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Efficacy of psychostimulant drugs for amphetamine abuse or dependence

  1. Clara Pérez-Mañá1,*,
  2. Xavier Castells2,
  3. Marta Torrens3,
  4. Dolors Capellà4,
  5. Magi Farre1

Editorial Group: Cochrane Drugs and Alcohol Group

Published Online: 2 SEP 2013

Assessed as up-to-date: 1 AUG 2013

DOI: 10.1002/14651858.CD009695.pub2


How to Cite

Pérez-Mañá C, Castells X, Torrens M, Capellà D, Farre M. Efficacy of psychostimulant drugs for amphetamine abuse or dependence. Cochrane Database of Systematic Reviews 2013, Issue 9. Art. No.: CD009695. DOI: 10.1002/14651858.CD009695.pub2.

Author Information

  1. 1

    Universitat Autònoma de Barcelona, Human Pharmacology and Clinical Neurosciences Research Group, Hospital del Mar Research Institute-IMIM, Parc de Salut Mar, and Department of Pharmacology, Therapeutics and Toxicology, Barcelona, Catalonia, Spain

  2. 2

    Universitat de Girona, Unit of Clinical Pharmacology, TransLab Research Group, Department of Medical Sciences, Girona, Catalonia, Spain

  3. 3

    Hospital del Mar Research Institute-IMIM, Parc de Salut Mar, Institute of Neuropsychiatry and Addiction, Disorders by Use of Substances Research Group, Barcelona, Spain

  4. 4

    Faculty of Medicine, Universitat de Girona, Unit of clinical pharmacology, Department of medical sciences, Girona, Catalonia, Spain

*Clara Pérez-Mañá, Human Pharmacology and Clinical Neurosciences Research Group, Hospital del Mar Research Institute-IMIM, Parc de Salut Mar, and Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Doctor Aiguader 88, Barcelona, Catalonia, 08003, Spain. cperez@imim.es.

Publication History

  1. Publication Status: New
  2. Published Online: 2 SEP 2013

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Characteristics of included studies [ordered by study ID]
Anderson 2012

MethodsDouble-blind, randomised, placebo-controlled clinical trial

Stastitical analysis: modified ITT


Participantsn = 210 methamphetamine-dependent outpatients (DSM-IV), 20 with ADHD, 7 alcohol dependents

Mean age: 39 years

Gender: 124 men

Race: African-American: 10, Caucasian: 148, Other: 52

Employed: not reported (NR)

History: < 18 days of methamphetamine use during last month: 84, > 18 days of methamphetamine use during last month: 126, lifetime methamphetamine use: NR

Route of methamphetamine use: NR


InterventionsThree parallel groups:

1. Modafinil 200 mg qd (fixed posology), N = 72

2. Modafinil 400 mg qd (fixed posology), N = 70

2. Placebo, N = 68

+ CBT (36 sessions) + HIV counselling + motivational enhancement therapy (1 session)

Duration: 12 weeks

Multiple site (USA)


OutcomesAmphetamine use assessed with three-times-weekly UA

Sustained abstinence (defined as at least 3 weeks of continuous abstinence)

Retention in treatment

Craving

Depressive symptoms assessed by means of HAM-D

Overall functioning assessed by means of CGI

Dropouts due to adverse events


NotesAuthor's affiliation: university and other public institutions

Funding: public

Assessment of compliance: self-report, pill count, modafinil and metabolite in urine


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdapative urn randomisation used

Allocation concealment (selection bias)Low riskCentral allocation. Using telephone. Pharmacy controlled

Blinding (detection bias): Objective measures
Objective measures
Low riskOutcome or outcome measurement was not likely to be influenced by lack of blinding

Blinding (performance bias): Objective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Blinding (detection bias): Subjective measures
Subjective measures
Low riskStudy medication and matched placebo have identical appearance. Blinding can be achieved when the study medication with mild behavioural effects (modafinil) is compared with placebo

Blinding (performance bias): Subjective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Incomplete outcome data (attrition bias): Objective measures except retention in treatment or dropout
Objective outcomes
High riskHigh attrition in all study groups (globally 53%). Missing outcome data balanced in numbers across intervention groups. Reasons for dropping out not reported. Analysis performed without imputation methods

Incomplete outcome data (attrition bias): Subjective measures
Subjective measures
High riskHigh attrition in all study groups (globally 53%). Missing outcome data balanced in numbers across intervention groups. Reasons for dropping out not reported. Analysis performed without imputation methods

Selective reporting (reporting bias)Low riskThe study protocol is available and the study report includes all outcomes

Other biasLow riskThe study appears to be free of other sources of bias

Das 2009

MethodsDouble-blind, randomised, placebo-controlled clinical trial

Stastitical analysis: ITT


Participantsn = 30 methamphetamine-dependent outpatients (SCID) who have sex with men. 1 opioid dependent

Mean age: 36.5 years

Gender: 30 men

Race: African-American: 3, Caucasian: 16, Other: 11

Employed: 10

History: days of methamphetamine use during last month: NR, lifetime methamphetamine use: NR

Route of methamphetamine use: 26 ip, 14 in, 15 iv, 7 oral, 7 rectal


InterventionsTwo parallel groups:

1. Bupropion XL 300 mg qd. (fixed posology), N = 20

2. Placebo, N = 10

+ Counseling (12 sessions)

Duration: 12 weeks

Single site (USA)


OutcomesAmphetamine use assessed with one-time-weekly UA

Sustained abstinence (defined as at least 3 weeks of continuous abstinence)

Retention in treatment

Depressive symptoms assessed by means of Center for Epidemiologic Studies Depression Rating Scale (CES-D)

Dropouts due to adverse events


NotesAuthor's affiliation: university and other public institutions

Funding: public

Assessment of compliance: MEMS caps and self-report


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomization code"

Allocation concealment (selection bias)Low riskPharmacy staff and biostatistician who prepared allocation did not have contact with study participants

Blinding (detection bias): Objective measures
Objective measures
Low riskOutcomes assessed by means of objective measures are unlikely to be influenced by lack of blinding

Blinding (performance bias): Objective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Blinding (detection bias): Subjective measures
Subjective measures
Low riskStudy medication and matched placebo have identical appearance. Blinding can be achieved when the study medication with mild behavioural effects (bupropion) is compared with placebo

Blinding (performance bias): Subjective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Incomplete outcome data (attrition bias): Objective measures except retention in treatment or dropout
Objective outcomes
Low riskVery low attrition in both study groups. Missing outcome data balanced in numbers across intervention groups. Missing data have been imputed using appropriate methods (worst case scenario)

Incomplete outcome data (attrition bias): Subjective measures
Subjective measures
Low riskVery low attrition in both study groups. Missing outcome data balanced in numbers across intervention groups. Data analysed with and without imputation methods

Selective reporting (reporting bias)Low riskThe study protocol is available, and the study report includes all outcomes

Other biasUnclear riskDifferent numbers of partners. Different annual income between groups, and participants are paid for participation

