PMC:3780360 / 33654-45394 JSONTXT

{"project":"2_test","denotations":[{"id":"24069004-14990863-41849015","span":{"begin":385,"end":388},"obj":"14990863"},{"id":"24069004-2234615-41849016","span":{"begin":701,"end":704},"obj":"2234615"},{"id":"24069004-21798285-41849017","span":{"begin":725,"end":728},"obj":"21798285"},{"id":"24069004-16548935-41849018","span":{"begin":1413,"end":1416},"obj":"16548935"},{"id":"24069004-16548924-41849019","span":{"begin":1843,"end":1846},"obj":"16548924"},{"id":"24069004-16402286-41849020","span":{"begin":2016,"end":2019},"obj":"16402286"},{"id":"24069004-17076916-41849021","span":{"begin":2021,"end":2024},"obj":"17076916"},{"id":"24069004-22683090-41849022","span":{"begin":2988,"end":2991},"obj":"22683090"},{"id":"24069004-12716966-41849023","span":{"begin":3400,"end":3403},"obj":"12716966"},{"id":"24069004-12482086-41849024","span":{"begin":3405,"end":3408},"obj":"12482086"},{"id":"24069004-2343913-41849025","span":{"begin":3566,"end":3569},"obj":"2343913"},{"id":"24069004-8101394-41849025","span":{"begin":3566,"end":3569},"obj":"8101394"},{"id":"24069004-11729018-41849025","span":{"begin":3566,"end":3569},"obj":"11729018"},{"id":"24069004-18588536-41849025","span":{"begin":3566,"end":3569},"obj":"18588536"},{"id":"24069004-9106242-41849026","span":{"begin":4096,"end":4099},"obj":"9106242"},{"id":"24069004-16314880-41849027","span":{"begin":4283,"end":4286},"obj":"16314880"},{"id":"24069004-14963101-41849028","span":{"begin":4424,"end":4427},"obj":"14963101"},{"id":"24069004-20192949-41849029","span":{"begin":4565,"end":4568},"obj":"20192949"},{"id":"24069004-15668727-41849030","span":{"begin":4768,"end":4771},"obj":"15668727"},{"id":"24069004-20192949-41849031","span":{"begin":5065,"end":5068},"obj":"20192949"},{"id":"24069004-18705688-41849032","span":{"begin":5451,"end":5454},"obj":"18705688"},{"id":"24069004-20010552-41849033","span":{"begin":5456,"end":5459},"obj":"20010552"},{"id":"24069004-21937688-41849034","span":{"begin":5648,"end":5651},"obj":"21937688"},{"id":"24069004-12060782-41849044","span":{"begin":6194,"end":6197},"obj":"12060782"},{"id":"24069004-16972078-41849045","span":{"begin":6199,"end":6202},"obj":"16972078"},{"id":"24069004-20010552-41849046","span":{"begin":6621,"end":6624},"obj":"20010552"},{"id":"24069004-21798285-41849047","span":{"begin":7121,"end":7124},"obj":"21798285"},{"id":"24069004-21937688-41849048","span":{"begin":7126,"end":7129},"obj":"21937688"},{"id":"24069004-16055773-41849049","span":{"begin":7753,"end":7755},"obj":"16055773"},{"id":"24069004-14990863-41849050","span":{"begin":7757,"end":7760},"obj":"14990863"},{"id":"24069004-8508730-41849051","span":{"begin":8134,"end":8137},"obj":"8508730"},{"id":"24069004-7938127-41849052","span":{"begin":8418,"end":8421},"obj":"7938127"},{"id":"24069004-16290108-41849053","span":{"begin":9542,"end":9545},"obj":"16290108"},{"id":"24069004-10681113-41849054","span":{"begin":10636,"end":10638},"obj":"10681113"},{"id":"24069004-16055773-41849055","span":{"begin":11252,"end":11254},"obj":"16055773"},{"id":"24069004-20525029-41849056","span":{"begin":11567,"end":11569},"obj":"20525029"}],"text":"Human studies\nHuman studies aimed at understanding the interaction of the ECBS with biological and behavioral correlates of addiction to psychostimulants have mostly focused on ECBS-related risk factors leading to drug dependence. Interestingly, cannabis use is strongly associated with the abuse and/or dependence of several class of drugs including psychostimulants such as cocaine (222). Moreover, exogenous cannabinoids have been shown to modulate the acute rewarding effects of cocaine. These lines of evidence may suggest an association between ECBS and liability to psychostimulant by pointing toward a possible involvement of the ECBS in the motivational effects mediated by psychostimulants (223) [reviewed in Ref. (224)]. Based on these observations, scientific efforts have been devoted to investigate the influence of various genetic (e.g., ECBS-related genes) and environmental characteristics (e.g., previous or current exposure to cannabinoid agonists) in individual progression from occasional use to psychostimulant addiction.