Δ-9-Tetrahydrocannabinol and Cannabidiol produce dissociable effects on prefrontal cortical executive function and regulation of affective behaviors

Abstract

The use of cannabis for therapeutic and recreational purposes is growing exponentially. Nevertheless, substantial questions remain concerning the potential cognitive and affective side-effects associated with cannabis exposure. In particular, the effects of specific marijuana-derived phytocannabinoids on neural regions such as the prefrontal cortex (PFC) are of concern, given the role of the PFC in both executive cognitive function and affective processing. The main biologically active phytocannabinoids, ∆-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with multiple neurotransmitter systems important for these processes directly within the PFC. Considerable evidence has demonstrated that acute or chronic THC exposure may induce psychotomimetic effects, whereas CBD has been shown to produce potentially therapeutic effects for both psychosis and/or anxiety-related symptoms. Using an integrative combination of cognitive and affective behavioral pharmacological assays in rats, we report that acute intra-PFC infusions of THC produce anxiogenic effects while producing no impairments in executive function. In contrast, acute infusions of intra-PFC CBD impaired attentional set-shifting and spatial working memory, without interfering with anxiety or sociability behaviors. In contrast, intra-PFC CBD reversed the cognitive impairments induced by acute glutamatergic antagonism within the PFC, and blocked the anxiogenic properties of THC, suggesting that the therapeutic properties of CBD within the PFC may be present only during pathologically aberrant states within the PFC. Interestingly, the effects of PFC THC vs. CBD were found to be mediated through dissociable CB1 vs. 5-HT1A-dependent receptor signaling mechanisms, directly in the PFC.

In the evidence

This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.

• State of the evidence: Cannabis for anxiety ↕Mixed

  Intra-prefrontal THC produced anxiogenic effects, while intra-prefrontal CBD did not affect anxiety but blocked THC's anxiogenic properties.

  Synthesized October 22, 2026

Comparable studies

Other preclinical and animal studies on cannabis for anxiety, most cited first.