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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Exp Clin Psychopharmacol. Author manuscript; available in PMC 2010 July 26.
Published in final edited form as:
PMCID: PMC2909584
NIHMSID: NIHMS219067

Cognitive Function as an Emerging Treatment Target for Marijuana Addiction

Abstract

Cannabis is the most widely used illicit substance in the world and demand for effective treatment is increasing. However, abstinence rates following behavioral therapies have been modest, and there are no effective pharmacotherapies for the treatment of cannabis addiction. We propose a novel research agenda and a potential treatment strategy, based on observations that both acute and chronic exposure to cannabis are associated with dose-related cognitive impairments, most consistently in attention, working memory, verbal learning, and memory functions. These impairments are not completely reversible upon cessation of marijuana use and moreover may interfere with the treatment of marijuana addiction. Therefore, targeting cognitive impairment associated with chronic marijuana use may be a promising novel strategy for the treatment of marijuana addiction. Preclinical studies suggest that medications enhancing the cholinergic transmission may attenuate cannabis-induced cognitive impairments, but these cognitive enhancing medications have not been examined in controlled human studies. Preliminary evidence from individuals addicted to other drugs suggests that computerized cognitive rehabilitation may also have utility to improve cognitive function in marijuana users. Future clinical studies optimally designed to measure cognitive function as well as drug use behavior would be needed to test the efficacy of these treatments for marijuana addiction.

Keywords: marijuana, cannabis, cognitive function, acetylcholine, cholinesterase inhibitors

1. Introduction

Marijuana (cannabis) is the most widely used illicit substance in the world. In the US, there are approximately 2 to 3 million new users of marijuana every year, and significantly, two thirds of them are between 12 and 17 years of age (Compton, Grant, Colliver, Glantz, & Stinson, 2004; ONDCP, 2008; SAMHSA, 2008). It is estimated that one out of 12 marijuana users will eventually become dependent on marijuana (Wagner & Anthony, 2002).

As with other addictions, cannabis-dependent individuals continue to use marijuana despite significant problems associated with its use. Marijuana use has been associated with low academic achievement, early school dropout, delinquency, legal problems, unemployment, cigarette smoking, and risk for the development of psychotic disorder (Ferdinand et al., 2005; Friedman, Glassman, & Terras, 2001; Hall & Degenhardt, 2009; Henquet et al., 2005). Although, there may be alternative explanations for these associations that need to be ruled out before a causal link can be established (Hall & Degenhardt, 2009; Sewell, Poling, & Sofuoglu, 2009). For example, the association between marijuana and nicotine addiction, could be due to common genetic vulnerability (Agrawal et al., 2008). However, reports from several countries (including the US, UK, and the Netherlands) indicate that the average age of initiation of marijuana use is decreasing, while the average delta-9-tetrahydrocannabinol (THC, the main psychoactive ingredient of cannabis) content of cannabis is increasing (ElSohly et al., 2000; Pijlman, Rigter, Hoek, Goldschmidt, & Niesink, 2005; Potter, Clark, & Brown, 2008). This may result in greater addictive potential as well as increased negative consequences of marijuana use.

While individuals seeking treatment for marijuana use problems was once comparatively rare (R.S. Stephens, Babor, Kadden, Miller, & MTP Research Group, 2002), increased treatment-seeking has been observed among marijuana users, making marijuana one of the most common illicit drugs of use among admissions to treatment programs in the US (SAMHSA, 2008). Currently, there are no effective medications for the treatment of marijuana addiction and available behavioral treatments are modestly effective (Nordstrom & Levin, 2007). Thus, development of effective treatment strategies, specifically for cannabis use disorders (dependence or abuse), is urgently needed.

Many studies have demonstrated that chronic exposure to marijuana is associated with dose-related cognitive impairments, most consistently in attention, working memory, verbal learning, and memory functions (Solowij & Battisti, 2008). Some studies also indicate that cognitive impairments in psychomotor speed, attention, memory and executive functions, are not fully reversible one month after cessation of marijuana use (Bolla, Brown, Eldreth, Tate, & Cadet, 2002; Medina et al., 2007). These findings could be due to long-lasting effects of marijuana or impairment of baseline cognitive functioning in marijuana users, compared to those who do not use marijuana. As reported recently, cognitive impairments in marijuana users may be predictive of poor treatment response (Aharonovich, Brooks, Nunes, & Hasin, 2008), raising the possibility that improving cognitive functioning may emerge as an important treatment strategy for marijuana use disorders. In this review, we articulate the rationale and a possible research agenda for greater focus on cognitive functioning as a treatment target for marijuana dependence. First we present an overview of the currently available treatments for marijuana addiction and review the neurocognitive effects of marijuana. We then outline potential treatments for neurocognitive impairment in marijuana users.

2. Current Treatments of Marijuana Addiction

Behavioral Treatments

The behavioral therapies that have been evaluated as treatments for marijuana addiction are those that have been demonstrated to be effective for other substance use disorders. These include contingency management (CM), motivational enhancement therapy (MET), cognitive-behavioral therapy (CBT), and combinations of those approaches. Early work by Roffman and Stephens evaluating motivational and cognitive approaches and brief treatments for cannabis abuse/dependence reported abstinence rates of approximately 15% at follow-up (R.S. Stephens, Roffman, & Curtin, 2000; R.S. Stephens, Roffman, & Simpson, 1994). Evaluations of very brief motivational approaches alone have produced mixed results in samples of young adult marijuana users (Martin & Copeland, 2008; McCambridge, Slym, & Strang, 2008; Walker et al., 2006). In particular, one study found that adolescents who participated in brief MET reduced their quantity and frequency of cannabis use, and reported less cannabis dependence symptoms at 3-month follow-up (Martin & Copeland, 2008). However, two other studies with adolescents found that although participants reduced their cannabis use over time, there were no significant differences in reductions between MET and a drug information and advice condition (McCambridge et al., 2008), or a delayed feedback control condition (Walker et al., 2006).

The Marijuana Treatment Project, a large multisite trial of behavioral treatments, compared the effectiveness of delayed treatment, compared to 2 sessions of brief treatment or 9 sessions of extended treatment. The results indicated significantly better outcomes for the extended treatment compared to the brief treatment and for both active treatments over the delayed treatment control (MTP Research Group, 2004). However, abstinence rates, which were as high as 23% for the extended treatment condition at the end of treatment, fell to 15% at follow-up.

Several studies have evaluated the efficacy of contingency management approaches, which provide tangible reinforcers contingent on submission of marijuana-free urine specimens, alone and in combination with other therapies (A.J. Budney, Higgins, Radonovich, & Novy, 2000; A. J. Budney, Moore, Rocha, & Higgins, 2006; Carroll et al., 2006; Kadden, Litt, Kabela-Cormier, & Petry, 2007). In general, while approaches which include CM are associated with higher rates of within-treatment abstinence from marijuana, the effects of CM tend to fall off more rapidly after treatment ends compared with those which include CBT. A recent cost analysis suggested CBT may prove a more cost-effective approach for cannabis dependence given its relative durability (Olmstead, Sindelar, Easton, & Carroll, 2007).

Thus, while the small but growing literature on behavioral treatments for cannabis use disorders suggests that significant effects over control or comparison conditions have been found with some consistency for contingency management and CBT, effect sizes and abstinence rates at follow-up remain modest (Denis, Lavie, Fatseas, & Auriacombe, 2006). One year abstinence rates ranging from 9 to 28 percent (A. J. Budney, Roffman, Stephens, & Walker, 2007; Denis et al., 2006; Kadden et al., 2007) indicate that there is room for improvement. Brief MET has shown some promise in reducing marijuana use over time (Martin & Copeland, 2008), but these findings are not consistent in the literature (McCambridge et al., 2008; Walker et al., 2006). Thus, it may be beneficial to investigate ways to enhance these treatments. In addition, effective pharmacological treatments for marijuana addiction should be explored.