\n\n“The gateway theory” and addiction to psychostimulants\nAssociation of prior or concomitant cannabis consumption with other illicit drugs including psychostimulants such as methamphetamine and cocaine, forms the basis of a well-known hypothesis – “ the gateway theory,” which suggests a causal role for cannabis in the development of subsequent drug use and addiction (225). While data indicate that smoking cannabis is positively associated with cocaine consumption, it would be inappropriate to assume that cannabis per se leads to cocaine use. A study from Lynskey et al. in human twins reveals that early cannabis use in life increases the odds of subsequent cocaine use, supporting the causative model of the “gateway theory.” However, results of this study have been refuted by Kandel et al. (226) which argues that several additional genetic, social, and environmental factors, such as life experiences, might link cannabis use with subsequent cocaine consumption (227, 228). Actual neurobiological causal mechanisms underlying this “gateway theory” remain mostly unidentified. Interestingly, Tomasiewicz and colleagues show that Δ9-THC exposure induces epigenetic dysregulation of the endogenous opioid proenkephalin in adolescents; these findings indicate that cannabis exposure, in and of itself, can be considered as a risk factor that acts “above the genome” and can “write” on the existing epigenetic background of adolescent neurodevelopment. Thus, in adolescents, Δ9-THC exposure-mediated epigenetic effects may act in concert with other environmental or social factors to augment future behavioral responses to drugs of abuse via stable and long-term regulation of genes at the transcriptional level. However, while these data establish a direct link between Δ9-THC-induced changes in proenkephalin expression and susceptibility to opiate drugs, no studies have confirmed that this mechanism can be applied to psychostimulants (229).\n\nGenetic determinants of the ECBS and psychostimulant addiction\nIt is worth mentioning that not every subject who experiences the pleasurable effects of psychostimulants will become a chronic user. Indeed it is more likely that additional factors such as: (1) genetic variabilities (e.g., polymorphisms in the catechol O-methyltransferase gene (Val158met) and in the serotonin transporter gene (5-HTTLPR) (230, 231); (2) monoamine receptors deficiency – either genetically or as a result of their drug excesses – also contribute to the psychostimulants addiction process (232–235) (see Table 1). In the ECBS, different genetic variants of the CB1 receptors – CNR1 – and FAAH genes have been associated with increased susceptibility to drug addiction. Indeed, genetic analyses demonstrate that the CNR1 gene exhibits elevated numbers of (AAT)n triplet repetition in a sample of 192 non-Hispanic Caucasian subjects. Interestingly, this CNR1 polymorphism increases the risk of intravenous drug use in this population, with strongest correlation observed in cocaine, amphetamine, and marijuana dependence (236). Similarly, a study from Ballon and colleagues shows that detection of this CNR1 polymorphism in a sample of 142 African-Caribbean individuals predisposed them to cocaine addiction (237). Unfortunately, while single sequence repetitions can alter transcriptional rates and thereby induced gene overexpression or silencing (238), the functional nature of the microsatellite polymorphism triplet repetition (AAT)n in modulating CNR1 gene expression remains blurred (239). It has been hypothesized that the presence of long alleles with high numbers of AAT triplets alter CNR1 transcriptional gene expression, ultimately leading to low levels of CNR1 protein synthesis (240). A recent meta-analysis of 11 studies aimed at investigating the contribution of three CNR1 polymorphisms (rs1049353, rs806379, and the AAT triplet repetitions) to drug dependence vulnerability confirmed the presence of (AAT)n repeats, but only in the Caucasian population [reviewed in Ref. (239)]. Unfortunately, the effect of the three CNR1 polymorphisms appeared to be insignificant and showed high heterogeneity. Important caveats have to be considered when looking at these studies. First, the ethnicity of the different subjects may prove important, as some studies included several ethnic groups in their samples, and in some cases, these groups were not even mentioned (241, 242). Some reports also examined CNR1 gene polymorphisms in connection with a different phenotype or stage of drug addiction such as craving, drug consumption, dependence, or drug withdrawal (243). Furthermore, a detailed description of the repercussions of CNR1 polymorphisms on CB1 function from a neurobiological standpoint is lacking from the reviewed studies.