Cbd oil as treatment for psychosis

Cannabidiol as a potential treatment for psychosis

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Abstract

Psychotic disorders such as schizophrenia are heterogeneous and often debilitating conditions that contribute substantially to the global burden of disease. The introduction of dopamine D2 receptor antagonists in the 1950s revolutionised the treatment of psychotic disorders and they remain the mainstay of our treatment arsenal for psychosis. However, traditional antipsychotics are associated with a number of side effects and a significant proportion of patients do not achieve an adequate remission of symptoms. There is therefore a need for novel interventions, particularly those with a non-D2 antagonist mechanism of action. Cannabidiol (CBD), a non-intoxicating constituent of the cannabis plant, has emerged as a potential novel class of antipsychotic with a unique mechanism of action. In this review, we set out the prospects of CBD as a potential novel treatment for psychotic disorders. We first review the evidence from the perspective of preclinical work and human experimental and neuroimaging studies. We then synthesise the current evidence regarding the clinical efficacy of CBD in terms of positive, negative and cognitive symptoms, safety and tolerability, and potential mechanisms by which CBD may have antipsychotic effects.

Introduction

Psychotic disorders such as schizophrenia are heterogeneous and often debilitating conditions that contribute substantially to the global burden of disease. 1 Patients with psychosis present with a range of psychopathology across positive, negative and cognitive symptom domains. The introduction of dopamine (primarily D2) receptor antagonists in the 1950s revolutionised the treatment of psychotic disorders and they remain the mainstay of our treatment arsenal for psychosis. 2 However, a significant proportion of patients either do not respond to traditional antipsychotics or do not achieve a complete or adequate remission of symptoms. 3 In addition, most current antipsychotics only target the positive symptoms of psychosis, with little effect on negative or cognitive symptoms. 2 Dopamine-acting antipsychotics are also associated with a number of side effects, 4 some of which can be severe and which may contribute to nonadherence. There is therefore a need for novel interventions, particularly those with a non-D2 antagonist mechanism of action, and which may thereby avoid some of the adverse effects of modulating the dopamine system directly. In line with this, over recent years there has been increasing interest in the development of treatments with alternate mechanisms of action. 5

Accumulating evidence implicates the endocannabinoid system in the pathophysiology of psychosis. 6,7 A recent meta-analysis concluded that patients with psychosis have significantly higher levels of the endocannabinoid anandamide both in cerebrospinal fluid and in blood, and higher expression of the main central cannabinoid 1 receptor (CB1) on peripheral immune cells. 8 This elevated endocannabinoid tone was observed at all stages of illness, from the prodrome to chronic psychosis. 8 Alterations in CB1 receptor expression have also been observed in postmortem tissue and in vivo in patients with psychosis. 9 –11 If the endocannabinoid system plays a role in psychosis pathophysiology, it raises the interesting possibility that pharmacological compounds that modulate this system may have therapeutic value.

Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa, has been heralded as one such potential treatment. While the main psychoactive ingredient in cannabis, delta-9-tetrohydrocannabinol (THC), has anxiogenic, psychotomimetic and amnestic effects, CBD is non-intoxicating and has potential anxiolytic, antipsychotic and anticonvulsant properties, and no detrimental effects on memory. 12 Epidemiological findings support these opposing effect profiles; extensive evidence implicates cannabis use as a risk factor for the development of psychosis and poor outcomes in cannabis-using patients. 13,14 –19 However, the adverse effects of cannabis use on the risk of onset and subsequent outcome in psychosis are particularly evident in those using high potency skunk-like cannabis (i.e. with high levels of THC and low levels of CBD) as opposed to those using hash-like cannabis (i.e. with lower THC and higher CBD). 15,20 –22 This pattern of findings is consistent with evidence that CBD not only has opposing effects to THC but may also block some of its adverse (and particularly psychotomimetic) effects. 23,24

Importantly, CBD has a different mechanism of action to dopamine receptor antagonists and could therefore represent a completely novel class of antipsychotic treatment. 25 This would be associated with numerous benefits. First, by avoiding dopamine receptor antagonism, adverse effects such as extrapyramidal symptoms and increased prolactin may be avoided. Second, if CBD acts via different molecular pathways to current antipsychotics, it could be used not only as monotherapy but potentially as an adjunctive treatment alongside existing antipsychotics, with potential complementary gains in efficacy. While CBD is currently being tested in relation to a number of psychiatric disorders and physical health conditions, 12 this review synthesises and summarises the current evidence regarding the therapeutic potential of CBD as a treatment for psychosis.

Evidence for antipsychotic potential of cannabidiol

The accumulating evidence regarding the antipsychotic potential of CBD has emerged from a number of different sources. This includes preclinical work, experimental studies in healthy human volunteers comparing the neurocognitive effects of THC and CBD as well as studies examining whether CBD can block or attenuate the symptomatic effects of THC.

Preclinical evidence

Indirect evidence for the antipsychotic and anxiolytic effects of CBD comes from preclinical studies, where specific features of psychotic disorders are modelled in animals and allow potential therapeutic effects to be examined from molecular to behavioural levels. 26

Hyperlocomotion

Hyperlocomotion is thought to be a model of positive psychotic symptoms and can be rescued using antipsychotics. 26 CBD has been shown to reduce hyperlocomotion induced by amphetamine (dopamine agonist) and ketamine [N-methyl- d -aspartate (NMDA) receptor antagonist] while at the same time not inducing catalepsy, 27 which suggests that it has antipsychotic-like beneficial effects without the detrimental motor side effects, with a profile resembling that of the atypical antipsychotic clozapine. 28

Pre-pulse inhibition deficits

Pre-pulse inhibition (PPI) deficits represent sensorimotor gating abnormalities, thought to be a stable trait (bio)marker that is present across the psychosis spectrum. 29 Peripubertal CBD has been found to prevent the development of PPI deficits in the spontaneously hypertensive rat strain model, 30 which suggests that CBD may have long-lasting prophylactic effects, while it did not negatively impact PPI in control mice.

Social withdrawal and cognition

Methylazoxymethanol treatment induces numerous behavioural and cognitive deficits (social interaction and novel object recognition) as well as a range of pathophysiological manifestations analogous to those in schizophrenia, 31 including altered CB1 expression in prefrontal cortex. Peripubertal CBD reversed the methylazoxymethanol-induced alterations in CB1 expression and the schizophrenia-like phenotype, neither of which are rescued by haloperidol. 32 CBD has been found to reduce social withdrawal induced by THC but not polyinosinic-polycytidylic acid. 33,34 CBD can also attenuate MK-801 (an NMDA receptor antagonist)-induced changes in social behaviours, cognition and expression of various glial markers. 35 These latter findings suggest potential neuroprotective and anti-inflammatory properties of CBD, 12 which is supported by independent evidence that CBD can promote hippocampal neurogenesis and rescue memory function, 36,37 consistent with human studies showing that CBD attenuates THC-elicited cognitive impairment. 23,38

Human experimental and neuroimaging studies

Complementary insight into the antipsychotic potential of CBD has come from neuroimaging studies, which provide a means to noninvasively examine the systems (i.e. neural substrates) on which CBD may act to produce its antipsychotic and anxiolytic effects in vivo.

