Methods	Design: placebo-controlled parallel trial
Participants	Participants: methadone-maintained inpatients meeting DSM-III-R criteria for opioid and cocaine dependence (non-depressed AsPD subgroup) Sex: 11 male; 8 female (for the AsPD subgroup) Age: mean 33.0 (SD 4.5) years (for the AsPD subgroup) Unit of allocation: individual participant Number randomised: 19 (desipramine, n = 7; amantadine, n = 8; control, n = 4) (see note 1) Number completing: 11 (desipramine, n = 5; amantadine, n = 3; control, n = 3) (see note 1) Setting: inpatient; single site; USA (Yale) Inclusion criteria: AsPD diagnosis without depression (DSM-III-R; SCID-II); opioid and cocaine dependency (DSM-III-R) Exclusion criteria: concurrent DSM-III-R depression; zidovudine treatment for AIDS; medical contra-indications including asthma, renal dysfunction, high blood pressure and diabetes; current alcoholism; refusal to use adequate birth control if female Ethnicity: white (68%, n = 13) (for the AsPD subgroup) Baseline characteristics: for AsPD subgroup (see note 1): married (74%, n = 14); mean methadone dose 57 (SD 11) mg/day; mean time on methadone 4.5 (SD 2.7) months; mean time using heroin 12.0 (SD 6.2) years; mean time using cocaine 7.5 (SD 6.1) years; mean expenditure on cocaine 1141 (SD 1379) US Dollars/month; lifetime diagnosis alcohol misuse disorder (58%), mean time intoxicated 1.7 (SD 3.6) days/month; mean Addiction Severity Index factor scores: psychiatric, 4.3 (SD 2.4); medical, 3.3 (SD 2.0) ; job, 5.9 (SD 2.7); alcohol, 3.5 (SD 2.5); drug, 8.2 (SD 0.7); family, 5.6 (SD 2.1)
Interventions	Three conditions: amantadine/ desipramine/ placebo amantadine (oral, 300 mg, once daily) (n = 8 randomised) desipramine (oral, 150 mg, once daily) (n = 7 randomised) placebo (oral, once daily) (n = 4 randomised) Duration of intervention: 12 weeks Duration of trial: 12 weeks Length of follow up: participants were not followed up beyond the end of the intervention period Dose adjustment: no information given
Outcomes	Primary outcomes None Secondary outcomes Leaving the study early: treatment retention in the first and the last 6 weeks of treatment Substance misuse: urinalysis to detect cocaine-free urine samples (on-site enzyme-multiplied immunoassay (EMIT) system); total US Dollars/week spent on cocaine (self report) Other outcomes Depression (Beck Depression Inventory)
Notes	1. Study also reported data for an additional 75 participants without AsPD; these data are not included
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Investigators described a “ … randomised, double-blind trial …” (p.32, col 2). No further details reported. Insufficient information to permit judgement on adequacy of sequence generation. Clarification has been requested from the trial investigators, but no further information was available at the time this review was prepared
Allocation concealment?	Unclear	Investigators described a “ … randomised, double-blind trial …” (p.32, col 2). No further details reported. Insufficient information to permit judgement on adequacy of allocation concealment. Clarification has been requested from the trial investigators, but no further information was available at the time this review was prepared
Blinding? of participants	Unclear	Investigators described the trial as “ double-blind ” (p.32, col 2). No further details reported. Clarification has been requested from the trial investigators, but no further information was available at the time this review was prepared
Blinding? of personnel	Unclear	Investigators described the trial as “ double-blind ” (p.32, col 2). No further details reported. Clarification has been requested from the trial investigators, but no further information was available at the time this review was prepared
Blinding? of outcome assessors	Unclear	Investigators describe the trial as “ double-blind ” (p.32, col 2). No further details reported. Clarification has been requested from the trial investigators, but no further information was available at the time this review was prepared
Incomplete outcome data addressed? All outcomes	No	Incomplete outcome data arise from participants not completing the study and applies to all measured outcomes. The investigators reported that “fifteen patients left the study for medication non-compliance, four for incarceration, and one for medical reasons” (p. 32, col 2), but these figures apply to the whole sample including non-AsPD participants. For the AsPD subgroup, 5/8 (63%) were missing from the amantadine group, 2/7 (29%) were missing from the desipramine group and 1/4 (25%) missing from the control group - all for reasons that are unclear and no breakdown by experimental group was provided. Clarification has been requested from the trial investigators but no further information was available at the time this review was prepared
Free of selective reporting?	Yes	Study protocol is not available but it seems clear that the published report includes all expected outcomes, including those that were pre-specified
Free of other bias?	No	Two potential sources of bias were identified. First, it is not clear whether patients continued to receive general substance misuse counselling and behavioural contingency management during this trial, and if so whether this was similar for both treatment and control conditions. This is important since the latter involves monetary incentives in return for a clean urine sample. Differences in percentages of cocaine-free urine samples may be related to that rather than the effects of medications. Second, urinanalysis was carried out twice weekly, but the detectability window for cocaine is 6-8 hours (Wolff 1999) which increases the possibility of false negative results. It is noteworthy that four participants meeting criteria for AsPD plus dysthymia were included in the non-ASP group and so their results are not included; investigators justify this because “the diagnosis of depression has been reported to favourably affect the treatment outcome of patients with antisocial personality disorder” (page 32, col 1)