\nTable 1 ECBS and factors contributing to vulnerability to psychostimulants in humans. Polymorphisms in the gene coding for the endocannabinoid-inactivating enzyme FAAH may constitute another risk factor for problematic drug use, as described by initial reports identifying C385A, a mis-sense single nucleotide polymorphism (SNP) causing reduced FAAH enzymatic activity (245, 246). Indeed, a study from Sipe et al. reveals significant association between C385A SNP and street drug abuse in a sample of 1737 Caucasian subjects with addictive disorders. Neuroimaging studies combined with genetic analysis reveal that low FAAH activity enhances AEA protein expression levels which, in turn, modulate brain regions implicated in drug addiction and reward circuitry such as the OFC, AC gyrus, and NAc (242). Additional neuroimaging studies show that C385A carriers exhibit increased ventral striatal reactivity – a correlate for heightened impulsivity and reward sensitivity. C385A carriers display low threat-related amygdala reactivity – a pattern observed in individuals with high familial risk of alcoholism. Moreover, C385A polymorphism-reduced FAAH functional activity increases risk-taking behavior associated with addiction through abnormal impulsivity and threat perception [reviewed in Ref. (224, 243)]. Contribution of SNPs that modulate FAAH functions to stimulant addiction remain to be explored as the aforementioned data were not obtained in individuals specifically addicted to stimulants.\n\nEffect of exogenous cannabinoids on psychostimulant reward\nAs mentioned previously (see The Endocannabinoid System), an intriguing characteristic of psychostimulants abuse is the concurrent consumption of cannabis. Parallel to studies on the long-term effects of cannabis exposure on subsequent psychostimulant use, researchers also examined the acute rewarding effects of cannabis use on concurrent psychostimulant addiction (91, 222). However, studies aimed at investigating such interactions are sparse. Conflicting results from Foltin et al. and Lukas et al. provide evidence that cannabinoids modulate cocaine-mediated euphoric actions. First, data from Foltin and colleagues show that human volunteers who smoked cannabis prior to intravenous cocaine experience a prolongation of the “high” sensation (248). Second, a study from Lukas and colleagues reveals that smoking Δ9-THC, 30 min prior to intranasal cocaine decreases the latency to onset of cocaine-induced euphoria significantly, from 1.87 to 0.53 min, as well as the duration of cocaine-induced dysphoria, from 2.1 to 0.5 min (249). Interestingly, when both drugs are administered concomitantly, no changes are observed in cocaine- and Δ9-THC-induced positive subjective properties. Furthermore, Δ9-THC increases the peak plasma levels and bioavailability of cocaine considerably. This increase might be the result of Δ9-THC-induced vasodilation of the nasal mucosa which, in turn, reduces cocaine-induced vasoconstriction, thereby increasing cocaine’s absorption. In addition, the discrepancies between these two studies might be also due to pharmacodynamic mechanisms including differences in cocaine absorption or in the ratio of CBD/Δ9-THC levels found in the type of cannabis used for each study.\nUsing fMRI technology combined with script-guided imagery paradigm in which subjects imagined being in a real-life stressful situation, Rajita Sinha’s group found that cannabis abuse contributed to stress-induced blood-oxygen-level-dependent (BOLD) contrast in a group of cocaine-dependent individuals. More specifically, cannabis consumption decreases emotional stress cue-induced frontal and cingulate activation in cocaine-dependent individuals (247). These findings suggest an abnormal cognitive control mechanism during affective processing in association with heavy cannabis use. An important caveat to consider in the latter study is that cocaine-dependent individuals were abstinent for several weeks prior to the neuroimagery session and were not current users of cannabis. Thus the study did not allow to examine the acute effect of cannabis on neural and behavioral responses. However, the fact that this cannabis-induced alteration in stress-response can be translated to cocaine craving and relapse vulnerability has definitely piqued further interest, and initial data on this