THC and CBD have been shown to have opposite effects on regional brain activation across a variety of cognitive tasks in healthy individuals. 24 Interestingly, this has been found in brain regions where patients with psychosis show dysfunction and during tasks that are known to be impaired by cannabis use. Using a double-blind, placebo-controlled, repeated-measures design, 15 healthy volunteers were studied on three occasions with functional magnetic resonance imaging (fMRI) after receiving a single dose of CBD (600 mg), THC (10 mg) or placebo. 24 In this series of experiments, THC-induced psychotic symptoms were directly related to the attenuating effects of THC on striatal activation during verbal recall and salience processing, 24,39 suggesting that the psychotogenic effects of THC may be mediated in part by effects on the striatum. In contrast, CBD augmented activation in the same regions during the task and did not induce psychotic symptoms. When viewing fearful faces, THC augmented activation in the amygdala, which was associated with induction of anxiety symptoms and increased physiological anxiety (measured using skin conductance response). 24 Conversely, CBD attenuated amygdala activation and this was significantly associated with the concurrant CBD-induced decrease in physiological anxiety (skin conductance response), suggesting that these effects may account for the anxiolytic properties of CBD. THC and CBD also had directly opposing effects on activation in the hippocampus during response inhibition, 24 the superior temporal cortex when listening to speech, 24 the occipital cortex during visual processing and on functional connectivity within regions processing attentional salience. 24,40

Further evidence for the protective effects of CBD against the psychotomimetic, anxiogenic, and cognition-impairing effects of THC comes from experimental studies where the two cannabinoids have been co-administered. THC can be used as an experimental model of psychosis in humans because its acute administration in healthy individuals can induce transient psychotic-like symptoms (including both positive and negative symptoms), as well as cognitive deficits resembling those seen in schizophrenia. 41 –47 In one study, six healthy volunteers received intravenous THC (1.25 mg) on two occasions, once preceded by intravenous placebo and once by CBD (2.5 mg) in a double-blind, within-subject design. 24 At the group level, THC administration with placebo pretreatment was associated with transient psychotomimetic effects, which was not observed under the CBD pretreatment condition. 24 A larger between-group study (n = 48) showed that relative to placebo, pretreatment with 600 mg oral CBD reduced the paranoia and impairments in episodic memory elicited by 1.5 mg intravenous THC. 23

In summary, a growing body of literature suggests that CBD attenuates the propsychotic, anxiety and cognitive effects elicited by THC in healthy individuals at both the neurophysiological and behavioural (psychopathological) level. In addition, CBD has opposite effects to THC on regional brain activation and functional connectivity across a range of cognitive tasks (including salience processing, learning and memory, response inhibition and fear processing) in regions known to be disrupted in patients with psychosis. 24,39,40 Together, this accumulating evidence supports a potential therapeutic role for CBD in the treatment of psychosis and is consistent with independent evidence that CBD has antipsychotic effects in patients with the disorder (see below).

Cannabidiol in psychosis: current clinical evidence

Positive and negative psychotic symptoms

Initial studies

The 1990s saw the first studies investigating the effects of CBD in patients with psychosis. Results from a single (n = 1) case study of a 19-year-old female with acutely exacerbated schizophrenia reported that oral CBD, titrated up to 1500 mg/day over 4 weeks, was associated with a reduction in psychotic symptoms as measured with the Brief Psychiatric Rating Scale (BPRS). 48 A subsequent case series examined the effects of oral CBD monotherapy (up to 1280 mg/day) for 30 days in three patients with treatment-resistant schizophrenia. 49 Here, one patient showed mild improvement in BPRS scores while two did not, but CBD was well tolerated: there were no side effects reported even up to the maximum dosage. 49 CBD has now been investigated in a number of larger-scale studies including randomised controlled trials ( Table 1 ). The current review was not intended to be a fully systematic review, but to our knowledge, the information regarding previous clinical trials of CBD in psychosis is a complete and accurate record of all relevant studies up to July 2019.

Table 1.

Overview of studies investigating cannabidiol in patients with psychosis.

Study Design CBD regimen Outcome assessment Results
Zuardi 48 One patient with schizophrenia; open label case-report Up to 1500 mg/day for 4 weeks BPRS Significant reduction in positive symptoms
Zuardi 49 3 treatment-resistant patients with schizophrenia; open-label monotherapy case series Up to 1280 mg/day for 4 weeks BPRS Mild improvement in one patient, no response in two patients
Zuardi 50 Six patients with Parkinson’s disease with psychotic symptoms; open-label pilot study Up to 600 mg/day for 4 weeks BPRS, Parkinson Psychosis Questionnaire Significant reduction in psychotic symptoms
Zuardi 51 Two patients with bipolar I disorder experiencing a manic episode with psychotic features; rater-blinded case series Up to 1200 mg/day for 24 days Young Mania Rating Scale, BPRS No symptomatic improvement after CBD monotherapy either alone (n = 1) or in addition to improvements following CBD plus olanzapine (n = 1)
Hallak 52 28 patients with schizophrenia; baseline performance compared with that after placebo (n = 10), 300 mg CBD (n = 9) or 600 mg CBD (n = 9) administration 1 month later Single dose of 300 or 600 mg Stroop Colour Word Test Stroop test performance significantly improved in placebo and 300 mg CBD group; numerical (nonsignificant) improvement in 600 mg CBD group
Leweke 53 39 patients with schizophrenia; randomised, double-blind, monotherapy trial of CBD (n = 19) compared with the antipsychotic amisulpride (n = 20) Up to 800 mg/day for 4 weeks BPRS, PANSS Significant reduction in positive, negative, total and general symptoms in both groups. Significantly fewer side-effects in CBD group
Leweke 54 29 patients with schizophrenia; randomised, double-blind, placebo-controlled crossover study 600 mg/day for 2 weeks PANSS Numerical but nonsignificant improvement in psychotic symptoms associated with CBD treatment
McGuire 55 88 patients with schizophrenia; randomised, double-blind trial of add-on CBD (n = 43) versus placebo (n = 45) 1000 mg/day for 6 weeks PANSS, CGI, GAF, Cognition Significant reduction in positive symptoms and CBD-treated patients more likely rated as improved/not as severely unwell by treating clinicians (CGI)
Boggs 56 36 patients with schizophrenia; randomised, double-blind trial of add-on CBD (n = 18) versus placebo (n = 18) 600 mg/day for 6 weeks PANSS, MATRICS No effects of CBD on cognition or positive, negative or total symptoms
Bhattacharyya 57 33 patients at CHR for psychosis; randomised, double-blind design; 16 CHR subjects assigned to CBD and 17 to placebo; 19 controls Single dose of 600 mg fMRI (brain activation during verbal learning task) CBD normalised brain function in CHR individuals in regions where CHR individuals showed abnormal activation under placebo

BPRS, Brief Psychiatric Rating Scale; CBD, cannabidiol; CGI, Clinical Global Impression Scale; CHR, clinical high risk; fMRI, functional Magnetic Resonance Imaging; GAF, Global Assessment of Functioning Scale; MATRICS, MATRICS Consensus Cognitive Battery (MCCB); PANSS, Positive and Negative Syndrome Scale.

CBD as monotherapy
CBD as adjunctive treatment

More recently, in a 6-week multicentre, randomised, double-blind, parallel-group trial, CBD (1000 mg/day; n = 43) was compared with placebo (n = 45) as an add-on treatment to existing antipsychotic regimens in patients with schizophrenia. 55 There was a significant reduction in PANSS positive symptoms from baseline to 6-week study endpoint in the CBD compared with the placebo group (PANSS treatment difference = −1.4, 95% CI = −2.5 to −0.2; p = 0.019). CBD-treated patients were also more likely to have been rated as improved (Clinical Global Impression Scale; CGI-I treatment difference = −0.5, 95% CI = −0.8 to −0.1; p = 0.018) and as not severely unwell (–0.3, 95% CI = −0.5 to 0.0; p = 0.044) by the treating clinician. 55 Although the magnitude of these effects appears modest, it is common for treatments to fail in add-on trial designs because the tested treatment needs to show an effect over and above that of the existing treatment (here, antipsychotics, which have relatively large effect sizes). 4,63,64 The fact that CBD produced such an additional effect over that of concomitant antipsychotic treatment is therefore promising. There were also numerical (but nonsignificant) increases in the level of general functioning [Global Assessment of Functioning (GAF) scale treatment difference = 3.0, 95% CI = −0.4 to 6.4; p = 0.08] and cognitive performance in the CBD treatment arm compared with the placebo arm, but no significant differences emerged in a number of other outcomes, including on negative, total and general PANSS scores. 55 The number of adverse events was similar between the CBD (30 adverse events in 15 patients) and the placebo (35 adverse events in 16 patients) treatment arms, with the most common side effects including diarrhoea, nausea and headache. Most side effects were mild and did not require intervention.

