In healthy men with minimal prior cannabis use, the two main psychoactive compounds in cannabis had opposite effects on anxiety and brain activity. Delta9-tetrahydrocannabinol (THC) increased anxiety, intoxication, sedation, and psychotic symptoms, while cannabidiol (CBD) showed a trend toward reducing anxiety. When participants viewed intensely fearful faces, THC increased skin conductance fluctuations (a measure of autonomic arousal), whereas CBD decreased them. CBD also dampened brain activation in the amygdala and anterior and posterior cingulate cortex, and this suppression correlated with reduced arousal. THC mainly altered activation in frontal and parietal areas. These distinct neural effects may explain why cannabis can both relieve and provoke anxiety.
Acute administration of 300 mg of cannabidiol (CBD) reduced subjective anxiety after a public speaking test in healthy adults, while 100 mg and 900 mg did not, confirming an inverted U-shaped dose-response curve similar to that seen in animal studies. Clonazepam (1 mg) also reduced anxiety but caused more sedation and smaller increases in blood pressure compared to CBD 300 mg. The public speaking test itself increased anxiety, heart rate, and blood pressure across all groups.
In a rat model of schizophrenia-like symptoms induced by ketamine, the combination of cannabidiol and sodium nitroprusside given during brain development prevented hyperactivity and memory problems in both sexes, while each drug alone had limited effects. The model produced different symptoms in males and females: females showed greater hyperactivity and long-term memory deficits, whereas males showed reduced pleasure-seeking and short-term memory impairments. The combined treatment was more effective in females, and distinct behavioral patterns were seen between sexes. This suggests that a combination of these two compounds may offer a sex-specific preventive strategy for schizophrenia symptoms.
Mice lacking the PI3Kγ gene did not respond to standard doses of ketamine or to classic antidepressants such as imipramine and fluoxetine, as measured by the forced swimming test. This unresponsiveness required a chronic deficiency of the PI3Kγ-mediated pathway, not just acute inhibition. The findings suggest PI3Kγ plays a role in antidepressant activity and may be involved in treatment resistance observed in some patients with major depressive disorder.