Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis

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 (Delta-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 Delta-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 Delta-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls. Delta-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 Delta-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.

Figure 1. Psychotomimetic & Perceptual Alterations Effects

Perceptual Alterations measured by the Clinician and Subject Rated subscales of the Clinician Administered Dissociative Symptoms Scale (T bars indicate S.E.M.s). Frequent users had smaller Δ-9-THC induced increases in CADSS-Clinician Subscale Scores scores and PANSS Total scores relative to controls.

Figure 2. Subjective Effects (VAS: Visual Analog Scale)

Subjective symptoms of ‘high’ and anxiety measured on the Visual Analog Scale (T bars indicate SEMs). ‘high’: Δ-9-THC transiently increased scores on VAS ‘high’: equivalently in both groups. ‘anxiety’: Δ-9-THC transiently increased VAS ‘anxiety’ scores but to a lower extent in frequent users compared to controls.

Figure 3. Learning and Recall (Hopkins Verbal Learning Task)

Immediate and Delayed verbal recall measured by the Hopkins Verbal Learning Task (T bars indicate SEMs). Immediate recall: frequent users performed worse at baseline, but had smaller Δ-9-THC-induced impairments than controls. Delayed recall: Δ-9-THC impaired delayed recall in both groups. Only in frequent users, recall was worse on placebo than the low dose.

Figure 4. Plasma Cortisol and Prolactin

Plasma cortisol and prolactin levels (T bars indicate SEMs). Frequent users showed reduced Δ-9-THC-induced increases in plasma cortisol and lower overall prolactin levels.