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| ID | Type | Description | Link |
|---|---|---|---|
| R01DA015764 | U.S. NIH Grant/Contract | View source | |
| R01DA15764-1 | |||
| DPMC |
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| Name | Class |
|---|---|
| National Institute on Drug Abuse (NIDA) | NIH |
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Children born to women who abuse drugs have a high risk of being born with birth defects and developmental problems. Methadone is a drug that is commonly used for treating opioid dependence. However, its use by a pregnant woman can cause severe withdrawal symptoms in a newborn because of the prenatal exposure. The purpose of this study is to evaluate the effectiveness of buprenorphine, another drug, versus methadone in reducing withdrawal symptoms in children born to opioid-dependent women.
Women who use drugs during pregnancy place their unborn children at high risk for being born addicted to drugs. Such children may also be born with birth defects and may experience learning and behavioral problems. Methadone, a synthetic narcotic, is commonly prescribed to treat opioid addiction. It may not be an optimal solution for opioid-dependent pregnant women, however, because a large percentage of children born to women taking methadone experience severe drug withdrawal symptoms at birth that often require medical treatment. Common opioid withdrawal symptoms, described as neonatal abstinence syndrome (NAS) in babies, include tremors, irritability, sleep problems, seizures, dehydration, and fever. Buprenorphine is a medication that has been approved to treat opioid dependence in individuals who are not pregnant but has not been approved for pregnant individuals. Past research has shown that use of buprenorphine in pregnant women results in improved birth outcomes over methadone. The purpose of this study is to evaluate the effectiveness of buprenorphine versus methadone at reducing opioid withdrawal symptoms in babies born to opioid-dependent women.
This study will enroll opioid-dependent pregnant women who are 13 to 30 weeks pregnant and will follow each woman and her child throughout the pregnancy until 6 weeks postpartum. All participants will undergo an initial screening that will last several hours. Participants will then be randomly assigned to receive either methadone or buprenorphine on a daily basis, and will be required to visit the clinic each day to receive their medication. Outcome measurements will be assessed at weekly study visits throughout the pregnancy, and will include drug use, HIV risk behaviors, medication dose adequacy and safety, treatment retention, and psychosocial functioning. Urine samples will be collected 3 times a week, and blood will be drawn throughout the pregnancy for safety monitoring. Outcome measurements related to the baby will include head circumference measurement, length of hospital stay, severity and frequency of withdrawal symptoms, and amount of medication needed to control withdrawal symptoms.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Buprenorphine | Experimental | Buprenorphine |
|
| Methadone | Active Comparator | Methadone |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methadone | Drug | daily oral dosing 20-140 mg |
| |
| Buprenorphine |
| Measure | Description | Time Frame |
|---|---|---|
| Child's Head Circumference Measurement (Measured at Birth) | birth | |
| Child's Length of Hospital Stay | delivery until hospital discharge (min=2 days, max=79 days) | |
| Number of Children Requiring Treatment for Neonatal Abstinence Signs (NAS) | Neonatal abstinence syndrome (NAS) characterized by hyperirritability of the central nervous system and dysfunction in the autonomic nervous system, gastrointestinal tract, and respiratory system.11 When left untreated, NAS can result in serious illness (e.g., diarrhea, feeding difficulties, weight loss, and seizures) and death. | From birth until hospital discharge (min=4 days, max=10, depending on site) |
| Child's Peak Daily Total NAS Score | NAS was measured with the MOTHER NAS scale, which includes 28 items, 19 of which are used for scoring and medication decisions. Scores can range from 0 to 42, with higher scores indicating more severe withdrawal. | minimum twice daily from birth until NAS no longer measured (min=10 days) |
