Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin and glutamate systems

William E. Fantegrossi, Cathryn D. Wilson, and Michael D. Berquist III

Drug Metabolism Reviews, 2018, 50, (1), 65–73.

doi : 10.1080/03602532.2018.1428343

Abstract

An association between marijuana use and schizophrenia has been noted for decades, and the recent emergence of high-efficacy synthetic cannabinoids (SCBs) as drugs of abuse has lead to a growing number of clinical reports of persistent psychotic effects in users of these substances. The mechanisms underlying SCB-elicited pro-psychotic effects is unknown, but given the ubiquitous neuromodulatory functions of the endocannabinoid system, it seems likely that agonist actions at cannabinoid type-1 receptors (CB1Rs) might modulate the functions of other neurotransmitter systems known to be involved in schizophrenia. The present review surveys what is currently known about the interactions of CB1Rs with dopamine, serotonin and glutamate systems, because all three of those neurotransmitters are well-established in the pathophysiology of schizophrenia and psychosis. Identification of molecular mechanisms underlying the pro-psychotic effects of SCB drugs of abuse may establish certain classes of these substances as particularly dangerous, guiding regulations to control availability of these drugs. Likewise, an understanding of the pharmacological interactions which lead to schizophrenia and psychosis subsequent to SCB exposure might guide the development of novel therapies to treat afflicted users.

Introduction

The continuing emergence of novel “marijuana substitute” smoking blends such as K2 and Spice frustrates regulatory efforts to curtail availability of the dangerous synthetic cannabinoids (SCBs) present in these products. These SCBs are often much more potent and efficacious at cannabinoid CB1 and CB2 receptors (CB1R/CB2R) than the main psychoactive constituent of marijuana, Δ9-tetra-hydrocannabinol (Δ9-THC), suggesting a capacity to induce more intense in vivo effects than cannabis. Epidemiological studies suggest that cannabis use, particularly in adolescence, increases risk for psychotic episodes later in life (D’Souza et al., 2009; Evins et al., 2012) and preclinical studies have also demonstrated pro-psychotic effects of Δ9-THC in rodents treated during the adolescent period (Rubino and Parolaro, 2013). Fergusson and colleagues (2006) reviewed six prospective studies of cannabis users and found that all of them demonstrated increased risks of psychosis or psychotic symptoms with odds ratios ranging from 1.77 to 10.9. Alarmingly, reports of acute and lasting psychosis elicited by use of SCBs are rapidly accumulating in the clinical literature (Glue et al., 2013; Spaderna et al., 2013; Durand et al., 2013; Oluwabusi et al., 2013; Hermanns-Clausen et al., 2013; Peglow et al., 2012; Tung et al., 2012; Brakoulias, 2012; Hurst et al., 2011; Benford and Caplan, 2011; Every-Palmer, 2011; Every-Palmer, 2010; Müller et al., 2010; Monte et al., 2017; Vallersnes et al., 2016; Roberto et al., 2016), but the mechanism of psychosis remains poorly understood. Thus, in addition to other toxicities (Seely et al., 2012; Tai and Fantegrossi, 2017), SCB use may also elicit clinically relevant and persistent adverse mental health consequences. As growing numbers of young Americans are exposed to emerging SCB drugs of abuse, it is critical to understand the mechanisms by which SCBs induce a lasting vulnerability to psychosis and begin to define the molecular changes that underlie this effect so that efficacious therapies can be developed. Specifically, this review will focus on the role of CB1 receptors in the regulation of brain dopamine, serotonin and glutamate systems, because these neurotransmitters are al associated with schizophrenia and psychosis (Sawa and Snyder, 2003) and because their release is regulated by CB1 receptors (Howlett et al., 2004). Any or all of these neurotransmitters could therefore mediate the pro-psychotic effects of SCBs. The goal of this review is to address the current lack of knowledge regarding the persistent pro-psychotic effects of SCBs, and to highlight the unique public health challenges posed by these novel compounds. The data here reviewed will demonstrate that SCBs are not simply alternate forms of marijuana, but are dangerous drugs of abuse with persistent adverse neuropsychiatric sequelae arising from their use.

CB1 and CB2 Receptors

In the brain, there are two well-characterized cannabinoid receptors subtypes: cannabinoid type-1 receptors (CB1R; found on presynaptic neurons and densely expressed in the prefrontal cortex and in the hippocampus (Eggan and Lewis, 2007; Tsou et al., 1999)) and cannabinoid type-2 receptors (CB2R; highly-expressed in the peripheral tissues of the immune system, nervous system, and gastrointestinal system (Munro et al., 1993; Navarrete et al., 2013;Wright et al., 2005)). Although CB2R are also found in brain regions such as the prefrontal cortex, hippocampus and hypothalamus (reviewed in Demuth and Molleman, 2006; den Boon et al., 2012; Kim and Li, 2015; Onaivi et al., 2008; Wang et al., 2016), they are not thought to be involved in psychoactive effects of cannabis or SCBs (reviewed in Pertwee, 2006; Reggio, 2010; Caballero and Tseng, 2012). Therefore, this review will focus primarily on the role of CB1R in pro-psychotic effects of marijuana and SCBs.

Dopamine

Pharmacological treatment of schizophrenia (and arguably the entire field of psychopharmacology itself) began with the discovery that chlorpromazine was an efficacious therapeutic against mania and psychosis. The clinical efficacy of chlorpromazine was a serendipitous discovery, but its mechanism of action was eventually defined as antagonism of dopamine receptors (Carlsson and Lindquist, 1963), allowing for the rational design of antipsychotics and cementing dopamine hyperfunction as the most plausible pathophysiology underlying schizophrenia and psychosis. As the study of dopamine receptors matured, both D1-like and D2-like dopamine receptors have come to be associated with primary psychotic symptoms (D2-like receptors) and cognitive dysfunctions (D1-like receptors) which accompany schizophrenia. Although other neurotransmitter systems are certainly implicated in the etiology of schizophrenia and psychosis (see below), dopamine systems remain the primary targets of antipsychotic medications, and disfunction of central dopamine circuits remains the predominant hypothesized mechanism underlying the illness.

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