Approximately one third of patients diagnosed with schizophrenia do not achieve adequate symptom control with standard antipsychotic
drugs (APs). Some of these may prove responsive to clozapine, but non-response to APs remains an important clinical problem
and cause of increased health care costs.
In a significant proportion of patients, schizophrenia is associated with natural and iatrogenic metabolic abnormalities (obesity, dyslipidaemia,
impaired glucose tolerance or type 2 diabetes mellitus), hyperadrenalism and an exaggerated HPA response to stress, and chronic
The endocannabinoid system (ECS) in the brain plays an important role in maintaining normal mental health. ECS modulates emotion,
reward processing, sleep regulation, aversive memory extinction and HPA axis regulation. ECS overactivity contributes to visceral fat
accumulation, insulin resistance and impaired energy expenditure.
The cannabis plant synthesises a large number of pharmacologically active compounds unique to it known as phytocannabinoids. In contrast
to the euphoric and pro-psychotic effects of delta-9-tetrahydrocannabinol (THC), certain non-intoxicating phytocannabinoids have
emerged in pre-clinical and clinical models as potential APs. Since the likely mechanism of action does not rely upon dopamine D2 receptor
antagonism, synergistic combinations with existing APs are plausible.
The anti-inflammatory and immunomodulatory effects of the non-intoxicating phytocannabinoid cannabidiol (CBD) are well established
and are summarised below. Preliminary data reviewed in this paper suggest that CBD in combination with a CB1 receptor neutral antagonist
could not only augment the effects of standard APs but also target the metabolic, inflammatory and stress-related components of the