Cannabidiol as an Adjunctive Treatment for Schizophrenia

Cannabis is a complex plant with more than 100 types of cannabinoids. Its main psychoactive compound is δ-9-tetrahydrocannabinol (THC), which activates cannabinoid receptors to produce its “feeling high” effects. Cannabidiol (CBD) is another cannabinoid that has attracted growing attention recently. Unlike THC, CBD does not bind to cannabinoid receptors and has shown different, sometimes counteractive, effects. Currently, there are more than 100 clinical trials registered on the ClinicalTrials.gov website on the potential therapeutic effects of CBD.

The FDA has recently approved the first cannabis plant-derived medication, Epidiolex (an oral solution of pure CBD), for treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients aged 2 years and older.¹ Consequently, DEA scheduled Epidiolex in Schedule V of the Controlled Substances Act (CSA), the least restrictive schedule.² Though Epidiolex is only approved for the above rare seizure disorders, physicians may recommend it off-label for other conditions, based on their own judgment. It is important to note, however, that the only approved form of CBD is Epidiolex and off-label recommendation of other forms of CBD does not follow the same rules.

The evidence for cannabidiol

The association between cannabis use and psychosis is well-known in epidemiological studies, and a dose-response relationship is consistently reported with an odds ratios of 3.90 (95% CI, 2.84 to 5.34) for the risk of schizophrenia in heavy cannabis users.³ However, use of cannabis strains with high CBD content has been associated with fewer psychotic symptoms.⁴ Whereas THC produces acute psychotic-like symptoms in healthy volunteers, pre-treatment with CBD decreases the THC-induced psychotic symptoms and cognitive impairments.^5-7

The potential beneficial effects of CBD on cognition in patients with schizophrenia have critical importance, since cognitive deficits are common in schizophrenia (up to 75%-85% of patients), usually precede other symptoms, and respond minimally to the available pharmacological treatments.

The very first case report on the use of CBD as an antipsychotic medication was published by Zuardi and colleagues⁸ (Table). In this study, a 19-year-old female patient with schizophrenia was treated with CBD up to 1500 mg daily for 4 weeks, which resulted in improvement of acute psychotic symptoms. Findings from a study in 2006 that looked at the effects of CBD as monotherapy for treatment-resistant schizophrenia in three individuals show that improvement was seen in only one patient.⁹ A later study on the antipsychotic effects of CBD (at flexible doses up to 400 mg/d) on 6 individuals who had Parkinson disease showed improvement of psychotic symptoms over the course of 4 weeks.¹⁰

Since then, the antipsychotic properties of CBD have been investigated in three clinical trials with mixed results (Table). In 2012, Leweke and colleagues¹¹ published the first double blind randomized controlled clinical trial on the therapeutic effects of CBD (600-800 mg/d for 4 weeks) compared with amisulpride on acute psychosis in individuals with schizophrenia (N = 42). The study concluded that CBD is as effective as amisulpride in treating psychotic symptoms and has fewer adverse effects, including less extra pyramidal symptoms and weight gain.

More recently, the effects of CBD on psychosis were explored in two double-blind randomized placebo-controlled clinical trials. McGuire and colleagues¹² used CBD as an adjunctive medication in treatment of acute psychosis in individuals who had schizophrenia or other non-affective psychotic disorders. Participants (N = 88) received either CBD 1000 mg daily (in two divided doses) or placebo in addition to their routine antipsychotic medications (continued unchanged during the study) for 6 weeks.

Compared with the placebo group, the CBD group showed greater improvement of positive psychotic symptoms over the course of the treatment. Mean improvement of PANSS positive score was 3.2 (SD 2.60) in the CBD group compared with 1.7 (SD 2.76) in the placebo group. Moreover, by the end of the treatment, more patients in the CBD group were rated as “improved” on the CGI-I scale compared with those in the placebo group (78.6% and 54.6%, respectively). Patients who received CBD also showed a trend-level improvement in their cognitive functioning, and a significant improvement of their motor speed compared with controls.

In a similar study, Boggs and colleagues¹³ 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.

Mechanism of action

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.

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.

Conclusion

In addition to the potential therapeutic effects of CBD for schizophrenia, CBD may also have a role in preventing or treating the psychosis related to recreational use of cannabis in vulnerable individuals. Cannabis continues to be the most commonly used illicit drug in the US, and with the spreading legalization for medical and recreational purposes, a lower proportion of people perceive the risk associated with regular cannabis use. At the same time, there is a decreasing ratio of CBD-to-THC in street cannabis from 1:14 in 1995 to 1:80 in 2014. Low CBD content may affect the overall impact of frequent cannabis use on mental health, which may become evident in the future. When discussing the medicinal use of cannabis, it is important to distinguish CBD, with its potential beneficial effects, from THC, with its controversial adverse effects, especially on individuals with psychotic disorders.

Disclosures:

Dr Bassir Nia is Assistant Professor of Psychiatry, Yale University School of Medicine, New Haven, CT. Dr Bassir Nia reports that she has no conflicts of interest concerning the subject matter of this article.

References:

1. US Food and Drug Administration. FDA Approves First Drug Comprised of an Active Ingredient Derived From M arijuana to Treat Rare, Severe Forms of Epilepsy. 2018. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm611046.htm. Accessed February 7, 2019.

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.

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