Neural Mechanisms for the Cannabinoid Modulation of Cognition and Affect in Man : A Critical Review of Neuroimaging Studies

Sagnik Bhattacharyya, Zerrin Atakan, Rocio Martin-Santos, Jose A. Crippa and Philip K. McGuire

Current Pharmaceutical Design, 2012, 18, 5045-5054

 

Abstract

Pharmacological challenge in conjunction with neuroimaging techniques has been employed for over two decades now to understand the neural basis of the cognitive, emotional and symptomatic effects of the main ingredients of cannabis, the most widely used illicit drug in the world. This selective critical review focuses on the human neuroimaging studies investigating the effects of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two main cannabinoids of interest present in the extract of the cannabis plant.

These studies suggest that consistent with the polymorphic and heterogeneous nature of the effects of cannabis, THC and CBD have distinct and often opposing effects on widely distributed neural networks that include medial temporal and prefrontal cortex and striatum, brain regions that are rich in cannabinoid receptors and implicated in the pathophysiology of psychosis. They help elucidate the neurocognitive mechanisms underlying the acute induction of psychotic symptoms by cannabis and provide mechanistic understanding underlying the potential role of CBD as an anxiolytic and antipsychotic. Although there are ethical and methodological caveats, pharmacological neuroimaging studies such as those reviewed here may not only help model different aspects of the psychopathology of mental disorders such as schizophrenia and offer insights into their underlying mechanisms, but may suggest potentially new therapeutic targets for drug discovery.

Keywords : Cannabis, THC, CBD, neuroimaging, fMRI, PET, memory, salience, anxiety, psychotic symptoms.

INTRODUCTION

Pharmacological challenge studies involving the cannabinoids present in the extract of Cannabis sativa (C sativa) or their synthetic counterparts in combination with neuroimaging offer a way to model aspects of various psychiatric illnesses in man and understand their neural underpinnings [1]. These studies are also an invaluable tool to perturb the endocannabinoid system under controlled experimental conditions in order to understand its role in regulating human cognitive and emotional processes. Cannabis is the most commonly used illicit drug world-wide that is consumed by an estimated 4% of the adult population [2]. Modulation of cognitive and emotional processes in man by the extracts of Cannabis sativa has been known for a long time and extensively investigated in experimental and observational studies [3-7]. Evidence from human studies has complemented that from basic research on the role of the endocannabinoid system in the modulation of cognitive and emotional function [reviewed by [8]]. However, precise investigation of the neural basis of the acute effects of cannabinoids on cognitive and emotional processing as well as psychopathology in man was not possible in vivo until the availability of sophisticated neuroimaging techniques for human research over the past couple of decades. While the earliest studies [reviewed in [1, 9]] mainly investigated the effects of chronic use or of acute administration of cannabis on the resting cerebral blood flow (rCBF), more recent studies have employed neuroimaging technologies with better spatial resolution to investigate the modulation of the neural correlates of cognitive and emotional processes by cannabinoids. Renewed interest in the link between regular cannabis use and development of psychotic disorders coupled with interest in the therapeutic potential of certain cannabinoids has provided a strong impetus to this line of investigation. Interpretation of evidence emerging from studies that have examined the chronic effects of cannabis use is difficult, because it is confounded by i) diversity in dose, potency and composition of cannabis used, ii) inter-individual variation in the duration of cannabis use, iii) neuroadaptive processes related to tolerance, withdrawal and/ or sensitization and iv) the fact that cannabis use seldom occurs in isolation. Hence, the purpose of this article is to critically review current understanding of the neurocognitive basis of the acute effects of the different cannabinoids in man as evident from neuroimaging studies, with a particular emphasis on the distinctive and often opposite effects of the different cannabinoids that have been examined to date.

The extract of C sativa has over 60 different cannabinoids [10] and about 400 chemicals. However, the major psychoactive ingredient of the plant is delta-9-tetrahydrocanabinol (THC) which is thought to be responsible for most of its psychotropic effects [11].

Most of the available evidence regarding the acute effects of cannabis on human cognition, behaviour and the brain relates to evidence regarding the effect of either the crude extract, pure CBD or pure THC. Systematic experimental studies have generally shown that the main cognitive domains impaired by the acute administration of THC include learning and memory [6, 12, 13], psychomotor control [14-18] and attention [12, 19]. However, acute impairments in memory [6] and psychomotor control [20, 21] or an adverse effect on driving ability [22] have not been consistently reported by all studies. There is much less agreement regarding the persistence of the longer term effects of cannabis use [12, 23-27].

Nevertheless, these have been the main cognitive domains that have been investigated employing neuroimaging techniques in conjunction with challenge with THC or cannabis rich in THC. On the other hand, studies that have combined neuroimaging with administration of CBD have been mainly driven by the anxiolytic potential of CBD based on observations in laboratory animals [28-32] and healthy human volunteers [33, 34]. In this paper, neuroimaging studies investigating the effects of THC and CBD will be critically reviewed followed by a review of the literature comparing the effects of THC and CBD in man.

(…)

Neural_Mechanisms_for_the_Cannabinoid_Mo(1)