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 [1
]. The symptomatology is highly heterogeneous and often overlaps with comorbid disorders, such as affective or substance use disorders [2
]. Psychotic symptoms are grouped into three dimensions: Positive symptoms (e.g., delusions, hallucinations), negative symptoms (e.g., blunted affect, anhedonia), and cognitive symptoms (e.g., attention, memory, executive functioning; see for reviews [4
]). Different combinations of symptoms and comorbidity lead to different clinical profiles and treatment needs. However, the pharmacological treatment of schizophrenia is mainly based on dopamine blockade, the effect of which is limited to the positive symptoms [7
]. Moreover, two-thirds of the patients experience a suboptimal response with dopaminergic treatment [8
], and these results are even worse when comorbid substance use disorders (SUDs) are present [9
]. 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
]). The cannabinoid receptors are predominantly present in the central nervous system, in particular, in several limbic and cortical brain structures [12
]. The eCB system is a retrograde messenger system that regulates both excitatory glutamate and inhibitory GABA neurotransmission according to an ‘on-demand’ principle: Endocannabinoids are released when and where they are needed [10
]. 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
]. 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
The role of the eCB system in the pathophysiology of schizophrenia has been suggested in an accumulating amount of evidence [20
]. First, epidemiological studies suggest that cannabis use increases the risk for developing schizophrenia [22
] and lowers the age of onset of the disorder [23
]. 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 Δ9-tetrahydrocannabinol; THC) [22
]. 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, effects that resemble negative symptoms (e.g., blunted affect, lack of spontaneity) and deficits in cognition (reviewed in [28
]). Importantly, in schizophrenia patients, enhanced levels of endocannabinoids were demonstrated in cerebrospinal fluid and blood [29
], and increased CB receptor density and availability were shown in the brain [32
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
]). 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 [35
]. 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
]. Finally, endocannabinoid concentrations are affected by active drug seeking behaviour and eCB signalling seems to modulate the rewarding effects of addictive drugs [38
SUDs and psychotic disorders such as schizophrenia co-occur frequently. Prevalence rates of any SUD (excluding nicotine and caffeine) in patients with schizophrenia are up to 45% [39
], with the most frequently used substances being cannabis and alcohol. Considering nicotine use disorders, the prevalence rates rise up to 60%–90% [40
]. 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 [40
]. In addition, SUDs are also related to poor medication adherence, increasing the risk of relapse [39
]. For example, in patients with schizophrenia, cannabis use has been related to higher relapse rates, increased severity of symptoms, and poor outcome [41
]. 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) effects 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
]. In addition, CBD may lower the risk for developing psychosis that is related to cannabis use [48
]. These effects are possibly mediated by the opposite effects 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 [28
]. Therefore, CBD displays a highly favourable profile for development as a new antipsychotic agent [48
]. Similarly, CBD may serve as a treatment for SUDs, since evidence from preclinical studies suggests that CBD reduces negative withdrawal effects, motivation for self-administration, and reinstatement of drug use [37
]. 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 effects of CBD in both disorders. However, one may expect that CBD treatment may be most effective 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
]) 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 efficacy 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.
4. Discussion and Conclusions
The current review aimed to provide a detailed and up-to-date systematic literature overview of studies that investigated the efficacy of CBD treatment for schizophrenia and/or SUD. Based on this overview, a second aim was to examine whether there is a specific subgroup of patients with schizophrenia, SUD, or both that may benefit most from CBD treatment. In some but not all studies, CBD seemed effective as a treatment for psychosis and SUD. CBD may have the capacity to alleviate positive, negative, and cognitive symptoms in schizophrenia, as well as craving and withdrawal in SUD. Although most of the studies showed promising results, differences in study design, patient population, and use of concomitant medication make it difficult to define specific subgroups to whom CBD should be administered. In addition, CBD doses and administration were different between studies and most of the reviewed studies did not describe the source of CBD (i.e., synthetic or cannabis extracted), which may have different efficacy. However, the results of the reviewed studies suggested some features that may contribute to the identification of patients who may benefit most from CBD treatment.
