DOI : 10.2174/13816128113199990432

Abstract :

Background : In recent years, growing concerns about the effects of cannabis use on mental health have renewed interest in cannabis research. In particular, there has been a marked increase in the number of neuroimaging studies of the effects of cannabinoids. We conducted a systematic review to assess the impact of acute cannabis exposure on brain function in humans and in experimental animals.

Methods : Papers published until June 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 pharmacological challenge studies involving the acute experimental administration of cannabinoids in occasional or naïve cannabis users, and naïve animals were considered.

Results : Two hundred and twenty-four studies were identified, of which 45 met our inclusion criteria. Twenty-four studies were in humans and 21 in animals. Most comprised studies of the acute effects of cannabinoids on brain functioning in the context of either resting state activity or activation during cognitive paradigms. In general, THC and CBD had opposite neurophysiological effects. There were also a smaller number of neurochemical imaging studies: overall, these did not support a central role for increased dopaminergic activity in THC-induced psychosis. There was a considerable degree of methodological heterogeneity in the imaging literature reviewed.

Conclusion : Functional neuroimaging studies have provided extensive evidence for the acute modulation of brain function by cannabinoids, but further studies are needed in order to understand the neural mechanisms underlying these effects. Future studies should also consider the need for more standardised methodology and the replication of findings.

Keywords : Animals, cannabis, cannabis users, THC, CBD, brain function, neuroimaging, systematic review, CB1 cannabinoid receptors.

INTRODUCTION
Cannabis remains the most commonly used illegal drug with estimated annual prevalence of 125 to 203 million people worldwide [1]. Following steady increases throughout the 1990s and early 2000s, the prevalence of cannabis use has stabilized more recently but still remains disturbingly high [1, 2]. The extract of Cannabis sativa contains multiple compounds, with over 60 different cannabinoids reported, of which delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most studied ones [3, 4]. THC, the main psychoactive constituent of cannabis, is thought to be responsible for most of its psychotropic effects [5]. Its administration in healthy subjects can induce intoxication, anxiety, psychotic symptoms [6], as well as modulatory effects on different cognitive domains [4], such as learning and memory [7], psychomotor control [8] and attention [9]. In contrast, CBD is the major non psychotomimetic constituent of cannabis, and it has been found to induce anxiolytic effects both in animals and humans [10, 11], and even antipsychotic properties [12, 13] without impairing memory
or other cognitive functions [4, 14]. Thus, CBD may be potentially able to reduce some symptomatic effects of THC such as anxiety and psychosis [12]. However, it is relevant to note that concentrations of THC and CBD in the different preparations of cannabis (marihuana, hashish, skunk) have changed in the last few years, with claims of a sharp increase in the THC/CBD rate [1, 15]. This may result in a heightened risk of psychiatric symptoms, such as psychosis [16, 17].

Although it is thought that the endocannabinoid system may play a critical role in the mechanism of action of cannabis, the neurophysiological basis of the different and even opposite psychiatric and cognitive effects of cannabis outlined above still remains uncertain. The vast majority of CB1 receptors are located in the central nervous system, particularly in brain regions that are critical for executive functioning, attention, memory and reward processing, such as the prefrontal cortex, anterior cingulate cortex, basal ganglia, medial temporal areas (e.g., hippocampus and amygdala) and cerebellum [18]. CB1 receptors are mainly localized in gammaaminobutyric acid (GABA) and glutamatergic terminals, where they inhibit neurotransmitter release [19, 20]. However, CB1 receptor activation also affects the release of other neurotransmitters, such as dopamine, which may be related to the reinforcing effects of cannabinoids [21], as well as to an increased risk of psychosis [22]. CB2 receptors are primarily expressed in peripheral cells of the immune system, but recent evidence indicates that they are also present within the central nervous system [23]. Although the effects of THC are thought to be mediated by a partial agonism at the central CB1 receptors [24], CBD has low affinity for CB1 receptors [25] and its precise molecular mechanism of action, which may involve a wide variety of mechanisms [4, 26], remains unclear.

Neuroimaging techniques provide a highly useful approach to investigate the neural basis of the effects of cannabinoids. In recent years, renewed interest in gene-environment interplay, such as the cannabis-psychosis link [27-29], and the potential therapeutic effect of certain cannabinoids (such as CBD [12]), have led to a significant increase in the number of human studies using neuroimaging techniques to determine the functional and structural brain effects of cannabinoids. Several recent reviews have examined this topic, especially regarding chronic cannabis use [30-38].

Additionally, pharmacological challenge studies involving the acute experimental administration of cannabinoids or their synthetic equivalents, in combination with neuroimaging methods, offer novel opportunities to study in vivo the effects of these substances on brain functioning [30]. In the present review, we have conducted a systematic literature search of neuroimaging studies investigating the acute effects of cannabinoids on brain functioning both in animals and in humans (naïve or occasional users). These papers have examined patterns of change in dopamine release, brain activation or cerebral blood flow either at rest or during different cognitive paradigms, after acute experimental administration of cannabinoids. Papers published until June 2012 were included, following a comprehensive search strategy and pre-determined protocol in accordance with PRISMA guidelines [39].

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