cbd antipsychotic

December 15, 2021 By admin Off

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 [34,35,36,37]). 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 [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 [34,36]. Finally, endocannabinoid concentrations are affected by active drug seeking behaviour and eCB signalling seems to modulate the rewarding effects of addictive drugs [38].

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 [2,3]. 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 [4,5,6]). 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.

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 [22] 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 Δ9-tetrahydrocannabinol; THC) [22,25,26,27]. 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, 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 [29,30,31], and increased CB receptor density and availability were shown in the brain [32,33].

1. Introduction.

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 [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 [10,11,13]. 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 [14,15,16,17]. 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].

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 [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 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 efficacy 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 effects in the early stages of illness. A potential biomarker is the level of anandamide in blood. CBD and THC mixtures showed positive effects 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 effects of CBD on psychotic disorders in different stages of illness, together with the effects on comorbid substance use. These studies should use standardized measures to assess cannabis use. In addition, future efforts should be taken to study the relationship between the eCB system, GABA/glutamate, and the immune system to reveal the underlying neurobiology of the effects of CBD.

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., [37,48,49]) 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 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.

Clinical trials and case reports published up to February 2019, which described the effects of CBD on the symptomatology of psychotic disorders (i.e., schizophrenia and related disorders), SUD, or both were included. Reviews, non-English articles, pre-clinical or animal studies, studies that investigate CBD tolerability and pharmacokinetics or compare the acute effects of CBD with THC, and articles describing psychiatric or neurologic disorders other than psychotic disorders and SUD were excluded.

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% [39,40], 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 [41,42,43,44,45]. 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) effects of the intervention on substance use.

A literature search was conducted in the PubMed database. The following two searches were used: (1) “(((cannabidiol [MeSH Terms]) OR CBD[Text Word])) AND ((((((Substance-Related Disorders[MeSH Terms]) OR addiction[Text Word]) OR addictive behavior[Text Word]) OR drug abuse[Text Word])) OR drug dependence[Text Word])”, (2) “(((((((Schizophrenia Spectrum and Other Psychotic Disorders[MeSH Terms])) OR schizophrenia[Text Word]) OR schizophrenic[Text Word]) OR psychosis[Text Word]) OR psychotic[Text Word])) AND ((cannabidiol[MeSH Terms]) OR CBD[Text Word])”.

2. Experimental Section.

The searches resulted in 214 articles, which included one duplicate ( Figure 1 ). The articles were screened by two authors independently, according to the PRISMA guidelines [50]. After full-text screening, ten articles from the systematic search were included and six additional papers were selected through references in other papers. Of these 16 included articles, seven studies were related to CBD treatment for schizophrenia and eight studies described the treatment of SUD with CBD-containing compounds. Only one study assessed the effects of the treatment with medicinal cannabis for patients with a psychotic disorder and a comorbid cannabis use disorder.

3. Results.

Conclusion Research on the effects of CBD has been undertaken for many other neuropsychiatric conditions, including its potential use in epilepsy, PTSD, depression, dystonia, and Huntington disorder as well as diseases that involve other organs and systems such as inflammation, immune response, ischemia, diabetes, cancer, and many others. Most these indications are at the level of preclinical studies in laboratory animals. 15.

The only CBD formulation approved by the FDA is Epidiolex® (GW Pharmaceuticals) to treat rare forms of epilepsy in children and adolescents and is not currently available for use in schizophrenia. Although there are controlled good laboratory and manufacturing practices (GMP/GLP) and purified synthetic analogs for CBD exist, further safety and efficacy studies are needed.

Anxiolytic effects of CBD The CBD dose-response relationship appears to have a particular feature. The anxiolytic effects of CBD, described in the early 1980s and confirmed by later animal and human studies clearly follow this dose-response pattern. 15 In 1990, CBD was tested in a range of doses in rats with the elevated plus-maze model and was found to act according to a bell-shaped dose-response curve. CBD induced an anxiolytic-like effect only at intermediate doses. 16.

CBD effects on Parkinson psychosis It seems that the antipsychotic effect of CBD is not limited to patients with schizophrenia. Antipsychotic effects of CBD (150 to 400 mg/d) were seen in patients with Parkinson disease who presented with psychotic symptoms for at least 3 months, which could not be controlled by reducing antiparkinsonian drug regimens. 19 In this study, we observed a reduction in psychotic symptoms ( Figure 2 ), in addition to a significant improvement in global functioning (as assessed with the Unified Parkinson Disease Rating Scale and the Clinical Global Impression scale).

