Gateway drug effect
Gateway drug effect (alternatively, stepping-stone theory, escalation hypothesis, or progression hypothesis) is a comprehensive catchphrase for the often observed effect that the use of a psychoactive drug is coupled to an increased probability of the use of further drugs. Possible causes are biological alterations in the brain due to the earlier drug and similar attitudes of users across different drugs (common liability to addiction).
- 1 Sequence of first-time use
- 2 Associations aside from first-time use
- 3 Causes
- 4 History
- 5 See also
- 6 References
- 7 Further reading
- 8 External links
Sequence of first-time use
The concept of gateway drug is based on observations that the sequence of first-time use of different drugs is not random but shows trends. On the basis of established techniques of longitudinal studies such trends can be described precisely in terms of statistical probability. As to the interpretation of the observed trends, it is important to note the difference between sequence and causation. Both may – but need not – be coupled, a question which is subject of further research, e.g., by physiological experiments.
Examples of trends
From a sample of 6,624 people who had not used other illegal drugs before their cannabis consumption the overall probability of later use of other illegal drugs was estimated to be 44.7%. Subgroup analyses showed that personal and social conditions, such as gender, age, marital status, mental disorders, family history of substance abuse, overlapping illegal drug distribution channels, alcohol use disorder, nicotine dependence, ethnicity, urbanicity, and educational attainment influenced the height of probability.
A study of drug use of 14,577 US 12th graders showed that alcohol consumption was associated with an increased probability of later use of tobacco, cannabis, and other illegal drugs. Adolescents who smoked cigarettes before age 15 were up to 80 times more likely to use illegal drugs. Studies indicate vaping serves as a gateway to traditional cigarettes and cannabis use.
Large-scale longitudinal studies in the UK and New Zealand from 2015 and 2017 showed an association between cannabis use and an increased probability of later disorders in the use of other drugs.
Students who regularly consume caffeinated energy drinks have a greater risk of alcohol use disorder, cocaine use and misuse of prescription stimulants. The elevated risk remains after accounting for prior substance use and other risk factors. 
Associations aside from first-time use
The role of cannabis use in regard to alcohol use and Alcohol Use Disorder (AUD) is not fully understood. Some studies suggest better alcohol treatment completion for those who use cannabis while other studies find the opposite. A recent review of 39 studies which examined the relation between cannabis use and alcohol use found that 16 studies support the idea that cannabis and alcohol are substitutes for each other, 10 studies found that they are complements, 12 found that they are neither complementary nor substitutes, and one found that they are both.
A study involving self-reported data from a sample of 27,461 people examined the relationship of cannabis use and AUD. These respondents had no prior diagnosis of AUD. Of the 27,461 people, 160 had reported cannabis use within the past year. At the end of a three year period it found that those who had previously reported cannabis use were associated with a five times greater odds of being diagnosed with AUD than those who had not. After adjustment for select confounders (age, race, marital status, income, and education), these odds were reduced to 2 times greater risk. Another sample of self-reported data from 2,121 persons included only those who had already been diagnosed with AUD. In this sample it was found that those who had reported cannabis use in the past year (416 people) were associated with 1.7 greater odds of AUD persistence three years later. After adjustment for the same confounders as before, these odds were reduced to 1.3.
Because a sequence of first-time use can only indicate the possibility – but not the fact – of an underlying causal relation, different theories concerning the observed trends were developed. The scientific discussion (state of 2016) is dominated by two concepts, which appear to cover almost all possible causal connections if appropriately combined. These are the theories of biological alterations in the brain due to an earlier drug use and the theory of similar attitudes across different drugs.
Alterations in the brain
Adolescent rats repeatedly injected with tetrahydrocannabinol increased the self-administration of heroin (results based on 11 male rats and >50 male rats), morphine (study based on 12 male rats) and also nicotine (34 rats). There were direct indications that the alteration consisted of lasting anatomical changes in the reward system of the brain. Because the reward system is anatomically, physiologically, and functionally almost identical across the class of mammals, the importance of the findings from animal studies for the reward system in the human brain in relation to the liability to the use of further drugs has been pointed out in several reviews.
