<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02233829</url>
  </required_header>
  <id_info>
    <org_study_id>140187</org_study_id>
    <secondary_id>14-AA-0187</secondary_id>
    <nct_id>NCT02233829</nct_id>
  </id_info>
  <brief_title>Dopamine Rhythms in Health and Addiction</brief_title>
  <official_title>Dopamine Rhythms in Health and Addiction</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute on Alcohol Abuse and Alcoholism (NIAAA)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - Dopamine is a chemical signal linked to the rewarding effects of drugs. Certain genes make&#xD;
      these effects sensitive to the time of day they are taken. Cocaine can affect these genes in&#xD;
      the brain. Researchers want to measure brain dopamine at different times of day.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To look for changes to a person s biological clock in the function of the dopamine reward&#xD;
      system. To test if cocaine disrupts this.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  Adults age 21-55 with a cocaine use disorder.&#xD;
&#xD;
        -  Healthy volunteers age 21-55.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened with medical history, physical exam, interview, and blood&#xD;
           and urine tests. Their breath will be tested for alcohol and recent smoking.&#xD;
&#xD;
        -  Participants will have 3 overnight clinic visits.&#xD;
&#xD;
        -  Visit 1: They will have blood and urine collected and a heart test.&#xD;
&#xD;
        -  A plastic tube (catheter) will be placed into a vein in each arm by needle.&#xD;
&#xD;
        -  Participants will have a PET scan in a donut-shaped machine. They will lie on a bed that&#xD;
           slides in and out of it, wearing a cap. A radiotracer (measures dopamine) and a drug&#xD;
           (blocks dopamine removal) will be injected via catheter. Vital signs will be measured&#xD;
           and blood will be drawn throughout.&#xD;
&#xD;
        -  Visit 2: repeats Visit 1, except at night.&#xD;
&#xD;
        -  Visit 3, participants will have urine collected.&#xD;
&#xD;
        -  They will have MRI scans in a metal cylinder surrounded by a magnetic field. They will&#xD;
           lie on a table that slides in and out of it, with a coil over their head.&#xD;
&#xD;
        -  Participants may answer questions, take computer or paper tests, and perform simple&#xD;
           actions.&#xD;
&#xD;
        -  For 1 week, participants will wear a wrist device that measures daily activity.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Objectives:&#xD;
&#xD;
      The primary objective is to assess if there is disruption of circadian DA rhythms in cocaine&#xD;
      addiction. The secondary objective is to assess if dopamine modulates the sensitivity of the&#xD;
      brain reward network in a circadian dependent manner.&#xD;
&#xD;
      Study Population:&#xD;
&#xD;
      Non-treatment seeking cocaine abusers (moderate or severe cocaine use disorder as per DSM-IV&#xD;
      or DSM 5) and healthy controls. Males and females will be included.&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will undergo two PET scans with [11C]raclopride using a bolus infusion paradigm&#xD;
      to assess baseline D2R availability followed by an infusion to assess changes in DA as&#xD;
      measured by [11C]raclopride s displacement following an intravenous injection of&#xD;
      methylphenidate (MP). They will also undergo a total of 4 MRI scans, two after placebo and&#xD;
      two after MP to assess the circadian variations in the sensitivity of the brain reward&#xD;
      network. The two [11C]raclopride scans will be done on separate days at least one week apart,&#xD;
      one in the morning starting between (7-9 AM) and one in the early evening (5-7 PM) and they&#xD;
      will be followed by an MRI scan to assess the sensitivity of the brain reward network under&#xD;
      the influence of MP in the morning (9-11AM) and in the evening (7-9 PM). For the Placebo MRI&#xD;
      scans participants will be tested either on separate days or on the morning of the evening&#xD;
      session or on the evening prior to the morning session. We will use the MRI scans to assess&#xD;
      the sensitivity of the brain reward circuit to visual presentation of drug or food cues and&#xD;
      to evaluate resting functional connectivity.&#xD;
&#xD;
      Outcome Parameters:&#xD;
&#xD;
      Main outcome measure is to assess if there are differences in DA release between the morning&#xD;
