The Neuropsychology of Cannabis and other Substance use in Schizophrenia: Review of the Literature and Critical Evaluation of Methodological Issues

Abstract

Research on the neuropsychology of substance use in schizophrenia has been steadily growing over the past decade. However, significant gaps remain in the knowledge of individual substances and their relationship to cognition in the schizophrenia spectrum disorders. Approximately 65 studies to date have directly examined this relationship. Of these, approximately 20 have focused on nicotine, 15 on alcohol, 10 on cocaine, three on stimulants/hallucinogens, one on benzodiazepines, 10 on polydrug abuse, and seven on cannabis. Research on cannabis is especially lacking, given that worldwide it is the most commonly used illicit drug in schizophrenia, is used at higher rates in schizophrenia than in the general population, and makes its own unique contribution to the onset and prognosis of schizophrenia. In the present paper an overview of the neuropsychology literature on substance use in schizophrenia is presented, with special emphasis on cannabis. This incorporates a discussion of the methodological limitations inherent in these studies, and range of potential confounding variables that were not considered or controlled, providing directions for future research into the cognitive correlates of cannabis and other substance use in schizophrenia.

Keywords

cannabis cognition cognitive neuropsychology schizophrenia substance

Evidence of altered neuropsychological functioning is widely documented in both schizophrenia and substance use. Much less is known, however, about cognitive functions in persons with schizophrenia and comorbid substance use because mental illness is excluded as a confounding factor in substance use research, and conversely, substance use is excluded as a confounding factor in schizophrenia research. This issue was first noted more than a decade ago [1]. Since then, research has been steadily growing. However, significant gaps remain in the knowledge of individual substances and their relationship to cognition in the schizophrenia spectrum disorders.

To date approximately 65 studies have directly examined this relationship. These studies were identified by searching the MEDLINE and PsycINFO databases. Keywords included ‘schizophrenia, psychosis’ combined with ‘cognitive/cognition, neuropsychology/neuropsychological’ combined with ‘substance, dual diagnosis, comorbid, alcohol, cocaine, cannabis/marijuana/THC/cannabinoid, nicotine/tobacco/cigarette, caffeine, amphetamine/stimulant/speed, hallucinogen/LSD/ecstasy, heroin/opiate/narcotic, sedative/benzodiazepine’. Studies were included in the review if the method involved direct examination of the relationship between self-reported substance use and neuropsychological functioning in schizophrenia, or involved direct administration of a substance (analogous to recreational drug use) to persons with schizophrenia, followed by measurement of cognitive functioning.

Of the 65 studies that have been conducted to date, the majority have focused on nicotine use [2–21]. Other studies have focused on use of alcohol [22–36], cocaine [32, 37–44], stimulants/hallucinogens [32, 45, 46], benzodiazepines [47], and polydrug use, which pertains to the combined effects of two or more substances [28, 48–56].

With respect to cannabis, only seven studies to date have examined the relationship to cognition in the schizophrenia spectrum disorders [26, 32, 57–63]. However, two of these studies did not set out to focus solely on cannabis [26, 32]. Cannabis in these studies appeared to be examined in a post-hoc fashion in context of investigating substance use in general. It is surprising that so few studies have attempted to investigate cannabis separately from other substances, given that cannabis is the most commonly used illicit drug in schizophrenia [64–66], is used at higher rates in the schizophrenia population than in the general population [67–70], and makes its own unique contribution to the onset and prognosis of schizophrenia [71, 72].

This paper presents a brief overview of the literature on substance use in general, followed by a more detailed analysis of the literature on cannabis. This incorporates a critical review of methodological limitations, and focuses on a discussion of potential confounds and other relevant issues that have been largely ignored in the literature of schizophrenia with comorbid cannabis and other substance use.

Substance use and cognition in schizophrenia

The majority of research on the neuropsychological correlates of substance use in schizophrenia has focused on nicotine. With more than 20 studies conducted to date, there is general consensus that nicotine improves many aspects of cognitive functioning, including attention, working memory, processing speed, executive functions, and memory [8, 11–14, 16, 19–21]. In addition, studies have demonstrated cognitive deficits associated with smoking cessation and nicotine withdrawal in schizophrenia [4, 6, 12]. Only few studies have demonstrated no actual differences between smokers and non-smokers on tests of executive functions, attention, working memory, learning and memory, language, and visuospatial constructional abilities [2, 7, 14].

Alcohol has been the second most commonly studied substance in terms of its relationship to the neuropsychology of schizophrenia. The majority of studies have demonstrated greater cognitive impairments in persons with schizophrenia and comorbid alcohol use, and such impairments have been observed in the domains of attention, working memory, executive functions, memory, visuospatial construction, and perceptual functions [22–25, 27, 30, 36]. Few studies have failed to detect any differences in cognitive performance between schizophrenia persons with and without comorbid alcohol use [26, 30, 31].

Studies have demonstrated that schizophrenia participants with comorbid cocaine use show greater impairments on tasks of learning and memory [40–42] and motor functioning [44], yet are less disordered or show comparable performance to non-users in other aspects of cognition such as attention [38, 41, 42] and executive functions [38, 39, 41]. However, few studies have demonstrated no differences between schizophrenia participants with and without comorbid cocaine use on any neuropsychological measures including memory [37, 38], while others have shown that schizophrenia participants with comorbid cocaine use indeed perform better than non-users on tasks of motor speed [43] and selected executive functions [43, 44].

