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“What goes up must come down,” and “For every action there is an equal and opposite reaction” are two laws of physics pronounced by Isaac Newton. Robert Louis Stevenson’s Dr. Jekyll and Mr. Hyde dramatized how these laws also hold sway in the world of psychopharmacology.
The main psychoactive ingredient in cannabis, THC, activates cannabinoid (CB1) receptors naturally found in the brain. This activation is stronger and longer than activation by our natural cannabinoid chemistry. The neurotransmitters anandamide and 2-AG produced by the brain to stimulate these receptors are subtle and brief. The brain’s system of THC-like transmitters and their unique receptors functions to regulate and balance the rest of brain chemistry.
THC arrives in the brain like a gentle tsunami. THC molecules stimulate CB1 receptors far above normal physiologic levels. Most people enjoy an upwelling of unique feelings and thoughts that change the texture of experience. The “high” lasts for approximately 4 hours when cannabis is inhaled and 8 hours when ingested orally. The effect dissipates within 24 hours except for mild impacts on highly complex tasks such as flying a plane.
Characteristics of being high that stand out for many people are physical relaxation, emotional calming, increased appetite (the “munchies”), freshened and vivified sensations, and ease of falling asleep. While these characteristics do not describe everything people treasure about cannabis experience, they are important for understanding the signs of using cannabis too frequently.
It is useful to understand why pilots show slight impairments 24 hours after being high. Our natural cannabinoid chemistry regulates the experience of novelty, the “zing” added to unexpected stimuli to draw attention to them. THC’s strong stimulation of CB1 receptors lowers the bar for experiencing novelty. However, even with a single exposure to THC, the number of receptors is reduced, called downregulation, in an effort to re-establish chemical balance. It takes more than 24 hours to upregulate receptors back to their normal level.
The pilots tested a day after being high had fewer than the normal number of receptors. This produced the opposite of THC’s effect. Instead of being more sensitive to novel stimuli, the pilots were temporarily less sensitive. As a result, their responses to unexpected events were slower and less well organized.
Animal studies show that a daily dose of THC downregulates CB1 receptors 20-60% in different areas of the brain. People who use cannabis regularly have 20% fewer receptors in their brain’s cortex. A month of total abstinence is required to upregulate to normal levels.
The inconvenient truth is that too frequent cannabis use has a cumulative impact on the number of CB1 receptors. Exposure to cannabis again before upregulation occurs increases downregulation and reduces our natural cannabinoid system’s function. A state of relative cannabinoid deficiency therefore lingers between times of cannabis use.
Signs of chronically downregulated receptors are the opposite of the characteristics of being high. Unless a person has recently consumed cannabis to counteract downregulation, they will experience the following unpleasantries:
- Restlessness and feeling fidgety, often worse when trying to fall asleep.
- Anxiety and irritability.
- Loss of appetite.
- Boredom (the opposite of novelty).
- Insomnia.
Rigorous honesty is needed to become aware of these signs. All five are part of normal experience, so they can be easily dismissed. Attention has to be paid to their temporal relationship to cannabis use and abstention.
The first patient I heard complain of these signs was in the mid-1990’s when higher potency cannabis hybrids arrived in San Francisco. A businessman who smoked the new pot to relax at the end of a day noted that his anxiety and insomnia worsened on two successive family vacations when he was unable to use cannabis. His experience illustrates how a trial period of abstinence from time to time is necessary to assess whether your CB1 receptors are chronically downregulated.
Truly heavy daily cannabis users often report experiencing restlessness, irritability, anxiety, lack of appetite, and boredom upon waking each morning. Eight hours of abstinence while sleeping reveal how deeply downregulated their natural cannabinoid system has become. Some take a few hits before getting out of bed in order to feel more normal.
A common way committed cannabis users rationalize and dismiss these signs is to see them as proof of an underlying disease for which cannabis is the perfect medicine, far safer than the toxic drugs aggressively marketed by unscrupulous pharmaceutical companies. And, of course, restless legs syndrome, anxiety disorder, and insomnia are all legitimate medical concerns. The only way to discern whether these conditions are signs of CB1 downregulation or symptoms of disease is to abstain for up to six weeks. THC-induced insomnia has been documented to last that long. Few devoted users are willing to tolerate discomfort long enough to see if the problems fade, especially when relief is just a hit away.
Awareness of the five signs of chronic cannabinoid receptor downregulation will most benefit healthcare professionals and recreational cannabis users. Physicians and therapists will stop chasing useless treatments for irritability, anxiety, and insomnia when patients continue using cannabis too frequently. Instead, they will help people confront the real issue, hopefully with empathic understanding and encouragement. Skilled addiction medicine professionals will use the signs to gradually evoke cognitive dissonance in heavy users and to break the denial held by their significant others.
The five signs give adult recreational users the information needed to manage their use safely. (Adolescents run distinctly different risks.) An occasional brief period of abstinence is all it takes to assess their use. Like taking the time to check your blood pressure or stepping on the scale to check your weight. Not doing these assessments is to neglect your health and potentially a sign of denial. Perhaps no sign of an unhealthy relationship with cannabis is more clear than a blanket denial that cannabis use entails some risk. Knowing the five signs of cannabinoid receptor downregulation and knowing their meaning makes managing this risk and maintaining safety possible.
The bottom line: Know your limits.
