THC (Tetrahydrocannabinol), one of the two basic chemicals in the cannabis plant, is a psychoactive substance. CBD (Cannabidiol) is a chemical without psychoactive properties. Both of these substances are chemicals that can be evaluated medically in the right dose and under the control of a physician. Cannabis used as a drug contains THC in the range of 5% to 20%, while this rate is less than 0.3% in industrial cannabis. Researchers study cannabis by analyzing these cannabinoids.
Cannabis and cannabinoid research is being done limitedly due to the bans and restrictions on cannabis. Still, there is some research that illuminates the effects of cannabis and cannabinoids on humans. Cannabis can be utilized as a medicine thanks to these studies. In this article, I will share details of several types of cannabis and cannabinoid research about the effects of cannabis on human brain functioning and development. Let’s start!
What Are Cannabis and Cannabinoids?
Of the 489 compounds found in the cannabis plant (Cannabis sativa or Cannabis indica), 70 are psychoactive compounds called cannabinoids. The most effective and most concentrated of these cannabinoids are two molecules called delta 9-tetrahydrocannabinol (THC) and cannabidiol (CBD). While THC is known to have anxiety-producing effects, CBD has an anxiety-relieving effect. In most studies examining the effect of cannabinoids, synthetic cannabinoids or THC are used because it is considered the main active ingredient of cannabis.
This is also a factor to consider when applying the findings of the studies to the daily use of cannabis consumers. Cannabinoids exert their effects by binding to CB1 receptors, which are parts of our body’s internal cannabinoid signaling system and are mostly found on the cell membranes of neurons (they also bind to CB2 receptors, but these are irrelevant since they are mostly found in the immune system). These receptors are normally activated by endocannabinoids such as n-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol.
Since THC has a close chemical structure with these molecules, it similarly binds to CB1 receptors and triggers some chemical reactions inside the cell. As a result of these reactions, it inhibits the release of some neurotransmitters in GABAergic interneurons (and to a lesser extent in glutamatergic neurons). Accordingly, the effects associated with cannabis consumption occur.
Research About the Effects of Cannabis and Cannabinoids on the Human Brain
Although there are various ways of consumption of cannabis today, the most common ones are to breathe in the smoke by burning it like a cigarette or to take it into the body through digestion by mixing it into foods with certain fat content (because THC is a fat-soluble molecule). When inhaled, THC mixes directly with the blood from the lungs, so its effect is faster and greater. Ongoing debates about cannabis in neuroscience and psychology include how addictive it is compared to other drugs, how much damage it causes to the brain, and whether these damages are acute effects or permanent structural changes.
Since experimental control can be achieved much better in animal studies and in vitro cellular studies, more precise results can be obtained in this regard. However, it has not been possible to obtain such precise results in human studies due to ethical reasons and method deficiencies. First of all, 9.1% of individuals who consume cannabis for life develop clinical addiction, while this rate is 15.4% for alcohol, 16.7% for cocaine, 23.1% for heroin, and 32.9% for tobacco. However, a study of 10,641 cannabis consumers over the age of 18 in Australia showed that 10.7% of consumers met the definitions of “substance abuse” and 21% “substance abuse” according to DSM-IV criteria.
It is useful to keep these ratios in mind when examining the effects of cannabis on the brain; Because, as in every substance addiction, permanent changes occur in the dopaminergic reward circuits of the brain in cannabis, and these changes affect the lives of individuals behaviorally (especially self-control mechanisms). Although a relatively low percentage of cannabis consumers develop addiction on clinical criteria, in 2005 1.7% of the population in the United States, or 4 million people, suffered from cannabis addiction.
When we look at the cannabis studies examining the brain structurally, we see that differences in white or gray matter densities are reported in the areas of the frontal and parietal lobes that do not overlap with each other. Although there are MRI studies in which volumetric reduction was observed in brain regions such as the right parahippocampal gyrus and left parietal lobe, this finding could not be repeated in some other studies. It has been suggested that these inconsistencies are due to substance use history, amount of consumption, associated psychological problems among subjects, or methodological differences in the experiments.
Of the reported brain changes, the most consistent are those that occur in the hippocampus, parahippocampal complex, and amygdala. These findings indicate that long-term cannabis use leads to structural modifications in regions associated with memory and executive and emotional processing.