Using similar methodology in a 6-week, randomised, parallel-group trial, Boggs and colleagues compared 600 mg/day adjunctive CBD versus placebo in 36 stable, antipsychotic-treated patients with chronic schizophrenia. 56 In this latter study, there were no effects of adjunctive CBD relative to placebo on positive, negative or total PANSS symptoms, nor were there any effects on cognitive performance (the primary outcome of the trial, measured using the MATRICS consensus battery; MCCB). In fact, only the placebo group were found to have improved MCCB composite scores over time, which the authors suggest may be due to regression to the mean or practice effects, with this pattern not seen in the CBD group, perhaps due to increased sedation or inhibited learning effects. 56 Overall, CBD was well tolerated, with no worsening of psychosis, mood, suicidality or movement side effects.

The reasons for the contrasting results with the two larger clinical trials remain unclear and warrant consideration. 53,55 One factor could be the lower CBD dose (600 mg/day) used by Boggs and colleagues, 56 compared with the higher doses of 800 and 1000 mg/day in the earlier trials. 53,55 While 600 mg (even as a single acute dose) has been shown to modulate brain function across a variety of tasks in healthy individuals, and can prevent the acute induction of psychotic symptoms following THC, 24 it is possible that a higher therapeutic dose is needed in the context of patients with psychosis. 56 This is consistent with the results from a further earlier study, which also used 600 mg/day in patients with schizophrenia, and which showed nonsignificant results for total PANSS symptom reduction, 54 although there were also a number of design issues associated with this study. Research conducted outside of the psychosis literature suggests that specific effects of CBD follow an inverted-U dose-response curve. This could have pragmatic implications for CBD as a novel pharmacotherapy because individual-patient dose titration would introduce practical challenges in the clinic. In two studies testing multiple doses of acute CBD against anxiety induced by public speaking, only the intermediate doses of CBD (300 mg) significantly reduced anxiety while lower and higher doses did not. 65,66 Animal models of anxiety confirm this dose-response effect, with anxiolytic effects observed at lower doses which disappear at higher doses. 12,67 However, the dose-response range is thought to be narrower for the anxiolytic compared with the antipsychotic effects of CBD, 67,68 at least in preclinical studies. 28 Higher doses are also likely required for antipsychotic versus anxiolytic effects (for review see Crippa and colleagues). 12 Future research is required to determine the precise dose-response ranges for specific therapeutic (i.e. antipsychotic and anxiolytic) effects for specific psychotic disorders and other clinical popluations. 12

Other possible factors that may explain lack of beneficial effect of CBD treatment in the study by Boggs and colleagues may relate to illness stage and symptom severity of the respective samples. 56 The participants in the negative Boggs and colleagues study were older (mean age = 47) and had chronic schizophrenia with stable symptoms, whereas those in the study of Leweke and colleagues were younger (mean age = 30) and were included only if they specifically had an acute exacerbation of psychotic symptoms. 53 This is reflected in the higher mean baseline symptom scores in the Leweke study (PANSS total = 93; positive = 24) compared with the Boggs and colleagues study (total = 80; positive = 20). 53,56 However, the negative findings are harder to reconcile with the positive findings of McGuire and colleagues, 55 where the levels of symptoms were comparable (PANSS total = 80; positive = 18) and the mean age was 41 years. The Boggs and colleagues and McGuire and colleagues studies also took a similar methodological approach (add-on design), 55,56 although the McGuire study had much higher statistical power (n = 88 versus n = 36). Together, these findings may suggest that younger patients in an earlier stage of illness may benefit more from CBD treatment, potentially because intervening early arrests pathophysiological processes before more severe or enduring neural changes (that may be less amenable to later intervention) take place. 5 A further potential difference between the studies relates to the existing antipsychotic treatment regimens within the add-on design. While McGuire and colleagues provide specific data on the exact antipsychotic medications used by their sample, only summary classification data are provided by Boggs and colleagues. 55,56 Nevertheless, in comparison, over 90% of the antipsychotics used in both the CBD and placebo groups from the McGuire study were second-generation, and only ~8% were first-generation. However, in the Boggs study, 55% of the CBD group and 72% of the placebo group were taking second-generation antipsychotics, while 50% of the CBD group and 28% of the placebo group were taking first-generation. Current evidence suggests there are small but significant differences in efficacy between different individual antipsychotics within both first and second-generation classifications. 4 It is therefore possible that the different baseline mix of concurrent antipsychotics could be a contributing factor to the disparity in results.

Potential effects of CBD on cognition

The psychopathology associated with psychotic disorders is often thought of in terms of positive and negative symptoms. However, cognitive dysfunction is a prominent feature that is strongly associated with loss of social/occupational function and disability. 69,70 Cognitive symptoms are also refractory to any type of current treatment. 2 A number of initial studies have examined whether CBD may improve aspects of cognition in patients with psychosis.

As outlined above, the clinical trial by Boggs and colleagues observed no significant effects of CBD on cognition, which was the study’s primary outcome. 56 The largest clinical trial of CBD in patients with psychosis also assessed cognition, using the Brief Assessment of Cognition in Schizophrenia (BACS). 55 While there were no statistically significant effects of CBD on cognition overall, there were numerical increases in BACS composite score, motor speed performance and executive functioning in the CBD relative to the placebo group. 55 Studies of CBD administration in healthy people also show that CBD can attenuate the acute amnestic effects of THC administration, 23 while it does not appear to affect learning and memory in the absence of existing impairments. 71

A separate study examined the acute effects of a single dose of CBD on cognitive function in 28 patients with schizophrenia. 52 Performance on the Stroop Colour Word Test, which indexes selective attention, was compared at baseline (no drug) to one of three parallel-arm conditions 1 month later: placebo (n = 10), 300 mg CBD (n = 9) and 600 mg CBD (n = 9). While performance improved (numerically) in all three arms from baseline to the second session, indicating a learning effect, only those receiving placebo and the lower CBD dose (300 mg) showed a statistically significant improvement. 52 The authors suggest that sedative effects of CBD may underlie the lack of improvement (related to learning/practice effects) in the higher-dose CBD group. Overall, whether CBD has beneficial effects on cognition in patients with psychosis is currently unclear and remains an important avenue for future research.

Early intervention: prior to psychosis onset

CBD has also been indicated for use prior to the onset of psychosis in patients at clinical high risk for the disorder. These individuals present with clinically significant attenuated psychotic symptoms and have 20–30% risk of developing psychosis within 2 years. 72 Accumulating evidence suggests that the pathophysiological processes driving psychosis evolve over the course of the disorder, with the clinical high-risk state offering a unique opportunity for preventative intervention. 5 However, recent meta-analyses have concluded that existing treatments are not effective for preventing transition to psychosis nor for reducing symptoms, 73,74 representing a significant unmet clinical need. Furthermore, because many of these individuals will not transition to psychosis, pharmacotherapies also need to be safe and well tolerated.

Using a randomised, double-blind, placebo-controlled, parallel-arm design, 33 antipsychotic-naive individuals at clinical high risk for psychosis and 19 healthy controls were studied using a verbal learning fMRI task. 57 A total of 16 high-risk subjects received a single oral dose of CBD (600 mg) and 17 received placebo. Control participants were not given any drug. The results showed that a single dose of CBD normalised brain function in clinical high-risk individuals in regions where high-risk individuals showed abnormal activation under placebo conditions. These specific regions, including the hippocampus, midbrain and striatum, are also strongly implicated in the pathophysiology of psychosis onset. 75,76 The normalisation of aberrant brain function in these regions by CBD could underlie the therapeutic effects observed in previous studies in patients with established psychosis and anxiety disorders. 53,55,77

In terms of effects following continued treatment, results from the same study investigating the effect of 3-week treatment with CBD (600 mg/day) on symptoms and functional brain activation are awaited. 78 In summary, initial evidence supports CBD as a potential novel treatment for people at clinical high risk for psychosis, and its benign side-effect profile as evident from other data (see below) makes it a particularly suitable candidate treatment for this patient group. Whether CBD can actually alter the course of the disorder and prevent the onset of psychosis will require larger-scale clinical trials over longer durations. Such studies have recently been initiated and the results are anticipated to make a significant contribution to the evidence base.