In two studies of direct dexamphetamine administration to individuals with schizophrenia, improvements were observed in tasks of reaction time, psychomotor speed, spatial working memory, executive functions, and language production [45, 46]. Another study found that self-reported recreational use of stimulants and hallucinogens was associated with better performance on one aspect of memory (immediate serial learning) [32].

One study investigated the effects of direct benzodiazepine administration to schizophrenia participants, and found that this drug significantly delayed information processing on an auditory selective attention task [47]. No other neuropsychological tests were administered in that study.

With respect to other studies of substance use in schizophrenia, several have focused on ‘polydrug’ use whereby the substances under investigation were not examined in terms of their individual effects but, rather, on their combined effects on cognition (e.g. alcohol plus one or more illicit substances). A large proportion of this literature has reported better cognitive performance associated with substance use in the domains of executive functions, motor speed, memory, and visuospatial ability [49, 51–54]. Other studies have found no differences between schizophrenia persons with and without comorbid substance use on selected aspects of cognition including memory, attention, and executive functions [48, 50, 51].

Cannabis use and cognition in schizophrenia

Liraud and Verdoux investigated the independent relationships between alcohol and cannabis use, and cognition in 77 patients [26]. Of these, 35 had a psychotic disorder (schizophrenia, schizoaffective disorder, or other psychotic disorder), and 42 had a mood disorder (bipolar disorder or major depression). After controlling the effects of relevant confounds (i.e. age, gender, level of education, age at onset of psychiatric illness, and current substance abuse/dependence), only performance on a test of inhibition was associated with lifetime cannabis abuse/dependence, on which the scores of the cannabis users reflected poorer performance than the non-users. The authors concluded that cannabis use has limited effects on neuropsychological performance in patients with a psychiatric disorder.

Pencer and Addington investigated the independent relationships between five substances (including cannabis) and cognition in patients experiencing their first episode of psychosis; 266 patients were assessed at initial presentation, then 159 and 90 of these patients were respectively re-assessed 1 year and 2 years later [32]. Only performance on a category naming task at 1 year follow up was significantly correlated with level of cannabis use over the preceding year, whereby greater level of cannabis use was associated with worse performance. The authors concluded that individuals with psychotic disorders who show mild–moderate abuse of substances do not generally exhibit more cognitive impairment than those who do not use these substances.

In a double-blind, randomized, placebo-controlled trial, D'Souza et al. compared the effects on cognition of two doses (2.5 mg and 5 mg) of i.v. Δ⁹-tetrahydrocannabinol (THC) in 13 stabilized schizophrenia patients and 22 healthy controls [57, 58]. Participants were dosed on three occasions, at least 1 week apart. Cognitive assessment was commenced 30 min after THC or placebo administration. Compared to cognitive performance following placebo administration, the schizophrenia and control participants given THC demonstrated impairments in cognitive domains such as memory and attention. Moreover, the schizophrenia group performed more poorly than the control group in these domains. The authors concluded that THC is associated with transient exacerbation of cognitive deficits in schizophrenia, and that such data do not provide a reason to explain why schizophrenia patients use or misuse cannabis.

In a retrospective chart review of substance use, Kumra et al. examined measures of intellectual functioning in 28 treatment-refractory inpatient schizophrenia adolescents [59]. They reported that a history of cannabis abuse/dependence was associated with better full scale and verbal IQ scores.

Stirling et al. initiated recruitment of 112 individuals in 1987 who had experienced their first psychotic episode within the previous 2 years, 69 of whom sat a neuropsychological battery 10–12 years later, and documented those who had a history of cannabis use at the time of illness onset [60, 61]. After controlling age at onset of mental illness, those with a history of cannabis use performed significantly better than those without a history of cannabis use on measures of memory, verbal fluency, visual spatial construction, sequencing, and face recognition. Moreover, those who admitted to some level of sustained cannabis use during the follow-up period performed significantly better on several of these measures than those who had not used cannabis during the follow-up period.

Jockers-Scherübl et al. recruited a total of 78 participants [62]. Of these, 19 were schizophrenia participants and 18 were healthy controls who had consumed an average of at least 0.5 g cannabis per day for a minimum of 2 years (for the schizophrenia participants, this level of cannabis use was required prior to disease onset). There were also 21 healthy controls who had no history of cannabis abuse and 20 schizophrenia participants who had no history of substance abuse. The aim of that study was to examine the residual effects of long-term cannabis abuse on cognitive performance following 28 days abstinence (as screened by 4 weekly consecutive urine testing). Cognitive measures included those of memory, executive functions, attention, processing/psychomotor speed, visual spatial construction, and verbal comprehension. After controlling a range of confounding variables such as age, gender, nicotine abuse, and premorbid IQ, the healthy controls performed better than the schizophrenia group on all cognitive measures. Moreover, the schizophrenia participants with comorbid cannabis use performed significantly better than the non-users on a test of psychomotor speed, and when age of regular cannabis abuse was considered, those schizophrenia participants who had commenced abuse before the age of 17 years performed significantly better than those who had commenced abuse at ≥17 years on the same test of psychomotor speed, and on a test of cognitive flexibility.

Sevy et al. administered a comprehensive neuropsychological battery to 14 schizophrenia patients with a current diagnosis of cannabis abuse/dependence, 13 schizophrenia patients with no current or past diagnosis of substance or alcohol use disorders, and 20 healthy controls [63]. The neuropsychological battery contained measures of premorbid IQ, attention, working memory, processing speed, verbal learning and memory, selected tests of executive functions, and an assessment of emotion-based decision making (Iowa Gambling Task). After controlling years of education and premorbid IQ, both schizophrenia groups demonstrated impaired performance in all cognitive domains compared to the healthy controls. Furthermore, the schizophrenia patients with current cannabis abuse/dependence performed significantly better than the non-users on a test of immediate attention span.

