Cannabidiol as a potential treatment for psychosis
Cathy Davies and Sagnik Bhattacharyya
Therapeutic Advances in Psychopharmacology, 2019, Vol. 9, 1–16
Psychotic disorders such as schizophrenia are heterogeneous and often debilitating
conditions that contribute substantially to the global burden of disease. The introduction of
dopamine D2 receptor antagonists in the 1950s revolutionised the treatment of psychotic
disorders and they remain the mainstay of our treatment arsenal for psychosis. However,
traditional antipsychotics are associated with a number of side effects and a significant
proportion of patients do not achieve an adequate remission of symptoms. There is therefore a
need for novel interventions, particularly those with a non-D2 antagonist mechanism of action.
Cannabidiol (CBD), a non-intoxicating constituent of the cannabis plant, has emerged as a
potential novel class of antipsychotic with a unique mechanism of action. In this review, we
set out the prospects of CBD as a potential novel treatment for psychotic disorders. We first
review the evidence from the perspective of preclinical work and human experimental and
neuroimaging studies. We then synthesise the current evidence regarding the clinical efficacy
of CBD in terms of positive, negative and cognitive symptoms, safety and tolerability, and
potential mechanisms by which CBD may have antipsychotic effects.
Keywords : antipsychotics, cannabidiol, cannabinoids, cannabis, psychosis, schizophrenia,
Psychotic disorders such as schizophrenia are heterogeneous and often debilitating conditions that
contribute substantially to the global burden of disease.1 Patients with psychosis present with a
range of psychopathology across positive, negative and cognitive symptom domains. The introduction
of dopamine (primarily D2) receptor antagonists in the 1950s revolutionised the treatment of
psychotic disorders and they remain the mainstay of our treatment arsenal for psychosis.2 However,
a significant proportion of patients either do not respond to traditional antipsychotics or do not
achieve a complete or adequate remission of symptoms.3 In addition, most current antipsychotics
only target the positive symptoms of psychosis, with little effect on negative or cognitive symptoms.2 Dopamine-acting antipsychotics are also associated with a number of side effects,4 some of which can be severe and which may contribute to nonadherence. There is therefore a need for novel interventions, particularly those with a non-D2 antagonist mechanism of action, and which may thereby avoid some of the adverse effects of modulating the dopamine system directly. In line with this, over recent years there
has been increasing interest in the development of treatments with alternate mechanisms of action.5
Accumulating evidence implicates the endocannabinoid system in the pathophysiology of psychosis.6,7 A recent meta-analysis concluded that patients with psychosis have significantly higher levels of the endocannabinoid anandamide both in cerebrospinal fluid and in blood, and higher expression of the main central cannabinoid 1 receptor (CB1) on peripheral immune cells.8 This elevated endocannabinoid tone was observed at all stages of illness, from the prodrome to chronic psychosis.8 Alterations in CB1 receptor expression have also been observed in postmortem tissue and in vivo in patients with psychosis.9–11
If the endocannabinoid system plays a role in psychosis pathophysiology, it raises the interesting
possibility that pharmacological compounds that modulate this system may have therapeutic value.
Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa, has been heralded as one such potential treatment. While the main psychoactive ingredient in cannabis, delta- 9-tetrohydrocannabinol (THC), has anxiogenic, psychotomimetic and amnestic effects, CBD is non-intoxicating and has potential anxiolytic, antipsychotic and anticonvulsant properties, and no detrimental effects on memory.12 Epidemiological findings support these opposing effect profiles; extensive evidence implicates cannabis
use as a risk factor for the development of psychosis and poor outcomes in cannabis-using patients. 13,14–19 However, the adverse effects of cannabis use on the risk of onset and subsequent outcome in psychosis are particularly evident in those using high potency skunk-like cannabis (i.e. with high levels of THC and low levels of CBD) as opposed to those using hash-like cannabis (i.e. with lower THC and higher CBD).15,20–22 This pattern of findings is consistent with evidence that CBD not only has opposing effects to THC but may also block some of its adverse (and particularly psychotomimetic) effects.23,24
Importantly, CBD has a different mechanism of action to dopamine receptor antagonists and could therefore represent a completely novel class of antipsychotic treatment.25 This would be associated
with numerous benefits. First, by avoiding dopamine receptor antagonism, adverse effects such as extrapyramidal symptoms and increased prolactin may be avoided. Second, if CBD acts via different molecular pathways to current antipsychotics, it could be used not only as monotherapy but potentially as an adjunctive treatment alongside existing antipsychotics, with potential complementary gains in efficacy. While CBD is currently being tested in relation to a number of psychiatric disorders and physical health conditions, 12 this review synthesises and summarises the current evidence regarding the therapeutic potential of CBD as a treatment for psychosis.
Evidence for antipsychotic potential of cannabidiol
The accumulating evidence regarding the antipsychotic potential of CBD has emerged from a number
of different sources. This includes preclinical work, experimental studies in healthy human volunteers
comparing the neurocognitive effects of THC and CBD as well as studies examining whether CBD can block or attenuate the symptomatic effects of THC.