| Total Amount of Morphine Sulfate That a Neonate Receives to Treat NAS | Total amount in mg | Start of NAS treatment until discontinuation of NAS treatment (min=0 days, max=76 days) |
| Measure | Description | Time Frame |
|---|---|---|
| Mother's Self-report of Drug Use (Measured Monthly by Time Line Follow Back) | monthly from study entry until discontinuation or delivery (min=29 days, max=239 days) | |
| Mother's HIV Risk Behaviors (Measured Monthly by Risk Behavior Assessment) | monthly from study entry until discontinuation or delivery (min=29 days, max=239 days) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Hendree E. Jones, PhD | Johns Hopkins University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Johns Hopkins University School of Medicine | Baltimore | Maryland | 21224 | United States | ||
| Wayne State University |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23786504 | Derived | Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR. Nonserious adverse events in randomized trials with opioid-dependent pregnant women: direct versus indirect measurement. Am J Addict. 2012 Nov;21 Suppl 1:S1-4. doi: 10.1111/j.1521-0391.2012.00289.x. | |
| 23523131 | Derived | Holbrook AM, Jones HE, Heil SH, Martin PR, Stine SM, Fischer G, Coyle MG, Kaltenbach K. Induction of pregnant women onto opioid-agonist maintenance medication: an analysis of withdrawal symptoms and study retention. Drug Alcohol Depend. 2013 Sep 1;132(1-2):329-34. doi: 10.1016/j.drugalcdep.2013.02.031. Epub 2013 Mar 21. |
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Of the 1074 screened: 243 did not give consent. 656 were excluded for a variety of reasons ranging from an estimated gestation age outside the range, to impending legal issues, to multiple-fetus pregnancy.
1074 Patients were screened for eligibility. 175 underwent randomization. 86 were assigned to receive buprenorphine. 58 of the patients assigned to buprenorphine completed the study. 89 were assigned to receive methadone. 73 of the patients assigned to methadone completed the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Methadone | Methadone Methadone : daily oral dosing 20-140 mg |
| FG001 | Buprenorphine | Buprenorphine Buprenorphine : sl daily 2-32 mg |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Methadone | Methadone Methadone : daily oral dosing 20-140 mg |
| BG001 | Buprenorphine | Buprenorphine Buprenorphine : sl daily 2-32 mg |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Child's Head Circumference Measurement (Measured at Birth) | Posted | Mean | 95% Confidence Interval | cm | birth |
|
|
Entire course of the study, from baseline to end of study period (min=26 days, max=239 days)
weekly assessment by self-report and clinician review with patient
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Methadone: Mothers | Methadone Methadone : daily oral dosing 20-140 mg |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abnormal fetal health | Pregnancy, puerperium and perinatal conditions | MedDRA (10.0) | Systematic Assessment | Mothers only |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abnormal fetal health | Pregnancy, puerperium and perinatal conditions | MedDRA (10.0) | Systematic Assessment | Mothers only |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Hendree Jones | Departments of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology, Johns Hopkins University School of Medicine | 919-485-2664 | hjones18@jhmi.edu |
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| ID | Term |
|---|---|
| D009293 | Opioid-Related Disorders |
| D019966 | Substance-Related Disorders |
| D016739 | Behavior, Addictive |
| ID | Term |
|---|---|
| D000079524 | Narcotic-Related Disorders |
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
| D003192 | Compulsive Behavior |
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| ID | Term |
|---|---|
| D008691 | Methadone |
| D002047 | Buprenorphine |
| ID | Term |
|---|---|
| D007659 | Ketones |
| D009930 | Organic Chemicals |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