      and the evening (displacement of [11C]raclopride binding after MP) and to determine if these&#xD;
      diurnal patterns differ in cocaine addiction. Secondary outcome measures are: To assess if DA&#xD;
      signaling correlates with reactivity of brain regions to exposure of food and drug cues and&#xD;
      with functional connectivity of the reward network and to assess if the reactivity of the&#xD;
      reward network shows circadian variability. We will also assess if differences in DA&#xD;
      signaling between morning and evening correlate with circadian typology and with measures of&#xD;
      spontaneous motor activity and with sleeping patterns.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Suspended</overall_status>
  <why_stopped>
    FDA Clinical and IRB Administrative Holds&#xD;
  </why_stopped>
  <start_date>September 6, 2014</start_date>
  <completion_date type="Anticipated">December 31, 2027</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2026</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To determine if there is disruption in circadian rhythms in cocaine use disorder (CUD) as compared to healthy controls.</measure>
    <time_frame>end of study</time_frame>
    <description>To assess if there are diurnal rhythms in DA signaling and in reward brain circuits and to determine if these are disrupted in cocaine addiction.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Measuring dopamine signaling</measure>
    <time_frame>end of study</time_frame>
    <description>To assess if DA signaling correlates with reactivity of brain reward regions to exposure of drug and with functional connectivity of thereward network and to assess if the reactivity of reward network shows circadian variability.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring circadian typology</measure>
    <time_frame>end of study</time_frame>
    <description>To determine if differences in the measures of DA signaling between morning and evening correlate with circadian typology.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring sleep patterns</measure>
    <time_frame>end of study</time_frame>
    <description>To determine if measures of DA signaling correlate with measures of spontaneous motor activity and with sleeping patterns.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">112</enrollment>
  <condition>Cocaine Abuse</condition>
  <arm_group>
    <arm_group_label>Evening MRI/PET/Raclopride/IV Methylphenidate Session</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The PET [11C] raclopride scan will be done between 5-7 PM. After iv catheters are inserted blood sampling starts and continues throughout study. Cardiac monitoring is initiated and continues until physician discontinues post PET scan. Bolus-plus-infusion method for [11C]raclopride and the administration of intravenous MP (0.5 mg/kg) forty-five minutes after initial bolus injection of [11C]raclopride. Scan to be done for a total of 100 minutes.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Morning MRI/PET/Raclopride/IV Methylphenidate Session</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Morning Session [11C]raclopride PET scan: To be started between 7-8 AM. After iv catheters are inserted, genetic blood samples are drawn and then blood sampling starts and continues throughout study. Cardiac monitoring is initiated and continues until physician discontinues post PET scan. Bolus-plusinfusion method for [11C]raclopride and the administration of intravenous MP (0.25 mg/kg) fortyfive minutes after initial bolus injection of [11C]raclopride. Scan to be done for a total of 100 minutes.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Brain Dopamine Reactivity</intervention_name>
    <description>IV methylphenidate, used under IND #124, 912 is injected into the subject s bloodstream to be used in conjunction with PET imaging to show displacement of [11C]raclopride.</description>
    <arm_group_label>Evening MRI/PET/Raclopride/IV Methylphenidate Session</arm_group_label>
    <arm_group_label>Morning MRI/PET/Raclopride/IV Methylphenidate Session</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Brain Dopamine Receptor</intervention_name>
    <description>The radiotracer [11C] raclopride is used for imaging dopamine receptors and dopamine release.</description>
    <arm_group_label>Evening MRI/PET/Raclopride/IV Methylphenidate Session</arm_group_label>
    <arm_group_label>Morning MRI/PET/Raclopride/IV Methylphenidate Session</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA - ALL PARTICIPANTS:&#xD;