Psychosis in nonschizophrenia spectrum disorders

Additional complementary evidence for the use of CBD in psychosis comes from a study of Parkinson’s disease psychosis. In a small, open-label pilot study, six patients with Parkinson’s disease psychosis received oral CBD for 4 weeks, titrated from a mean dose of 150–400 mg/day in addition to their current treatment regimens. 50 CBD was associated with a significant decrease in psychotic symptoms and was well tolerated, with no side effects clinically observed. CBD also improved total scores on the Unified Parkinson’s Disease Rating Scale and did not worsen cognition or motor function. While caution is warranted due to the small sample size and lack of placebo control, these results support the view that CBD is safe, well-tolerated and may have efficacy for the treatment of psychosis in nonschizophrenia spectrum disorders. Phase II clinical trials of CBD for Parkinson’s disease psychosis and behavioural symptoms (including psychotic symptoms) in Alzheimer’s disease are now being planned.

In addition to its antipsychotic properties, the wider pharmacological profile of CBD, which includes anxiolytic, sedative, anticonvulsant and thus potential mood-stabilising effects, raises the possibility of therapeutic potential for bipolar disorder (with or without psychosis) as well as unipolar mood disorders. 12,79 Aside from anecdotal reports, 79 CBD has so far been tested in two patients with bipolar I disorder experiencing a manic episode with psychotic features. 51 Two female inpatients received placebo for 5 days, followed by oral CBD titrated from 600 to 1200 mg/day for 24 days. One patient received concomitant olanzapine between day 6 and 20, while the other patient did not. Symptoms were assessed using the BPRS and Young Mania Rating Scale. CBD provided no additional benefit over that seen after combined CBD and olanzapine treatment in the first patient, and there was no benefit of CBD monotherapy in the second patient. 51 These negative findings concur with the lack of CBD effects seen in an animal (hyperlocomotion) model of mania. 80 Nevertheless, whether CBD is effective for other specific symptoms in bipolar disorder (such as bipolar depression and anxiety) is currently unknown but clinical trials are now underway. 12 While outside the remit of this review, it is also worth noting that CBD has purported antidepressant-like effects (albeit so far in preclinical studies), thought to be mediated by serotonin 5-HT1A receptors, 81 which could suggest therapeutic potential for mood disorders such as depression. 12,28

Safety and side effects

While CBD has been found to be safe and well tolerated in the three (relatively short-term) clinical trials in psychosis to date, 53,55,56 the total volume of data is still small and thus insufficient adverse events may yet have accumulated. When measured in terms of ‘patient-years’ (i.e. the number of patients treated with a new drug multiplied by the duration of treatment), data from at least 1000 patient-years or more are recommended for robust estimates of safety and tolerability. 82 This follows the notion that the greater the clinical use and experience of prescribing drugs in different clinical scenarios, the better (and more nuanced) our knowledge of its true risk-benefit profile. However, 1000 patient-years equates to, for example, 1000 patients taking CBD for 1 year or 500 patients for 2 years. The largest RCT of CBD in psychosis to date randomised 43 patients to receive CBD for 6 weeks. 55 This highlights the significant gulf between the current state of knowledge and the benchmark for sufficient risk-benefit evidence. Larger randomised controlled trials with longer durations of treatment are therefore needed.

Considering the wider literature (not restricted to studies in psychosis), doses of up to 1500 mg/day have been well tolerated in humans with few or no side effects, although such doses have mainly been administered to very few patients in case series reports. 28,48,49 The first comprehensive review of CBD-related (in vivo and in vitro) side effects suggested that CBD is nontoxic in cell lines and has no adverse effects on physiological parameters such as heart rate, blood pressure and body temperature, gastrointestinal transit, and psychomotor or psychological function. 83 A second review extended these findings and confirmed that overall, CBD has a favourable safety profile. 84 However, CBD is not entirely side-effect free; in vitro work suggests that CBD may affect cell viability, fertilisation potential and drug transporter/P-glycoprotein function, 83,84 and reports of (mostly mild) clinical adverse effects are starting to accumulate as the body of available literature becomes substantiated. The most common adverse effects in clinical studies include diarrhoea, tiredness or sedation, and changes in appetite and weight. 83

Sedation

The idea that CBD may induce sedation is a recurring theme, 52,56 and there are numerous purported links between the endocannabinoid system and the sleep–wake cycle. One of the earliest studies showed that 600 mg of CBD induced sedation in a small sample of healthy people. 85 In people with insomnia, a therapeutic effect suggestive of sedation (increased sleep time, less frequent awakenings) was noted after 160 mg/day CBD. 86 However, other studies have shown that CBD counteracts the sedative effects of THC, 87 and a recent study investigating the effects of 300 mg CBD (versus placebo) on the sleep-wake cycle reported no effects on sedation, albeit this was in healthy individuals. 88 A review concluded that this effect is dose-based, with lower doses having a stimulating effect on the sleep–wake cycle, but higher doses having a sedative effect. 89 Given the aforementioned evidence that higher doses of CBD are likely needed to produce antipsychotic effects, particularly in patients with psychotic disorders (e.g. 800 mg/day or more), sedative side effects may be particularly prevalent when used for this indication and warrant further investigation.

Gastrointestinal

Studies in epilepsy report diarrhoea in approximately 15–20% of CBD-treated individuals. 90 In the largest study in patients with psychosis, 9% of those receiving CBD versus 4% receiving placebo reported this side effect. 55 While the severity was often mild and resolved without treatment, the one withdrawal (out of n = 43) in the CBD group was due to nausea, diarrhoea, abdominal pain and vomiting. 55 Despite the initial review by Bergamaschi and colleagues suggesting no effects on gastric motility, 83 the emerging pattern of findings is that diarrhoea is one of the most common side effects of CBD. This suggests that it does, in fact, increase gastrointestinal transit in humans which could affect its ultimate acceptability. 84

Hepatic drug metabolism

CBD is a potent inhibitor of CYP3A4 and CYP2D6, which belong to the cytochrome P450 family of enzymes that together metabolise more than 60% of prescribed drugs, including many antidepressants, antipsychotics and benzodiazepines. 91 –94 CBD could, therefore, have effects on the circulating concentrations of other medications. 83 In the context of psychosis, where concomitant antipsychotic treatment is likely, such effects could require careful monitoring and dose adjustment.

Liver enzymes

A meta-analysis of studies conducted in epilepsy found that CBD was associated with significantly increased serum aminotransferases, with a risk ratio of 14.14 (95% CI = 4.48–44.60) in studies using 20 mg/kg CBD. 91 While the potential for hepatic toxicity was identified in this meta-analysis, no events within the individual studies met criteria for lasting liver injury (i.e. based on bilirubin). 91 Monitoring of hepatic function, particularly during the first 30 days of treatment, is therefore recommended. 91,95 Given the potentially serious nature and consequences of this potential side effect, future research should attempt to evaluate such effects (and in additional patient populations).

Unregulated over-the-counter CBD products

One consequence of the explosion of public interest in CBD is that a vast array of unregulated products, purporting to contain CBD, are now widely available from online and high-street stores. 96 These products should explicitly not be used for medicinal purposes (for review see Freeman and colleagues) 96 because they are unregulated, not pharmaceutical grade nor produced under good manufacturing practice conditions; 96 their ingredients and dose are uncontrolled, with existing evidence showing that dosage is highly variable and contrary to labelling 97 ; and there is the potential for such products to be contaminated with high levels of other cannabinoids (such as THC), 96 –98 which could be detrimental to mental health and especially harmful to those with psychotic disorders. At best, such products represent an expensive placebo due to the typically low doses of CBD per administration (e.g. 25 mg/dose compared with 600–1000 mg/day in clinical studies), 48,55,96 but at worst, these products could be actively harmful due to the high risk of contamination with other cannabinoids. This is particularly the case for individuals with psychotic disorders, but also for children, young adults and adolescents, where cannabinoid exposure during these critical periods of brain development and maturation could have particularly severe and enduring pervasive effects. 99

In summary, CBD appears to show a favourable safety and tolerability profile but there remains a paucity of data, particularly in terms of chronic exposure in humans. Whether CBD has adverse effects on liver enzymes and hepatic metabolism, and thus potential interactions with other drugs, remains an important avenue for future research. Going forward, future clinical trials should aim to collect explicit information regarding side effects. While these future studies may indeed show that CBD is associated with common gastrointestinal and possibly sedative side effects, the risk–benefit ratio may still be favourable, especially when compared with the current status quo of treatments for psychosis: antipsychotics.