Some studies have found that lifetime cannabis use correlates with decreased hippocampus volume and psychotic symptoms. Age at onset of use is also an important factor affecting these effects statistically. Since brain development is not yet complete (this development process continues until the mid-20s in men and early 20s in women), starting regular use in adolescence has been associated with more pronounced structural changes.
In a literature review by Lorenzetti et al., which focused on neuroimaging studies examining the structural effects of cannabis on the brain, it was stated that there was evidence of abnormalities in the medial temporal, prefrontal, and cerebellar regions. Morphological changes in the hippocampus were consistent across studies, although findings in most brain regions were mixed.
In the study in 2014 on 31 infrequent cannabis consumers and 26 regular cannabis consumers who did not use other drugs and did not have psychiatric disorders, regular consumers had a more intense gray matter reduction in the medial temporal cortex, temporal pole, parahippocampal gyrus, left insula, and orbitofrontal cortex than infrequent consumers. These changes were strongly positively correlated with individual monthly cannabis consumption and negatively correlated with age at first cannabis use. In addition to these findings, an increase in gray matter was observed in the cerebellum of regular consumers.
There is evidence that the temporal pole is involved in the relationship between emotions and sensory stimuli. In previous studies, changes in personality and social behavior have been observed in patients with damage to this region. These functions have not been tested in cannabis consumers; However, such a result can be expected indirectly. Although gray matter atrophy in the medial temporal cortex is also seen in alcohol addiction, it is not seen in behavioral addictions such as heroin addiction and gambling; This indicates that the effect seen is directly related to cannabis consumption.
In a study conducted on rats, it was observed that THC, the active ingredient of cannabis, caused volumetric shrinkage in hippocampal neurons and a 44% decrease in the number of synapses, even 7 months after the exposure time. It has been found in previous studies that structural and functional changes in the hippocampus are associated with poor memory performance and psychotic symptoms. It has also been observed that cannabis consumption causes low hippocampus activity in verbal and visual learning tasks.
In previous fMRI studies, differences in brain activity have been observed in cannabis consumers in the ventromedial prefrontal and orbitofrontal cortices and insula, brain regions associated with motivational and emotional aspects of decision making. In another study, substance abusers and patients with ventromedial prefrontal cortex damage similarly showed a tendency to make decisions with immediate payoffs.
Cannabis and Cannabinoid Research on Cognitive Performance
Studies examining cerebral blood flow during cannabis consumption have shown that a high metabolic activity occurs in the cortex in general during consumption. On the other hand, in some studies examining the long-term effects of cannabis on those who stop using cannabis, low metabolic activity has been detected in the whole brain, frontal lobes, and cerebellum. Apart from these, many fMRI studies have shown that there are different levels of activity in various parts of the brain with regular cannabis use; but there is not much evidence about their permanence.
A 2003 meta-analysis study of 15 studies meeting methodological criteria from 40 individual cannabis studies found that there was only a small-scale regression in learning and memory functions from reaction time, attention, verbal, executive, perceptual-motor, motor, learning, and memory functions, when long-term and regular cannabis consumers are compared.
Since the acute effects of cannabis include regression of memory functions, it is plausible that this effect persists in the long term. However, some other studies have reported that heavy cannabis consumers perform worse than control groups on measures such as memory, executive functions, self-control, psychomotor speed, verbal memory, language functions, and processing speed, even after 25-28 days of abstinence.
In a study using 45 former heavy consumers, 63 current heavy consumers, and 72 non-consumer subjects, subjects underwent neuropsychological testing on days 0, 1, 7, and 28, when they were supervised for not consuming cannabis. In this study, it was observed that only on days 0, 1, and 7, current heavy consumers showed a statistically significant deficit in the verbal memory test compared to other groups. This led the researchers to think that the cognitive effect of cannabis might be due to the withdrawal and residual effects.
Two studies separating subjects as current heavy cannabis consumers, current light cannabis consumers, former regular consumers, and non-consumers followed long-term and subjected them to neuropsychological performance tests at ages 9-12 and 17-20. Among these groups, only a 4-point decrease in IQ score was observed in current intensive consumers, as well as a decrease in memory tests and information processing speed. The lack of this effect in old consumers indicates that there may be a recovery in cognitive functions after a certain period of time.
