Elsevier

NeuroImage

Volume 26, Issue 2, June 2005, Pages 480-492
NeuroImage

Neural substrates of faulty decision-making in abstinent marijuana users

https://doi.org/10.1016/j.neuroimage.2005.02.012Get rights and content

Abstract

Persistent dose-related cognitive decrements have been reported in 28-day abstinent heavy marijuana (MJ) users. However, the neural substrates of these decrements in cognitive performance are not known. This study aimed to determine if 25-day abstinent MJ users show persistent dose-related alterations in performance and brain activity using PET H215O during the Iowa Gambling Task-IGT (a decision-making task). Eleven heavy MJ users and 11 non-drug users participated. The MJ group resided in an inpatient research unit at the NIH/NIDA-IRP for 25 days prior to testing to ensure abstinence. A dose-related association was found between increased MJ use and lower IGT performance and alterations in brain activity. The MJ group showed greater activation in the left cerebellum and less activation in the right lateral orbitofrontal cortex (OFC) and the right dorsolateral prefrontal cortex (DLPFC) than the Control group. When the MJ group was divided into Moderate (8–35 joints/week) and Heavy users (53–84 joints/week), the Heavy MJ group showed less activation in the left medial OFC and greater activation in the left cerebellum than the Moderate group. However, brain activity and task performance were similar between the Moderate MJ users and the Control group, suggesting a “threshold effect”. These preliminary findings indicate that very heavy users of MJ have persistent decision-making deficits and alterations in brain activity. Specifically, the Heavy MJ users may focus on only the immediate reinforcing aspects of a situation (i.e., getting high) while ignoring the negative consequences. Thus, faulty decision-making could make an individual more prone to addictive behavior and more resistant to treatment. Finally, it is unclear if these neurologic findings will become progressively worse with continued heavy MJ use or if they will resolve with abstinence from MJ use.

Introduction

In 2002, marijuana (MJ) was the most commonly used illicit drug, with 14.6 million current users in the United States alone. Of these 14.6 million current users, 4.8 million users smoked MJ on 20 or more days a month (Overview of Findings from the 2002 National Survey on Drug Use and Health, 2002) and Americans spent 10.4 billion dollars on MJ during that time (Office of the National Drug Control Policy. National Drug Control Strategy, 2004). Although MJ is often considered more benign than other drugs, this assumption may need modification. In the past decade, the use of MJ has remained relatively constant; however, the prevalence of adults in the United States with a diagnosable MJ use disorder (i.e., MJ abuse or dependence) has increased significantly especially in women, and in Black and Hispanic men (Compton et al., 2004). These results suggest that the addiction potential of MJ may have increased. Nevertheless, it has been advocated that MJ has benefits that outweigh any adverse consequences when used to alleviate untoward symptoms of a variety of medical conditions (The National Organization for the Reform of Marijuana Laws (NORML), 1997). Thus, with worldwide changes in the regulation of MJ for medicinal applications, more research is mandatory to empirically determine the risks and benefits of marijuana. From a neurotoxicologic perspective, potential detrimental effects of MJ should first be determined in a group using heavy amounts of MJ prior to investigating individuals using smaller amounts of MJ for medicinal purposes.

Residual neurobehavioral effects associated with heavy recreational use of MJ include subtle decrements in memory, executive functioning, psychomotor speed, and manual dexterity (Block and Ghoneim, 1993, Bolla et al., 2002, Fletcher et al., 1996, Pope and Yurgelun-Todd, 1996, Pope et al., 2001, Solowij, 1998, Solowij et al., 2002). However, because the period of abstinence prior to testing in most of these studies was only 12–72 h, it is difficult to determine if many of the published results were due to persistent alterations in brain functioning, drug residues in the brain, or withdrawal symptoms (e.g., sleep disturbance, anxiety, irritability) (Haney et al., 1999). In the few studies examining 28-day abstinence MJ users, the results have been equivocal. One study concluded that the cognitive deficits appear reversible after 7 days of abstinence (Pope et al., 2001), whereas another study concluded that decrements in cognitive performance were persistent after 28 days of abstinence and were related to the number of joints smoked per week (Bolla et al., 2002). Demographic differences in the study groups are likely responsible for the discrepant findings. For example, higher functioning individuals may be less behaviorally susceptible to subtle changes in brain function (Bolla et al., 2002).

Most neuroimaging studies investigating the effects of MJ on brain activity have involved the acute administration of delta-9-tetra-hydrocannabinol (THC), one of the active ingredients in MJ. For example, positron emission tomography (PET) imaging studies in humans have found both increased and decreased metabolism in the prefrontal cortices [anterior cingulate (ACC), orbitofrontal (OFC)], temporal cortices, and the cerebellum (Mathew et al., 1997, Mathew et al., 2002, O'Leary et al., 2002, O'Leary et al., 2003, Volkow et al., 1991, Volkow et al., 1996). More specifically, THC administration caused dose-related increased activity in the OFC, insula, cingulate gyrus, and subcortical structures, primarily in the right hemisphere (Mathew et al., 2002, Mathew et al., 1997).

