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Tetrahydrocannabinol (THC) and the endocannabinoid system
The human brain is made of a complex network of neurons and receptors responsible for mediating normal physiological functions of the human body. Cannabinoids are known to exert different psychotropic actions on the human brain. Medical researches into the pharmacology of endocannabinoids have confirmed that these endogenous molecules activate the cannabinoid receptors in the brain—an action that regulates the processes of homeostasis, cellular communication, appetite regulation, metabolism, and memory formation. Beyond the central nervous system, cannabinoid receptors are distributed sparsely in the adipocytes, gastrointestinal tract, and the skeletal system.
Cannabis sativa has been cultivated for centuries, with different theories devised to explain the vast effects of its extracts on the human body. The constituents of this plant are collectively referred to as “cannabinoids.” THC (delta-9-tetrahydrocannabinol) is the active constituent in Cannabis sativa with numerous neurochemical effects on the human body. THC is similar in structure to anandamide—a naturally occurring endogenous cannabinoid that acts as a neurotransmitter in the central nervous system. This molecule has been known to play major roles in activating the biological functions of the endocannabinoid system. However, the actions of anandamide on the brain are transient as it becomes easily deactivated in the body system.
Neuronal activation works based on a structural recognition basis. Since THC is similar in structure to anandamide, the cannabinoid receptors in the brain and peripheral recognize THC as an agonist and respond as expected. The response triggered by THC in the brain depends on the target receptors affected. Activation of the CB1 receptors located in the hypothalamic nuclei modulates the feeding behavior readily. It makes logical sense that there is anecdotal evidence supporting the use of THC in medicine as an alternative therapy approach—the bioavailability and stability of THC are extended when compared with anandamide.
Physiological effects of THC on the brain
THC increases risk of psychosis
Epidemiological studies and reviews have provided strong indications supporting the purported link between THC and the development of psychotic symptoms. The biological mechanism by which THC induces euphoria and hallucination in humans is still poorly understood. However, study data have suggested that THC increases the levels of dopamine in the different areas of the brain. Resultantly, the increased flow of dopamine in the striatal and mesocorticolimbic pathways affects the dopamine system’s actions of cognition modulation, motor functions, and emotion regulation.
A sibling pair analysis published by the Archives of General Psychiatry examined the association between cannabis use and psychosis-related outcomes—non-affective psychosis, hallucinations, and delusions inventory score—in young adults. Conclusive results from the 3,801 adult subjects involved in this study support the hypothesis that long-term THC use is associated with the development of psychosis in humans. It is still early to state if psychosis-inducing effect of THC on the human brain is definite; however, this has limited its use in medicine.
Memory and concentration
THC reacts readily with the cannabinoids receptors located in the hippocampus and hence alters the brain’s ability to form new memories while also shifting the normal attentional focus. Evidence supporting the link between THC use and memory formation are derived from animal study models since there are no publications yet describing trials in humans. Imaging studies conducted to evaluate the impacts of cannabis use in humans have produced inconclusive results. In essence, some analysis reports no structural changes in the hippocampus of heavy cannabis users. Still, numerous studies are suggesting that THC isolates are associated with altered neuronal transmission and tissue reduction in the hippocampal region.
The National Institute of Drug Abuse published a paper summarizing the effect of THC, used as unrefined marijuana, on memory formation and the hippocampus. Extracts from these reports suggest that cumulative exposure to THC hastens the age-related loss of hippocampal neurons leading to lower scores in the test of verbal memory but has no significant effect on information processing speed and executive function.
Brain reward system
Neurologic studies have identified a central neuronal circuitry grouped as dopaminergic neurons in an area of the mesencephalon referred to as the ventral tegmental area (VTA). The axon of these neurons targets GABAergic spiny neurons in the cortex and certain areas of the medial forebrain known as the nucleus accumbens (NAc). This complex neural network within the brain is responsible for reward mediation and reinforcement. Reward mediation depends on environmental stimuli that influence dopaminergic activation of the brain reward system. Cannabinoid receptors in these regions are important in addition to assessment and reward-seeking behavior in humans.
THC is believed to dampen reward response in young adults and consequently cause users to seek extensive thrill and pleasure more than normal subjects. In 2018, a review published by the Journal of Neuropharmacology reported that endogenous cannabinoids like THC increase the level of work an organism is willing to do for food intake and also enhances pleasure indications for palatable food. In essence, THC disrupts the brain views satiety causing individuals to seek more.
Neural noise is described as increased non-uniform variations of electrical stimulations in the brain that impair neuronal communication. Numerous studies have linked decreased cognitive skills and slowing brain activity to neural noise. Limited studies are detailing the pathophysiology of neuronal noise in young adults since it is observed more in aged individuals. A double-blind, randomized study on the relationship between intravenous THC and neuronal noise was published by the Journal of Biological Psychiatry in 2015.
Using 24 healthy human subjects, the investigators concluded that a dose equivalent of a single joint produces a psychosis-like effect and significantly increases neural noise in humans. However, the effect produced is dose-dependent and might occur at varied dose regimen in cannabis users.
Brain size variation
The suggestion that consistent use of cannabis can affect the brain architecture started as a myth with little or no scientific support. Decades ago, the little scientific evidence available was inconsistent to make an informed conclusion. Recently, animal model studies have revealed the neurotoxic effect of THC on the brain cells causing tissue shrinkage and DNA structure damage. Experts have suggested that it reduces the rate of brain cell generation and hampers synaptic plasticity. With the aid of modern imaging methods, investigators provided convincing evidence suggesting that THC induces a decrease in the volume of gray matter in regular users. The report published by the Journal of Neuropsychopharmacology identified different regions of the brain affected. These regions include the left insula, temporal pole, temporal cortex, parahippocampal gyrus, and orbitofrontal cortex.
No doubt, the effect of tetrahydrocannabinol on the brain is extensive and sometimes depends on the duration of use, compound purity, and dose administered.