Pharmacotherapies

Cannabis effects are mediated by two types of cannabinoid receptor, designated CB1 and CB2 (Brown, 2007; Howlett et al., 2002). The CB1 receptors are densely distributed in the hippocampus, prefrontal cortex, anterior cingulate, basal ganglia, and cerebellum (Herkenham et al., 1990). CB1 receptors are predominantly located in the presynaptic terminals and modulate the release of other neurotransmitters including GABA, glutamate, norepinephrine, and acetylcholine (ACh) (Heifets & Castillo, 2009). CB2 receptors are found mostly within the immune cells. The endogenous cannabinoids (endocannabinoid), anandamide (AEA) and 2-arachidonyl glycerol (2-AG) also target these receptors and have a wide range of functions including modulation of pain, motor activity, motivation, reward, stress response, and cognitive processes (Heifets & Castillo, 2009).

Several potential medications have been identified for the pharmacological treatment of marijuana addiction, with some promising initial findings (Hart, 2005). The cannabis antagonist, rimonabant, appears to attenuate the subjective and physiological effects of smoked marijuana (Huestis et al., 2001). Unfortunately, rimonabant has been withdrawn from the market due to adverse events including depression and suicidality (Le Foll, Gorelick, & Goldberg, 2009). There are several other cannabinoid antagonists that are in development (Janero & Makriyannis, 2009). For example, cannabidiol, a major ingredient of cannabis, blocks THC-induced acute psychotic symptoms and anxiety in humans (Bhattacharyya et al., 2009; Zuardi, 2008). The oral cannabinoid agonist, THC, has been shown to attenuate marijuana withdrawal symptoms in both outpatient and controlled human laboratory studies (A. J. Budney, Vandrey, Hughes, Moore, & Bahrenburg, 2007). The combination of lofexidine and oral THC showed promising results in alleviating withdrawal and preventing relapse in a human laboratory model (Haney et al., 2008). Lofexidine inhibits noradrenergic activity by stimulating α2-adrenergic receptors (Louis, Jarrott, & Conway, 1988). Nevertheless, to date, no pharmacological agent has demonstrated efficacy in randomized clinical trials (Nordstrom & Levin, 2007).

3. Neurocognitive Effects of Marijuana

In rodents and non-human primates, THC and synthetic cannabinoids impair learning and memory processes assessed with a range of tasks including, the eight-arm radial-maze (Han & Robinson, 2001; Mallet & Beninger, 1998; Nava, Carta, Battasi, & Gessa, 2000; Winsauer, Lambert, & Moerschbaecher, 1999; Zimmerberg, Glick, & Jarvik, 1971), two-component instrumental discrimination task (Han & Robinson, 2001; Mallet & Beninger, 1998; Nava et al., 2000; Winsauer et al., 1999; Zimmerberg et al., 1971), time interval estimation task based on a fixed-interval schedule (Han & Robinson, 2001; Mallet & Beninger, 1998; Nava et al., 2000; Winsauer et al., 1999; Zimmerberg et al., 1971), conditional discriminations (Han & Robinson, 2001; Mallet & Beninger, 1998; Nava et al., 2000; Winsauer et al., 1999; Zimmerberg et al., 1971), and two-task procedure tasks (Han & Robinson, 2001; Mallet & Beninger, 1998; Nava et al., 2000; Winsauer et al., 1999; Zimmerberg et al., 1971). Consistent with preclinical studies, marijuana or THC administration in humans have been reported to produce acute, transient, dose-related impairments in learning, short-term memory, working memory, time-estimation, inhibitory control, decision making, and attention (Hart, van Gorp, Haney, Foltin, & Fischman, 2001; Heishman, Huestis, Henningfield, & Cone, 1990; Hooker & Jones, 1987; Leweke et al., 1998; Marks & MacAvoy, 1989; McDonald, Schleifer, Richards, & de Wit, 2003; Miller, McFarland, Cornett, & Brightwell, 1977; Ramaekers et al., 2006). In these studies, verbal learning and memory, working memory, and sustained attention functions were most consistently impaired following acute cannabis administration (Solowij & Battisti, 2008).

Chronic heavy marijuana use is alsoassociated with impairments in verbal learning and memory, sustained attention, and executive functioning (Bolla et al., 2002; Pope, Gruber, & Yurgelun-Todd, 1995; Pope & Yurgelun-Todd, 1996; Solowij, 1995; Solowij, Michie, & Fox, 1995; Solowij, Stephens, Roffman, Babor, Kadden, Miller, Christiansen, McRee, Vendetti et al., 2002). In a recent study, after 20 days of abstinence, adolescent marijuana users, compared to controls, showed deficits in psychomotor speed, attention, memory and executive functioning (Medina et al., 2007). Number of lifetime marijuana use episodes was associated with greater cognitive deficits, suggesting a cumulative dose effect of marijuana use (Medina et al., 2007). Further, following a 28-day abstinence, heavy marijuana users performed more poorly than lighter userson a verbal learning and memory task (Bolla et al., 2002), while others reported recovery of cognitive function after 28 days of abstinence (Pope, Gruber, Hudson, Huestis, & Yurgelun-Todd, 2001). The persistence of cognitive impairments, for at least weeks following abstinence from marijuana use, supports the need to address cognitive impairments early in treatment.

In contrast to these studies, other studies reported minimal (Grant, Gonzalez, Carey, Natarajan, & Wolfson, 2003) or no lasting effects of chronic cannabis use on overall IQ, attention, working memory, and abstract reasoning (Fried, Watkinson, & Gray, 2005; Jager, Kahn, Van Den Brink, Van Ree, & Ramsey, 2006). Important to note that, cannabis-induced cognitive impairments may be dependent on the age of onset of cannabis use; in particular, those starting before the age of 17 having greater impairment (Kempel, Lampe, Parnefjord, Hennig, & Kunert, 2003; Pope et al., 2003). Thus, age of onset and other baseline variables, like IQ (Bolla et al., 2002), may explain the conflicting findings regarding long-term marijuana use on cognitive outcomes.

Chronic cannabis exposure is associated with varying degrees of tolerance depending on the outcome measures (Lichtman & Martin, 2005). In a previous study, subjective high and sedation were lower in frequent marijuana users, compared to occasional users, in response to a single oral dose of 15 mg THC (Kirk & de Wit, 1999). In contrast, there were no differences between groups for performance on the digit symbol substitution test, suggesting lack of tolerance to cannabis-induced cognitive impairment (Kirk & de Wit, 1999). Two recent studies compared occasional and frequent marijuana users for the acute THC-induced cognitive impairment (D’Souza et al., 2008; Ramaekers, Kauert, Theunissen, Toennes, & Moeller, 2009). Frequent users had attenuated impairment to divided attention, verbal learning and memory tasks but not to vigilance (D’Souza et al., 2008), or motor inhibition tasks (Ramaekers et al., 2009) suggesting differential tolerance for the THC responses. These findings are consistent with preclinical studies demonstrating that chronic treatment with cannabinoid agonist lead to differential molecular, cellular, and behavioral changes that are dependent on the brain region and the outcome measures (Lichtman & Martin, 2005; McKinney et al., 2008).

The potential neural substrates of these deficits have been examined in both preclinical and human functional imaging studies. The hippocampus, a region that is long associated with learning and memory, has been closely examined for cannabis-induced cognitive impairment. The hippocampus shows a high density of CB1 receptors, as well as endogenous cannabinoid anandamide (Mackie, 2005). In rats, injection of cannabinoid agonist CP-55,940 systemically or into the hippocampus similarly disrupted working memory performance (Lichtman, Dimen, & Martin, 1995). Further, cannabinoid agonists inhibit hippocampal long-term potentiation (LTP), the putative neural substrates of learning and memory (Collins, Pertwee, & Davies, 1995; Davies, Pertwee, & Riedel, 2002; Hoffman, Oz, Yang, Lichtman, & Lupica, 2007; Misner & Sullivan, 1999; Terranova, Michaud, Le Fur, & Soubrie, 1995). Mice strains lacking CB1 receptors have been reported to show enhanced LTP (Bohme, Laville, Ledent, Parmentier, & Imperato, 2000) and an enhanced memory function (Reibaud et al., 1999). These findings further support the role of CB1 receptors in learning and memory functions. Consistent with these preclinical findings, long-term heavy marijuana users had reduced hippocampus and amygdala volumes, and the size of the left hippocampus was correlated to the severity of marijuana use (Yucel et al., 2008). These data suggest that hippocampus plays a critical role in cannabis-induced disruption in learning and memory, although other brain regions, especially the prefrontal cortex, also contribute to cognitive impairment induced by cannabis (Egerton, Allison, Brett, & Pratt, 2006). For example, marijuana abusers were shown to have lowerregional cerebral blood flow (rCBF) during a resting condition in the ventral prefrontalcortex even after 26-hours of abstinence (Block et al., 2000). Similarly, long-term marijuana users had hypoactivity in the anterior cingulate cortex and the left lateral prefrontal cortex (LPFC) during the Stroop test performance (Eldreth, Matochik, Cadet, & Bolla, 2004; Gruber & Yurgelun-Todd, 2005).