These seven studies provide inconsistent evidence. This is likely to be at least, in part, attributable to methodological variability between the studies, as well as methodological limitations within each study, including poor control of confounding variables. These factors obfuscate the connection between cognition and comorbid cannabis use in individuals with schizophrenia.

Methodological limitations and confounds

Absence of an adequate control group

Four of the seven studies under review did not include a control group [26, 32, 59, 61]. This limits interpretation of their findings because without a normal control group for comparison, it cannot be determined if the cognitive performance of the schizophrenia group was frankly impaired (i.e. fell below the normal range of performance), or in fact, was within the normal range of performance.

Limited range of cognitive functions measured

Three of the seven studies administered a limited range of cognitive measures which did not adequately examine the range of functions that have been shown to be altered in both persons with schizophrenia and cannabis use. In one instance, cognitive assessment was restricted to global measures of intellectual functioning (i.e. Full Scale IQ, Verbal IQ, and Performance IQ) [59]. In two instances, assessment was limited to memory (e.g. immediate and delayed recall and recognition), some aspects of executive functions (e.g. cognitive flexibility and inhibition), and aspects of attention/processing speed (e.g. sustained attention and distractibility) [26, 58]. The remaining four studies used more extensive batteries that included measures of executive functions (e.g. cognitive flexibility and sequencing), memory (e.g. learning and immediate/delayed recall), face recognition, aspects of attention/processing speed (e.g. immediate attention, working memory, sustained attention, and motor speed), visual spatial abilities, verbal comprehension, and emotion-based decision making [32, 61–63]. However, no study to date has examined a range of other abilities in the executive functions and attention/processing speed domains (such as planning and organization and selective attention), which have been shown to be impaired in individuals with schizophrenia [73] and in cannabis users [74, 75]. Moreover, no study to date has assessed perceptual organization (i.e. the ability to combine stimulus components into object representations and make sense of distorted or fragmented perceptual information), which has also been shown to be impaired in both individuals with schizophrenia [76–78] and cannabis users [79–81].

Level of education and premorbid functioning

Certain studies have suggested that either better or preserved cognitive functioning observed among schizophrenia persons with comorbid substance use may be accounted for by higher premorbid intellectual functioning, level of education, social functioning, and/or socioeconomic status [49, 53, 55, 56]. Similarly, poorer symptomatic and functional outcomes observed among other persons with schizophrenia and comorbid substance use have been associated with financial and legal problems, unstable housing and homelessness, and family burden [65].

Liraud and Verdoux considered level of education as a potential confound [26], Stirling et al. and Jockers-Scherübl et al. controlled differences in premorbid functioning [61, 62], and Sevy et al. controlled both level of education and premorbid functioning when analysing differences in cognitive performance between cannabis users and non-users [63]. D'Souza et al. reported a significant difference between the schizophrenia and control groups with respect to education, but they did not specify if this confound was controlled for in their analyses [58]. The remaining two studies did not mention or consider level of education or premorbid functioning as potential confounds [32, 59].

Gender differences

Examples of gender differences in schizophrenia with respect to the neurobiological and neuropsychological substrates have been well documented in the literature [82]. Moreover, studies have indicated that male subjects predominantly constitute the psychosis population with comorbid substance use [65], have an earlier onset and more severe course of mental illness, poorer response to medications, a poorer premorbid history, and greater cognitive deficits [83].

Consequently, research in this area needs to consider potential differences in outcomes from data analysis, if there is an unequal proportion of male and female subjects between groups of substance users and non-users. Given that males predominantly constitute the psychosis population with comorbid substance use, one approach may be to concentrate on recruiting only male subjects, in order to sample persons who are most representative of the target population. Alternatively, studies may need to treat differences in the proportions of male and female subjects as a potential confounding variable, or indeed, specifically examine differences in cognitive performance between male and female individuals with schizophrenia and comorbid substance use. While four of the seven studies under review specified that gender was considered in their range of potential confounds [26, 59, 61, 62], two studies did not [32, 58]. In the study by Sevy et al. there was no difference in the proportion of male and female subjects [63].

Recruitment of individuals without a schizophrenia spectrum disorder

While six of the seven studies selected diagnostically homogenous groups, Liraud and Verdoux included two main diagnostic groups, namely, individuals with a schizophrenia spectrum disorder and persons with a mood disorder [26]. Participants were not analysed according to diagnostic grouping, and it was therefore unclear to what extent the difference in cognitive performance between the cannabis users and non-users reflected the profile of the schizophrenia group.

Limited range and conflation of cannabis use indices

All seven studies to date used only a single index to classify cannabis use. Moreover, this single index of cannabis use was either not clearly elucidated [61], was too restricted, and/or tended to be too broad. D'Souza et al. examined only the acute effects of THC on cognition, and failed to consider the effects of cannabis use beyond the acute phase of use [58]. THC and cannabinoids are highly lipid-soluble and accumulate in fatty tissues, reaching peak concentrations in 4–5 days. Because of the sequestration in fat, the tissue elimination half-life of THC is 4–12 days, and complete elimination of a single dose may take up to 30 days [75, 84–86]. Thus, the implications of cannabis use for cognition clearly extend beyond a single occasion of use, or the phase of acute intoxication. Conversely, Jockers-Scherübl et al. examined only the residual effects of cannabis in which participants had been abstinent for at least 28 days prior to cognitive assessment, thus, the effects of non-acute cannabis use in the interim period (e.g. use in the past week) were not investigated [62].