In mice nicotine increased the probability of later consumption of cocaine and the experiments permitted concrete conclusions on the underlying molecular biological alteration in the brain. The biological changes in mice correspond to the epidemiological observations in humans that nicotine consumption is coupled to an increased probability of later use of cannabis and cocaine, as well as other drugs.
In rats alcohol increased the probability of later addiction to cocaine and again relevant alterations in the reward system were identified. These observations thus correspond to the epidemiological findings that the consumption of alcohol in humans is coupled to a later increased risk of a transition from cocaine use to cocaine addiction.
Controlled animal and human studies showed that caffeine (energy drinks) in combination with alcohol increased the craving for more alcohol more strongly than alcohol alone. These findings correspond to epidemiological data that users of energy drinks generally showed an increased tendency to take alcohol and other drugs.
According to the concept of similar attitudes across different drugs (common liability to addiction), a number of personal, social, genetic and environmental factors can lead to a generally increased interest in various drugs. The sequence of first-time use would then depend on these factors. Violations of the typical sequence of first-time drug usage give credit to this theory. For example, in Japan, where cannabis use is uncommon, 83.2% of the users of illicit drugs did not use cannabis first. The concept received additional support from a large-scale genetic analysis that showed a genetic basis for the connection of the prevalence of cigarette smoking and cannabis use during the life of a person.
The results of a twin study presented indications that familial genetic and familial environmental factors do not fully explain these associations, and are possibly only relevant for sequences of some drugs. In 219 same-sex Dutch identical and non-identical twin pairs, one co-twin had reported cannabis use before the age of 18 whereas the other had not. In the cannabis group the lifetime prevalence of later reported use of party drugs was four times higher and the lifetime prevalence of later reported use of hard drugs was seven times higher than in the non-cannabis group. The authors concluded that at least family influences – both genetic and social ones – could not explain the differences. The study noted that, besides a potential causal role of cannabis use, non shared environment factors could play a role in the association such as differing peer affiliations that preceded the cannabis use.
Another twin study (of 510 same sex twin pairs) also examined the association of earlier cannabis use and later hard drug use. Like other studies it examined later drug use differences between siblings where one sibling had used cannabis early and the other had not. The study examined identical twins (who share approximately 100% of their genes) and non-identical twins (who share approximately 50% of their genes) separately and adjusted for additional confounders such as peer drug use. It found, after confounder adjustment, that the associations with later hard drug use existed only for non-identical twins. This suggests a significant genetic factor in the likelihood of later hard drug usage. The study suggested that a causal role of cannabis use in later hard drug usage is minimal, if it exists at all, and that cannabis use and hard drug use share the same influencing factors such as genetics and environment.
While the phrase gateway drug was first popularized by anti-drug activists such as Robert DuPont in the 1980s, the underlying ideas had already been discussed since the 1930s by using the phrases stepping-stone theory, escalation hypothesis, or progression hypothesis.
- Vanyukov MM, Tarter RE, Kirillova GP, et al. (June 2012). "Common liability to addiction and "gateway hypothesis": theoretical, empirical and evolutionary perspective". Drug Alcohol Depend (Review). 123 Suppl 1: S3–17. doi:10.1016/j.drugalcdep.2011.12.018. PMC 3600369. PMID 22261179.
- D. B. Kandel (Ed.): Stages and Pathways of Drug Involvement: Examining the Gateway Hypothesis, Cambridge University Press, 2002, ISBN 978-0-521-78969-1, pp. 3-10.
- Secades-Villa, R; Garcia-Rodríguez, O; Jin, C. J.; Wang, S; Blanco, C (2015). "Probability and predictors of the cannabis gateway effect: A national study". International Journal of Drug Policy. 26 (2): 135–142. doi:10.1016/j.drugpo.2014.07.011. PMC 4291295. PMID 25168081.