&#xD;
               1. Between 21 and 55 years of age.&#xD;
&#xD;
               2. Ability to provide written informed consent.&#xD;
&#xD;
        INCLUSION CRITERIA - SPECIFIC FOR COCAINE USE DISORDER (CUD) PARTICIPANTS:&#xD;
&#xD;
          1. DSM-IV or DSM-5 diagnosis of a moderate or severe cocaine use disorder established&#xD;
             through history and clinical exam.&#xD;
&#xD;
          2. Non-treatment seeking cocaine users (actively consuming cocaine - last use within one&#xD;
             week of study as assessed by self-reports).&#xD;
&#xD;
          3. Minimum 10 years history of cocaine abuse predominantly via smoking or injection -&#xD;
             self-report.&#xD;
&#xD;
          4. Must consume at least 4 grams of cocaine per week - self-report.&#xD;
&#xD;
        EXCLUSION CRITERIA - ALL PARTICIPANTS:&#xD;
&#xD;
          1. Unwilling or unable to refrain from use within 24 hours of scheduled study procedures:&#xD;
             psychoactive medications or medications that may affect study results e.g.,&#xD;
             antibiotics (must finish course at least 24 hours prior to a scheduled procedure),&#xD;
             antidiarrheal preparations, anti-inflammatory drugs [systemic corticosteroids are&#xD;
             exclusionary], anti-nausea, cough/cold preparations) (self-report, medical history).&#xD;
             The following medications are allowable for entry on this study: analgesics&#xD;
             (non-narcotic and narcotic for OUD participants); antacids; antiasthma agents that are&#xD;
             not systemic corticosteroids; antifungal agents for topical use; antihistamines&#xD;
             (non-sedating); H2-Blockers/PPI (proton pump inhibitors); laxatives. The use of&#xD;
             antihyperlipidemics and/or diuretics are permitted if they have been taken for at&#xD;
             least 1 month before procedure visits and dose has been stabilized as determined by&#xD;
             medical history and physical exam. The episodic use of benzodiazepines such as&#xD;
             alprazolam ((TM)Xanax), diazepam ((TM)Valium) and lorazepam ((TM)Ativan), will not&#xD;
             exclude participants from this study unless they have been taken within the last 24&#xD;
             hours prior to the study.&#xD;
&#xD;
          2. Current or past DSM-IV or DSM-5 diagnosis of a psychiatric disorder (other than&#xD;
             cocaine for the cocaine abusers, and nicotine/caffeine for any of the participants)&#xD;
             that required hospitalization (any length), or chronic medication management (more&#xD;
             than 4 weeks) and that could impact brain function at the time of the study as&#xD;
             determined by history and clinical exam.&#xD;
&#xD;
          3. The following current chronically used medications are exclusionary from the study:&#xD;
             stimulant or stimulant-like medications (amphetamine, methylphenidate, modafinil) ;&#xD;
             analgesics containing narcotics (for controls only); anorexics (sibuteramine);&#xD;
             antianginal agents; antiarrhythmics; antiasthma agents that are systemic&#xD;
             corticosteroids; antibiotics; anticholinergics; anticoagulants; anticonvulsants;&#xD;
             antidepressants; antidiarrheal preparations; antifungal agents (systemic);&#xD;
             antihistamines (sedating); antihypertensives; anti-inflammatory drugs (systemic);&#xD;
             antineoplastics; antiobesity; antipsychotics; antivirals (except for treatment of HSV&#xD;
             with agents without CNS activity, e.g. acyclovir, ganciclovir, famciclovir,&#xD;
             valacyclovir); anxiolytics (benzodiazepine or barbiturates); hormones (exceptions:&#xD;
             thyroid hormone replacement, oral contraceptives, and estrogen replacement therapy);&#xD;
             insulin; lithium; muscle relaxants; psychotropic drugs not otherwise specified (nos)&#xD;
             including herbal products (no drugs with psychomotor effects or with anxiolytics,&#xD;
             stimulant, antipsychotic, or sedative properties); sedatives/hypnotics. Note that&#xD;
             nicotine and/or caffeine use will not exclude participants and that the use of cocaine&#xD;
             will not exclude participants with CUD.&#xD;
&#xD;
          4. Major medical problems that can permanently impact brain function (e.g., CNS including&#xD;
             seizures and psychosis; cardiovascular including hypertension [BP &gt; 140/90] and&#xD;
