## The neuropsychopharmacology of cannabis : A review of human imaging studies

Michael A.P. Bloomfield, Chandni Hindocha, Sebastian F. Green, Matthew B.Wall, Rachel Lees, Katherine Petrilli, Harry Costello, M. Olabisi Ogunbiyi, Matthijs G. Bossong, Tom P. Freeman

Pharmacology & Therapeutics, 2019, 195, 132-161

doi : 10.1016/j.pharmthera.2018.10.006

### a b s t r a c t

The laws governing cannabis are evolving worldwide and associated with changing patterns of use. The main psychoactive drug in cannabis is Δ9-tetrahydrocannabinol (THC), a partial agonist at the endocannabinoid CB1 receptor. Acutely, cannabis and THC produce a range of effects on several neurocognitive and pharmacological systems. These include effects on executive, emotional, reward and memory processing via direct interactions with the endocannabinoid system and indirect effects on the glutamatergic, GABAergic and dopaminergic systems. Cannabidiol, a non-intoxicating cannabinoid found in some forms of cannabis, may offset some of these acute effects. Heavy repeated cannabis use, particularly during adolescence, has been associatedwith adverse effects on these systems, which increase the risk of mental illnesses including addiction and psychosis. Here, we provide a comprehensive state of the art review on the acute and chronic neuropsychopharmacology of cannabis by synthesizing the available neuroimaging research in humans.We describe the effects of drug exposure during development, implications for understanding psychosis and cannabis use disorder, and methodological considerations. Greater understanding of the precisemechanisms underlying the effects of cannabismay also give rise to new treatment targets.

Keywords : Addiction, Cannabis, Cognition, Development, Neuroimaging, Psychosis

### Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

2. Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

3. The acute effects of cannabis and THC . . . . . . . . . . . . . . . . . . . . . . . 135

4. The chronic effects of cannabis and THC . . . . . . .  . . . . . . . . . . . . . . 140

5. Developmental effects of cannabis. . . . . . . . . . . . . . . . . . . . . .. . . . . . 153

6. Cannabis use disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . 153

7. Cannabis and psychoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

8. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Conflict of interest statement . . . . . . . . . . . . . . . . . . . .  . . . . . . . . . . . . . 156
Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . 156
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . 156

### 1. Introduction

Cannabis is one of the most widely used recreational drugs in the world (United Nations Office on Drugs and Crime (UNODC), 2018). The past year prevalence of cannabis use disorders in the United States has been estimated at 2.9%, or 30.6% among past-year users (Hasin et al., 2015). There has been concern over the link between cannabis use and psychiatric illness since the 1960s (Advisory Committee on Drug Dependence, 1969; Kolansky & Moore, 1972; Tennant & Groesbeck, 1972), which has intensified following a series of large scale epidemiological studies (Andreasson et al. 1987; Murray et al., 2007) and wide public debate. A changing legal landscape for the drug has been associatedwith increasing usage and reductions in the perception of harm (Cerdá et al., 2017). Acute intoxication and chronic heavy use of cannabis have been associated with a range of effects. The potential long-term deleterious effects of particular concern are when heavy cannabis use occurs during adolescence, a key developmental period
for the brain (Bossong & Niesink, 2010). Positive subjective acute effects described as the ‘high’ include euphoria, relaxation and sensory intensification (Green et al., 2003). Adverse acute effects include anxiety, paranoia, impaired psychomotor performance and cognitive dysfunction (Broyd et al., 2016; Curran et al., 2016). Chronic heavy use of the drug is associatedwith increased risk of dependence, psychosis and cognitive impairment (Broyd et al., 2016; Curran et al., 2016; Marconi et al., 2016). However, two large meta-analyses suggest that the adverse effects of chronic cannabis use on cognition may improve following abstinence (Schreiner & Dunn, 2012; Scott et al., 2018).