matter already exists. Indeed, the effects of cannabis consumption on abstinence and relapse to cocaine use have been provided in a study from Labigalini and colleagues, in which 25 cocaine-crack dependent individuals reported to smoke cannabis in order to get relief from abstinence mediated-cocaine-withdrawal symptoms. From this sample, 68% of addicts achieved crack-cocaine cessation while using cannabis during the 9 months duration of the study (90). However, the self-reported nature of this study and its limited duration suggest cautiousness in interpreting its outcome. In a more recent study, Aharonovich et al. drew opposite conclusions on the consequences of smoking cannabis on cocaine relapse. In this study, researchers investigated whether cannabis use after the discharge of 144 drug-addicts from inpatient treatment program could help them to maintain abstinence and thereby preventing relapse to cocaine use. Results from this study suggest that smoking cannabis reduced the achievement of sustained remission and increased relapse to cocaine use (91) (see Table 1). Surprisingly, a study from Jutras-Aswad et al. supports the assumption that irregular cannabis use increases risky behaviors (syringe sharing) of cocaine and opioid users, as opposed to regular cannabis use, suggesting a complex dose-effect relationship between cannabis and addictive behaviors (22). The possibility that cannabis use by recently abstinent cocaine-dependent individuals influences relapse to drug and other related behaviors remains poorly documented.\n"}

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studies\nHuman studies aimed at understanding the interaction of the ECBS with biological and behavioral correlates of addiction to psychostimulants have mostly focused on ECBS-related risk factors leading to drug dependence. Interestingly, cannabis use is strongly associated with the abuse and/or dependence of several class of drugs including psychostimulants such as cocaine (222). Moreover, exogenous cannabinoids have been shown to modulate the acute rewarding effects of cocaine. These lines of evidence may suggest an association between ECBS and liability to psychostimulant by pointing toward a possible involvement of the ECBS in the motivational effects mediated by psychostimulants (223) [reviewed in Ref. (224)]. Based on these observations, scientific efforts have been devoted to investigate the influence of various genetic (e.g., ECBS-related genes) and environmental characteristics (e.g., previous or current exposure to cannabinoid agonists) in individual progression from occasional use to psychostimulant addiction.\n\n“The gateway theory” and addiction to psychostimulants\nAssociation of prior or concomitant cannabis consumption with other illicit drugs including psychostimulants such as methamphetamine and cocaine, forms the basis of a well-known hypothesis – “ the gateway theory,” which suggests a causal role for cannabis in the development of subsequent drug use and addiction (225). While data indicate that smoking cannabis is positively associated with cocaine consumption, it would be inappropriate to assume that cannabis per se leads to cocaine use. A study from Lynskey et al. in human twins reveals that early cannabis use in life increases the odds of subsequent cocaine use, supporting the causative model of the “gateway theory.” However, results of this study have been refuted by Kandel et al. (226) which argues that several additional genetic, social, and environmental factors, such as life experiences, might link cannabis use with subsequent cocaine consumption (227, 228). Actual neurobiological causal mechanisms underlying this “gateway theory” remain mostly unidentified. Interestingly, Tomasiewicz and colleagues show that Δ9-THC exposure induces epigenetic dysregulation of the endogenous opioid proenkephalin in adolescents; these findings indicate that cannabis exposure, in and of itself, can be considered as a risk factor that acts “above the genome” and can “write” on the existing epigenetic background of adolescent neurodevelopment. Thus, in adolescents, Δ9-THC exposure-mediated epigenetic effects may act in concert with other environmental or social factors to augment future behavioral responses to drugs of abuse via stable and long-term regulation of genes at the transcriptional level. However, while these data establish a direct link between Δ9-THC-induced changes in proenkephalin expression and susceptibility to opiate drugs, no studies have confirmed that this mechanism can be applied to psychostimulants (229).