Comorbid substance use disorder in schizophrenia: A selective overview of neurobiological and cognitive underpinnings


Correspondence: Patrizia Thoma, PhD, Department of Neuropsychology, Institute of Cognitive Neuroscience, Ruhr-University Bochum, Universitätsstraße 150, 44780 Bochum, Germany. Email:


Although individuals with schizophrenia show a lifetime prevalence of 50% for suffering from a comorbid substance use disorder, substance abuse usually represents an exclusion criterion for studies on schizophrenia. This implies that surprisingly little is known about a large group of patients who are particularly difficult to treat. The aim of the present work is to provide a brief and non-exhaustive overview of the current knowledgebase about neurobiological and cognitive underpinnings for dual diagnosis schizophrenia patients. Studies published within the last 20 years were considered using computerized search engines. The focus was on nicotine, caffeine, alcohol, cannabis and cocaine being among the most common substances of abuse. All drugs of abuse target dopaminergic, glutamatergic and GABAergic transmission which are also involved in the pathophysiology of schizophrenia. Current literature suggests that neurocognitive function might beless disrupted in substance-abusing compared to non-abusing schizophrenia patients, but in particular the neuroimaging database on this topic is sparse. Detrimental effects on brain structure and function were shown for patients for whom alcohol is the main substance of abuse. It is as yet unclear whether this finding might be an artifact of age differences of patient subgroups with different substance abuse patterns. More research is warranted on the specific neurocognitive underpinnings of schizophrenia patients abusing distinct psychoactive substances. Treatment programs might either benefit from preserved cognitive function as a resource or specifically target cognitive impairment in different subgroups of addicted schizophrenia patients.

AS MANY AS 50% of all schizophrenia patients fulfill the criteria for a dual diagnosis (DD) of schizophrenia and substance use disorder at some point during their lifetime.[1] The comorbidity affects both first-episode[2] and prodromal cases.[3] Apart from tobacco and caffeine, alcohol, cannabis and cocaine represent the most common substances of abuse,[4, 5] and the present review will focus on these. Compared to non-addicted schizophrenia patients, DD patients are typically male,[6] younger at illness onset,[7] show more extrapyramidal,[8] positive[6] and depressive symptoms,[9] fewer negative symptoms,[10] a lower quality of life,[11] a higher incidence of violent behaviour,[12] homelessness,[13] unemployment[9] as well as lower treatment compliance.[14] Elevated rates of substance use have been documented in non-psychotic first-degree relatives of patients with schizophrenia, for example, for nicotine, alcohol and cannabis use.[15-17] In turn, alcohol and cannabis abuse have been associated with more frontal lobe and thalamus abnormities and increased risk for developing psychosis in individuals with high familial risk for developing schizophrenia.[18, 19] As substance use disorder renders treatment more difficult and increases treatment costs,[20] further insights into the basis of substance use disorder and schizophrenia comorbidity are of relevance for the development of effective intervention strategies.


The purpose of the present work is to provide a brief, but selective overview of theoretical views as well as neurobiological and cognitive correlates of DD schizophrenia. PubMed- and Web of Knowledge-listed studies involving patients with a DD of schizophrenia and substance (ab)use, published since 1990, were taken into account, with a focus on nicotine, caffeine, alcohol, cannabis and cocaine as the most common substances of abuse. During the search, the following key words and variations (e.g. as noun vs adjective) were used in variable combinations: ‘dual diagnosis’, ‘schizophrenia’, ‘(comorbid) substance use’, ‘structure’, ‘volume’, ‘function’, ‘(f)MRI’, ‘cognition’, ‘neuropsychology’ and ‘executive’. These key words were also used in combination with the substances of interest ‘nicotine/smoke’, ‘caffeine/coffee’, ‘alcohol’, ‘cannabis’, ‘cocaine’. Only studies explicitly focusing on patients with a dual diagnosis of schizophrenia and substance (ab)use relative to single diagnosis schizophrenia patients and/or a healthy control group were considered. A selection of primarily the most recent studies mirroring the result pattern of the majority of studies for a given topic was included in the current manuscript in those cases where the literature on a given topic was too abundant (e.g. for nicotine/schizophrenia). In such cases, the interested reader will be referred to other reviews. In our work, we thus intend to provide a comprehensive but non-exhaustive, and thus not strictly systematic overview of various issues related to the diagnosis of DD rather than to carry out a systematic review of studies.

