Animal and human studies indicate that cannabidiol (CBD), a major constituent of cannabis, has anxiolytic properties. However, no study to date has investigated the effects of this compound on human pathological anxiety and its underlying brain mechanisms. The aim of the present study was to investigate this in patients with generalized social anxiety disorder (SAD) using functional neuroimaging. Regional cerebral blood flow (rCBF) at rest was measured twice using (99m)Tc-ECD SPECT in 10 treatment-naïve patients with SAD. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping. Relative to placebo, CBD was associated with significantly decreased subjective anxiety (p < 0.001), reduced ECD uptake in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus (p < 0.001, uncorrected), and increased ECD uptake in the right posterior cingulate gyrus (p < 0.001, uncorrected). These results suggest that CBD reduces anxiety in SAD and that this is related to its effects on activity in limbic and paralimbic brain areas.

Ingestion of cannabis can modulate anxiety levels, although the direction of this effect is variable. Long-term cannabis use has been associated with anxiety symptoms,^1-4 panic attacks,⁵ and an increased risk of anxiety disorders,^6-8 although the latter remains controversial.^9,10 Acute increases in anxiety can also occur following cannabis use.^11,12 However, cannabis use can also lead to sedation and relaxation, with users often reporting that they take the drug to alleviate psychosocial stress, anxiety, and agoraphobia,^2,13-15 increasing the likelihood of subsequent cannabis abuse.^11,16 Also, patients with psychotic disorders report that they use cannabis to reduce the anxiety associated with psychotic symptoms^17,18 and increased anxiety is a feature of withdrawal from regular cannabis use.¹⁹ There is thus evidence that cannabis can have both anxiogenic and anxiolytic effects. These apparently conflicting observations may partly reflect the fact that Cannabis sativa contains multiple compounds that may have different psychoactive properties.²⁰ In particular, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the most abundant and both can modulate anxiety. Immediate administration of Δ9-THC can increase anxiety²¹ but has also been reported to reduce anxiety and improve sleep.^22,23 This may parallel evidence from studies in experimental animals reporting that low doses of Δ9-THC have anxiolytic effects whereas high doses are anxiogenic.^24-26 In contrast, CBD has anxiolytic effects in both animals and humans,^27-31 and when coadministered with Δ9-THC, it can reduce the anxiety and psychotic symptoms induced by the latter cannabinoid.³² These differences in the behavioral effects of Δ9-THC and CBD are paralleled by differences in their mechanism of action at the molecular level. Δ9-Tetrahydrocannabinol binds to neuronal CB1 receptors,³³ which are found on GABAergic and glutamatergic neurons throughout the brain and are thought to be receptors for endogenous anandamide.^34-36 Since CBD has a very low affinity for the cannabinoid CB1 receptor^37,38 and does not bind to benzodiazepine receptors,²⁹ the molecular mechanisms underlying its anxiolyticlike activity are still unclear. It may activate vanilloid receptors and inhibit the cellular uptake and enzymatic hydrolysis of anandamide,^39,40 activate serotonin 5HT_1A receptors,⁴¹ and inhibit uptake of adenosine.⁴²

The growing concern about cannabis use, the most commonly used illicit drug worldwide, has led to a significant increase in the number of human studies using neuroimaging techniques to determine the effect of cannabis on brain structure and function. We conducted a systematic review to assess the evidence of the impact of chronic cannabis use on brain structure and function in adults and adolescents. Papers published until August 2012 were included from EMBASE, Medline, PubMed and LILACS databases following a comprehensive search strategy and pre-determined set of criteria for article selection. Only neuroimaging studies involving chronic cannabis users with a matched control group were considered. One hundred and forty-two studies were identified, of which 43 met the established criteria. Eight studies were in adolescent population. Neuroimaging studies provide evidence of morphological brain alterations in both population groups, particularly in the medial temporal and frontal cortices, as well as the cerebellum. These effects may be related to the amount of cannabis exposure. Functional neuroimaging studies suggest different patterns of resting global and brain activity during the performance of several cognitive tasks both in adolescents and adults, which may indicate compensatory effects in response to chronic cannabis exposure. However, the results pointed out methodological limitations of the work conducted to date and considerable heterogeneity in the findings. Chronic cannabis use may alter brain structure and function in adult and adolescent population. Further studies should consider the use of convergent methodology, prospective large samples involving adolescent to adulthood subjects, and data-sharing initiatives.