Elkashef 2008 a

MethodsDouble-blind, randomised, placebo-controlled clinical trial

Stastitical analysis: nearly ITT


Participantsn = 151 methamphetamine-dependent outpatients (DSM-IV). 20 with ADHD

Mean age: 36 years

Gender: 101 men

Race: African-American: 4, Caucasian: 112, Other: 35

Employed: NR

History: days of methamphetamine use during last month: NR, lifetime methamphetamine use: 10.2 years

Route of methamphetamine use: 98 ip, 25 in, 28 iv, 0 oral, 0 rectal


InterventionsTwo parallel groups:

1. Bupropion 300 mg tid. (fixed posology), N = 79

2. Placebo, N = 72

+ CBT (1 session per week) + CM + groupal CBT (3 sessions per week)

Duration: 12 weeks

Multiple site (USA)


OutcomesAmphetamine use assessed with one-time-weekly UA

Sustained abstinence (defined as at least 3 weeks of continuous abstinence)

Self-reported amphetamine use

Retention in treatment

Craving assessed by means of BSCS

Depressive symptoms assessed by means of HAM-D

Addiction Severity Index


NotesAuthor's affiliation: university and other public institutions

Funding: public

Assessment of compliance: weekly tablet count


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdaptive urn randomisation was used to balance groups

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding (detection bias): Objective measures
Objective measures
Low riskOutcome or outcome measurement was not likely to be influenced by lack of blinding

Blinding (performance bias): Objective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Blinding (detection bias): Subjective measures
Subjective measures
Low riskStudy medication and matched placebo have identical appearance, and blinding can be achieved when the study medication with mild behavioural effects (bupropion) is compared with placebo

Blinding (performance bias): Subjective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Incomplete outcome data (attrition bias): Objective measures except retention in treatment or dropout
Objective outcomes
Unclear riskModerate attrition in both study groups (globally 48%). Missing outcome data balanced in numbers across intervention groups but reasons not reported. Missing data have not been imputed

Incomplete outcome data (attrition bias): Subjective measures
Subjective measures
Unclear riskModerate attrition in both study groups (globally 48%). Missing outcome data balanced in numbers across intervention groups but reasons not reported. Missing data have not been imputed

Selective reporting (reporting bias)Unclear riskSome reported outcomes are not included in Clinicaltrials.gov

Other biasHigh riskADHD was not balanced between groups (8% bupropion vs 19% placebo)

Galloway 2011

MethodsDouble-blind, randomised, placebo-controlled clinical trial

Stastitical analysis: ITT


Participantsn = 60 methamphetamine-dependent outpatients (DSM-IV-TR), 9 with ADHD

Mean age: 37.3 years

Gender: 34 men

Race: African-American: NR, Caucasian: 41, Other: NR

Employed: NR

History: days of methamphetamine use during past month: 17.1, lifetime methamphetamine use: NR

Route of methamphetamine use: 44 ip as primary route


InterventionsTwo parallel groups:

1. Dexamphetamine 60 mg qd (fixed posology), N = 30

2. Placebo, N = 30

+ individual motivational psychotherapy (9 sessions)

Duration: 8 weeks

Single site (USA)


OutcomesAmphetamine use assessed with two-times-weekly UA

Self-reported amphetamine use

Retention in treatment

Craving

Dropouts due to adverse events


NotesAuthor's affiliation: public but not university

Funding: public

Assessment of compliance: unused capsules count


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAn urn randomisation method was used

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement. Method of concealment is not described

Blinding (detection bias): Objective measures
Objective measures
Low riskOutcome or outcome measurement was not likely to be influenced by lack of blinding

Blinding (performance bias): Objective measuresUnclear riskGiven that the studied intervention has powerful behavioural effects, it is likely that blinding was broken; this could have yielded to the provision of additional interventions, depending on the treatment the participant was receiving

Blinding (detection bias): Subjective measures
Subjective measures
Unclear riskStudy medication and matched placebo have identical appearance, but it is unclear that blinding can be achieved when the study medication with powerful behavioural effects (dexamphetamine) is compared with placebo

Blinding (performance bias): Subjective measuresUnclear riskGiven that the studied intervention has powerful behavioural effects, it is likely that blinding was broken; this could have yielded to the provision of additional interventions, depending on the treatment the participant was receiving

Incomplete outcome data (attrition bias): Objective measures except retention in treatment or dropout
Objective outcomes
Low riskLow attrition in both study groups (globally 15%). Missing outcome data balanced in numbers across intervention groups, similar reasons for missing data across groups. No imputation methods used

Incomplete outcome data (attrition bias): Subjective measures
Subjective measures
Low riskLow attrition in both study groups (globally 15%). Missing outcome data balanced in numbers across intervention groups, similar reasons for missing data across groups. No imputation methods used

Selective reporting (reporting bias)Low riskMore outcomes present in Clinicaltrials.gov than in the published report. But typical outcomes for those studies are reported

Other biasLow riskThe study appears to be free of other sources of bias

Heinzerling 2010

MethodsDouble-blind, randomised, placebo-controlled clinical trial

Stastitical analysis: ITT


Participantsn = 71 methamphetamine-dependent outpatients (DSM-IV-TR)

Mean age: 38.4 years

Gender: 50 men

Race: African-American: 4, Caucasian: 36, Other: 29

Employed: 54

History: days of methamphetamine use during past month: 9.3 days, lifetime methamphetamine use: 14.5 years

Route of methamphetamine use: 49 ip, 17 in, 4 iv, 1 oral


InterventionsTwo parallel groups:

1. Modafinil 400 mg qd (fixed posology), N = 34

2. Placebo, N = 37

+ CBT + CM (12 sessions)

Duration: 12 weeks

Multiple site (USA)


OutcomesAmphetamine use assessed with three-times-weekly UA

Sustained abstinence (defined as at least 3 weeks of continuous abstinence)

Retention in treatment

Depressive symptoms assessed by means of BDI-II

Craving

Dropouts due to adverse events


NotesAuthor's affiliation: university

Co-funding: public and private

Assessment of compliance: pill count and self-report


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAn urn randomisation procedure used

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding (detection bias): Objective measures
Objective measures
Low riskOutcome or outcome measurement was not likely to be influenced by lack of blinding

Blinding (performance bias): Objective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Blinding (detection bias): Subjective measures
Subjective measures
Low riskStudy medication and matched placebo have identical appearance, and blinding can be achieved when the study medication with mild behavioural effects (modafinil) is compared with placebo

Blinding (performance bias): Subjective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Incomplete outcome data (attrition bias): Objective measures except retention in treatment or dropout
Objective outcomes
High riskHigh attrition in both study groups (globally 62%). Missing outcome data balanced in numbers across intervention groups. Reasons for missing data partially described. No imputation methods used

Incomplete outcome data (attrition bias): Subjective measures
Subjective measures
High riskHigh attrition in both study groups (globally 62%). Missing outcome data balanced in numbers across intervention groups. Reasons for missing data partially described. No imputation methods used

Selective reporting (reporting bias)Low riskMore outcomes present in Clinicaltrials.gov than in the published report. But typical outcomes for those studies are reported

Other biasLow riskThe study appears to be free of other sources of bias

Konstenius 2010

MethodsDouble-blind, randomised, placebo-controlled clinical trial. Relapse prevention trial

