Gateway Drug Research Articles

The Gateway Hypothesis of substance abuse: developmental, biological and societal perspectives.

The Gateway Hypothesis describes how tobacco or alcohol use precedes marijuana and other illicit drug use. We review the epidemiological data, explore the underlying molecular mechanisms in mice and discuss the societal implications of the hypothesis, including the use of e-cigarettes by young people. Our mouse model identifies biological processes underlying the hypothesis, showing that nicotine is a gateway drug that exerts a priming effect on cocaine through increased global acetylation in the striatum.

Predictors of onset of cannabis and other drug use in male young adults: results from a longitudinal study.

BackgroundThe use of cannabis and other illegal drugs is particularly prevalent in male young adults and is associated with severe health problems. This longitudinal study explored variables associated with the onset of cannabis use and the onset of illegal drug use other than cannabis separately in male young adults, including demographics, religion and religiosity, health, social context, substance use, and personality. Furthermore, we explored how far the gateway hypothesis and the common liability to addiction model are in line with the resulting prediction models.MethodsThe data were gathered within the Cohort Study on Substance Use Risk Factors (C-SURF). Young men aged around 20 years provided demographic, social, health, substance use, and personality-related data at baseline. Onset of cannabis and other drug use were assessed at 15-months follow-up. Samples of 2,774 and 4,254 individuals who indicated at baseline that they have not used cannabis and other drugs, respectively, in their life and who provided follow-up data were used for the prediction models. Hierarchical logistic stepwise regressions were conducted, in order to identify predictors of the late onset of cannabis and other drug use separately.ResultsNot providing for oneself, having siblings, depressiveness, parental divorce, lower parental knowledge of peers and the whereabouts, peer pressure, very low nicotine dependence, and sensation seeking were positively associated with the onset of cannabis use. Practising religion was negatively associated with the onset of cannabis use. Onset of drug use other than cannabis showed a positive association with depressiveness, antisocial personality disorder, lower parental knowledge of peers and the whereabouts, psychiatric problems of peers, problematic cannabis use, and sensation seeking.ConclusionsConsideration of the predictor variables identified within this study may help to identify young male adults for whom preventive measures for cannabis or other drug use are most appropriate. The results provide evidence for both the gateway hypothesis and the common liability to addiction model and point to further variables like depressiveness or practising of religion that might influence the onset of drug use.

A molecular basis for nicotine as a gateway drug.

A molecular basis for nicotine as a gateway drug.

Evidence Backs Gateway Hypothesis in Drug Addiction

Evidence Backs Gateway Hypothesis in Drug Addiction

Parent, peer, and executive function relationships to early adolescent e-cigarette use: A substance use pathway?

IntroductionLittle is known about influences on e-cigarette use among early adolescents. This study examined influences that have been previously found to be associated with gateway drug use in adolescents: demographic (age, gender, ethnicity, free lunch), social contextual influences of parents and peers, and executive function deficits (EF). MethodsA cross-sectional survey was administered to 410 7th grade students from two diverse school districts in Southern California (M age;=12.4years, 48.3% female, 34.9% on free lunch (low socioeconomic status), 45.1% White, 25.4% Hispanic/Latino, 14.9% Mixed/bi-racial.) Logistic regression analyses examined influences of demographic, parent e-cigarette ownership and peer use, and EF on lifetime e-cigarette, and gateway drug use (cigarette and/or alcohol use). ResultsLifetime use prevalence was 11.0% for e-cigarettes, 6.8% for cigarettes, and 38.1% for alcohol. Free lunch and age were marginally related to e-cigarette use (p<.10). Parent e-cigarette ownership was associated with use of all substances, while peer use was associated with gateway drug use (p's<.05-.001). EF deficits were associated with use of all substances five times more likely than others to use e-cigarettes and over twice as likely to use gateway drugs. ConclusionsE-cigarette and gateway drug use may have common underlying risk factors in early adolescence, including parent and peer modeling of substance use, as well as EF deficits. Future research is needed to examine longitudinal relationships of demographics, parent and peer modeling, and EF deficits to e-cigarette use in larger samples, trajectories of e-cigarette use compared to use of other substances, and the potential of EF skills training programs to prevent e-cigarette use.