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| Drug |
sl daily 2-32 mg |
|
| Mother's Measures of Dose Adequacy and Acceptance Over Time (Measured Weekly by Dose Adequacy Measure) | Pregnant women maintained on an opioid agonist medication may require upward adjustment to their medication during the course of pregnant. The Dose Adequacy Measure represented a recordation of dosing adjustments during the course of the study. | from study entry until discontinuation or delivery (min=29 days, max=239 days) |
| Mother's Psychosocial Functioning at Delivery as Measured by the Addiction Severity Index Psychosocial Index Score | The Addiction Severity Index is a structured clinical interview that assesses problem severity in 7 areas of functioning: alcohol use, drug use, medical, legal, employment, psychosocial, and psychiatric status. Each area of functioning yields a composite scale score between 0 and 1, with higher scores indicating greater problem severity in that area. Only the psychosocial index was examined in this study. | at delivery |
| Detroit |
| Michigan |
| 48207 |
| United States |
| Thomas Jefferson University | Philadelphia | Pennsylvania | 19107 | United States |
| Brown University | Providence | Rhode Island | 02912 | United States |
| Vanderbilt University | Nashville | Tennessee | 37232 | United States |
| University of Vermont | Burlington | Vermont | 05401 | United States |
| Medical University of Vienna | Vienna | A1090 | Austria |
| St. Joseph's Health Centre | Toronto | Ontario | M6R 1B5 | Canada |
| 23279924 | Derived | Jones HE, Heil SH, Tuten M, Chisolm MS, Foster JM, O'Grady KE, Kaltenbach K. Cigarette smoking in opioid-dependent pregnant women: neonatal and maternal outcomes. Drug Alcohol Depend. 2013 Aug 1;131(3):271-7. doi: 10.1016/j.drugalcdep.2012.11.019. Epub 2012 Dec 29. |
| 23106931 | Derived | McNicholas LF, Holbrook AM, O'Grady KE, Jones HE, Coyle MG, Martin PR, Heil SH, Stine SM, Kaltenbach K. Effect of hepatitis C virus status on liver enzymes in opioid-dependent pregnant women maintained on opioid-agonist medication. Addiction. 2012 Nov;107 Suppl 1(0 1):91-7. doi: 10.1111/j.1360-0443.2012.04043.x. |
| 23106930 | Derived | Holbrook AM, Baxter JK, Jones HE, Heil SH, Coyle MG, Martin PR, Stine SM, Kaltenbach K. Infections and obstetric outcomes in opioid-dependent pregnant women maintained on methadone or buprenorphine. Addiction. 2012 Nov;107 Suppl 1(Suppl 1):83-90. doi: 10.1111/j.1360-0443.2012.04042.x. |
| 23106929 | Derived | Benningfield MM, Dietrich MS, Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Fischer G, Martin PR. Opioid dependence during pregnancy: relationships of anxiety and depression symptoms to treatment outcomes. Addiction. 2012 Nov;107 Suppl 1(0 1):74-82. doi: 10.1111/j.1360-0443.2012.04041.x. |
| 23106928 | Derived | Coyle MG, Salisbury AL, Lester BM, Jones HE, Lin H, Graf-Rohrmeister K, Fischer G. Neonatal neurobehavior effects following buprenorphine versus methadone exposure. Addiction. 2012 Nov;107 Suppl 1(0 1):63-73. doi: 10.1111/j.1360-0443.2012.04040.x. |
| 23106927 | Derived | Gaalema DE, Scott TL, Heil SH, Coyle MG, Kaltenbach K, Badger GJ, Arria AM, Stine SM, Martin PR, Jones HE. Differences in the profile of neonatal abstinence syndrome signs in methadone- versus buprenorphine-exposed neonates. Addiction. 2012 Nov;107 Suppl 1(0 1):53-62. doi: 10.1111/j.1360-0443.2012.04039.x. |
| 23106926 | Derived | Kaltenbach K, Holbrook AM, Coyle MG, Heil SH, Salisbury AL, Stine SM, Martin PR, Jones HE. Predicting treatment for neonatal abstinence syndrome in infants born to women maintained on opioid agonist medication. Addiction. 2012 Nov;107 Suppl 1(0 1):45-52. doi: 10.1111/j.1360-0443.2012.04038.x. |
| 23106925 | Derived | Salisbury AL, Coyle MG, O'Grady KE, Heil SH, Martin PR, Stine SM, Kaltenbach K, Weninger M, Jones HE. Fetal assessment before and after dosing with buprenorphine or methadone. Addiction. 2012 Nov;107 Suppl 1(0 1):36-44. doi: 10.1111/j.1360-0443.2012.04037.x. |
| 23106924 | Derived | Jones HE, Fischer G, Heil SH, Kaltenbach K, Martin PR, Coyle MG, Selby P, Stine SM, O'Grady KE, Arria AM. Maternal Opioid Treatment: Human Experimental Research (MOTHER)--approach, issues and lessons learned. Addiction. 2012 Nov;107 Suppl 1(0 1):28-35. doi: 10.1111/j.1360-0443.2012.04036.x. |