Stastitical analysis: ITT


Participantsn = 24 amphetamine-dependent outpatients (DSM-IV) with ADHD, abstinent for a minimum of 2 weeks

Mean age: 37.4 years

Gender: 18 men

Race: African-American: NR, Caucasian: NR, Other: NR

Employed: 5

History: days of methamphetamine use during past month: NR, lifetime methamphetamine use: 13.9 years

Route of methamphetamine use: NR


InterventionsTwo parallel groups:

1. Methylphenidate 18 to 72 mg qd (flexible posology), N = 12

2. Placebo, N = 12

+ individual skills training program (12 sessions)

Duration: 12 weeks

Single site (Sweden)


OutcomesAmphetamine use assessed with two-times-weekly UA

Sustained abstinence (defined as at least 3 weeks of continuous abstinence)

Retention in treatment

Craving

Depressive symptoms assessed by means of BDI-II

Anxiety symptoms assessed by BAI

Dropouts due to adverse events


NotesAuthor's affiliation: university

Co-funding: public and private

Assessment of compliance: pill count


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRanzomisation performed with Trombul software

Allocation concealment (selection bias)Low riskRandomisation done by an independent pharmacist. Randomisation list was kept at the pharmacy until the end of the trial and was collected and opened thereafter

Blinding (detection bias): Objective measures
Objective measures
Low riskOutcome or outcome measurement was not likely to be influenced by lack of blinding

Blinding (performance bias): Objective measuresUnclear riskGiven that the studied intervention has powerful behavioural effects, it is likely that blinding was broken, which could have yielded to the provision of additional interventions, depending on the treatment the participant was receiving

Blinding (detection bias): Subjective measures
Subjective measures
Unclear riskIt is unclear whether blinding can be achieved when the study medication with powerful behavioural effects (methylphenidate) is compared with placebo

Blinding (performance bias): Subjective measuresUnclear riskGiven that the studied intervention has powerful behavioural effects, it is likely that blinding was broken, which could have yielded to the provision of additional interventions, depending on the treatment the participant was receiving

Incomplete outcome data (attrition bias): Objective measures except retention in treatment or dropout
Objective outcomes
Unclear riskModerate attrition in both study groups (globally 29%). Missing outcome data not balanced in numbers across intervention groups. Reasons for missing data across groups not reported. Imputation by worst case scenario

Incomplete outcome data (attrition bias): Subjective measures
Subjective measures
Unclear riskModerate attrition in both study groups (globally 29%). Missing outcome data not balanced in numbers across intervention groups. Reasons for missing data across groups not reported. Imputation methods not reported

Selective reporting (reporting bias)Low riskThe report includes expected outcomes (current controlled trials)

Other biasLow riskThe study appears to be free of other sources of bias

Longo 2010

MethodsDouble-blind, randomised, placebo-controlled clinical trial

Stastitical analysis: ITT


Participantsn = 49 methamphetamine-dependent outpatients (DSM-IV)

Mean age: 31.9 years

Gender: 30 men

Race: NR

Employed: 24

History: NR

Route of methamphetamine use: 42 iv


InterventionsTwo parallel groups:

1. Dexamphetamine mean of 80 mg qd (flexible posology), N = 23

2. Placebo, N = 26

+ CBT (4 sessions)

Duration: 12 weeks maintenance and 4 weeks dose reduction

Single site (Australia)


OutcomesAmphetamine use assessed with hair samples (baseline, month 3, follow-up)

Self-reported amphetamine use

Retention in treatment

Dropouts due to adverse events


NotesAuthor's affiliation: university

Funding: public

Assessment of compliance: dispensing under pharmacist supervision


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA computer randomisation list was used to select random permuted blocks

Allocation concealment (selection bias)Low riskRandomisation performed by pharmacy assistant not involved in dosing or dispensing the medication

Blinding (detection bias): Objective measures
Objective measures
Low riskOutcome or outcome measurement was not likely to be influenced by lack of blinding

Blinding (performance bias): Objective measuresUnclear riskGiven that the studied intervention has powerful behavioural effects, it is likely that blinding was broken, which could have yielded to the provision of additional interventions, depending on the treatment the participant was receiving

Blinding (detection bias): Subjective measures
Subjective measures
Unclear riskIt is unclear whether blinding can be achieved when the study medication with powerful behavioural effects (dexamphetamine) is compared with placebo

Blinding (performance bias): Subjective measuresUnclear riskGiven that the studied intervention has powerful behavioural effects, it is likely that blinding was broken, which could have yielded to the provision of additional interventions, depending on the treatment the participant was receiving

Incomplete outcome data (attrition bias): Objective measures except retention in treatment or dropout
Objective outcomes
High riskHigh attrition (globally 53%). Attrition was higher in the placebo group. Reasons for missing data reported and similar; nevertheless some participants dropped out because they believed they were on placebo. No imputation methods used

Incomplete outcome data (attrition bias): Subjective measures
Subjective measures
High riskHigh attrition (globally 53%). Attrition was higher in the placebo group. Reasons for missing data reported and similar; nevertheless some participants dropped out because they believed they were on placebo. No imputation methods used

Selective reporting (reporting bias)Unclear riskProtocol not available in a register. Lack of typical outcomes like drug use assessed by means of UA

Other biasLow riskThe study appears to be free of other sources of bias

Mancino 2011

MethodsDouble-blind, randomised, placebo-controlled clinical trial. Relapse prevention trial

Stastitical analysis: not ITT, not PP


Participantsn = 9 methamphetamine-dependent outpatients (DSM-IV)

Mean age: 32.5 years

Gender: 5 men

Race: NR

Employed: NR

History: NR

Route of methamphetamine use: NR


InterventionsTwo parallel groups:

1. Modafinil 400 mg qd, N = 6

2. Placebo, N = 3

+ Psychotherapy not specified (weekly)

Duration: 8 weeks

Single site (USA)


OutcomesAmphetamine use assessed with three-times-weekly UA

Withdrawal symptoms

Retention in treatment

Dropouts due to adverse events


NotesAuthor's affiliation: university

Funding: NR

Assessment of compliance: NR


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskUrn randomisation

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding (detection bias): Objective measures
Objective measures
Low riskOutcome or outcome measurement was not likely to be influenced by lack of blinding

Blinding (performance bias): Objective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Blinding (detection bias): Subjective measures
Subjective measures
Unclear riskBlinding theoretically can be achieved when a study medication with mild behavioural effects (modafinil) is compared with placebo. Nevertheless, information on whether medications used were identical in appearance is insufficient

Blinding (performance bias): Subjective measuresUnclear riskInformation is insufficient to permit judgement

Incomplete outcome data (attrition bias): Objective measures except retention in treatment or dropout
Objective outcomes
High riskHigh attrition (globally 78%). Reasons for missing data across groups not reported. Imputation methods not reported

Incomplete outcome data (attrition bias): Subjective measures
Subjective measures
High riskHigh attrition (globally 78%). Reasons for missing data across groups not reported. Imputation methods not reported

