The Potential of Cannabidiol as a Treatment for Psychosis and Addiction : Who Benefits Most ? A Systematic Review
Albert Batalla, Hella Janssen, Shiral S. Gangadin and Matthijs G. Bossong
Journal of Clinical Medicine, 2019, 8, 1058
doi : 10.3390/jcm8071058
The endogenous cannabinoid (eCB) system plays an important role in the pathophysiology of both psychotic disorders and substance use disorders (SUDs). The non-psychoactive cannabinoid compound, cannabidiol (CBD) is a highly promising tool in the treatment of both disorders. Here we review human clinical studies that investigated the ecacy of CBD treatment for schizophrenia, substance use disorders, and their comorbidity. In particular, we examined possible profiles of patients who may benefit the most from CBD treatment. CBD, either as monotherapy or added to regular antipsychotic medication, improved symptoms in patients with schizophrenia, with particularly promising eects in the early stages of illness. A potential biomarker is the level of anandamide in blood. CBD and THC mixtures showed positive eects in reducing short-term withdrawal and craving in cannabis use disorders. Studies on schizophrenia and comorbid substance use are lacking. Future studies should focus on the eects of CBD on psychotic disorders in dierent stages of illness, together with the eects on comorbid substance use. These studies should use standardized measures to assess cannabis use. In addition, future eorts should be taken to study the relationship between the eCB system, GABA/glutamate, and the immune system to reveal the underlying neurobiology of the eects of CBD.
Keywords : cannabidiol; CBD; cannabis; psychosis; schizophrenia; substance use disorders; addiction
Schizophrenia is a complex mental disorder, which has a profound impact on patients. The burden of schizophrenia is explained by the early onset, often in early adulthood or late adolescence, its chronic course, and its relatively high prevalence . The symptomatology is highly heterogeneous and often overlaps with comorbid disorders, such as aective or substance use disorders [2,3]. Psychotic symptoms are grouped into three dimensions: Positive symptoms (e.g., delusions, hallucinations), negative symptoms (e.g., blunted aect, anhedonia), and cognitive symptoms (e.g., attention, memory, executive functioning; see for reviews [4–6]). Dierent combinations of symptoms and comorbidity lead to dierent clinical profiles and treatment needs. However, the pharmacological treatment of schizophrenia is mainly based on dopamine blockade, the eect of which is limited to the positive symptoms . Moreover, two-thirds of the patients experience a suboptimal response with dopaminergic treatment , and these results are even worse when comorbid substance use disorders (SUDs) are present . Therefore, there is an urgent need for alternative and more effective pharmacological interventions aimed to reduce the burden of complex and overlapping symptom profiles.
One of these interventions may involve the endocannabinoid (eCB) system, which is a promising new pharmacological target in this respect. The eCB system consists of at least two types of receptors and their endogenous ligands (i.e., endocannabinoids; [10,11]). The cannabinoid receptors are predominantly present in the central nervous system, in particular, in several limbic and cortical brain structures . The eCB systemis a retrogrademessenger systemthat regulates both excitatory glutamate and inhibitoryGABA neurotransmission according to an ‘on-demand’ principle: Endocannabinoids are released when and where they are needed [10,11,13]. This endocannabinoid-mediated regulation of synaptic transmission is a widespread phenomenon in the brain and is thought to play an important role in higher brain functions, such as cognition, motor function, and processing of sensory input, reward, and emotions [14–17]. eCB receptors are also present on immune cells in the central nervous system (i.e., microglia), which suggests their involvement in processes such as cytokine release, immune suppression, and induction of both cell migration and apoptosis [18,19].
The role of the eCB system in the pathophysiology of schizophrenia has been suggested in an accumulating amount of evidence [20,21]. First, epidemiological studies suggest that cannabis use increases the risk for developing schizophrenia  and lowers the age of onset of the disorder [23,24].
