Review
What are the specific vs. generalized effects of drugs of abuse on neuropsychological performance?

https://doi.org/10.1016/j.neubiorev.2010.04.008Get rights and content

Abstract

Most substance abusers simultaneously use and abuse more than one substance, even when there is a clear drug of choice. This pattern creates a great challenge in relating neuropsychological findings in drug users to a certain drug. This review aims to: (i) discuss results from neuropsychological studies using different research methodologies that may improve our understanding of specific vs. generalized effects of different drugs on neuropsychological performance; and (ii) determine which neuropsychological mechanisms are impaired in the same way by the use of different drugs, and which impairments are specific to certain substances, including cannabis, psychostimulants, opioids and alcohol. We review evidence from human studies in chronic substance abusers using three methodologies: (i) studies on ‘pure’ users of one particular substance, (ii) studies that methodologically control the effects of drugs co-abused, and (iii) studies contrasting subgroups of polysubstance users with different drugs of choice. Converging evidence from these approaches indicates that all the drugs studied are commonly associated with significant alterations in the neuropsychological domains of episodic memory, emotional processing, and the executive components of updating and decision-making. However, there is evidence of a greater reliability in the association of certain substances with specific neuropsychological domains. Specifically, there are relatively more robust effects of psychostimulants and alcohol use on impulsive action and cognitive flexibility, of alcohol and MDMA use on spatial processing, perceptual speed and selective attention, cannabis and methamphetamine on prospective memory deficits, and cannabis and MDMA on processing speed and complex planning. The magnitude of both generalized and specific neuropsychological effects is overall attenuated in samples achieving long-term abstinence, but there are persistent psychostimulant-related effects on updating, inhibition, flexibility and emotional processing, and opioid-related effects on updating and decision-making.

Introduction

The use of psychoactive substances is associated with neuropsychological deficits in mechanisms related to emotion, memory and executive functions. Impairment of these functions does not only interfere with the cognitive performance of drug users in a general manner (thus influencing their quality of life, their academic/work performance, or their ability to receive cognitive treatment), but they also affect the core aspect of addiction: the tendency to continue drug use despite its increasingly negative consequences. The interaction between: (1) motivational and memory mechanisms, which amplify the reinforcing value associated with the substance, and (2) poor performance of the executive control mechanisms, in charge of regulating automated behaviors, is at the root of the dependence on different drugs (Bechara, 2005, Garavan and Hester, 2007, Goldstein and Volkow, 2002, Verdejo-García and Bechara, 2009). Therefore, one possibility is that all drugs of abuse produce generalized impairments in these neuropsychological mechanisms. In this case, the specific neuropsychological effects of a substance (e.g., a stimulant) and those produced by another substance (e.g., an opioid) would overlap, even though their pharmacological effects are quite different. This possibility would reduce the scientific interest in studying a certain substance in isolation, and it would support the explanatory power of studies performed on polysubstance users (which are most of those found in the literature). The alternative possibility is that each substance, depending on its characteristic pharmacological effects, produces a specific neuropsychological profile differing from the neuropsychological profiles of other drugs. This hypothesis would reduce the explanatory value of the research on polysubstance use, as it would mask the characteristic effects of each drug on neuropsychological performance. Although studies with animals have elegantly addressed this question, research with humans is clearly hindered by the difficulties to select ‘pure’ users of one drug only. In spite of this limitation, some studies have dealt with the problem by sampling populations with cultural peculiarities (Fishbein et al., 2007, Halpern et al., 2004), investigating substances with a relatively low co-abuse rate (e.g., alcohol or cannabis) (Fein et al., 2004, Fried et al., 2005), or controlling polysubstance use through methodological designs or statistical techniques (Bolla et al., 2000, Morgan, 1999, Morgan et al., 2006). The objectives of this review are: (1) to critically examine neuropsychological studies carried out on drug users from both approaches and (2) to determine which neuropsychological mechanisms are impaired in the same manner by the use of different drugs, and which deficits are specific to certain substances. Given these fundamental objectives, this will be a systematic review analyzing both specific and general neuropsychological effects of the abuse of cannabis, stimulants (cocaine and methamphetamine), 3,4-methylenedioxymethamphetamine (MDMA; “Ecstasy”), opioids (heroin and methadone) and alcohol on mechanisms of emotion, memory and executive control. Due to the inherent diversity of the concept of “executive control”, the review will be approached from a multi-component perspective, encompassing mechanisms of updating (including tests of working memory, controlled access and production of information and reasoning), inhibition (including tests of impulsive action—response inhibition and self-regulation, and impulsive choice—reflection-impulsivity, time estimation, delay discounting), flexibility (including attentional/set-shifting and reversal learning tests) and decision-making (including probabilistic choice and gambling decision tests) (Verdejo-García and Pérez-García, 2007). We present a brief definition of each of the neuropsychological domains addressed in the review, and a list of the neuropsychological tests typically used to measure them, in Table 1. It is important to mention that dysfunctions in some of these neuropsychological domains (e.g., inhibition or decision-making) have been proposed to precede initial drug use and to predispose certain individuals to being attracted to different drugs (Dalley et al., 2007, Verdejo-García et al., 2008); therefore, although this review is focused on neuropsychological effects of drugs use, we prevent ourselves from providing strong causal assumptions throughout the text.