In neuroimaging studies without the direct administration of THC, persistent alterations in brain functioning have been reported in abstinent MJ abusers (Block et al., 2000). These alterations include reports of increased and decreased activity during resting conditions as well as during performance of cognitive activation tasks (Block et al., 2002). The brain regions most frequently reported to be affected by MJ use include the prefrontal cortex, the hippocampus, and the cerebellum (Block et al., 2000, Block et al., 2002, Wilson et al., 2000). Dysfunction of any of these brain regions may disrupt cognitive abilities (i.e., decision-making, executive function, memory), thus making it difficult for the heavy MJ user to refrain from drug use. It is also likely that the presence of these abnormalities might substantially hamper any potential therapeutic benefits of either behavioral or pharmacological treatments to these patients.

Publications from neuroimaging studies investigating MJ users during abstinence are very limited. In addition, few of these studies have used cognitive activation during brain image acquisition. Moreover, the periods of abstinence prior to testing have generally been reported to be shorter than 72 h. Furthermore, because decision-making and its neurologic substrates have not been thoroughly studied in abstinent MJ users, it has been difficult to develop heuristic models of the long-term effects of the drug on the brain. Decision-making as a cognitive process is paramount for the development of adaptive behaviors. It involves the evaluation of whether a response or behavior will illicit reward or punishment (i.e., the operation occurring after coding of the stimulus features) (input) and the selection of the behavior determined to be optimum prior to acting on that behavior (output) (Clark and Robbins, 2002, Ernst et al., 2002). This process is dependent on emotional and motivational coding, working memory, conflict monitoring and resolution, as well as response activation and inhibition. Good decision-making involves primarily a right hemispheric neural network (Ernst et al., 2002) due, in part, to the emotional processing of the rewards, punishment, and risks. Because it is posited that substance abusers may have dysfunctional decision-making, this cognitive domain has been studied and found to be faulty in polysubstance abusers (Grant et al., 2000), cocaine users (Bartzokis et al., 2000, Bolla et al., 2003), methadone maintenance patients (Mintzer and Stitzer, 2002), and marijuana users (Whitlow et al., 2004). Thus, when taken together, these observations support the contention that substance abusers may indeed choose immediate gratification of their cravings without careful consideration of negative consequences; these behaviors would likely perpetuate substance abuse and dependence.

As a first step towards addressing these issues, we measured regional cerebral blood flow (rCBF) using H215O in 25-day abstinent MJ users during performance on a decision-making task, the Iowa Gambling Task (IGT). We hypothesized that Heavy MJ users would show abnormalities in brain activation in the OFC and DLPFC compared to a non-drug using control group (Block et al., 2000, Mathew et al., 1997, Volkow et al., 1996). These two regions are known to be engaged while performing the IGT in healthy controls (Ernst et al., 2002). We were unable to postulate whether activation in the MJ would be increased or decreased in these specific brain regions since at the initiation of the study it was unknown how MJ users would perform on the IGT task. In addition, no study had been conducted using this specific cognitive activation task in 25-day abstinent heavy MJ users. This study was an extension of our interest in determining the persistent effects of drugs of abuse on brain functioning. In our previous work, we observed functional disturbances in the OFC and dorsolateral prefrontal cortex (DLPFC) of 25-day abstinent cocaine abusers during the performance of the same decision-making task (Bolla et al., 2003). The OFC is part of a neural network that is prominent in the process of addiction and reward (Bartzokis et al., 2000, Bonson et al., 2002, Childress et al., 1999, Grant et al., 1996, Grant et al., 2000, Wang et al., 1999), and alterations in OFC and DLPFC functioning have been associated with faulty decision-making as assessed by the IGT (Bechara et al., 1994, Bolla et al., 2003, Ernst et al., 2002). Based on our previous neurobehavioral findings (Bolla et al., 2002), we also predicted the existence of a dose-dependent relationship between the amount of MJ used, task performance, and brain functional activity. In addition to task-relevant regions, we hypothesized that group differences would be observed in regions dense with cannabinoid receptors such as the cerebellum and hippocampus (Mailleux et al., 1992, Ong and Mackie, 1999). These same regions have also been shown to be altered in previous neuroimaging studies of MJ users (Block et al., 2000, Mathew et al., 1997, Volkow et al., 1996). We sought to extend those observations by investigating MJ users who were observed under controlled settings during 25 days of abstinence since previous imaging studies had studied MJ users much earlier during the course of withdrawal.