Is the order of substance initiation predictive of further substance use and misuse? A French population-based study

Background According to the Gateway theory (GT), licit drugs use lead to cannabis use, which can itself be followed by the initiation of other illicit drugs (OID). The aim of this study was to evaluate if the order of initiation sequence could influence further substance use or misuse among young adults. Method Data from the 2010 Health Barometer, a French nationwide population-based study on drug use, were used (22,774 subjects aged from 15 to 64). …

A Molecular Basis for Nicotine as a Gateway Drug

On the historic occasion of the 122nd Shattuck Lecture and the 200th anniversary of the New England Journal of Medicine, we chose to address a topic that is at once scientific and personally historic. In recent debates over legalizing marijuana, from all-out acceptance in Colorado to narrow decriminalization in Maryland, the scientific question of the role of marijuana as a gateway drug (i.e., a drug that lowers the threshold for addiction to other agents) has loomed large. Both opponents and proponents of legalization have distorted what science does and does not tell us — and both sides have overlooked the . . .

OR15-1 * THE GATEWAY HYPOTHESIS, COMMON LIABILITY TO ADDICTIONS OR THE ROUTE OF ADMINISTRATION MODEL? AN ORIGINAL MODELLING PROCESS LINKING THE THREE THEORIES

Background. The aim of this study was to describe the patterns of transition across tobacco, cannabis and other illicit drugs (OID) use by investigating simultaneously the Gateway theory (GT), the Common liability model (CLM) and the Route of administration model (RAM). Method. A French nationwide retrospective cohort on drug use was reconstituted from the reports of 1,063 young adults on their lifetime experience with tobacco, cannabis and OID. A multi-state model was fitted, modelling all possible pathways from no use to initiation of the three substances. This model was adjusted on drug-use liability, a latent variable constructed with an item response theory model and reflecting early onset, high levels of use and poly-substance use. Results. The most likely onset sequence was the gateway sequence: no use-tobacco-cannabis-OID. The liability variable was mainly associated with the beginning of the sequence whatever the substance used first: an increase of 1 for this variable was associated with a 1.9 [1.7-2.0] times greater likelihood of starting the sequence with tobacco, a 3.0 [2.3-3.9] times greater likelihood of starting with cannabis and a 5.1 [2.1-125.0] times greater likelihood of starting by OID. The liability variable was also associated, for subjects who had not yet initiated OID, with the initiation of cannabis after tobacco and the initiation of tobacco after cannabis. Conclusions. This study, using an original modelling procedure to describe onset sequences, is in line with a substance use process involving simultaneously GT, CLM and RAM. This suggests shared influences of individual and environmental characteristics. The common liability could contribute to initiation of the use sequence, whatever the first substance used. The rest of the sequence seems to follow a gateway pattern (tobacco, cannabis and then OID) in most cases, which could be the consequence of variations in substance availability during the life. Our drug use liability variable was finally associated, for subjects who had not yet initiated OID, with the transitions between tobacco and cannabis, which would suggest reciprocal relationships between these two substances in line with RAM.

All gates lead to smoking: The ‘gateway theory’, e-cigarettes and the remaking of nicotine

The idea that drug use in ‘softer’ forms leads to ‘harder’ drug use lies at the heart of the gateway theory, one of the most influential models of drug use of the twentieth century. Although hotly contested, the notion of the ‘gateway drug’ continues to rear its head in discussions of drug use—most recently in the context of electronic cigarettes. Based on a critical reading of a range of texts, including scholarly literature and media reports, we explore the history and gestation of the gateway theory, highlighting the ways in which intersections between academic, media and popular accounts actively produced the concept. Arguing that the theory has been critical in maintaining the distinction between ‘soft’ and ‘hard’ drugs, we turn to its distinctive iteration in the context of debates about e-cigarettes. We show that the notion of the ‘gateway’ has been transformed from a descriptive to a predictive model, one in which nicotine is constituted as simultaneously ‘soft’ and ‘hard’—as both relatively innocuous and incontrovertibly harmful.

