Apart from its recreational use, cannabis is of great importance for researchers in terms of the potential therapeutic uses of the components (cannabinoids) it contains. Researchers are trying to determine the nature and extent of the long-term damage that cannabis use causes on learning, memory, attention, executive functions, inhibition, decision making, planning, problem-solving, reaction time, and psychomotor functioning. The disease most commonly associated with cannabis is dementia. So what is the relationship between cannabis and dementia?
Cannabis use and dementia are thought to be interrelated. Research shows that cannabis use can cause negative effects on learning and memory functions. This, in long term, may make cannabis users more prone to dementia. Knowing the effect of cannabis use on mental health is important both in terms of the cognitive function of the person playing a role in addiction treatments and the use of cannabinoids in the right place and time in the clinic. Let’s take a closer look at the effects of cannabis on memory and its relationship with dementia.
What Is the Relationship Between Cannabis and Dementia?
One of the most common complaints of cannabis addicts is the memory problems they experience in their daily lives. This highlights the importance of the potential relationship between cannabis and dementia. In the last 20 years, a large number of studies have been conducted investigating whether regular cannabis use results in permanent learning and memory damage beyond the acute effect. In these studies, in addition to learning and memory areas, the performance of users in other cognitive areas such as attention, reaction time, and executive functions are also evaluated.
According to meta-analysis studies, cannabis use most affects learning and memory performance among all these cognitive domains. For example, in a meta-analysis study based on the findings of 15 different studies, it was found that individuals using cannabis outperformed the control group in only learning and forgetting/retrieval domains from eight different cognitive domains. In another meta-analysis study, the negative effect observed in learning and forgetting/retrieval domains was confirmed by including new studies.
Current memory impairment includes memory dimensions such as verbal instant and delayed recall, verbal learning, verbal recognition, and visual recognition, as in acute effect studies. Related tasks are retrospective measures that require learning the presented material, keeping it in mind for a while, and then recalling it. Some researchers prefer to use measurements that better reflect memory problems in daily life. For example, prospective memory is defined as the process of remembering to perform a targeted action for a certain time in the future. Examples include taking medicine at a certain time or remembering an appointment.
According to meta-analysis studies, cannabis use most affects prospective memory performance among other memory areas. For example, according to self-report measures, cannabis users experience more prospective memory problems in their daily lives. The prospective memory performance of these individuals, as measured by virtual reality tasks in the laboratory environment, is also lower than the control group.
Some researchers state that this effect is due to a problem in the retrospective component of prospective memory (eg, remembering to go to the grocery store but forgetting what to buy). These recent studies show that prospective memory damage can also be included among the memory areas affected by cannabis use.
There are inconsistencies in the findings regarding the effect of cannabis use on working memory. While some studies have found that cannabis users have poorer working memory performance; In some studies, it was found that they performed at the same level as the control group. As in acute effect studies, the negative effect is more pronounced in complex tasks. Researchers state that performance differences that are observed due to ceiling performances occur in brain activation patterns during the task.
This pattern is usually in the form of diffuse, compensatory activation in which additional brain areas are also activated, unlike the control group. This situation is interpreted as the participants’ spending more cognitive effort to fulfill the requirements of the task or applying additional strategies and making up for their existing inadequacies.
Acute Effect of Cannabis on Dementia and Animal Studies
The negative effect of Δ9-THC and synthetic cannabinoid receptor agonists on various aspects of learning and memory is a reliable finding that is often repeated in animal studies. This finding can be associated with cannabis and dementia relation. Most of the findings indicate that while cannabinoids do not affect the retrieval of previously learned knowledge (long-term or reference memory), they impair functions related to short-term memory or working memory.
Working memory is the process required to recognize and react to new information that changes from trial to trial, and these processes occur through functions such as attention, connection, encoding, and retrieval. Working memory includes the use of information specific to a single trial in the next trial (trial-specific information), while reference memory includes the use of repetitive information throughout the task throughout all trials.
Delayed match-to-sample is among the frequently used methods in studying memory mechanisms in animals. In this process, a sample stimulus is presented to the subject and taught to give a response related to this stimulus. Then the stimulus is removed for a while (waiting period) and at the end of this period, it is presented simultaneously with one or more stimuli. Recognizing the sample stimulus from among the options and giving the reaction in the first stage is considered as a memory indicator.
In studies, it was found that after a single Δ9-THC application, rats made more errors depending on the dose and waiting time. The fact that these animals performed on par with the control group in short waiting times shows that there is no substance-induced general decrease in performance, but on the contrary, short-term memory processes are specifically affected.
