Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence, Cathrin Rohleder et al., 2016

Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence

Cathrin Rohleder, Juliane K. Müller, Bettina Lange and F. M. Leweke

Frontiers in Pharmacology, 2016, Volume 7, Article 422.

doi: 10.3389/fphar.2016.00422


There is urgent need for the development of mechanistically different and less side-effect prone antipsychotic compounds. The endocannabinoid system has been suggested to represent a potential new target in this indication. While the chronic use of cannabis itself has been considered a risk factor contributing to the development of schizophrenia, triggered by the phytocannabinoid delta-9-tetra-hydro-cannabinol (19-THC), cannabidiol, the second most important phytocannabinoid, appears to have no psychotomimetic potential. Although, results from animal studies are inconsistent to a certain extent and seem to depend on behavioral paradigms, treatment duration and experimental conditions applied, cannabidiol has shown antipsychotic properties in both rodents and rhesus monkeys. After some individual treatment attempts, the first randomized, doubleblind controlled clinical trial demonstrated that in acute schizophrenia cannabidiol exerts antipsychotic properties comparable to the antipsychotic drug amisulpride while being accompanied by a superior, placebo-like side effect profile. As the clinical improvement by cannabidiol was significantly associated with elevated anandamide levels, it appears likely that its antipsychotic action is based on mechanisms associated with increased anandamide concentrations. Although, a plethora of mechanisms of action has been suggested, their potential relevance for the antipsychotic effects of cannabidiol still needs to be investigated. The clarification of these mechanisms as well as the establishment of cannabidiol’s antipsychotic efficacy and its hopefully benign side-effect profile remains the subject of a number of previously started clinical trials.

Keywords : schizophrenia, psychosis, animal models, clinical trials, CBD



Cannabis sativa has been known and used by humans for several 1000 years and the knowledge that it contains an intoxicating principle dates back to 1000 to 1500 B.C. (Adams, 1942). The two major compounds of cannabis – delta-9-tetrahydrocannabinol (19-THC) and cannabidiol – have been chemically identified in the 1940th (Adams et al., 1940a,b,c; Adams, 1942; Todd, 1946). Two decades later, remaining uncertainties regarding the exact position of double bonds were eliminated as new imaging techniques like NMR spectroscopy and X-ray structure determination became available (Mechoulam and Shvo, 1963; Gaoni and Mechoulam, 1964; Jones et al., 1977).

Along with its chemical identification, 19-THC has been identified as the major propsychotic compound of Cannabis sativa (Adams and Baker, 1940; Adams et al., 1940b; Allentuck and Bowman, 1942; Wollner et al., 1942; Mechoulam et al., 1970). However, the underlying neurobiological principles remained conjectural until it was observed that cannabinoid drugs inhibit adenylatecyclase activity in neuroblastoma cells (Howlett, 1984), and the subsequent discovery of the G-protein coupled type1 cannabinoid receptor (CB1R) (Devane et al., 1988; Matsuda et al., 1990). A few years later, the type 2 cannabinoid receptor (CB2R) (Munro et al., 1993) as well as the two major endogenous ligands
to cannabinoid receptors–anandamide (Devane et al., 1992) and 2-arachidonoyl-sn-glycerol (Mechoulam et al., 1995; Stella et al., 1997) –were discovered. The architecture of the endocannabinoid system (ECS)–including endocannabinoids, cannabinoid receptors as well as synthesizing and degrading
enzymes–has been vividly summarized and illustrated in recent reviews by Lutz et al. (2015) and Lu and Mackie (2016).

Studies indicating that cannabis abuse might be a stressor for psychotic relapse and exacerbation of schizophrenic symptoms as well astheobservationthat 19-THCinduced schizophrenia-like neuro-psychological and psychopathological alterations in healthy volunteers, led to the hypothesis that a dysfunctional ECS is involved in the etiology of psychoses (Emrich et al., 1997). In the mean time, several studies reported diverse acute 19-THC effects in healthy participants and schizophrenic patients,thereby confirming the ECS hypothesis (Leweke et al., 1999, 2000; D’Souza et al., 2004, 2005; Koethe et al., 2006; Bhattacharyya et al., 2009; Fusar-Poli et al., 2009; Koethe et al., 2009; Mason et al., 2009; Sherif et al., 2016). In addition, several epidemiological studies (for review see, Gage et al., 2016) substantiated the view that cannabis use has to be considered an important environmental risk factor for the development of schizophrenia in vulnerable individuals. However, the actual lifetime risk seems to be influenced by the dose (Zammit et al., 2002; Moore et al., 2007) and frequency of cannabis consumption (Di Forti et al., 2009), the potency of consumed cannabis preparations (Di Forti et al., 2009, 2014) and age of onset (Arseneault et al., 2002).

While a dysfunctional ECS seems to contribute to the pathophysiology of schizophrenia, the endocannabinoid anandamide is considered to have protective effects by counteracting neurotransmitter imbalances (Leweke, 2012). Therefore,it has been suggested that modulating the ECS might be a new, promising pharmacological target for schizophrenia.

To date, two main approaches targeting the ECS have been systematically studied in humans : first,trials using CB1R antagonists to treat both psychotic and cognitive symptoms of schizophrenia, and, second,trials using the second most important phytocannabinoid cannabidiol (Leweke et al., 2016).
In addition, a single clinical case series on dronabinol (19-THC) in treatment-refractory severe chronic schizophrenia has been conducted (Schwarcz et al., 2009).

In contrast to 19-THC, cannabidiol appears to have no psychotomimetic potential, but shows antipsychotic effects in rodents and humans. Thus, this review focuses on (1) preclinical studies investigating cannabidiol as a potential antipsychotic in animal models of aspects of schizophrenia, (2) clinical evidence for its antipsychotic action, and, (3) potential mechanisms of action and their potential relevance for the antipsychotic effects of cannabidiol.