4. Neurobiological Mediators of the Cognitive Impairment by Marijuana

The exact neurobiological mechanisms underlying the marijuana-induced cognitive impairment remain to be elucidated (Egerton et al., 2006). Accumulating evidence from preclinical studies suggests that the cholinergic system may have an important role in the cognitive impairment induced by marijuana (Carta, Nava, & Gessa, 1998; Gessa, Casu, Carta, & Mascia, 1998; Gessa, Mascia, Casu, & Carta, 1997; Mishima, Egashira, Matsumoto, Iwasaki, & Fujiwara, 2002; Nava et al., 2000; Nava, Carta, Colombo, & Gessa, 2001). Acetylcholine (ACh) is the neurotransmitter for the cholinergic system. ACh participates in many CNS functions including attention, working memory, motivation, and reward (Briand, Gritton, Howe, Young, & Sarter, 2007; Smythies, 2005). These diverse cholinergic effects are mediated by nicotinic and muscarinic type ACh receptors. Cholinergic neurons are either projection neurons, terminating diffusely in the brain including in the hippocampus, prefrontal cortex, or interneurons, which are located mainly in the striatum and nucleus accumbens (Mesulam, 2004). While cholinergic projection neurons are critical in cognitive function, cholinergic interneurons integrate the cortical and subcortical information related to motivation and reward (Berlanga et al., 2003). ACh is implicated in pathophysiology of Alzheimer’s disease, schizophrenia, and other disorders associated with declined cognitive function (Smythies, 2005; M. Sofuoglu & Mooney, 2009).

Cannabinoid agonist THC inhibit cholinergic transmission in the brain and performance deficits induced by cannabis on the working maze task resemble those observed with the cholinergic antagonist scopolamine (Varvel, Hamm, Martin, & Lichtman, 2001). Consistent with these findings, CB1 receptors located on the cholinergic terminals have been shown to control ACh release (Degroot et al., 2006). In many preclinical studies, administration of THC or cannabinoid agonists tetrahydrocannabinol or WIN 55,212-2 reduced ACh release in the hippocampus in freely moving rats or in hippocampal slices (Carta et al., 1998; Gessa et al., 1998; Gessa et al., 1997; Mishima et al., 2002; Nava et al., 2000; Nava et al., 2001). The reduction in cannabis-induced ACh release in hippocampus was significantly correlated with the impairment of working memory (Gessa et al., 1998). Further, tolerance did not develop to the THC-induced reduction in ACh release in hippocampus (Gessa et al., 1998). These findings are consistent with the studies showing lack of tolerance to some marijuana-induced cognitive impairments (Kirk & de Wit, 1999). This cannabinoid effect on ACh release seems to be less in the medial-prefrontal cortex and is not observed in the striatum (Gessa et al., 1998).

Of particular clinical interest, the cholinesterase inhibitors physostigmine or tetrahydroaminoacridine, dose-dependently reversed the THC –induced reduction in correct choices and increase in errors in the 8-arm radial maze task in rats (Mishima et al., 2002). Further, tetrahydroaminoacridine at 1 mg/kg, which improved the impairment of spatial memory, also reversed the THC-induced release of Ach in dorsal hippocampus (Mishima et al., 2002). Similar findings were observed using another cholinesterase inhibitor, eptastigmine, in rats. In that study, CP 55,940 dose-dependently impaired working-memory function deficits including errors, correct choices, and average time. Pretreatment with eptastigmine, significantly reversed the CP 55,940-induced impairment for mean total number of errors and mean number of correct choices (Braida & Sala, 2000). These effects seem to be mediated by the M1 and M3 type muscarinic cholinergic receptors (Fukudome et al., 2004; Ohno-Shosaku et al., 2003). There is also a functional interaction between the nicotinic and cannabis receptors. In preclinical studies, nicotine enhanced the cannabis-induced hypothermia, antinociception, anxiolytic-like response, and conditioned place preference but attenuated cannabis tolerance (Valjent, Mitchell, Besson, Caboche, & Maldonado, 2002). Nicotine also facilitated cannabis discrimination in rats (Solinas et al., 2007) but another study failed to replicate these findings in mice (Vann et al., 2009). Consistent with these findings, a 21-mg nicotine patch, compared to placebo, enhanced several responses to marijuana cigarettes including the heart rate and the subjective rating of “stimulated” on the Addiction Research Center Inventory (ARCI) in humans (Penetar et al., 2005). In adolescent tobacco smokers with or without cannabis use history, Jacobson et al. (Jacobsen, Pugh, Constable, Westerveld, & Mencl, 2007) reported that nicotine intake by cigarette smoking may alleviate cannabis-related verbal memory and learning impairment. These preliminary findings suggest that nicotine may attenuate cannabis-induced verbal memory deficits.

5. Neurocognitive Impairment and Treatment of Marijuana Addiction

Although the acute and chronic effects of marijuana on cognitive function have been well documented, the impact of cognitive function on treatment outcomes has not been well-studied (Bolla et al., 2002; Hart et al., 2001; Heishman et al., 1990; Hooker & Jones, 1987; Leweke et al., 1998; Marks & MacAvoy, 1989; McDonald et al., 2003; Miller et al., 1977; Pope et al., 1995; Pope & Yurgelun-Todd, 1996; Ramaekers et al., 2006; Solowij, 1995; Solowij et al., 1995; Solowij, Stephens, Roffman, Babor, Kadden, Miller, Christiansen, McRee, & Vendetti, 2002). In a recent study, Aharonovich and colleagues evaluated 20 marijuana dependent patients enrolled in a randomized treatment study, which included cognitive behavioral therapy (CBT) and motivational enhancement therapy (MET). Cognitive impairments in abstract reasoning, spatial and processing accuracy were predictive of poor treatment retention (Aharonovich et al., 2008). While limited by a very small sample size, these findings are consistent with previous reports of negative effects of cognitive impairments on treatment retention among cocaine and poly-drug users (Aharonovich et al., 2006; Aharonovich, Nunes, & Hasin, 2003; Bates, Pawlak, Tonigan, & Buckman, 2006; Donovan, Kivlahan, & Walker, 1984; O’Leary, Donovan, Chaney, & Walker, 1979). In a study with poly-drug users, participants who scored low (<7) on the Block Design and Digit Symbol subtest of the WAIS-R (Wechsler Adult Intelligence Scale-Revised) remained in treatment a significantly shorter amount of time (Fals-Stewart, 1993; Fals-Stewart & Schafer, 1992). In a follow-up study, poly-drug users in a residential treatment program who obtained a neuropsychological test battery summary score of T < 40, had shorter lengths of stay in treatment and were viewed less favorably by treatment staff (Fals-Stewart, 1993). Moreover, in recent research, poly-drug users with lower estimated WAIS-R IQ scores were less engaged in treatment than participants with higher estimated IQ scores (Katz et al., 2005). Research with cocaine users found similar results; such that participants with low cognitive scores were more likely to drop out of treatment (Aharonovich et al., 2006; Aharonovich et al., 2003). In particular, dropouts had significantly poorer scores on tests of cognitive speed, accuracy, and attention (Aharonovich et al., 2006). The results of these studies suggest that cognitive functioning significantly affects substance users’ ability to engage and remain in treatment. Although there is a dearth of research is this area with marijuana users, the literature with poly-drug and cocaine users highlights the potential of greater focus on the clinical and prognostic significance of the cognitive impairments in treatment-seeking marijuana users.