Selective reporting (reporting bias)Low riskThe study protocol is available, and the study publication includes all outcomes. Information obtained from Clinicaltrials.gov

Other biasHigh riskTerminated because of lack of funding.The article is not published in a journal (no peer review process is involved for data included in the register)

Shearer 2009

MethodsDouble-blind, randomised, placebo-controlled clinical trial

Stastitical analysis: ITT


Participantsn = 80 methamphetamine-dependent outpatients (DSM-IV) who used amphetamines 2 to 3 days per week or more often. 10 with opioid dependence

Mean age: 36 years

Gender: 50 men

Race: NR

Employed: 42

History: days of methamphetamine use during past month: 19.5, lifetime methamphetamine use: 7 years

Route of methamphetamine use: NR ip, NR in, 50 iv, NR oral, NR rectal


InterventionsTwo parallel groups:

1. Modafinil 200 mg qd (fixed posology), N = 38

2. Placebo, N = 42

+ cognitive-behavioural intervention (4 sessions)

Duration: 10 weeks

Multiple-site trial (Australia)


OutcomesAmphetamine use assessed with one-time-weekly UA

Self-reported amphetamine use

Retention in treatment

Dropouts due to adverse events


NotesAuthor's affiliation: university and other public institutions

Co-funding: public and private

Assessment of compliance: MEMS bottles and modafinilic acid in urine


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number tables, in blocks

Allocation concealment (selection bias)Low riskCentral allocation, pharmacy controlled

Blinding (detection bias): Objective measures
Objective measures
Low riskOutcome or outcome measurement was not likely to be influenced by lack of blinding

Blinding (performance bias): Objective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Blinding (detection bias): Subjective measures
Subjective measures
Low riskStudy medication and matched placebo have identical appearance, and blinding can be achieved when the study medication with mild behavioural effects (modafinil) is compared with placebo

Blinding (performance bias): Subjective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Incomplete outcome data (attrition bias): Objective measures except retention in treatment or dropout
Objective outcomes
High riskHigh attrition in both study groups (globally 68%). Reasons for missing data across groups reported and similar. Imputation by worst case scenario and last observation carried forward. No imputation for missing data due to treatment dropout

Incomplete outcome data (attrition bias): Subjective measures
Subjective measures
High riskHigh attrition in both study groups (globally 68%). Reasons for missing data across groups reported and similar. Imputation by worst case scenario and last observation carried forward. No imputation for missing data due to treatment dropout

Selective reporting (reporting bias)Low riskThe report includes expected outcomes (cited in Clinicaltrials.gov)

Other biasLow riskThe study is apparently free of other sources of bias

Shoptaw 2008

MethodsDouble-blind, randomised, placebo-controlled clinical trial

Stastitical analysis: ITT


Participantsn = 73 methamphetamine-dependent outpatients (DSM-IV TR)

Mean age: 34.6 years

Gender: 47 men

Race: African-American: 2, Caucasian: 41, Other: 30

Employed: 57

History: days of methamphetamine use during past month: 15.7 days, lifetime methamphetamine use: 9.6 years

Route of methamphetamine use: 47 ip, 16 in, 9 iv, 1 oral, 0 rectal


InterventionsTwo parallel groups:

1. Bupropion SR 150 mg bid (fixed posology), N = 36

2. Placebo, N = 37

+ CBT + CM ( 12 sessions)

Duration: 12 weeks

Multisite trial (USA)


OutcomesAmphetamine use assessed with three-times-weekly UA

Sustained abstinence (defined as at least 3 weeks of continuous abstinence)

Retention in treatment

Depressive symptoms assessed by means of BDI

Dropouts due to adverse events


NotesAuthor's affiliation: university

Funding: public

Assessment of compliance: weekly pill counts, reports of medication taking


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information to permit judgement

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding (detection bias): Objective measures
Objective measures
Low riskOutcome or outcome measurement was not likely to be influenced by lack of blinding

Blinding (performance bias): Objective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Blinding (detection bias): Subjective measures
Subjective measures
Low riskStudy medication and matched placebo have identical appearance, and blinding can be achieved when the study medication with mild behavioural effects (modafinil) is compared with placebo

Blinding (performance bias): Subjective measuresLow riskGiven that the studied intervention has mild behavioural effects, it is unlikely that blinding was broken

Incomplete outcome data (attrition bias): Objective measures except retention in treatment or dropout
Objective outcomes
High riskHigh attrition in both study groups (globally 66%). Missing outcome data balanced in numbers across intervention groups, similar reasons for missing data across groups. No imputation methods used

Incomplete outcome data (attrition bias): Subjective measures
Subjective measures
High riskHigh attrition in both study groups (globally 66%).

Missing outcome data balanced in numbers across intervention groups, similar reasons for missing data across groups. No imputation methods used

Selective reporting (reporting bias)Unclear riskFewer outcomes present in Clinicaltrials.gov than in the published report

Other biasLow riskThe study appears to be free of other sources of bias

Tiihonen 2007

MethodsDouble-blind, randomised, placebo-controlled clinical trial

Stastitical analysis: ITT


Participantsn = 53 amphetamine-dependent outpatients (DSM-IV)

Mean age: 35.63 years

Gender: 24 men

Race: African-American: 0, Caucasian: 34, Other: 0

Employed: NR

History: days of methamphetamine use during past month: NR, lifetime methamphetamine use: 15.9

Route of methamphetamine use: 0 ip, 0 in, 34 iv, 0 oral, 0 rectal


InterventionsThree parallel groups:

1. Methylphenidate OROS 54 mg qd (fixed posology), N = 17

2. Aripiprazole 15 mg qd, N = 19

3. Placebo, N = 17

+ unstructured psychosocial treatment

Duration: 20 weeks

Number of centres: NR (Finland)


OutcomesAmphetamine use assessed with two-times-weekly UA

Retention in treatment

Dropouts due to adverse events


NotesAuthor's affiliation: university and other public institutions

Funding: public

Assessment of compliance: NR


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised using a randomised plan generator in blocks of six participants

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding (detection bias): Objective measures
Objective measures
Low riskOutcome or outcome measurement was not likely to be influenced by lack of blinding

Blinding (performance bias): Objective measuresUnclear riskGiven that the studied intervention has powerful behavioural effects, it is likely that blinding was broken, which could have yielded to the provision of additional interventions, depending on the treatment the participant was receiving

Blinding (detection bias): Subjective measures
Subjective measures
Unclear riskStudy medication and matched placebo have identical appearance, but it is unclear whether blinding can be achieved when the study medication with powerful behavioural effects (methylphenidate) is compared with placebo

Blinding (performance bias): Subjective measuresUnclear riskGiven that the studied intervention has powerful behavioural effects, it is likely that blinding was broken, which could have yielded to the provision of additional interventions, depending on the treatment the participant was receiving

Incomplete outcome data (attrition bias): Objective measures except retention in treatment or dropout
Objective outcomes
High riskHigh attrition in both study groups (globally 71%). Missing outcome data balanced in numbers across intervention groups. Reasons for missing data across groups not reported. Imputation by worst case scenario

Incomplete outcome data (attrition bias): Subjective measures
Subjective measures
High riskHigh attrition in both study groups (globally 71%).