The main psychoactive substance in cannabis is Δ9- tetrahydrocannabinol (THC) (Wachtel et al., 2002) which was first isolated fromhashish in 1964 by Gaoni andMechloulam. THC is gaining interest for its broad therapeutic potential. This includes putative antiepileptic properties (Friedman & Devinsky, 2015), analgesic properties in neuropathic and chronic pain (Abrams et al., 2007; Mucke et al., 2018; Narang et al., 2008; Svendsen et al., 2004; Wilsey et al., 2008), anti-emetic properties in cancer (Davis, 2016; Smith, Azariah, et al., 2015), and anti-spastic properties in stroke and multiple sclerosis (Collin et al., 2007; Marinelli et al., 2017). THC was originally described as an agonist of endocannabinoid CB1 receptors (CB1R) (Felder et al. 1992), however, there is growing evidence of partial agonist properties at this site fromboth in vitro (Breivogel & Childers, 2000; Govaerts et al., 2004; Kelley & Thayer, 2004; Petitet et al., 1998; Shen & Thayer, 1999; Sim et al., 1996) and in vivo (Paronis et al., 2012) studies. The CB1R is a widespread G protein-coupled receptor (Pertwee, 2008) found at high concentrations in key brain regions associated with reward, emotional and cognitive processing including the neocortex (particularly frontal and limbic areas), hippocampus, amygdala, cerebellum, thalamus and basal ganglia (see Fig. 1) (Glass et al., 1997). THC alters signalling of endocannabinoid transmitters such as 2-arachidonoyl-glycerol and anandamide. These ligands are released endogenously by neurons and act on CB1Rs in adjacent γ-aminobutyric acid (GABA)-ergic and glutamatergic nerve terminals resulting in retrograde signalling (see Fig. 2) (Bloomfield et al., 2016; Castillo et al., 2012). THC also demonstrates
partial agonist properties in vitro at the CB2 receptor, but with lower efficacy than at CB1R. (Pertwee, 2008). As THC has a number of double bonds and stereoisomers, this review focuses on the main THC isomer found in cannabis, (−)-trans-Δ9-tetrahydrocannabinol, which is also referred to in some older studies by its alternative name Δ1-tetrahydrocannabinol and as a pharmaceutical preparation using the International Non-Proprietary Name dronabinol.

The cannabis plant synthesises at least 143 other cannabinoids in addition to THC (Hanuš et al. 2016) such as cannabidiol (CBD). With its excellent safety and tolerability profile and lack of intoxicating effects, CBD has generated significant interest as a novel treatment for psychosis, (Leweke et al., 2012; McGuire et al., 2017) epilepsy (Devinsky et al., 2017; Devinsky et al., 2018), anxiety disorders (Bergamaschi et al., 2011; Crippa et al., 2004) and addictions (Hindocha, Freeman, et al., 2018; Morgan et al., 2013; Ren et al., 2009). When administered alone, CBD has minimal activity at CB1Rs, but it can inhibit the effects of cannabinoid agonists by acting as a negative allosteric modulator of CB1Rs (Laprairie et al., 2015). Moreover, CBD can inhibit the reuptake and hydrolysis of the endocannabinoid
anandamide (Bisogno et al., 2001). CBD has many additional targets within and beyond the endocannabinoid system, including activation of 5-HT1A receptors, α1-adrenoceptors and μ-opioid receptors (for a review see Pertwee, 2008). Whilst a balance of THC and CBD is typically found in hashish or resin products produced by landrace crops, cannabis plants are increasingly selected to produce THC only (Potter et al. 2008). The acute harms of THC are dose-dependent (Curran et al., 2002; D’Souza et al., 2004) and may be offset by CBD (Bhattacharyya et al., 2010; Englund et al., 2013; Hindocha et al., 2015; Morgan et al., 2010). THC levels and the THC:CBD ratio in cannabis have risen considerably in the USA and Europe in the last two decades (ElSohly et al., 2016; Pijlman et al., 2005; Potter et al., 2018; Zamengo et al., 2015), which may increase the harms from repeated use (Di Forti et al., 2015; Freeman & Winstock, 2015; Freeman, van der Pol, et al., 2018; Schoeler et al., 2016). In this article, we refer to cannabis containing THC only or with unknown quantities of CBD as ‘cannabis’, and we explicitly state when cannabis contains significant levels of CBD.

