Chronic effects of cannabis use on the human reward system: An fMRI study

Abstract

Cannabis is one of the most used drugs of abuse. It affects the brain reward system in animals, and has proven rewarding and addictive potential in humans. We used functional MRI to measure brain activity during reward anticipation in a monetary reward task. Long-term cannabis users were compared to healthy controls. An additional control group consisting of nicotine users was included. Cannabis users showed attenuated brain activity during reward anticipation in the nucleus accumbens compared to non-smoking controls, but not compared to smoking controls. Cannabis users showed decreased reward anticipation activity in the caudate nucleus, compared to both non-smoking and smoking controls. These data suggest that nicotine may be responsible for attenuated reward anticipation activity in the accumbens, but that differences in the caudate are associated with the use of cannabis. Our findings imply that chronic cannabis use as well as nicotine, may cause an altered brain response to rewarding stimuli.

Introduction

Cannabis is one of the most widely used drugs since ancient times. Nowadays, it is commonly accepted that the drug has addictive potential. In the Dutch population cannabis use has increased in the past decade, and although daily use has become less frequent, a growing group of (daily) users seeks treatment to be able to deal with their heavy use (for a review see EMCDDA, 2007). This may be associated with the fact that the potency of cannabis has increased significantly in recent years (Pijlman et al., 2005, TNDM, 2006).

Cannabis has an effect on the reward system, as is clearly shown in animal studies (Gardner, 2002, Tanda and Goldberg, 2003, Wise, 1996). The rewarding effects of cannabis might be responsible for its addictive properties. Like most other drugs of abuse, prolonged cannabis exposure decreases baseline sensitivity of reward systems in animal studies (Gardner and Vorel, 1998, Kenny, 2007, Tanda and Goldberg, 2003), implying that in frequent cannabis users more reward is needed to reach the same subjective feeling of reward than in non-users. Indeed, chronic cannabis use, as well as use of other drugs, is associated with anhedonia (Bovasso, 2001, Janiri et al., 2005), i.e. an inability to experience pleasure from normally pleasurable life events. Anhedonia is an important symptom in several psychiatric disorders, such as depression, addiction, and schizophrenia (Schlaepfer et al., 2008), and is correlated with craving and relapse in addiction (Janiri et al., 2005, Lubman et al., 2009). It is associated with a dysfunctional reward system (Keedwell et al., 2005, Schlaepfer et al., 2008), indicating that anhedonia in chronic cannabis use may be due to impaired reward processing. However, there is no direct evidence for an altered response in the brain reward system in humans after chronic cannabis use.

An endocannabinoid system has been uncovered, with both cannabinoid receptors and endocannabinoid ligands (for a review see Mechoulam et al., 1998), that has a neuromodulatory role in the central nervous system (Pazos et al., 2005). There are at least two types of cannabinoid receptors, but in the brain mainly CB1 receptors are found. High densities of CB1 receptors are found in the basal ganglia, the cerebellum, and the hippocampus (Ameri, 1999, Gardner and Vorel, 1998). CB1 receptors modulate GABAergic, glutamatergic and dopaminergic neurotransmission. The endocannabinoid system has been associated with several neurological and psychiatric disorders, and therefore, there is much interest in this system regarding its potential role in therapy (Pacher et al., 2006).

The main psycho-active constituent of cannabis is Δ⁹-tetrahydrocannabinol (THC), which works directly on the endocannabinoid system (Mechoulam et al., 1998). From animal studies it is known that the acute effect of THC in the brain includes an elevation of dopaminergic transmission in the nucleus accumbens (Gardner and Vorel, 1998, Tanda and Goldberg, 2003), most likely through CB1 receptor activation on GABAergic neurons in the ventral tegmental area and the nucleus accumbens (Lupica et al., 2004). A recent positron emission tomography (PET) study has confirmed that also in humans, dopamine release occurs in the striatum after acute THC administration (Bossong et al., 2009). Long-term effects include a decrease in dopamine neurotransmission in areas of the reward system (Tanda and Goldberg, 2003). The mechanism for this is not yet fully elucidated, but both down-regulation and desensitization of CB1 receptors after chronic cannabis use have been reported (Howlett et al., 2004, Sim-Selley, 2003). It has been postulated that subjects prone to drug abuse suffer from a hypodopaminergic reward system. According to this reward deficiency hypothesis (Blum et al., 2000), drugs of abuse are the only way to effectively normalize reward functioning.

Although many animal studies have been performed to elucidate the influence of cannabis on reward systems in the brain, little is known about the effects of cannabis on the brain reward system in humans. The aim of this study is to investigate the long-term effects of cannabis on the human reward system. To assess effects of chronic cannabis use on reward, we used monetary reward as a substitute of natural rewards to induce brain responses. Hence, a monetary incentive delay (MID) task is used, that has proven to effectively activate areas associated with reward (Kirsch et al., 2003, Knutson et al., 2001a). Brain activity during the MID task is measured with functional magnetic resonance imaging (fMRI). We focussed specifically on the nucleus accumbens, since this area is an important region of the reward system as has been shown in animal studies (Ameri, 1999, Gardner and Vorel, 1998) and humans (Knutson et al., 2001a). In the MID task, brain activity during the appetitive, or anticipatory phase of reward is separated from activity during reward outcome. Areas important for anticipation of reward are the nucleus accumbens, the caudate nucleus, putamen, and thalamus. During reward outcome, focus lies on more frontal areas, such as the orbitofrontal cortex and the mesial prefrontal cortex (Knutson et al., 2001b).

Given that cannabis is often consumed together with nicotine and that these substances interact in animals (Valjent et al., 2002, Viveros et al., 2006) and in humans (Penetar et al., 2005), it is important to assess the effects of nicotine. Nicotine may alter the reward system also, given that it is an addictive drug (Fagen et al., 2003). Therefore, non-using controls are needed as a reference of a normal functioning reward system. A control group consisting of regular smokers was included, as well as a control group that does not use cannabis or nicotine. Due to the cross-sectional nature of the study, we cannot exclude that other factors than chronic cannabis use may contribute to the results (e.g. pre-existing characteristics). For the sake of readability, we applied the term ‘chronic use’ throughout the paper.

We hypothesized that the responsiveness of the reward system is affected in long-term cannabis users compared to non-users. If the reward deficiency hypothesis (Blum et al., 2000) were true, a possible effect of cannabis would be an attenuation of neural responses in the nucleus accumbens, as this area is a key structure in the brain reward system which may show decreased sensitivity after long-term cannabis use.