Cannabidiol (CBD)

It’s worth considering cannabidiol’s potential in treating the unmet needs of patients with schizophrenia. The first small-scale clinical studies with CBD treatment of patients with psychotic symptoms confirm the potential of CBD as an effective, safe and well-tolerated antipsychotic compound [1]:

“Although, unlike THC, CBD is devoid of any psychotropic effects, evidence is increasing that CBD has anxiolytic and antipsychotic properties. Although the mode of action of CBD is not fully understood, there are indications that it acts as a cannabinoid CB1/CB2 receptor inverse agonist, and that it inhibits the uptake and metabolism of anandamide, thereby enhancing levels of endogenous cannabinoids”

  • CBD can antagonise CB1Rs and CB2Rs at relatively low concentrations. This antagonism, however, seems to be non-competitive in nature, with evidence suggesting that CBD could act as a CB1R or CB2R inverse agonist.
  • Other evidence indicates that CBD is not rimonabant-like in action and thus appears very unlikely to produce unwanted CNS effects. CBD is a very low-affinity CB1 ligand that can nevertheless affect CB1 receptor activity in vivo in an indirect manner. More recently, it was discovered that cannabidiol behaved as a non-competitive negative allosteric modulator of CB1  [link]
  • CBD can also facilitate eCB-mediated neurotransmission by decreasing AEA hydrolysis or reuptake
  • CBD can, at µM concentration range, act as an agonist of 5-HT1ARs in vitro and in vivo.  Activation of 5-HT1A receptors mediates CBDs anxiolytic and antidepressive effects
  • CBD can activate TRPV1Rs, facilitating glutamate release. These receptors are expressed in several brain areas related to anxiety such as the amygdala, hippocampus, prefrontal cortex, and PAG. Interaction with TRPV1Rs has also been suggested to explain the antipsychotic-like effects of CBD on MK-801 induced disruption of PPI
  • CBD can inhibit adenosine uptake and displays antagonism of the putative cannabinoid receptor GPR55
  • a CB1R antagonist, but not a 5-HT1AR antagonist, is able to prevent the beneficial effects of CBD in the marble burying test, a model for OCD.
  • acts as a PPARγ agonist, stimulating hippocampal neurogenesis
  • Cannabidiol ameliorates the prepulse inhibition disruption induced by amphetamine, with an increase of anandamide availability possibly playing a role [link]

See more:

Endocannabinoid system and psychiatry: in search of a neurobiological basis for detrimental and potential therapeutic effects

Are cannabidiol and Δ9 -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review.

Human studies are promising:

“Five studies have been published in which patients with psychotic symptoms were treated with CBD. In a first case report, Zuardi et al. (1995) described symptomatology of a 19-year-old female schizophrenia patient who was treated with CBD for 26 days (maximum of 1500 mg/day orally). CBD treatment resulted in the improvement of symptomatology as measured with the Brief Psychiatric Rating Scale (BPRS). This improvement was not achieved with haloperidol treatment (Zuardi et al., 1995). In a follow-up study from the same group, three treatment-resistant schizophrenia patients were treated with CBD for four weeks (maximum of 1280 mg/day orally). Although all patients tolerated CBD well and no side effects were reported, only one of the three patients showed mild improvement on the BPRS after CBD monotherapy (Zuardi et al., 2006). In a third study, six patients with Parkinson’s disease who experienced psychotic symptoms received CBD daily for four weeks (maximum of 600 mg/day orally). CBD treatment significantly decreased symptomatology as measured with the BPRS without any adverse effects (Zuardi et al., 2009). Using a Stroop Colour Word Test, Hallak et al. (2010) tested the effect of single doses of CBD administration on selective attention in 28 schizophrenia patients. All patients attended two experimental sessions, the first one without the administration of drugs and the second after oral administration of either placebo, 300 mg CBD or 600 mg CBD. Comparison of the first and second sessions revealed improved performance in all three groups, with patients who received placebo and CBD 300 mg performing significantly better than those who received CBD 600 mg. No effects of CBD administration were found on symptomatology (Hallak et al., 2010). In the largest clinical trial with CBD treatment of schizophrenia patients to date, Leweke et al. (2012) performed a double-blind, randomised clinical trial of CBD (N = 20) vs the conventional antipsychotic compound amisulpride (N = 19). After four weeks of treatment (maximum of 800 mg/day orally), both CBD and amisulpride resulted in significant clinical improvement as measured with both the PANSS and BPRS. However, CBD treatment displayed a markedly superior side-effect profile, reflected in significantly smaller changes in extrapyramidal symptoms, weight gain and prolactin levels”

Repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-like effects and attenuates molecular changes observed after chronic administration of an NMDAR antagonist [2, 3]

“…repeated treatment with CBD or the atypical antipsychotic clozapine attenuates or reverses the schizophrenia-like behavioral disruption and changes in the expression of astrocytic and microglial markers observed after chronic administration of the NMDA receptor antagonist MK-801. These data reinforce the proposal that CBD may induce antipsychotic-like effects. Although the possible mechanism of action of these effects is still unknown, it may involve CBD anti-inflammatory and neuroprotective properties.”


To conclude:

“Given the high tolerability and superior cost-effectiveness, CBD may prove to be an attractive alternative to current antipsychotic treatment, possibly in specific subgroups of patients. However, to date the vast majority of the current evidence comes from experimental non-clinical studies and case reports. Although promising, this does not provide evidence that CBD has antipsychotic properties. Therefore, the only clinical evidence currently available for CBD as an antipsychotic agent is the relatively small (n=42) clinical trial published by Leweke et al. (2012). A large double blind randomized clinical trial in a new study population, comparing CBD to an atypical antipsychotic agent is required to truly advance the field. Moreover, illuminating pharmacological pathways through which CBD reduces the experience of psychotic symptoms could also lead to the design of new synthetic agents that act through the endocannabinoid system in ameliorating psychotic symptoms.” [4]


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