Modulation of intravenous cocaine effects by chronic oral cocaine in humans
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Rationale: Agonist therapies have proven effective for the treatment of substance dependence disorders; limited data is available on their feasibility for treating cocaine dependence. Objectives: This laboratory study was designed to test the safety and utility of employing an agonist substitution therapy for the treatment of cocaine dependence in humans. Methods: Oral cocaine served as the agonist treatment and was administered chronically over a range of doses to volunteers with cocaine abuse histories (n=8). Oral capsules were administered daily under blind conditions (q.i.d.) during this 5-week inpatient study using a dose-rising sequence (0 mg 10 days; 25 mg 3 days, 50 mg 4 days, 100 mg 10 days, 0 mg 7 days). During each of these oral dosing periods, an i.v. cocaine challenge (0, 25, and 50 mg, 1 h apart) was administered at least once. Physiological, subjective and pharmacokinetic measures were collected before and after i.v. drug administration; additional measures were collected daily. Results: Oral cocaine produced no subjective effects or signs of toxicity but produced dose-related physiological effects. Significant interactions between oral and i.v. cocaine were observed; cocaine (100 mg, p.o.) significantly decreased responses to the 25-mg but not the 50-mg dose of i.v. cocaine for heart rate, mydriasis, and some subjective measures. There was no evidence of significant additive effects, although heart rate responses to i.v. cocaine were exaggerated during the final wash-out period. Conclusions: These data indicate that treatment with a cocaine "agonist" – in this case oral cocaine – can modestly attenuate the subjective and physiological responses to cocaine in humans under conditions that are safely tolerated.
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