By Josh Kaplan, Ph.D.
The body has a cannabinoid system comprised of the chemicals, 2-AG and anandamide, and the cannabinoid receptors (CB1 and CB2) that they act on. Activating CB1 receptors in the brain weakens the communication between brain cells, while CB2 receptors have an important role in inflammatory and immune responses. THC acts on these receptors, but other cannabinoids act on a host of other targets, contributing to cannabis’ vast therapeutic range.
In order for cannabis to have an impact on brain and body function, it must act on a system that’s naturally expressed in the body. For cannabis, this system is known as the endocannabinoid system. It was termed the “endocannabinoid system” (endo- short for endogenous which means to originate from within) because it was known to mediate the effects of the cannabinoid, THC. The endocannabinoid system consists of chemicals that are transmitted between brain cells and their receptors5. There two primary endogenous cannabinoid chemicals that are produced by cells in the body are 2-AG and anandamide. Sticking with the brain for simplicity sake, these chemicals are created and released by brain cells when there’s an increase in brain activity6. You can think of these endogenous cannabinoids as providing a break when brain activity escalates.
2-AG and anandamide block brain cell communication by activating cannabinoid receptors. Cannabinoid receptors are proteins expressed on brain cells, that when activated, dampen the communication between them. This is an important function in the healthy brain, and when it breaks down, leads to problems with learning and memory, and a host of psychiatric disorders7.
There are two types of cannabinoid receptors, cannabinoid receptor type I (CB1) and cannabinoid receptor type II (CB2). CB1 receptors are found throughout the brain and body. In the brain, they’re the main cannabinoid receptor on the communicating brain cells, called neurons. Consequently, CB1 receptors are the primary mediator of cannabis’ high-inducing effects. CB2 receptors are also found throughout the body and are largely present in immune tissues. They’re are also found in the brain, although to a lesser extent than CB1 receptors8,9. CB2 receptor levels fluctuate and are highest in cases of neuropsychiatric disease and following injury10-13. This expression is largely limited to the support and immune cells and represent a promising pharmacological target to treat disease.
Cannabinoid effects in the brain
To understand how activating cannabinoid receptors influence brain function, imagine that you are controlling the volume of a television with a remote control. The remote control and the television each represent a neuron (i.e., a communicating brain cell). You can control the volume of the television by sending a signal to the television, and that causes a change in the television’s function. This is essentially how neurons communicate; they release chemicals, called neurotransmitters, that travel to the neighboring neuron and cause a change in how they behave. Most commonly, signals only go from the remote control to the television. However, in the case of endogenous cannabinoids, the television sends a message to the remote control to shut off its signal. 2-AG and anandamide are produced by the downstream neuron (the television) and are sent back to the upstream neuron (the remote control) to shut off the ability to release more neurotransmitters in a retrograde fashion.
How plant-derived cannabinoids affect CB receptors
THC reduces neurotransmitter release by activating CB1 receptors on the upstream neuron (the remote control in our analogy). However, it does so in a slightly different and more inconsistent manner than the endogenous cannabinoids14. So the reason you get high from consuming THC, and why you don’t get high from the endogenous cannabinoids, is that 1) THC acts differently than the endogenous cannabinoids on CB1 receptors, and 2) activates CB1 receptors independent of brain activity, as opposed to only when those brain cells become highly active.
Other cannabinoids from the plant may act on CB receptors in the brain, but they often have different effects than THC. An additional abundant cannabinoid, CBD, blocks THC’s effects on CB1 receptors, but can activate CB2 receptors. THCV is another cannabinoid that can block CB1 receptors at low doses, but activates them at high doses15. Just from the three cannabinoids briefly described, there are an appreciable range of effects that cannabinoids have on CB receptors.
Beyond CB1 and CB2
CB1 and CB2 receptors are just two of many targets that plant-based cannabinoids have in the brain and body. The wide range of potential targets gives cannabis its profound medicinal potential. For instance, CBD can relieve anxiety by activating receptors for the neurotransmitter, serotonin16, and protects against epileptic seizures by blocking a receptor known as GPR5517. The list of potential targets for CBD and other cannabinoids is vast, and these targets can become selectively activated through proper dosing15 . Therefore, establishing the proper dose of cannabinoids is critical for achieving optimal therapeutic benefits while avoiding unwanted side-effects.
Multiple cannabinoids, when used in combination, can enhance the therapeutic benefits of individual cannabinoids. Like turning up the gain on an amplifier, the benefits revealed from use of a single cannabinoid, like THC or CBD, can be improved upon by adding multiple cannabinoids and the terpenes in which they’re dissolved18. Scientific research over the last few decades has established the foundation for developing powerful cannabis-based therapeutics that are comprised of specific cannabinoids and terpene combinations at specific doses.
Summary: The body has an endogenous cannabinoid system comprised of signaling chemicals, 2-AG and anandamide, and their CB1 and CB2 receptors. THC has its high-inducing effects by activating CB1 receptors in the brain. Other plant-derived cannabinoids have diverse effects on CB receptors and additional targets in the brain and body that mediate cannabis’ therapeutic benefits.
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