Acute and chronic effects of cannabinoids on effort-related decision-making and reward learning: an evaluation of the cannabis ‘amotivational’ hypotheses
Will Lawn, Tom P. Freeman, Rebecca A. Pope, Alyssa Joye, Lisa Harvey, Chandni Hindocha, Claire Mokrysz, Abigail Moss, Matthew B. Wall, Michael A.P. Bloomfield, Ravi K. Das, Celia J.A. Morgan, David J. Nutt, H. Valerie Curran
Psychopharmacology, 2016, 233, 3537–3552
Doi : 10.1007/s00213-016-4383-x
Rationale : Anecdotally, both acute and chronic cannabis use have been associated with apathy, amotivation, and other reward processing deficits. To date, empirical support for these effects is limited, and no previous studies have assessed both acute effects of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), as well as associations with cannabis dependence.
Objectives : The objectives of this study were (1) to examine acute effects of cannabis with CBD (Cann + CBD) and without CBD (Cann-CBD) on effort-related decision-making and (2) to examine associations between cannabis dependence, effort-related decision-making and reward learning.
Methods : In study 1, 17 participants each received three acute vaporized treatments, namely Cann-CBD (8 mg THC), Cann + CBD (8 mg THC + 10 mg CBD) and matched placebo, followed by a 50 % dose top-up 1.5 h later, and completed the Effort Expenditure for Rewards Task (EEfRT). In study 2, 20 cannabis-dependent participants were compared with 20 non-dependent, drug-using control participants on the EEfRT and the Probabilistic Reward Task (PRT) in a non-intoxicated state.
Results : Cann-CBD reduced the likelihood of high-effort choices relative to placebo (p = 0.042) and increased sensitivity to expected value compared to both placebo (p = 0.014) and Cann + CBD (p = 0.006). The cannabis-dependent and control groups did not differ on the EEfRT. However, the cannabis dependent group exhibited a weaker response bias than the control group on the PRT (p = 0.007).
Conclusions : Cannabis acutely induced a transient amotivational state and CBD influenced the effects of THC on expected value. In contrast, cannabis dependence was associated with preserved motivation alongside impaired reward learning, although confounding factors, including depression, cannot be disregarded. This is the first well powered, fully controlled study to objectively demonstrate the acute amotivational effects of THC.
Keywords : Cannabis . Cannabinoids . THC . Cannabidiol . Motivation . Reward . Effort-related decision-making . Reinforcement learning . Addiction
The endocannabinoid system, which includes the cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptors and their endogenous ligands, is putatively involved in reward processing and addiction (Curran et al. 2016; Maldonado et al. 2006; Parsons and Hurd 2015). Δ-9-Tetrahydrocannabinol (THC), the main active compound in cannabis, is a CB1 receptor partial agonist (Petitet et al. 1998), whichmay modestly increase dopamine release in the human striatum (Bossong et al. 2015). Dopamine is considered critical in various reward processes (Berridge and Robinson 1998; Schultz et al. 1997). Individuals who met DSM-IV criteria for cannabis dependence or abuse showed reduced striatal dopamine synthesis capacity (Bloomfield et al. 2014a), which was negatively correlated with their apathy scores (Bloomfield et al. 2014b).
However, other studies have shown no difference between cannabis users and non-users in dopamine receptor density (Albrecht et al. 2013; Sevy et al. 2008; Stokes et al. 2009; Urban et al. 2012). In terms of alterations to the endocannabinoid system, cannabis dependence has been associated with reduced levels of CB1 receptors (D’Souza et al. 2015; Hirvonen et al. 2012) and reduced anandamide levels in cerebrospinal fluid (Morgan et al. 2013b).
Cannabis contains many cannabinoids, other than THC. Of particular interest is cannabidiol (CBD) which has a complex mode of action, including inhibition of the metabolism and reuptake of anandamide, inhibition of adenosine uptake, agonism of the 5-HT1a receptor (McPartland et al. 2015) and agonism at the GPR55 receptor (Ryberg et al. 2007). Acute THC has dose-related amnestic (Curran et al. 2002), psychotic (Morrison et al. 2009) and anxiogenic (Morrison et al. 2009) effects. CBD has been shown to attenuate or block these negative effects (Bhattacharyya et al. 2010; Englund et al. 2013; Morgan et al. 2010b). Furthermore, CBD may have some antiaddictive properties in animals and humans ( Morgan et al. 2010a, 2013a; Ren et al. 2009), and use of high-THC/low- CBD cannabis was especially predictive of cannabis dependence, compared with other types of cannabis (Freeman and
Winstock 2015). Given these opposing pharmacological and psychological effects of THC and CBD, we hypothesized that CBD may buffer the effects of THC on reward processing.
Historically, cannabis use has been associated with reduced motivation (McGlothlin and West 1968). Early, poorly controlled studies into the acute effects of cannabis found both amotivational (Miles et al. 1974) and null (Mendelson et al. 1976) effects. More recently, both pro-motivational (Foltin et al. 1990) and amotivational (Cherek et al. 2002) effects have been reported. However, the former study did not provide traditional rewards (e.g. money, food) in return for work, preferred work activities were earned instead. Furthermore, the latter study had a sample of only five participants. Hence, there is very little well-conducted, empirical research into the acute effects of cannabis on motivation to earn rewards. Moreover, to the authors’ knowledge, no one has examined the effects of CBD on motivational processing in humans.
Early studies of chronic effects of cannabis found no difference when comparing heavy with light cannabis users on fixed ratio button-pressing tasks for rewards (Mello and Mendelson 1985; Mendelson et al. 1976). Survey data has also failed to demonstrate a link between long-term cannabis use and amotivation (Barnwell et al. 2006; Musty and Kaback 1995), although cannabis use has been shown to predict anhedonia (Bovasso 2001). Daily, adolescent cannabis users had a lower motivation for monetary reward than non-users, although comorbid mental health problems and other drug use were not reported and may have confounded group differences (Lane et al. 2005). Studies that have investigated anticipatory BOLD response for monetary reward, thought to be an indicator of intact reward processing, have found opposing results, with one showing reduced (van Hell et al. 2010) and another showing enhanced (Nestor et al. 2010) striatal activation in dependent cannabis users compared to healthy controls.