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Cocaine use is associated with great harm to individuals and society. As of today, psychotherapeutic interventions for cocaine use disorder (CUD) demonstrate only modest effect sizes, and no pharmacotherapy has been approved due to gaps in understanding the disease. However, a novel pharmacotherapeutic target, i.e. glutamatergic neurotransmission, emerged from animal models of addiction. Specifically, after chronic cocaine administration, glutamate concentrations in the nucleus accumbens (NAcc) of rodents are reduced, while there is an overflow of glutamate during cue-induced cocaine-seeking. Recently, this glutamatergic imbalance has also been observed in humans with CUD. Additionally, promising findings with regard to novel psychotherapeutic approaches came from neurofeedback training (NFT) studies where participants use cognitive strategies to regulate their activity within a specific brain region based on \u201creal-time\u201d feedback about its activity as assessed by real-time functional magnetic resonance imaging (rt-fMRI). For example, participants with CUD successfully learned to regulate their brain activity in reward areas of the midbrain using reward imagery and to reconstitute reward sensitivity to non-drug related reinforcers like, e.g. social interactions, athletic or professional achievements. We therefore investigate the therapeutic potential and the underlying mechanisms of two interventions, a single dose of ketamine and a reward imagery rt-fMRI NFT in 120 participants with CUD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We examine a single ketamine infusion, three sessions of reward imagery rt-fMRI NFT, and the combination of those interventions contrasted to a placebo infusion or a sham NFT in 120 participants with CUD. The study is designed in a randomized, placebo-controlled, double-blind fashion with four study arms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>We expect both interventions to have a positive effect on the proportion of cocaine use days. We predict glutamate levels in the reward system to increase with the ketamine infusion and to reduce craving, a re-enhanced sensitivity towards natural rewards resulting from the rt-fMRI NFT, and synergistic effects of the combined interventions. This neurobiologically informed approach has the potential to open new avenues for the treatment of CUD through individualised and integrated pharmaco-psychotherapy.<\/jats:p>\n                    <jats:p>Trial registration.<\/jats:p>\n                    <jats:p>NCT06125054 ClinicalTrials.gov. Registered on October 26, 2023.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13063-025-08982-9","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T13:05:12Z","timestamp":1758805512000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Co-Boost: boosting and guiding neuroplasticity by combining ketamine with neurofeedback-assisted learning\u2014towards an individualised and integrated pharmaco-psychotherapy for cocaine addiction: study protocol for a randomised, placebo-controlled, double-blind, parallel-group, single-centre trial"],"prefix":"10.1186","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2104-083X","authenticated-orcid":false,"given":"Anna S.","family":"Trippel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ladina P.","family":"Gubser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Etna J. 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