Cannabinoids and Schizophrenia: Therapeutic Prospects

Abstract

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 systemic inflammation. 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 schizophrenia phenotype.

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…Oral CBD before ⌬ 9 -THC (600 mg, administered 3.5 h before 1.5 mg ⌬ 9 -THC iv) inhibited both paranoia and impairment of episodic memory (243). It was hypothesized that CBD in combination with a CB1 receptor antagonist could target the metabolic, inflammatory, and stressrelated components of the schizophrenia phenotype (731). Indeed, CBD may attenuate immune responses associated with psychotic disorders (182), as it inhibits both the production of proinflammatory cytokines and microglia activation (534).…”

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…The 2 major phyto-cannabinoid constituents with central nervous system activity are THC, responsible for the euphoric and mind-altering effects, and CBD, which lacks these psychoactive effects. Preclinical and clinical studies show CBD possesses a wide range of therapeutic properties, including antipsychotic, analgesic, neuroprotective, anticonvulsant, antiemetic, antioxidant, anti-inflammatory, antiarthritic, and antineoplastic properties (see [11,12,[16][17][18][19] for reviews). A review of potential side effects in humans found that CBD was well tolerated across a wide dose range, up to 1500 mg/day (orally), with no reported psychomotor slowing, negative mood effects, or vital sign abnormalities noted [20].…”

“…CBD has a broad pharmacological profile, including interactions with several receptors known to regulate fear and anxiety-related behaviors, specifically the cannabinoid type 1 receptor (CB 1 R), the serotonin 5-HT 1A receptor, and the transient receptor potential (TRP) vanilloid type 1 (TRPV1) receptor [11,12,19,21]. In addition, CBD may also regulate, directly or indirectly, the peroxisome proliferator-activated receptor-γ, the orphan G-protein-coupled receptor 55, the equilibrative nucleoside transporter, the adenosine transporter, additional TRP channels, and glycine receptors [11,12,19,21].…”

“…In addition, CBD may also regulate, directly or indirectly, the peroxisome proliferator-activated receptor-γ, the orphan G-protein-coupled receptor 55, the equilibrative nucleoside transporter, the adenosine transporter, additional TRP channels, and glycine receptors [11,12,19,21]. In the current review of primary studies, the following receptor-specific actions were found to have been investigated as potential mediators of CBD's anxiolytic action: CB 1 R, TRPV1 receptors, and 5-HT 1A receptors.…”

The Hormesis of Thinking: A Deeper Quantum Thermodynamic Perspective?

“…It is interesting that many studies suggest that major psychiatric conditions are associated with inflammation [171]; in particular, there appears to be a correlation between suicide and inflammatory markers [172]. It is therefore of particular relevance that many anti-depressants apparently inhibit the ETC [173], suggesting that some of their effects could be explained by hormesis.…”