             clinically significant arrhythmias except bradycardia; metabolic, autoimmune,&#xD;
             endocrine; +HIV) as determined by history.&#xD;
&#xD;
          5. Any clinically significant laboratory finding as determined during the screening&#xD;
             procedures that could impact brain function or study procedures as evidenced from&#xD;
             clinical laboratory results. Since half of the participants in the study will have a&#xD;
             diagnosis of cocaine use disorder (CUD), we expect some clinically significant&#xD;
             findings that would reflect their recent cocaine use. As an example, a participant&#xD;
             might have a mildly elevated Creatinine Kinase as a result of recent cocaine use. The&#xD;
             test would reflect an acute rhabdomyolysis due to recent cocaine use, and it would be&#xD;
             clinically significant. Nevertheless, if it is a mild episode as expected with cocaine&#xD;
             use, it would not affect brain functioning or increase the risk of the procedures for&#xD;
             the participants in the study. Therefore, not all abnormal laboratory findings that&#xD;
             have clinical significance will be excluded. If a finding reflects altered brain&#xD;
             function (e.g., arrhythmias or renal failure) it will be exclusionary for the study.&#xD;
&#xD;
          6. Have had previous radiation exposure (from X-rays, PET scans, or other exposure) that,&#xD;
             with the exposure from this study, would exceed NIH annual research limits as&#xD;
             determined by medical history and physical exam.&#xD;
&#xD;
          7. Head trauma with loss of consciousness for more than 30 minutes as determined by&#xD;
             medical history and physical exam.&#xD;
&#xD;
          8. Pregnant or breast feeding: Females must have negative urine pregnancy test and are&#xD;
             not currently breastfeeding. Post-menopausal or surgically sterile (tubal ligation or&#xD;
             hysterectomy); or not sexually active with a male partner and able to get pregnant; or&#xD;
             documented agreement to use an effective form of birth control. Acceptable forms of&#xD;
             contraception include: hormonal contraceptives (birth-control pills, injectable&#xD;
             hormones, vaginal-ring hormones); IUD; diaphragm with spermicide; condom with&#xD;
             spermicide.&#xD;
&#xD;
          9. History of coagulation disorder as evidenced from clinical laboratory results, medical&#xD;
             history.&#xD;
&#xD;
         10. History of glaucoma as determined by medical history. Since glaucoma is screened for&#xD;
             clinically at about the age of 40, any subjects 40 or older will undergo a glaucoma&#xD;
             screening test if they have not been tested by their primary care physician. A result&#xD;
             of 21 mmHg or higher will exclude.&#xD;
&#xD;
         11. Presence of ferromagnetic objects in the body that are contraindicated for MRI of the&#xD;
             head (pacemakers or other implanted electrical devices, brain stimulators, some types&#xD;
             of dental implants, aneurysm clips, metallic prostheses, permanent eyeliner, implanted&#xD;
             delivery pump, or shrapnel fragments) or fear of enclosed spaces - self-report&#xD;
             checklist.&#xD;
&#xD;
         12. Personal or family history for cerebral aneurism.&#xD;
&#xD;
         13. Past or present history of chest pain and trouble breathing with activity.&#xD;
&#xD;
         14. Diabetes as assessed by medical history.&#xD;
&#xD;
         15. High risk for silent heart diseases as evidenced by high levels of high-sensitivity&#xD;
             C-reactive protein or homocysteine in blood, or being overweight or obese. In addition&#xD;
             patients with high cholesterol or a family history of heart disease will be evaluated&#xD;
             by a cardiologist to determine their eligibility for participation. The cardiologist&#xD;
             might request additional tests if he deems it necessary to ensure fitness for&#xD;
             participation (ie treadmill stress test). Specifically the cardiologist involved will&#xD;
             review the findings of 1) an inability to reach these endpoints, 2) the development of&#xD;
             chest pain, 3) significant ST segment changes, 4) significant arrhythmias, and 5) an&#xD;
