According to the Mental Health Blog
Cannabidiol offers a novel pharmacodynamic profile as an anxiolytic agent. It is believed that administration of CBD (cannabidiol) modulates neurotransmission in a multitude of ways. Literature shows that cannabidiol alters 5-HT1A, GPR55, CB1/CB2, and mu/delta opioid receptor sites – while simultaneously enhances hippocampal neurogenesis. The combination of these neurophysiological effects likely contributes to its efficacy as a novel anxiolytic.
5-HT1A partial agonist: Modulation of neurotransmission at the 5-HT1A receptor is understood to provide anxiolytic, antidepressant, and neuroprotective effects. Research has demonstrated the effect of cannabidiol as a 5-HT1A receptor partial agonist, meaning it binds to the receptor site but only stimulates the receptor partially (relative to a full agonist). Studies with cloned human cell cultures note that cannabidiol displaces 5-HT1A agonists from 5-HT1A receptor sites in a dose-dependent manner.
In other words, the greater the amount of CBD oil administered following administration of a 5-HT1A agonist, the more significant the displacement. Researchers mention that this mechanism differs from THC which is incapable of displacing 5-HT1A agonists from the 5-HT1A receptor. Partial agonism of the 5-HT1A receptor site is associated with an array of therapeutic effects including increased serotonin (or serotonergic effects), increased dopamine (in medial PFC, striatum, hippocampus), releasing acetylcholine, and hippocampal neurogenesis.
A study published in 2008 indicated that CBD injections into the dorsolateral periaqueductal gray area of rats reduced anxiety via 5-HT1A receptor interaction. Researchers noted that the 5-HT1A receptors were more involved than cannabinoid receptors (e.g. CB1) in reducing anxiety. The study concluded that cannabidiol interacts directly with 5-HT1A receptors to yield an anxiolytic response.
Although the 5-HT1A partial agonism exerted by CBD may not be an outright cure for anxiety, it is likely to help many individuals. Studies conducted on humans with panic disorder note impairments in 5-HT1A receptor function and poor 5-HT1A binding. The bottom line is that individuals with anxiety could have dysfunctional 5-HT1A activation and may resort to commercialized 5-HT1A partial agonists (e.g. Buspar) as treatments.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/16258853
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Hippocampal neurogenesis: One hypothesized mechanism by which pharmaceutical anxiolytics may decrease anxiety is via hippocampal neurogenesis – or growth of new neurons within the hippocampus. It appears as though cannabidiol administration induces hippocampal neurogenesis in animal models, and for this reason, similar outcomes may occur in humans. A rat study involving the chronic administration of 5-HT1A partial agonist (tandospirone) increases the biomarker of doublecortin – indicating the emergence of new neurons in the hippocampus.
Some researchers believe that hippocampal neurogenesis may play a critical role in attenuating symptoms of severe anxiety and/or depression. Although not all 5-HT1A partial agonists may induce hippocampal neurogenesis, there’s evidence to suggest that cannabidiol does. A study published in 2013 assessed the anxiolytic effects of CBD in mice exposed to chronic stress.
Results from the study indicated that CBD administration increased neuronal proliferation and neurogenesis in the hippocampal region. It is also thought that CBD’s modest affinity for cannabinoid receptors CB1 and CB2 may contribute to hippocampal neurogenesis. Stimulation of the CB1/CB2 receptor sites upregulates endocannabinoid signaling and leads to neuronal growth.
Regardless of how CBD oil induces hippocampal neurogenesis, the growth of new brain cells may be enough to decrease anxiety. A report published in 2015 documented that increasing adult neurogenesis (regardless of the modality) is sufficient enough to decrease anxiety. Therefore, it could be that CBD is an effective anxiolytic predominantly through mechanisms implicated in neurogenesis.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23298518
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CB1 + CB2 receptor (inverse agonist): Most evidence suggests that CBD oil has a low affinity for CB1 and CB2 receptor sites as an inverse agonist. In other words, it binds to the CB1 and CB2 receptors but exerts the pharmacologically opposite effect to an agonist. This differs from a CB1/CB2 antagonist which solely binds to these receptors and blocks stimulation from endocannabinoids.
It also is distinct from THC which acts as a CB1/CB2 partial agonist, thereby stimulating the receptor sites. If it acted the same as THC at the CB1/CB2 receptor sites, its therapeutic potential may be reduced. Moreover, since cannabidiol acts as an inverse agonist at the CB1/CB2 receptor sites, it doesn’t induce psychological euphoria and/or pleasure associated with a downstream dopaminergic enhancement in the mesolimbic pathway (resulting from CB1/CB2 agonist).
