Oral and fecal microbiota perturbance in cocaine users: Can rTMS-induced cocaine abstinence support eubiosis restoration?

The effects of cocaine on microbiota have been scarcely explored. Here, we investigated the gut (GM) and oral (OM) microbiota composition of cocaine use disorder (CUD) patients and the effects of repetitive transcranial magnetic stimulation (rTMS). 16S rRNA sequencing was used to characterize GM and OM, whereas PICRUST2 assessed functional changes in microbial communities, and gas-chromatography was used to evaluate fecal short and medium chain fatty acids. CUD patients reported a significant decrease in alpha diversity and modification of the abundances of several taxa in both GM and OM. Furthermore, many predicted metabolic pathways were differentially expressed in CUD patients' stool and saliva samples, as well as reduced levels of butyric acid that appear restored to normal amounts after rTMS treatment. In conclusion, CUD patients showed a profound dysbiotic fecal and oral microbiota composition and function and rTMS-induced cocaine abstinence determined the restoration of eubiotic microbiota.

A randomised, double-blind, sham-controlled study of left prefrontal cortex 15 Hz repetitive transcranial magnetic stimulation in cocaine consumption and craving.

BACKGROUND: Cocaine use disorder (CUD) is a global health issue with no effective treatment. Repetitive Transcranial Magnetic Stimulation (rTMS) is a recently proposed therapy for CUD. METHODS: We conducted a single-center, randomised, sham-controlled, blinded, parallel-group research with patients randomly allocated to rTMS (15 Hz) or Sham group (1:1) using a computerised block randomisation process. We enrolled 62 of 81 CUD patients in two years. Patients were followed for eight weeks after receiving 15 15 Hz rTMS/sham sessions over the left dorsolateral prefrontal cortex (DLPFC) during the first three weeks of the study. We targeted the DLFPC following the 5 cm method. Cocaine lapses in twice a week urine tests were the primary outcome. The secondary outcomes were craving severity, cocaine use pattern, and psychometric assessments. FINDINGS: We randomly allocated patients to either an active rTMS group (32 subjects) or a sham treatment group (30 subjects). Thirteen (42%) and twelve (43.3%) of the subjects in rTMS and sham groups, respectively, completed the full trial regimen, displaying a high dropout rate. Ten/30 (33%) of rTMS-treated patients tested negative for cocaine in urine, in contrast to 4/27 of placebo controls (p = 0.18, odd ratio 2.88, CI 0.9-10). The Kaplan-Meier survival curve did not state a significant change between the treated and sham groups in the time of cocaine urine negativisation (p = 0.20). However, the severity of cocaine-related cues mediated craving (VAS peak) was substantially decreased in the rTMS treated group (p<0.03) after treatment at T1, corresponding to the end of rTMS treatment. Furthermore, in the rTMS and sham groups, self-reported days of cocaine use decreased significantly (p<0.03). Finally, psychometric impulsivity parameters improved in rTMS-treated patients, while depression scales improved in both groups. CONCLUSIONS: In CUD, rTMS could be a useful tool for lowering cocaine craving and consumption. TRIAL REGISTRATION: The study number on clinicalTrials.gov is NCT03607591.

Efficacy of high-frequency (15Hz) repetitive transcranial magnetic stimulation (rTMS) of the left premotor cortex/dorsolateral prefrontal cortex in decreasing cocaine intake (the MagneTox study): A study protocol for a randomized placebo-controlled pilot trial.

BACKGROUND: Cocaine use disorder (CUD) is very common and has psychological and physical consequences. Patients with CUD present hypoactivity of the prefrontal cortical area. Thus, excitatory repetitive transcranial magnetic stimulation (rTMS) targeting the premotor cortex/dorsolateral prefrontal cortex (PMC/DLPFC), given its ability to increase prefrontal area excitability and to modulate cortico-limbic activity, could result in a decrease in cocaine intake. METHODS: We designed a protocol for a monocentric, randomized, double-blind, placebo-controlled, parallel-group pilot trial, with the principal aim of assessing the efficacy of rTMS on the reduction of cocaine intake. Patients with CUD will be recruited according to inclusion and exclusion criteria, and then randomized to undergo active or sham rTMS. Our rTMS protocol will consist of 15 days of 15Hz rTMS targeting the left PMC/DLPFC. Toxicological and psychiatric assessments, urine drug tests, the Cocaine Craving Questionnaire (CCQ) and the Visual Analogic Scale (VAS) will be used to assess changes from baseline in cocaine intake and craving, mood and quality of life. DISCUSSION: Only a few studies have evaluated the efficacy of rTMS for CUD treatment in humans, with limitations concerning small sample size, short treatment duration, different rTMS protocols and the absence of a placebo-controlled group. Our study will attempt to overcome these shortcomings and will provide data that can be used for future larger studies of non-invasive left PMC/DLPFC stimulation as a treatment for CUD.