\n\nGenetic determinants of the ECBS and psychostimulant addiction\nIt is worth mentioning that not every subject who experiences the pleasurable effects of psychostimulants will become a chronic user. Indeed it is more likely that additional factors such as: (1) genetic variabilities (e.g., polymorphisms in the catechol O-methyltransferase gene (Val158met) and in the serotonin transporter gene (5-HTTLPR) (230, 231); (2) monoamine receptors deficiency – either genetically or as a result of their drug excesses – also contribute to the psychostimulants addiction process (232–235) (see Table 1). In the ECBS, different genetic variants of the CB1 receptors – CNR1 – and FAAH genes have been associated with increased susceptibility to drug addiction. Indeed, genetic analyses demonstrate that the CNR1 gene exhibits elevated numbers of (AAT)n triplet repetition in a sample of 192 non-Hispanic Caucasian subjects. Interestingly, this CNR1 polymorphism increases the risk of intravenous drug use in this population, with strongest correlation observed in cocaine, amphetamine, and marijuana dependence (236). Similarly, a study from Ballon and colleagues shows that detection of this CNR1 polymorphism in a sample of 142 African-Caribbean individuals predisposed them to cocaine addiction (237). Unfortunately, while single sequence repetitions can alter transcriptional rates and thereby induced gene overexpression or silencing (238), the functional nature of the microsatellite polymorphism triplet repetition (AAT)n in modulating CNR1 gene expression remains blurred (239). It has been hypothesized that the presence of long alleles with high numbers of AAT triplets alter CNR1 transcriptional gene expression, ultimately leading to low levels of CNR1 protein synthesis (240). A recent meta-analysis of 11 studies aimed at investigating the contribution of three CNR1 polymorphisms (rs1049353, rs806379, and the AAT triplet repetitions) to drug dependence vulnerability confirmed the presence of (AAT)n repeats, but only in the Caucasian population [reviewed in Ref. (239)]. Unfortunately, the effect of the three CNR1 polymorphisms appeared to be insignificant and showed high heterogeneity. Important caveats have to be considered when looking at these studies. First, the ethnicity of the different subjects may prove important, as some studies included several ethnic groups in their samples, and in some cases, these groups were not even mentioned (241, 242). Some reports also examined CNR1 gene polymorphisms in connection with a different phenotype or stage of drug addiction such as craving, drug consumption, dependence, or drug withdrawal (243). Furthermore, a detailed description of the repercussions of CNR1 polymorphisms on CB1 function from a neurobiological standpoint is lacking from the reviewed studies.\nTable 1 ECBS and factors contributing to vulnerability to psychostimulants in humans. Polymorphisms in the gene coding for the endocannabinoid-inactivating enzyme FAAH may constitute another risk factor for problematic drug use, as described by initial reports identifying C385A, a mis-sense single nucleotide polymorphism (SNP) causing reduced FAAH enzymatic activity (245, 246). Indeed, a study from Sipe et al. reveals significant association between C385A SNP and street drug abuse in a sample of 1737 Caucasian subjects with addictive disorders. Neuroimaging studies combined with genetic analysis reveal that low FAAH activity enhances AEA protein expression levels which, in turn, modulate brain regions implicated in drug addiction and reward circuitry such as the OFC, AC gyrus, and NAc (242). Additional neuroimaging studies show that C385A carriers exhibit increased ventral striatal reactivity – a correlate for heightened impulsivity and reward sensitivity. C385A carriers display low threat-related amygdala reactivity – a pattern observed in individuals with high familial risk of alcoholism. Moreover, C385A polymorphism-reduced FAAH functional activity increases risk-taking behavior associated with addiction through abnormal impulsivity and threat perception [reviewed in Ref. (224, 243)]. Contribution of SNPs that modulate FAAH functions to stimulant addiction remain to be explored as the aforementioned data were not obtained in individuals specifically addicted to stimulants.