Potential mechanisms underlying the antipsychotic effects of cannabidiol

The idea that CBD may have therapeutic potential emerged from observations that it has opposite effects to THC at the pharmacological/molecular, neural (systems) and behavioural level. 24,28,42 The main molecular target for THC is the CB1 receptor, where it has partial agonist effects. 25 The molecular mechanisms of CBD are less clear, but its demonstrable ability to attenuate the effects of THC led to the notion that it may be an inverse agonist/antagonist at CB1 receptors. Although, in contrast to THC, CBD has low affinity for CB1, 25 it does appear to ‘antagonise the agonists’ of this receptor even at relatively low concentrations, 100 potentially via negative allosteric modulation. 101

Another mechanism by which CBD may have antipsychotic effects is via upregulation of the endocannabinoid anandamide, likely by inhibiting its degrading enzyme, fatty acid amide hydrolase. 53,102 This is consistent with the aforementioned findings of Leweke and colleageus, 53 where CBD increased serum anandamide levels in patients with psychosis, with this increase significantly associated with the concomitant reduction in psychotic symptoms. Additional pharmacological effects of CBD that have been described include activation of 5-HT1A receptors, 103 transient receptor potential vanilloid type 1, 102 GPR55 receptors and potentially various other mechanisms. 25,104,105,106

CB1 receptors are widely expressed in brain with the highest concentrations in mesocorticolimbic regions. 107 –110 Consistent with this distribution, based on human experimental studies involving cannabinoid administration, CB1 receptors appear to be involved in numerous cognitive processes subserved by corticolimbic circuitry, 44,111 such as learning and memory, 24,47 salience processing, 39,40 and response inhibition, 24 which are also known to be impaired in patients with psychosis. 111 Abundant evidence from experimental studies of healthy volunteers shows that CBD modulates brain function (in the opposite direction to THC) during each of these cognitive processes in their respective neural substrates. 24,39,40,47 This suggests that, at the brain systems level, the mechanism of the antipsychotic effects of CBD may be mediated through modulation of function of these neural substrates. Consistent with this, in patients at clinical high risk for psychosis, CBD was also found to normalise activation in key brain regions strongly implicated in psychosis onset and psychotic symptoms (such as the hippocampus, midbrain and striatum). 57,75,76

Conclusion

Initial clinical trials suggest that CBD is safe, well-tolerated and may have antipsychotic effects in patients with psychosis. There is some indication that CBD may be particularly effective in the early stages of the disorder, such as in patients at clinical high risk and those with first episode psychosis. Neuroimaging research suggests that CBD may exert its therapeutic effects via modulation of brain function in regions known to be altered in patients with psychosis across a variety of cognitive paradigms. Questions remain regarding the full side-effect profile of CBD, with reports of increased liver enzymes and potential for hepatic toxicity, but the most commonly reported side effects (such as diarrhoea and sedation) are likely to be both mild and benign. A more substantial body of evidence, including larger studies with longer-term CBD administration (e.g. up to 2 years), is required to accurately estimate the risk-benefit profile of CBD. Pending such evidence, if CBD treatment were ultimately associated mainly with common sedative and gastrointestinal side effects, these would likely still indicate a favourable tolerability profile compared with the side-effect profiles of currently licensed antipsychotic treatments. Given that CBD has antipsychotic effects without directly acting on dopamine receptors, it could represent a completely novel class of treatment for psychosis. CBD may also have therapeutic value prior to the onset of frank psychosis in patients at clinical high risk for the disorder, and in patients with nonschizophrenia spectrum disorder psychosis, such as Parkinson’s disease. Unregulated over-the-counter products containing CBD should explicitly not be used for medicinal purposes. In sum, CBD currently represents a promising potential novel treatment for patients with psychosis. If the success observed in initial clinical studies are replicated in large-scale trials with chronic administration, CBD has the potential to become the first licensed nondopaminergic treatment for psychosis.

Footnotes

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and publication of this article: SB has been supported by grants from the UK Medical Research Council (MRC) (MR/J012149/1) and the National Institute for Health Research (NIHR Clinician Scientist Award; NIHR CS-11-001). SB has also been supported by the NIHR Mental Health Biomedical Research Centre (BRC) at South London and Maudsley National Health Service (NHS) Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the MRC or the Department of Health and Social Care. The funders had no role in the preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.

Conflict of interest statement: The authors declare that there is no conflict of interest.

Ethical Statement: Ethical approval was not required because this is a review.

Contributor Information

Cathy Davies, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK.

Sagnik Bhattacharyya, Department of Psychosis Studies, 6th Floor, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, 16 De Crespigny Park, London, SE5 8AF, UK.

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Articles from Therapeutic Advances in Psychopharmacology are provided here courtesy of SAGE Publications

Cannabidiol (CBD) as a novel treatment in the early phases of psychosis

The pharmacological interventions available for individuals in the early stages of psychosis are extremely limited. For those at clinical high risk for psychosis, there is no licensed treatment available. For those with first-episode psychosis, all licensed antipsychotic medications act via dopamine D2 receptors. While treatment with antipsychotics is transformative in some patients, in others, it is ineffective. In addition, these medications can often cause adverse effects which make patients reluctant to take them. This is a particular problem in the early phases of psychosis, when patients are being treated for the first time, as unpleasant experiences may colour their future attitude towards treatment. Recent research has suggested that cannabidiol (CBD), a compound found in the Cannabis sativa plant, may have antipsychotic effects and relatively few adverse effects and could therefore be an ideal treatment for the early phases of psychosis, when minimising adverse effects is a clinical priority. In this review, we consider CBD’s potential as a treatment in the clinical high risk and first-episode stages of psychosis. First, we describe the limitations of existing treatments at these two stages. We then describe what is known of CBD’s mechanisms of action, effectiveness as a treatment for psychosis, adverse effects and acceptability to patients. We discuss how some of the outstanding issues about the utility of CBD in the early phases of psychosis may be resolved through ongoing clinical trials. Finally, we consider the impact of recreational cannabis use and over-the-counter cannabinoids preparations and discuss the potential therapeutic role of other compounds that modulate the endocannabinoid system in psychosis.

Introduction

Psychosis is mainly treated using antipsychotic drugs, which were first introduced in the 1950s. These medicines are still the only effective pharmacological treatment for the disorder. However, in around a third of patients, they do not relieve psychotic symptoms (Boter et al. 2009), and even when they are effective, they can cause serious side effects which often make patients reluctant to take them (Sendt et al. 2015). This is a particular problem in the early phases of psychosis, when people are being treated for the first time, as unpleasant experiences at this stage may colour their attitude towards treatment in the longer term (Liu and Demjaha 2013; Bjornestad et al. 2017). There is thus a long-standing need for alternative pharmacological treatments.

Cannabidiol (CBD) is a naturally occurring phytocannabinoid produced by the Cannabis sativa plant. It is an approved treatment for rare childhood epilepsy syndromes (Wise 2018) and, unlike delta-9-tetrahydrocannabinol (THC), is not intoxicating (Schoedel et al. 2018). The first evidence that CBD may have beneficial effects in patients with psychosis came from case studies (Zuardi et al. 1995, 2006, 2009; Makiol and Kluge 2019). More recently, small-scale clinical trials have compared the effects of CBD with those of antipsychotic medication or placebo, with the majority reporting positive results and all reporting minimal adverse effects (Leweke et al. 2012; Boggs et al. 2018; McGuire et al. 2018) (see below). In the present review, we examine the evidence that CBD may be useful as a novel treatment in psychosis, with a particular emphasis on its use in the early phases of the disorder.

Methods

A critical review of the past literature was conducted. Relevant articles were retrieved through targeted searches on international databases (Google Scholar and Clinicaltrials.gov) using the terms ‘cannabidiol’, ‘CBD’, ‘schizophrenia’ and ‘psychosis’ and critically reviewed by the authors of the paper. We additionally reviewed the citations of relevant systematic reviews and consulted with experts in the fields of cannabinoid psychopharmacology and psychosis. The review did not follow a systematic literature search, data extraction or reporting approach.

