Juan Esteban Perez, MD​

Tags:  Neuro-psychiatric, CBD, THC, Psychosis, Modulation, Psychotropic

 

The problem: Consumption of tetrahydrocannabinol (THC) has been associated with neuropsychiatric side effects, including anxiety, paranoia, and hallucinations.  It has also been associated with and alteration of “salience attribution.” That term refers to the degree to which stimuli receive an individual’s attention). Dysregulation of salience attribution is often observed in psychotic conditions such as schizophrenia. The non-psychoactive Cannabidiol (CBD) has been shown to counteract this effect, although the mechanism remains unclear.     

 

Why do this study? CBD mitigation of neuropsychiatric risk in the consumption of high potency cannabis has been reported, but the precise neurobiological mechanism has not been determined. Uncovering the role and molecular alterations caused by THC/CBD can provide important information about the development and potential therapeutic options of psychotic conditions.

 

The study: The study consisted of examining the effect of THC and CBD in the activation/inactivation of proteins in the ventral hippocampus (vHipp), a region of the brain associated with emotional processing and the development of schizophrenia and psychosis. This study was performed on rats, in accordance with recommendations by the Canadian Council on Animal Care.

 

Under stereotactic guidance, catheters were inserted bilaterally in the region of the ventral hippocampus. Rats were then randomized to receive infusions of THC, CBD, THC + CBD or control (no active substance). Experiments were conducted to assess affective and anxiety-related behaviors, as well as neuronal excitability (via glass microelectrodes inserted into the vHipp region via stereotactic guidance) following infusion of the respective test substances. A subset of rats also received an infusion of test substances and were subsequently euthanized 5 minutes later, to asses immediate vHipp protein expression.

 

Rats who received an infusion of THC alone exhibited an increase in behavior consistent with increased anxiety, while rats who had a combined infusion of CBD and THC exhibited an anxiolytic effect.  These THC rats also had neuronal activity measurements that showed increased dopaminergic neuronal firings in the vHipp region compared to control (p =0.028), CBD (p<0.001) and THC + CBD (p=0.011).

Similar results were observed in protein expression assays. THC administration resulted in a greater proportion of pERK (active form) in relationship to ERK (inactivated form), compared to the control group. CBD administration alone did not result in a greater proportion of activated proteins when compared to control. However, the administration of THC and CBD resulted in a decreased expression of pERK compared to control.

 

Conclusions: CBD appears to modulate the neuropsychiatric side-effects of THC by decreasing the activation of the protein ERK (to active form pERK), resulting in a decrease in dopaminergic neuronal firing in the vHipp.

 

What does this study add? This study elucidates the mechanism in which CBD mitigates the neuropsychiatric effects of THC, and provides information regarding a potential pathway to further characterize and treat patients who develop psychotic diseases.

 

 

Funder: The study was supported by the Canadian Institutes of Health Research (CIHR), the National Science and Engineering Research Council of Canada (NSERC), MITAC’s and a Vanier CGS (Canada Graduate Scholarship) awarded to RH

 

Author conflicts: The authors have no conflicts of interest to disclose

 

Commentary: (David Casarett MD)

 

There are at least two interesting findings in this study.  The first, which the authors rightly focus on, is the elucidation of the mechanism by which CBD may modulate some of the neuropsychiatric effects of THC.  That finding, although preliminary, points to interesting directions for future research, and the way that this study might be adapted for humans.  The second finding may be even more interesting, though.  This study describes objective evidence that CBD can modulate the psychoactive effects of THC.  This phenomenon is widely reported and is part of the conventional wisdom that underlies the so-called “entourage effect.”  But studies demonstrating its applicability have been limited.  So in addition to the basic science of how this might happen, this study is also valuable because it adds to the growing evidence that CBD may, in fact, modulate some of the negative effects of THC.