This risk increases with a higher frequency of cannabis use (e.g., daily use), and with the consumption of more potent cannabis (i.e., a higher amount of D9-tetrahydrocannabinol; THC) [22,25–27]. Second, modulation of the eCB system by the administration of THC (i.e., the main psychoactive component in cannabis) to healthy volunteers showed that THC can induce positive psychotic symptoms, eects that resemble negative symptoms (e.g., blunted aect, lack of spontaneity) and deficits in cognition (reviewed in ). Importantly, in schizophrenia patients, enhanced levels of endocannabinoids were demonstrated in cerebrospinal fluid and blood [29–31], and increased CB receptor density and availability were shown in the brain [32,33].
In addition to its role in schizophrenia, there is overwhelming evidence that the eCB system is implicated in the pathophysiology of addiction, in particular in processes such as drug-seeking behaviour, reward, withdrawal, and relapse (see for reviews [34–37]). For example, animal studies have shown that addictive properties reflected in behaviours such as self-administration or conditioned place preference of opiates, nicotine, and alcohol are absent or attenuated in cannabinoid CB1-receptor knockout mice and after administration of CB1 antagonists . In addition, whereas the drug seeking behaviour of drugs of abuse was blocked with CB1 antagonists, it was reinstated after the administration of CB1 agonists [34,36]. Finally, endocannabinoid concentrations are aected by active drug seeking behaviour and eCB signalling seems to modulate the rewarding eects of addictive drugs .
SUDs and psychotic disorders such as schizophrenia co-occur frequently. Prevalence rates of any SUD (excluding nicotine and caeine) in patients with schizophrenia are up to 45% [39,40], with the most frequently used substances being cannabis and alcohol. Considering nicotine use disorders, the prevalence rates rise up to 60%–90% . Persistent use of licit or illicit drugs has been associated with adverse consequences in the overall course of psychotic disorders, and increased morbidity and mortality . In addition, SUDs are also related to poor medication adherence, increasing the risk of relapse . For example, in patients with schizophrenia, cannabis use has been related to higher relapse rates, increased severity of symptoms, and poor outcome [41–45]. Despite the high co-occurring rates, patients with comorbid SUDs and psychotic disorders are often excluded from clinical trials, which limits the generalization of results and ignores the potential (positive or negative) eects of the intervention on substance use.
While THC can trigger both schizophrenia and SUD and worsen the course of both disorders, the non-psychoactive cannabinoid compound cannabidiol (CBD) may have opposite or even beneficial effects. For example, CBD may have the ability to counteract psychotic symptoms and cognitive impairment associated with cannabis use as well as with acute THC administration [46,47]. In addition, CBD may lower the risk for developing psychosis that is related to cannabis use . These eects are possibly mediated by the opposite eects of CBD and THC on brain activity patterns in key regions implicated in the pathophysiology of schizophrenia, such as the striatum, hippocampus, and prefrontal cortex . Therefore, CBD displays a highly favourable profile for development as a new antipsychotic agent . Similarly, CBD may serve as a treatment for SUDs, since evidence from preclinical studies suggests that CBD reduces negative withdrawal eects, motivation for self-administration, and reinstatement of drug use . As a result, CBD-containing compounds are increasingly being investigated in the context of substance abuse in humans as well.
The eCB system appears an interesting target for schizophrenia, SUDs, and their comorbidity, due to the implication of the eCB system in their pathophysiology and the beneficial eects of CBD in both disorders. However, one may expect that CBD treatment may be most eective in a subgroup of patients, for example patients who show alterations in the eCB system or have a specific symptom profile. CBD may restore an imbalance in the eCB system, which may result in clinical improvement.
Although previous excellent reviews (e.g., [37,48,49]) described the potential of CBD as a treatment for psychosis and SUD, this review provides a detailed and up-to-date systematic literature overview of clinical studies that investigated the ecacy of CBD treatment for schizophrenia and/or SUD. In addition, this review examined whether there are specific subgroup of patients with schizophrenia, SUD, or both that may benefit the most from CBD treatment.