Liraud and Verdoux, Kumra et al. and Sevy et al. defined cannabis use solely with respect to abuse/dependence according to the DSM-IV [26, 59, 63, 87], while Pencer and Addington used a 5-point rating scale ranging from ‘none’ to ‘extremely severe’ to determine level of cannabis use over the preceding year [32].

A single index of cannabis use does not accurately reflect the variable and fluctuating level of cannabis use that may occur over time in the schizophrenia population. For instance, classifying cannabis use solely in terms of DSM-IV abuse/dependence, or solely in terms of the acute or long-term residual effects, fails to consider factors such as recency and frequency of use, which have been found to impact on cognition in the normal population [88]. In addition, it has been shown that individuals who use substances such as cannabis over a prolonged period can become sensitized to the drug whereby behavioural responses occur more intensely, at shorter latencies, and endure for longer periods at lower doses of the drug [89]. This admits the possibility that cannabis may affect cognition in schizophrenia when used at a less hazardous level than that required to meet DSM-IV criteria for abuse/dependence.

It is of concern also that in the analysis of any given index of substance use, other indices of substance use have been conflated, which masks the distinction between past and current use. Past and current cannabis use may have quite different effects on an individual's present cognitive performance, and it is unwarranted to subsume both patterns of use under a single grouping.

Only Liraud and Verdoux controlled current cannabis abuse/dependence when analysing the relationship between cognitive functions and lifetime cannabis abuse/dependence [26]. Other investigators did not specify which indices or patterns of cannabis use (e.g. recency of use, frequency of use) were controlled when analysing differences in intellectual functioning between individuals with and without a lifetime history of cannabis abuse/dependence [59], or a history of cannabis use prior to the onset of mental illness [61]. Conversely, some investigators did not control previous lifetime history of cannabis abuse/dependence, or other previous differences in patterns of cannabis consumption when examining the relationship between cognitive functions and more recent/current cannabis use [32, 61–63].

Absence of drug screening procedures

Liraud and Verdoux acknowledged they did not screen for recreational drug use prior to assessment [26]. In addition, three other studies did not specify drug screening procedures prior to cognitive assessment [32, 59, 61]. Some research indicates that reliability and validity of self-reported drug use is often inaccurate due to minimization, denial, or other factors [90–92]. Therefore, when investigating associations between non-acute effects of cannabis use and cognition in schizophrenia, it is important to screen and control for the acute effects of recreational drugs as required.

Medications

The effects of other psychoactive drugs on cognitive performance need to be considered in addition to the effects exerted by cannabis use. Virtually all patients with schizophrenia are on at least one psychotropic drug, the most common being an antipsychotic. Atypical antipsychotics have generally been found to improve cognitive performance compared to conventional antipsychotics [93–95]. Moreover, Kavanagh et al. identified medication side-effects as a correlate of cannabis misuse in individuals with psychosis [65]. The authors postulated that increased cannabis use, which adversely affects mental health, may lead to the need for increased dosage levels or use of depot (conventional) medications, leading, in turn, to increased medication side-effects. Consequently, class of antipsychotics needs to be considered as a potential confounding variable between subgroups.

Many people with schizophrenia are also on a regimen that may include anticholinergics, antidepressants, mood stabilizers, and sedatives. It is well known that each of these drugs can also affect brain functioning and cognition. For example, antidepressants have been shown to improve cognitive performance [96], while mood stabilizers, sedatives, and anticholinergics have been associated with impaired cognitive performance [97–99]. However, a large proportion of neuropsychological studies in schizophrenia with comorbid substance use have failed to consider their potential confounding effects.

Of the seven studies under review, Jockers-Scherübl et al. mentioned that there was no difference between the cannabis users and non-users in terms of class of antipsychotics prescribed, but the authors did not elaborate on the use of other psychiatric medications [62]. Sevy et al. reported similar levels of typical/atypical antipsychotics and anticholinergics between the cannabis users and non-users [63]. The remaining five studies did not specify if class of antipsychotics differed between the cannabis users and non-users, nor other types of psychiatric medications [26, 32, 58, 59, 61].

Psychiatric symptoms

Psychiatric symptoms (i.e. positive, negative, and depression/anxiety symptoms) can differentially affect cognition [100–103]. For example, some research has demonstrated that negative symptoms are more strongly associated with deficits in executive functions, memory, sustained attention, and sensory-motor function, and positive symptoms are not related to cognitive deficits [100], while other research has demonstrated that positive symptoms are indeed characterized by their own set of cognitive deficits [101]. Depression has also been characterized by neuropsychological deficits associated with abnormalities in regional brain function and, in particular, the medial prefrontal cortex [102], while state and trait anxiety are associated with altered memory and attention processes [103].

In view of this research, it may therefore be important for studies that examine the relationship between cognitive performance and factors other than symptoms (such as substance use), to control differences in symptom levels between substance users and non-users. Liraud and Verdoux did not report levels of psychiatric symptoms within their schizophrenia group [26]. There was no difference in positive and negative symptom scores between cannabis users and non-users in the studies by Jockers-Scherübl et al. [62] and Sevy et al. [63], therefore this was not an issue of concern, but specific levels of depression and anxiety were not mentioned. The remaining four studies under review did report varying levels of positive and negative symptoms between the cannabis users and non-users (but did not specify levels of depression and anxiety) [32, 58, 59, 61], however, it does not appear that these variations in symptom levels were controlled in the analyses of cognitive performance.