Reasons for missing data across groups not reported. No imputation methods used

Selective reporting (reporting bias)Low riskThe report includes expected outcomes (cited in Current Controlled Trials)

Other biasHigh riskInterim analysis of a longer trial. Age baseline differences between groups

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Brensilver 2013Subanalysis of an included study (Shoptaw 2008)

Christian 2007Not a randomised clinical trial

Dean 2009Subanalysis of an included study (Shoptaw 2008)

Hartz 2001Not assessing the efficacy of any psychostimulant for amphetamine dependence

Marinelli-Casey 2008Not assessing the efficacy of any psychostimulant for amphetamine dependence

McCann 2012Re-analysis of an included study (Elkashef 2008 a)

Shearer 2001No placebo group

Shearer 2010Subanalysis of an included study (Shearer 2009)

Whinchell 2012Re-analysis of an included study (Elkashef 2008 a)

 
Characteristics of ongoing studies [ordered by study ID]
Akhondzadeh L

Trial name or titleSlow-release methylphenidate in the treatment of methamphetamine dependence

MethodsRandomised, double-blind, placebo-controlled study; 12-week trial; phase II to III

ParticipantsMethamphetamine-dependent outpatients (DSM-IV-TR)

Interventions1. Sustained-released methylphenidate 54 mg/d

2. Placebo

OutcomesAmphetamine use

Craving

Addiction Severity Index

Starting dateMarch 2012

Contact informationShahin  Akhondzadeh

s.akhond@sina.tums.ac.ir

Notes

Franck J

Trial name or titleClinical trial of sustained-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adult criminal offenders with amphetamine addiction

MethodsSingle-centre double-blind randomised placebo-controlled with parallel groups: 24 weeks' duration

ParticipantsPrison inmates with ADHD and amphetamine addiction (DSM-IV)

Interventions1. Sustained-release methylphenidate 18 to 180 mg qd

2. Placebo

+ Relapse prevention

OutcomesAmphetamine and other drug use

Relapse to crime

ADHD symptoms

Psychiatric symptoms

Craving

Self-reported drug use

Plasma concentration of methylphenidate

Starting dateApril 2007

Contact informationJohan Frank

johan.franck@ki.se

Notes

Galloway GP a

Trial name or titleA dose-ranging study of modafinil for methamphetamine dependence

MethodsRandomised, double-blind, dose-ranging study; 4-week trial, phase II

ParticipantsMethamphetamine-dependent participants

Interventions1. Modafinil 100-mg, 400-mg or 600-mg tablets qd

2. Placebo

OutcomesAmphetamine use

Starting dateDecember 2009

Contact informationGantt Galloway

Gantt@cpmcri.org

Notes

Galloway GP b

Trial name or titleA randomised, placebo-controlled trial of modafinil for methamphetamine dependence

MethodsRandomised, double-blind, 4-week trial, phase II

ParticipantsMethamphetamine-dependent outpatients

Interventions1. Modafinil 600-mg capsule

2. Placebo

+ Motivational enhancement therapy

OutcomesAmphetamine use

Starting dateOctober 2011

Contact informationKathleen Garrison

garrisk@cpmcri.org

Notes

Gorgon L

Trial name or titlePhase II, double-blind, placebo-controlled trial of bupropion for methamphetamine dependence

MethodsDouble-blind, placebo-controlled, parallel-assignment, phase II

ParticipantsMethamphetamine-dependent participants (DSM-IV), at least one positive urine specimen after the start of screening

Interventions1. Bupropion 150 mg for the first 3 days. Increased to 150 mg bid until taper

2. Placebo

OutcomesAbstinence at the end

Sustained abstinence

Starting dateMay 2008

Contact informationLiza Gorgon

lgorgon@nih.gov

Notes

Heinzerling K

Trial name or titleStudy of medical treatment for methamphetamine addiction

MethodsRandomised, double-blind, 12-week trial, phase II

ParticipantsMethamphetamine-dependent participants (DSM-IV)

Interventions1. Bupropion 300 mg qd

2. Placebo

+ CBT

OutcomesClinical phenotype of frequency of baseline MA use in 30 days preceding the baseline period using self-report and results of thrice-weekly urine drug screens for MA metabolites during baseline

Starting dateJanuary 2009

Contact informationKeith Heinzerling

Kheinzerling@mednet.ucla.edu

Notes

Ling W

Trial name or titleMethylphenidate to treat methamphetamine dependence

MethodsRandomised, double-blind, parallel-assignment, 4-year trial, phase II

ParticipantsMethamphetamine-dependent participants (DSM-IV-TR)

Interventions1. Methylphenidate 18 mg/d during week 1; 36 mg/d during week 2; 54 mg/d during remainder of study

2. Placebo

+ CBT

OutcomesAmphetamine use

Retention in treatment

Starting dateOctober 2010

Contact informationJasmin Hernandez

jashernandez@ucla.edu

Maureen Hillhouse

hillhous@ucla.edu

Notes

 
Comparison 1. Psychostimulants vs placebo for amphetamine dependence

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Amphetamine use (UA)7463Mean Difference (IV, Random, 95% CI)-0.26 [-0.85, 0.33]

 2 Amphetamine use (hair analysis)122Mean Difference (IV, Random, 95% CI)0.53 [-6.02, 7.08]

 3 Sustained abstinence6559Risk Ratio (M-H, Random, 95% CI)1.12 [0.84, 1.49]

 4 Self-reported amphetamine use3133Mean Difference (IV, Random, 95% CI)-0.81 [-6.16, 4.54]

 5 Retention in treatment11791Risk Ratio (M-H, Random, 95% CI)1.01 [0.90, 1.14]

 6 Amphetamine craving2144Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.44, 0.59]

 7 Dropouts due to any adverse event10640Risk Difference (M-H, Random, 95% CI)0.01 [-0.03, 0.04]

 8 Dropouts due to cardiovascular adverse events8370Risk Difference (M-H, Random, 95% CI)0.01 [-0.03, 0.04]

 9 Dropouts due to psychiatric adverse events7290Risk Difference (M-H, Random, 95% CI)-0.02 [-0.06, 0.02]

 
Comparison 2. Subgroup analysis: type of drug

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Amphetamine use (UA)7Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 Bupropion
2103Mean Difference (IV, Random, 95% CI)-1.52 [-4.20, 1.17]

    1.2 Dexamphetamine
160Mean Difference (IV, Random, 95% CI)-0.30 [-2.66, 2.06]

    1.3 Methylphenidate
124Mean Difference (IV, Random, 95% CI)1.5 [-4.24, 7.24]

    1.4 Modafinil
3286Mean Difference (IV, Random, 95% CI)-0.21 [-0.84, 0.42]

 2 Amphetamine use (hair analysis)1Mean Difference (IV, Random, 95% CI)Subtotals only

    2.1 Dexamphetamine
122Mean Difference (IV, Random, 95% CI)0.53 [-6.02, 7.08]

 3 Sustained abstinence6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Bupropion
3254Risk Ratio (M-H, Random, 95% CI)1.36 [0.87, 2.14]

