Is there a role for cannabidiol in psychiatry ?, Julia Machado Khoury et al., 2017

Is there a role for cannabidiol in psychiatry ?

Julia Machado Khoury , Maila de Castro Lourenço das Neves, Marco Antônio Valente Roque,
Daniela Alves de Brito Queiroz , Andre Augusto Corrêa de Freitas, Angelo de Fatima,
Fabrıcio Moreira and Frederico Duarte Garcia

The World Journal of Biological Psychiatry, 2017, 16 p.

Doi : 10.1080/15622975.2017.1285049



Objectives : Understanding whether cannabidiol (CBD) is useful and safe for the treatment of psychiatric disorders is essential to empower psychiatrists and patients to take good clinical decisions. Our aim was to conduct a systematic review regarding the benefits and adverse events (AEs) of CBD in the treatment of schizophrenia, psychotic disorders, anxiety disorders, depression, bipolar disorder and substance-use disorders.

Methods : We conducted a literature search in PubMed, Scielo, and databases. Evidence was classified according to the WFSBP task forces standards.

Results : Bibliographic research yielded 692 records. After analysis, we included six case reports and seven trials, comprising 201 subjects. Most the studies published presented several drawbacks and did not reach statistical significance. We have not found evidence regarding major depressive and bipolar disorders. The level of evidence for cannabis withdrawal is B; cannabis addiction is C2; treatment of positive symptoms in schizophrenia and anxiety in social anxiety disorder is C1. Discrete or no AEs were reported. The most frequently reported AEs are sedation and dizziness.

Conclusion : The evidence regarding efficacy and safety of CBD in psychiatry is still scarce. Further larger well-designed randomised controlled trials are required to assess the effects of CBD in psychiatric disorders.

KEYWORDS : Cannabidiol; pharmacotherapy; psychiatry; adverse effects; psychiatric disorders



A growing body of research on the endocannabinoid system (ECS) and phytocannabinoids has been produced in the last 20 years (Di Marzo & Piscitelli 2015; Khoury et al. 2016; Ligresti et al. 2016). The ECS comprises endogenous cannabinoids (e.g., anandamide and 2-archydonioilglycerol), cannabinoid
receptors type 1 (CB1) and 2 (CB2) and the enzymes responsible for synthesis and degradation of endocannabinoids. CB1 receptors are abundant in the central nervous system (CNS), particularly in the cortex, basal ganglia, hippocampus and cerebellum. CB2 receptors are expressed primarily in the immune and gastrointestinal systems and are also present in neurons, microglia and vascular elements of the CNS (Lu & Mackie 2016).

Cannabinoids have emerged as a new class of drugs with potential effects over a broad range of neurological and psychiatric disorders (Campos et al. 2016). Phytocannabinoids are terpenophenolic molecules derived from the Cannabis sativa plant (Campos et al. 2016). D-9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most concentrated substances found in Cannabis extracts (Mechoulam et al. 1965) and the most widely studied. Unlike THC, CBD does not cause psychoto-mimetic, cognitive or motor effects in humans, and in pre-clinical models CBD acts as a partial agonist of cannabinoid receptors CB1 and CB2 (Pertwee 2005).

The action of CBD in psychiatric disorders is not completely understood. Some effects of CBD seem to
be induced by its agonistic effect on the CB1 receptor, although CBD may also antagonise CB1 receptors agonists (Pertwee et al. 2002). Given the low affinity of CBD for CB1 and CB2 receptors, it probably acts through inhibition of hydrolysis or reuptake of anandamide, which may facilitate endocannabionoid-mediated neurotransmission (Bisogno et al. 2001; Bitencourt et al. 2008; Gomes et al. 2011; Leweke et al. 2012). Recent studies have reported that CBD inhibits the anandamide agonistic effects in CB1 and CB2 receptors, and has antioxidant and neuroprotective effects (Campos et al. 2016). Moreover, Laprairie et al. (2015) demonstrated that CBD also acts as a non-competitive negative allosteric modulator of CB1 receptors.

These authors suggest that this allosteric modulation, in concurrence with effects not mediated by CB1
receptors, may be responsible for the in vivo effects of CBD. The research of possible therapeutic actions of CBD started in the 1970s (Karniol et al. 1974). CBD seems to produce a broad spectrum of potential therapeutic properties in animal models and human pre-clinical and clinical studies, notably antiepileptic, sedative, anxiolytic, antipsychotic, antidepressant and neuroprotective effects (Bergamaschi et al. 2011; Campos et al. 2016). The mechanisms yielding such effects in psychiatric
disorders are not completely understood.

The favourable evidence on the use of CBD for the treatment of some types of epilepsy (Devinsky et al.
2016; GW Pharmaceuticals 2016) resistant to usual therapies, mainly those types caused by rare metabolic syndromes, has fostered a significant debate among the medical community in the last few years. Some countries, such as the UK, Canada, the Netherlands and some states in the United States authorised the use of CBD formulations for the treatment of epilepsy resistant to other medications (Whiting et al. 2015). In 2014, the Brazilian Federal Council of Medicine (FCM) approved the compassionate use of CBD for the treatment of children and adolescents with epilepsy resistant
to usual treatments (Conselho Federal de Medicina 2014). Compassionate use corresponds to the prescription of a new drug, not yet registered by National Agency for Sanitary Surveillance (Anvisa), for patients who have severe disease and did not respond to drugs registered in the country. Moreover, the FCM authorised only neurologists, neurosurgeons and psychiatrists to prescribe CBD in these conditions and prohibits the prescription of Cannabis in natura for medical use. Understanding whether CBD is a useful and safe treatment of psychiatric disorders is essential to empower psychiatrists and patients to make good clinical decisions. In this study, we performed a systematic literature review regarding therapeutic effects, adverse effects (AEs) and long-term safety of CBD for the treatment of patients with psychiatric disorders. Our primary goal was to assess clinical evidence evaluating the use and clinical safety of CBD for the treatment of schizophrenia, psychotic disorders, anxiety disorders, depression, bipolar disorder and substance-use disorders.