Early-age onset of psychotic illness

Age at onset of psychiatric illness is an important consideration given that many reports in the neuropsychological literature have shown that patients with early-age onset of psychosis (i.e. before 17 years of age) are likely to exhibit greater cognitive impairments than patients with later-age onset. Age at onset of illness has been shown to be associated with a history of obstetric complications, a higher rate of premorbid language and motor abnormalities, a poorer response to antipsychotic treatment, and an overall poorer prognosis [104]. Furthermore, cannabis use is higher among younger persons, which may also contribute to an earlier onset of psychotic illness [62]. Two of the seven studies under review considered age at onset of illness as a confound [26, 61], but this potential confound was not considered by two other studies [32, 58]. There was no difference in age at onset of psychosis between cannabis users and non-users in the studies by Jockers-Scherübl et al. [62] and Sevy et al. [63], and all participants in the study by Kumra et al. were only 15–18 years of age [59], so it is unlikely that the groups would have differed significantly in this respect.

Duration of mental illness

Cognitive impairments that are identified either prior to or at the onset of schizophrenia appear to be relatively stable throughout the course of the disorder, with minimal evidence of a progressive cognitive decline beyond the normal effects of ageing [34, 82, 105]. However, long-term use of psychotropic medications can affect regulation of dopamine [106], glutamate [107], and serotonin [108, 109], and hence alter neuronal function over the course of time. Given that duration of treatment is closely related to duration of illness, the latter should be considered as a potential confound in neuropsychological research.

Differences in duration of mental illness were most likely not an issue in three of the studies reviewed here [32, 59, 61], because participants in each study were quite young and/or were recruited soon after their first psychotic episode, and were therefore relatively homogenous in this respect. Sevy et al. specified that there was no difference in duration of mental illness between the cannabis users and non-users [63]. In contrast, Liraud and Verdoux, D'Souza et al. and Jockers-Scherübl et al. did not specify if they considered or controlled duration of mental illness in their more heterogeneous groups [26, 58, 62].

Early-age onset and duration of substance use

Chronic substance use can lead to changes in neuronal structure and composition by causing downregulation of receptors and decreased receptor binding. This, in turn, can result in reduced prefrontal neurotransmission [89, 110], which could adversely impact on cognition. Moreover, substances such as cannabis may be more toxic for the developing brain than for the mature brain [111]. Consequently, research that examines the relationship between substance use and cognition in schizophrenia needs to consider potential confounding effects of both duration of substance use and early-age onset of substance use on measures of cognitive functions. Such factors have largely not been taken into account in research of schizophrenia and comorbid substance use.

Of the seven studies under review, only Jockers-Scherübl et al. investigated differences in cognitive performance between those with early-age onset of cannabis use and later-age onset of use [62], but lifetime duration of cannabis use was not considered. None of the remaining six studies to date that have conferred attention to cannabis specified controlling age at onset or duration of substance use [26, 32, 58, 59, 61, 63].

History of other substance use

Earlier in this article, a brief review of the literature on the neuropsychology of other substances in schizophrenia was provided. That review demonstrated that other substances including alcohol, cocaine, stimulants, and polydrug use are associated with altered cognitive performance. Consequently, the potential lifetime effects of other substances need to be considered and controlled when investigating the impact of a single substance on cognition such as cannabis.

Control for the effects of use of substances other than cannabis has been generally poor. D'Souza et al. required that participants in their study had not met criteria for substance abuse (other than cannabis) in the past 3 months, or dependence in the past year, but did not elaborate on previous lifetime history of other substance abuse or dependence [58]. Liraud and Verdoux included participants with a history of alcohol abuse/dependence in their cannabis abuse group, but did not clearly specify if alcohol use was controlled in their analyses [26]. Pencer and Addington did not specify if participants who met criteria for current cannabis abuse/dependence and who also met criteria for current abuse/dependence of one or more other substances (e.g. alcohol and hallucinogens) were excluded from the analyses specific to cannabis, or if the effects of the other substances were controlled [32]. In the study by Kumra et al., 75% of the participants admitted to using alcohol in addition to cannabis, and one participant had a history of cocaine use [59]. However it was unclear what percentage of these participants met criteria for alcohol abuse/dependence, or if a history of alcohol and cocaine misuse was controlled. Stirling et al. made no mention of what other substances had or had not previously been used by participants in their group [61]. Jockers-Scherübl et al. stated that patients ‘with any drug abuse or dependence other than cannabis’ were excluded, but it is not clear of this pertained to current abuse/dependence or a lifetime history of other substance abuse/dependence [62]. Sevy et al. stated that seven of their schizophrenia participants had concurrent alcohol use disorders (three of whom also had cocaine use disorders and one of whom had an opioid use disorder), but did not specify if these other substance use disorders were controlled in the analyses for cannabis [63].

Nicotine and caffeine use

The prevalence of cigarette smoking is extremely high in schizophrenia [112–115], such that abnormalities in nicotinic acetylcholine receptor expression and function have been suggested to underlie the neuropathophysiology of the disorder [116–118]. It has also been suggested that people with schizophrenia smoke heavily to ameliorate cognitive impairments and psychiatric symptomatology [19, 119]. As discussed earlier in the present paper, there is general consensus that nicotine improves many aspects of cognitive functioning, including attention, working memory, processing speed, executive functions, and memory [8, 11–14, 16, 19–21]. In addition, studies have demonstrated cognitive deficits associated with smoking cessation and nicotine withdrawal in schizophrenia [4, 6, 12].