In a study of 54 identical twins, one of whom had long-term use of cannabis and the other never consumed marijuana, there was only one difference in visual construction between ex-consumer and non-consumer twins. Less activity was observed in the prefrontal cortex and hippocampal regions during learning tests in individuals who normally consume cannabis frequently but leave it under supervision for a short time (such as 25 days) before the study.
Epidemiological studies have also found correlations between cannabis and various mental health problems. For example, heavy cannabis consumers have been found to have higher rates of psychotic symptoms, depression, and anxiety. Similar to the studies mentioned above, positive correlations were found between mental health problems as well as cognitive functions such as learning, memory, decision-making and processing speed, and cannabis consumption, and this effect increases depending on the dose.
Taken together, these studies show that cannabis consumers experience some loss of cognitive performance relative to non-consumers, researchers say. But this effect appears to be on a small scale and diminishes or disappears within weeks. In addition, cognitive declines are mostly seen in cases of intense and frequent use.
Other researchers also state that studies examining cognitive function declines caused by cannabis in adults are usually conducted shortly after the last cannabis consumption, and there are studies showing that these declines decrease or disappear if consumption is stopped for a few weeks before the tests. But most studies consistently confirm that during periods of frequent cannabis use, problems such as loss of cognitive function, learning and memory difficulties, and slowing of decision-making and processing speed are experienced.
Cannabis and Cannabinoid Research on Animal Models
CB1 receptors are most commonly found in the hippocampus, amygdala, cerebellum, prefrontal cortex, and striatum regions of the brain. It is a finding that emerged in early animal studies in this area that THC causes dose-related toxicity and acute structural changes in brain regions where these receptors are dense.
Although the exact role of cannabinoid receptors in each region is not known, it has been shown experimentally that they play a role in memory function in the hippocampus and in the voluntary motor control in the basal ganglia (striatum). These receptors also take part in dopaminergic reward circuits connected to the striatum, and behavioral disorders in decision-making mechanisms, including substance addictions due to cannabis consumption, have been linked to these functions of cannabinoids.
While some animal studies have shown that CB1 receptor agonists (molecules that bind to and activate these receptors) such as THC cause structural changes and neuron death in the hippocampus, other studies have shown that THC has potent antioxidant effects and cannabinoid agonists, in general, have neuroprotective effects. They are even used in drug development studies. In another study, it was reported that chronic low-dose cannabinoid administration protects neurons against effects such as reduction in neurogenesis, loss of cognitive function, and inflammation that occur with aging.
Some studies in cell culture have reported increased cell death rates in brain cells exposed to THC. In fact, injections of THC applied to tumors in rat brains have been shown to inhibit uncontrolled cell division, and the use of THC in cancer treatment has been discussed. It has also been found that THC protects neurons against ischemia and glutamate toxicity.
In some primate and rodent studies, high doses of cannabinoids up to 60mg/kg for 1-3 months have been found to have adverse effects on the hippocampus, amygdala, and cerebral cortex, resulting in reductions in the neuron cell body, synapse number, pyramidal neuron density, and dendrite lengths. It has been observed that these effects vary depending on the dose. However, these findings were obtained immediately after the cannabinoid administration was stopped.
In a few studies examining long-term rats in cognitive processes and memory tests, it was found that some of the negative effects that emerged after the application were stopped disappeared within 15-30 days. Although the findings of the toxic effects of THC and cannabinoids on adult neurons are not very clear, there are many studies showing that they cause cell death and have toxic effects in mammalian neurons during prenatal, newborn, and adolescence periods.
In a study in both adult and small rats, after 3-6 months of cannabinoid administration, learning difficulties were observed in small rats, although this effect was not seen in adult rats, even after 1-3 months. Other studies comparing adult and adolescent rats also confirm that adolescent rats show more severe cognitive deficits and behavioral disorders than adults.