Cannabis and THC can induce transient positive psychotic symptoms in healthy individuals (Bhattacharyya et al., 2010; D’Souza et al., 2004; Moreau, 1845; Morrison & Stone, 2011; Morrison et al., 2009; Morrison et al., 2011). Increased sensitivity to the acute psychotogenic effects of cannabis has been found in people with higher schizotypal personality traits (Mason et al., 2009) and those with genetic vulnerability (Morgan et al. 2016). This increased sensitivity also has been shown to be a predictor of subsequent psychotic disorders (Arendt et al., 2005). THC can also elicit schizophreniform negative symptoms which are distinct from sedation (Morrison& Stone, 2011). There is consistent epidemiological evidence that the drug is a risk factor for schizophreniform psychotic disorders (Di Forti et al., 2015), exhibiting dose-dependence (Gage et al., 2016; Marconi et al., 2016; Moore et al., 2007) and dose-duration effects (Di Forti et al., 2009). Even in cannabis users who do not have frank schizophrenia, drug use is associated with increased paranoia; (Freeman et al., 2015; Freeman et al., 2013) a cardinal symptomof the illness. The available evidence indicates that cannabis causes psychosis in susceptible individuals (Murray et al., 2007). However, there is some evidence to suggest that causal effects of cannabis on risk of psychosis may be smaller than reverse causation frompsychosis risk to cannabis use (Gage et al., 2016; Pasman et al., 2018). Studies in non-human animals showthat THC produces morphological changes in brain regions with high CB1R expression including the hippocampus (Chan et al., 1998), amygdala (Heath et al. 1980) and cortex (Downer et al. 2001). These include reductions in synapses (Heath et al., 1980), cell body size (Scallet et al., 1987) and dendritic length (Landfield et al., 1988). Additionally, THC and cannabis produce complex effects on neuropharmacology including the dopaminergic system (Bloomfield et al., 2016). Alterations in brain structure and function have also been found in human cannabis users, particularly in CB1R-rich areas of the brain that support executive, memory and emotional processing (Lorenzetti, Solowij, and Yucel, 2016; Yücel et al., 2007).

Heavy cannabis use has been associated with a range of neurocognitive effects of relevance to mental illness, which may persist after acute intoxication (Broyd et al., 2016; Curran et al., 2016; Volkow et al., 2016). These include negative effects on attention (Crane et al., 2013), executive function (Crean et al., 2011), learning (Crane et al., 2013), memory (Jager et al., 2010), psychotic experiences (D’Souza et al., 2004; Fletcher & Honey, 2006), anhedonia and anxiety (Dorard et al., 2008). These deficits may be reversible as a meta-analysis of neurocognitive performance after at least 25 days of abstinence from cannabis found no evidence of impairment (Schreiner & Dunn, 2012). An additional meta-analysis of 69 studies found that cognitive impairments in frequent userswere of a small effect size, and found no evidence for impairment after more than 72 hours of abstinence (Scott et al., 2018).

It is thus timely to review the human imaging literature on the neuropsychopharmacology of cannabis.We build upon and extend recent review articles (Blest-Hopley et al., 2018; Lorenzetti, Alonso-Lana, et al., 2016; Weinstein et al., 2016; Yanes et al., 2018) by incorporating multiple structural, functional, and pharmacological neuroimaging modalities with a focus on both the adolescent and adult brain to present a comprehensive overview of the neuropsychopharmacology of cannabis. We will begin by describing the effects of acute pharmacological challenge of either cannabis or THC before considering neuroimaging studies of heavy cannabis users. As our focus is on cannabiswewill omit imaging studies of synthetic cannabinoids (sometimes referred to collectively as “spice”).Wewill give additional consideration to the neuropharmacology of cannabis during development because CB1R expression peaks during the foetal period and adolescence (Jacobus et al., 2014), key periods associated with neuroanatomical re-modelling (Bossong & Niesink, 2010; Raznahan et al., 2014). This is because of potential harms associated with maternal cannabis exposure during gestation and breast-feeding, and because adolescence and young adulthood is the period of peak cannabis use (Copeland et al., 2013), and may be a particularly vulnerable period to the acute effects of cannabinoids (Curran et al., 2016). Given the public health implications, we will synthesise the literature on implications for understanding psychosis and cannabis use disorder before describing important methodological considerations.

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