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How Tolerance Works: The Biology of Cannabis Tolerance and Receptor Downregulation

XJ-13 - Quality ConcentratesWhat is tolerance and how does it relate to cannabis use? It’s a question that is often answered inaccurately and dishonestly by opponents (and in some cases, proponents) of cannabis, fueled by a history of misinformation about what’s actually going when we talk about cannabis tolerance.

But there is a large body of knowledge that exists in the scientific and clinical realms describing our current and evolving understanding of tolerance. In a general sense, tolerance describes the way that our bodies change and react over time when exposed to certain stimuli.

This kind of molecular and physiological tolerance is most often discussed in the press as it pertains to drug and alcohol abuse. But, really, the underlying causes and theories which circulate through the scientific community can explain our bodies’ changes to a much larger range of things such as pain and other sensory stimuli.

This article will look at tolerance and how it relates to cannabis use on a number of levels. What are the scientific basics of what we mean when we read or use the term, “tolerance?”

Different Categories of Tolerance

Functional Tolerance results when the brain functions adapt to compensate for the disruption caused by a substance in both behavior and bodily functions. In other words, as our brains become more accustomed to the way a certain substance affects our bodies, it becomes more adept at usual and customary functions even when under the influence. 

In alcohol use, functional tolerance can oftentimes facilitate the consumption of increasing amounts of alcohol as the drinker does not experience any noticeable impairments to behavior as a result of drinking.

But when it comes to cannabis use, functional tolerance actually translates more closely to a user’s decreasing susceptibility to some of the side effects than can occur from strong doses of THC. These THC-induced effects can include dizziness, disorientation, and paranoia. While these consequences are definitely avoidable as long as a user is careful not to choose a strain that has too high a THC content, more veteran users will find that their tolerance to such effects increases over time as the brain adjusts to strong THC strains, allowing the pleasurable and sought after effects of euphoria, relaxation, and creativity to take hold instead.

Metabolic Tolerance results when the body responds to increased levels of a particular substance by augmenting its own abilities to break down and metabolize that substance for faster elimination from the body.

In alcohol use, metabolic tolerance results in a drinker’s ability to consume more alcohol without feeling its effects as much because the body has become more efficient at breaking the substance down. This can cause damage to the body’s metabolic organs though, including the stomach, liver, and kidneys. The body’s ability to more quickly metabolize alcohol also means that it becomes more efficient at metabolizing other substances such as sedatives, though. This concurrent effect means that chronic drinkers are at higher risk for abuse of certain drugs because of the body’s increasing tolerance to their effects, requiring higher and higher doses.

In cannabis use, metabolic tolerance is a much more benign affair. There are various ways of introducing cannabis and its constituent cannabinoids to the brain and body (i.e. smoking, eating, topical absorption, etc.). Though the body’s metabolic processes for breaking down the cannabinoids into their active form may improve over time, this is not an indication of dependence nor addiction. The increased metabolism also does not cause concurrent problems with the body’s breakdown of other substances, making cannabis use a safe substance that doesn’t have contraindications with other medications that someone may be on.

Tolerance at the Cellular Level

But what’s driving the development of functional and/or metabolic tolerance in cannabis use?

As with every reaction our body has to its environment, the underlying causes can be traced to a cellular level.

Cannabinoid Type 1 Receptors (CB1R) are distributed throughout the body as part of the human body’s naturally occurring cannabinoid receptor system.  These receptors are found on the surfaces of the cells that control all our bodily processes. When they bind with a cannabinoid, these receptors can trigger a series of cellular signalling events that dictate and regulate our body’s reactions to different conditions in our environment. This regulatory signalling system is highly sophisticated. Not only do the ligands, or binding molecules, involved in this system have a highly nuanced effect on their downstream cascades, but the receptors themselves can be adjusted according to the situation based on a process called “downregulation.”

The Principles of Downregulation

Receptors on the cellular surface are simply very specific proteins that are produced as a result of the cell’s DNA. A very specific portion of every cell’s genome, or full DNA blueprint, gives precise instructions for how to make a particular protein. But a cell’s DNA isn’t constantly churning out equal amounts of all proteins. There are on and off switches distributed throughout the blueprint that are activated depending on how much of a ligand is detected in the cellular environment. A cell’s nucleus (where the DNA is housed) can amp up or tamp down the concentration of ligand-specific receptors based on how much of the associated binding molecule is available. This is referred to as upregulation and downregulation, respectively.

While upregulation and downregulation is different depending on the type of receptors or type of ligands we’re dealing with, the process of downregulation of CB1 receptors is well-observed and well-documented in cannabis use .

Because of the presence of natural endogenous cannabinoids (or, endocannabinoids) in our bodies, there is a usual, or basal, concentration of CB1R on the cellular surface. But when a cell detects a larger than usual concentration of cannabinoids in the cellular vicinity, its DNA will downregulate the amount of CB1R that are stuck on the cell’s surface.

The evidence so far shows that for cannabis users, regardless of whether they are infrequent or frequent users, the number of CB1 receptors after cannabis consumption is significantly decreased compared to study participants that do not consume cannabis. Based on what we know about the theories behind downregulation of receptors, this indicates that the human body is detecting higher than usual levels of various cannabinoid ligands in the blood stream and responding by producing fewer cannabinoid receptors on the surfaces of nerve cells.

This downregulation is an integral process in the body’s abilities to adapt to its changing environments.

Two Levels of Self-Titration: The Body’s Built-in Cannabis Safety  Net 

One of the strongest arguments for cannabis’s safety and efficacy as both a recreational and medical treatment option for consumers  is the freedom to self-titrate when smoking. This is a term which basically means consumers can decide how much cannabis they want to consume as they are consuming it.  Users can adjust the amount of smoke they inhale and how long they hold it in their lungs.  

The scientific results around downregulation of cannabinoid type 1 receptors in the body in response to the presence of more cannabinoids in the blood suggest that the body is also doing a type of self-titrating as it adjusts the concentration of receptors available for binding. The more receptors are available for binding, the better that THC and other cannabinoids can exert action on the body and brain. But if the body senses that too many of its receptors on the cell surface are already being bound by the increased levels of cannabinoids present after cannabis consumption, it will subsequently decrease the amount of receptors available, effectively putting a ceiling on how much the body can be influenced by cannabis!

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