Keywords: Cannabis (marijuana); cannabidiol; delta9-tetrahydrocannabinol; functional MRI; neuroimaging.
Copyright © 2021 Batalla, Bos, Postma and Bossong.
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.
Conflict of interest statement
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.
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Δ9-THC is known for producing psychoactive effects in the body through the activation of two receptors in the central nervous system called CB1 and CB2.[2,3] The activation of these receptors triggers physiological processes across multiple organ systems, most notably the release of neurotransmitters from the central nervous system that impart the psychoactive effects associated with feeling “high”.
Multiple reviews have concluded that sufficient evidence is still lacking on the effects of CBD on mental disorders or their symptoms.[9,10] One study found that CBD may reduce nightmares and sleep disturbances in those with PTSD, but again, larger scale, well-designed trials are warranted to confirm this relationship.
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Compounds like THC bind with CB1 receptors in the brain to produce intoxicating effects. While some people use marijuana to gain these effects, they can be undesirable to others. We know that CBD inhibits the binding action of molecules such as THC to CB1 receptors. Therefore, it can minimize many of THC’s undesirable effects such as anxiety and memory problems.
But first, it is important to note that hemp and marijuana are just broad classifications of cannabis. A type of flowering plant belonging to the Cannabaceae family, the cannabis plant has three main species. Cannabis Indica, Cannabis Sativa, and Cannabis Ruderalis are the three main species. Legally, the difference between hemp and marijuana stems from the THC content, as specified in the Agricultural Act of 2018.
Marijuana refers to varieties of cannabis that have a THC content exceeding 0.3% by dry weight. While the THC content varies amongst marijuana plants, some strains are bred to contain as high as 30% THC. These high levels mean that the use of marijuana will cause an intoxicating ‘high,’ which is characterized by a euphoric and relaxing feeling. However, it is also used for medicinal purposes in states that have legalized it. Marijuana often comes in different strains, including Indica, Sativa, and even both. It is possible to cross-breed different varieties of marijuana.
CBD works by interacting indirectly with these receptors, producing different effects from THC. In addition, it affects the ECS by inhibiting the breakdown of anandamide, which leads to increased levels of the molecule. Hemp plants are so rich with cannabidiol that they are naturally the best source for CBD extraction. The effects of hemp on the brain are mostly due to CBD’s interactions with the ECS.
Numerous studies have revealed that CBD actually helps to protect brain cells from damage. One way CBD helps to protect brain cells is through its effect on CB2 receptors present in the brain. Inflammation is one of the main causes of brain damage. CBD interacts with CB2 receptors in the brain producing anti-inflammatory responses in the immune cells found in the brain. This helps to lower damage to the brain caused by inflammation.
There are two main types of receptors, CB1 and CB2, though there are many others. CB1 receptors reside mainly in the central nervous system, and affect functions such as mood, appetite, pain, and coordination. CB2 receptors are prevalent in the immune system, and they affect pain and inflammation. THC binds closely to CB1 receptors in the brain, more specifically anandamide CB1 receptors to produce the psychoactive effects or “high” THC is known for.
CBD can be beneficial in the treatment of epilepsy by reducing the stimulation of cells in the brain that cause seizures. This is because CBD boosts the release of GABA, an inhibitory neurotransmitter. Epidiolex is a drug that can effectively reduce the number and severity of epileptic seizures. It is the only cannabis drug that the FDA has approved.