Harrison‐Read 1996.

Methods	Study design: Randomised controlled trial Study grouping: Parallel group Blinding: Double Duration: 3 weeks Single‐centre
Participants	Baseline characteristics Flumazenil IV challenge Male, N (%): 1 (25) Age, mean (SD): 46 Years of benzodiazepine use, mean (SD): 8.25 Placebo Male, N (%): 2 (33) Age, mean (SD): 42.3 Years of benzodiazepine use, mean (SD): 8.5 Inclusion criteria: People were recruited to the study if they had been taking benzodiazepines in usual therapeutic doses (< 30 mg per day of diazepam or equivalent) for 3 months or more, and if they had experienced withdrawal problems on discontinuing medication. Exclusion criteria: (i) regular intake of any other psychotropic medication, (ii) a diagnosis of schizophrenia, epilepsy, or cardiorespiratory disease Pretreatment: No significant pretreatment differences
Interventions	Intervention characteristics Flumazenil IV challenge 1 mg injected over 30 s, followed by an individually tailored phased withdrawal schedule which, if followed correctly, would produce complete abstinence (100% dose reduction) after 3 weeks following the challenge test(N = 4) Placebo (vehicle solution alone) followed by identical benzodiazepine taper schedule(N = 6)
Outcomes	Benzodiazepine dose reduction of 70% Serious adverse events Benzodiazepine mean dose Benzodiazepine withdrawal symptoms: BWSQ Non‐serious adverse events
Identification	Sponsorship source: Roche Products Ltd supplied unmarked ampoules of flumazenil and vehicle solution and a grant towards the cost of the project. Country: UK Setting: Outpatients (inpatients when receiving flumazenil challenge) Declarations of interest: Not mentioned Comments: The study was approved by the local ethics committee but, owing to the unexpectedly severe reactions shown in some participants, it was felt to be unethical to continue with the study after 10 participants had been tested using the original protocol. Author's name: Harrison‐Read PE Institution: Academic Unit of Psychiatry, St Charles Hospital, Exmoor Street, London W10 6DZ Email: Address: Academic Unit of Psychiatry, St Charles Hospital, Exmoor Street, London W10 6DZ
Notes	Study discontinued due to unacceptable adverse effects (marked panic reaction in the 4 participants who received flumazenil), beginning within 30 seconds of the end of the injection.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "High risk and low risk subjects were allocated separately at random to placebo or flumazenil challenge by an independent pharmacist." Comment: Description of how the sequence was generated was insufficient.
Allocation concealment (selection bias)	Low risk	Comment: Allocation was done by independent pharmacist.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "This ’challenge test’ was carried out double‐blind, with both subject and experimenter being unaware of the identify of the substance being injected" Comment: Described as double‐blind and using placebo
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "Immediately afterwards, the subject began filling in the BWSQ and the MRS, and then repeated these measures at 5, 15, 25, 35, 45 and 60 min post‐injection. Pulse and blood pressure were recorded as before" Comment: Description is insufficient to judge the risk of bias.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: All randomised participants analysed.
Selective reporting (reporting bias)	Low risk	Comment: No reason to suspect selective outcome reporting
Other bias	High risk	Comment: As the reaction to acute challenge with flumazenil proved to be unexpectedly severe, the study was stopped after only 10 participants had been recruited for the study: 4 were allocated to the flumazenil group and 6 to the placebo group. Despite separately randomising high‐ and low‐risk participants, the early cessation of the study led to unequal distribution between the 2 treatment groups: 1 out of the 4 participants in the flumazenil group and 3 out of the 6 in the placebo group were high‐risk participants. In addition, the study was supported by a company.