How cannabis tolerance works and why it develops so quickly

May 6 2019, 3:25 pm

Cannabis newbies often marvel at how little it can take to get high, while seasoned users are constantly flummoxed by the meagre lifts left to them after prolonged use.

Cannabis highs are short, typically only lasting a few hours, but those who used to take a couple small hits from a joint quickly find those smokey sips just don’t hack it anymore. Tolerance develops quickly, and the reason for that lies in our complex biology.

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Cannabis and the brain

Tetrahydrocannabinol (THC), the psychoactive compound in cannabis, is just one of over 100 cannabinoids that scientists have identified. While a multitude of them have been identified in cannabis alone, one place you might not expect to find them is in the human body.

Endocannabinoids exist within us and are produced naturally as part of the endocannabinoid system (ECS), a biological system that controls physiological and cognitive processes like hunger, lethargy, or stress reduction. Our ECS uses cannabinoids as a means of unlocking particular receptors in the brain.

This is the same reason that cannabinoids found outside the body (aka phytocannabinoids, like THC), have such a powerful effect. Our body comes with all the tools to experience cannabis already in the form of the body’s CB1 and CB2 (cannabinoid type-1 and -2) receptors.

Normally, cannabinoids like anandamide use CB1 as a gateway to elicit a response. The receptor is the lock, cannabinoids are the key. When they come into contact, a signal is sent along the chain producing the desired reaction. Activating the CB1 and CB2 receptors can have a multitude of impacts on the body including cellular physiology, synaptic function, gene transcription, cell motility, and more.

CB1 receptors are abundant in the central nervous system, “particularly in cortex,
basal ganglia, hippocampus, and cerebellum.” The CB2 receptor is less understood than its counterpart, but is believed to play an important roll in development.

“When exogenous cannabinoids enter the system, the body will technically see that as an aide to the system,” said Dr. Nicco Reggente, a neurologist and CEO of StrainGenie, a company using a Netflix-type algorithm to match medical patients with better cannabis.

“That’s why cannabis can be so effective and therapeutic… your body gets an unregulated boost in its endocannabinoid activity.”

According to a 2018 study, Review of the neurological benefits of phytocannabinoids, THC, CBD, and the over 60 other phytocannabinoid compounds in the plant have been identified as acting on both CB1 and CB2 receptors separately and simultaneously. They have also been shown to inhibit or activate receptor functions. 

This unique interaction can differ from person to person. Whether it be euphoria, hunger or stress reduction, by flooding the body with more cannabinoids than it would produce on its own, cannabis creates a reaction that’s short and powerful.

Cannabis tolerance

Cannabis tolerance is built up based on the reactions of the different receptors to consistently high levels of cannabinoids.

According to Dr. Reggente, the body is constantly trying to achieve homeostasis, a level of normalcy in its functions. A key part of this regulation is the ECS. This means while your family may not know that you smoke cannabis often, your brain is taking note. It begins to make the receptors that take in cannabinoids less sensitive in order to reduce those effects.

“Your body still wants to achieve homeostasis and it’s being thrown out of that homeostasis because you’re ingesting phytocannabinoids that are throwing you off balance,” said Reggente, during an interview with Grow. “The body’s like, ‘I have got to get used to this new situation. This new situation and I’m being bombarded with THC every day. I can’t be this receptive to it because it’s going to shift anything out of balance.’ So what it does is it curtails the excitation that it receives from those phytocannabinoids.

“That witnessed in the end consumer as tolerance.”

Don’t fret: the CB1 receptor lock remains in place, but the body does make some changes. The key part of this is how the receptors respond to desensitize themselves.

“The CB1 receptors operate on a type of lock and key model,” said Reggente. “The lock is actually malleable so that the key will only use part of it by changing the shape so that it’s not accepting the whole key and is only accepting a part.

“Just like making that slit to your mailbox a little bit slimmer [so] that now you’re only letting in specific letters.”

There’s also evidence to suggest that more than just CB1 and CB2 receptors influence the body’s desensitization to cannabis. Beyond what are called the “canonical cannabinoid receptors,” the Transient Receptor Potential (TRP) channels may also influence how our bodies react to THC. TRP channels mediate a variety of sensations that affect vision, taste, smell, hearing, and touch. While the aforementioned receptors are the body’s primary means of mediating cannabinoid activity, TRP channels interact with the compounds as well. In lab tests, these channels have been shown to desensitize themselves from synthetic cannabinoids.

A study published in the journal Nature laid out some observations on the matter. It found that “chronic exposure to THC and other cannabinoid agonists causes a reduction in the number and signalling efficiency of CB1 receptors as a homeostatic response.”

These changes coincide with the development of tolerance to cannabis’ side effects, “such as decreased motility and impaired memory,” says the study. The rate of this downregulation is different in different regions of the brain. However, the same study found that even in long-term chronic users, CB1 receptors returned to normal after four weeks of abstinence from cannabis use.

So in other words, a little green break never hurt anyone.