In recognition tasks that do not require operant conditioning, the innate tendency of rats to discover new objects is utilized. First, the rats are presented with an object for a short period of time to explore, and this object is removed during a certain cooldown. Afterward, this object is presented together with a new object and the animal’s more interest in the new object is accepted as a memory indicator. In the current studies, it was found that after cannabinoid administration, rats could not distinguish between new and old objects and were equally interested in both. In the same studies, it was observed that the current effect was also valid when another rat was used instead of the object and the recognition memory was constructed with olfactory cues.
Other learning and memory models used to investigate the cannabinoid effect are more related to spatial learning functions. For example, in T-mazes, it is an indicator of working memory that the animal remembers the maze arm it entered for a certain waiting period and fulfills the requirement to enter the other arm at the end of this period. Confirming the effect of cannabinoids on working memory, it was observed that animals made erroneous choices by re-entering the arm they entered in the previous experiment while under the effect of Δ9-THC.
In eight-armed radial labyrinths, only some of the eight arms are fed and the animal is taught which arms have food through repeated trials. After a certain waiting period, it is a memory function that the animals enter only the arms containing the bait and do not try the other arms. In these studies, it was found that animals under the influence of cannabinoids were more likely to enter the wrong arms without feed.
Another frequently used spatial learning model, Morris’ Water Tank maze has a hidden platform a few centimeters below the large, circular tank filled with water. In these studies, the animal left in the tank learns the location of the platform based on visual cues and reaches the platform in a shorter time. In studies, it was observed that there was no significant decrease in the time to reach the platform of rats after cannabinoid administration.
On the contrary, the fact that the speed of reaching an invisible, visible platform was not different from the control group indicates that there is no substance-induced motor activity decline and that memory processes are specifically affected. Other researchers, on the other hand, compared performances in the working memory version, in which the platform was relocated at the first trial of each session, with the reference memory version, where it was kept constant throughout the task, and found that working memory performance was selectively affected.
The effects of acute cannabinoid applications on short-term memory or working memory are temporary and return to normal after a certain period of time, depending on the task used, the dose, and the method of drug administration. In addition, the fact that this effect occurs at lower doses than the analgesia, hypothermia, and motor effects of cannabinoids confirms selective memory damage. On the other hand, there is also evidence that animals underperform on memory tasks even after a certain period of time after a single, extremely low dose of Δ9-THC.
Acute Effect of Cannabis on Humans and Dementia
In studies conducted to prove the relationship of cannabis with dementia, participants are exposed to various doses of Δ9-THC and placebo at regular intervals, and their memory performance is evaluated at the end of each application. In these studies, in which verbal learning and memory paradigms are generally used, participants are presented with a list of words and asked to remember these words immediately (instant free recall test) or after a certain period of time (delayed free recall test) or to recognize new words (recognition test).
Current findings show that the instant and/or delayed word recall performance of the participants decreased after oral dronabinol or Δ9-THC which is taken in the form of cigarettes or administered intravenously. In recognition tests, on the other hand, there is an effect that manifests itself with an increase in classification bias in the memory list of distractor words (number of false alarms). In addition to the word list, it has been shown that the recall of a text after a certain period of time decreases due to Δ9-THC.
In studies in which spatial n-backward, Sternberg recognition test, forward/backward number space, and delayed-to-sample matching tasks were used in terms of working memory, it was shown that the performance of the participants decreased after acute Δ9-THC. On the other hand, in some studies, limited performance drops were observed, which did not include the correct number of responses, but only showed itself with an increase in response times. The source of the inconsistency in the findings is that some tasks do not require a lot of cognitive resources and are not sensitive enough to reveal the potentially disruptive effect (ceiling performance effect).
Contrary to the current findings, there are also studies that could not prove the impairing effect of acute Δ9-THC on verbal recall performance. One of the possible reasons for this is the high level of cannabis use in the sample and therefore the participants developed tolerance to the acute memory effect. Generally, studies are conducted with individuals with a history of cannabis use due to ethical concerns, but individuals with a low amount and frequency of use are preferred to exclude a possible tolerance effect (eg, users who use cannabis at most once a month).
In a study that directly tests the development of tolerance, the verbal memory performances of two groups with low and high substance use history were compared after Δ9-THC, and it was found that the group with a high frequency of cannabis use was less affected by Δ9-THC. This finding indicates that cannabis addicts develop tolerance to the acute memory effect and researchers should consider the substance use level of the sample. However, in the same study, the finding that the group with high cannabis use had a lower memory performance after placebo administration than the other group shows that cannabis use creates a permanent, chronic effect beyond the acute substance effect.
The acute memory effect varies depending on the type of cannabis used. Cannabis high in Δ9-THC and low in cannabidiol is particularly harmful. For example, it was found that people who are given cannabidiol in the pure form before Δ9-THC did not have a Δ9-THC-induced decrease in delayed verbal recall performance. In another study, the acute memory effect was evaluated on the participants’ own use of cannabis, and it was found that those with a low cannabidiol ratio had lower delayed and instant text recall performance than other users.