Epidemiological aspects

Individuals with schizophrenia are three times more likely to initiate smoking and five times less likely to quit smoking than the general population[21] with current prevalence rates amounting up to 80%.[22] Smoking increases the elimination of caffeine, and patients might consume more coffee to make up for this.[23] Although caffeine seems to be less frequently abused by schizophrenia patients than by people without schizophrenia (current prevalence rates of 59% vs 70%), heavy caffeine consumption – defined as ≥200 mg/day – is more frequent in schizophrenia and clearly associated with severity of smoking.[24] For the time period between 1996 and 2008, the median current prevalence of alcohol use disorders in patients with schizophrenia was reported to amount to 9.4% and the median lifetime prevalence to 20.6%, denoting a slight decrease as compared to previous reviews.[25] In a meta-analysis from the same time period estimating the rate of cannabis use disorder in schizophrenia patients, a median current prevalence of 16.0% and a median lifetime prevalence of 27% was observed.[26] Both alcohol and cannabis abuse have a detrimental effect on the clinical outcomes in schizophrenia. In the case of cannabis, it has additionally been discussed whether it can actually cause schizophrenia based on reports of a three- to sixfold dose-dependent increase in the risk for psychosis among cannabis users. It has been suggested that this is probably due to environment–gene interactions.[27-29] However, in a further meta-analysis, the conclusion was reached that ‘there is insufficient knowledge to determine the level of risk associated with cannabis use in relation to psychotic symptoms’.[30] For instance, although cannabis use seems to precede the onset of psychosis in most individuals with DD schizophrenia, other factors, such as demographic (male sex, worse socioeconomic status, better premorbid childhood social adjustment) and clinical variables (more severe positive symptoms) also seem to contribute to this association.[31] Thus, overall, the relation between cannabis use and schizophrenia is quite complex and the risk of developing psychosis due to cannabis use might be lower than expected.

Cocaine dependence has received considerably less attention than the former substances in association with schizophrenia, although the lifetime prevalence of cocaine use disorder has been found to range between 15% and 50% in the general population of schizophrenia patients (see Chambers et al.[32]) and to amount to 20% in first-episode schizophrenia patients.[33]

Taken together, among DD patients, prevalence rates for the substances of abuse considered in this article are high overall, but it remains difficult to determine to what extent the rates of abuse of a given drug are also due to interactions with other substances of abuse, as, for example, illustrated by the reciprocal relation between nicotine and caffeine consumption. Also, there may be considerable regional variability with regard to the lifetime prevalence rates depending on factors such as the availability of certain drugs and the legal situation in a given country, which might facilitate or discourage the use of a specific drug. For instance, in one study, a community-dwelling Australian sample of over 180 schizophrenia patients was characterized by a complete absence of cocaine abuse.[34]

Neurobiology of comorbid substance use in schizophrenia

Psychosocial determinants of substance use

Apart from the neurobiological and neurocognitive vulnerability factors that represent the focus of the present overview, a variety of psychological and social factors have been found to be associated with substance use in patients with schizophrenia. Substance-abusing individuals with schizophrenia were found to score higher on measures of sensation seeking and impulsivity than those without a comorbid substance use disorder[35, 36] and to show increased euphoric and stimulatory responses to the acute administration relative to healthy controls.[37] Motivational factors associated with substance use seem to largely correspond to those reported by non-psychotic drug users. Among the most common reasons, the desire to relax, to increase pleasure, to ‘get high’, to reduce negative affect and/or psychotic symptoms (e.g. hearing voices) and to be more sociable were reported as the most frequent subjective causes.[38] Stress is another psychological factor thought to play a role in the mediation of the psychosis/substance use comorbidity. Stress is co-determined by a variety of genetic (e.g. genetic vulnerability) and environmental factors (e.g. early life trauma) and may induce the affected individual to select maladaptive strategies – like using drugs – in an attempt to alleviate stress-associated symptoms. Increased premorbid sociability might augment the probability that a person will become exposed to drugs and subsequently consider drug use as a coping method.[39] Regular drug use will then lead to pathological alterations of dopamine-mediated reward pathways and of corticotrophin-releasing and hypothalamic-pituary-adrenal stress circuits in the brain. Typically, over time, allostatic processes involving a downregulation of the reward system and a sensitization of stress circuits will occur – thus worsening anhedonia and stress-associated symptoms after drug use is discontinued.[40-42] These changes may lead to the characteristic pattern of compulsory drug use associated with substance dependence and induce the individual to resort to even more dysfunctional coping responses in the long term (see Brady and Sinha[43] for a detailed account). Blanchard and colleagues[44] proposed an affect regulation model which integrates evidence on personality, stress and coping in individuals with DD schizophrenia. According to this model, personality dimensions like increased disinhibition/impulsivity and negative affectivity/neuroticism predispose DD individuals towards an increased reactivity to stress. In combination with poor interpersonal problem-solving skills and maladaptive coping strategies, this results in drug use as an attempt to regulate negative affect.

Theories on the co-occurrence of schizophrenia and substance use disorder

Several theoretical approaches have been proposed as explanations of the frequent co-occurrence of schizophrenia and substance abuse, partly taking into account evidence that has been presented in the previous paragraphs. First, according to diathesis stress models, drug abuse can act as an environmental stressor in vulnerable individuals and precipitate the onset of schizophrenia. This notion is supported by the fact that substance abuse has been linked to an earlier age at onset of psychosis.[45]

The opposite approach is adopted by the ‘cumulative risk factor hypothesis’[9] according to which schizophrenia patients are at a higher risk for substance abuse because of their poor cognitive abilities, low social, educational and vocational functioning and disadvantageous life circumstances. Although plausible, there is as yet no firm scientific proof for this assumption.[46]

According to the prominent self-medication hypothesis,[47] schizophrenia patients use drugs to reduce the symptoms of their disorder and to counter the side-effects of their antipsychotic medication. Although this theory cannot explain why in some cases drug abuse precedes the onset of psychosis, it is supported by findings that substance abuse can, at least in the short term, lead to an amelioration of negative symptoms and cognitive deficits in schizophrenia patients.[48]

In contrast to Khantzian's self-medication model, Blanchard's affect regulation model (see previous paragraph)[44] holds that stable personality traits, and not fleeting symptoms, are responsible for increasing long-term risk for abuse in a subgroup of schizophrenia patients. This allows for the possibility that drug use can precede psychosis and occur independently of symptom status.

