Oral ketamine as a positive control in abuse liability studies

Abstract

Background NMDA receptor antagonists are currently being developed for the treatment of several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and neuropathic pain conditions. Some high affinity NMDA receptor antagonists (e.g. phencyclidine and ketamine) have dissociative properties and are established agents of abuse. Other NMDA receptor antagonists such as memantine, amantadine or dextromethorphan do not exhibit significant potential for abuse. Therefore based on the pre-clinical and/or clinical pharmacological profiles, a clinical abuse potential evaluation may be required for a new NMDA receptor antagonist or a new formulation of an existing NMDA receptor antagonist. Positive (abused) control drugs such as ketamine are required in the conduct of human abuse liability studies. Most published studies have evaluated intravenous ketamine as a comparator drug. Purpose The present study was designed to assess the subjective effects of oral ketamine. Methods Twenty-nine healthy, experienced recreational drug users were given d-amphetamine (d-AMP) 20 mg p.o. in a single-blinded within-day qualifying day in which they could receive three doses of placebo and one dose of d-AMP. Sixteen subjects reliably reported liking d-AMP and 11 subjects (9 males, 2 females) entered a single-blind controlled dose escalating study in which they received ketamine 65 mg, 100 mg or 150 mg (intravenous formulation dissolved in juice) or placebo-juice orally. Subjective and physiologic measures were evaluated for up to 8 hours post-drug administration. Results Graded dose related effects and differences from placebo were reported across a wide range of abuse measures (e.g. VAS feeling high, VAS liking, subjective price value, Cole ARCI euphoria). Pharmacologic effect characteristics of the class (e.g. floating, confusion) were also found. Ketamine 65 mg was readily distinguished from placebo on most measures. Doses of 150 mg were well tolerated in the 4 subjects who received this dose. Conclusions These pharmacological data suggest that oral doses of ketamine (60 -150 mg) can be used as positive controls for studies for NMDA receptor antagonist mediated effects. Clinical Pharmacology & Therapeutics (2004) 75, P72–P72; doi: 10.1016/j.clpt.2003.11.271