The ratio of Δ9-THC contained in commercial cannabis to cannabidiol has increased from 14 times to 80 times in recent years. In addition, the Δ9-THC ratio used in the studies is much lower than the Δ9-THC ratio of cannabis on the market. Such data indicate that the memory problems of cannabis users in their daily lives may be far beyond existing laboratory findings in terms of severity and extent. In short, a single dose of Δ9-THC has a detrimental effect on memory performance. While not much research has been done on how long this effect lasts, one study found that word list recall performance returned to normal after 6 hours and text recall performance within 24 hours after oral intake of Δ9-THC.
In general, there is a temporary effect that may differ both in nature and duration of action, depending on the memory task used, the Δ9-THC administration method, the dose, and the substance use history of the sample. For example, the intravenous or inhalation method produces a quicker and shorter-term effect than oral and sublingual consumption. The current effect is only valid for information learned while under the influence of substances (especially verbal information), as in animal studies, and is limited to short-term memory or working memory. It does not include the retrieval of memories in long-term memory.
Chronic Effect of Cannabis on Learning and Memory
Both human and animal studies show that the ability to learn and remember new things under the influence of cannabinoids is impaired. At the same time, the lower performance of cannabis addicts in verbal learning and memory tasks in studies in which the acute substance effect was excluded reflects the potential chronic negative effect of substance use. In these studies, which generally used a cross-sectional design, it is not possible to talk about a causal effect of cannabis use due to the possibility of premorbid effects.
However, the findings obtained from longitudinal studies in which this effect was excluded also confirm selective memory damage. Especially in adolescence and/or long-term, high-frequency cannabis use, much more significant damage is observed. Among the studies, the fact that there are differences in characteristics such as the sample’s history of cannabis use (amount, frequency, age of onset), the level of difficulty of the cognitive tasks used, the duration of abstinence from cannabis and its derivatives before performance measurement, and other substance use limit direct comparisons between the findings and raises the need for standardization.
In chronic effects studies, participants are asked to stay away from cannabis and its derivatives for a certain period of time (eg, 12-72 h) to exclude acute substance effects. However, due to the lipophilic feature of Δ9 – THC in chronic use and its accumulation in fat deposits, measurements taken after short-term abstinence always contain the risk of acute effects. This issue was conceptualized by the researchers as the “residual” effect of the substance, and the residual effect observed after 12-24 hours of abstinence was differentiated from both acute and chronic effects.
In this direction, there is a possibility that the learning and memory damage observed in some studies may be caused by the residual substance effect. In addition, withdrawal symptoms that can be caused by not using cannabis for a while are another confounding variable that can lead to performance declines. Findings obtained from studies in which these two possibilities were excluded will be informative about the persistence of the current effect.
In a study in which participants were asked to stay away from cannabis and its derivatives for 1 month and intermittent measurements were taken during this period, it was found that the verbal memory performance of the participants on the seventh day was lower than the control group, but they showed equal performance with the control group on the 28th day. In a meta-analysis of 13 studies in which measurements were taken after at least 1 month of abstinence, it was found that cannabis use did not have a significant negative effect on learning and memory. In another meta-analysis, it was found that as the withdrawal period of the participants increased, the negative effect gradually decreased, and the performances measured after 10 days of abstinence were much better.
Another informative approach to the persistence of the effect is to work with people who have quit using cannabis for a while. In these studies, it was observed that the memory performance of individuals who had not used cannabis for a minimum of 3 months was not different from those who had never used cannabis. Similarly, over an eight-year longitudinal study, it was found that the performance of people who stopped using cannabis gradually increased and eventually showed similar performance to those who never used it. In line with the finding that 28 days of abstinence is sufficient to eliminate the existing memory-impairing effect, it was found that the learning and memory performance of individuals who did not use cannabis for a minimum of 4 weeks were not different from the control group.
All these findings indicate that there is a learning and memory impairment that disappears after a certain period of time (eg, 1 month) after cessation of cannabis use. However, some studies have shown that parameters related to substance use history are also determinative in this regard. For example, in the measurements taken after 1 month of abstinence, it was shown that the decrease in the memory performance of those with a high weekly frequency of cannabis use continued.
In parallel, individuals who started using cannabis before the age of 18 were found to underperform on many measures, even if they had not used cannabis for the past year. In addition, there are many findings that there are structural and functional changes in the brain in long-term and high-frequency cannabis use, especially cannabis use during adolescence. Beyond the behavioral performances, there is not enough data yet on how permanent such changes are.
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