- Kluger B, Triolo P, Jones W, Jankovic J (2015). "The therapeutic potential of cannabinoids for movement disorders". Movement Disorders. 30 (3): 313–27. doi:10.1002/mds.26142. PMC 4357541. PMID 25649017.
- Kirby, T; Barry, A. E. (2012). "Alcohol as a gateway drug: A study of US 12th graders" (PDF). Journal of School Health. 82 (8): 371–9. doi:10.1111/j.1746-1561.2012.00712.x. PMID 22712674.
- Fadus, Matthew C.; Smith, Tracy T.; Squeglia, Lindsay M. (2019). "The rise of e-cigarettes, pod mod devices, and JUUL among youth: Factors influencing use, health implications, and downstream effects". Drug and Alcohol Dependence. 201: 85–93. doi:10.1016/j.drugalcdep.2019.04.011. ISSN 0376-8716. PMID 31200279.
- Courtney KE, Mejia MH, Jacobus J (2017). "Longitudinal Studies on the Etiology of Cannabis Use Disorder: A Review". Current Addiction Reports. 4 (2): 43–52. doi:10.1007/s40429-017-0133-3. PMC 5644349. PMID 29057198.
- Badiani A, Boden JM, De Pirro S, Fergusson DM, Horwood LJ, Harold GT (2015). "Tobacco smoking and cannabis use in a longitudinal birth cohort: evidence of reciprocal causal relationships". Drug and Alcohol Dependence. 150: 69–76. doi:10.1016/j.drugalcdep.2015.02.015. PMID 25759089.
- Taylor M, Collin SM, Munafò MR, MacLeod J, Hickman M, Heron J (2017). "Patterns of cannabis use during adolescence and their association with harmful substance use behaviour: findings from a UK birth cohort". Journal of Epidemiology and Community Health. 71 (8): 764–770. doi:10.1136/jech-2016-208503. PMC 5537531. PMID 28592420.
- "Energy drinks and risk to future substance use". www.drugabuse.gov. National Institute on Drug Abuse. 8 August 2017. Retrieved 29 March 2019.
- National Academies of Sciences, Engineering, and Medicine. Health and Medicine Division. Board on Population Health and Public Health Practice. Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems (2018). "Public Health Consequences of E-Cigarettes". National Academies of Sciences. doi:10.17226/24952. PMID 29894118.CS1 maint: multiple names: authors list (link)
- Subbaraman, MS (2014). "Can cannabis be considered a substitute medication for alcohol?". Alcohol and Alcoholism (Oxford, Oxfordshire). 49 (3): 292–8. doi:10.1093/alcalc/agt182. PMC 3992908. PMID 24402247.
- Subbaraman, MS (18 September 2016). "Substitution and Complementarity of Alcohol and Cannabis: A Review of the Literature". Substance Use & Misuse. 51 (11): 1399–414. doi:10.3109/10826084.2016.1170145. PMC 4993200. PMID 27249324.
- Yurasek Ali M., Aston Elizabeth R., Metrik Jane (2017). "Yurasek, A.M., Aston, E.R. & Metrik (2017). Co-use of Alcohol and Cannabis: A Review, J. Curr Addict Rep 4: 184. | SpringerLink". Current Addiction Reports. 4 (2): 184–193. doi:10.1007/s40429-017-0149-8.CS1 maint: multiple names: authors list (link)
- Weinberger, A. H.; Platt, J; Goodwin, R. D. (2016). "Is cannabis use associated with an increased risk of onset and persistence of alcohol use disorders? A three-year prospective study among adults in the United States". Drug and Alcohol Dependence. 161: 363–7. doi:10.1016/j.drugalcdep.2016.01.014. PMC 5028105. PMID 26875671.
- Morral, A. R.; McCaffrey, D. F.; Paddock, S. M. (2002). "Reassessing the marijuana gateway effect". Addiction. 97 (12): 1493–1504. doi:10.1046/j.1360-0443.2002.00280.x. PMID 12472629. (Review).