ADHD as a risk factor for early onset and heightened adult problem severity of illicit substance use: An accelerated gateway model

The primary aims of the present study were to assess ADHD history as a risk factor for earlier initiation and current use of licit and illicit substances among a sample of drug using adults. It was hypothesized that ADHD history would accelerate the Gateway Theory of drug use. Participants included 941 drug-using African American and Caucasian individuals in Baltimore, Maryland. The sample consisted of 124 (13.2%) participants who reported a history of ADHD and 817 (86.8%) who reported no history of ADHD. The accelerated gateway hypothesis was supported, as a history of self-reported ADHD was significantly associated with younger ages of initiation for alcohol, cigarettes, marijuana, and cocaine use. Participants with a history of ADHD were also more likely to engage in recent HIV-risk behavior, such as injection drug use and needle sharing. This study provides compelling data in support of an accelerated gateway model for substance use related to ADHD history and increased problem severity in adulthood. Targeted substance use prevention and intervention may be beneficial for those with ADHD.

E-cigarettes--prevention, pulmonary health, and addiction.

E-cigarettes are coming into wider use. They are advertised as an aid to smoking cessation, but there is concern that they may also serve as a gateway drug for cigarette smoking. The authors systematically searched the PubMed database for relevant publications on the mechanism of action of e-cigarettes, the nature of their emissions, their assessment by potential users, their efficacy in smoking cessation, and their potential for addiction. There have been many reports of epidemiologically uninformative case series in which smokers were helped to stop smoking by the use of e- cigarettes. Only two controlled trials have shown that e-cigarettes have approximately the same effect as nicotine substitution therapy when used as an aid to smoking cessation. The effect is nearly independent of nicotine content. E-cigarettes are also consumed, to a small extent, by nonsmokers. As far as can be estimated toxicologically at present, the danger to active and passive smokers of e-cigarettes is presumably orders of magnitude less than that of tobacco smokers, although the variable composition of the fluids used in e-cigarettes introduces a degree of uncertainty. Preclinical and initial clinical data, including some data from randomized controlled trials, indicate that e-cigarettes may be useful as an aid to smoking cessation or as a means of lowering risk in high-risk groups. In contrast to the demonstrated efficacy of multimodal smoking-cessation programs with pharmacological and psychotherapeutic support, the efficacy of e-cigarettes in smoking cessation has not yet been satisfactorily shown. Valid and informative clinical trials are urgently needed. These should also be designed to determine what predisposition(s), if any, might make the use of e-cigarettes more or less successful than that of other aids to smoking cessation. Moreover, e-cigarettes might be a gateway drug for cigarette smoking; thus, no clear recommendation about their use can be made at present.

Profile of nicotine use among alcohol dependent patients visiting a tertiary care center in north India.

Background:Use of tobacco among alcohol dependent population is quite frequent. This co-morbidity increases the risk for various diseases. Understanding the pattern of tobacco use with co-morbid alcohol use may help in planning appropriate prevention/treatment strategies. The study aimed at examining the profile and pattern of nicotine use among alcohol dependent patients visiting a tertiary care treatment center in North India.Materials and Methods:Male patients fulfilling diagnostics and statistical manual of mental disorder fourth edition, criteria for nicotine and alcohol diagnostics and statistical dependence, attending the out-patient department of the tertiary care treatment center were recruited after obtaining informed consent. The socio-demographic profile, drug use history, nicotine associated health problems and general health problem were recorded. Motivation to stop tobacco use was assessed qualitatively using the direct questions about their interest and intentions to quit.Results:A total of 150 subjects were included in the study. The mean age of the study sample was 37.6 ± 10.44 years. Tobacco was reported as the gateway drug in 90% of the cases. Exclusive bidi use reported in 42% of the subjects. Mean duration of bidi and co-morbid alcohol use was higher than cigarette or smokeless tobacco use. Self-reported health problems associated with nicotine use and general health was reported by 41% and 39% of the subjects. Unsuccessful past quit attempts was present in 85% cases. More than 90% of subjects remained interested in quitting the tobacco use. An increased liver enzyme (aspartate transaminase, alanine transaminase and gamma-glutamyl transferase) were observed in 43, 32 and 47% of the cases.Conclusion:The results suggest the nicotine and alcohol dependent patients represent a separate population requiring higher attention from the treating physician.

