How Does CBD Interact with the Endocannabinoid System?

Apr 9th 2020

Cannabidiol (CBD) is the second most abundant active cannabinoid in cannabis. Unlike tetrahydrocannabinol (THC), cannabidiol alone does not cause intoxicating effects. According to the World Health Organization, CBD is safe and effective for a number of medical conditions. 

CBD acts as a ligand that can bind to cannabinoid receptors. Cannabinoid ligands, receptors, and regulatory enzymes make up the endocannabinoid system. Together, they control a range of vital bodily functions, including sleep, mood, memory, perception of pleasure and pain. All of these functions contribute to homeostasis, a state of balance required to keep humans healthy. It is thought that the endocannabinoid system maintains homeostasis through communicating with other systems in the body.

CBD and Cannabinoid Receptors

Cannabinoid receptors are found on the cell membranes of various organs, which triggers signaling pathways when bound by ligands. The two major types of cannabinoid receptors are CB1 and CB2. CB1 receptors are primarily expressed in the brain and therefore mediate many of the psychological effects of cannabinoids. CB2 receptors are primarily distributed on immune cells and also to a lesser degree in brain cells.

Inside the body, cannabinoid receptors are bound by endogenous cannabinoids, also known as endocannabinoids. In addition, exogenous ligands that come from outside the body may also bind to these receptors and share similar effects. CBD is considered an exogenous cannabinoid as it comes from the cannabis plant. It can bind to both CB1 and CB2 receptors as well as other targets beyond the endocannabinoid system. 

How Does CBD Affect the Endocannabinoid System?

CBD is considered a “multitasking molecule” as scientists have proposed more than 20 possible mechanisms of action. To date, CBD’s far-reaching physiological effects are still poorly understood. Nevertheless, it is known that although CBD can bind to both cannabinoid receptors, it restrains instead of activating CB1 signaling. Potential outcomes of this negative modulation mean that CBD doesn’t have the potential adverse effects of impaired learning, memory and psychosis attributed to THC in some cases. Being an antagonist to CB1 is likely why CBD does not elicit intoxicating effects but instead demonstrates antipsychotic properties.

Similarly, CBD also does not activate CB2 receptors and instead acts as an antagonist. It is unclear what physiological effects this interaction triggers, but anti-inflammatory effects have been proposed. This is likely due to a high prevalence of CB2 in immune cells. 

Potential Benefits of CBD for Health

CBD is most well-known for its therapeutic effect in treating childhood epilepsy. Even in the nineteenth century, medicinal cannabis was used to treat seizures. Today, extensive randomized controlled trials have shown that purified CBD can lead to a 26-28% reduction in the seizure frequency over placebo. In some cases, patients became and remained seizure-free. 

Beyond epilepsy, CBD is also known for its therapeutic potential in treating psychotic symptoms. In a landmark study published in the journal of Translational Psychiatry, CBD was put to trial with a potent medication for schizophrenia, amisulpride. Surprisingly, CBD reduced psychotic symptoms equally effectively, but it had a much better side-effect profile. In another randomized controlled trial, CBD showed an additive effect when combined with conventional antipsychotic drugs. Patients were able to control hallucinations and delusions better when CBD was used. Therefore, these results warrant further development of CBD as a safe, antipsychotic drug. In fact, a large-scale trial is currently underway.

For healthy people, there is evidence that CBD could reduce the level of anxiety in scenarios such as public speaking. In a randomized controlled trial, CBD helped people diagnosed with social anxiety disorder reduce anxiety, cognitive impairment, and discomfort. In addition, CBD is associated with reductions in irritability, anxiety, sleep problems and hyperactivity symptoms in children with autism.

Although cannabis is often demonized as an addictive substance, CBD specifically may actually be an antidote for addictions. A randomized placebo-controlled trial, CBD significantly reduced drug-induced craving and anxiety in heroin-addicted individuals. This finding supports the notion that CBD could be a treatment option for opioid use disorder, although more research is needed to confirm this.

How Does CBD Affect the Non-endocannabinoid System?

CBD can act via a range of non-endocannabinoid pathways. It is a blocker of many receptors including ENT, GPR55, and the TRPM8 channel. Among them, GPR55 is a protein that triggers the onset of seizures. It is thought that blocking its activity, CBD can alleviate epileptic symptoms. 

In addition, CBD binds to receptors that control pain signaling and inflammation, including TPVR-1, Adenosine A2A receptor, and the receptor for the neurotransmitter serotonin, 5HT1A. As an agonist for 5HT1A, CBD’s physiological effect is similar to selective serotonin reuptake inhibitor drugs, which are therapeutics for treating depression. As such, it is worth investigating CBD’s therapeutic potential for depression. 

Indirect Effects of CBD on the Endocannabinoid System

CBD’s diverse interactions with the non-endocannabinoid system could, in turn, affect the endocannabinoid system indirectly. For example, research has shown that CBD inhibits the reuptake and enzymatic degradation of endogenous cannabinoid ligand anandamide, resulting in higher anandamide levels. These changes seem to dampen learned fear and disrupt its consolidation, thereby encouraging recovery from anxiety and fear-related disorders such as post-traumatic stress disorder (PTSD). Enhanced anandamide signaling was also linked to the antipsychotic effects of CBD in the treatment of schizophrenia. 

The Bottom Line

In conclusion, CBD is an exogenous cannabinoid that can bind to myriad receptors and elicit multiple beneficial effects in the body. It can directly bind to the two major cannabinoid receptors and act as an antagonist, thereby demonstrating antipsychotic properties.

Beyond the endocannabinoid system, CBD also binds to receptors from a diverse spectrum of pathways. This profoundly extends its functions and results in potential physiological changes including reductions in pain, anxiety, and inflammation. Through modulating these pathways, CBD’s effect may in turn feed back to the endocannabinoid system indirectly. These intricate interactions are only beginning to be understood.

Couple these scientific findings with anecdotes from patients using CBD and therapeutic potential of CBD already appears promising.