- Fergusson, D. M.; Boden, J. M.; Horwood, L. J. (2006). "Cannabis use and other illicit drug use: Testing the cannabis gateway hypothesis". Addiction. 101 (4): 556–569. doi:10.1111/j.1360-0443.2005.01322.x. PMID 16548935.
- Ellgren, M; Spano, S. M.; Hurd, Y. L. (2007). "Adolescent cannabis exposure alters opiate intake and opioid limbic neuronal populations in adult rats". Neuropsychopharmacology. 32 (3): 607–615. doi:10.1038/sj.npp.1301127. PMID 16823391.
- Tomasiewicz HC, Jacobs MM, Wilkinson MB, Wilson SP, Nestler EJ, Hurd YL (2012). "Proenkephalin mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability". Biol Psychiatry. 72 (10): 803–10. doi:10.1016/j.biopsych.2012.04.026. PMC 3440551. PMID 22683090.CS1 maint: multiple names: authors list (link)
- Cadoni, C; Pisanu, A; Solinas, M; Acquas, E; Di Chiara, G (2001). "Behavioural sensitization after repeated exposure to Delta 9-tetrahydrocannabinol and cross-sensitization with morphine". Psychopharmacology. 158 (3): 259–266. doi:10.1007/s002130100875. PMID 11713615.
- Panlilio, L. V.; Zanettini, C; Barnes, C; Solinas, M; Goldberg, S. R. (2013). "Prior Exposure to THC Increases the Addictive Effects of Nicotine in Rats". Neuropsychopharmacology. 38 (7): 1198–1208. doi:10.1038/npp.2013.16. PMC 3656362. PMID 23314220.
- O'Connell LA, Hofmann HA (2011). "The vertebrate mesolimbic reward system and social behavior network: a comparative synthesis". J Comp Neurol. 519 (18): 3599–639. doi:10.1002/cne.22735. PMID 21800319.
- Alcaro A, Panksepp J (2011). "The SEEKING mind: primal neuro-affective substrates for appetitive incentive states and their pathological dynamics in addictions and depression" (PDF). Neurosci Biobehav Rev. 35 (9): 1805–20. doi:10.1016/j.neubiorev.2011.03.002. PMID 21396397.
- Panksepp J (2011). "The basic emotional circuits of mammalian brains: do animals have affective lives?" (PDF). Neurosci Biobehav Rev. 35 (9): 1791–804. doi:10.1016/j.neubiorev.2011.08.003. PMID 21872619.
- Panlilio LV, Justinova Z (2018). "Preclinical Studies of Cannabinoid Reward, Treatments for Cannabis Use Disorder, and Addiction-Related Effects of Cannabinoid Exposure". Neuropsychopharmacology. 43 (1): 116–141. doi:10.1038/npp.2017.193. PMC 5719102. PMID 28845848.
- Parsons LH, Hurd YL (2015). "Endocannabinoid signalling in reward and addiction". Nature Reviews. Neuroscience. 16 (10): 579–94. doi:10.1038/nrn4004. PMC 4652927. PMID 26373473. (Review).
- Covey DP, Wenzel JM, Cheer JF (2015). "Cannabinoid modulation of drug reward and the implications of marijuana legalization". Brain Research. 1628 (Pt A): 233–43. doi:10.1016/j.brainres.2014.11.034. PMC 4442758. PMID 25463025., PDF (Review).
- Renard J, Rushlow WJ, Laviolette SR (2016). "What Can Rats Tell Us about Adolescent Cannabis Exposure? Insights from Preclinical Research". Canadian Journal of Psychiatry. 61 (6): 328–34. doi:10.1177/0706743716645288. PMC 4872245. PMID 27254841., PDF (Review).
- E. R. Kandel; D. B. Kandel (2014). "A Molecular Basis for Nicotine as a Gateway Drug". New England Journal of Medicine. 371 (10): 932–943. doi:10.1056/NEJMsa1405092. PMC 4353486. PMID 25184865.
