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Abstract
Use of Cannabis, the most widely used illicit drug worldwide, is associated with acute anxiety, and anxiety disorders following regular use. The precise neural and receptor basis of these effects have not been tested in man. Employing a combination of functional MRI (fMRI) and positron emission tomography (PET), we investigated whether the effects of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive ingredient of cannabis, on anxiety and on amygdala response while processing fearful stimuli were related to local availability of its main central molecular target, cannabinoid-1 (CB1) receptors in man. Fourteen healthy males were studied with fMRI twice, one month apart, following an oral dose of either delta-9-THC (10 mg) or placebo, while they performed a fear-processing task. Baseline availability of the CB1 receptor was studied using PET with [11C]MePPEP, a CB1 inverse agonist radioligand. Relative to the placebo condition, delta-9-THC induced anxiety and modulated right amygdala activation while processing fear. Both these effects were positively correlated with CB1 receptor availability in the right amygdala. These results suggest that the acute effects of cannabis on anxiety in males are mediated by the modulation of amygdalar function by delta-9-THC and the extent of these effects are related to local availability of CB1 receptors.
Highlights
Cannabis is the world’s most commonly used illicit substance[1]
We recently reported that the anxiogenic effects of delta-9-THC in humans were related to its effect on neural activity in the amygdala[3], a region that plays a critical role in mediating anxiety[11] and is rich in CB1 receptors[12]
There was no significant effect of interaction (p = 0.24) between drug treatment and emotional valence on Skin conductance response (SCR) amplitude, the effect of emotional valence on SCR amplitude was in opposite direction in the two drug conditions, such that while the amplitude of SCR was greater while viewing fearful faces as opposed to neutral faces under the placebo condition, this was opposite direction under the influence of delta-9-THC
Summary
Cannabis is the world’s most commonly used illicit substance[1]. most recreational users smoke cannabis for its relaxing effects, the drug has a range of adverse effects including the induction of acute anxiety[2,3,4,5] and, development of anxiety disorders in regular users[6]. Using neuroanatomically localized microinjection of drugs, studies in freely moving rodents have linked anxiogenic effects of delta-9-THC to a specific CB1 receptor-dependent effect in the amygdala, while anxiolytic effects have been linked to its effects in the prefrontal cortex or hippocampus[9] It is unclear whether the effects of delta-9-THC on anxiety and on amygdala function during the processing of fearful stimuli are related to local availability of the CB1 receptor in humans. In the present study, we investigated whether the acute effects of delta-9-THC on anxiety and on amygdala function as measured using fMRI during the processing of fear were related to availability of CB1 receptors in the amygdala in an independent sample of healthy male volunteers, with minimal previous cannabis and other illicit drug use. We predicted that there would be a direct correlation between baseline CB1 availability in the amygdala and effect of delta-9-THC on anxiety and amygdala response during the processing of fear, with greater CB1 availability being linked to greater effect of delta-9-THC on anxiety and amygdala activity
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