6. Treatment Approaches Targeting Neurocognitive Impairment in Marijuana Users

6A. Behavioral Approaches

Among behavioral approaches, computerized cognitive rehabilitation has demonstrated some promise among schizophrenics as well as in drug users in residential settings (Bell, Bryson, Greig, Corcoran, & Wexler, 2001; Fals-Stewart, 1994). Computerized neurocognitive rehabilitation interventions are designed to enhance cognitive skills though exercises that target problem-solving skills, attention, memory, and abstract reasoning (Fals-Stewart & Lam, in press). The PSYCogReHab program has been used in several studies (Fals-Stewart & Lam, in press; Fals-Stewart & Lucente, 1994; Grohman, Fals-Stewart, & Donnelly, 2006) and consists of four modules (Foundations, Visuospatial, Problem Solving, and Memory) that aim to enhance function in several domains, including: executive functioning, memory, planning, organization technology, decision making, judgment, sequencing/systems thinking, attention training, visual attention, focusing, concentration, auditory attention, and sensory integration. The modules adapt to the individual’s performance, and mastery of a task must be achieved before the individual can move on to the next task. Research in the area of cognitive rehabilitation shows that cognitively-impaired poly-drug abusers who receive computer-assisted cognitive rehabilitation improved in cognitive performance tests, were rated as more engaged in treatment, and remained in treatment longer compared to control participants (Fals-Stewart & Lucente, 1994; Grohman et al., 2006). Recent research replicated these findings, providing strong evidence that cognitive improvement can be accelerated, which in turn can lead to better treatment outcomes (Fals-Stewart & Lam, in press). Computerized cognitive rehabilitation approaches have not yet been evaluated among marijuana users.

6B. Pharmacological Approaches

There are several cognitive-enhancers that may potentially be used for the treatment of cannabis addiction (M. R. Farlow, 2009; Monti & Contestabile, 2009; Tarditi, Caricasole, & Terstappen, 2009). In this review, we will focus on the cholinesterase inhibitors since preclinical studies suggest that increasing synaptic ACh levels with cholinesterase inhibitors may alleviate cannabis-induced spatial and working memory deficits (Mishima et al., 2002). Several cholinesterase inhibitors, including tacrine, rivastigmine, donepezil, and galantamine are available for clinical use for the treatment of dementia (Birks, 2006; M. Farlow, 2002; Giacobini, 2004). These medications have also been evaluated for other disorders characterized with cognitive impairment, including Parkinson’s disease, traumatic brain injury, and schizophrenia (Camicioli & Gauthier, 2007; Khateb, Ammann, Annoni, & Diserens, 2005; Ochoa & Clark, 2006). The pharmacological as well as side effect profiles of the various cholinesterase inhibitors differ among each other. Cholinesterase inhibitors have a good safety profile and their potential use in cannabis addicted individuals is feasible. The most common side effects of cholinesterase inhibitors include diarrhea, nausea, vomiting, loss of appetite, and dizziness (Birks, 2006; Hansen et al., 2008; Ritchie, Ames, Clayton, & Lai, 2004). Tacrine has limited use due to hepatotoxicity and short half-life. Previous studies have shown that while a wide-range of cognitive functions including learning, memory and visuospatial abilities seem to be improved with cholinesterase inhibitors, these medications may be particularly effective in improving attentional function (Galvin et al., 2008; Lucas-Meunier, Fossier, Baux, & Amar, 2003). Attention, which refers to the individual’s ability to selectively concentrate on one aspect of the environment while ignoring potential distracters, underlies or contributes to many other cognitive functions (Knudsen, 2007). As recently reviewed by De Wit (de Wit, 2009), a relationship between attentional processes and drug addiction has started to emerge more clearly. Lapses in attention have been proposed as an important antecedent of the drug-seeking response in addicted individuals (Acheson & de Wit, 2008; de Wit, 2009). In a recent study with abstinent cocaine users, we have shown that galantamine treatment, improved sustained attention function (M. Sofuoglu, Poling, Sewell, Waters, & Carroll, 2009) assessed with the Rapid Visual Information Task. Systematic human studies examining the cholinergic system in cannabis-induced cognitive impairment have not yet been undertaken.

7. Summary: Cognitive impairment as a treatment target for marijuana addiction

In this review, we have summarized available evidence demonstrating that marijuana users show impaired cognitive functioning, especially in working memory and verbal learning/memory functions. Moreover, there is preliminary evidence that impaired cognitive functioning predicts poor treatment response in marijuana users. Preclinical studies suggest that cholinesterase inhibitors may alleviate the cognitive impairments induced by cannabis but they have not yet been examined for the treatment of marijuana addiction in humans. Studies conducted in individuals addicted to other drugs suggest that cognitive rehabilitation may be an effective strategy to improve cognitive function and treatment outcomes in drug users. Work in this area is nascent, however, and multiple basic questions have not been addressed, including:

1) Will cognitive improvement lead to better treatment outcomes in marijuana users?

As summarized above, cognitive deficits in marijuana users including working memory, response inhibition, and verbal learning functions have been well-documented. There is some evidence that cognitive deficits in marijuana users may be associated with poorer retention in treatment. However, it is not clear whether improvement in cognitive functions will lead to better retention or better treatment outcomes for marijuana addiction.

2) What is the potential therapeutic role of cognitive enhancing medications in marijuana users?

Most behavioral treatments for addictions are predicated on the ability of the patient to attend to treatment, understand interventions and behavioral change strategies, and be able to implement them (Ersche & Sahakian, 2007; Fals-Stewart & Bates, 2003; Fals-Stewart, Schafer, Lucente, Rustine, & Brown, 1994). Intact cognitive functioning may be particularly crucial for more complex approaches such as CBT that emphasize cognitive re-training and learning of new behavioral skills. Moreover, inhibitory function and ability to maintain awareness of long term goals are key elements of good treatment outcomes irrespective of treatment type. Thus, medications like cholinergic enhancers may be effective for the pharmacotherapy of addiction by reducing drug use through enhancing inhibitory control. Alternatively, cholinergic enhancers can be used to augment response to behavioral treatments for marijuana addiction. There are several examples of augmentation of behavioral treatment with cognitive enhancer cycloserine for the treatment of phobias and other anxiety disorders (McNally, 2007; Ressler et al., 2004; Santa Ana et al., 2009; Wilhelm et al., 2008). Such augmentation strategies remain to be evaluated for the treatment of marijuana addiction.

3) What specific cognitive functions are most strongly related to improved treatment outcome?

The cognitive antecedents of addictive behaviors are the focus of intense research (de Wit, 2009; M. Sofuoglu, 2010; Vocci, 2008). Among cognitive functions, reduced inhibitory control, also commonly called impulsivity, has been the centerpiece for the continuation of drug use behavior (Everitt et al., 2007; Kalivas & Volkow, 2005; Porrino, Smith, Nader, & Beveridge, 2007). However, inhibitory function is a complex construct with multiple dimensions including response inhibition and faulty decision making (or insensitivity to consequences) (Colzato, van den Wildenberg, & Hommel, 2007; Fillmore & Rush, 2002; Li et al., 2008; Li, Milivojevic, Kemp, Hong, & Sinha, 2006). More recently, attention and working memory have also been recognized as separate dimensions of inhibitory control (Chambers, Garavan, & Bellgrove, 2009; Hester & Garavan, 2004; Posner & Rothbart, 2007). The importance of these cognitive functions in predicting treatment outcomes in addicted populations remain to be determined.

To summarize, the evaluation of pharmacological or behavioral interventions targeting cognitive functioning in marijuana users suggests several potential areas for future research. In particular, the cognitive functions that are most predictive of treatment outcomes among marijuana users are not yet well studied in clinical trials. Selecting validated cognitive tests with good psychometric properties and that are sensitive to pharmacological or behavioral interventions will be a crucial step, as will exploration of the extent to which improvements in cognitive functioning can be evaluated through functional imaging techniques (Hester & Garavan, 2004; Jacobsen et al., 2007; Yucel et al., 2008). Finally, optimal timing of initiating treatments is a key issue, particularly regarding whether treatments will be more effective if introduced after an initial period of abstinence or whether they can be used to facilitate abstinence if started while the individual is still using marijuana. Clinical studies optimally designed to measure cognitive function as well as drug use behavior, would be needed to address these questions.

Acknowledgments

Support was provided by NIDA grants K02-DA-021304 (MS), K05-DA00457 (KMC), P50-DA09241, and the Veterans Administration VISN 1 MIRECC.