A related account[32, 49] proposes that schizophrenia patients tend to use drugs to counteract dysfunction of the dopaminergic brain reward circuitry. In fact, altered reward processing has been extensively demonstrated in schizophrenia,[50, 51] and it has been suggested that schizophrenia patients tend to overvalue the positive consequences of drug use and devalue its negative consequences.[52]

Other authors hold that pre-existing brain abnormalities might predispose some individuals towards developing both psychosis and addiction. Based on a rodent model of DD schizophrenia, Chambers et al.[53] proposed that developmental temporo-limbic abnormalities and prefrontal dysfunction related to psychosis vulnerability on the one hand and drug abuse history on the other have detrimental effects within cortico-striatal circuits, further increasing the vulnerability towards the development and maintenance of a DD comorbidity.

To summarize, all of these models are in part supported by empirical evidence. One problem particularly for the theories which propose a specific temporal order of the onset of psychosis and the onset of substance abuse (e.g. the self-medication hypothesis) is the difficulty of retrospective assessment. Overall, the current consensus is that, most probably, different contributions of these factors play a role in the cause in individual cases.[54]

Neurotransmitter systems

All drugs of abuse act on neurotransmitter systems implicated in the pathophysiology of schizophrenia, either directly or indirectly. The three neurotransmitter systems most frequently found to be involved in schizophrenia are dopamine, GABA and glutamate. In particular, hyperactivity of the mesolimbic dopamine system has been linked to the positive symptoms and hypoactivity of the mesocortical dopamine system to the negative symptoms of schizophrenia. On the other hand, reduced activity in glutamatergic and GABAergic systems has also been discussed as a relevant process arising during the early stages of schizophrenia development.[55, 56]

Overall, current literature suggests that from a neurobiological point of view, two factors might contribute to the frequent co-occurrence of schizophrenia and substance use disorder: The first factor is a shared pathology of the relevant neurotransmitter systems, above all dysfunction of the dopaminergic brain reward circuitry.[57] Similarly, it has been hypothesized that malfunctioning of glutamatergic NMDA receptors might play a role in the schizophrenia/addiction comorbidity.[58] However, despite evidence of deficient glutamate neurotransmission in schizophrenia and addiction separately, the hypothesis has as yet not been addressed in humans suffering from DD schizophrenia. The second factor is an enhancement of the effects of the pre-existing pathophysiological vulnerabilities by the consequences of the drug consumption itself.

Nicotine exerts its effects by binding to nicotinic acetylcholine receptors, which are composed of alpha and beta subunits. Nicotine addiction is mediated by the high-affinity α4, β2-receptor subtypes in the dopamine-mediated reward pathways of the ventral tegmental area and of the nucleus accumbens (for more comprehensive reviews see Williams and Gandhi,[59] and Kumari and Postma[48]). Nicotine also acts as an agonist at α7 nicotinic acetylcholine receptors which are, for example, located in the hippocampus. Animal models of schizophrenia suggest that the action of nicotine at these receptor subtypes, which, in turn, interact with the glutamatergic system, might be responsible for improvements of working memory performance in schizophrenia patients, found following the acute administration of nicotine.[60]

It is not uniformly recognized in the literature that caffeine is a drug of dependence, although tolerance and withdrawal syndromes have been demonstrated both in animals and in humans. Caffeine has been found to stimulate dopamine release in the prefrontal cortex and in the caudate, but – in contrast to other drugs of abuse – not in the shell of the nucleus accumbens. Also, it lacks the relaxing effect of other drugs.[61] Caffeine primarily modulates acetylcholinergic and serotoninergic systems and increases norepinephrine secretion. Also, it acts as a non-specific adenosine receptor antagonist. Adenosine has neuromodulatory, sedative, anticonvulsant and anxiolytic effects, and caffeine seems to counteract these.[59]

Ethanol produces a wide range of effects on those neurotransmitter systems that are relevant to schizophrenia. Ethanol has been shown to activate GABAA-receptors while inhibiting glutamatergic NMDA and kainate glutamate receptors. It is also thought to facilitate dopamine release by activating dopaminergic neurons in the ventral tegmental area and thereby indirectly elevating dopamine transmission in the nucleus accumbens. There is additional evidence of ethanol-induced interactions between GABAergic and dopaminergic systems in the ventral tegmental area (see Pierce and Kumaresan[62]).

