Clinical trials allow us to draw conclusions about the safety and effectiveness of potential therapeutic agents in humans, while animal studies and in vitro experiments allow researchers to explore their biological actions in greater detail. However, because the latter class of studies are not conducted in humans, the results don’t always lead to the clinical application that we hope for—the majority of drugs that start in human clinical trials never become approved. Nonetheless, animal studies provide us with a strong foundation of biological knowledge, and are where the initial breakthroughs in research are made.
CBD’s ability to target a specific serotonin receptor, the serotonin 1A receptor, is associated with a remarkable range of therapeutic possibilities. Professor Roger Pertwee, an English pharmacologist renowned for his research on cannabinoids, spoke with Leafly about this aspect of CBD biology.
Why does THC get you high but not CBD?
Although it is a cannabinoid, CBD does not directly interact with the two classical cannabinoid receptors (CB1 and CB2). Instead, it affects signaling through CB1 and CB2 receptors indirectly. This partly explains why, in contrast to THC, CBD is non-intoxicating. In addition to its indirect influence on the CB1 and CB2 receptors, CBD can increase levels of the body’s own naturally-produced cannabinoids (known as endocannabinoids) by inhibiting the enzymes that break them down.
A neuron’s sensitivity to a specific neurotransmitter depends on whether or not it contains a receptor that “fits” that transmitter, like an electrical socket fits a plug. If a neuron contains receptors that match a particular neurotransmitter, then it can respond directly to that transmitter. Otherwise, it generally can’t. All neurons contain multiple neurotransmitter receptors, allowing them to respond to some neurotransmitters but not others.
CBD’s therapeutic potential with respect to addiction also extends to the serotonin system. Animal studies have demonstrated that CBD directly activates multiple serotonin receptors in the brain. These interactions have been implicated in its ability to reduce drug-seeking behavior. CBD’s influence on the serotonin system may also account in part for its anti-anxiety properties, which have been robustly demonstrated across both human and animal studies.
Background: Accumulating evidence suggests that the non-intoxicating cannabinoid compound cannabidiol (CBD) may have antipsychotic and anxiolytic properties, and thus may be a promising new agent in the treatment of psychotic and anxiety disorders. However, the neurobiological substrates underlying the potential therapeutic effects of CBD are still unclear. The aim of this systematic review is to provide a detailed and up-to-date systematic literature overview of neuroimaging studies that investigated the acute impact of CBD on human brain function. Methods: Papers published until May 2020 were included from PubMed following a comprehensive search strategy and pre-determined set of criteria for article selection. We included studies that examined the effects of CBD on brain function of healthy volunteers and individuals diagnosed with a psychiatric disorder, comprising both the effects of CBD alone as well as in direct comparison to those induced by ∆9-tetrahydrocannabinol (THC), the main psychoactive component of Cannabis. Results: One-ninety four studies were identified, of which 17 met inclusion criteria. All studies investigated the acute effects of CBD on brain function during resting state or in the context of cognitive tasks. In healthy volunteers, acute CBD enhanced fronto-striatal resting state connectivity, both compared to placebo and THC. Furthermore, CBD modulated brain activity and had opposite effects when compared to THC following task-specific patterns during various cognitive paradigms, such as emotional processing (fronto-temporal), verbal memory (fronto-striatal), response inhibition (fronto-limbic-striatal), and auditory/visual processing (temporo-occipital). In individuals at clinical high risk for psychosis and patients with established psychosis, acute CBD showed intermediate brain activity compared to placebo and healthy controls during cognitive task performance. CBD modulated resting limbic activity in subjects with anxiety and metabolite levels in patients with autism spectrum disorders. Conclusion: Neuroimaging studies have shown that acute CBD induces significant alterations in brain activity and connectivity patterns during resting state and performance of cognitive tasks in both healthy volunteers and patients with a psychiatric disorder. This included modulation of functional networks relevant for psychiatric disorders, possibly reflecting CBD’s therapeutic effects. Future studies should consider replication of findings and enlarge the inclusion of psychiatric patients, combining longer-term CBD treatment with neuroimaging assessments.
Copyright © 2021 Batalla, Bos, Postma and Bossong.
Conflict of interest statement
Keywords: Cannabis (marijuana); cannabidiol; delta9-tetrahydrocannabinol; functional MRI; neuroimaging.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
CBD ’s anti-inflammatory and anti-anxiety effects are in part attributable to its inhibition of adenosine reuptake. By delaying the reuptake of this neurotransmitter, CBD boosts adenosine levels in the brain, which regulates adenosine receptor activity. A1A and A2A adenosine receptors play significant roles in cardiovascular function, regulating myocardial oxygen consumption and coronary blood flow. These receptors have broad anti-inflammatory effects throughout the body.
Here are some of the ways that CBD confers its manifold therapeutic effects.
Whereas cannabidiol directly activates the 5- HT1A serotonin receptor and several TRPV ion channels, some studies indicate that CBD functions as an antagonist that blocks, or deactivates, another G protein-coupled receptor known as GPR55 .
CBD as a reuptake inhibitor
Although CBD has little binding affinity for either of the two cannabinoid receptors ( CB1 and CB2 ), cannabidiol modulates several non-cannabinoid receptors and ion channels. CBD also acts through various receptor-independent pathways—for example, by delaying the “reuptake” of endogenous neurotransmitters (such as anandamide and adenosine) and by enhancing or inhibiting the binding action of certain G-protein coupled receptors.
GPR55 , when activated, also promotes cancer cell proliferation, according to a 2010 study by researchers at the Chinese Academy of Sciences in Shanghai. This receptor is expressed in various types of cancer.
GPR55 promotes osteoclast cell function, which facilitates bone reabsorption. Overactive GPR55 receptor signaling is associated with osteoporosis.
According to a team of Stony Brook University scientists, CBD functions as an anandamide reuptake and breakdown inhibitor, thereby raising endocannabinoid levels in the brain’s synapses. Enhancing endocannabinod tone via reuptake inhibition may be a key mechanism whereby CBD confers neuroprotective effects against seizures, as well as many other health benefits.