    3.2 Modafinil
2281Risk Ratio (M-H, Random, 95% CI)1.09 [0.64, 1.83]

    3.3 Methylphenidate
124Risk Ratio (M-H, Random, 95% CI)0.89 [0.53, 1.49]

 4 Self-reported amphetamine use3Mean Difference (IV, Random, 95% CI)Subtotals only

    4.1 Methylphenidate
124Mean Difference (IV, Random, 95% CI)0.5 [-4.76, 5.76]

    4.2 Modafinil
180Mean Difference (IV, Random, 95% CI)-4.40 [-8.44, -0.36]

    4.3 Dexamphetamine
129Mean Difference (IV, Random, 95% CI)7.71 [-5.10, 20.52]

 5 Retention in treatment11Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Bupropion
3254Risk Ratio (M-H, Random, 95% CI)0.98 [0.81, 1.18]

    5.2 Dexamphetamine
2109Risk Ratio (M-H, Random, 95% CI)1.42 [0.61, 3.29]

    5.3 Methylphenidate
258Risk Ratio (M-H, Random, 95% CI)0.90 [0.42, 1.94]

    5.4 Modafinil
4370Risk Ratio (M-H, Random, 95% CI)1.00 [0.79, 1.26]

 6 Amphetamine craving2Std. Mean Difference (IV, Random, 95% CI)Subtotals only

    6.1 Bupropion
173Std. Mean Difference (IV, Random, 95% CI)-0.19 [-0.65, 0.27]

    6.2 Modafinil
171Std. Mean Difference (IV, Random, 95% CI)0.34 [-0.13, 0.80]

 7 Dropouts due to any adverse event10Risk Difference (M-H, Random, 95% CI)Subtotals only

    7.1 Bupropion
2103Risk Difference (M-H, Random, 95% CI)5.82 [-0.07, 0.07]

    7.2 Dexamphetamine
2109Risk Difference (M-H, Random, 95% CI)-0.01 [-0.12, 0.10]

    7.3 Methylphenidate
258Risk Difference (M-H, Random, 95% CI)0.02 [-0.08, 0.11]

    7.4 Modafinil
4370Risk Difference (M-H, Random, 95% CI)0.01 [-0.04, 0.07]

 8 Dropouts due to cardiovascular adverse events8Risk Difference (M-H, Random, 95% CI)Subtotals only

    8.1 Bupropion
2103Risk Difference (M-H, Random, 95% CI)0.02 [-0.04, 0.09]

    8.2 Dexamphetamine
149Risk Difference (M-H, Random, 95% CI)-0.04 [-0.14, 0.07]

    8.3 Methylphenidate
258Risk Difference (M-H, Random, 95% CI)0.0 [-0.09, 0.09]

    8.4 Modafinil
3160Risk Difference (M-H, Random, 95% CI)0.01 [-0.04, 0.05]

 9 Dropouts due to psychiatric adverse events7Risk Difference (M-H, Random, 95% CI)Subtotals only

    9.1 Bupropion
2103Risk Difference (M-H, Random, 95% CI)-0.02 [-0.09, 0.04]

    9.2 Dexamphetamine
149Risk Difference (M-H, Random, 95% CI)-0.04 [-0.14, 0.07]

    9.3 Methylphenidate
258Risk Difference (M-H, Random, 95% CI)0.02 [-0.08, 0.11]

    9.4 Modafinil
280Risk Difference (M-H, Random, 95% CI)-0.03 [-0.10, 0.05]

 
Comparison 3. Subgroup analysis: type of dependence

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Amphetamine use (UA)7Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 Amphetamine dependence
124Mean Difference (IV, Random, 95% CI)1.5 [-4.24, 7.24]

    1.2 Methamphetamine dependence
6449Mean Difference (IV, Random, 95% CI)-0.28 [-0.87, 0.31]

 2 Amphetamine use (hair analysis)1Mean Difference (IV, Random, 95% CI)Subtotals only

   2.1 Amphetamine dependence
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 Methamphetamine dependence
122Mean Difference (IV, Random, 95% CI)0.53 [-6.02, 7.08]

 3 Sustained abstinence6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Amphetamine dependence
124Risk Ratio (M-H, Random, 95% CI)0.89 [0.53, 1.49]

    3.2 Methamphetamine dependence
5535Risk Ratio (M-H, Random, 95% CI)1.24 [0.88, 1.74]

 4 Self-reported amphetamine use3Mean Difference (IV, Random, 95% CI)Subtotals only

    4.1 Amphetamine dependence
124Mean Difference (IV, Random, 95% CI)0.5 [-4.76, 5.76]

    4.2 Methamphetamine dependence
2109Mean Difference (IV, Random, 95% CI)0.07 [-11.39, 11.52]

 5 Retention in treatment11Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Amphetamine dependence
258Risk Ratio (M-H, Random, 95% CI)0.90 [0.42, 1.94]

    5.2 Methamphetamine dependence
9733Risk Ratio (M-H, Random, 95% CI)1.03 [0.91, 1.16]

 6 Amphetamine craving2Std. Mean Difference (IV, Random, 95% CI)Subtotals only

   6.1 Amphetamine dependence
00Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    6.2 Methamphetamine dependence
2144Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.44, 0.59]

 7 Dropouts due to any adverse event10Risk Difference (M-H, Random, 95% CI)Subtotals only

    7.1 Amphetamine dependence
258Risk Difference (M-H, Random, 95% CI)0.02 [-0.08, 0.11]

    7.2 Methamphetamine dependence
8582Risk Difference (M-H, Random, 95% CI)0.00 [-0.03, 0.04]

 8 Dropouts due to cardiovascular adverse events8Risk Difference (M-H, Random, 95% CI)Subtotals only

    8.1 Amphetamine dependence
258Risk Difference (M-H, Random, 95% CI)0.0 [-0.09, 0.09]

    8.2 Methamphetamine dependence
6312Risk Difference (M-H, Random, 95% CI)0.01 [-0.03, 0.04]

 9 Dropouts due to psychiatric adverse events7Risk Difference (M-H, Random, 95% CI)Subtotals only

    9.1 Amphetamine dependence
7290Risk Difference (M-H, Random, 95% CI)-0.02 [-0.06, 0.02]

    9.2 Methamphetamine dependence
5232Risk Difference (M-H, Random, 95% CI)-0.03 [-0.07, 0.02]

 
Comparison 4. Subgroup analysis: comorbid ADHD as inclusion criterion

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Amphetamine use (UA)7Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 ADHD
124Mean Difference (IV, Random, 95% CI)1.5 [-4.24, 7.24]

    1.2 No ADHD
6449Mean Difference (IV, Random, 95% CI)-0.28 [-0.87, 0.31]

 2 Amphetamine use (hair analysis)1Mean Difference (IV, Random, 95% CI)Subtotals only

   2.1 ADHD
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 No ADHD
122Mean Difference (IV, Random, 95% CI)0.53 [-6.02, 7.08]

 3 Sustained abstinence6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 ADHD
124Risk Ratio (M-H, Random, 95% CI)0.89 [0.53, 1.49]

