According to the literature there is no need to titrate the dose of CBD. For risperidone, dose will start at 2 mg and after four days be increased to 2 mg BID. In clinical practice, risperidone is usually titrated within 2–7 days to 4 mg which is a dose that most subjects can tolerate with few adverse effects. To make the groups comparable, the dose of CBD will start at 300 mg once daily and after four days be increased to 300 mg BID. Participants can ingest the total dose once daily if they so prefer. If participants experience intolerable side effects after increasing the dose to two times daily after the first four days, it will be possible to reduce the dose to once daily after discussion and agreement with the investigator.
Velligan DI, Sajatovic M, Hatch A, Kramata P, Docherty JP. Why do psychiatric patients stop antipsychotic medication? A systematic review of reasons for nonadherence to medication in patients with serious mental illness. Patient Preference Adherence. 2017;Volume 11:449–68. https://doi.org/10.2147/PPA.S124658.
Results of this trial, both positive, negative and inconclusive findings, will be published by the investigators in international journals and presented at national and international meetings and conferences.
Sobell LC, Sobell MB. Timeline Follow-Back. In: Litten RZ, Allen JP. (eds). Measuring Alcohol Consumption. Totowa: Humana Press; 1992. https://doi.org/10.1007/978-1-4612-0357-5_3.
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
ORCID iD: Cathy Davies https://orcid.org/0000-0003-3011-8643
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
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
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
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.
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.
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