             inability to appropriately increase blood pressure or heart rate with exercise in&#xD;
             order to determine if the participant is suitable for inclusion in the study.&#xD;
&#xD;
         16. Cannot lie comfortably flat on your back for up to 2 hours in the PET and MRI scanners&#xD;
             - self-report.&#xD;
&#xD;
         17. Weight &gt; 400 pounds which is the maximum weight the PET scanner can hold.&#xD;
&#xD;
         18. Study investigators and staff, as well as their superiors, subordinates and immediate&#xD;
             family members (adult children, spouses, parents, siblings).&#xD;
&#xD;
               -  Note that subjects will not be excluded from enrollment onto this study if their&#xD;
                  urine test is positive for drugs on initial screening. The following guidelines&#xD;
                  will be followed for positive drug screens on study procedure days:&#xD;
&#xD;
                    -  If a Healthy Volunteer subject s urine drug screen test is positive on days&#xD;
                       involving imaging (MRI and/or PET) and NP testing, the procedures will be&#xD;
                       postponed and rescheduled. We will allow for up to 3 rescheduled study days&#xD;
                       resulting from positive urine drug screens. If the drug test is positive on&#xD;
                       the third rescheduled visit, the participant will be withdrawn from the&#xD;
                       study.&#xD;
&#xD;
                    -  If a CUD subject s urine drug screen test is positive for drugs (except&#xD;
                       cocaine), the procedures will be postponed and rescheduled to another day.&#xD;
                       We will not place a limit on rescheduling study days in this participant&#xD;
                       group.&#xD;
&#xD;
                         -  Note: At any time a subject expresses that he/she wants to get&#xD;
                            treatment for their cocaine use, we will immediately refer him/her to a&#xD;
                            treatment program. The subject will be withdrawn from the study at that&#xD;
                            time.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gene-Jack Wang, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute on Alcohol Abuse and Alcoholism (NIAAA)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-AA-0187.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <reference>
    <citation>Wang GJ, Volkow ND, Fowler JS, Logan J, Pappas NR, Wong CT, Hitzemann RJ, Netusil N. Reproducibility of repeated measures of endogenous dopamine competition with [11C]raclopride in the human brain in response to methylphenidate. J Nucl Med. 1999 Aug;40(8):1285-91.</citation>
    <PMID>10450679</PMID>
  </reference>
  <reference>
    <citation>Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, Netusil N, Fowler JS. Brain dopamine and obesity. Lancet. 2001 Feb 3;357(9253):354-7. doi: 10.1016/s0140-6736(00)03643-6.</citation>
    <PMID>11210998</PMID>
  </reference>
  <reference>
    <citation>Dunn JP, Cowan RL, Volkow ND, Feurer ID, Li R, Williams DB, Kessler RM, Abumrad NN. Decreased dopamine type 2 receptor availability after bariatric surgery: preliminary findings. Brain Res. 2010 Sep 2;1350:123-30. doi: 10.1016/j.brainres.2010.03.064. Epub 2010 Mar 31.</citation>
    <PMID>20362560</PMID>
  </reference>
  <verification_date>August 11, 2023</verification_date>
  <study_first_submitted>September 6, 2014</study_first_submitted>
  <study_first_submitted_qc>September 6, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 9, 2014</study_first_posted>
  <last_update_submitted>August 12, 2023</last_update_submitted>
  <last_update_submitted_qc>August 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>C-11 Raclopride</keyword>
  <keyword>PET</keyword>
  <keyword>Circadian Rhythm</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cocaine-Related Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dopamine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>.Data is analyzed by subject group and not on an individual basis.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02233829
org study id: 140187
secondary id: 14-AA-0187
nct id: NCT02233829
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      - Dopamine is a chemical signal linked to the rewarding effects of drugs. Certain genes make
      these effects sensitive to the time of day they are taken. Cocaine can affect these genes in
      the brain. Researchers want to measure brain dopamine at different times of day.