Research into CBD treatment for psychosis provided evidence for a few possible clinical and biological characteristics of the subgroup. The effects of CBD were studied in patients in both early and later stages of psychotic disorders. Overall, acutely psychotic and early onset patients demonstrated reductions of positive and negative symptoms [51
], while treatment resistant and chronic patients showed less promising improvement [56
]. Even though Makiol and Kluge (2019) described a chronic schizophrenia patient who exhibited great clinical improvement (i.e., change of total PANSS score: 49) [53
], the majority of the results suggest that CBD may be more effective in the early stage of psychotic disorders. This is in line with previous studies suggesting that immune dysregulation (i.e., microglial activation) is mainly involved in the early stage of psychotic disorders [67
]. As cannabinoid receptors are also present on microglia, it is possible that CBD exerts its effects by decreasing microglial activity [69
]. Furthermore, anandamide levels in serum could serve as a possible biomarker for the efficacy of CBD treatment. For instance, Leweke et al. (2012) reported a significant increase in anandamide levels after CBD treatment, which was associated with the improvement of psychotic symptoms (i.e., decrease of total PANSS score) [54
]. This is in concurrence with a previously reported inverse association between elevated anandamide levels in cerebrospinal fluid and psychotic symptoms in antipsychotic-naïve patients [29
Research into CBD treatment for SUD primarily focussed on cannabis dependence. Taken collectively, CBD shows promise in the treatment of cannabis dependence as it reduces craving and withdrawal in almost all studies. However, these studies have heterogeneous study designs and administration methods. The differences in administration and dosages may provide a possible explanation for the different results observed in the included studies. For instance, THC/CBD mixtures might be more effective in reducing some features of cannabis dependence (i.e., craving, use and withdrawal) than pure CBD. Moreover, the level of cannabis dependence and intrinsic motivation for treatment, may help to define a possible subgroup of patients in which CBD is more effective. Dependent users (i.e., those with a severity dependence scale score ≥3), showed reduced anxiety, depression, and psychotic-like symptoms after a 10-week treatment with CBD, compared with nondependent users [63
]. However, studies that include individuals with more symptoms at baseline can show greater reductions after treatment. Therefore, it is difficult to determine whether symptom severity is truly a patient characteristic that could predict better outcomes after CBD treatment. Solowij et al. (2018) also found that cannabis-related experiences decreased after treatment [63
], which is in accordance with previous studies that indicate that CBD counteracts the effects induced by THC [46
]. Intrinsic motivation for treatment seems an important aspect as well, as it may increase medication adherence [65
]. Conversely, patients that do not seek treatment are less inclined to follow strict study protocols [66
]. The majority of the discussed studies recruited individuals with cannabis dependence from the community, which suggests that these individuals were at least open for treatment. To a certain extent, this may explain why the study by Schipper et al. (2018) found that CBD administration was not effective [66
], as they included individuals that did not seek treatment.
Considering the efficacy of CBD in both psychotic disorders and SUD, one can speculate that CBD should also be effective in the treatment of the comorbidity. However, only Schipper et al. (2018) studied this population, with negative results [66
]. As discussed previously, these patients were treatment resistant for SUD and showed lack of motivation for treatment. An additional limitation of this study was the good baseline functioning in five out of seven patients. Moreover, this study administered CBD in a formulation that contained very little THC, which possibly explains why the participants preferred street cannabis.
Future studies could take these limitations into account and should focus on examining the effects of CBD in the different stages of psychotic disorders, considering the high prevalence of comorbid SUD. Studies into psychotic disorders could use CBD (i.e., either as monotherapy or add-on) to treat psychotic symptoms and to prevent relapse in early stages, while exploring the effects on comorbid substance use (e.g., cannabis). These studies should use standardized measures to assess cannabis use. In later stages and comorbid treatment-resistant SUD, CBD studies may aim to reduce cannabis use, using harm-reduction strategies (e.g., gradually shift the THC/CBD ratio in medicinal cannabis in favour of CBD) [70
]. Currently, nine ongoing clinical trials that study the effects of CBD on psychotic disorders or SUD (including alcohol and cocaine misuse) are registered in clinicaltrials.gov
, of which one (NCT03883360) includes patients with recent-onset psychotic disorder and cannabis use. Therefore, more results on this topic are expected in the near future.
It remains unclear if the efficacy of CBD in schizophrenia, addiction, and their comorbidity could be explained by shared or different biological mechanisms. To elucidate this, future efforts should be taken to study the relationship between the eCB system, GABA/glutamate, and the immune system. For example, neuroimaging studies (e.g., positron-emission tomography, PET and magnetic resonance spectroscopy, MRS) could measure CB1 receptor densities and markers for glia in patients with schizophrenia and/or SUD who were treated with CBD.
In conclusion, CBD treatment is a promising and novel tool with several potential applications in the treatment of psychotic disorders, substance use disorders, and their comorbidity. Large-scale trials are needed to establish its clinical utility.