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Pharmacokinetics and Safety Assessment of l‐Tetrahydropalmatine in Cocaine Users: A Randomized, Double‐Blind, Placebo‐Controlled Study

Cocaine use disorder (CUD) remains a significant public health challenge. l‐Tetrahydropalmatine (l‐THP), a well‐tolerated and nonaddictive compound, shows promise for the management of CUD. Its pharmacologic profile includes blockade at dopamine and other monoamine receptors and attenuation of cocaine self‐administration, reinstatement, and rewarding properties in rats. This study evaluated the safety of l‐THP in human cocaine users and its influence on the safety and pharmacokinetics (PK) of cocaine. Twenty‐four cocaine‐using adult men were randomized to receive l‐THP (30 mg twice a day orally) or placebo double‐blind for 4 days, with an intranasal cocaine (40 mg) challenge on the fourth day. Safety and tolerability were evaluated using vital signs, ECG, clinical laboratory tests, and standardized self‐report instruments. Peripheral venous blood was collected periodically and later assayed for l‐THP and cocaine using highly sensitive and specific ultraperformance liquid chromatography‐fluorescence detection (UPLC‐FLD) methods. Twenty subjects completed the study, of whom 19 provided complete PK data. The short 3.5‐day course of l‐THP was safe and well tolerated and did not affect cocaine's PK or its acute cardiovascular effects. The cocaine AUC0→∞ was 211.5 and 261.4 h·ng/mL, and the Cmax was 83.3 and 104.5 ng/mL for the l‐THP and placebo groups, respectively. In addition there were no significant differences in the number of side effects reported in each group (l‐THP group 22 [48%], placebo group 24 [52%]) or vital signs including, heart rate, blood pressure, complete blood count, or ECG. These findings suggest that oral THP has promise for further development as a treatment for CUD.