References

  • Acheson A, de Wit H. Bupropion improves attention but does not affect impulsive behavior in healthy young adults. Exp Clin Psychopharmacol. 2008;16(2):113–123. [PubMed]
  • Agrawal A, Lynskey MT, Pergadia ML, Bucholz KK, Heath AC, Martin NG, et al. Early cannabis use and DSM-IV nicotine dependence: a twin study. Addiction. 2008;103(11):1896–1904. [PMC free article] [PubMed]
  • Aharonovich E, Brooks AC, Nunes EV, Hasin DS. Cognitive deficits in marijuana users: Effects on motivational enhancement therapy plus cognitive behavioral therapy treatment outcome. Drug Alcohol Depend. 2008;95(3):279–283. [PMC free article] [PubMed]
  • Aharonovich E, Hasin DS, Brooks AC, Liu X, Bisaga A, Nunes EV. Cognitive deficits predict low treatment retention in cocaine dependent patients. Drug Alcohol Depend. 2006;81(3):313–322. [PubMed]
  • Aharonovich E, Nunes E, Hasin D. Cognitive impairment, retention and abstinence among cocaine abusers in cognitive-behavioral treatment. Drug Alcohol Depend. 2003;71(2):207–211. [PubMed]
  • Bates ME, Pawlak AP, Tonigan JS, Buckman JF. Cognitive impairment influences drinking outcome by altering therapeutic mechanisms of change. Psychol Addict Behav. 2006;20(3):241–253. [PMC free article] [PubMed]
  • Bell M, Bryson G, Greig T, Corcoran C, Wexler BE. Neurocognitive enhancement therapy with work therapy: Effects on neuropsychological test performance. Archives of General Psychiatry. 2001;58:763–768. [PubMed]
  • Berlanga ML, Olsen CM, Chen V, Ikegami A, Herring BE, Duvauchelle CL, et al. Cholinergic interneurons of the nucleus accumbens and dorsal striatum are activated by the self-administration of cocaine. Neuroscience. 2003;120(4):1149–1156. [PubMed]
  • Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T, et al. Opposite Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Human Brain Function and Psychopathology. Neuropsychopharmacology 2009 [PMC free article] [PubMed]
  • Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006;(1):CD005593. [PubMed]
  • Block RI, O’Leary DS, Hichwa RD, Augustinack JC, Ponto LL, Ghoneim MM, et al. Cerebellar hypoactivity in frequent marijuana users. Neuroreport. 2000;11(4):749–753. [PubMed]
  • Bohme GA, Laville M, Ledent C, Parmentier M, Imperato A. Enhanced long-term potentiation in mice lacking cannabinoid CB1 receptors. Neuroscience. 2000;95(1):5–7. [PubMed]
  • Bolla KI, Brown K, Eldreth D, Tate K, Cadet JL. Dose-related neurocognitive effects of marijuana use. Neurology. 2002;59(9):1337–1343. [PubMed]
  • Braida D, Sala M. Cannabinoid-induced working memory impairment is reversed by a second generation cholinesterase inhibitor in rats. Neuroreport. 2000;11(9):2025–2029. [PubMed]
  • Briand LA, Gritton H, Howe WM, Young DA, Sarter M. Modulators in concert for cognition: modulator interactions in the prefrontal cortex. Prog Neurobiol. 2007;83(2):69–91. [PMC free article] [PubMed]
  • Brown AJ. Novel cannabinoid receptors. Br J Pharmacol. 2007;152(5):567–575. [PubMed]
  • Budney AJ, Higgins ST, Radonovich KJ, Novy PL. Adding voucher-based incentives to coping skills and motivational enhancement improves outcomes during treatment for marijuana dependence. Journal of Consulting and Clinical Psychology. 2000;68:1051–1061. [PubMed]
  • Budney AJ, Moore BA, Rocha HL, Higgins ST. Clinical trial of abstinence-based vouchers and cognitive-behavioral therapy for cannabis dependence. J Consult Clin Psychol. 2006;74(2):307–316. [PubMed]
  • Budney AJ, Roffman R, Stephens RS, Walker D. Marijuana dependence and its treatment. Addict Sci Clin Pract. 2007;4(1):4–16. [PMC free article] [PubMed]
  • Budney AJ, Vandrey RG, Hughes JR, Moore BA, Bahrenburg B. Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms. Drug Alcohol Depend. 2007;86(1):22–29. [PubMed]
  • Camicioli R, Gauthier S. Clinical trials in Parkinson’s disease dementia and dementia with Lewy bodies. Can J Neurol Sci. 2007;34(Suppl 1):S109–117. [PubMed]
  • Carroll KM, Easton CJ, Nich C, Hunkele KA, Neavins TM, Sinha R, et al. The use of contingency management and motivational/skills-building therapy to treat young adults with marijuana dependence. Journal of Consulting and Clinical Psychology. 2006;74(5):955–966. [PMC free article] [PubMed]
  • Carta G, Nava F, Gessa GL. Inhibition of hippocampal acetylcholine release after acute and repeated Delta9-tetrahydrocannabinol in rats. Brain Res. 1998;809(1):1–4. [PubMed]
  • Chambers CD, Garavan H, Bellgrove MA. Insights into the neural basis of response inhibition from cognitive and clinical neuroscience. Neurosci Biobehav Rev. 2009;33(5):631–646. [PubMed]
  • Collins DR, Pertwee RG, Davies SN. Prevention by the cannabinoid antagonist, SR141716A, of cannabinoid-mediated blockade of long-term potentiation in the rat hippocampal slice. Br J Pharmacol. 1995;115(6):869–870. [PubMed]
  • Colzato LS, van den Wildenberg WP, Hommel B. Impaired inhibitory control in recreational cocaine users. PLoS ONE. 2007;2(11):e1143. [PMC free article] [PubMed]
  • Compton WM, Grant BF, Colliver JD, Glantz MD, Stinson FS. Prevalence of marijuana use disorders in the United States: 1991–1992 and 2001–2002. JAMA. 2004;291:2114–2121. [PubMed]
  • D’Souza DC, Ranganathan M, Braley G, Gueorguieva R, Zimolo Z, Cooper T, et al. Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis. Neuropsychopharmacology. 2008;33(10):2505–2516. [PubMed]
  • Davies SN, Pertwee RG, Riedel G. Functions of cannabinoid receptors in the hippocampus. Neuropharmacology. 2002;42(8):993–1007. [PubMed]
  • de Wit H. Impulsivity as a determinant and consequence of drug use: a review of underlying processes. Addict Biol. 2009;14(1):22–31. [PubMed]
  • Degroot A, Kofalvi A, Wade MR, Davis RJ, Rodrigues RJ, Rebola N, et al. CB1 receptor antagonism increases hippocampal acetylcholine release: site and mechanism of action. Mol Pharmacol. 2006;70(4):1236–1245. [PubMed]
  • Denis C, Lavie E, Fatseas M, Auriacombe M. Psychotherapeutic interventions for cannabis abuse and/or dependence in outpatient settings. Cochrane Database Syst Rev. 2006;3:CD005336. [PubMed]
  • Donovan DM, Kivlahan DR, Walker RD. Clinical limitations of neuropsychological testing in predicting treatment outcome among alcoholics. Alcohol Clin Exp Res. 1984;8(5):470–475. [PubMed]
  • Egerton A, Allison C, Brett RR, Pratt JA. Cannabinoids and prefrontal cortical function: insights from preclinical studies. Neurosci Biobehav Rev. 2006;30(5):680–695. [PubMed]
  • Eldreth DA, Matochik JA, Cadet JL, Bolla KI. Abnormal brain activity in prefrontal brain regions in abstinent marijuana users. Neuroimage. 2004;23(3):914–920. [PubMed]
  • ElSohly MA, Ross SA, Mehmedic Z, Arafat R, Yi B, Banahan BF., 3rd Potency trends of delta9-THC and other cannabinoids in confiscated marijuana from 1980–1997. J Forensic Sci. 2000;45(1):24–30. [PubMed]
  • Ersche KD, Sahakian BJ. The neuropsychology of amphetamine and opiate dependence: Implications for treatment. Neuropsychology Review. 2007;17:317–336. [PubMed]
  • Everitt BJ, Hutcheson DM, Ersche KD, Pelloux Y, Dalley JW, Robbins TW. The orbital prefrontal cortex and drug addiction in laboratory animals and humans. Ann N Y Acad Sci. 2007;1121:576–597. [PubMed]