Caffeine is also a psychoactive substance and potential drug of abuse [120] that acts as an antagonist at adenosine receptors [121], inhibiting the release of other neurotransmitters, including dopamine, serotonin, acetylcholine, noradrenaline, and gamma-aminobutyric acid (GABA) [122]. There is general consensus that caffeine enhances performance of humans on tasks of attention and processing speed, and can alter memory performance [123].

Given the high prevalence of nicotine and caffeine consumption in schizophrenia [65, 121, 124, 125], it is difficult to exclude current consumers from research studies. Therefore, steps need to be taken to minimize the potential effects of nicotine and caffeine on cognition. Specifically, no nicotine intake within one hour of cognitive assessment should be permitted, given that the effects of nicotine on cognitive functions are only short-lived (i.e. last at most 10 min in humans) [126]. Similarly no caffeine consumption within one hour of commencing cognitive assessment should be permitted, given that the effects of caffeine begin during the first minutes after consumption, and attain a maximum 20–30 min later [123].

Only D'Souza et al. stipulated that all participants refrain from consuming caffeinated beverages within 2 weeks of commencing the study, and they did not permit nicotine use within one hour prior to cognitive assessment [58]. Jockers-Scherübl et al. did not permit nicotine use within 30 min of cognitive assessment, but use of caffeine was not mentioned in their study [62]. The remaining five studies did not consider or control caffeine and nicotine use [26, 32, 59, 61, 63].

History of acquired brain injury

The prevalence of acquired brain injury (ABI; e.g. head trauma and neurological conditions such as epilepsy) is significantly higher in schizophrenia than in other psychiatric populations, as well as the general population. This has led to a vast body of research on the relationship between psychosis and ABI [127–131].

Three of the seven studies appropriately excluded participants on grounds of ABI unrelated to schizophrenia [26, 32, 61]. However, the studies by Kumra et al., Jockers-Scherübl et al., and Sevy et al. did not indicate consideration of neurological history [59, 62, 63], and while the study by D'Souza et al. excluded participants ‘who were deemed clinically unstable as evidenced by recent or current hospitalization, homicidality, suicidality, and/or grave disability’ (p. 595), it is not clear as to whether a history of mild or moderate head injury (or even a history of a developmental disorder or intellectual disability) was encompassed in this exclusion criterion [58].

History of a developmental disorder or intellectual disability

Behaviours of a ‘pre-schizophrenia’ child or adolescent are characterized by attentional deficits, emotional lability, poor frustration tolerance, and disciplinary problems, which can readily be diagnosed as attention deficit hyperactivity disorder [132, 133]. In children there is also considerable overlap in symptom clusters and neurological signs associated with schizophrenia, schizotypal personality, and other developmental disorders including pervasive developmental disorders (e.g. autism) and learning disorders (e.g. dyslexia) [134–136]. Moreover, males with schizophrenia tend to be at higher risk than females for expressing developmental deficits prior to onset of mental illness [83].

There is therefore a high possibility that individuals with schizophrenia might be diagnosed as having a developmental disorder or intellectual disability during childhood or early adolescence, and in certain instances such a diagnosis may have been inaccurate. Consequently, neuropsychological research of schizophrenia should take one of two approaches. First, further evidence should be obtained to either substantiate or dismiss such a diagnosis if the researcher does not want to exclude potentially suitable participants and/or the sample size of the study cannot afford automatic exclusion. In contrast, if the sample size of the study can afford to exclude participants at the outset (regardless of whether or not such a diagnosis in childhood or adolescence was accurate), then automatic exclusion can take place.

Liraud and Verdoux, and Pencer and Addington excluded participants with a history of a developmental disability diagnosed in childhood (although it is not clear as to whether they screened eligibility for inclusion of participants who may have been misdiagnosed in childhood) [26, 32]. However, Kumra et al., Stirling et al., Jockers-Scherübl et al. and Sevy et al. did not specify excluding participants for this reason [59–63], and it is unclear if D'Souza et al. excluded individuals with a history of developmental disorder or intellectual disability [58].

Summary and directions for future research

In the present paper, a review of the research that has examined the relationship between substance use and neuropsychological functioning in schizophrenia is presented, and special focus was placed on cannabis. This review incorporated a discussion of the methodological limitations of the existing research, as well as a range of potential confounding variables that have not previously been considered or controlled.

Nicotine generally improves many aspects of cognitive functioning including attention, working memory, processing speed, executive functions, and memory [8, 11–14, 16, 19–21], although few studies have demonstrated no actual differences between smokers and non-smokers on a similar range of cognitive measures [2, 7, 14]. Alcohol has generally been associated with greater cognitive impairments [22–25, 27, 30, 36], although few studies have detected no differences between participants with and without comorbid alcohol use [26, 30, 31]. Comorbid cocaine users compared to non-users have demonstrated greater impairments in learning and memory [40–42] and motor functioning [44], yet in other studies they have demonstrated comparable or better performance in attention [38, 41, 42], executive functions [38, 39, 41, 43, 44], as well as motor speed [43] and memory [37, 38]. Amphetamines and stimulants/hallucinogens have led to improvements in tasks of reaction time, psychomotor speed, spatial working memory, executive functions, language production, and immediate learning [32, 45, 46]. Research on sedatives/benzodiazepines would suggest that these substances impair cognitive performance, specifically, in information processing [47].

With respect to other studies of substance use in schizophrenia, several have focused on ‘polydrug’ use whereby substances were not examined in terms of their individual effects, but rather, on their combined effects on cognition. A large proportion of that literature has reported better cognitive performance associated with substance use in schizophrenia in the domains of executive functions, motor speed, memory, and visuospatial ability [49, 51–54]. Other studies have found no differences at all between persons with and without comorbid substance use on selected aspects of cognition [48, 50, 51].

