Polysubstance dependence refers to a type of substance use disorder in which an individual uses at least three different classes of substances indiscriminately and does not have a favorite substance that qualifies for dependence on its own. Although any combination of three substances can be used, studies have shown that alcohol is commonly used with another substance. One study on polysubstance use categorized participants who used multiple substances according to their substance of preference. The results of a longitudinal study on substance use led the researchers to observe that excessively using or relying on one substance increased the probability of excessively using or relying on another substance.

The three substances were cocaine, alcohol, and heroin, which implies that those three are very popular. Other studies have found that opiates, cannabis, amphetamines, hallucinogens, inhalants, and benzodiazepines are often used in combination as well.

Cognition refers to what happens in the mind, such as mental functions like "perception, attention, memory, language, problem solving, reasoning, and decision making." Although many studies have looked at the cognitive impairments of individuals who are dependent on one substance, there are few researchers who have tried to determine the problems with cognitive functioning that are caused by dependence on multiple substances. Therefore, what is known about the effects of polysubstance dependence on mental abilities is based on the results of a few studies.

The effect of polysubstance dependence on learning ability is one area of interest to researchers. A study involving 63 polysubstance dependent women and 46 controls (participants who were not using substances) used the Benton Visual Retention Test (BVRT) and the California Verbal Learning Test (CVLT) to look at visual memory and verbal ability. This study showed that in polysubstance dependent women, verbal learning ability was significantly decreased, though visual memory was not affected. In addition, alcohol and cocaine use led to more severe issues with verbal learning, recall, and recognition.

Sometimes studies about specific groups in the general population can be informative. One study decided to test the cognitive abilities of participants in rave parties who used multiple substances. To do this, they compared 25 rave party attenders with 27 control participants who were not using substances. The results of this study indicated that in general, the rave attender group did not perform as well on tasks that tested speed of information processing, working memory, knowledge of similarities between words, ability to attend to a task with interference in the background, and decision making. Certain substances were associated with particular mental functions, but the researchers suggested that the impairments for working memory and reasoning were caused by the misuse of multiple substances.

Another study that tried to find differences between the effects of particular substances focused on people with polysubstance use who were seeking treatment for addictions to cannabis, cocaine, and heroin. They studied a group of people with polysubstance use and a group that was not dependent on any substances. Because alcohol was a common co-substance for nearly all of the people in the polysubstance use group, it was difficult to tell exactly which substances were affecting certain cognitive functions. The researchers found that the difference in the two groups' performance levels on executive function, or higher-level cognitive processing tasks were consistently showing that the polysubstance group scored lower than the control group. In general, this meant that multiple substances negatively affected the polysubstance group's cognitive functioning. More specifically, the researchers found that the amount of cannabis and cocaine affected the verbal part of working memory, the reasoning task, and decision making, while cocaine and heroin had a similar negative effect on visual and spatial tasks, but cannabis particularly affected visual and spatial working memory. These results suggest that the combined use of cannabis, cocaine, and heroin impair more cognitive functions more severely than if used separately.

Alcohol's negative effects on learning, spatial abilities and memory has been shown in many studies. This raises a question: does using alcohol in combination with other substances impair cognitive functioning even more? One study decided to try to determine if people with polysubstance use who also recreationally use alcohol would display poorer performance on a verbal learning and memory test in comparison to those who consumed excessive amounts of alcohol specifically. The California Verbal Learning Test (CVLT) was used due to its ability to "quantify small changes in verbal learning and memory" by evaluating errors made during the test and the strategies used to make those errors. The results of this study showed that the group of people with polysubstance and alcohol use performed poorly on the CVLT recall and recognition tests compared to the group of people who exclusively consumed excessive alcohol only, which implies that polysubstance use impaired the memory and learning in a different way than the effects of alcohol alone can explain.

To examine whether abstinence for long periods of time helps people with polysubstance use recover their cognitive function, a group of researchers tested 207 polysubstance dependent men, of whom 73.4% were dependent on three or more substances. The researchers were interested in six areas of cognitive functioning, which included visual memory, verbal memory, knowledge of words, abstract reasoning, inhibition (interference), and attention. The study used the Benton Visual Retention Test (BVRT) for testing visual memory, the California Verbal Learning Test (CVLT) for verbal memory, the Wechsler Adult Intelligence Scale vocabulary portion for knowledge of words, the Booklet Category Test for abstract reasoning, the Stroop Neuropsychological Screening task for inhibition, and the Trail Making Test for attention. The results showed that neuropsychological ability did not improve with increases in the length of time abstinent. This suggests that polysubstance dependence leads to serious impairment which cannot be recovered much over the span of a year.