person dependence, with random slopes for time included where appropriate.

For EMA outcomes, multilevel models will account for the hierarchical structure of repeated event-based reports nested within participants. Primary EMA analyses will examine whether the frequency of intrusion entries and their phenomenological characteristics (i.e. vividness, intrusiveness, nowness, distress, fear, loss of control) change from baseline to post-intervention and whether these changes differ between treatment conditions and diagnostic groups. Time variables derived from entry timestamps (e.g. time since EMA start and/or relative to the intervention sessions) will be included as appropriate to capture temporal trends, and models of EMA entry frequency will account for differences in monitoring duration across participants.

For MRS data, analogous mixed-effects models will test intervention-related changes in glutamate and related metabolites within the amygdala and NAcc, including diagnostic group as a factor to examine potential disorder-specific differences.

For fMRI data, voxel-wise general linear models will be estimated to investigate activation patterns during the SDI conditions neutral, stressful/rewarding, and trauma/cocaine. The following regressors will be modelled: rest period (30 s) and three repetitions of SDI individually (each 30 s) for each condition. Motion parameters (standard + temporal derivatives + squared + quadratic) will be included as regressors of no interest. First level contrasts between conditions (e.g. trauma-neutral or cocaine-neutral) will be estimated to determine brain activation specific to responses to traumatic or drug SDI.

For longitudinal analyses, we will enter the individual contrast images into group-level repeated-measures models to test intervention-related changes over time. Specifically, for each contrast we will compute the paired difference between post-intervention and pre-intervention (e.g.

$$[\mathrm{trauma}/\mathrm{cocaine}>\mathrm{neutral}{]}_{\mathrm{post}\text{-}\mathrm{intervention}}-[\mathrm{trauma}/\mathrm{cocaine}>\mathrm{neutral}{]}_{\mathrm{pre}\text{-}\mathrm{intervention}}$$

) and test whether the mean of this difference differs from zero at the voxel level across the brain.

Secondary endpoints, including clinical symptom scales (e.g. PCL-5, cocaine use and craving), blood-based biomarkers, and psychophysiological indices, will be analysed analogously using mixed-effects models. Exploratory moderation analyses (e.g. baseline symptom severity, psychotherapy experience, sex or gender) and maintenance of effects at the 3 month follow-up will be examined descriptively and modelled where feasible. Covariates such as age, gender, sex, weight, and smoking status will be included where theoretically justified. All tests will be two tailed (α = .05), and multiple comparisons within endpoint domains will be controlled using false discovery rate correction.

3. Discussion

This study aims to experimentally test whether pharmacological modulation of reconsolidation-related processes alters trauma- and cocaine-related intrusive memories in individuals with PTSD or CUD. By administering minocycline during guided imagery-based memory reactivation, the study examines the central mechanistic question of whether intrusive memories in both disorders show similar susceptibility to manipulation within the reconsolidation window. This approach aligns with contemporary process-based perspectives on psychopathology, which emphasize cognitive–affective mechanisms that may operate across diagnostic categories (Dalgleish et al., 2020).

By probing the effect of MMP-9 inhibition during memory reactivation, the study seeks to clarify whether reconsolidation-related plasticity contributes to the persistence and modulation of intrusive memory processes in both PTSD and CUD. Evidence of such modulation would support the broader reconsolidation framework (Gisquet-Verrier & Le Dorze, 2019; Kindt & Elsey, 2023), provide further insight into the role of extracellular matrix-dependent plasticity in human memory updating (Bach, Brown, et al., 2019), and further strengthen the conceptualization of PTSD and CUD as memory-related disorders (Gisquet-Verrier & Le Dorze, 2019; María-Ríos & Morrow, 2020).

The behavioural and EMA components allow examination of how reconsolidation interference manifests at the experiential level; for example, whether changes are reflected in frequency, sensory-affective qualities, or motivational drive (Kindt, 2018). At the same time, the inclusion of neurofunctional and neurochemical measures offers a complementary window into the neural systems implicated in pathological memory re-experiencing. Alterations in glutamatergic transmission or in activation patterns within salience- and emotion-processing circuits could elucidate the neural substrates of reconsolidation-related modulation and clarify whether similar mechanisms are engaged across PTSD and CUD. Together, this multimodal approach provides an integrated perspective on the cognitive–affective and neurobiological consequences of memory reactivation under MMP-9 inhibition.

The study design has several strengths. Its randomized, double-blind, placebo-controlled design provides a rigorous framework for evaluating pharmacological modulation effects, while the integration of EMA, clinical and laboratory assessments, and neuroimaging allows for a comprehensive characterization of both memory phenomena and their neural correlates. Importantly, the transdiagnostic and mechanistic orientation of the design enables direct comparison of modulation effects across trauma- and substance-related memories, offering an opportunity to examine shared versus disorder-specific memory processes.

Overall, this study is positioned to advance our understanding of intrusive memories and the partly overlapping mechanisms underlying PTSD and CUD. By examining behavioural, neurochemical, and neurofunctional indices before and after memory reactivation under minocycline or placebo, the study seeks to clarify the role of MMP-9-dependent plasticity in these processes. Such insights will, in turn, provide critical insights to inform future translational efforts and guide the development of targeted, memory-focused approaches in subsequent clinical research.

Funding Statement

The study is funded by the University of Zurich within the Clinical Research Priority Program ‘Synapse, Trauma, and Addiction’, with additional support from the Department of Adult Psychiatry and Psychotherapy of the PUK.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analysed in this study.

Author  contributions

Lina Dietiker: conceptualization, methodology, project administration, writing – original draft. Amelie Zacher: conceptualization, methodology, project administration, visualization, writing – original draft. Sofia de’Sperati: project administration, writing – original draft. Michèle Loosli: project administration, writing – review and editing. Luca B. Schmid: project administration, writing – review and editing. Madalina Wernigg: project administration, writing – review and editing. Charlotta Rühlman: conceptualization, supervision, writing – review and editing. Francesco Bavato: conceptualization, supervision, writing – review and editing. Niklaus Zölch: conceptualization, methodology, supervision, writing – review and editing. Erich Seifritz: resources, funding acquisition, writing – review and editing. Boris B. Quednow: conceptualization, methodology, resources, funding acquisition, supervision, writing – review and editing. Birgit Kleim: conceptualization, methodology, resources, funding acquisition, supervision, writing – review and editing.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplemental Material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/20008066.2026.2650920.