Changes of endogenous cannabinoids and cannabinoid receptors have been repeatedly shown to be associated with the development of schizophrenia.[63, 64] In addition, cannabinoid receptors interact with GABAergic transmission in both cortical and subcortical brain areas.[65] The main psychoactive ingredient of cannabis or marijuana is Δ9-tetrohydrocannibinol (Δ9-THC), which activates endogenous cannabinoid-1 (CB1) receptors. These can be found in high concentrations in the hippocampus, amygdala, cerebellum, basal ganglia (localized to the globus pallidus in particular) and in the prefrontal cortex.[66-68] Like ethanol, cannabis also enhances mesolimbic dopamine activity.[69]

Similarly, the most prominent effect of cocaine intake is an elevation of dopamine transmission, particularly in the nucleus accumbens. As a long-term effect, repeated cocaine administration was found to alter glutamate neurotransmission and to lead to behavioral sensitization to the effects of dopamine.[70]

Taken together, the action of virtually all drugs of abuse has a strong focus on the mesolimbic dopamine system as a final common pathway.[62]

Structural and functional brain changes in DD schizophrenia patients

Comparatively few studies have addressed brain structural changes associated with comorbid substance abuse in schizophrenia, and the available results are inconsistent.

Studies addressing the effects of smoking status on brain volumes in schizophrenia patients are sparse with one voxel-based morphometry study reporting relatively preserved frontotemporal grey matter volumes in smokers relative to non-smokers with schizophrenia.[71]

To the best of our knowledge, there are no published studies addressing the effects of caffeine on brain structure in schizophrenia.

As far as the effects of alcohol abuse, one study[72] reported no evidence of a higher rate of gross brain abnormalities (deep white matter hyperintensity signals, volume loss, ventricular enlargement or asymmetry) in the DD patients relative to the single-diagnosis patients. Other studies more consistently suggest alterations of brain structure in alcohol-abusing patients with schizophrenia, such as more pronounced shape abnormities in the hippocampus, thalamus, striatum and globus pallidus,[73] reduced cerebellar[74, 75] and pontine volumes[76] as well as disproportionately more pronounced prefrontal grey matter volume deficits[77] relative to schizophrenia patients without comorbid substance use and/or healthy controls. Detrimental effects of alcohol abuse on thalamic structures appear to be mitigated by the administration of typical neuroleptics in schizophrenia.[76] However, studies differed considerably in terms of the methodologies used to identify affected brain structures and with regard to the clinical and demographic characteristics of the patient samples. Findings reported by Schiffer et al.,[78] for instance, highlight the need to also consider the role of specific personality dimensions when interpreting the structural changes accompanying comorbid substance abuse in schizophrenia. In the sample investigated by these authors, severe grey matter volume and functional executive deficits were observed which were only partially exacerbated by comorbid addiction. However, there was a negative association between non-planning impulsivity and anterior cingulate and frontopolar grey matter volumes in the DD group suggesting that specific structure–function relations might be impaired when addiction co-occurs with psychosis, which could also be explained within the framework of Blanchard's affect regulation model (see above).

Regarding cannabis use, investigations have mainly centered on the question of whether cannabis has neurotoxic effects of brain structure in schizophrenia patients or whether premorbid alterations in brain structure put cannabis users at increased risk for developing schizophrenia. Szeszko et al.[79] investigated grey and white matter volumes in three prefrontal regions (superior frontal gyrus, anterior cingulate, orbitofrontal lobe) in young patients presenting with a first episode of schizophrenia with or without concurrent cannabis abuse. The DD group showed smaller volumes of the anterior cingulate grey matter relative to non-abusing schizophrenia patients and the authors argue that these structural changes might predispose young cannabis abusers with an increased risk for psychosis towards poor decision-making and risky behavior. DeLisi[80] concludes that such findings cannot be attributed to a presumed neurotoxic effect of cannabis itself but instead are more likely to reflect psychosis-related brain structure vulnerability. Accordingly, Cohen et al.[81] report small dose-dependent effects of juvenile cannabis use on cerebellar neuropathology in non-psychotic users but no evidence of an additional effect of cannabis use on cerebellar grey-matter pathology in first-episode schizophrenia. More pronounced white matter and grey matter deficits have been associated with early as compared to later cannabis use in patients with adolescent-onset schizophrenia. These deficits were not linked to cognitive impairments, which were of a similar magnitude in both patient groups as compared to controls.[82] In contrast to that, earlier findings from animal studies suggest that Δ9-tetrahydrocannabinol indeed might have neurotoxic effects on the frontal lobe.[83] In one of the very few investigations with a longitudinal approach, Rais and colleagues investigated the evolution of brain volumes and cortical thickness in 51 patients diagnosed with schizophrenia at onset and after 5 years in comparison with 31 healthy controls. Nineteen patients (ab)used cannabis, but no other illicit drugs. While cortical thickness did not differ at inclusion, excessive cortical thinning was found in patients relative to controls after 5 years with additional volume reductions in the dorsolateral prefrontal cortex, left anterior cingulate and left occipital lobe in the cannabis-abusing patient subgroup relative to the non-abusing patients. Similarly, this subgroup was characterized by a disproportionate decrease of grey matter volumes associated with an increase of ventricle volumes.[84-87]

Overall, the current database seems to support the emergence of structural brain deficits in association with (early) cannabis abuse. On the other hand, premorbid structural abnormities of fronto-temporo-cerebellar circuits might also render young cannabis users particularly vulnerable to the detrimental effects of schizophrenia on brain structure and function.