Cannabis Use and Brain Development in Adolescence
Adolescence is the period when a large number of cortical synapses are pruned, known as “pruning”. This process is important for brain development and can lead to cognitive problems if interrupted. Since the endocannabinoid system takes on various tasks in the cortical pruning process, it has been suggested by some researchers that the intake of exogenous cannabinoids such as THC at this age will hinder the development of the brain and cause damage to the brain.
There are some studies that confirm these hypotheses. For example, age at first cannabis consumption was found to be negatively correlated with white matter integrity in the brain. It has been determined that exposure to cannabis in the womb also has negative effects on the central nervous system and is associated with cognitive and behavioral disorders. In studies that included the age of first cannabis consumption in the research variables, positive correlations were found between the age of first consumption and cognitive function deficiencies. Studies on cannabis consumers in adolescence have produced results that are in line with the adult literature.
In studies examining the structural changes that occur in this age period, findings such as decreased gray matter volume in the cortex, decreased thickness of the prefrontal and insular cortex, decreased volume in the right medial orbitofrontal cortex, decreased volume in the hippocampus, an asymmetry between the volumes of the right and left hippocampus, and larger right amygdala volumes have been reported. In addition, there is a study showing that small orbitofrontal cortex volume is a precursor to cannabis consumption at an early age, so there may be causality in the opposite direction of what was expected in this finding.
In addition, there are findings showing that the structural changes that occur in consumers during adolescence continue even after 3-4 weeks of stopping consumption. But there are also a few studies showing that although these changes persist for longer than adults, they return to normal in the long run.
A long-term study that tested 1037 children aged 7-13 years who had not started cannabis consumption, and tested again at age 38, found that those who started heavy cannabis consumption before age 18 experienced more severe cognitive decline. What’s more, heavy consumers who start cannabis consumption in adolescence show these regressions a few years later, but not those who start in adulthood.
But later, some researchers suggested that there were parallel factors affecting the findings in this study, such as socioeconomic status and personality traits. In a study in which the total duration of cannabis consumption was kept the same (2.4 years), subjects who started consuming in adolescence performed worse in verbal learning and memory areas than those starting in adulthood.
Although there are studies showing a statistical interaction between schizophrenia and psychosis risk factors and cannabis consumption (especially starting consumption at an early age), there are no causal findings and more studies are needed to clarify this relationship. In addition, differences were found in the endocannabinoid systems and especially in CB1 receptors of patients with schizophrenia and depression.
Some researchers have suggested that these differences may both cause schizophrenia and develop a vulnerability to the negative effects of cannabis. A mutation in the ABH12 enzyme that breaks down endocannabinoids can be given as an example of these differences. In fact, in a study conducted on rats, it was observed that in the case of insufficient nutritional intake in the womb, disorders in the gene expression of CB1 and CB2 receptors and the molecules that bind to them in the hippocampus occur.
The main problem with human studies, including most of the studies mentioned here, is the failure to establish cause-effect relationships. Since it is not ethically possible to take a group of people who did not originally consume cannabis and make them use drugs regularly, it is necessary to select individuals who are already users for the study. As such, we cannot observe pre-drug use differences between experimental groups, as the subjects were not randomly selected.
In other words, although unlikely, theoretically, differences in brain structure between regular cannabis users and occasional users may actually have existed before cannabis use and may even have driven them to this different user behavior.
The presence of genetic and neurobehavioral risk factors, which are precursors of substance addictions, has been demonstrated in previous studies. This situation strengthens the possibility that substance users may have some differences in their brain structure prior to use. Also, most studies here have not examined the long-term effects of cannabis. In the current literature, there are findings that cognitive functions and changes in CB1 receptors return to normal values after a certain period of time after consumption is stopped.
When we evaluate all the studies mentioned in this article together, we can conclude that although we cannot suggest a definite causality due to methodological limitations, heavy cannabis consumption may cause structural changes in the brain and regression in cognitive functions. However, it is observed that these changes and regressions are to such a degree that they do not require clinical intervention, except in cases of addiction, and are greatly reduced if consumption is stopped for a long time.
More serious and permanent damage may occur in consumption during adolescence. In addition, in the presence of schizophrenic risk factors, cannabis consumption may be a triggering factor. Therefore, when evaluating cannabis consumption, in addition to its potential for medical and industrial use, all these factors and its addictive effect should be taken into account.
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