Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia (TRS), only 40% of people with TRS respond, and there is limited evidence for augmentation agents. Cannabidiol (CBD) reduces positive symptoms in individuals with schizophrenia, but no trials have specifically examined its efficacy in those with clozapine-resistant schizophrenia.

To examine the clinical efficacy of CBD augmentation in people with clozapine-resistant schizophrenia.

This is a 12-week randomised, placebo-controlled, double-blind, parallel-group trial (registration number: ACTRN12622001112752). We will recruit 88 individuals with clozapine-resistant schizophrenia, randomised (1:1) to 1000 mg daily CBD versus placebo. Eligible individuals will be aged between 18 and 64 years, fulfil DSM-IV criteria for schizophrenia or schizoaffective disorder, have a total PANSS (Positive and Negative Syndrome Scale) score ≥60, have received oral clozapine for at least 18 weeks and have a clozapine level of >350 ng/mL. Interim analyses will be conducted at 25, 50 and 75% recruitment; these will also provide an opportunity to reallocate participants dependent on conditional power. The primary endpoint will be the difference in PANSS positive scores at the end of week 12. Secondary endpoints include depression, anxiety, sleep, quality of life, alcohol consumption, change in weight and metabolic syndrome components, and neurocognitive measures, as well as safety and tolerability.

Novel treatments for clozapine-resistant schizophrenia are urgently needed. If found to be effective, CBD may have a role as a novel and safe adjunct to clozapine.

To investigate the effects of cannabidiol (CBD) on emotional and cognitive symptoms in rats with intra-nigral 6-hydroxydopamine (6-OHDA) lesions.

Adult male Wistar rats received bilateral intranigral 6-OHDA infusions and were tested in a battery of behavioural paradigms to evaluate non-motor symptoms. The brains were obtained to evaluate the effects of CBD on hippocampal neurogenesis.

6-OHDA-lesioned rats exhibited memory impairments and despair-like behaviour in the novelty-suppressed feeding test and forced swim test, respectively. The animals also exhibited dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), striatum, and ventral tegmental area and a reduction of hippocampal neurogenesis. CBD decreased dopaminergic neuronal loss in the SNpc, reduced the mortality rate and decreased neuroinflammation in 6-OHDA-lesioned rats. In parallel, CBD prevented memory impairments and attenuated despair-like behaviour that were induced by bilateral intranigral 6-OHDA lesions. Repeated treatment with CBD favoured the neuronal maturation of newborn neurons in the hippocampus in Parkinsonian rats.

The present findings suggest a potential beneficial effect of CBD on non-motor symptoms induced by intra-nigral 6-OHDA infusion in rats.

Hippocampal hyperperfusion has been observed in people at Clinical High Risk for Psychosis (CHR), is associated with adverse longitudinal outcomes and represents a potential treatment target for novel pharmacotherapies. Whether cannabidiol (CBD) has ameliorative effects on hippocampal blood flow (rCBF) in CHR patients remains unknown.

Using a double-blind, parallel-group design, 33 CHR patients were randomized to a single oral 600 mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Hippocampal rCBF was measured using Arterial Spin Labeling. We examined differences relating to CHR status (controls v. placebo), effects of CBD in CHR (placebo v. CBD) and linear between-group relationships, such that placebo > CBD > controls or controls > CBD > placebo, using a combination of hypothesis-driven and exploratory wholebrain analyses.

Placebo-treated patients had significantly higher hippocampal rCBF bilaterally (all pFWE<0.01) compared to healthy controls. There were no suprathreshold effects in the CBD v. placebo contrast. However, we found a significant linear relationship in the right hippocampus (pFWE = 0.035) such that rCBF was highest in the placebo group, lowest in controls and intermediate in the CBD group. Exploratory wholebrain results replicated previous findings of hyperperfusion in the hippocampus, striatum and midbrain in CHR patients, and provided novel evidence of increased rCBF in inferior-temporal and lateral-occipital regions in patients under CBD compared to placebo.

These findings suggest that hippocampal blood flow is elevated in the CHR state and may be partially normalized by a single dose of CBD. CBD therefore merits further investigation as a potential novel treatment for this population.

Cannabidiol (CBD) is a phytocannabinoid with great potential in clinical applications. The mechanism(s) of action of CBD require further investigation. Previous studies suggested that adenosine A2A receptors (A2ARs) could play a role in CBD-induced effects. Here, we evaluated the ability of CBD to modify the function of A2AR.

We used HEK-293T cells transfected with the cDNA encoding the human A2AR and Gαs protein, both modified to perform bioluminescence-based assays. We first assessed the effect of CBD on A2AR ligand binding using an A2AR NanoLuciferase sensor. Next, we evaluated whether CBD modified A2AR coupling to mini-Gαs proteins using the NanoBiT™ assay. Finally, we further assessed CBD effects on A2AR intrinsic activity by recording agonist-induced cAMP accumulation.

CBD did not bind orthosterically to A2AR but reduced the coupling of A2AR to Gαs protein and the subsequent generation of cAMP.

CBD negatively modulates A2AR functioning.