As can be seen from this overview of the literature, inconsistencies remain in the knowledge of how individual substances do or do not impact on cognitive functions in schizophrenia. In most instances the numbers of studies that have been conducted on each respective substance are still too small. Only approximately 15 studies have focused on alcohol, 10 on cocaine, minimal attention has been focused on benzodiazepines and other illicit drugs including amphetamines and lysergic acid diethylamide (LSD), and no studies to date have investigated caffeine. These substances are in need of investigation, especially given their prevalence of use. For example, in an epidemiological study conducted in Australia of the prevalence of substances used by 852 people with psychotic disorders [65], 69.8% reported current or prior tobacco use, 40.4% reported high levels of caffeine consumption, and 27.6% were identified with lifetime alcohol abuse or dependence. With respect to illicit drugs, cannabis was the most frequently used substance (40.9%), followed by amphetamines (17.8%), LSD (16.8%), heroin (14.3%), tranquillizers (13.6%), inhalants/solvents (12.3%), cocaine (12.3%), and phencyclidine (PCP) (10.0%). Other unspecified substances were reported by 13.7% of the sample.

Further to the fact that so few studies have been conducted on each respective substance, the differences in findings within each class of substance are also likely due to methodological variability between studies. For example, with respect to the literature on alcohol, some investigators have suggested that studies which recruit younger participants yield different results to studies recruiting older participants, because younger patients with alcoholism may not yet have incurred the detrimental effects of alcohol on cognitive functioning, whilst the additive effects of alcohol use over time on cognition are more evident in older patients [29]. Other studies have suggested that differences in cognitive functioning observed between schizophrenia persons with and without comorbid substance use may be accounted for by premorbid intellectual functioning, level of education, social functioning, and/or socioeconomic status [49, 53, 55, 56], factors that need to be considered and controlled in future research.

The literature on polydrug use is also in great need of further attention in terms of how different ‘cocktails’ of substances among polydrug users impact on cognition. For example, what differences in cognitive performance would be yielded between persons who consume alcohol plus one other illicit substance, versus persons who use two illicit substances? Which combinations of alcohol and/or illicit substances would yield better or compromised cognitive performance, and what are the additive effects on cognition of alcohol and/or illicit substances to two or more substances currently used? There is little known about these issues.

With respect to cannabis, given the very high rates of use and abuse in schizophrenia, coupled with the fact that only seven studies to date have focused on the relationship between cognition and cannabis use in this population, the connection between cannabis use and cognition in schizophrenia remains largely unclear and deserving of further examination.

Three of the seven studies under review found that cannabis use was associated with worse performance on tests of executive functions, memory, and attention [26, 32, 58], while the remaining four studies found that cannabis use was associated with better performance on tests of memory, executive functions, attention, psychomotor speed, and visual spatial construction [59, 61–63]. Again, this inconsistency is likely to be at least, in part, attributable to methodological variability between the studies, as well as methodological limitations within each study. For example, all seven studies used only a single index to classify cannabis use, which does not adequately reflect the variable and fluctuating level of cannabis use that may occur over time in the schizophrenia population. In three studies, cannabis use was defined solely with respect to abuse/dependence according to the DSM-IV [26, 59, 63]. In one study, only the acute effects of cannabis were examined [58], and in another study, only the residual, longer-term effects of cannabis were examined in participants who had been abstinent for at least 28 days [62]. Such indices of cannabis use fail to consider other factors such as recency and frequency of use, which have been found to impact on cognition in the normal population [88].

Future research therefore needs to examine the neuropsychological correlates of cannabis use in schizophrenia with regard to a wide range of prior limitations, and important confounding variables to determine a number of important issues.

First, research is needed to determine which indices of cannabis use are associated with better cognitive performance, and which indices of cannabis use are associated with worse cognitive performance in schizophrenia. The study by D'Souza et al. demonstrated that acute cannabis use/intoxication leads to impaired cognitive performance [58], while Jockers-Scherübl et al. demonstrated that residual effects of cannabis (following 28 days of abstinence) are associated with better cognitive performance [62]. Therefore the question is, at what point in time beyond the acute phase of use does cannabis begin to exert a beneficial impact on cognition? Is this beneficial impact observed within one day or week following most recent use? The study by Sevy et al. found that concurrent cannabis abuse/dependence according to DSM-IV criteria was associated with better cognitive performance [63], but a DSM-IV diagnosis does not stipulate recency, frequency, or even quantity of use. The authors stated that their concurrent users had a history of smoking approximately 0.5 g cannabis per day, ≥four days per week, but whether this was the pattern of use at the time of cognitive assessment, and whether or not the pattern of use was consistent across all participants at the time of assessment, remains unclear. Similarly, Stirling et al. stated that participants in their study who had admitted to some level of sustained cannabis use over the 10–12 year follow-up period performed better than those who had not [61], but it is unclear as to what constituted sustained use with respect to frequency and recency of use at the time of cognitive assessment.

Second, research needs to determine which neuropsychological functions are most enhanced and which are most compromised in relation to cannabis use in schizophrenia. In this respect a comprehensive range of cognitive functions in the domains of attention and processing speed, executive functions, memory, and perceptual organization need to be assessed, all of which are known to be altered in the independent areas of schizophrenia [137–142] and cannabis use [75, 79–81, 88, 143, 144].

