Reconsolidation Blockade of Intrusive Trauma- and Cocaine-related Memories

An investigation of the effect of matrix-metalloproteinase-(MMP)-9 inhibition with minocycline on the reconsolidation of trauma- or cocaine-related memories

Intrusive memories are involuntary recollections of past emotional events that can become pathological and persist over time, particularly in post-traumatic stress disorder (PTSD) and cocaine use disorders (CUD). Both PTSD and CUD are characterised by a hypersensitivity and -reactivity to cue-elicited memory reactivation and exhibit common neurological alterations, suggesting shared underlying mechanisms. As intrusive memories significantly contribute to maintaining the cycle of relapse in both disorders, it is important to find a way to attenuate them successfully. Research on memory reconsolidation has led to the development of different (pharmacological) approaches to disrupt the process, which have, however, yielded mixed and unspecific effects so far.

The present project aims to investigate the effect of MMP-9 inhibition with minocycline on the reconsolidation of intrusive memories in individuals with CUD or PTSD. Participants will be randomly assigned to a minocycline or placebo group. The study comprises a total of 5 visits during 3 weeks and one follow-up online survey (3 months after the intervention). Participants will receive the study medication before two imagery script-guided memory activation sessions. An ecological momentary assessment (EMA) approach will be employed to track intrusive memories, and glutamate concentration and neural activation will be measured with magnetic resonance spectroscopy (MRS) and functional magnetic resonance (fMRI), respectively, before and after the two imagery sessions.

Eligibility Criteria:
General Inclusion Criteria:

* Ability to read, understand and provide written informed consent
* Age between 18 and 60 years
* To be sufficiently fluent in German

Inclusion Criteria for the PTSD group:

- Current diagnosis of full PTSD according to the 5th version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), of subthreshold PTSD, as in meeting two to three of the DSM-5 criteria B-E, or of complex PTSD

Inclusion Criteria for the CUD group:

* Current diagnosis of mild, moderate, or severe CUD according to DSM-5
* Regular cocaine use in the last 12 months and at least one consumption event in the last 6 months

Inclusion Criteria for the Clinical Controls (PTSD+CUD group):

* Current diagnosis of full PTSD according to the 5th version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), of subthreshold PTSD, as in meeting two to three of the DSM-5 criteria B-E, or of complex PTSD
* Current diagnosis of mild, moderate, or severe CUD according to DSM-5
* Regular cocaine use in the last 12 months and at least one consumption event in the last 6 months

General Exclusion Criteria:

* Women who are pregnant or breast feeding or intending to become pregnant during the course of the study or within 3 months after
* Other clinically significant concomitant disease states, e.g., renal failure (i.e., estimated glomerular filtration rate (eGFR; CKD-EPI) lower than 60 ml/min/1.73 m2), hepatic dysfunction (i.e., alanine transaminase (ALT) higher than 90 U/I for women or 110 U/I for men, aspartate aminotransferase (AST) higher than 74 U/I, and/or gamma-glutamyl transferase (γGT) higher than 70 U/I for women or 120 U/I for men), cardiovascular disease, etc.
* Presence or history of severe neurological disorders, head injuries or systemic/rheumatic disease
* Diagnosis of schizophrenia, bipolar disorder, or autism spectrum disorder according to DSM-5
* Pacemaker, neurostimulator or any other head or heart implants as well as MRI-incompatible metal parts or possibility of metal fragments in the body (MR safety)
* Claustrophobia (MR safety)
* Dependence on a hearing aid (MR safety)
* Inability to follow the procedures of the study, e.g., due to language problems
* Participation in another study with investigational drugs within the 30 days preceding and during the present study
* More than three suicide attempts in the past, a suicide attempt within the last 12 months and/or acute suicidality

Exclusion Criteria for Healthy Controls:

* Any current psychiatric diagnosis according to DSM-5 except for mild or moderate substance use disorder (SUD) for nicotine, and mild SUD for alcohol and cannabis
* Diagnosis of CUD according to DSM-5 (lifetime)
* Diagnosis of PTSD according to DSM-5 (lifetime)

Exclusion Criteria for both the PTSD and CUD groups:

* Allergy to minocycline or to any other ingredient in the named drug
* Current intake of the following medications interacting with minocycline: acitretin, acetylcystein, aluminiumhydroxid, amitryptiline, any antibiotics, antidiabetic drug such as sulfonylurea, atazanavir, atomoxetine, anticoagulant drugs from the coumarin type, barbiturates, bupropion, carbamazepine, ciclosporin A, isotretinoin, methotrexate, phenytoin, and theophylline

Exclusion Criteria for only the PTSD group:

* Diagnosis of CUD according to DSM-5 (lifetime)
* Current diagnosis of severe SUD for nicotine, moderate SUD for alcohol and cannabis, and mild SUD for all other substances according to DSM-5

Exclusion Criteria for only the CUD group:

* Diagnosis of PTSD according to DSM-5 (lifetime)
* Current diagnosis of severe SUD for alcohol or cannabis, and mild SUD for all other substances (except for nicotine) according to DSM-5

Exclusion Criteria for Clinical Controls (PTSD+CUD group):

- Current diagnosis of severe SUD for alcohol or cannabis, and mild SUD for all other substances (except for nicotine) according to DSM-5