    3.2 No ADHD
5535Risk Ratio (M-H, Random, 95% CI)1.24 [0.88, 1.74]

 4 Self reported amphetamine use3Mean Difference (IV, Random, 95% CI)Subtotals only

    4.1 ADHD
124Mean Difference (IV, Random, 95% CI)0.5 [-4.76, 5.76]

    4.2 No ADHD
2109Mean Difference (IV, Random, 95% CI)0.07 [-11.39, 11.52]

 5 Retention in treatment11Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 ADHD
124Risk Ratio (M-H, Random, 95% CI)0.7 [0.41, 1.20]

    5.2 No ADHD
10767Risk Ratio (M-H, Random, 95% CI)1.03 [0.92, 1.16]

 6 Amphetamine craving2Std. Mean Difference (IV, Random, 95% CI)Subtotals only

   6.1 ADHD
00Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    6.2 No ADHD
2144Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.44, 0.59]

 7 Dropouts due to any adverse event10Risk Difference (M-H, Random, 95% CI)Subtotals only

    7.1 ADHD
124Risk Difference (M-H, Random, 95% CI)0.08 [-0.12, 0.29]

    7.2 No ADHD
9616Risk Difference (M-H, Random, 95% CI)0.00 [-0.03, 0.04]

 8 Dropouts due to cardiovascular adverse events8Risk Difference (M-H, Random, 95% CI)Subtotals only

    8.1 ADHD
124Risk Difference (M-H, Random, 95% CI)0.0 [-0.15, 0.15]

    8.2 No ADHD
7346Risk Difference (M-H, Random, 95% CI)0.01 [-0.03, 0.04]

 9 Dropouts due to psychiatric adverse events7Risk Difference (M-H, Random, 95% CI)Subtotals only

    9.1 ADHD
124Risk Difference (M-H, Random, 95% CI)0.08 [-0.12, 0.29]

    9.2 No ADHD
6266Risk Difference (M-H, Random, 95% CI)-0.02 [-0.06, 0.02]

 
Comparison 5. Subgroup analysis: data publication

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Amphetamine use (UA)7Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 Published data
3138Mean Difference (IV, Random, 95% CI)-0.22 [-0.83, 0.39]

    1.2 Unpublished data
4335Mean Difference (IV, Random, 95% CI)-0.86 [-3.21, 1.50]

 2 Amphetamine use (hair analysis)1Mean Difference (IV, Random, 95% CI)Subtotals only

   2.1 Published data
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 Unpublished data
122Mean Difference (IV, Random, 95% CI)0.53 [-6.02, 7.08]

 3 Sustained abstinence6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Published data
173Risk Ratio (M-H, Random, 95% CI)1.03 [0.49, 2.17]

    3.2 Unpublished data
5486Risk Ratio (M-H, Random, 95% CI)1.13 [0.83, 1.54]

 4 Self reported amphetamine use3Mean Difference (IV, Random, 95% CI)Subtotals only

    4.1 Published data
2104Mean Difference (IV, Random, 95% CI)-2.25 [-7.02, 2.51]

    4.2 Unpublished data
129Mean Difference (IV, Random, 95% CI)7.71 [-5.10, 20.52]

 5 Retention in treatment11791Risk Ratio (M-H, Random, 95% CI)1.01 [0.90, 1.14]

    5.1 Published data
11791Risk Ratio (M-H, Random, 95% CI)1.01 [0.90, 1.14]

   5.2 Unpublished data
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 6 Amphetamine craving (at the end of study)2Std. Mean Difference (IV, Random, 95% CI)Subtotals only

   6.1 Published data
00Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    6.2 Unpublished data
2144Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.44, 0.59]

 7 Dropouts due to any adverse event10Risk Difference (M-H, Random, 95% CI)Subtotals only

    7.1 Published data
5292Risk Difference (M-H, Random, 95% CI)0.00 [-0.04, 0.05]

    7.2 Unpublished data
5348Risk Difference (M-H, Random, 95% CI)0.01 [-0.05, 0.07]

 8 Dropouts due to cardiovascular adverse events8Risk Difference (M-H, Random, 95% CI)Subtotals only

    8.1 Published data
2103Risk Difference (M-H, Random, 95% CI)0.02 [-0.04, 0.09]

    8.2 Unpublished data
6267Risk Difference (M-H, Random, 95% CI)-5.83 [-0.04, 0.04]

 9 Dropouts due to psychiatric adverse events7Risk Difference (M-H, Random, 95% CI)Subtotals only

    9.1 Published data
3152Risk Difference (M-H, Random, 95% CI)-0.03 [-0.08, 0.03]

    9.2 Unpublished data
4138Risk Difference (M-H, Random, 95% CI)-0.01 [-0.07, 0.05]

 
Comparison 6. Subgroup analysis: clinical trial reporting quality (incomplete outcome data)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Amphetamine use (UA)7Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 Low or intermediate risk of bias
3114Mean Difference (IV, Random, 95% CI)-0.79 [-2.55, 0.98]

    1.2 High risk of bias
4359Mean Difference (IV, Random, 95% CI)-0.19 [-0.82, 0.43]

 2 Amphetamine use (hair analysis)1Mean Difference (IV, Random, 95% CI)Subtotals only

   2.1 Low or intermediate risk of bias
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 High risk of bias
122Mean Difference (IV, Random, 95% CI)0.53 [-6.02, 7.08]

 3 Sustained abstinence6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Low or intermediate risk of bias
3205Risk Ratio (M-H, Random, 95% CI)1.21 [0.75, 1.94]

    3.2 High risk of bias
3354Risk Ratio (M-H, Random, 95% CI)1.07 [0.70, 1.63]

 4 Self reported amphetamine use3Mean Difference (IV, Random, 95% CI)Subtotals only

    4.1 Low or intermediate risk of bias
124Mean Difference (IV, Random, 95% CI)0.5 [-4.76, 5.76]

    4.2 High risk of bias
2109Mean Difference (IV, Random, 95% CI)0.07 [-11.39, 11.52]

 5 Retention in treatment11Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Low or intermediate risk of bias
6372Risk Ratio (M-H, Random, 95% CI)0.99 [0.86, 1.13]

    5.2 High risk of bias
5419Risk Ratio (M-H, Random, 95% CI)1.12 [0.83, 1.53]

 6 Amphetamine craving2Std. Mean Difference (IV, Random, 95% CI)Subtotals only

   6.1 Low or intermediate risk of bias
00Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    6.2 High risk of bias
2144Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.44, 0.59]

 7 Dropouts due to any adverse event10Risk Difference (M-H, Random, 95% CI)Subtotals only

    7.1 Low or intermediate risk of bias
3114Risk Difference (M-H, Random, 95% CI)0.03 [-0.04, 0.10]

    7.2 High risk of bias
7526Risk Difference (M-H, Random, 95% CI)-0.00 [-0.04, 0.04]

 8 Dropouts due to cardiovascular adverse events8Risk Difference (M-H, Random, 95% CI)Subtotals only

    8.1 Low or intermediate risk of bias
254Risk Difference (M-H, Random, 95% CI)0.0 [-0.10, 0.10]

    8.2 High risk of bias
6316Risk Difference (M-H, Random, 95% CI)0.01 [-0.03, 0.04]

 9 Dropouts due to psychiatric adverse events7290Risk Difference (M-H, Random, 95% CI)-0.02 [-0.06, 0.02]

    9.1 Low or intermediate risk of bias
254Risk Difference (M-H, Random, 95% CI)0.03 [-0.09, 0.14]

    9.2 High risk of bias
5236Risk Difference (M-H, Random, 95% CI)-0.02 [-0.07, 0.02]

 
Comparison 7. Sensitivity analysis of the safety measures

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Dropouts due to any adverse event7567Risk Ratio (M-H, Random, 95% CI)1.18 [0.63, 2.20]