- Keyes, K. M.; Hamilton, A; Kandel, D. B. (2016). "Birth Cohorts Analysis of Adolescent Cigarette Smoking and Subsequent Marijuana and Cocaine Use". American Journal of Public Health. 106 (6): 1143–9. doi:10.2105/AJPH.2016.303128. PMC 4880234. PMID 27077359.
- Ren M, Lotfipour S (2019). "Nicotine Gateway Effects on Adolescent Substance Use". West J Emerg Med. 20 (5): 696–709. doi:10.5811/westjem.2019.7.41661. PMC 6754186. PMID 31539325.
- Griffin EA, Melas PA, Zhou R, Li Y, Mercado P, Kempadoo KA (2017). "Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5". Sci Adv. 3 (11): e1701682. doi:10.1126/sciadv.1701682. PMC 5665598. PMID 29109977.CS1 maint: multiple names: authors list (link)
- Anderson EM, Penrod RD, Barry SM, Hughes BW, Taniguchi M, Cowan CW (2019). "It is a complex issue: emerging connections between epigenetic regulators in drug addiction". Eur J Neurosci. 50 (3): 2477–2491. doi:10.1111/ejn.14170. PMID 30251397.CS1 maint: multiple names: authors list (link)
- Lopez-Quintero C, Pérez de los Cobos J, Hasin DS, Okuda M, Wang S, Grant BF (2011). "Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)". Drug Alcohol Depend. 115 (1–2): 120–30. doi:10.1016/j.drugalcdep.2010.11.004. PMC 3069146. PMID 21145178.CS1 maint: multiple names: authors list (link)
- Bickel WK, Snider SE, Quisenberry AJ, Stein JS, Hanlon CA (2016). "Competing neurobehavioral decision systems theory of cocaine addiction: From mechanisms to therapeutic opportunities". Prog Brain Res. 223: 269–93. doi:10.1016/bs.pbr.2015.07.009. PMC 5495192. PMID 26806781.CS1 maint: multiple names: authors list (link)
- Curran CP, Marczinski CA (2017). "Taurine, caffeine, and energy drinks: Reviewing the risks to the adolescent brain". Birth Defects Res. 109 (20): 1640–1648. doi:10.1002/bdr2.1177. PMC 5737830. PMID 29251842.
- Arria AM, Caldeira KM, Kasperski SJ, O'Grady KE, Vincent KB, Griffiths RR (2010). "Increased alcohol consumption, nonmedical prescription drug use, and illicit drug use are associated with energy drink consumption among college students". J Addict Med. 4 (2): 74–80. doi:10.1097/ADM.0b013e3181aa8dd4. PMC 2923814. PMID 20729975.CS1 maint: multiple names: authors list (link)
- Degenhardt, L; Dierker, L; Chiu, W. T.; Medina-Mora, M. E.; Neumark, Y; Sampson, N; Alonso, J; Angermeyer, M; Anthony, J. C.; Bruffaerts, R; De Girolamo, G; De Graaf, R; Gureje, O; Karam, A. N.; Kostyuchenko, S; Lee, S; Lépine, J. P.; Levinson, D; Nakamura, Y; Posada-Villa, J; Stein, D; Wells, J. E.; Kessler, R. C. (2010). "Evaluating the drug use "gateway" theory using cross-national data: Consistency and associations of the order of initiation of drug use among participants in the WHO World Mental Health Surveys". Drug and Alcohol Dependence. 108 (1–2): 84–97. doi:10.1016/j.drugalcdep.2009.12.001. PMC 2835832. PMID 20060657.
- Stringer, S; Minică, C. C.; Verweij, K. J.; Mbarek, H; Bernard, M; Derringer, J; Van Eijk, K. R.; Isen, J. D.; Loukola, A; MacIejewski, D. F.; Mihailov, E; Van Der Most, P. J.; Sánchez-Mora, C; Roos, L; Sherva, R; Walters, R; Ware, J. J.; Abdellaoui, A; Bigdeli, T. B.; Branje, S. J.; Brown, S. A.; Bruinenberg, M; Casas, M; Esko, T; Garcia-Martinez, I; Gordon, S. D.; Harris, J. M.; Hartman, C. A.; Henders, A. K.; et al. (2016). "Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium". Translational Psychiatry. 6 (3): e769. doi:10.1038/tp.2016.36. PMC 4872459. PMID 27023175.