To the best of our knowledge, there are as yet no structural magnetic resonance imaging (MRI) studies focusing on cocaine-abusing patients with schizophrenia. However, studies involving non-psychotic cocaine abusers suggest that, like alcohol abuse, chronic cocaine abuse might entail volume reduction in fronto-cerebellar regions. This pattern was observed for prefrontal grey matter volumes in cocaine-dependent men, using a region of interest analysis of MRI brain scans, and for cerebellar grey matter volumes in cocaine-dependent men and women, using an optimized voxel-based morphometry approach.[88, 89]

Functional MRI (fMRI) studies addressing alterations in brain activity, as approximated by blood–oxygen-level-dependent (BOLD) signal changes, of patients with a DD of schizophrenia and substance abuse working on cognitive tasks are also sparse. Studies involving acute nicotine administration partly suggest improvement of cognitive function, for example, regarding smooth pursuit eye movements[90] with activity in the hippocampus, a region rich in cholinergic α7-receptors, decreasing after nicotine administration in schizophrenia patients and healthy controls but with the effect being dampened in the patients. In another study, administration of a nicotine patch enhanced performance on a dichotic listening two-back task and facilitated the connectivity of anterior cingulate – thalamic networks associated with task performance in schizophrenia patients to a larger degree than in controls who showed worse performance in the nicotine patch versus placebo comparison.[91] However, in the case of more complex cognitive functions, like sustained attention or working memory, normalization or enhancement of brain function is not always reliably observed.[92] Thus, overall, the effect of acute nicotine administration in patients with schizophrenia may depend on the task at hand. The effect of chronic as opposed to acute nicotine use on brain activity in schizophrenia patients may be a whole different story, but again, to the best of our knowledge, there is a dearth of studies addressing this explicitly, apart from conflicting reports on the issue of whether smoking status or daily caffeine intake does or does not confound the BOLD-signal underlying the processing of simple sensorimotor tasks significantly.[93-95]

Mancini-Marie et al.[96] assessed schizophrenia patients with and without comorbid substance use disorder (cannabis and/or alcohol) while they were watching emotionally distressing pictures from the International Affective Picture System. Surprisingly, DD patients rated their emotional experience as more intense and showed more preserved activation of the medial prefrontal cortex thought to play a prominent role in social cognition. In a follow-up study,[97] the authors had the same patient groups watch an emotional film with social content. Again, the DD patients reported a more intense emotional experience and activated the right superior parietal cortex as well as the left medial prefrontal cortex more strongly than single-diagnosis patients.

Overall, this evidence might provide support for the counterintuitive notion that, at least in some cases, DD patients, and polysubstance abusers in particular, show relative preservation of brain structures and superior socioemotional functioning, which might help them to lead the relatively complex life of a drug addict in the first place.[98] However, the emergence of structural and/or functional deficits in association with substance abuse may be modified by additional factors, such as age at onset of consumption (e.g. more detrimental effects of cannabis use when use is initiated during puberty), type of medication and personality factors (e.g. reported for alcohol abuse).

Cognitive changes in DD schizophrenia patients

Both schizophrenia and substance use disorder are associated with cognitive impairment,[99, 100] but little is known about the cognitive performance of patients suffering from both disorders. As presented above, all substances of abuse achieve their reinforcing effects via elevation of mesolimbic dopaminergic activity.[101] Given the strong involvement of the dopaminergic system in cognition[102] and its dysregulation in schizophrenia (see above), disproportionately severe cognitive impairment might be expected in DD patients. However, although some studies reported impaired executive function[103] in DD patients, many studies yielded a comparable cognitive status of DD and non-addicted schizophrenia patients in the domains of learning, visuospatial abilities, memory, attention, verbal fluency, and executive function,[11, 104-106] and some investigations even reported a superior performance of DD patients.[107-109] Most consistently, it was reported that speed of processing is relatively preserved in DD relative to non-addicted schizophrenia patients, irrespective of the substance of abuse, which might reflect better basic processing.[110] A major problem in the evaluation of these findings is the use of heterogenous neuropsychological test batteries. Particularly the multifaceted construct of executive control function has frequently been tapped by a single test only. Executive functions are superordinate cognitive control mechanisms involved in the flexible and adaptive regulation of goal-directed behavior, particularly in novel situations for which automated behavioral routines are not available.[111] They depend upon the functional integrity of fronto-subcortical circuitry, which has been shown to be compromised both in schizophrenia[112] and in substance abuse disorder.[113] Contemporary models view executive function as a complex construct with multitasking, working memory, cognitive flexibility and response inhibition representing the most important dissociable subprocesses.[114-116] Thoma and colleagues[117, 118] assessed the executive domains of cognitive flexibility, response inhibition, working memory and divided attention in polysubstance-abusing schizophrenia patients in comparison with single-diagnosis patients, non-psychotic depressive, non-psychotic alcohol-dependent as well as healthy controls. Although the schizophrenia groups showed poorer performance than the other groups, there was no evidence of an exacerbation of the cognitive deficits in the DD group. The picture did not change when only the subsample of patients (n = 11) who abused alcohol was analyzed. Executive function seems to be predicted by different clinical variables in schizophrenia patients with and without DD. While in DD patients, age and number of previous psychotic episodes predicted executive performance as indexed by a global composite score, age and negative symptoms served as predictors in the group of individuals with schizophrenia without substance use history. This also highlights the need to consider substance use as a relevant factor when assessing executive performance in schizophrenia.[119] While most DD patients abuse several substances at the same time, current literature suggests that it is also worthwhile considering the cognitive status of DD patients separately for the different substances of abuse which will present the focus of the following paragraphs.