Research has shown that administration of cannabidiol actually inhibits agonist effects at the CB1/CB2 receptor sites. Although the effects of CB1 inverse agonist aren’t fully elucidated, many speculate that CB2 inverse agonist may contribute to cannabidiol’s anti-inflammatory effects. Due to the fact that neuroinflammation is associated with anxiety disorders, we could hypothesize that a decrease in inflammation may yield anxiolytic responses in a subset of CBD users.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/17245363/
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Opioid receptor modulator: Another possible mechanism by which CBD may alleviate symptoms of anxiety is through allosteric modulation of mu-opioid receptor (MOR) and delta-opioid receptor (DOR) sites. Though it is known that allosteric modulation of the MOR and DOR is capable of reducing anxiety, it isn’t fully understood how. Some speculate that MOR and DOR sites affect GABAergic and dopaminergic neurotransmission.
Certain individuals may be more prone to anxiety than others as a result of mu-opioid receptor expression and/or activation. Research indicates that mu-opioid receptors participate in the modulation of anxiety based on the specific region of the brain in which they are stimulated. What’s more, a report published in 2015 indicated that the neural circuitry associated with the DOR (delta opioid receptor) can induce OR inhibit anxiety.
Selective delta receptor agonists have been shown (in animal studies) to reduce anxiety-like behavior and block anxiogenic effects of stressors. Specifically, modulation of the DOR in the central amygdala may predict the severity of an individual’s anxiety. There’s reason to believe that allosteric MOR and DOR modulation provided by CBD could reduce anxiety in a subset of individuals – especially when combined with aforestated 5-HT1A and CB1/CB2 effects.
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Other possible mechanisms of CBD Oil for anxiety…
Although the 5-HT1A receptor partial agonism is thought to facilitate a majority of CBD’s anxiolytic effects – hippocampal neurogenesis, opioidergic modulation, and CB1/CB2 inverse agonism likely also contribute. Lesser researched mechanisms of CBD that could also decrease anxiety include: FAAH inhibition, adenosine reuptake inhibition, GPR55 antagonism, intracellular calcium (Ca2+) increases, and PPAR agonism. Of these mechanisms, inhibition of FAAH may be most significant in regards to anxiety attenuation.
- Adenosine 2A receptor: Administration of CBD is thought to act upon the adenosine 2A receptor site, possibly contributing to its anxiolytic and anti-inflammatory effects. Adenosine receptors are known to influence cardiovascular processes (cardiac rhythm, circulation), immune function, sleep, pain regulation, and blood flow. The adenosine 2A receptor interacts with G proteins to alter cAMP (cyclic adenosine monophosphate). Dysfunction of the adenosine 2A receptor may disrupt neurotransmission of glutamate and dopamine and simultaneously cause inflammation, neurodegeneration, and possibly anxiety.
- GPR55 antagonism: GPR55 (G-protein-coupled receptor 55) is a receptor expressed predominantly within the caudate nucleus and putamen. It is often referenced as an atypical cannabinoid receptor due to the fact that it is activated by cannabinoids. A study published in 2015 investigated the role of GPR55 function in anxiety. Researchers concluded that GPR55 may modulate anxiety-related behaviors in rats. In the study, it was discovered that GPR55 antagonists lead to increased anxiety. Cannabidiol is thought to act as a GPR55 antagonist which may improve bone health and decrease proliferation of cancer cells – but may not help anxiety.
- FAAH inhibitor: The anxiolytic efficacy of CBD may be a result of its ability to act as an enzymatic inhibitor of FAAH (fatty acid amide hydroxylase). FAAH is an enzyme responsible for metabolizing endocannabinoids such as anandamide, but when inhibited, these endocannabinoid concentrations are increased. Increased concentrations of endocannabinoids such as anandamide and 2-AG, both of which bind to peripheral CB1/CB2 receptor sites.
- PPAR agonism: Agonism of PPARs (peroxisome proliferator activated receptors) may have a variety of benefits including anticancer, neuroprotective (via removal of beta-amyloid plaques), and antipsychotic effects. Cannabidiol bolsters PPAR-alpha signaling and simultaneously decreases inflammation. Although PPAR agonism may not directly foster an anxiolytic effect, it cannot be ruled out as a potential synergistic contributor.
- TRPV1 receptor: The TRPV1 (transient receptor potential cation channel subfamily V member 1) receptor is a “vanilloid receptor” associated mostly with the modulation of body temperature and nociception. Cannabidiol is believed to act as a TRPV1 receptor agonist, thereby stimulating the receptor which may reduce sensations of pain and lower inflammation. It is possible that the nociceptive effect associated with TRPV1 agonist also reduces anxiety.
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