Brief Summary:

Background: Cocaine use disorders (CUD) is a multifactoral disease, involving several brain areas. One of the most investigated is the Dorsolateral Prefrontal Cortex (DLPFC) involved in impulsiveness control. Effective treatments for CUD are still needed and repetitive Transcranial Magnetic Stimulation (rTMS) is widely studied for its potential in reducing cocaine craving and consumption.

Objectives: The main outcome is to test if rTMS can be related to neuroplasticity and neurotrophism through changes in Brain-Derived Neurotrophic Factor (BDNF) and its precursor (pro-BDNF) levels.

Eligibility: Healthy, right-handed adults ages 18-65 who do have cocaine use disorder (moderate to severe).

Design: This is a randomized, sham-controlled study. The study includes a rTMS continued treatment phase compared to healthy control (HC) evaluation.

Prior to participating, participants will be screened with:

• Medical history
• Anamnestic sheet
• Physical exam
• Urine tests After being enrolled, participants and HC will undergo venous blood sample (BDNF and proBDNF levels).

During the continued rTMS phase, participants with cocaine use disorder will be randomized to receive real or sham rTMS; a former arm is also provided and is made up of HC. RTMS will be delivered in 10 days, over 2 weeks (5 days/week). After the last rTMS session a blood sample for neurotrophines levels will be collected.

Treatment includes:

• rTMS: A coil is placed on the head. At each session, participants will receive two rTMS sessions, with a 50 mins interval. At the beginning of each rTMS session, they view cocaine-related images for few minutes (cue-induced stimuli).
• BDNF/proBDNF levels: A venous blood sample will be collected before the first stimulation and after the last stimulation of the intensive-stimulation period (first two weeks), this sample will be also collected from HC. The blood sample will be centrifuged within 20 minutes of sampling at 1000 × g for 15 minutes. Then, the serum will be aliquoted and stored at -80 ° C until analysis.
• Urine toxicological screen

RTMS has been shown to reduce craving in CUD. The purpose of this study is to assess the effects of rTMS at 15 Hz frequency on neurotrophines serum levels . For this purpose, the investigators will recruit cocaine user. After screening and informed consent, participants will undergo active or sham rTMS for two consecutive weeks (twice a day) during the continued treatment phase; a third arm of HC will receive no treatment. A venous blood sample will be collected before the first stimulation and after the last stimulation of the first two weeks treatment.

Procedure: The project consists of: Screening Visit (baseline) and the continued treatment phase, In the screening visit, a clinical interview to assess the eligibility of participant (following the inclusion and exclusion criteria) will be performed. All participants will be randomly assigned to one of the two treatment arms with rTMS (15Hz, 15Hz-Sham). Participants will receive 2 sessions of rTMS (active or sham), twice per day for 10 consecutive days, for a total of 20 rTMS sessions. A venous blood sample will be collected before the first stimulation and after the last stimulation of the continued treatment phase to asses the BDNF and pro-BDNF level.

Inclusion Criteria (for CUD patient):

1. Current diagnosis of cocaine use disorder (from moderate to severe), based on the Diagnostic and Statistical Manual of Mental Disorder - Fifth Edition (DSM-5);
2. Abstinence from cocaine for at least 48 hrs.

Exclusion Criteria (for CUD patient):

1. Current DSM-5 diagnosis of substance and/or alcohol use disorders other than nicotine;
2. Current DSM-5 diagnosis of schizophrenia, bipolar disorder, or other psychotic disorder;
3. Use in the past 4 weeks of any medication with known pro-convulsant action; or current regular use of any psychotropic medications (benzodiazepines, antipsychotic medications, tricyclic antidepressants, anti-epileptics, mood stabilizers);
4. Any history of any clinically significant neurological disorder, including organic brain disease, epilepsy, stroke, brain lesions, multiple sclerosis, previous neurosurgery, or personal history of head trauma that resulted in loss of consciousness for > 5 minutes and retrograde amnesia for > 30 minutes;

Inclusion Criteria (for HC):

1. 18-65 years

Exclusion Criteria (for CUD patient):

1. Current DSM-5 diagnosis of substance use disorders other than nicotine;
2. Current DSM-5 diagnosis of schizophrenia, bipolar disorder, or other psychotic disorder;

With regard to the treatment, to ensure that both participants and investigators are blind to the condition (active or sham), the selection of the operation mode (15 Hz, sham) will be pre-programmed by member of the that will not be involved in data collection and analysis. Study personnel will not know which mode is being activated. Sham stimulation will use the same coil placement as that used for active stimulation. Outcomes Assessors will not be present during the rTMS sessions.