| 23106923 | Derived | Jones HE, Heil SH, Baewert A, Arria AM, Kaltenbach K, Martin PR, Coyle MG, Selby P, Stine SM, Fischer G. Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review. Addiction. 2012 Nov;107 Suppl 1(0 1):5-27. doi: 10.1111/j.1360-0443.2012.04035.x. |
| 22088886 | Derived | Unger A, Jagsch R, Bawert A, Winklbaur B, Rohrmeister K, Martin PR, Coyle M, Fischer G. Are male neonates more vulnerable to neonatal abstinence syndrome than female neonates? Gend Med. 2011 Dec;8(6):355-64. doi: 10.1016/j.genm.2011.10.001. Epub 2011 Nov 15. |
| 21142534 | Derived | Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR, Fischer G. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010 Dec 9;363(24):2320-31. doi: 10.1056/NEJMoa1005359. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
| Primary | Child's Length of Hospital Stay | Posted | Mean | 95% Confidence Interval | days | delivery until hospital discharge (min=2 days, max=79 days) |
|
|
|
| Primary | Number of Children Requiring Treatment for Neonatal Abstinence Signs (NAS) | Neonatal abstinence syndrome (NAS) characterized by hyperirritability of the central nervous system and dysfunction in the autonomic nervous system, gastrointestinal tract, and respiratory system.11 When left untreated, NAS can result in serious illness (e.g., diarrhea, feeding difficulties, weight loss, and seizures) and death. | Posted | Number | participants | From birth until hospital discharge (min=4 days, max=10, depending on site) |
|
|
|
| Primary | Child's Peak Daily Total NAS Score | NAS was measured with the MOTHER NAS scale, which includes 28 items, 19 of which are used for scoring and medication decisions. Scores can range from 0 to 42, with higher scores indicating more severe withdrawal. | Posted | Mean | 95% Confidence Interval | Score on the scale | minimum twice daily from birth until NAS no longer measured (min=10 days) |
|
|
|
| Primary | Total Amount of Morphine Sulfate That a Neonate Receives to Treat NAS | Total amount in mg | Posted | Mean | 95% Confidence Interval | mg | Start of NAS treatment until discontinuation of NAS treatment (min=0 days, max=76 days) |
|
|
|
| Secondary | Mother's Self-report of Drug Use (Measured Monthly by Time Line Follow Back) | frequency of use during the course of the study was too low to estimate the parameter with sufficient accuracy | Posted | Number | percentage of drug use | monthly from study entry until discontinuation or delivery (min=29 days, max=239 days) |
|
|
|
| Secondary | Mother's HIV Risk Behaviors (Measured Monthly by Risk Behavior Assessment) | frequency of occurrence too low to be estimated with accuracy | Posted | Number | percentage of HIV risk behaviors | monthly from study entry until discontinuation or delivery (min=29 days, max=239 days) |
|
|
|
| Secondary | Mother's Measures of Dose Adequacy and Acceptance Over Time (Measured Weekly by Dose Adequacy Measure) | Pregnant women maintained on an opioid agonist medication may require upward adjustment to their medication during the course of pregnant. The Dose Adequacy Measure represented a recordation of dosing adjustments during the course of the study. | intra-subject variability in dosing (typically 1 dose) over course of the trial was too small to estimate the parameter of interest with sufficient accuracy | Posted | Number | dose increase per trimester | from study entry until discontinuation or delivery (min=29 days, max=239 days) |
|
|
|
| Secondary | Mother's Psychosocial Functioning at Delivery as Measured by the Addiction Severity Index Psychosocial Index Score | The Addiction Severity Index is a structured clinical interview that assesses problem severity in 7 areas of functioning: alcohol use, drug use, medical, legal, employment, psychosocial, and psychiatric status. Each area of functioning yields a composite scale score between 0 and 1, with higher scores indicating greater problem severity in that area. Only the psychosocial index was examined in this study. | Posted | Mean | 95% Confidence Interval | Score on the scale | at delivery |