Cognitive effects of nicotine and caffeine in individuals with schizophrenia

While the research focus for most drugs abused by schizophrenia patients clearly lies on the consequences of chronic use, for nicotine, the acute effects are more often considered than the chronic effects. Acute nicotine administration – either via cigarette smoking or skin patches/nicotine gums/subcutaneous injections – has been found to transiently ameliorate various sensory processing impairments associated with the genetic risk for schizophrenia, like deficient gating of the acoustically elicited P50 wave,[120] reduced prepulse inhibition of the startle response[121] as well as deviant smooth pursuit eye movement[122] and antisaccade[123] performance. Additionally, attention[124] and working memory[60] seem to be beneficially affected but not necessarily normalized, for example,[92] by nicotine consumption in schizophrenia patients. These improvements have been associated with stimulation of dysfunctional cholinergic α7-receptors in the hippocampus and in the anterior cingulate by nicotine. More recently, it has been suggested that the acute effects of nicotine consumption might differ from those of chronic nicotine consumption. While beneficial effects on symptoms and cognition might only be associated with acute nicotine administration, chronic nicotine use might lead to deterioration of these symptoms. Particularly when nicotine exposure starts in young years, prefrontal circuits might be pathologically altered as a consequence in young schizophrenia patients (see Winterer[125]). On the other hand, some reports suggest that non-smokers with schizophrenia might show poorer performance on measures of processing speed, response inhibition, sustained attention and risk/reward decision-making than current smokers with schizophrenia.[124, 126] Following nicotine withdrawal, schizophrenia patients seem to show relatively stronger impairments in attentional and executive function than healthy controls.[127] On the other hand, executive dysfunction has been associated with tobacco dependence treatment failure in smokers with schizophrenia.[128] Even considering the beneficial acute effects, obviously, smoking as such cannot be encouraged in patients, primarily due to the carcinogenic effects of the other compounds of cigarette smoke and other associated health risks. In contrast to alcohol, cocaine and cannabis, nicotine and caffeine are also being considered as pharmacological agents in the treatment of schizophrenia. The interested reader is referred to, for example, the work by Kumari and Postma[48] reviewing the effects of acute and chronic nicotine consumption on cognitive performance in more detail.

Although there is a considerable body of literature dealing with the beneficial and detrimental effects of caffeine on cognition and sleep in healthy individuals (see Snel and Lorist[129]), to the best of our knowledge, studies addressing these and other health-related issues of caffeine consumption in individuals with schizophrenia are lacking.

Cognitive performance of alcohol-abusing schizophrenia patients

Several studies found more pronounced cognitive impairment in alcohol-dependent relative to non-dependent patients with schizophrenia.[130-132] In a recent meta-analysis, Potvin et al.[110] concluded that in schizophrenia patients, alcohol abuse was mainly associated with lower working memory capacities, and several studies corroborated an additive effect of alcohol abuse and schizophrenia on delayed verbal memory, executive functioning and sensory gating.[133, 134] Overall, these results are in line with evidence of ethanol-induced neurotoxic effects on fronto-hippocampal circuits,[135, 136] which have been associated with the mediation of executive control and memory.[137] The detrimental long-term effects of alcohol on brain structure and function seem to manifest themselves more strongly in older schizophrenia patients, [130, 131, 138] and better cognitive functioning in younger patients may mask the effects of alcohol on cognition in schizophrenia in the initial stages.[139]

Cognitive performance of cannabis-abusing schizophrenia patients

Loberg and Hugdahl[140] identified 24 studies focusing on the cognitive performance of cannabis-abusing and single-diagnosis schizophrenia patients. In 15 studies, cannabis-using schizophrenia patients showed better cognitive performance than non-using patients, eight studies reported minimal or no differences in cognitive functioning between the two groups and only one study reported poorer performance on a decision-making task (Iowa Gambling task) of the cannabis-using group. Coulston et al.[141] reported a positive relation between the frequency and recency of cannabis abuse of schizophrenia patients and enhanced performance in the domains of attention and psychomotor speed.

Studies carried out after the review by Loberg and Hugdahl[140] was published confirm the general picture of better performance on measures of processing speed, verbal learning, memory, verbal fluency and executive function in cannabis-abusing schizophrenia patients relative to single-diagnosis schizophrenia patients.[142, 143] By contrast, Scholes and Martin-Iverson[144] reported an increased number of perseverative errors on a measure of cognitive flexibility in cannabis-abusing schizophrenia patients. This illustrates that cannabis abuse may sometimes be associated with at least minimal impairment of specific executive function domains in schizophrenia which might be associated with concurrent abuse of other substances. A recent meta-analysis which rigorously took into account only those studies focusing on schizophrenia patients abusing cannabis exclusively also denoted overall superior performance in cannabis-using patients.[145]

