The How Behind the High of Cannabis

Approximately 4 percent of all adults living on planet Earth, 192 million people, used cannabis last year. Often, the user expects that some aspect of their brain function will be altered in a manner that is consistent with their expectations. The magnitude of the effects varies among individuals for many reasons. Males respond differently than females, extroverts respond differently than introverts, young people respond differently than old people, and healthy people respond differently than those with psychiatric disease. Expectation and the placebo effect always play a significant role.

Dosage matters. The brain contains quite a lot of cannabis receptors that are scattered almost everywhere in the brain. Therefore, as the amount of cannabis inhaled or ingested increases the perceptual effects will increase as more and more of the brain becomes affected. For this reason, acute exposure to a high dose of cannabis can produce cognitive changes that mimic psychosis, including perceptual distortions, cognitive disorganization, and mania. In reality, for the majority of cannabis users, these symptoms are usually very mild and disappear when the active ingredients are inactivated and excreted.

The effects of cannabis also differ depending upon the route of administration. For example, orally consumed cannabis differs markedly from that of smoked or vaporized. Smoked and vaporized cannabis produces rapid peak blood levels that return to normal within two to four hours. Vaporization has become more popular than smoking possibly because it produces higher peak THC levels than smoking.

Human neuroimaging studies have reported increased cerebral blood flow and metabolism in the frontal lobes when the level of THC is at its highest in the blood. In contrast, cerebral blood flow has been reported to be decreased when human subjects report the highest subjective levels of intoxication. Apparently, the subjective high is dissociated from the concentration of THC in the blood.

The psychoactive effects of THC are subjectively more intense during the distribution and elimination phases of serum THC levels. This implies that the subjective effects produced by THC occur when the levels of THC in the blood and brain are changing. Each person’s history of cannabis use, and the subsequent pharmacological tolerance that inevitably develops, further contribute to this dissociation and explains why frequent cannabis users need higher THC concentrations than occasional users to obtain the desired level of high.

To understand the psychoactive action of THC in the brain, it is also necessary to understand the interactions of THC with other components of the plant. Today, most cannabis products contain combinations of THC and CBD; these are roughly classified as THC-dominant, CBD-dominant, or a hybrid combination. It should be noted that when the relative concentrations of these two molecules are altered, there is a cascade of unknown changes in the concentration of the roughly 60 other cannabinoids in the plant. Essentially, the psychoactive experience will be an aggregate of the actions of all of the molecules that can easily interact with each other. For example, high doses of CBD can mitigate the neurocognitive effects of THC due to its competitive actions of cannabinoid receptors (CBD is a very low potency agonist at cannabinoid receptors).

What does THC do in the brain? In truth, the actions of THC are very simple to explain. The complication comes from the fact that cannabinoid receptors are everywhere in the brain. Thus, the cannabis experience depends on which receptors in different brain regions are being stimulated at any particular instant in time. THC mostly acts by preventing the release of many different neurotransmitters from neurons. This is important because neurons release neurotransmitters to communicate with each other. If a neuron is unable to release its neurotransmitter it becomes unable to communicate and the levels of its neurotransmitter increase inside the neuron. As a consequence of the actions of THC, the level of the neurotransmitters glutamate, GABA, dopamine, and acetylcholine increase in the brain.

Considerable progress has been made towards a detailed understanding of the actions of the components of the cannabis plant. Some of the older reported associations between THC-induced changes in brain activity and psychoactive experience have been based on simple correlations. Mechanistic pharmacological studies and placebo-controlled studies are scarce and still require replication.