Safety and tolerability of oral lisdexamfetamine in adults with methamphetamine dependence: a phase-2 dose-escalation study

Abstract Background: Methamphetamine (MA) dependence is a growing global health issue with no effective pharmacotherapy. Lisdexamfetamine (LDX) is approved for use in the treatment of attention-deficit/hyperactivity disorder (ADHD) and binge eating disorder (BED) in doses ranging from 30 to 70mg/day. LDX has a longer duration of action and lower abuse potential than other amphetamines, and presents a promising candidate for agonist-type treatment of MA dependence. People seeking treatment for MA dependence may require doses of LDX higher than used in ADHD and BED. We examined the safety of LDX at 250mg/day among adults with MA dependence, approximately equivalent to previously trialled doses of dexamphetamine. Methods: We conducted a dose-escalating, phase-2, open label, single-group study of oral LDX at two Australian drug treatment services. Eligible participants were MA dependent adults who reported use of MA on at least 14 of the preceding 28 days. Once daily, supervised LDX doses of 100 to 250mg/day were provided as a single-blinded, ascending-descending dose regimen over 8 weeks. The primary outcomes were safety, drug tolerability, and regimen completion at the end of Week 4 (maximum dose). Participants were followed through to Week 12. Secondary outcomes included: change in MA use; craving; withdrawal; severity of dependence; risk behaviour; change in other substance use; medication acceptability; potential for non-prescription use; adherence; and neurocognitive functioning. Results: Fourteen of 16 participants (87.5%) successfully completed the four week escalation regimen to 250mg/day. Two participants withdrew from the trial in the first week. No participant was withdrawn due to adverse events. MA use decreased significantly (p=0.013) from a median of 21 days (IQR: 16-23) to 13 days (IQR: 11-17) over the four week escalation period.Conclusions: LDX at a dose of up to 250 mg/day was safe and well tolerated in this population, with high retention. Larger trials of LDX as a pharmacotherapy for MA dependence are warranted. Trial Registration : Australian and New Zealand Clinical Trials Registry ACTRN12615000391572.