  • Fals-Stewart W. Neurocognitive defects and their impact on substance abuse treatment. Journal of Addictions & Offender Counseling. 1993;13(2):46–57.
  • Fals-Stewart W. The effect of cognitive rehabilitation on the neuropsychological status of patients in drug abuse treatment who display neurocognitive impairment. Rehabilitation Psychology. 1994;39:75–94.
  • Fals-Stewart W, Bates ME. The neuropsychological test performance of drug-abusing patients: An examination of latent cognitive abilities and risk factors. Experimental and Clinical Psychopharmacology. 2003;11:34–45. [PubMed]
  • Fals-Stewart W, Lam WKK. Computer-assisted cignitive rehabilitation for the treatment of patients with substance use disorders: A randomized clinical trial. Experimental and Clinical Psychopharmacology (in press) [PubMed]
  • Fals-Stewart W, Lucente S. The effect of cognitive rehabilitation on the neuropsychological status of patients in drug abuse treatment who display neurocognitive impairment. Rehabilitation Psychology. 1994;39(2):75–94.
  • Fals-Stewart W, Schafer J. The relationship between length of stay in drug-free therapeutic communities and neurocognitive functioning. Journal of Clinical Psychology. 1992;48(4):539–543. [PubMed]
  • Fals-Stewart W, Schafer J, Lucente S, Rustine T, Brown L. Neurobehavioral consequences of prolonged alcohol and substance abuse: A review of findings and treatment implications. Clinical Psychology Review. 1994;14(8):755–778.
  • Farlow M. A clinical overview of cholinesterase inhibitors in Alzheimer’s disease. Int Psychogeriatr. 2002;14(Suppl 1):93–126. [PubMed]
  • Farlow MR. Treatment of mild cognitive impairment (MCI) Curr Alzheimer Res. 2009;6(4):362–367. [PubMed]
  • Ferdinand RF, Sondeijker F, van der Ende J, Selten JP, Huizink A, Verhulst FC. Cannabis use predicts future psychotic symptoms, and vice versa. Addiction. 2005;100(5):612–618. [PubMed]
  • Fillmore MT, Rush CR. Impaired inhibitory control of behavior in chronic cocaine users. Drug Alcohol Depend. 2002;66(3):265–273. [PubMed]
  • Fried PA, Watkinson B, Gray R. Neurocognitive consequences of marihuana--a comparison with pre-drug performance. Neurotoxicol Teratol. 2005;27(2):231–239. [PubMed]
  • Friedman AS, Glassman K, Terras BA. Violent behavior as related to use of marijuana and other drugs. J Addict Dis. 2001;20(1):49–72. [PubMed]
  • Fukudome Y, Ohno-Shosaku T, Matsui M, Omori Y, Fukaya M, Tsubokawa H, et al. Two distinct classes of muscarinic action on hippocampal inhibitory synapses: M2-mediated direct suppression and M1/M3-mediated indirect suppression through endocannabinoid signalling. Eur J Neurosci. 2004;19(10):2682–2692. [PubMed]
  • Galvin JE, Cornblatt B, Newhouse P, Ancoli-Israel S, Wesnes K, Williamson D, et al. Effects of galantamine on measures of attention: results from 2 clinical trials in Alzheimer disease patients with comparisons to donepezil. Alzheimer Dis Assoc Disord. 2008;22(1):30–38. [PubMed]
  • Gessa GL, Casu MA, Carta G, Mascia MS. Cannabinoids decrease acetylcholine release in the medial-prefrontal cortex and hippocampus, reversal by SR 141716A. Eur J Pharmacol. 1998;355(2–3):119–124. [PubMed]
  • Gessa GL, Mascia MS, Casu MA, Carta G. Inhibition of hippocampal acetylcholine release by cannabinoids: reversal by SR 141716A. Eur J Pharmacol. 1997;327(1):R1–2. [PubMed]
  • Giacobini E. Cholinesterase inhibitors: new roles and therapeutic alternatives. Pharmacol Res. 2004;50(4):433–440. [PubMed]
  • Grant I, Gonzalez R, Carey CL, Natarajan L, Wolfson T. Non-acute (residual) neurocognitive effects of cannabis use: a meta-analytic study. J Int Neuropsychol Soc. 2003;9(5):679–689. [PubMed]
  • Grohman K, Fals-Stewart W, Donnelly K. Improving treatment response of cognitively impaired veterans with neuropsychological rehabilitation. Brain Cogn. 2006;60(2):203–204. [PubMed]
  • Gruber SA, Yurgelun-Todd DA. Neuroimaging of marijuana smokers during inhibitory processing: a pilot investigation. Brain Res Cogn Brain Res. 2005;23(1):107–118. [PubMed]
  • Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet. 2009;374(9698):1383–1391. [PubMed]
  • Han CJ, Robinson JK. Cannabinoid modulation of time estimation in the rat. Behavioral Neuroscience. 2001;115(1):243–246. [PubMed]
  • Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Foltin RW. Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacology (Berl) 2008;197(1):157–168. [PMC free article] [PubMed]
  • Hansen RA, Gartlehner G, Webb AP, Morgan LC, Moore CG, Jonas DE. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. Clin Interv Aging. 2008;3(2):211–225. [PMC free article] [PubMed]
  • Hart CL. Increasing treatment options for cannabis dependence: a review of potential pharmacotherapies. Drug Alcohol Depend. 2005;80(2):147–159. [PubMed]
  • Hart CL, van Gorp W, Haney M, Foltin RW, Fischman MW. Effects of acute smoked marijuana on complex cognitive performance. Neuropsychopharmacology. 2001;25(5):757–765. [PubMed]
  • Heifets BD, Castillo PE. Endocannabinoid signaling and long-term synaptic plasticity. Annu Rev Physiol. 2009;71:283–306. [PubMed]
  • Heishman SJ, Huestis MA, Henningfield JE, Cone EJ. Acute and residual effects of marijuana: profiles of plasma THC levels, physiological, subjective, and performance measures. Pharmacol Biochem Behav. 1990;37(3):561–565. [PubMed]
  • Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ. 2005;330(7481):11. [PMC free article] [PubMed]
  • Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A. 1990;87(5):1932–1936. [PubMed]
  • Hester R, Garavan H. Executive dysfunction in cocaine addiction: evidence for discordant frontal, cingulate, and cerebellar activity. J Neurosci. 2004;24(49):11017–11022. [PubMed]
  • Hoffman AF, Oz M, Yang R, Lichtman AH, Lupica CR. Opposing actions of chronic Delta9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation. Learn Mem. 2007;14(1–2):63–74. [PMC free article] [PubMed]
  • Hooker WD, Jones RT. Increased susceptibility to memory intrusions and the Stroop interference effect during acute marijuana intoxication. Psychopharmacology. 1987;91(1):20–24. [PubMed]
  • Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54(2):161–202. [PubMed]
  • Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, et al. Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry. 2001;58(4):322–328. [PubMed]
  • Jacobsen LK, Pugh KR, Constable RT, Westerveld M, Mencl WE. Functional correlates of verbal memory deficits emerging during nicotine withdrawal in abstinent adolescent cannabis users. Biol Psychiatry. 2007;61(1):31–40. [PubMed]
  • Jager G, Kahn RS, Van Den Brink W, Van Ree JM, Ramsey NF. Long-term effects of frequent cannabis use on working memory and attention: an fMRI study. Psychopharmacology (Berl) 2006;185(3):358–368. [PubMed]
  • Janero DR, Makriyannis A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis. Expert Opin Emerg Drugs. 2009;14(1):43–65. [PubMed]
  • Kadden RM, Litt MD, Kabela-Cormier E, Petry NM. Abstinence rates following behavioral treatments for marijuana dependence. Addict Behav. 2007;32(6):1220–1236. [PMC free article] [PubMed]
  • Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry. 2005;162(8):1403–1413. [PubMed]
  • Katz EC, King SD, Schwartz RP, Weintraub E, Barksdale W, Robinson R, et al. Cognitive ability as a factor in engagement in drug abuse treatment. American Journal of Drug and Alcohol Abuse. 2005;31(3):359–369. [PubMed]
  • Kempel P, Lampe K, Parnefjord R, Hennig J, Kunert HJ. Auditory-evoked potentials and selective attention: different ways of information processing in cannabis users and controls. Neuropsychobiology. 2003;48(2):95–101. [PubMed]
  • Khateb A, Ammann J, Annoni JM, Diserens K. Cognition-enhancing effects of donepezil in traumatic brain injury. Eur Neurol. 2005;54(1):39–45. [PubMed]
  • Kirk JM, de Wit H. Responses to oral delta9-tetrahydrocannabinol in frequent and infrequent marijuana users. Pharmacol Biochem Behav. 1999;63(1):137–142. [PubMed]
  • Knudsen EI. Fundamental components of attention. Annu Rev Neurosci. 2007;30:57–78. [PubMed]
  • Le Foll B, Gorelick DA, Goldberg SR. The future of endocannabinoid-oriented clinical research after CB(1) antagonists. Psychopharmacology (Berl) 2009 [PMC free article] [PubMed]
  • Leweke M, Kampmann C, Radwan M, Dietrich DE, Johannes S, Emrich HM, et al. The effects of tetrahydrocannabinol on the recognition of emotionally charged words: an analysis using event-related brain potentials. Neuropsychobiology. 1998;37(2):104–111. [PubMed]
  • Li CS, Huang C, Yan P, Bhagwagar Z, Milivojevic V, Sinha R. Neural correlates of impulse control during stop signal inhibition in cocaine-dependent men. Neuropsychopharmacology. 2008;33(8):1798–1806. [PMC free article] [PubMed]
  • Li CS, Milivojevic V, Kemp K, Hong K, Sinha R. Performance monitoring and stop signal inhibition in abstinent patients with cocaine dependence. Drug Alcohol Depend. 2006;85(3):205–212. [PubMed]
  • Lichtman AH, Dimen KR, Martin BR. Systemic or intrahippocampal cannabinoid administration impairs spatial memory in rats. Psychopharmacology (Berl) 1995;119(3):282–290. [PubMed]
  • Lichtman AH, Martin BR. Cannabinoid tolerance and dependence. Handb Exp Pharmacol. 2005;(168):691–717. [PubMed]
  • Louis WJ, Jarrott B, Conway EL. Sites of actions of alpha 2 agonists in the brain and periphery. Am J Cardiol. 1988;61(7):15D–17D. [PubMed]
  • Lucas-Meunier E, Fossier P, Baux G, Amar M. Cholinergic modulation of the cortical neuronal network. Pflugers Arch. 2003;446(1):17–29. [PubMed]
  • Mackie K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol. 2005;(168):299–325. [PubMed]
  • Mallet PE, Beninger RJ. The cannabinoid CB1 receptor antagonist SR141716A attenuates the memory impairment produced by delta9-tetrahydrocannabinol or anandamide. Psychopharmacology (Berl) 1998;140(1):11–19. [PubMed]
  • Marks DF, MacAvoy MG. Divided attention performance in cannabis users and non-users following alcohol and cannabis separately and in combination. Psychopharmacology. 1989;99(3):397–401. [PubMed]
  • Martin G, Copeland J. The adolescent cannabis check-up: randomized trial of a brief intervention for young cannabis users. J Subst Abuse Treat. 2008;34(4):407–414. [PMC free article] [PubMed]
  • McCambridge J, Slym RL, Strang J. Randomized controlled trial of motivational interviewing compared with drug information and advice for early intervention among young cannabis users. Addiction. 2008;103(11):1809–1818. [PubMed]
  • McDonald J, Schleifer L, Richards JB, de Wit H. Effects of THC on behavioral measures of impulsivity in humans. Neuropsychopharmacology. 2003;28(7):1356–1365. [PubMed]
  • McKinney DL, Cassidy MP, Collier LM, Martin BR, Wiley JL, Selley DE, et al. Dose-related differences in the regional pattern of cannabinoid receptor adaptation and in vivo tolerance development to delta9-tetrahydrocannabinol. J Pharmacol Exp Ther. 2008;324(2):664–673. [PMC free article] [PubMed]
  • McNally RJ. Mechanisms of exposure therapy: how neuroscience can improve psychological treatments for anxiety disorders. Clin Psychol Rev. 2007;27(6):750–759. [PubMed]
  • Medina KL, Hanson KL, Schweinsburg AD, Cohen-Zion M, Nagel BJ, Tapert SF. Neuropsychological functioning in adolescent marijuana users: subtle deficits detectable after a month of abstinence. J Int Neuropsychol Soc. 2007;13(5):807–820. [PMC free article] [PubMed]
  • Mesulam MM. The cholinergic innervation of the human cerebral cortex. Prog Brain Res. 2004;145:67–78. [PubMed]
  • Miller LL, McFarland D, Cornett TL, Brightwell D. Marijuana and memory impairment: effect on free recall and recognition memory. Pharmacology, Biochemistry & Behavior. 1977;7(2):99–103. [PubMed]
  • Mishima K, Egashira N, Matsumoto Y, Iwasaki K, Fujiwara M. Involvement of reduced acetylcholine release in Delta9-tetrahydrocannabinol-induced impairment of spatial memory in the 8-arm radial maze. Life Sci. 2002;72(4–5):397–407. [PubMed]
  • Misner DL, Sullivan JM. Mechanism of cannabinoid effects on long-term potentiation and depression in hippocampal CA1 neurons. J Neurosci. 1999;19(16):6795–6805. [PubMed]
  • Monti B, Contestabile A. Memory-enhancing drugs: a molecular perspective. Mini Rev Med Chem. 2009;9(7):769–781. [PubMed]
  • MTP Research Group. Brief treatments for cannabis dependence: Findings from a randomized multisite trial. Journal of Consulting and Clinical Psychology. 2004;72:455–466. [PubMed]
  • Nava F, Carta G, Battasi AM, Gessa GL. D(2) dopamine receptors enable delta(9)-tetrahydrocannabinol induced memory impairment and reduction of hippocampal extracellular acetylcholine concentration. Br J Pharmacol. 2000;130(6):1201–1210. [PubMed]
  • Nava F, Carta G, Colombo G, Gessa GL. Effects of chronic Delta(9)-tetrahydrocannabinol treatment on hippocampal extracellular acetylcholine concentration and alternation performance in the T-maze. Neuropharmacology. 2001;41(3):392–399. [PubMed]
  • Nordstrom BR, Levin FR. Treatment of cannabis use disorders: a review of the literature. Am J Addict. 2007;16(5):331–342. [PubMed]
  • O’Leary MR, Donovan DM, Chaney EF, Walker RD. Cognitive impairment and treatment outcome with alcoholics: preliminary findings. J Clin Psychiatry. 1979;40(9):397–398. [PubMed]
  • Ochoa EL, Clark E. Galantamine may improve attention and speech in schizophrenia. Hum Psychopharmacol. 2006;21(2):127–128. [PubMed]
  • Ohno-Shosaku T, Matsui M, Fukudome Y, Shosaku J, Tsubokawa H, Taketo MM, et al. Postsynaptic M1 and M3 receptors are responsible for the muscarinic enhancement of retrograde endocannabinoid signalling in the hippocampus. Eur J Neurosci. 2003;18(1):109–116. [PubMed]
  • Olmstead TA, Sindelar JL, Easton CJ, Carroll KM. The cost-effectiveness of four treatments for marijuana dependence. Addiction 2007 [PMC free article] [PubMed]
  • ONDCP, O. o. N. D. C. P. Marijuana: The Greatest Cause of Illegal Drug Abuse. Washington, DC 20503: Executive Office of the President; 2008.
  • Penetar DM, Kouri EM, Gross MM, McCarthy EM, Rhee CK, Peters EN, et al. Transdermal nicotine alters some of marihuana’s effects in male and female volunteers. Drug Alcohol Depend. 2005;79(2):211–223. [PubMed]
  • Pijlman FT, Rigter SM, Hoek J, Goldschmidt HM, Niesink RJ. Strong increase in total delta-THC in cannabis preparations sold in Dutch coffee shops. Addict Biol. 2005;10(2):171–180. [PubMed]
  • Pope HG, Jr, Gruber AJ, Hudson JI, Cohane G, Huestis MA, Yurgelun-Todd D. Early-onset cannabis use and cognitive deficits: what is the nature of the association? Drug Alcohol Depend. 2003;69(3):303–310. [PubMed]