|
|
|
| 14 |
| 89 |
| 83 |
| 89 |
| EG001 | Buprenorphine: Mothers | Buprenorphine Buprenorphine : sl daily 2-32 mg | 8 | 86 | 66 | 86 |
| EG002 | Methadone: Neonates | Neonates born to mothers maintained on methadone | 6 | 73 | 34 | 73 |
| EG003 | Buprenorphine: Neonates | Neonates born to mothers maintained on buprenorphine | 1 | 58 | 29 | 58 |
|
| cardiovascular | Cardiac disorders | MedDRA (10.0) | Systematic Assessment |
|
| gastrointestinal | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| genitourinary | Renal and urinary disorders | MedDRA (10.0) | Systematic Assessment |
|
| Illicit drug use | Psychiatric disorders | MedDRA (10.0) | Systematic Assessment | Mothers only |
|
| musculoskeletal | Musculoskeletal and connective tissue disorders | MedDRA (10.0) | Systematic Assessment |
|
| neurological | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
|
| obstetrical | Pregnancy, puerperium and perinatal conditions | MedDRA (10.0) | Systematic Assessment |
|
| postsurgical | Surgical and medical procedures | MedDRA (10.0) | Systematic Assessment |
|
| psychological | Psychiatric disorders | MedDRA (10.0) | Systematic Assessment | Mothers only |
|
| psychosocial | Social circumstances | MedDRA (10.0) | Systematic Assessment | Mothers only |
|
| respiratory | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| sexually transmitted diseases | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| skin conditions | Skin and subcutaneous tissue disorders | MedDRA (10.0) | Systematic Assessment |
|
| sleep disturbances | Nervous system disorders | MedDRA (10.0) | Systematic Assessment | Mothers only |
|
| other | General disorders | MedDRA (10.0) | Systematic Assessment |
|
|
| abnormal appetite | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| abnormal laboratory values | General disorders | MedDRA (10.0) | Systematic Assessment |
|
| blood-borne disorders | Blood and lymphatic system disorders | MedDRA (10.0) | Systematic Assessment |
|
| cardiovascular | Cardiac disorders | MedDRA (10.0) | Systematic Assessment |
|
| endocrinologic | Endocrine disorders | MedDRA (10.0) | Systematic Assessment |
|
| eye, ear, nose, or throat problems | Ear and labyrinth disorders | MedDRA (10.0) | Systematic Assessment |
|
| fever | General disorders | MedDRA (10.0) | Systematic Assessment |
|
| gastrointestinal | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| genitourinary | Renal and urinary disorders | MedDRA (10.0) | Systematic Assessment |
|
| hematopoietic or lymphatic symptoms | Blood and lymphatic system disorders | MedDRA (10.0) | Systematic Assessment |
|
| Illicit drug use | Psychiatric disorders | MedDRA (10.0) | Systematic Assessment |
|
| dental problems | General disorders | MedDRA (10.0) | Systematic Assessment |
|
| musculoskeletal | Musculoskeletal and connective tissue disorders | MedDRA (10.0) | Systematic Assessment |
|
| neuromuscular | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
|
| neurological | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
|
| obstetrical | Pregnancy, puerperium and perinatal conditions | MedDRA (10.0) | Systematic Assessment |
|
| postsurgical | Surgical and medical procedures | MedDRA (10.0) | Systematic Assessment |
|
| psychological | Psychiatric disorders | MedDRA (10.0) | Systematic Assessment | Mothers only |
|
| psychosocial | Social circumstances | MedDRA (10.0) | Systematic Assessment | Mothers only |
|
| respiratory | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| sexually transmitted diseases | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| skin conditions | Skin and subcutaneous tissue disorders | MedDRA (10.0) | Systematic Assessment |
|
| sleep disturbances | Nervous system disorders | MedDRA (10.0) | Systematic Assessment | Mothers only |
|
| somatic | Nervous system disorders | MedDRA (10.0) | Systematic Assessment | Mothers only |
|
| other AE | General disorders | MedDRA (10.0) | Systematic Assessment |
|
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| D007175 | Impulsive Behavior |
| D001519 | Behavior |
| D000470 |
| Alkaloids |
| D006571 | Heterocyclic Compounds |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |