Δ-9-tetrahydrocannabinol (Δ-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 Δ-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 Δ-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 Δ-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Δ-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Δ-9-THC. Δ-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 Δ-9-tetrahydrocannabinol. Δ-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 Δ-9-THC.
In healthy individuals, Δ-9-tetrahydrocannabinol (Δ-9-THC), the main psychoactive ingredient of the Cannabis sativa plant, can induce psychotic symptoms and anxiety, and can impair memory (D’Souza et al, 2004) and psychomotor control (McDonald et al, 2003; Ramaekers et al, 2006). In patients with schizophrenia, Δ-9-THC may exacerbate existing psychotic symptoms, anxiety and memory impairments (D’Souza et al, 2005), and Δ-9-THC is thought to be the ingredient responsible for the increased risk of developing schizophrenia following regular cannabis use (Moore et al, 2007). In contrast, Cannabidiol (CBD), the other major psychoactive constituent of C. sativa, has anxiolytic (Crippa et al, 2004) and possibly antipsychotic properties (Zuardi et al, 2006; Morgan and Curran, 2008; Zuardi, 2008), does not impair memory or other cognitive functions (Fadda et al, 2004; Ilan et al, 2005). Although CBD has been shown to have neuroprotective effects (Hampson et al, 1998; Mechoulam et al, 2002; Lastres-Becker et al, 2005), Δ-9-THC may have neurotoxic as well as neuroprotective effects (Sarne and Mechoulam, 2005). Moreover, when co-administered with Δ-9-THC, CBD may be able to reduce some of the symptomatic effects of Δ-9-THC like anxiety and paranoia (Karniol et al, 1974; Dalton et al, 1976; Zuardi et al, 1982). CBD may thus have therapeutic potential as a treatment for cannabis-induced psychopathology, and as an anxiolytic and an antipsychotic (Zuardi, 2008). However, none of the earlier studies (Karniol et al, 1974; Dalton et al, 1976; Zuardi et al, 1982) had used standardized rating scales to formally assess psychotic symptoms.
The neural basis for these distinct effects of Δ-9-THC and CBD on psychiatric symptoms and cognitive function is unclear. Recent data from experimental animals and in vitro studies suggest that Δ-9-THC and CBD may have opposing effects on brain cannabinoid (CB1) receptors (Pertwee, 2008). Although the effects of Δ-9-THC are thought to be mediated by a partial agonism at the central CB1 receptors (Pertwee, 2008), the precise molecular mechanism of action of CBD is unclear and may involve a wide variety of mechanisms (Mechoulam et al, 2007). In the absence of this information, examination of the downstream effects of CBD in the brain in terms of neural activation and behavior provides another mode of unravelling its effects. To date, functional neuroimaging studies of Δ-9-THC and CBD in man have examined the effects of each compound separately, but have not compared them with each other directly (Borgwardt et al, 2008; Phan et al, 2008; Bhattacharyya et al, 2009; Fusar-Poli et al, 2009). In this study, we sought to address this issue by using functional magnetic resonance imaging (fMRI) to contrast the acute effects of Δ-9-THC and CBD on regional brain function and the mental state in the same healthy volunteers. We then examined their interaction at the behavioral level, by assessing the extent to which pretreatment with CBD could prevent the acute symptomatic effects of subsequently administered Δ-9-THC. The first hypothesis tested was that Δ-9-THC and CBD would have opposite effects on regional brain activation during a set of four tasks that engaged cognitive processes known to be affected by cannabis use: verbal memory, response inhibition, sensory processing, and emotional processing (Hall and Solowij, 1998). Our second hypothesis was that CBD pretreatment would diminish the effects of Δ-9-THC-induced psychotic symptoms.