We investigated the influence of oral cannabidiol (CBD) on vacuous chewing movements (VCM) and oxidative stress parameters induced by short- and long-term administration of haloperidol in a rat model of tardive dyskinesia (TD).

Haloperidol was administered either sub-chronically via the intraperitoneal (IP) route or chronically via the intramuscular (IM) route to six experimental groups only or in combination with CBD. VCM and oxidative stress parameters were assessed at different time points after the last dose of medication.

Oral CBD (5 mg/kg) attenuated the VCM produced by sub-chronic administration of haloperidol (5 mg/kg) but had minimal effects on the VCM produced by chronic administration of haloperidol (50 mg/kg). In both sub-chronic and chronic haloperidol groups, there were significant changes in brain antioxidant parameters compared with CBD only and the control groups. The sub-chronic haloperidol-only group had lower glutathione activity compared with sub-chronic haloperidol before CBD and the control groups; also, superoxide dismutase, catalase, and 2,2-diphenyl-1-picrylhydrazyl activities were increased in the sub-chronic (IP) haloperidol only group compared with the CBD only and control groups. Nitric oxide activity was increased in sub-chronic haloperidol-only group compared to the other groups; however, the chronic haloperidol group had increased malondialdehyde activity compared to the other groups.

Our findings indicate that CBD ameliorated VCM in the sub-chronic haloperidol group before CBD, but marginally in the chronic haloperidol group before CBD. There was increased antioxidant activity in the sub-chronic group compared to the chronic group.

Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), i.e. the neural hub for processing reward and aversive responses.

As socially stressful events pose particular challenges at developmental stages, this research applied the resident–intruder paradigm as a model of social stress, to highlight behavioural neuroendocrine and molecular maladaptive plasticity in rats at withdrawal from binge-like alcohol exposure in adolescence. In search of a rescue agent, cannabidiol (CBD) was selected due to its favourable effects on alcohol- and stress-related harms.

Binge-like alcohol exposed intruder rats displayed a compromised defensive behaviour against the resident and a blunted response of the stress system, in addition to indexes of abnormal dopamine (DA)/glutamate plasticity and dysfunctional spine dynamics in the NAc. CBD administration (60 mg/kg) was able to: (1) increase social exploration in the binge-like alcohol exposed intruder rats, at the expenses of freezing time, and in control rats, which received less aggressive attacks from the resident; (2) reduce corticosterone levels independently on alcohol previous exposure; (3) restore DA transmission and (4) facilitate excitatory postsynaptic strength and remodelling.

Overall, the maladaptive behavioural and synaptic plasticity promoted by the intersection between binge-like alcohol withdrawal and exposure to adverse social stress can be rescued by a CBD détente effect that results in a successful defensive strategy, supported by a functional endocrine and synaptic plasticity. The current data highlight CBD's relevant therapeutic potential in alcohol- and stress-related harms, and prompt further investigation on its molecular targets.

The mechanisms underlying the antipsychotic potential of cannabidiol (CBD) remain unclear but growing evidence indicates that dysfunction in the insula, a key brain region involved in the processing of motivationally salient stimuli, may have a role in the pathophysiology of psychosis. Here, we investigate whether the antipsychotic mechanisms of CBD are underpinned by their effects on insular activation, known to be involved in salience processing.

A within-subject, crossover, double-blind, placebo-controlled investigation of 19 healthy controls and 15 participants with early psychosis was conducted. Administration of a single dose of CBD was compared with placebo in psychosis participants while performing the monetary incentive delay task, an fMRI paradigm. Anticipation of reward and loss were used to contrast motivationally salient stimuli against a neutral control condition.

No group differences in brain activation between psychosis patients compared with healthy controls were observed. Attenuation of insula activation was observed following CBD, compared to placebo. Sensitivity analyses controlling for current cannabis use history did not affect the main results.

Our findings are in accordance with existing evidence suggesting that CBD modulates brain regions involved in salience processing. Whether such effects underlie the putative antipsychotic effects of CBD remains to be investigated.

This study seeks to determine the prevalence and nature of cannabis use in patients with headache in a tertiary headache clinic and to explore patients’ empiric experience in using cannabinoids therapeutically.

Many patients with headache report cannabinoid use as an effective abortive and/or preventive therapy. Mounting evidence implicates cannabinoids in pain mechanisms pertaining to migraine and other headache types.

A cross-sectional study surveyed 200 patients presenting with any headache disorder to a tertiary headache clinic in Calgary, Alberta. Descriptive analyses were applied to capture information about headache diagnoses and the frequency, doses and methods of cannabinoid delivery employed, as well as patients’ perceptions of therapeutic benefit and selected negative side effects.

Active cannabinoid users comprised 34.0% of respondents. Approximately 40% of respondents using cannabinoids engaged in very frequent use (≥300 days/year). Of cannabinoid modalities, liquid concentrates were most popular (39.2%), followed by smoked cannabis (33.3%). Patients endorsed cannabinoid use for both prevention and acute therapy of headaches, often concurrently. Sixty percent of respondents felt cannabinoids reduced headache severity, while 29.2% perceived efficacy in aborting headaches. Nearly 5% of respondents volunteered that they had encountered a serious problem such as an argument, fight, accident, or work issue as a result of their cannabis use. Approximately 35.4% of users had attempted to reduce their use.

