The effects of oral flupenthixol and intramuscular (i.m.) flupenthixol decanoate in combination with intravenous (i.v.) cocaine were evaluated in male cocaine abusers. Participants resided at an inpatient research unit for 27 days followed by an 11-day outpatient period. Oral flupenthixol (2.5 or 5.0 mg; p.o.) followed by flupenthixol decanoate (10 or 20 mg; i.m.) and placebo were investigated in individuals who were randomly assigned to one of three groups under double-blind conditions (placebo, low or high dose flupenthixol). During the inpatient period, participants had four fixed cocaine dosing sessions; each session they were administered four doses of i.v. cocaine (approx. 48 mg/70 kg), spaced 14 min apart. These sessions occurred once before medication (baseline phase), once following oral medication (oral phase), and twice following intramuscular medication (IM phase). Out of 23 participants, 18 completed the study; 4 of the 5 non-completers were in the high dose flupenthixol group. Overall, there were few subjective, cardiovascular, or cocaine pharmacokinetic differences between the placebo group and the low dose flupenthixol group, indicating that the low dose of flupenthixol was well tolerated, but ineffective. In the high dose flupenthixol group, two out of seven individuals (29%) experienced a dystonic reaction following oral flupenthixol and were medically discharged. Taken together, these findings indicate that flupenthixol is not a good candidate for treating cocaine abusers.