      Objectives:

      - To look for changes to a person s biological clock in the function of the dopamine reward
      system. To test if cocaine disrupts this.

      Eligibility:

        -  Adults age 21-55 with a cocaine use disorder.

        -  Healthy volunteers age 21-55.

      Design:

        -  Participants will be screened with medical history, physical exam, interview, and blood
           and urine tests. Their breath will be tested for alcohol and recent smoking.

        -  Participants will have 3 overnight clinic visits.

        -  Visit 1: They will have blood and urine collected and a heart test.

        -  A plastic tube (catheter) will be placed into a vein in each arm by needle.

        -  Participants will have a PET scan in a donut-shaped machine. They will lie on a bed that
           slides in and out of it, wearing a cap. A radiotracer (measures dopamine) and a drug
           (blocks dopamine removal) will be injected via catheter. Vital signs will be measured
           and blood will be drawn throughout.

        -  Visit 2: repeats Visit 1, except at night.

        -  Visit 3, participants will have urine collected.

        -  They will have MRI scans in a metal cylinder surrounded by a magnetic field. They will
           lie on a table that slides in and out of it, with a coil over their head.

        -  Participants may answer questions, take computer or paper tests, and perform simple
           actions.

        -  For 1 week, participants will wear a wrist device that measures daily activity.
Objectives:

      The primary objective is to assess if there is disruption of circadian DA rhythms in cocaine
      addiction. The secondary objective is to assess if dopamine modulates the sensitivity of the
      brain reward network in a circadian dependent manner.

      Study Population:

      Non-treatment seeking cocaine abusers (moderate or severe cocaine use disorder as per DSM-IV
      or DSM 5) and healthy controls. Males and females will be included.

      Design:

      Participants will undergo two PET scans with [11C]raclopride using a bolus infusion paradigm
      to assess baseline D2R availability followed by an infusion to assess changes in DA as
      measured by [11C]raclopride s displacement following an intravenous injection of
      methylphenidate (MP). They will also undergo a total of 4 MRI scans, two after placebo and
      two after MP to assess the circadian variations in the sensitivity of the brain reward
      network. The two [11C]raclopride scans will be done on separate days at least one week apart,
      one in the morning starting between (7-9 AM) and one in the early evening (5-7 PM) and they
      will be followed by an MRI scan to assess the sensitivity of the brain reward network under
      the influence of MP in the morning (9-11AM) and in the evening (7-9 PM). For the Placebo MRI
      scans participants will be tested either on separate days or on the morning of the evening
      session or on the evening prior to the morning session. We will use the MRI scans to assess
      the sensitivity of the brain reward circuit to visual presentation of drug or food cues and
      to evaluate resting functional connectivity.

      Outcome Parameters:

      Main outcome measure is to assess if there are differences in DA release between the morning
      and the evening (displacement of [11C]raclopride binding after MP) and to determine if these
      diurnal patterns differ in cocaine addiction. Secondary outcome measures are: To assess if DA
      signaling correlates with reactivity of brain regions to exposure of food and drug cues and
      with functional connectivity of the reward network and to assess if the reactivity of the
      reward network shows circadian variability. We will also assess if differences in DA
      signaling between morning and evening correlate with circadian typology and with measures of
      spontaneous motor activity and with sleeping patterns.
allocation: N/A
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: To determine if there is disruption in circadian rhythms in cocaine use disorder (CUD) as compared to healthy controls.
time frame: end of study
description: To assess if there are diurnal rhythms in DA signaling and in reward brain circuits and to determine if these are disrupted in cocaine addiction.
measure: Measuring dopamine signaling
time frame: end of study
description: To assess if DA signaling correlates with reactivity of brain reward regions to exposure of drug and with functional connectivity of thereward network and to assess if the reactivity of reward network shows circadian variability.
measure: Measuring circadian typology
time frame: end of study
description: To determine if differences in the measures of DA signaling between morning and evening correlate with circadian typology.
measure: Measuring sleep patterns
time frame: end of study
description: To determine if measures of DA signaling correlate with measures of spontaneous motor activity and with sleeping patterns.
arm group label: Evening MRI/PET/Raclopride/IV Methylphenidate Session
arm group type: Active Comparator
description: The PET [11C] raclopride scan will be done between 5-7 PM. After iv catheters are inserted blood sampling starts and continues throughout study. Cardiac monitoring is initiated and continues until physician discontinues post PET scan. Bolus-plus-infusion method for [11C]raclopride and the administration of intravenous MP (0.5 mg/kg) forty-five minutes after initial bolus injection of [11C]raclopride. Scan to be done for a total of 100 minutes.
arm group label: Morning MRI/PET/Raclopride/IV Methylphenidate Session
arm group type: Active Comparator
description: Morning Session [11C]raclopride PET scan: To be started between 7-8 AM. After iv catheters are inserted, genetic blood samples are drawn and then blood sampling starts and continues throughout study. Cardiac monitoring is initiated and continues until physician discontinues post PET scan. Bolus-plusinfusion method for [11C]raclopride and the administration of intravenous MP (0.25 mg/kg) fortyfive minutes after initial bolus injection of [11C]raclopride. Scan to be done for a total of 100 minutes.
intervention type: Drug
intervention name: Brain Dopamine Reactivity
description: IV methylphenidate, used under IND #124, 912 is injected into the subject s bloodstream to be used in conjunction with PET imaging to show displacement of [11C]raclopride.
arm group label: Evening MRI/PET/Raclopride/IV Methylphenidate Session
arm group label: Morning MRI/PET/Raclopride/IV Methylphenidate Session
intervention type: Radiation
intervention name: Brain Dopamine Receptor
description: The radiotracer [11C] raclopride is used for imaging dopamine receptors and dopamine release.
arm group label: Evening MRI/PET/Raclopride/IV Methylphenidate Session
arm group label: Morning MRI/PET/Raclopride/IV Methylphenidate Session
criteria: 
gender: All
minimum age: 21 Years
maximum age: 55 Years
healthy volunteers: No
last name: Gene-Jack Wang, M.D.
role: Principal Investigator
affiliation: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-AA-0187.html
description: NIH Clinical Center Detailed Web Page
citation: Wang GJ, Volkow ND, Fowler JS, Logan J, Pappas NR, Wong CT, Hitzemann RJ, Netusil N. Reproducibility of repeated measures of endogenous dopamine competition with [11C]raclopride in the human brain in response to methylphenidate. J Nucl Med. 1999 Aug;40(8):1285-91.
PMID: 10450679
citation: Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, Netusil N, Fowler JS. Brain dopamine and obesity. Lancet. 2001 Feb 3;357(9253):354-7. doi: 10.1016/s0140-6736(00)03643-6.
PMID: 11210998
citation: Dunn JP, Cowan RL, Volkow ND, Feurer ID, Li R, Williams DB, Kessler RM, Abumrad NN. Decreased dopamine type 2 receptor availability after bariatric surgery: preliminary findings. Brain Res. 2010 Sep 2;1350:123-30. doi: 10.1016/j.brainres.2010.03.064. Epub 2010 Mar 31.
PMID: 20362560
responsible party type: Sponsor
mesh term: Cocaine-Related Disorders
mesh term: Dopamine
sharing ipd: No
ipd description: .Data is analyzed by subject group and not on an individual basis.