How Cannabis Defeats Itself When Used Too Frequently

Subtle but pervasive changes can occur between uses.

Posted Jun 05, 2020

In previous posts, I've laid the foundation for how cannabis works. Understanding THC’s interaction with the brain’s important natural cannabinoid chemistry and physiology will now make sense of the impact that overly frequent cannabis use has on the brain and mental functioning. 

Because THC stimulates our brain’s natural cannabinoid receptors (CB1) far more strongly and longer than the endogenous cannabinoid neurotransmitters anandamide and 2-AG, cannabis use throws brain chemistry out of balance temporarily, usually to people’s enjoyment. This loss of chemical equilibrium lasts an average of 4 hours when cannabis is inhaled and 8 hours when ingested orally before the liver metabolizes the THC and it is eliminated in the feces (55%) and urine (20%).

Most occasional cannabis users feel little or no effect the following day, but an interesting experiment reveals a subtle impact 24 hours after smoking a single joint. Private licensed pilots with over 200 hours of flight experience had their baseline skills measured in a flight simulator, then were provided a joint containing 10 or 20 mgs of THC to smoke. This was considered the equivalent of a moderate social dose in the mid 1980s.  

A variety of pilot actions during routine landings were impaired 24 hours after smoking the joint, including the number and size of adjustments to stabilize the plane, distance off center on landing, and vertical and lateral deviation on approach to landing. Pilots showed no awareness of these impairments. Performance returned to baseline 48 hours after being high.

When the task became more complex by introducing turbulent weather conditions calling on pilots to react in real time to avoid trouble, responses were slower and less well organized than their baseline performance. In other words, the pilots’ response to novel events was altered (see the post How Cannabis Makes Everything So Interesting for clarification on the role our internal cannabinoid system plays in the experience of novelty.)

When THC stimulates CB1 receptors in the amygdala, cannabinoid tone increases, lowering the bar for any stimulus being imbued with a sense of novelty. Novelty draws our attention to unexpected stimuli. This phenomenon is largely responsible for cannabis making everything more interesting. But this is not the end of the story.

Whenever neurons containing CB1 receptors are over-stimulated by THC’s stronger and longer activation, a homeostatic response follows in an effort to rebalance the brain. The phrase “over-stimulated” means only that THC’s stimulation of CB1 receptors exceeds normal physiologic levels, leading to greater than normal negative feedback on the neuron’s release of transmitters with each firing. THC quells neuronal activity not by reducing the rate of nerve cell firing, but rather the amount of transmitter released each time the neuron fires.

As a result, neurons immediately react to THC’s over-stimulation by reducing the number of CB1 receptors. This reduction of receptors is called downregulation. A variety of mechanisms, including pulling receptors inside the cell so they are no longer available to be stimulated, begins with a single exposure to cannabis. By downregulating CB1 receptors, neurons partially regain some balance. Fewer receptors reduce the amount of negative feedback produced by cannabinoid stimulation and a more physiologic balance is re-established. 

After THC has been metabolized and eliminated, CB1 receptors begin upregulating back to their normal level of availability. Upregulation after a single or occasional dose of cannabis occurs rapidly. Most people feel unaffected the following day.

The experiment described above demonstrates that careful measurement of skills involved in complex tasks requiring serious concentration, fine hand-eye coordination and optimal response to unexpected events are all still objectively subnormal compared to baseline performance. This fact has persuaded many serious athletes to avoid cannabis use in the days prior to competitive sporting events.

With lingering CB1 receptor downregulation 24 hours after smoking a joint, the pilots were still in a state of mildly reduced cannabinoid tone. The lower than normal number of available receptors left anandamide and 2-AG with fewer opportunities to have an impact. Reducing cannabinoid tone has the opposite effect on the perception of novelty as increased cannabinoid tone. Reduced cannabinoid tone raises the bar for experiencing an event as novel. Therefore, pilots’ responses to unexpected events were slower and less well organized the day after being high.

Downregulation becomes cumulative when cannabis use is repeated before CB1 receptors have fully upregulated after the last exposure to THC. Laboratory animals given a daily dose of THC for two weeks have 20-60% fewer CB1 receptors depending on what area of the brain is being measured.  

Since human beings are also animals, we share the same fate when cannabis use is too frequent for the brain to re-establish normal physiologic balance in its endocannabinoid system. Postmortem analyses of human brains find levels of CB1 downregulation in heavy cannabis users comparable to those found in laboratory animals. Modified MRI imaging demonstrates a 20% reduction in CB1 receptors in the brain’s outer cortex in individuals currently using cannabis heavily. Total abstinence upregulates receptors again over four weeks.

Cannabinoid receptor downregulation is a very annoying and inconvenient truth. Multiple subtle but pervasive cognitive and emotional impairments result and these will be described in future posts. Downregulation is the first of two flies in the cannabis ointment complicating a psychoactive drug that otherwise appears simple. Downregulation is one aspect of addiction, which will be also discussed in upcoming posts. 

On the other hand, the signs of CB1 downregulation can be described, identified, and used as markers for when your brain’s limits have been exceeded. Clearly understanding the markers of exceeding your brain’s limits enables people to use cannabis safely, and to pull back when signs of too frequent use appear. Understanding the markers of cumulative CB1 downregulation is especially important because every individual’s limits are different, and different at different times of their lives. A following blog post will discuss these markers in detail.

There is no chart indicating the specific amount and frequency of cannabis use that is safe. Each individual has to determine the safe limits for his or her own physiology.

The bottom line is that it is useful, and sometimes important, to know your limits.