CB1 (Cannabinoid-1 Receptor)
A vitally important protein in the body’s endogenous cannabinoid system (ECS). CB1 is the main target of delta-9-THC, the primary intoxicating ingredient in cannabis. THC is an agonist, or activator of the CB1. THC must bind to the CB1 receptor for a person to feel the cannabinoid’s intoxicating effects.
“THC makes you feel high by activating your body’s CB1 receptors.”
“The body has two main cannabinoid receptors — CB1 and CB2.”
More About CB1
Cannabinoid receptors are an essential component of the body’s endogenous, or endocannabinoid system (ECS). Every function in our body requires balance, or homeostasis, to perform at maximum capacity. The ECS helps the body maintain homeostasis through its three main components: “messenger” molecules called cannabinoids, the receptors that these molecules bind to, and the enzymes that break them down for the body to synthesize. Pain, stress, appetite, energy, metabolism, cardiovascular function, reward and motivation, reproduction, and sleep are all functions that the ECS can modulate.
The body’s most studied cannabinoid receptors are the Cannabinoid-1 and Cannabinoid-2 receptors (CB1 and CB2). CB1 receptors are largely found in the central nervous system, where they regulate a wide variety of brain functions, and sporadically throughout the body including in the skin. Anandamide and 2-Arachidonoylglycerol (2-AG), the two most prominent endogenous cannabinoids, or cannabinoids produced within the body, both bind to CB1 receptors. CB1 is also the receptor target for tetrahydrocannabinol (THC), the central intoxicating component of marijuana — making it a major player in the euphoric effects of cannabis.
In humans, the CB1 protein is encoded, or produced by the CNR1 gene. Like all other proteins our bodies make, the “blueprints” for how to build them reside in our DNA. Random or inherited edits or mutations in these blueprints are extremely common. Among the general public, you’ll find people carrying different versions of the CNR1, the CB1 receptor blueprint. This may, at least partially, account for some of the differences in human reactions to cannabis compounds such as THC and CBD.
Repeated use of cannabis causes tolerance through a decrease in CB1 expression throughout the brain. But even 48 hours of abstinence from cannabis can resensitize the system and bring the expression of CB1 proteins back to a level that is on par with non-cannabis users.
CB1 is a G protein-coupled receptor (GPCR), a large and diverse group of cell membrane receptors. It is also the most widely expressed GPCR in the entire nervous system — found in virtually all areas of the brain and virtually all neuron types.
CB1 receptors span the membrane, or wall of a cell with its active, binding side facing outward. CB1 receptors are like a lock waiting for its key. Both endogenous and phytocannabinoids (cannabinoids from outside the body) find active CB1 receptors and “unlock” them. G-proteins, located on the inside of the cell, bind to the tail of a CB1 receptor, and are released to deliver messages when the CB1 receptor is activated by an agonist molecule like THC.
CB1 receptors are present on the inside of cell walls as well, but scientists are still unsure whether these receptors are active or just waiting to be recycled back to the cell’s surface. Recent structural data on CB1 receptors reveals that they may have a binding pocket uniquely suited to receive signals from THC. This may explain why THC is a CB1 agonist, and therefore intoxicating to humans.
In addition to being the main binding site for THC, CB1 receptors can be activated by allosteric modulators through an alternative binding site. Allosteric modulation of CB1 may provide new opportunities for therapeutic effect, while avoiding potentially unwanted effects of THC.
Function of CB1
CB1 is the target of endocannabinoids, anandamide and 2-AG. These cannabinoids are referred to as “retrograde messengers” because they float backward across the gap between two neurons, in the opposite direction of other neurotransmitters. After these molecules bind to the CB1 receptor, G proteins are released from the intracellular tail of CB1, activating a number of other intracellular processes. One of the most important intracellular processes mediated by the CB1 is the impact on neurotransmitter release.
The CB1 receptor’s major role in the brain is to regulate the release of neurotransmitters such as serotonin, dopamine, and glutamate. Think of the CB1 receptor as a crossing guard for neurotransmitters, allowing them to cross on a crosswalk at controlled intervals. Activity at the CB1 essentially reduces the probability that a neuron will release its neurotransmitters.
What happens when an agonist, or activating molecule binds to the CB1? Activation of the CB1 receptor can result in several discernible effects, ranging from therapeutic to hindering.
High and Effects
CB1 receptors are present in the brain’s limbic and reward circuitry, where they influence dopamine transmission and produce a euphoric high when triggered by THC.
In addition to facilitating the euphoric effects of cannabis, CB1 is also involved in the brain’s top-down control of pain. CB1’s main point of pain mitigation is in the midbrain, where the pain “headquarters” is located. Both cannabinoids and opioids alleviate pain through this descending pathway. This is the reason THC is a more effective pain reliever than CBD. In order to have a profound alleviating effect on pain, many patients may need to recruit CB1 receptors in the brain. CBD doesn’t activate CB1 receptors, and is, therefore, less effective in some people to alleviate pain compared with THC. However, CBD is an effective anti-inflammatory, so for some people it is effective on its own.
Sedation and Motor Impairment
Sedation and impairment of motor skills brought on by endocannabinoid signaling are likely mediated by CB1 receptors in the basal ganglia, where the brain coordinates movement.
Cognitive and Memory Impairment
Cannabis’ ability to affect cognition and impair memory occurs through the activation of CB1 receptors in the hippocampus.
Cannabis is known for its ability to produce an abnormally fast heart rate, also known as tachycardia. CB1 receptors located on cardiac cells may play a role in tachycardia when directly activated. CB1 receptors are prominent in areas of the autonomic nervous system, including the medulla, which is responsible for involuntary life functions like breathing and heart rate. CB1 receptors are abundant in the medulla oblongata, where the tip of the spinal cord connects with the brain and where the body’s involuntary vital functions are controlled.
As part of the endocannabinoid system, CB1 receptors, especially in the hypothalamus, play a big role in appetite and metabolism. CB1 has a role in both the “energetic,” or survival-based drive to eat, and the “hedonic” drive, or the drive to eat for pleasure. Newly discovered interactions between the ECS and the gut microbiome, or “community” of microorganisms within the gut, may also play a role in the body’s metabolic functions.