This study paved the way for a new, double-blind, placebo controlled RCT with parallel groups of Parkinson patients treated with two doses of CBD (75 and 300 mg/d) for 6 weeks. In an effort to evaluate whether CBD was effective in other Parkinson symptoms, patients with dementia or psychotic symptoms were excluded from the study to avoid the influence of psychotic symptoms. The results showed that CBD induced a significant improvement in non-motor symptoms, including daily life activities and rapid eye movement sleep behavior disorder. 20.


This article was originally published on May 15, 2020, and has since been updated. -Ed.

This dose-response curve was also observed in healthy volunteers subjected to anxiety induced by the simulation of public speaking test and by public speaking in real settings. 17,18 In the first situation, volunteers were asked to speak for a few minutes in front of a video camera, while in the second each subject had to speak in front of a group of other research participants. In both situations, treatment with CBD 300 mg was associated with significant decreases in anxiety symptoms, but this effect was not observed with lower or higher doses.

To date, three randomized controlled trials (RCTs) have evaluated the therapeutic effects of CBD in schizophrenia patients. The first one, using a double-blind procedure, included 39 patients treated with either CBD (800 mg/d; n = 20) or the atypical antipsychotic amisulpride (800 mg/d; n = 19) for 4 weeks. The two drugs led to a similar significant reduction in both positive and negative psychotic symptoms, but fewer adverse effects were seen in the CBD group. 12.

We know that cannabis contains about 100 cannabinoid compounds and that the psychotomimetic effects of the plant are induced by tetrahydrocannabinol (THC). 4 We’ve also known since the early 1970s that the effects of cannabis could not be attributed solely to THC. 5 Other cannabinoids have their intrinsic actions, including the significant effects of cannabidiol (CBD). 6.

In the other two RCTs, CBD was administered as an adjunctive treatment for 6 weeks with placebo control; however, the results were contradictory. CBD treatment (1000 mg/d; n = 42) was associated with a significant reduction in positive symptoms from baseline to the endpoint compared with placebo (n = 44) in one study ( Figure 1 ). 13 Results from the other RCT, which used a very similar methodology but a lower CBD dose (600 mg/d; n =20), found no significant symptomatic differences between treatments with CBD and placebo (n = 19). 14 A possible explanation for the contradictory results may be the difference in CBD doses (600 mg vs 1000 mg).

Antipsychotic properties of CBD In 1982, a study of the interactions between THC and CBD in healthy volunteers provided the first evidence that CBD might have antipsychotic properties. Our group administered oral CBD concomitantly with a high dose of THC to investigate whether CBD could attenuate THC-induced anxiety. Surprisingly, in addition to alleviating anxiety, CBD reduced the psychotic symptoms commonly induced by THC. 7.

The same response pattern was observed in preclinical tests using other models of induced anxiety, cognitive impairment, and schizophrenia-like behavior. 18 The findings suggest that this inverted U-shaped curve response pattern may be extended to other therapeutic effects of CBD, with different effective doses and therapeutic windows for each condition.

Effects of CBD on schizophrenia The next step was to evaluate the effects of CBD in a patient with schizophrenia. The patient was a chronically psychotic woman with many adverse effects from traditional antipsychotics, which provided the ethical justification for this first clinical test. After 4weeks of treatment, the patient had a marked reduction in her psychotic symptoms as assessed by standardized rating scales. This published case report stimulated the undertaking of randomized controlled clinical trials (RCTs). 11.

The association between Cannabis sativa (cannabis) and psychosis is as old as its history. The Pen-ts’ao ching, the world’s oldest pharmacopeia attributed to the Chinese emperor Shen-Nung (2700 BC), says “ . . . ma-fen (the fruit of cannabis) if taken in excess will produce visions of devils . . . over the long term, it makes one communicate with spirits.” 1 In the West, acute administration of cannabis was used as an experimental psychotomimetic by Jacques-Joseph Moreau, a French psychiatrist, in the 19th century, and it continues to be used to this day. 1,2 This acute psychotomimetic effect is transitory; however, consistent evidence indicates that the chronic and intense use of the plant, especially if started in adolescence, contributes to the occurrence of schizophrenia. 3.