Review

Limitations of existing interventions for the clinical high risk state

The majority of patients with psychosis can recall experiencing an earlier prodromal phase (Jackson et al. 1995), typically featuring a decline in overall functioning and the emergence of ‘attenuated’ psychotic symptoms (Fusar-Poli et al. 2020). Anxiety and depressive symptoms are also common. Prospective studies indicate that 15–30% of people presenting with this syndrome will go on to develop a first episode of psychosis within 3 years (Fusar-Poli et al. 2020), which is why it is referred to as a clinical high risk (CHR) state.

In the short term, clinical services for people at CHR aim to relieve the presenting symptoms and address any related psychological or social problems. In the longer term, they aim to reduce the risk of progression to a psychotic disorder. The interventions offered vary between centres and usually include case management and clinical monitoring (Schmidt et al. 2015). In addition, a number of specific pharmacological and psychological interventions have been evaluated in clinical trials over the last 20 years. However, the results have been inconsistent, and recent meta-analyses indicate that neither antipsychotic medications, cognitive behavioural therapy, family therapy nor omega-3 fatty acids are more effective than case management alone in reducing severity of attenuated positive psychotic symptoms or the risk of developing a psychotic disorder (Davies et al. 2018a, b). Furthermore, as they are antipsychotic naive and often younger, CHR individuals are more sensitive to the adverse effects of antipsychotics than patients with established psychosis (Liu and Demjaha 2013; Stafford et al. 2015) and few are willing to take them (Welsh and Tiffin 2014). Thus, at present, there is no licensed treatment for either the presenting symptoms of the CHR state or for reducing the risk of later psychosis in this group. This represents a major unmet clinical need.

Limitations of existing treatments for first-episode psychosis

Antipsychotic medication is the most important component in the treatment of first-episode psychosis. In the short term, it is used to control the acute presenting symptoms (Huhn et al. 2019). Once these have remitted, continuing with treatment reduces the risk of subsequent relapse (Kishi et al. 2019). In about two-thirds of first-episode patients, the response to treatment of their presenting symptoms is good (Boter et al. 2009) and requires relatively low doses of antipsychotic medication. However, in about a third, these drugs are less effective. In addition, the beneficial effects of these drugs are mainly limited to positive psychotic symptoms; they have less impact on cognitive impairments or negative symptoms (Keefe et al. 2007; Krause et al. 2018). A further issue is that patients with psychosis are often reluctant to take antipsychotic medications, because of their reputation for side effects (Sendt et al. 2015) and because they are associated with schizophrenia, which is perceived as stigmatising (Yılmaz and Okanlı 2015). This reluctance is particularly evident in first-episode patients after their initial symptoms have resolved, as the benefits of prophylactic treatment may not be clear until after a relapse has occurred.

There is thus a clear need for alternative treatments. At present, if initial treatment is ineffective, standard clinical practice involves switching to a different antipsychotic medication. However, there is surprisingly little evidence that this is effective (Kahn et al. 2018). The only treatment that is effective when conventional antipsychotic medication has failed is with clozapine, an antipsychotic with a unique pharmacological profile (Siskind et al. 2016). However, clozapine can only be prescribed when at least two different antipsychotics have been ineffective, so it is not available to patients at the onset of psychosis or after their first antipsychotic treatment. Moreover, clinicians are sometimes reluctant to initiate treatment with clozapine due to the risk of serious adverse effects and the need for regular blood monitoring (Howes et al. 2012).

The mechanism of action of CBD in psychosis

CBD is a particularly interesting candidate as a novel treatment for psychosis because its molecular mechanism of action appears to be different to that of antipsychotic medications, which are either antagonists or partial agonists at the dopamine D2 receptor (Kaar et al. 2020). CBD has a variety of central actions that could plausibly contribute to an effect on psychosis. One putative mechanism is direct activity at cannabinoid (CB) receptors. Both CB1 and CB2 receptors have been proposed as relevant targets (Zhang et al. 2014; Cortez et al. 2020; Borgan et al. 2021). CBD is a negative allosteric modulator of the receptors, limiting their response to their endogenous ligands: the endocannabinoids (Laprairie et al. 2015; Martínez-Pinilla et al. 2017). At much higher concentrations, CBD may act as an antagonist at the orthosteric sites of CB1 and CB2 receptors, although it seems unlikely that this occurs at clinically relevant concentrations (McPartland et al. 2015). It has also been proposed that CBD can prevent the internalisation of CB1 receptors (Laprairie et al. 2015) and could therefore help normalise the abnormally low CB1 receptor densities observed in patient populations (Borgan et al. 2021). However, the effect of CBD on this measure has not yet been investigated in vivo.

CBD may also act by inhibiting the metabolism of endocannabinoids. In the first clinical trial in psychosis, CBD treatment was associated with increased anandamide levels which were in turn correlated with reductions in psychotic symptoms (Leweke et al. 2012). In support of this theory, a recent study found that the levels of fatty acid amide hydrolase (FAAH), the enzyme which metabolises anandamide and other related ligands, were inversely correlated with severity of psychotic symptoms in patients with psychosis (Watts et al. 2020). It has been suggested that the exact mechanism of action may be via interruption of the fatty acid-binding proteins which transport endocannabinoids intracellularly (Elmes et al. 2015). Other ligands, such as palmitoylethanolamine, and effects of CBD on other receptors, such as GPR55 and TRPV1 (which are related to the endocannabinoid system), could also have a role, but the evidence supporting these is relatively sparse and is still limited to data from pre-clinical studies (Tzavara et al. 2006; Ryberg et al. 2007; Long et al. 2009; Muller et al. 2020).

Serotonergic receptors have also been proposed as a relevant target. Animal research using the NMDA receptor antagonist MK-801, a pharmacological model of psychosis, found that CBD’s antipsychotic effect can be blocked by a 5-HT1A receptor antagonist, but not by CB1R or CB2R antagonists (Rodrigues da Silva et al. 2020). A recent clinical trial in patients with schizophrenia found that a 5-HT1A receptor agonist, SEP-363856, was more effective than placebo at reducing psychosis symptom scores after 4 weeks of treatment, highlighting the potential relevance of serotonergic pathways to the treatment of psychosis (Koblan et al. 2020).

A single in vitro study reported that CBD may act as a partial agonist at dopamine D2 receptors (Seeman 2016). This was the first study to report such an effect and it requires replication. Moreover, if CBD is primarily acting on dopaminergic pathways, it is surprising that it does not cause akathisia, an effect which is observed with all other partial agonists (Frankel and Schwartz 2017).

Finally, an important consideration for clinical trials of CBD is that it is a potent inhibitor of cytochrome P450 (CYP) enzymes (Brown and Winterstein 2019). Treatment with CBD might therefore increase the plasma levels of some antipsychotic medications and thereby alter their effects. This possibility has yet to be examined in clinical trials of CBD in psychosis. It was explored in a previous trial of adjunctive CBD treatment, but the numbers of participants taking different antipsychotics were too small to permit statistical analysis (McGuire et al. 2018). Potential effect of CBD on the metabolism of other drugs has also been an issue in assessing the effectiveness of CBD in epilepsy (Groeneveld and Martin 2020). CYP enzymes are also present in the brain (Ferguson and Tyndale 2011) and may even contribute to endocannabinoid metabolism (Zelasko et al. 2015).

Evidence for the effectiveness of CBD in CHR subjects

Recent functional neuroimaging studies have found differences in brain activation in the hippocampus, striatum, insula and midbrain between CHR individuals and healthy controls. A single dose (600 mg) of CBD attenuated these neural differences in CHR subjects but did not significantly alter symptom levels or have adverse effects (Bhattacharyya et al. 2018b; Wilson et al. 2019; Davies et al. 2020). One week of CBD (600 mg) treatment in the same CHR sample was not associated with significant effects on the symptomatic or cortisol response to an experimental stressor and had no adverse effects (Appiah-Kusi et al. 2020). The results of 3 weeks of treatment in this sample are currently in preparation, and the preliminary data indicate that this longer period of treatment is associated with significant symptomatic as well as neuroimaging effects (Bhattacharyya et al. 2018a; Bossong et al. 2019).