This survey shows that over one-third of patients with headache disorders in a tertiary headache clinic use cannabis as a treatment for their headaches. Of these, about 25% and 60% perceive improvements in headache frequency and severity, respectively. The results of this survey will aid neurologists and headache specialists in understanding the landscape of cannabinoid use in a more severely affected population and inform future-controlled studies of cannabinoids in headache patients.

Acute cannabis administration can produce transient psychotic-like effects in healthy individuals. However, the mechanisms through which this occurs and which factors predict vulnerability remain unclear. We investigate whether cannabis inhalation leads to psychotic-like symptoms and speech illusion; and whether cannabidiol (CBD) blunts such effects (study 1) and adolescence heightens such effects (study 2).

Two double-blind placebo-controlled studies, assessing speech illusion in a white noise task, and psychotic-like symptoms on the Psychotomimetic States Inventory (PSI). Study 1 compared effects of Cann-CBD (cannabis containing Δ-9-tetrahydrocannabinol (THC) and negligible levels of CBD) with Cann+CBD (cannabis containing THC and CBD) in 17 adults. Study 2 compared effects of Cann-CBD in 20 adolescents and 20 adults. All participants were healthy individuals who currently used cannabis.

In study 1, relative to placebo, both Cann-CBD and Cann+CBD increased PSI scores but not speech illusion. No differences between Cann-CBD and Cann+CBD emerged. In study 2, relative to placebo, Cann-CBD increased PSI scores and incidence of speech illusion, with the odds of experiencing speech illusion 3.1 (95% CIs 1.3–7.2) times higher after Cann-CBD. No age group differences were found for speech illusion, but adults showed heightened effects on the PSI.

Inhalation of cannabis reliably increases psychotic-like symptoms in healthy cannabis users and may increase the incidence of speech illusion. CBD did not influence psychotic-like effects of cannabis. Adolescents may be less vulnerable to acute psychotic-like effects of cannabis than adults.

Recent evidence suggests that cannabidiol (CBD), a non-intoxicating ingredient present in cannabis extract, has an antipsychotic effect in people with established psychosis. However, the effect of CBD on the neurocognitive mechanisms underlying psychosis is unknown.

Patients with established psychosis on standard antipsychotic treatment were studied on separate days at least one week apart, to investigate the effects of a single dose of orally administered CBD (600 mg) compared to a matched placebo (PLB), using a double-blind, randomized, PLB-controlled, repeated-measures, within-subject cross-over design. Three hours after taking the study drug participants were scanned using a block design functional magnetic resonance imaging (fMRI) paradigm, while performing a verbal paired associate learning task. Fifteen psychosis patients completed both study days, 13 completed both scanning sessions. Nineteen healthy controls (HC) were also scanned using the same fMRI paradigm under identical conditions, but without any drug administration. Effects of CBD on brain activation measured using the blood oxygen level-dependent hemodynamic response fMRI signal were studied in the mediotemporal, prefrontal, and striatal regions of interest.

Compared to HC, psychosis patients under PLB had altered prefrontal activation during verbal encoding, as well as altered mediotemporal and prefrontal activation and greater mediotemporal-striatal functional connectivity during verbal recall. CBD attenuated dysfunction in these regions such that activation under its influence was intermediate between the PLB condition and HC. CBD also attenuated hippocampal-striatal functional connectivity and caused trend-level symptom reduction in psychosis patients.

This suggests that normalization of mediotemporal and prefrontal dysfunction and mediotemporal-striatal functional connectivity may underlie the antipsychotic effects of CBD.

Cannabis use is decreasing in England and Wales, while demand for cannabis treatment in addiction services continues to rise. This could be partly due to an increased availability of high-potency cannabis.

Adults residing in the UK were questioned about their drug use, including three types of cannabis (high potency: skunk; low potency: other grass, resin). Cannabis types were profiled and examined for possible associations between frequency of use and (i) cannabis dependence, (ii) cannabis-related concerns.

Frequent use of high-potency cannabis predicted a greater severity of dependence [days of skunk use per month: b = 0.254, 95% confidence interval (CI) 0.161–0.357, p < 0.001] and this effect became stronger as age decreased (b = −0.006, 95% CI −0.010 to −0.002, p = 0.004). By contrast, use of low-potency cannabis was not associated with dependence (days of other grass use per month: b = 0.020, 95% CI −0.029 to 0.070, p = 0.436; days of resin use per month: b = 0.025, 95% CI −0.019 to 0.067, p = 0.245). Frequency of cannabis use (all types) did not predict severity of cannabis-related concerns. High-potency cannabis was clearly distinct from low-potency varieties by its marked effects on memory and paranoia. It also produced the best high, was preferred, and most available.

High-potency cannabis use is associated with an increased severity of dependence, especially in young people. Its profile is strongly defined by negative effects (memory, paranoia), but also positive characteristics (best high, preferred type), which may be important when considering clinical or public health interventions focusing on cannabis potency.