Although it has been suggested that the superior cognitive performance in the cannabis group might be a consequence of self-medication effects,[32] this explanation seems unlikely as cannabis abuse usually precedes the onset of psychosis. Several authors[140, 146] agree that cannabis abuse may pave the way for schizophrenia by mimicking the cognitive vulnerability – albeit at a more moderate level – that otherwise represents a risk factor for the development of psychosis. In this case, patients developing schizophrenia by this route might also have higher premorbid cognitive functioning, given that in later stages of the illness they still show better cognitive performance than schizophrenia patients without comorbid substance abuse. A recent meta-analysis by Yucel et al.[147] supports this idea. The authors found that the superior cognitive performance in cannabis-abusing relative to non-abusing schizophrenia patients was driven by a subgroup of cognitively less vulnerable individuals who only might have developed a psychotic disorder after an early initiation of cannabis use and might never have developed schizophrenia had they never consumed cannabis. These individuals might constitute a more ‘healthy’ group, not only in terms of cognitive functioning, but also in terms of better premorbid social adjustment.[39] It is possible that these patients become introduced to drug consumption because of their superior cognitive and social abilities enabling them to lead the complex life of a drug addict in the first place.[148, 149] However, as the authors of these studies uniformly pointed out, longitudinal investigations are required to confirm this notion.

Cognitive performance of cocaine-abusing schizophrenia patients

There are fewer investigations of the cognitive status of cocaine-abusing schizophrenia patients and they have produced inconsistent results. Relative to single-diagnosis schizophrenia patients, cocaine-abusing patients were found to show better processing speed,[150] impaired memory,[151-153] superior performance on measures of attention and executive function[152, 154, 155] or comparable deficits in memory, attention and executive function.[156] The memory impairment has been partly attributed to cocaine-induced blocking of long-term potentiation effects in the hippocampus and/or by the depletion of dopamine and serotonin following acute cocaine abstinence. Both impaired long-term potentiation, which is critical for memory consolidation, and alterations of dopamine and serotonin levels have been linked to memory impairments (see Bowie et al.[130]). Neuropsychological impairments in cocaine-dependent patients with schizophrenia might not necessarily recover with abstinence.[156, 157]

Summary: DD patients and cognitive impairments

There is as yet no clear empirical evidence for a specific cognitive profile of DD patients. Methodological problems, such as the frequent use of correlational statistics in previous studies and the inclusion of patients with a remote history of substance use disorder in the single-diagnosis group, do not allow any firm conclusions about the current database.

Overall, the superior or equivalent cognitive performance of DD patients who mainly abuse drugs other than alcohol and the impairments of alcohol-dependent schizophrenia patients are consistent with the findings of structural brain changes which suggest a potential relative preservation of brain structure in polysubstance abusing DD patients who do not mainly abuse alcohol and more pronounced structural deficits in alcohol-abusing DD patients, both patterns being observed stated relative to the results in healthy controls.

One further issue worth considering is the fact that the extent that substance use versus psychosis is driving cognitive impairment is often difficult to determine. Even if a mental disorder emerged first, a high level of subsequent substance abuse can be primarily responsible for detrimental effects on cognition. On the other hand, even with substance abuse emerging first, psychosis may exert a primary impact on deteriorating cognitive function. Timing the onset of substance use versus psychosis is also notoriously difficult, as both disorders tend to evolve gradually, involving unclear prodromal signs, and the associated deteriorating cognitive and social functioning tends to blur the picture even further.

Relation between antipsychotic medication and substance abuse in schizophrenia

As most antipsychotic drugs act as antagonists on dopaminergic D2 receptors, it has been proposed that schizophrenia patients might subconsciously resort to drug abuse to restore blocked dopamine function in the prefrontal cortex and in areas associated with reward processing. This might, in the short term, reduce extrapyramidal side-effects, secondary negative symptoms and cognitive dysfunction associated with medication-induced D2-blockade. However, in the long term, this is likely to backfire and to exacerbate exactly these symptoms as a consequence of neuroadaptive mechanisms, like, for example, reduced dopaminergic transmission, that have been associated with chronic drug exposure.[40]

In line with this, typical antipsychotic agents like haloperidol, which usually involve a strong D2-blockade, have not proved helpful in the treatment of DD patients or have even been found to be associated with an increased rate of drug abuse in this sample of patients (e.g. Meszaros et al.[158]). Some of the atypical antipsychotics like clozapine, on the other hand, have been related to a decrease of substance abuse in patients with schizophrenia. The effects might vary according to the type of substances abused and depending on the specific antipsychotic agents. However, the database is still sparse and mostly focuses on one or two of the most commonly prescribed antipsychotic agents.[46] Conversely, substance use can limit the treatment effects of some antipsychotic agents. Smoking for instance, has been found to decrease plasma levels of common antipsychotics by approximately one-third, leading to a situation where heavy smokers can be undertreated with a recommended dose of a given antipsychotic agent. This and similar evidence highlights the need for carefully adapting the doses of antipsychotic medication to the individual case or to switch to drugs whose plasma levels are not affected by tobacco consumption, like, for example, apiprazole (see Winterer[125]).

