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
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.
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
Early intervention: prior to psychosis onset
Overview of studies investigating cannabidiol in patients with psychosis.
Ethical Statement: Ethical approval was not required because this is a review.
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.
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
In a similar study, Boggs and colleagues 13 investigated the therapeutic effects of adjunctive CBD 600 mg daily (in two divided doses) compared with placebo in a 6-week double blind placebo-controlled randomized clinical trial, in individuals with chronic schizophrenia (N = 36). However, their results showed no significant differences between CBD and placebo on psychotic symptoms or cognitive performances.
The current pharmacological treatment for schizophrenia is only partially effective and mainly for positive symptoms. This has led investigators to investigate new pharmacological targets and the endocannabinoid system has been one of the newest ones. Over the past few decades, increasing evidence has shown the presence of endocannabinoid system abnormalities in schizophrenia. 14 However, the current studies on the potential therapeutic effects of CBD are not conclusive and the mechanism of action is poorly understood. The discrepancies in clinical results could be related to different doses of CBD, stages of psychosis, or possibly heterogeneity of schizophrenia itself.
5. Martin-Santos R, Crippa JA, Batalla A, et al. Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des. 2012;18:4966-4979.
The exact mechanism of action is still unknown for CBD’s potential anti-psychotic properties. Unlike other antipsychotic medications, CBD does not greatly affect dopaminergic neurons, and unlike THC, it does not bind to cannabinoid receptors. However, CBD reportedly increases the CSF levels of anandamide, one of the main endocannabinoid ligands, by blocking its degrading enzyme, fatty acid amide hydrolase, or by competing with anandamide intracellular transporters. It is interesting to note that anandamide levels are negatively correlated with severity of psychotic symptoms, whereas increased anandamide levels in psychotic patients treated with CBD are correlated with clinical improvement. This may suggest that CBD contributes to amelioration of psychosis by increasing the endogenous levels of anandamide. However, further studies are needed to confirm this.
2. US Drug Enforcement Administration. FDA-Approved Drug Epidiolex Placed in Schedule V of Controlled Substance Act. 2018. https://www.dea.gov/press-releases/2018/09/27/fda-approved-drug-epidiolex-placed-schedule-v-controlled-substance-act. Accessed February 7, 2019.