- Lynskey, M. T.; Vink, J. M.; Boomsma, D. I. (2006). "Early onset cannabis use and progression to other drug use in a sample of Dutch twins". Behavior Genetics. 36 (2): 195–200. CiteSeerX 10.1.1.79.4510. doi:10.1007/s10519-005-9023-x. PMID 16402286., PDF
- Agrawal A, Lynskey MT (2014). "Cannabis controversies: how genetics can inform the study of comorbidity". Addiction. 109 (3): 360–70. doi:10.1111/add.12436. PMC 3943474. PMID 24438181. (Review).
- Cleveland, HH; Wiebe, RP (2008). "Understanding the association between adolescent marijuana use and later serious drug use: gateway effect or developmental trajectory?". Development and Psychopathology. 20 (2): 615–32. doi:10.1017/S0954579408000308. PMID 18423097.
- D. B. Kandel (Ed.): Stages and Pathways of Drug Involvement: Examining the Gateway Hypothesis, Cambridge University Press, 2002, ISBN 978-0-521-78969-1, p. 4.
- Erich Goode: Marijuana use and the progression to dangarous drugs, in: Miller, Loren, ed. (1974). Marijuana Effects on Human Behavior. Burlington: Elsevier Science. pp. 303–338. ISBN 978-1-4832-5811-9.
- Kandel, D (1975). "Stages in adolescent involvement in drug use". Science. 190 (4217): 912–914. doi:10.1126/science.1188374. PMID 1188374.
- Yamaguchi, K; Kandel, D. B. (1984). "Patterns of drug use from adolescence to young adulthood: II. Sequences of progression". American Journal of Public Health. 74 (7): 668–672. doi:10.2105/ajph.74.7.668. PMC 1651663. PMID 6742252.
- Kandel, D; Yamaguchi, K (1993). "From beer to crack: Developmental patterns of drug involvement". American Journal of Public Health. 83 (6): 851–855. doi:10.2105/ajph.83.6.851. PMC 1694748. PMID 8498623.
- D. B. Kandel (Ed.): Stages and Pathways of Drug Involvement: Examining the Gateway Hypothesis, Cambridge University Press, 2002, ISBN 978-0-521-78969-1.
- Wayne Hall, Rosalie Liccardo Pacula: Is cannabis a gateway drug? In: Same authors: Cannabis Use and Dependence. Public Health and Public Policy, Cambridge University Press, Cambridge, UK, New York, USA, 2003, ISBN 978-0-521-80024-2, chapt. 10, pp. 104–114.
Lay scientific books
- Mark A.R. Kleiman, Jonathan P. Caulkins, Angela Hawken: Is marijuana a "gateway drug"? In: Same authors: Drugs and Drug Policy. What Everyone Needs to Know, Oxford University Press, 2011, ISBN 978-0-19-983138-8, chapt. 4, question 8, pp. 81–83.
State of research before 1974
- Goode, Erich (1974). "Marijuana use and the progression to dangarous drugs". In Miller, Loren (ed.). Marijuana Effects on Human Behavior. Burlington: Elsevier Science. pp. 303–338. ISBN 978-1-4832-5811-9.
- Is marijuana a gateway drug?, website of the National Institute on Drug Abuse at the National Institutes of Health.
- Virginia Gewin: Smoking stokes cocaine cravings: Molecular mechanism found for controversial 'gateway drug' hypothesis, Nature News, November 2, 2011.
- Video: Eric Kandel and Denise Kandel: E-Cigarettes May Promote Illicit Drug Use and Addiction, Columbia University, January 16, 2015.