Pharmacological properties of cannabidiol in the treatment of psychiatric disorders : a critical overview
G. M. Mandolini, M. Lazzaretti, A. Pigoni, L. Oldani, G. Delvecchio and P. Brambilla
Epidemiology and Psychiatric Sciences, 2018, 27, 327–335.
© Cambridge University Press 2018
doi : 10.1017/S2045796018000239
Abstract : Cannabidiol (CBD) represents a new promising drug due to a wide spectrum of pharmacological actions. In order to relate CBD clinical efficacy to its pharmacological mechanisms of action, we performed a bibliographic search on PUBMED about all clinical studies investigating the use of CBD as a treatment of psychiatric symptoms. Findings to date suggest that (a) CBD may exert antipsychotic effects in schizophrenia mainly through facilitation of endocannabinoid signalling and cannabinoid receptor type 1 antagonism; (b) CBD administration may exhibit acute anxiolytic effects in patients with generalised social anxiety disorder through modification of cerebral blood flow in specific brain sites and serotonin 1A receptor agonism; (c) CBD may reduce withdrawal symptoms and cannabis/tobacco dependence through modulation of endocannabinoid, serotoninergic and glutamatergic systems; (d) the preclinical pro-cognitive effects of CBD still lack significant results in psychiatric disorders. In conclusion, current evidences suggest that CBD has the ability to reduce psychotic, anxiety and withdrawal symptoms by means of several hypothesised pharmacological properties. However, further studies should include larger randomised controlled samples and investigate the impact of CBD on biological measures in order to correlate CBD’s clinical effects to potential modifications of neurotransmitters signalling and structural and functional cerebral changes.
Key words : Antianxiety agents, antipsychotics, clinical drug studies, drugs new, psychopharmacology.
Cannabidiol (CBD) represents the second most abundant phytocannabinoid in Cannabis plant after the psychoactive tetrahydrocannabinol (Δ9-THC) and, in recent years, an increasing body of evidences emphasised its promising role as a treatment in several medical conditions (Fasinu et al. 2016). Indeed, CBD exhibits various therapeutic effects that range from antioxidant, anti-inflammatory and neuroprotective (Watt & Karl, 2017) to anticonvulsive (Perucca, 2017), anti-emetic (Parker et al. 2011) and analgesic (Lötsch et al. 2018).
Moreover, several animal studies and clinical trials on healthy controls suggested its potential role as an antipsychotic (Hahn, 2018), anxiolytic (Soares & Campos, 2017) and anti-craving (Lee et al. 2017) drug, as well as a pro-cognitive (Osborne et al. 2017) and antidepressant (de Mello Schier et al. 2014) compound. Therefore, it is not surprising that CBD has been considered as a new potential treatment in several psychiatric disorders.
In this regard, in order to link the so far hypothesised pharmacological mechanisms of action of CBD to its clinical effect in psychiatric disorders, we performed a bibliographic search in PubMed using ‘Cannabidiol AND Psychiatry’, ‘Cannabidiol AND Psychosis’, ‘Cannabidiol AND Schizophrenia’, ‘Cannabidiol AND Bipolar Disorder’, ‘Cannabidiol AND Depression’, ‘Cannabidiol AND Anxiety’, ‘Cannabidiol AND Substance Use Disorder’, ‘Cannabidiol AND Withdrawal Syndrome’ as key words. Additional articles were identified through the reference lists of the papers. We selected published studies from January 1995 until April 2018. We excluded both pre-clinical studies and clinical trials in healthy controls. Fourteen studies were finally included (five case reports, one open-label pilot study, one double-blinded controlled clinical trial, seven randomised double-blinded controlled clinical trials), matching methods and results summarised in Table 1.
CBD and psychosis
Eight studies evaluated the clinical effect of CBD in psychosis. Five of these studies found a beneficial effect of CBD in reducing psychotic symptoms in schizophrenia (SKZ) (Zuardi et al. 1995; Leweke et al. 2012; Leweke, 2013; McGuire et al. 2018) and in Parkinson’s disease (Zuardi et al. 2009), while the others found only mild effects or no improvement over psychotic symptoms in patients with SKZ (Zuardi et al. 2006; Boggs et al. 2018) or in bipolar disorder (BD) patients experiencing a manic episode with psychotic features (Zuardi et al. 2010). The majority of studies attributed the potential antipsychotic properties of CBD to its ability to directly inhibit the reuptake of anandamide, an endocannabinoid that exhibits neurogenic and anti-inflammatory activity (Pisanti et al. 2017) and plays a major role in mood regulation, cognition and behaviour (Di Marzo & Petrosino, 2007). Moreover, CBD can also reduce endocannabinoids degradation by blocking fatty acid amide hydrolase function (Pisanti et al. 2017). Consequently, the increase of endo-cannabinoids, such as anandamide, in postsynaptic neurons may regulate presynaptic release of γ-aminobutyric acid and glutamate aswell as stabilise dopamine neurotransmission (Gururajan & Malone, 2016). Moreover, CBD has low affinity for cannabinoid receptor type 1 (CB1R) and type 2 (CB2R)with a not specific indirect antagonism when these receptors are activated by Δ9-THC (Pisanti et al. 2017). Therefore, CBD may likely contrast Δ9-THC psychotropic activity through a non-competitive negative allosteric modulation of CB1R by binding to a distinct allosteric site (Laprairie et al. 2015). Furthermore, while the antipsychotic effect of CBD has been mainly related to the enhanced endocannabinoids signalling, some authors recently hypothesised that CBD may exert its antipsychotic action through a partial agonist activity on dopamine D2 receptors, similarly to the atypical antipsychotic aripiprazole (Seeman, 2016), and through the activation of vanilloid receptor 1, a non-selective calcium channel, thus facilitating glutamate pre-synaptic release (Campos et al. 2012). Interestingly, in the study carried out by Leweke et al. (Leweke et al. 2012), patients with SKZ were randomised to either amisulpride treatment or CBD administration for 28 days. The authors showed that both CBD and amisulpride groups had a significant reduction of psychotic symptoms and no difference in clinical efficacy was detected between the two different treatments. Moreover, the CBD group showed significantly higher serum level of both anandamide and fatty acid amide hydrolase substrates, a result which has been directly related to the CBD antipsychotic properties (Hahn, 2018). Finally, McGuire et al. (McGuire et al. 2018) detected a significant reduction of positive symptoms in patients with SKZ treated with CBD compared with placebo but the authors did not find any significant correlation between CBD plasma levels or its hydroxyl metabolites (6-OH-CBD, 7-OH-CBD) and the scores of scales assessing psychotic symptoms. In conclusion, overall these evidences suggest that CBD may exert antipsychotic effects in patients with SKZ (Zuardi et al. 1995; Leweke et al. 2012; Leweke, 2013; McGuire et al. 2018) and Parkinson’s psychosis (Zuardi et al. 2009). However, in three studies, CBD was ineffective to treat psychotic symptoms in BD patients (Zuardi et al. 2010) and outpatients with SKZ (Zuardi et al. 2006; Boggs et al. 2018). Moreover, the antipsychotic effect of CBD seemed to be related to the endo-cannabinoids plasma-level increase (Leweke et al. 2012), but not to CBD serum levels (McGuire et al. 2018). However, these results need further investigations. Therefore, since the facilitation of endocannabinoid signalling was the most likely hypothesised antipsychotic mechanism, the discrepancy of results among studies emphasised the need to evaluate endocannabinoid plasma-level changes in order to detect their potential contribution to the antipsychotic action.