Substance Abuse: Risk Factors for Turkish Youth

Objective: Substance abuse amongst youth has been growing in developed and developing nations, including Turkey. This growth is related to a number of factors, not the least of which are forces associated with development, globalization, and youth culture. The identification of risk factors for youth substance abuse for particular populations is an important approach to the development of prevention and intervention strategies. Methods: We analyzed the data from a survey of 31,272 youth ages 14 to 18 years enrolled in high schools in Istanbul that covered the use of various substances as well as a number of demographic, socioeconomic, cultural, psychopathological, and psychosocial risk factors. Our data consisted of answers to similar questions that were asked in European School Survey Project (ESPAD), Youth in Europe (YIE), and Monitoring of the Future Survey and the National Household Survey in USA. We used binary logistic regression analyses to generate risk profiles for each of the following categories of lifetime use: tobacco, alcohol, cannabis, other illicit drugs, and multiple (two or more) other illicit drugs. Results: We identified statistically significant risk profiles for these different substance categories. All the different risk factor categories contributed variably to the use of gateway drugs (tobacco, alcohol, marijuana, and other illicits), but the multiple use of other illicit drugs was associated primarily with a narrower set of psychopathological (suicidality, irritability, and antisocial problems) and psychosocial variables (family substance abuse and peer influence). Conclusions: These risk profiles share some commonality with those found amongst other populations. However, these unique risk profiles for Turkish youth can be useful in developing primary and secondary preventive interventions to address the growing substance use and abuse problems. Cross-sectional and longitudinal studies, focusing on time trends and risk factors of substance use in youth of emerging countries including Turkey, are needed.

D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus

The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We find that a single injection of cocaine does not alter LTP. However, pretreatment with nicotine followed by a single injection of cocaine causes a substantial enhancement of LTP. This priming effect of nicotine is unidirectional: There is no enhancement of LTP if cocaine is administrated prior to nicotine. The facilitation induced by nicotine and cocaine can be blocked by oral administration of the dopamine D1/D5 receptor antagonist (SKF 83566) and enhanced by the D1/D5 agonist (SKF 38393). Application of the histone deacetylation inhibitor suberoylanilide hydroxamic acid (SAHA) simulates the priming effect of nicotine on cocaine. By contrast, the priming effect of nicotine on cocaine is blocked in genetically modified mice that are haploinsufficient for the CREB-binding protein (CBP) and possess only one functional CBP allele and therefore exhibit a reduction in histone acetylation. These results demonstrate that the DG of the hippocampus is an important brain region contributing to the priming effect of nicotine on cocaine. Moreover, both activation of dopamine-D1 receptor/PKA signaling pathway and histone deacetylation/CBP mediated transcription are required for the nicotine priming effect in the DG.

Does premarital education decrease or increase couples’ later help-seeking?

Interventions intended to prevent relationship distress are expected to enhance relationship satisfaction and, in turn, reduce the need for later couples counseling. We test this prediction against an alternative possibility: participation in preventive interventions may operate as a gateway for later help-seeking, paradoxically increasing receipt of later couples counseling. A cross-sectional study of 2,126 married individuals examined whether participation in premarital education covaried inversely or directly with couples counseling. Consistent with the gateway hypothesis, receiving premarital education covaried with an increased likelihood of receiving couples counseling. The association between receipt of premarital education and pursuit of couples counseling was moderated by demographic indicators, with the association being stronger for African Americans and for individuals with lower incomes and less formal education. Encouraging the use of premarital interventions may increase the use of therapeutic interventions later in the relationship, especially among high-risk populations.

Mechanisms of Metabonomic for a Gateway Drug: Nicotine Priming Enhances Behavioral Response to Cocaine with Modification in Energy Metabolism and Neurotransmitter Level

Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP) models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. 1H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc) and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.

Neurotensin agonist attenuates nicotine potentiation to cocaine sensitization.

Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a “gateway drug”. Neurotensin (NT) is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13) analog, blocks behavioral sensitization (an animal model for psychostimulant addiction) to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control) followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine.

The mysterious Spotted Green Pigeon and its relation to the Dodo and its kindred.