In addition to the amelioration of attenuated psychotic symptoms, a primary aim of intervention in the CHR phase is to reduce the risk of later progression to a psychotic disorder. Assessing whether CBD can influence the risk of transition to psychosis is likely to require treatment over a relatively long duration, as the period of maximal risk is over the first 2 years following clinical presentation (Fusar-Poli et al. 2020). A further consideration is that because only 20% of CHR individuals will develop psychosis in 2 years, a trial of CBD as a preventive treatment would require a sample large enough to yield a transition subgroup of sufficient size to detect an effect on this outcome (Fusar-Poli et al. 2020). Recruitment of sufficiently large CHR samples requires large-scale multi-centre trials, and two such trials have recently started. If it was shown to be effective, CBD would be an excellent candidate treatment for a preventive intervention, as it has a particularly benign side effect profile (Chesney et al. 2020b), a critical requirement for clinical treatment in CHR subjects (McGorry et al. 2009; Morrison et al. 2019) especially if this is over a long period.

Evidence for the effectiveness of CBD in psychotic disorders

To date, there have only been three clinical trials of CBD in patients with psychosis (Table 1). Leweke et al. (2012) compared 4 weeks treatment with 800 mg CBD as monotherapy with amisulpride. There were no differences in efficacy, an encouraging result as it suggested that CBD could be as effective as an antipsychotic. The sample size was small (N = 42; 21 per arm) and the study lacked a placebo comparison. Although the same research group subsequently compared CBD with placebo in patients with psychosis (Leweke et al. 2014), the results have only been published as a conference abstract. Two trials have evaluated CBD as an adjunctive treatment to antipsychotic medication in psychosis. Boggs et al. (2018) found no differences between adjunctive CBD and placebo on either psychotic symptoms or cognitive performance in N = 36 patients (n = 18 per arm), after 6 weeks of treatment. The daily CBD dose was 600 mg. The largest study to date, by McGuire and colleagues (McGuire et al. 2018), tested a higher dose of CBD (1000 mg) as an adjunctive treatment for 6 weeks in N = 88 patients (n = 43 in the CBD arm and n = 45 in the placebo arm). Compared to placebo, CBD treatment was associated with improvements in both ratings of psychotic symptom severity and the clinician’s overall impression. Neither of the two adjunctive studies assessed blood antipsychotic levels, so the possibility that effects were related to pharmacokinetic interactions between CBD and antipsychotics cannot be excluded.

Collectively, these results suggest that CBD may have significant effects on psychotic symptoms in patients with psychosis. The negative results from the trial by Boggs et al. might reflect its small sample size (N = 36) and the use of a lower dose of CBD (600 mg) than in the other trials (800 mg and 1000 mg). However, none of the trials published to date have involved large samples, and the optimal dose of CBD for psychosis is unclear. Another consideration is that the Boggs et al. trial involved patients in the chronic stage of psychosis, with an average age of 47 years. Similarly, in the study by McGuire et al., the average age of participants was 41 years, and the trial by Leweke et al. recruited patients with a mean age of 30 years. None of these studies required that participants were in the early stages of psychosis, and the patients were significantly older than would be found in a first episode or a CHR population. This is an important point, as the response to treatment with antipsychotic medication is different in the early and the chronic phases of psychosis, and it is possible that the same may apply to treatment with CBD. In particular, the response to CBD may be altered by the effects of chronic illness and its treatment with antipsychotic medication. The impact of these potentially confounding factors can be minimised by studying patients in the early phases of psychosis.

Because all of the trials completed to date have involved modest sample sizes, there is a clear need for larger scale trials. In addition, they have all involved relatively short durations of treatment (4–6 weeks), and it is not known if better results could be obtained if treatment was provided for a longer period. Finally, all three trials have been in patients with chronic psychosis who had already been treated with antipsychotic medications for a number of years. The extent to which CBD is useful in patients with first-episode psychosis has yet to be tested in clinical trials.

Neuroimaging studies in first-episode samples have had encouraging results. O’Neill et al. used functional magnetic resonance imaging to assess brain activity in patients with first-episode psychosis (n = 15) and in healthy controls (n = 19) (O’Neill et al. 2020). Patients were scanned after administration of a single dose of CBD (600 mg) or placebo, while healthy controls received no drug treatment. Compared to healthy controls, under placebo conditions, patients showed differential prefrontal and medial temporal activation, and these differences were partially normalised after administration of CBD. A study using proton magnetic resonance spectroscopy in the same subjects found that, compared to placebo, administration of CBD was associated with reductions in psychotic symptom severity alongside a corresponding increase in hippocampal glutamate levels (O’Neill et al. 2021).

According to ClinicalTrials.gov, a total of seven randomised controlled trials of CBD in psychotic disorders are currently in progress (Table 2), and most are recruiting patients within the first few years of illness. Five are using CBD as an adjunctive therapy to antipsychotic medication, one is comparing CBD monotherapy with risperidone and one is a three-arm study comparing CBD monotherapy with olanzapine and placebo. The range of CBD doses being used is 300 to 1000 mg. The results of these studies will be informative for the clinical utility of CBD in the early phases of psychosis. As well as establishing efficacy, important questions include whether CBD is effective as a monotherapy and whether, as with antipsychotic medications, the effective dose is lower in the early stages of psychosis. Similarly, these trials may also clarify whether the effectiveness of CBD is affected by concurrent recreational cannabis use.

Table 2 Forthcoming randomised controlled trials of cannabidiol in schizophrenia and early psychosis registered at ClinicalTrials.gov

Importance of tolerability and acceptability of treatments in the early phases of psychosis

Non-adherence to antipsychotic medication is a major issue for patients with psychosis. It is associated with reduced quality of life and an increased risk of relapse (Novick et al. 2010; Hayhurst et al. 2014). This issue is particularly important in the early stages of psychosis, as younger patients are less likely to adhere to medications (Hickling et al. 2018). This may partly be because they are more likely to experience adverse effects, one of most commonly reported reasons for non-adherence (Wade et al. 2017). In a meta-analysis of studies examining medication adherence, the association between adverse effects and non-adherence was more pronounced in younger populations (Edgcomb and Zima 2018). This may be a particular issue for antipsychotic medications as they can cause several unpleasant adverse effects such as weight gain, sedation, sexual dysfunction and extrapyramidal symptoms (Young et al. 2015).

In contrast to antipsychotics, CBD has relatively few adverse effects and is well tolerated. In a meta-analysis of randomised controlled trials, the only adverse effect attributable to CBD was diarrhoea (Chesney et al. 2020b). In each of the three clinical trials mentioned above, there were no significant differences in the incidence of adverse effects between CBD and placebo. In a head-to-head comparison with the antipsychotic amisulpride, CBD was associated with significantly fewer extrapyramidal side effects, less weight gain and did not elevate prolactin levels (Leweke et al. 2012). Similarly, Boggs et al. found no difference between adjunctive CBD and placebo in extrapyramidal side effects (Boggs et al. 2018), and McGuire et al. also reported an absence of differences with placebo for weight gain, effects on liver function tests and levels of inflammatory markers and HDL cholesterol (McGuire et al. 2018). Moreover, across these three trials, only two out of a total of 84 subjects who received CBD dropped out because of adverse effects: one complained of sedation, the other gastrointestinal adverse effects. This benign side effect profile of CBD is particularly valuable in the early stages of the disorder, as negative experiences with treatment can have a long-term effects on future adherence (Lambert et al. 2004). Even if initial treatment with CBD was ineffective, a patient may be more likely to consider subsequent medications if their early experiences were not off-putting.

A further difference between CBD and antipsychotic medications is that CBD is not associated with stigma. In fact, the reverse is often the case. Many clinicians will be familiar with their patients using over-the-counter preparations of CBD (Chesney et al. 2020a). Over-the-counter CBD products are extremely popular in the UK; in 2019, over a million people were regular users (Gibbs et al. 2019). Many CBD product users cite its perceived benefits on anxiety, sleep problems, stress and general health and wellbeing (Moltke and Hindocha 2021), a perception which may positively impact adherence to CBD and therefore symptomatic and functional outcomes.