\n\nEffect of exogenous cannabinoids on psychostimulant reward\nAs mentioned previously (see The Endocannabinoid System), an intriguing characteristic of psychostimulants abuse is the concurrent consumption of cannabis. Parallel to studies on the long-term effects of cannabis exposure on subsequent psychostimulant use, researchers also examined the acute rewarding effects of cannabis use on concurrent psychostimulant addiction (91, 222). However, studies aimed at investigating such interactions are sparse. Conflicting results from Foltin et al. and Lukas et al. provide evidence that cannabinoids modulate cocaine-mediated euphoric actions. First, data from Foltin and colleagues show that human volunteers who smoked cannabis prior to intravenous cocaine experience a prolongation of the “high” sensation (248). Second, a study from Lukas and colleagues reveals that smoking Δ9-THC, 30 min prior to intranasal cocaine decreases the latency to onset of cocaine-induced euphoria significantly, from 1.87 to 0.53 min, as well as the duration of cocaine-induced dysphoria, from 2.1 to 0.5 min (249). Interestingly, when both drugs are administered concomitantly, no changes are observed in cocaine- and Δ9-THC-induced positive subjective properties. Furthermore, Δ9-THC increases the peak plasma levels and bioavailability of cocaine considerably. This increase might be the result of Δ9-THC-induced vasodilation of the nasal mucosa which, in turn, reduces cocaine-induced vasoconstriction, thereby increasing cocaine’s absorption. In addition, the discrepancies between these two studies might be also due to pharmacodynamic mechanisms including differences in cocaine absorption or in the ratio of CBD/Δ9-THC levels found in the type of cannabis used for each study.\nUsing fMRI technology combined with script-guided imagery paradigm in which subjects imagined being in a real-life stressful situation, Rajita Sinha’s group found that cannabis abuse contributed to stress-induced blood-oxygen-level-dependent (BOLD) contrast in a group of cocaine-dependent individuals. More specifically, cannabis consumption decreases emotional stress cue-induced frontal and cingulate activation in cocaine-dependent individuals (247). These findings suggest an abnormal cognitive control mechanism during affective processing in association with heavy cannabis use. An important caveat to consider in the latter study is that cocaine-dependent individuals were abstinent for several weeks prior to the neuroimagery session and were not current users of cannabis. Thus the study did not allow to examine the acute effect of cannabis on neural and behavioral responses. However, the fact that this cannabis-induced alteration in stress-response can be translated to cocaine craving and relapse vulnerability has definitely piqued further interest, and initial data on this matter already exists. Indeed, the effects of cannabis consumption on abstinence and relapse to cocaine use have been provided in a study from Labigalini and colleagues, in which 25 cocaine-crack dependent individuals reported to smoke cannabis in order to get relief from abstinence mediated-cocaine-withdrawal symptoms. From this sample, 68% of addicts achieved crack-cocaine cessation while using cannabis during the 9 months duration of the study (90). However, the self-reported nature of this study and its limited duration suggest cautiousness in interpreting its outcome. In a more recent study, Aharonovich et al. drew opposite conclusions on the consequences of smoking cannabis on cocaine relapse. In this study, researchers investigated whether cannabis use after the discharge of 144 drug-addicts from inpatient treatment program could help them to maintain abstinence and thereby preventing relapse to cocaine use. Results from this study suggest that smoking cannabis reduced the achievement of sustained remission and increased relapse to cocaine use (91) (see Table 1). Surprisingly, a study from Jutras-Aswad et al. supports the assumption that irregular cannabis use increases risky behaviors (syringe sharing) of cocaine and opioid users, as opposed to regular cannabis use, suggesting a complex dose-effect relationship between cannabis and addictive behaviors (22). The possibility that cannabis use by recently abstinent cocaine-dependent individuals influences relapse to drug and other related behaviors remains poorly documented.\n"}