BackgroundThe closely related and extinct Dodo (Raphus cucullatus) and Rodrigues Solitaire (Pezophaps solitaria), both in the subfamily Raphinae, are members of a clade of morphologically very diverse pigeons. Genetic analyses have revealed that the Nicobar Pigeon (Caloenas nicobarica) is the closest living relative of these birds, thereby highlighting their ancestors’ remarkable migration and morphological evolution. The Spotted Green Pigeon (Caloenas maculata) was described in 1783 and showed some similarities to the Nicobar Pigeon. Soon however the taxon fell into obscurity, as it was regarded as simply an abnormal form of the Nicobar Pigeon. The relationship between both taxa has occasionally been questioned, leading some ornithologists to suggest that the two may in fact be different taxa. Today only one of the original two specimens survives and nothing is known about the origin of the taxon. Due to its potential close relationship, the Spotted Green Pigeon may hold clues to the historical migration, isolation and morphological evolution of the Dodo and its kindred.ResultsWe use ancient DNA methodologies to investigate the phylogeny and authenticity of the Spotted Green Pigeon. A novel extraction method with the ability to retain and purify heavily fragmented DNA is used to investigate two feathers from the sole surviving specimen. Maximum Likelihood phylogenetic analyses reveal that the Spotted Green Pigeon is a unique lineage and together with the Nicobar Pigeon, is basal to the Dodo and Rodrigues Solitaire.ConclusionsThe distance observed for the Spotted Green Pigeon and Nicobar Pigeon is larger than that observed within other Pigeon species, indicating that the Spotted Green pigeon is a unique taxon, thereby also indicating it is a genuine addition to the list of extinct species. The phylogenetic placement of the Spotted Green Pigeon indicates that the ancestors of both Caloenas and therefore Raphinae displayed and shared the following traits: ability of flight, semi-terrestrial habits and an affinity towards islands. This set of traits supports the stepping stone hypothesis, which states that the Raphinae got to their respective localities by island hopping from India or Southeast Asia.

Etiology of drug abuse: a narrative analysis.

Introduction and Aim. Further gains in the prevention of drug abuse disorders require in-depth and holistic understanding of the risk factors of addiction from different perspectives. Lay persons and experts have different concepts of risk which could complement each other. The purpose of this study was to elaborate drug abuse risk factors through the story of individuals who had become drug dependent. Design and Methods. In this qualitative research, 33 individuals attending treatment centres for drug abuse were interviewed about the story of their addiction in Kerman, Iran. Interview questions were around the story of the participants. Results. All participants were male and in the age range of 18–40 years. Narrative analysis identified five themes as the main risk factors: family factors, peer pressure, the effect of gateway drugs (especially waterpipe), individual characteristics, and the community factors. More emphasis was placed upon the role of family factors, peer influence, and gateway effect. Discussion and Conclusion. This study elicited information from drug dependent subjects regarding the risk factors of drug abuse. According to drug dependent individuals' views, more attention should be devoted to family and peer influences by policy makers, in developing culture-based preventive strategies.

Functional interplay between stimulus-oriented and stimulus-independent attending during a prospective memory task

Recent studies have suggested that medial (medBA10) and lateral (latBA10) portions of the Brodmann area 10 subserve respectively stimulus-oriented (SO) and stimulus-independent (SI) attending during prospective memory (PM) tasks. We investigated this dissociation by manipulating the saliency (SO) and the memory load (SI) of PM cues. Sixteen healthy subjects participated to a functional imaging protocol with a 2×2×2 experimental design, including the factors: task (ongoing target vs. PM cue), Saliency (high vs. low; with targets/cues either embedded or standing out from distracters), and memory load (high vs. low; with 1 or 4 possible PM targets). We localized the medBA10 and latBA10 by means of a localizer task. In medBA10 we found a significant main effects of high Saliency and low memory load; whereas in the left latBA10, we found a significant task×load interaction, with maximal activation for PM cues presented in the high load condition. These results are in agreement with the gateway hypothesis: during a PM task medBA10 biases attention toward external salient stimuli, SO attending, while latBA10 biases attention toward internal mnemonic representations, SI attending. Additional whole-brain analyses highlighted activation of other areas besides BA10, consistent with recent proposals that emphasise the role of distributed networks during PM performance.