CBD’s low burden of adverse effects and acceptability to patients are especially relevant to intervention in the CHR state, as these individuals are at high risk for psychosis but do not have the disorder. Moreover, the majority will not subsequently transition to psychosis, so if treatment is administered as a preventive intervention, many individuals will receive medication even though they might never have needed it. There is therefore a consensus that if a pharmacological intervention is used in this group, it must have a benign adverse effect profile and not be associated with stigma, ensuring that the benefits of the treatment outweigh its costs (McGorry et al. 2009; Morrison et al. 2019).

The potentially confounding effects of recreational cannabis and over-the-counter cannabinoids

A high proportion of both CHR and first-episode psychosis subjects currently use, or have previously used, cannabis recreationally. The proportions vary considerably with the local population, but on average, around half of CHR subjects have ever used cannabis, a quarter continue to use it and about one in six meet the criteria for a cannabis use disorder (Farris et al. 2020). In first-episode samples, the prevalence of cannabis use disorder is 36% (95% CI: 31 to 41%), considerably higher than in chronic illness: 21% (95% CI: 17 to 25%) (Hunt et al. 2018). More recently, synthetic cannabinoids, which have very high affinity for cannabinoid receptors and can trigger severe psychotic reactions (Hobbs et al. 2018), have also become available. In one study of psychiatric inpatients, 11% of those with psychosis reported having ever used a synthetic cannabinoid, though the majority of these patients (83%) had no intention of using them ever again (Welter et al. 2017).

In first-episode patients, persistent cannabis use after illness onset exacerbates psychotic symptoms, increases the risk of later relapse and is associated with a relatively poor long-term outcome (Schoeler et al. 2016). In CHR individuals, meta-analyses indicate that lifetime use of cannabis is not associated with an increased risk of transition to psychosis (Kraan et al. 2016; Oliver et al. 2020) but that meeting diagnostic criteria for a cannabis use disorder is (Kraan et al. 2016). A change in cannabis use in people at high risk may also be a predictor of later psychosis. A prospective study of 83 individuals with a family history of schizophrenia (which excluded cannabis users at baseline) found that new onset cannabis use was associated with an increased incidence of psychosis in the next 3 years (χ 2 = 6.4, p = 0.011) (Padmanabhan et al. 2017). Another study in N = 134 CHR subjects found that the incidence of psychosis was higher in those who had continued to use cannabis compared to those who had discontinued cannabis use (χ 2 = 4.5, p = 0.034) (Valmaggia et al. 2014).

Recreational cannabis use thus has the potential to confound clinical trials of CBD in the early phases of psychosis. In addition, the putative therapeutic effects of CBD could be modified by interactions with the main intoxicating compound in cannabis, THC, which is a partial agonist at both CB1Rs and CB2Rs and has similar activity to anandamide (Pertwee 2008). THC is not rapidly broken down, and intoxication will typically persist for 3–4 h after administration. Prolonged cannabis use has been shown to affect the expression of cannabinoid receptors, FAAH and endocannabinoids (for a review, see Jacobson et al. 2019). Cannabis use may thus disrupt normal endocannabinoid signalling and the response to CBD.

A further consideration is that among patients with psychosis who are cannabis users, the administration of CBD could alter their recreational use of cannabis. Experimental studies in healthy volunteers have shown that pre-treatment with CBD can reduce the negative effects of THC on paranoia and cognitive function (Bhattacharyya et al. 2010; Englund et al. 2013).

In addition, several functional magnetic resonance imaging studies found that CBD has opposite effects to THC on activity in a variety of cortical and striatal areas (Bhattacharyya et al. 2010, 2012; Winton-Brown et al. 2011). More recently, a trial of CBD in regular cannabis users who wanted to stop found that it increased abstinence and reduced urinary THC metabolites over 4 weeks (Freeman et al. 2020). These studies raise the possibility that in patients with psychosis who are cannabis users, CBD might reduce the risk of cannabis exacerbating their symptoms and improve the chances of them reducing or stopping their cannabis use. Since cannabis use disorders are considerably more common in first-episode psychosis (Hunt et al. 2018), CBD may be a particular useful agent at this stage of the illness.

In view of the above, it might be argued that cannabis users should be excluded from clinical trials of CBD, particularly those recruiting patients in the early stages of psychosis. However, because cannabis use is so common in this population, this could limit inclusion to an unrepresentative subset of patients. An alternative approach would be to permit the inclusion of recreational users but carefully monitor their exposure to cannabis throughout the trial via serial urine and blood testing, and self-report measures, such as the Timeline Followback (Robinson et al. 2014).

Trial participants could also be using over-the-counter cannabinoid preparations, which may contain CBD and other cannabinoids. However, at present, the doses of CBD in these preparations are much smaller than those used in clinical trials, and it is unclear if they have any psychiatric effects (Chesney et al. 2020a).

The potential of other cannabinoids and endocannabinoid system modulators

Evidence that CBD may be effective in psychosis raises the possibility that other compounds with a similar mechanism of action might also be useful. This highlights the importance of determining which molecular mechanism underlies the effects of CBD in psychosis, as this would indicate the most promising therapeutic target for novel compounds. One candidate mechanism of action is the reduction of endocannabinoid metabolism through inhibition of the enzyme FAAH. Unfortunately, the development of FAAH inhibitors was hampered by serious adverse events in phase 1 trials of one compound (Mallet et al. 2016). Since then, there have not been any studies with FAAH inhibitors in patients with psychosis, though one has been evaluated in otherwise healthy volunteers with cannabis dependence (D’Souza et al. 2019). Compared to placebo, 4 weeks of treatment reduced cannabis withdrawal symptoms and cannabis use, without serious adverse events.

CB1R inverse agonists, such as rimonabant, have been tested in several clinical trials of schizophrenia (Meltzer et al. 2004; Sanofi-Aventis 2009; Boggs et al. 2012). However, they proved to be ineffective and concerns about adverse effects on mood and anxiety led to their abandonment as a novel psychiatric treatment (Christensen et al. 2007). Historically, it was thought that CB2Rs had little relevance to psychosis, but recent pre-clinical evidence suggests that they may regulate midbrain dopaminergic neurotransmission and could have beneficial effects on central immune function (Cortez et al. 2020). Nevertheless, compounds that act on CB2Rs have not yet been tested in human studies.

Tetrahydrocannabivarin (THCV) is a naturally occurring homologue of THC with a complex pharmacological profile. At low doses, it is a CB1R neutral antagonist and CB2R partial agonist (McPartland et al. 2015), and it may also have effects via GPR55, 5-HT1A receptors and TRP channels (Morales et al. 2017). THCV has not been tested in clinical trials of psychosis. An experimental study examined whether pre-treatment with THCV could block the effects of THC (Englund et al. 2016), but the results were inconclusive.

Conclusion

If large-scale clinical trials confirm that CBD is effective in the treatment of psychosis, it may be particularly useful in the early phases of the disorder. At present, there are no effective interventions for people at CHR for psychosis, and there is a consensus that pharmacological treatments in this population must have minimal adverse effects, especially if given for a prolonged period as a preventive intervention (McGorry et al. 2009). In first-episode psychosis, CBD may be especially helpful in patients who do not respond to treatment with antipsychotic medications and in patients who are reluctant to take antipsychotics because of concerns about side effects and stigmatisation. Large-scale trials in CHR and first-episode subjects are now needed to confirm the potential utility of CBD in the early phases of psychosis. Future trials could also investigate the molecular mechanism of action of CBD by assessing participants with neuroimaging and peripheral blood measures.

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EC is supported by a National Institute for Health Research Doctoral Research Fellowship (NIHR300273). DO is supported by the UK Medical Research Council (MR/N013700/1) and is a King’s College London member of the MRC Doctoral Training Partnership in Biomedical Sciences. PM is an NIHR Senior Investigator.

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Edward Chesney, Dominic Oliver & Philip McGuire

South London and Maudsley NHS Foundation Trust, London, UK

National Institute for Health Research Maudsley Biomedical Research Centre, London, UK

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Chesney, E., Oliver, D. & McGuire, P. Cannabidiol (CBD) as a novel treatment in the early phases of psychosis. Psychopharmacology (2021). https://doi.org/10.1007/s00213-021-05905-9

Received : 06 January 2021

Accepted : 15 June 2021

Published : 13 July 2021

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