Third, in the event that cannabis users should exhibit better or worse performance compared to non-users, it would be worthwhile for future research to establish whether such performance was classified in the ‘impaired’, ‘non-impaired’, or ‘above average’ ranges of performance relative to the normal population. There are well-established guidelines for determining these ranges of neuropsychological performance based on the normal population [145, 146].

Fourth, the issue of withdrawal from long-term cannabis use needs to be considered, especially when abstinence by heavy/daily users in the 24 hour period prior to cognitive assessment is required to avoid the acute/intoxicating effects of the drug. Until recently, researchers and practitioners have been reluctant to acknowledge the dependence potential of cannabis because of the lack of evidence for physiological withdrawal [147]. However, recent studies have indicated that a reliable set of symptoms occurs following cessation of cannabis use or oral THC administration. In two studies that compared heavy/daily cannabis users to former users and/or non-users [148, 149], current users reported greater levels of anger and aggression, irritability, anxiety, nervousness, restlessness, shakiness, negative mood, decreased appetite, weight loss, sleeping difficulty, strange dreams, stomach pain, and sweating. Most symptoms had their onset during the first day of abstinence [148], and peak effects were observed between two and six days [149]. In the context of these withdrawal symptoms, potential adverse effects on cognitive performance need to be considered when researchers want to investigate indices such as recency and frequency of use in schizophrenia.

If cannabis use (beyond the acute/intoxication phase of use) should be proven to exert a beneficial impact on selected aspects of cognition when a range of cannabis use indices are explored; a range of important potential confounding variables are considered; performance is evaluated against that of a control group; and a potential withdrawal syndrome is accounted for, this will have important implications for the treatment of cognitive impairment in persons with schizophrenia. Such treatment would involve the role of the cannabinoid system, for example, by way of an agonist or partial agonist on cannabinoid receptors (e.g. a cannabinoid).

Cannabinoids exert their effect by binding to specific endogenous cannabinoid receptors [74], known as the CB₁ and CB₂ receptors located in the Central Nervous System (CNS) and periphery respectively [150, 151]. The CB₁ receptors are widely distributed in the brain, but quite densely in the prefrontal cortex, particularly around the cingulate and superior frontal gyri [85, 152]. Functional imaging studies have demonstrated that the greatest increases in regional cerebral blood flow following cannabis use are in the anterior regions of the brain [153], and cannabinoids have been shown to mediate increases in prefrontal dopamine [152, 154], noradrenaline [155], acetylcholine [156, 157], and glutamate [152, 158]. In this context, cannabinoids have the capacity to enhance neuropsychological performance and also ameliorate the negative symptoms of schizophrenia, given that the cognitive impairments and chronic deficits associated with the illness are characterized by reduced blood flow, metabolic processes, and neurotransmission in the prefrontal cortex [159–163].

With regard to treatment for cognitive impairment by way of an agonist or partial agonist on cannabinoid receptors, the contribution of cannabis to the onset and course of schizophrenia needs to be considered. Specifically, CB₁ receptors are also located in subcortical regions including the basal ganglia (e.g. nucleus accumbens and globus pallidus), thalamus, hypothalamus, cerebellum, and brainstem [74, 86, 164–167]. Given that cannabinoids augment potassium-stimulated dopamine release in the mesolimbic system [154, 168], cannabis use can trigger or exacerbate the positive symptoms [169–172]. Studies have shown that schizophrenia patients with a history of cannabis abuse prior to disease onset experience their first episode at a significantly younger age, and those continuing cannabis use after onset of schizophrenia experience exacerbations more readily [62].

However, the onset and course of schizophrenia may not always be worsened by cannabis use. From a neurochemical perspective, the positive symptoms of schizophrenia are not only characterized by hyperdopaminergic states in subcortical regions, but also by elevated levels of other neurotransmitters including serotonin, acetylcholine, and noradrenaline in the hippocampus and subcortical regions [173–175]. In the CNS a fundamental action of cannabinoids is to inhibit long-term potentiation and neurotransmission from several types of neurons in the CNS. As such, the CB₁ receptor system is considered to play an important role in dampening neuro-excitability [150, 151, 176]. Evidence for the general inhibitory effects of cannabinoids have been found in various brain regions on neurotransmitters including serotonin, acetylcholine, and noradrenaline [151, 177, 178]. In this respect, cannabis and cannabinoids may play a role in exerting antipsychotic therapeutic efficacy for certain individuals with schizophrenia.

The notion that cannabis may have antipsychotic properties has been indirectly supported by observations that elevated levels of anandamide in the CSF of schizophrenia patients are negatively correlated with psychotic symptoms [179, 180], suggesting that anandamide elevation may reflect a protective mechanism or compensatory homeostatic adaptation to neurotransmitter imbalances associated with psychosis [180]. It is also of interest to note a case study reported by Zuardi et al. in which effective treatment of thought disturbance, hostility, and suspiciousness was undertaken for a patient with a cannabinoid, ‘cannabidiol’ [181].

In conclusion, future research is needed to investigate the relationship between individual substances as well as polydrug use and neuropsychological performance in schizophrenia. In particular, further attention on cannabis is required. The full range of limitations and lack of control over potential confounding variables exemplified in the seven studies on cannabis herein provides directions for future research, to enable valid conclusions to be drawn from data analysis. The effects of cannabis use on cognitive performance have important implications for treatment of cognitive impairment in persons with schizophrenia. There also exists a potential role of cannabinoids in the amelioration of negative symptoms, and antipsychotic therapeutic efficacy for a subgroup of the schizophrenia population.

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