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

J Clin Pharmacol. 2017 Feb;57(2):151-160. doi: 10.1002/jcph.789. Epub 2016 Aug 4.


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.

Keywords: addiction medicine; central nervous system; clinical pharmacology; clinical trials; drug metabolism; drug-drug interactions; pharmacokinetics.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Intranasal
  • Adult
  • Berberine Alkaloids / adverse effects
  • Berberine Alkaloids / pharmacokinetics*
  • Chromatography, High Pressure Liquid
  • Cocaine / administration & dosage
  • Cocaine / pharmacology
  • Cocaine-Related Disorders / metabolism*
  • Dopamine Antagonists / adverse effects
  • Dopamine Antagonists / pharmacokinetics*
  • Double-Blind Method
  • Electrocardiography / drug effects
  • Humans
  • Male
  • Middle Aged
  • Spectrometry, Fluorescence


  • Berberine Alkaloids
  • Dopamine Antagonists
  • tetrahydropalmatine
  • Cocaine