The main reason many people use marijuana is to experience that relaxing euphoric “high” that drives away stress and anxiety. But for some, cannabis has the opposite effect, triggering the very feelings of anxiety, nervousness and irritability that it’s supposed to relieve. Although these reactions are entirely contradictory, both are also entirely natural—and they can be explained by the complex responses of the body’s own vast network of cannabis receptors, the endocannabinoid system.
The Endocannabinoid System
Humanity’s relationship with marijuana is a long one, with records documenting its medicinal uses some 4,700 years ago. And the connection is far more ancient than that. The human body is home to an extensive network of cannabinoid receptor that are primed to respond to chemicals bearing a close resemblance to THC, one of the many active compounds in cannabis.
This system, called the endocannabinoid receptor system, wasn’t discovered until the early 1990s—but research since then has shown that the EC system plays a role in just about every function of the human body.
Endocannabinoid receptors occur in the central nervous system, the peripheral nervous system and areas of the brain responsible for higher order functions, such as the neocortex, hippocampus, cerebellum and hypothalamus. These receptors are also present in just about every organ, as well as the connective tissues and blood vessels.
Although research continues to reveal new discoveries about the functions of the endocannabinoid system, it’s clear that this system is involved with immune responses, pain modulation, mood and controlling inflammation. Activation of some parts of the EC system can also stimulate the growth of neural cells and slow the growth of cancer cells.
Like other receptor networks in the body, the EC system functions when a cannabinoid receptor is activated by a matching molecule, like a key fitting into a lock. So far, two cannabinoid receptors have been identified, and they respond in different ways. CB1, found mainly in the central nervous system, is responsible for psychoactive responses such as memory, mood and cognition, and CB2, which occurs primarily in the tissues, organs and peripheral nervous system, tends to regulate immune responses.
These receptors can be activated by the body’s own cannabinoid-like chemicals—or from consuming cannabis in any of its many forms. But not everyone’s endocannabinoid system is the same. Certain genes control the expression of neurotransmitters in the EC system, and variations in those genes can cause differences in how (and how much) those neurotransmitters are expressed.
Anandamide: The “Bliss Molecule”
Anandamide is one of those neurotransmitters—an endocannabinoid that binds to the same C1 cannabinoid receptors as THC, the psychoactive ingredient in marijuana. Anandamide, which gets its name from ananda, the Sanskrit word for bliss, has been called the “bliss molecule” for its key feature of promoting a state of happiness and contentment.
But anandamide does much more. It also plays an important role in supporting memory, thought and coordination, as well as in suppressing pain and slowing the proliferation of cancer cells. It’s also responsible for that exercise-induced euphoria known as “runner’s high.”
Anandamide levels are not fixed, and it’s possible to increase them with activities like exercise and intense creative work, which stimulate the release of endorphins, serotonin and dopamine, neurotransmitters that are related to pleasure and reward. Eating chocolate boosts anandamide levels, too, which can explain why so many people turn to chocolate to soothe disappointment and broken hearts. And the highly expensive black truffle contains anandamide all on its own. But because anandamide is so similar to THC, using cannabis is also a way to trigger its calming, mood-boosting properties. For some people, though, other factors interfere with that pleasurable effect.
FAAH—Is It the “Feel-Good Gene”?
Anandamide is a fragile neurotransmitter with a relatively short life. It’s regulated by a gene that produces an enzyme called fatty acid amide hydrolase, or FAAH, which is responsible for breaking it down. In the presence of higher levels of FAAH, more anandamide is broken down, leaving the system vulnerable to feelings of anxiety and depression. When that happens, the brain is more inclined to respond to the calming effects of cannabis.
But when less FAAH is available, more anandamide can continue to circulate in the brain. Those levels can fluctuate for a variety of reasons, but some people have a variant of the FAAH gene that allows higher levels of anandamide to circulate in the brain, causing more overall feelings of happiness and less inclination to recall frightening or disturbing events.
In a recent New York Times article, physician Richard Friedman called FAAH the “feel-good gene.” According to Friedman, people with this genetic variation tend to feel naturally more upbeat and calm, so that they don’t typically respond to the relaxing effects of THC in cannabis. On the other hand, people with the “normal” FAAH gene—about 80% of U.S. adults of European descent—have lower levels of anandamide, so for these people cannabis is more likely to have a pleasurable effect.
The existence of a "feel-good gene” that keeps anandamide levels high in some people remains controversial. But it may help to explain how the relationship between FAAH levels and anandamide can affect the way a user responds to cannabis.
Anandamide levels aren’t the only factor contributing to feelings of anxiety and nervousness when using cannabis. Strains with higher levels of THC can overwhelm the system, too—and some people may feel those anxious symptoms at one time but not at others. But the complex play of cannabis and the body’s own endocannabinoid system can have unexpected results—and the path to feeling good can leave some cannabis users feeling bad instead.