  • Pope HG, Jr, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D. Neuropsychological performance in long-term cannabis users. Arch Gen Psychiatry. 2001;58(10):909–915. [PubMed]
  • Pope HG, Jr, Gruber AJ, Yurgelun-Todd D. The residual neuropsychological effects of cannabis: the current status of research. Drug & Alcohol Dependence. 1995;38(1):25–34. [PubMed]
  • Pope HG, Jr, Yurgelun-Todd D. The residual cognitive effects of heavy marijuana use in college students. Jama. 1996;275(7):521–527. [PubMed]
  • Porrino LJ, Smith HR, Nader MA, Beveridge TJ. The effects of cocaine: a shifting target over the course of addiction. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(8):1593–1600. [PMC free article] [PubMed]
  • Posner MI, Rothbart MK. Research on attention networks as a model for the integration of psychological science. Annu Rev Psychol. 2007;58:1–23. [PubMed]
  • Potter DJ, Clark P, Brown MB. Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J Forensic Sci. 2008;53(1):90–94. [PubMed]
  • Ramaekers JG, Kauert G, Theunissen EL, Toennes SW, Moeller MR. Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users. J Psychopharmacol. 2009;23(3):266–277. [PubMed]
  • Ramaekers JG, Kauert G, van Ruitenbeek P, Theunissen EL, Schneider E, Moeller MR. High-potency marijuana impairs executive function and inhibitory motor control. Neuropsychopharmacology. 2006;31(10):2296–2303. [PubMed]
  • Reibaud M, Obinu MC, Ledent C, Parmentier M, Bohme GA, Imperato A. Enhancement of memory in cannabinoid CB1 receptor knock-out mice. Eur J Pharmacol. 1999;379(1):R1–2. [PubMed]
  • Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004;61(11):1136–1144. [PubMed]
  • Ritchie CW, Ames D, Clayton T, Lai R. Metaanalysis of randomized trials of the efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer disease. Am J Geriatr Psychiatry. 2004;12(4):358–369. [PubMed]
  • SAMHSA. Substance Abuse and Mental Health Services Administration. Results from the 2007 National Survey on Drug Use and Health: national findings. 2008.
  • Santa Ana EJ, Rounsaville BJ, Frankforter TL, Nich C, Babuscio T, Poling J, et al. D-Cycloserine attenuates reactivity to smoking cues in nicotine dependent smokers: a pilot investigation. Drug Alcohol Depend. 2009;104(3):220–227. [PMC free article] [PubMed]
  • Sewell RA, Poling J, Sofuoglu M. The effect of cannabis compared with alcohol on driving. Am J Addict. 2009;18(3):185–193. [PMC free article] [PubMed]
  • Smythies J. Section I. The cholinergic system. Int Rev Neurobiol. 2005;64:1–122. [PubMed]
  • Sofuoglu M. Cognitive Enhancement as a Pharmacotherapy Target for Stimulant Addiction. Addiction. 2010;105(1):38–48. [PMC free article] [PubMed]
  • Sofuoglu M, Mooney M. Cholinergic Functioning in Stimulant Addiction:Implications for Medications Development. CNS Drugs. 2009 (in press) [PMC free article] [PubMed]
  • Sofuoglu M, Poling J, Sewell A, Waters A, Carroll K. Galantamine effects on cogntive function in abstient cocaine users. 2009 (in submission)
  • Solinas M, Scherma M, Tanda G, Wertheim CE, Fratta W, Goldberg SR. Nicotinic facilitation of delta9-tetrahydrocannabinol discrimination involves endogenous anandamide. J Pharmacol Exp Ther. 2007;321(3):1127–1134. [PubMed]
  • Solowij N. Do cognitive impairments recover following cessation of cannabis use? Life Sciences. 1995;56(23–24):2119–2126. [PubMed]
  • Solowij N, Battisti R. The chronic effects of cannabis on memory in humans:a reviw. Current Drug Abuse Reviews. 2008;1:81–98. [PubMed]
  • Solowij N, Michie PT, Fox AM. Differential impairments of selective attention due to frequency and duration of cannabis use. Biological Psychiatry. 1995;37(10):731–739. [PubMed]
  • Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller M, et al. Cognitive functioning of long-term heavy cannabis users seeking treatment.[comment][erratum appears in JAMA2002 Apr 3;287(13):1651] JAMA. 2002;287(9):1123–1131. [PubMed]
  • Solowij N, Stephens RS, Roffman RA, Babor TF, Kadden RM, Miller M, et al. Cognitive functioning of long-term heavy cannabis users seeking treatment. JAMA. 2002;287:1123–1131. [PubMed]
  • Stephens RS, Babor TF, Kadden R, Miller M. MTP Research Group. The Marijuana Treatment Project: Rationale, design, and participant characteristics. Addiction. 2002;97:109–124. [PubMed]
  • Stephens RS, Roffman RA, Curtin L. Comparison of extended versus brief treatments for marijuana use. Journal of Consulting and Clinical Psychology. 2000;68:898–908. [PubMed]
  • Stephens RS, Roffman RA, Simpson EE. Treating adult marijuana dependence: A test of the relapse prevention model. Journal of Consulting and Clinical Psychology. 1994;62:92–99. [PubMed]
  • Tarditi A, Caricasole A, Terstappen G. Therapeutic targets for Alzheimer’s disease. Expert Opin Ther Targets. 2009;13(5):551–567. [PubMed]
  • Terranova JP, Michaud JC, Le Fur G, Soubrie P. Inhibition of long-term potentiation in rat hippocampal slices by anandamide and WIN55212-2: reversal by SR141716 A, a selective antagonist of CB1 cannabinoid receptors. Naunyn Schmiedebergs Arch Pharmacol. 1995;352(5):576–579. [PubMed]
  • Valjent E, Mitchell JM, Besson MJ, Caboche J, Maldonado R. Behavioural and biochemical evidence for interactions between Delta 9-tetrahydrocannabinol and nicotine. Br J Pharmacol. 2002;135(2):564–578. [PubMed]
  • Vann RE, Warner JA, Bushell K, Huffman JW, Martin BR, Wiley JL. Discriminative stimulus properties of delta9-tetrahydrocannabinol (THC) in C57Bl/6J mice. Eur J Pharmacol. 2009;615(1–3):102–107. [PMC free article] [PubMed]
  • Varvel SA, Hamm RJ, Martin BR, Lichtman AH. Differential effects of delta 9-THC on spatial reference and working memory in mice. Psychopharmacology (Berl) 2001;157(2):142–150. [PubMed]
  • Vocci FJ. Cognitive remediation in the treatment of stimulant abuse disorders: a research agenda. Exp Clin Psychopharmacol. 2008;16(6):484–497. [PubMed]
  • Wagner FA, Anthony JC. From first drug use to drug dependence; developmental periods of risk for dependence upon marijuana, cocaine, and alcohol. Neuropsychopharmacology. 2002;26(4):479–488. [PubMed]
  • Walker DD, Roffman RA, Stephens RS, Wakana K, Berghuis J, Kim W. Motivational enhancement therapy for adolescent marijuana users: a preliminary randomized controlled trial. J Consult Clin Psychol. 2006;74(3):628–632. [PMC free article] [PubMed]
  • Wilhelm S, Buhlmann U, Tolin DF, Meunier SA, Pearlson GD, Reese HE, et al. Augmentation of behavior therapy with D-cycloserine for obsessive-compulsive disorder. Am J Psychiatry. 2008;165(3):335–341. quiz 409. [PubMed]
  • Winsauer PJ, Lambert P, Moerschbaecher JM. Cannabinoid ligands and their effects on learning and performance in rhesus monkeys. Behav Pharmacol. 1999;10(5):497–511. [PubMed]
  • Yucel M, Solowij N, Respondek C, Whittle S, Fornito A, Pantelis C, et al. Regional brain abnormalities associated with long-term heavy cannabis use. Arch Gen Psychiatry. 2008;65(6):694–701. [PubMed]
  • Zimmerberg B, Glick SD, Jarvik ME. Impairment of recent memory by marihuana and THC in rhesus monkeys. Nature. 1971;233(5318):343–345. [PubMed]
  • Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev Bras Psiquiatr. 2008;30(3):271–280. [PubMed]