Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology

Abstract

Delta-9-tetrahydrocannabinol (Delta-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects. We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether Delta-9-THC and CBD had opposite effects on regional brain function. We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by Delta-9-THC. Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of Delta-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Delta-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Delta-9-THC. Delta-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by Delta-9-tetrahydrocannabinol. Delta-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of Delta-9-THC.

Figure 1

Cognitive tasks performed during the fMRI experiments: (a) verbal memory, (b) viewing fearful faces, (c) response inhibition, and (d) visual processing.

Figure 2

Plots showing changes in psychotic symptoms as indexed by PANSS positive symptoms subscale (a), anxiety as indexed by the State Trait Anxiety Inventory (STAI) state (b), VAMS tranquilization or calming subscale (c) following oral administration of Δ-9-THC, CBD, or placebo during the fMRI experiments.

Figure 3

(a) Opposite effects of Δ-9-THC and CBD on prefrontal and striatal activation during word retrieval. The left side of the brain is shown on the left side of the images. (b) The bar graph (mean±SEM) shows that striatal activation (x axis; arbitrary units) in (a) was attenuated by Δ-9-THC but augmented by CBD. (c) Opposite effects of Δ-9-THC and CBD on amygdalar activation while subjects viewed fearful faces. The left side of the brain is shown on the left side of the images. (d) The bar graph (mean±SEM) shows that amygdalar activation (x axis; arbitrary units) in (c) was augmented by Δ-9-THC and placebo but attenuated by CBD.

Figure 4

(a) Opposite effects of Δ-9-THC and CBD on parahippocampal activation during a response inhibition task. The left side of the brain is shown on the left side of the images. (b) The bar graph (mean±SEM) shows that left parahippocampal activation (x axis; arbitrary units) in (a) was attenuated by Δ-9-THC but augmented by CBD. (c) Opposite effects of Δ-9-THC and CBD on temporal activation during auditory processing. The left side of the brain is shown on the left side of the images. (d) The bar graph (mean±SEM) shows that activation (x axis; arbitrary units) in the right temporal cortex in (c) was attenuated by Δ-9-THC relative to placebo but augmented by CBD. (e) Opposite effects of Δ-9-THC and CBD on occipital activation during visual processing. The left side of the brain is shown on the left side of the images. (f) The bar graph (mean±SEM) shows that activation (x axis; arbitrary units) in the right occipital cortex in (e) was attenuated by Δ-9-THC relative to placebo but augmented by CBD.

Figure 5

(a) Plots (mean±SEM) showing that pretreatment with CBD attenuates the severity of psychotic symptoms (PANSS positive subscale) induced by Δ-9-THC. Administration of Δ-9-THC, 1.25 mg IV (red arrow) was immediately preceded by administration of either placebo or CBD, 5 mg IV (black arrow). (b) Plots showing PANSS positive subscale ratings for individual subjects 30 min after administration of Δ-9-THC following placebo pretreatment and CBD pretreatment. The corresponding rating at ‘time 0' (before the administration of Δ-9-THC) for all the subjects under both the pretreatment conditions was 8 (not shown here). The color reproduction of this figure is available on the html full text version of the manuscript.