Section snippets

Participants

Participants were recruited through newspaper advertisements. To control for any medical, neurologic, or psychiatric conditions, participants received full medical and psychiatric screening. Psychological screening consisted of drug use and psychological history using the Drug Use Survey Questionnaire (DUSQ) (Smith, 1991), Addiction Severity Index (ASI) (McLellan et al., 1980), and the Psychiatric Diagnostic Interview Schedule (DIS) (Robins et al., 1981). Medical screening consisted of complete

Demographics and drug use

The control group (n = 11) was matched to the MJ group (n = 11) on Shipley IQ score. All participants were men. There were no significant differences in years of education, maternal education, Shipley IQ, and Hollingshead Index of socioeconomic status, race, alcohol use, or proportion of smokers (Table 1). The control group was older than the MJ group (31 vs. 25 years, t = 2.33; P < 0.05). Drug use (joints/week, duration) was derived from participants' self-reports. Duration of use averaged 7.9

Discussion

Consistent with our hypotheses, 25-day abstinent MJ users have persistent neurocognitive and functional brain abnormalities. Specifically, MJ users had lower performance than the drug-free Control group on a decision-making task, the Iowa Gambling Task. In addition, MJ users show less of a learning effect than the Control group. These findings indicate that the MJ users may be hypersensitive to immediate rewards, less sensitive to losses or negative consequences, and slow to learn from previous

Acknowledgments

Supported by NIH grants DA 11426 (KB), the JHBMC-GCRC (MO1 RR02719), and the DHHS NIDA Intramural Research Program. We would like to thank all the nurses and staff at NIDA-IRP, the Brain Imaging Center, and the Bayview GCRC who contributed to this project. We especially thank Debra Hill, BA, for computer and database support, and Marilyn Huestis, PhD, and David Darwin, PhD, for their assistance in the quantitative analysis of tetrahydrocannabinol. Our appreciation also extends to Doris Duffy

References (61)

  • M. Ernst et al.

    Decision-making in a risk-taking task: a PET study

    Neuropsychopharmacology

    (2002)
  • K.O. Fagerstrom

    Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment

    Addict. Behav.

    (1978)
  • M. Glass et al.

    Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal, and adult human brain

    Neuroscience

    (1997)
  • S. Grant et al.

    Drug abusers show impaired performance in a laboratory test of decision making

    Neuropsychologia

    (2000)
  • R.J. Mathew et al.

    Marijuana intoxication and brain activation in marijuana smokers

    Life Sci.

    (1997)
  • R.J. Mathew et al.

    Time course of tetrahydrocannabinol-induced changes in regional cerebral blood flow measured with positron emission tomography

    Psychiatry Res.

    (2002)
  • J. Matochik et al.

    Frontal cortical tissue composition in abstinent cocaine abusers: a magnetic resonance imaging study

    NeuroImage

    (2003)
  • J.A. Matochik et al.

    Altered brain tissue composition in heavy marijuana users

    Drug Alcohol Depend.

    (2005)
  • M.Z. Mintzer et al.

    Cognitive impairment in methadone maintenance patients

    Drug Alcohol Depend.

    (2002)
  • D.S. O'Leary et al.

    Effects of smoking marijuana on brain perfusion and cognition

    Neuropsychopharmacology

    (2002)
  • W.Y. Ong et al.

    A light and electron microscopic study of the CBI cannabinoid receptor in primate brain

    Neuroscience

    (1999)
  • B.S. Peterson et al.

    An fMRI study of Stroop word-color interference: evidence for cingulate subregions subserving multiple distributed attentional systems

    Biol. Psychiatry

    (1999)
  • D. Tranel et al.

    Asymmetric functional roles of right and left ventromedial prefrontal cortices in social conduct, decision-making, and emotional processing

    Cortex

    (2002)
  • N.D. Volkow et al.

    Brain glucose metabolism in chronic marijuana users at baseline and during marijuana intoxication

    Psychiatry Res.

    (1996)
  • G. Wang et al.

    Regional brain metabolic activation during craving elicited by recall of previous drug experiences

    Life Sci.

    (1999)
  • C.T. Whitlow et al.

    Long-term heavy marijuana users make costly decisions on a gambling task

    Drug Alcohol Depend.

    (2004)
  • A. Bechara et al.

    Emotion, decision making and the orbitofrontal cortex

    Cereb. Cortex

    (2000)
  • A. Bechara et al.

    Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions

    Brain

    (2000)
  • R.I. Block et al.

    Effects of chronic marijuana use on human cognition

    Psychopharmacology

    (1993)
  • R.I. Block et al.

    Cerebellar hypoactivity in frequent marijuana users

    NeuroReport

    (2000)
  • Cited by (316)

    View all citing articles on Scopus
    View full text