However, it is not only the effect of antipsychotic agents that has to be considered in the treatment of DD patients but also the effect of drugs usually administered in an attempt to directly treat the concurrent substance use disorder. One such drug is acamprosate (calcium acetyl homotaurinate), which is usually prescribed to support postwithdrawal maintenance of alcohol abstinence. No adverse effects of the use of acamprosate on cognition could be detected in a recent study suggesting that it can be administered safely in DD patients.[159]

As the complex effects and interactions of the various psychopharmacological treatments are far beyond the scope of the current overview, the interested reader is referred to the review by Wobrock and Soyka[160] for detailed treatment recommendations addressing comorbid substance use in schizophrenia. In accordance with the evidence referenced above, the authors recommend second-generation antipsychotics in combination with early antidepressant treatment and anti-craving agents like naltrexone, depending on the psychopathological characteristics of the individual patient. In terms of psychosocial treatment, motivational interviewing, cognitive behavioral therapy, contingency management and family interventions have proved successful, but the different treatment elements have again to be tailored to the individual needs of each patient. Lubman et al.[161] deplore a lack of rigorously conducted randomized controlled treatment trials in this area and in investigations of psychopharmacological treatment in DD schizophrenia.

Limitations of current research on DD schizophrenia patients

There are several factors limiting the interpretation of current findings: for instance, diagnostic uncertainties and inconsistencies across studies are manifold. In clinical practice, it is difficult to disentangle drug-induced psychosis from schizophrenia with comorbid substance use disorder, as they might represent distinct diagnostic entities with specific neurocognitive profiles. Substance abuse and substance dependence have rarely been clearly defined nor has their duration been specified. Also, active users and thus acute effects of the drugs in question were investigated in some studies; other studies only included chronic users who had abstained from using the drug for at least several weeks. The effects of substance abuse seem to be more detrimental in older age and more pronounced when the substance of abuse is alcohol. However, in the studies involving abuse of substances other than alcohol, patients were on average younger than in studies focusing on alcohol-dependent schizophrenia patients. Urine drug screening was rarely part of the assessment and there was poor control of lifetime abuse of other drugs and of tobacco smoking. In a number of studies, only a limited range of cognitive functions have been assessed. As depression frequently co-occurs with both schizophrenia[162] and substance use disorders,[163] evaluation of depressive symptoms in all clinical groups should help to determine their contribution to cognitive dysfunction. Groups are also quite heterogeneous in terms of sex, positive and negative symptomatology, chronicity, age of onset of substance use and the nature of the substances abused. Up to now, brain imaging studies assessing brain structure and function in substance-abusing schizophrenia patients are sparse although they might shed light on the brain-behavior correlations in question. The picture is complicated further by the high co-occurrence of other Axis-I and Axis-II disorders on top of the substance use and schizophrenia. An increased risk for developing a comorbid substance use disorder in association with schizophrenia has for instance been related to the concurrent occurrence of panic attacks,[164] post-traumatic stress disorder,[165] childhood conduct disorder and adult antisocial personality disorder.[166] Severity of depressive symptoms seems to be increased in DD schizophrenia patients relative to non-addicted individuals with schizophrenia – although this may be partially confounded by an overlap with negative symptoms – and by sex, as male schizophrenia patients seem to experience more depressive symptoms and more DD patients are male.[167] However, the cross-sectional nature of the studies reporting these comorbidities does not allow us to determine causal relations between the different factors. It is possible that additional psychiatric symptoms increase the risk for developing a comorbid substance use disorder or, alternatively, that substance use may increase the risk for emergence of further psychiatric disorders in schizophrenia. There is also a need for longitudinal studies as a way forward in determining pathways to cognitive impairments and, albeit difficult, trying to disentangle the effects of the onset of psychosis versus substance use disorder. This might also more reliably reveal the effects of substances, such as cannabis, on the cognitive functioning of individuals who may initially have shown superior functioning.

Summary of Conclusions

Although interest in schizophrenia patients presenting with a comorbid substance use disorder has risen in recent years, more research is still warranted with respect to the distinct profiles of neurobiological and cognitive changes in schizophrenia patients with different patterns of substance abuse. Treatment programs should be tailored to suit the specific needs of the distinct subgroups of patients abusing psychoactive drugs. Future research should primarily take the following general points into account: (i) Most importantly, there is a need for longitudinal studies to allow for a delineation of the effects of the constituent factors adding to the emergence of the psychosis/substance use comorbidity and to be able determine how neurocognition and psychosocial characteristics change in the course of illness. (ii) The adherence to strict diagnostic guidelines is of primary importance in order to ensure that discrepant findings between studies (e.g. regarding the presence or absence of neuropsychological impairment) are not merely attributable to different clinical characteristics of the patient groups in question. (iii) The specific effects of the different substances of abuse and their interactions when consumed have to be addressed more systematically. (iv) Neuropsychological test batteries have to target and delineate the concepts of interest (like executive function) more specifically. (v) Personality characteristics, psychopathological features, severity, duration and frequency of drug use and the specific motivations for substance use are among the factors that should not be neglected when it comes to interpreting the findings from the various studies.

It remains to be acknowledged that the present overview is non-exhaustive and not systematic in a strict methodological sense, which leaves open the possibility that some of the conclusions might be affected by a subjective bias of the authors.


P. Thoma received conference travel support from GlaxoSmithKline in 2008, 2010 and 2011, which was not related in any form to the currently submitted work. Patrizia Thoma performed a search of the relevant articles, drafted the first version of the manuscript and revised the submitted and final version. Irene Daum contributed to the design of the review article, critically revised the first draft of the manuscript and approved the submitted and final version.