In the first part of the manuscript, we shall briefly present relevant evidence about specific effects of these substances based on animal and pharmacological studies using controlled drug administration in healthy individuals. In the second part of the manuscript, we perform a systematic review of neuropsychological studies investigating specific vs. generalized effects of these drugs through three different research approaches that can shed light on our objectives: (i) studies on selected samples of ‘pure’ users of certain substances, (ii) studies with methodological control of the effect of the co-abuse of drugs other than the one of interest, and (iii) studies on polysubstance users with different main drugs of choice. Finally, we will integrate the results, in order to provide insights about which skills are affected indistinctly by all drugs and which skills are differentially affected by specific substances taking into account the time line of drug effects (i.e., acute, short-term, mid-term and long-term).

Section snippets

Methods

First, in Section 3, we narratively review relevant findings from animal and human controlled drug-administration studies selected by the authors with the aim of providing a background about the selective pharmacological/neuropsychological effects of each of the individual substances studied.

For Sections 4 Studies on samples of relatively ‘pure’ users, 4.1 Cannabis, 4.2 Psychostimulants, 4.3 MDMA (‘Ecstasy’), 4.4 Opioids, 4.5 Alcohol, 4.6 Summary, 5 Methodologically controlled studies for

Cannabis

Cannabis produces its psychoactive effects in the brain by acting on the CB1 receptors. Animal evidence showed that the cannabinoid receptors are distributed in the brain in a similar way to the dopaminergic receptors, with high concentrations in the basal ganglia and hippocampus, although the highest concentrations of cannabinoid receptors are found in the cerebellum (Herkenham, 1992). Human imaging techniques have shown that the human brain also contains high densities of cannabinoid CB1

Studies on samples of relatively ‘pure’ users

In spite of the fact that they are quite difficult to conduct, since most drug users tend to use several substances simultaneously, studies on samples of mostly ‘pure’ users of one specific substance are ideally suited to reveal the neuropsychological effects of that particular substance.

Methodologically controlled studies for studying specific effects

The obvious difficulties in recruiting samples of ‘pure’ users of any drug have favored the development of studies that attempt to control for polysubstance use through methodological strategies. One of the most commonly used designs for this purpose is that in which researchers compare one group of polysubstance users of the drug of interest with a comparison group of polysubstance users of the same drugs except for the drug under study. In this way, potential differences between the two

Neuropsychological studies in polysubstance users with different principal drugs of choice

Most drug users are frequently users of more than one substance and even take more than one substance in the same session (National Institute of Drug Abuse, 1998). Regarding cocaine, Robinson et al. (1999) found that subjects who use this substance usually develop dependence on many other substances of a sedative nature, usually alcohol (Miller et al., 1990, Rounsaville et al., 1991). On the other hand, cocaine and heroin are often consumed together using freebase administration. Some studies

Correspondence between methodologies and quantitatively-derived estimations of neuropsychological effects of drug use: insights on generalized vs. specific effects

This final section provides an integration of the review's findings through the quantitative evaluation of the results obtained by the different research methodologies about the issues of (i) generalized vs. specific neuropsychological effects of different drugs of abuse (see Table 6), and (ii) which of these neuropsychological effects are durable across abstinence (see Table 7). In the text and tables of this section, we mainly highlight findings that achieved an average medium effect size

Acknowledgements

This work is supported by the Spanish Ministry of Science and Innovation (MICINN), under the FPU national plan (grant ref. AP 2005-1411) and Research Project SEJ 2006-08278, and the Junta de Andalucía through the Research Project P07.HUM 03089. This study complies with current Spanish law and all international ethical guidelines for human studies.

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