The early observation that CBD reduced THC-induced psychotic symptoms led us to carry out a pioneering study to test the effects of CBD in a model commonly used to identify drugs with an antipsychotic profile in laboratory animals. 9 The stereotypy induced in rats by a dopaminergic agonist was clearly reduced by CBD, without producing catalepsy (which is associated with the extrapyramidal adverse effects of classical antipsychotic drugs). This finding suggests that CBD has an atypical antipsychotic pattern. A series of other tests with different animal models confirmed and expanded the antipsychotic profile of CBD. 10.


Further mechanisms that could clarify the antipsychotic action of CBD include its ability to increase in hippocampal neurogenesis and neuroprotection, its interaction with 5HT1A, GPR55, and TRPV1 receptors, and its antioxidant and anti-inflammatory effects. For instance, some second-generation antipsychotics, such as ziprasidone and aripiprazole, also activate 5-HT1A receptors, which may, at least in part (in addition to the non-involvement of dopamine antagonism), explain the absence of extrapyramidal adverse effects of CBD. 10.

Mechanisms of action The specific pharmacological mechanisms underlying the antipsychotic action of CBD are not fully understood as this compound seems to interfere with neurotransmitter systems in diverse ways. 10 For instance, CBD inhibits the reuptake and metabolism of anandamide, which may be implicated in the antipsychotic effect of CBD, as the concentrations of this endocannabinoid in the cerebrospinal fluid of patients with schizophrenia are higher than those of controls, and are inversely correlated with psychotic symptoms. It suggests a feedback mechanism in which the anandamide increase outweighs the occurrence of psychotic symptoms. Moreover, prodromal psychosis patients present higher anandamide levels in the CSF than controls. 12 The clinical improvement produced by CBD in the patients with schizophrenia has been linked with increased CSF anandamide levels. The effects of CBD on anandamide regulation in different brain regions associated with the pathophysiology of schizophrenia could explain its antipsychotic action. 8.

More recently, this observation was confirmed in a study with THC administrated intravenously after oral pretreatment with CBD or placebo. 8 In addition to blocking the psychotic symptoms induced by THC, CBD and THC presented opposite effects relative to placebo in terms of activation of the striatum during verbal recall, as assessed by functional magnetic resonance imaging (fMRI).

It is essential to point out that CBD presents multiple actions in the CNS that may have a crucial role in the pharmacotherapy of the motor and non-motor effects of PD. This cannabinoid was shown to have neuroprotective properties by enhancing the recycling of old/damaged cell components via the facilitation of autophagic action. 15 Moreover, CBD exerts antioxidant activities, stimulates neurogenesis, regulates mood and sleep, improves cognition and motor activity and, restores dendritic arbor and BDNF levels in the hippocampus. 10.

Dr Zuardi is Full Professor, Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Brazil. Dr Crippa is Full Professor, Department of Neuroscience and Behavior, School of Medicine of Ribeirão Preto, University of São Paulo, Hospital das Clinicas Ribeirão Preto, São Paulo, and a member of the National Institute of Science and Technology for Translational Medicine, Brazilian National Council for Scientific and Technological Development, Brasília, Brazil. He is also a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE – National Health and Medical Research Council, NHMRC). T he authors report that they are coinventors of the patent “Fluorinated CBD compounds, compositions and uses thereof.” They are also recipients of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) productivity fellowships. In addition, Dr Crippa has received travel support from BSPG-Pharm, and he has received a grant from the University Global Partnership Network (UGPN)-Global priorities in cannabinoid research excellence program.

Accordingly, data from the three CBD RCTs in schizophrenia patients mentioned above suggest that the dose range to reduce psychotic symptoms (probably between 800 and 1000 mg/d), but not cognitive symptoms, should be higher than that used to induce anxiolytic effects (between 200 and 400 mg/d). However, precise dose ranges for each condition or symptom are yet to be determined in future RCTs with larger samples, different clinical populations, and multiple doses.

CBD can be easily purchased throughout most of the US, which raises concerns about the use of handcrafted, uncontrolled cannabis-enriched CBD. There are well-known harmful long-term effects of THC on the developing brain, cognitive impairments associated with cannabis, and worsening of psychotic symptoms and antipsychotic response, particularly in younger patients. Therefore, well-designed RCTs with larger samples using high-quality and reliable CBD are needed to ascertain the effectiveness and safety of CBD as an antipsychotic medication and for it to be FDA approved for use in schizophrenia.

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