1. ¹Schizophrenia Biological Research Center, VA Connecticut Healthcare System, West Haven, CT, USA
2. ²Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT, USA
3. ³Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
4. ⁴Division of Biostatistics, Department of Epidemiology and Public Health, Yale University, New Haven, CT, USA
5. ⁵Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA
6. ⁶The Nathan Kline Institute, Orangeburg, NY, USA

Correspondence: Professor DC D'Souza, Psychiatry Service, 116A, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516, USA. Tel: +1 203 932 5711 ext. 2594, 2571; Fax: +1 203 937 4860; E-mail: deepak.dsouza@yale.edu

Received 17 August 2007; Revised 23 October 2007; Accepted 28 October 2007; Published online 9 January 2008.

Abstract

Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis. Delta-9-Tetrahydrocannabinol (-9-THC) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals. Whether people who frequently use cannabis are either protected from or are tolerant to these effects of -9-THC has not been established. In a 3-day, double-blind, randomized, placebo-controlled study, the dose-related effects of 0, 2.5, and 5 mg intravenous -9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls. -9-THC (1) produced transient psychotomimetic effects and perceptual alterations; (2) impaired memory and attention; (3) increased subjective effects of 'high'; (4) produced tachycardia; and (5) increased serum cortisol in both groups. However, relative to controls, frequent users showed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol increasing effects of -9-THC but not to its euphoric effects. Frequent users also had lower prolactin levels. These data suggest that frequent users of cannabis are either inherently blunted in their response to, and/or develop tolerance to the psychotomimetic, perceptual altering, amnestic, endocrine, and other effects of cannabinoids.