 2 Dropouts due to cardiovascular adverse events3193Risk Ratio (M-H, Random, 95% CI)1.50 [0.30, 7.58]

 3 Dropouts due to psychiatric adverse events4217Risk Ratio (M-H, Random, 95% CI)0.62 [0.13, 2.99]

 
Comparison 8. Post hoc analysis

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Amphetamine use (UA)7473Mean Difference (IV, Random, 95% CI)-0.26 [-0.85, 0.33]

    1.1 Maintenance
5444Mean Difference (IV, Random, 95% CI)-0.62 [-2.29, 1.06]

    1.2 Relapse prevention
229Mean Difference (IV, Random, 95% CI)-0.21 [-0.84, 0.42]

 2 Amphetamine use (hair analysis)122Mean Difference (IV, Random, 95% CI)0.53 [-6.02, 7.08]

    2.1 Maintenance
122Mean Difference (IV, Random, 95% CI)0.53 [-6.02, 7.08]

 3 Sustained abstinence6559Risk Ratio (M-H, Random, 95% CI)1.12 [0.84, 1.49]

    3.1 Maintenance
5535Risk Ratio (M-H, Random, 95% CI)1.24 [0.88, 1.74]

    3.2 Relapse prevention
124Risk Ratio (M-H, Random, 95% CI)0.89 [0.53, 1.49]

 4 Self reported amphetamine use3133Mean Difference (IV, Random, 95% CI)-0.81 [-6.16, 4.54]

    4.1 Maintenance
3133Mean Difference (IV, Random, 95% CI)-0.81 [-6.16, 4.54]

 5 Retention in treatment11791Risk Ratio (M-H, Random, 95% CI)1.01 [0.90, 1.14]

    5.1 Maintenance
9758Risk Ratio (M-H, Random, 95% CI)1.03 [0.92, 1.16]

    5.2 Relapse prevention
233Risk Ratio (M-H, Random, 95% CI)0.69 [0.41, 1.17]

 6 Amphetamine craving2144Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.44, 0.59]

    6.1 Maintenance
2144Std. Mean Difference (IV, Random, 95% CI)0.07 [-0.44, 0.59]

 7 Dropouts due to any adverse event10640Risk Difference (M-H, Random, 95% CI)0.01 [-0.03, 0.04]

    7.1 Maintenance
8607Risk Difference (M-H, Random, 95% CI)0.00 [-0.03, 0.04]

    7.2 Relapse prevention
233Risk Difference (M-H, Random, 95% CI)0.06 [-0.11, 0.24]

 8 Dropouts due to cardiovascular adverse events8370Risk Difference (M-H, Random, 95% CI)0.01 [-0.03, 0.04]

    8.1 Maintenance
6337Risk Difference (M-H, Random, 95% CI)0.01 [-0.03, 0.04]

    8.2 Relapse prevention
233Risk Difference (M-H, Random, 95% CI)0.0 [-0.14, 0.14]

 9 Dropouts due to psychiatric adverse events7290Risk Difference (M-H, Random, 95% CI)-0.02 [-0.06, 0.02]

    9.1 Maintenance
5257Risk Difference (M-H, Random, 95% CI)-0.02 [-0.06, 0.02]

    9.2 Relapse prevention
233Risk Difference (M-H, Random, 95% CI)0.06 [-0.11, 0.24]

 
Summary of findings for the main comparison. Psychostimulants for amphetamine abuse or dependence

Psychostimulants for amphetamine abuse or dependence

Patient or population: Amphetamine abuse or dependence
Settings: Outpatients
Intervention: Psychostimulants

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlPsychostimulants

Amphetamine use (UA)
Negative urinalyses across the study
Follow-up: 8-12 weeks
The mean of the proportion of amphetamine-negative UA ranged in the control groups from 0.56 to 33.1The mean of the proportion of amphetamine-negative UA ranged in the intervention groups from 0.33 to 36.85473
(7 studies)
⊕⊝⊝⊝
very low1,2,3,4,5
MD -0.26

(-0.85 to 0.33)

Sustained abstinence
Negative urinalyses for at least 3 consecutive weeks
Follow-up: mean 8-12 weeks
Study populationRR 1.12
(0.84 to 1.49)
559
(6 studies)
⊕⊝⊝⊝
very low1,2,3,4,5

220 per 1000247 per 1000
(185 to 328)

Moderate

285 per 1000319 per 1000
(239 to 425)

Retention to treatment
Number of participants who competed treatment
Follow-up: 8-20 weeks
Study populationRR 1.01
(0.9 to 1.14)
791
(11 studies)
⊕⊕⊝⊝
low2,3,4,5,6

489 per 1000494 per 1000
(440 to 557)

Moderate

378 per 1000382 per 1000
(340 to 431)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1The outcome is not influenced by lack of blinding, but high attrition in trials has been noted.
2No statistical heterogeneity was found.
3The studied intervention includes different types of psychostimulants and different doses.
495% CI is wide, and the intervention effect over this outcome can range from no benefit to small effect.
5Funnel plot not suggested publication bias. Statistical power is low in using tests to detect publication bias for this comparison in this review.
6This comparison includes studies with treatment length ranging from 8 to 20 weeks.
 
Table 1. Baseline characteristics of the participants included in the RCT of the meta-analysis

Sample size

n
791

Gender

% male
64.9

Age

Mean age (years)
35.9

Race

% Caucasian

% African-American

% Other
70.5

3.8

25.7

Employment status

% currently employed
58.7

Type of dependence

% methamphetamine dependence

% amphetamine dependence
92.7

7.3

Mean days of use/month

Range
9.3-19.5

Mean length of amphetamine use (years)

Range of mean lifetime amphetamine use
7-15.9

Route of use

% ip

% iv

% in

% oral
59.0

22.8

17.6

0.6

Comorbidities

% nicotine dependent

% ADHD

% opioid dependent

% alcohol dependent

% major depression

% psychotic disorders
72.9

13.9

1.6

1,1

0.8

0

 Abbreviations: ADHD = attention deficit hyperactivity disorder, ip = intrapulmonary, iv = intravenous, in = intranasal. Baseline participant characteristics are presented for those trials reporting this information. Gender, age and type of dependence were available for all studies, whereas opioid dependence and alcohol dependence from 9 studies, psychotic disorders and major depression from 8, employment status from 7, lifetime amphetamine use and ADHD from 6, race from 5 studies and nicotine dependence days of amphetamine use in a month and route of amphetamine use in 4.