gateway drug effect

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.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: {{cite book | editor-last=Miller | editor-first=Loren| title=Marijuana Effects on Human Behavior | publisher=Elsevier Science | location=Burlington | year=1974 | isbn=978-1-4832-5811-9 | pages=303–338}}

The scientific and political discussion has intensified since 1975 after the publications of several longitudinal studies by Denise Kandel and others.{{Cite journal|pages=912–914|pmid=1188374|year=1975|last1=Kandel|first1=D|title=Stages in adolescent involvement in drug use|journal=Science|volume=190|issue=4217|doi=10.1126/science.1188374|bibcode=1975Sci...190..912K|hdl=10983/25298|s2cid=30124614|hdl-access=free}}{{Cite journal|pmc=1651663|year=1984|last1=Yamaguchi|first1=K|title=Patterns of drug use from adolescence to young adulthood: II. Sequences of progression|journal=American Journal of Public Health|volume=74|issue=7|pages=668–672|last2=Kandel|first2=D. B.|pmid=6742252|doi=10.2105/ajph.74.7.668}}{{Cite journal|pages=851–855|pmc=1694748|year=1993|last1=Kandel|first1=D|title=From beer to crack: Developmental patterns of drug involvement|journal=American Journal of Public Health|volume=83|issue=6|last2=Yamaguchi|first2=K|pmid=8498623|doi=10.2105/ajph.83.6.851}}

In 2019, a research report by the National Institute on Drug Abuse determined that marijuana use is "likely to precede use of other licit and illicit substances", and cited a longitudinal study in which "adults who reported marijuana use during the first wave of the survey were more likely than adults who did not use marijuana to develop an alcohol use disorder within 3 years; people who used marijuana and already had an alcohol use disorder at the outset were at greater risk of their alcohol use disorder worsening." They further claimed that marijuana use "is also linked to other substance use disorders including nicotine addiction." While stating that their "findings are consistent with the idea of marijuana as a "gateway drug"", they conceded that "the majority of people who use marijuana do not go on to use other, "harder" substances", and that "cross-sensitization is not unique to marijuana. Alcohol and nicotine also prime the brain for a heightened response to other drugs and are, like marijuana, also typically used before a person progresses to other, more harmful substances."

On the other hand, the 2018 report issued by the National Institute of Justice states "that the current state of research on this issue is limited, and the studies that have been conducted suffer from difficulties in collecting information and applying the findings to a larger population. The report further notes that although many of the reviewed studies found statistically significant associations between cannabis use and the users' later use of other illicit drugs, there is currently no conclusive evidence that cannabis use caused the later use of harder illicit drugs."

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.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.

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 use, overlapping illegal drug distribution channels, alcohol use disorder, nicotine dependence, ethnicity, urbanicity, and educational attainment influenced the height of probability.{{cite journal|pmc=4291295|year=2015|last1=Secades-Villa|first1=R|title=Probability and predictors of the cannabis gateway effect: A national study|journal=International Journal of Drug Policy|volume=26|issue=2|pages=135–142|last2=Garcia-Rodríguez|first2=O|last3=Jin|first3=C. J.|last4=Wang|first4=S|last5=Blanco|first5=C|doi=10.1016/j.drugpo.2014.07.011|pmid=25168081}}{{cite journal | vauthors = Kluger B, Triolo P, Jones W, Jankovic J | title = The therapeutic potential of cannabinoids for movement disorders | journal = Movement Disorders | volume = 30 | issue = 3 | pages = 313–27 | year = 2015 | pmid = 25649017 | pmc = 4357541 | doi = 10.1002/mds.26142 }}

A study of drug use of 14,577 U.S. 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.{{cite journal|pmid=22712674|url=http://www.mamacultiva.org/wp-content/uploads/2015/pdf/A8%20-%20Alcohol%20as%20a%20Gateway%20Drug%20A%20Study%20of%20US%2012th%20Graders.pdf|year=2012|last1=Kirby|first1=T|title=Alcohol as a gateway drug: A study of US 12th graders|journal=Journal of School Health|volume=82|issue=8|pages=371–9|last2=Barry|first2=A. E.|doi=10.1111/j.1746-1561.2012.00712.x|access-date=2016-05-26|archive-date=2016-06-04|archive-url=https://web.archive.org/web/20160604012851/http://www.mamacultiva.org/wp-content/uploads/2015/pdf/A8%20-%20Alcohol%20as%20a%20Gateway%20Drug%20A%20Study%20of%20US%2012th%20Graders.pdf|url-status=dead}} Studies indicate vaping serves as a gateway to traditional cigarettes and cannabis use.{{cite journal|last1=Fadus|first1=Matthew C.|last2=Smith|first2=Tracy T.|last3=Squeglia|first3=Lindsay M.|title=The rise of e-cigarettes, pod mod devices, and JUUL among youth: Factors influencing use, health implications, and downstream effects|journal=Drug and Alcohol Dependence|volume=201|year=2019|pages=85–93|issn=0376-8716|doi=10.1016/j.drugalcdep.2019.04.011|pmid=31200279|pmc=7183384}}

Large-scale longitudinal studies in the U.K. 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.{{cite journal | vauthors = Courtney KE, Mejia MH, Jacobus J | title = Longitudinal Studies on the Etiology of Cannabis Use Disorder: A Review | journal = Current Addiction Reports | volume = 4 | issue = 2 | pages = 43–52 | year = 2017 | pmid = 29057198 | doi = 10.1007/s40429-017-0133-3 | pmc=5644349}}{{cite journal | vauthors = Badiani A, Boden JM, De Pirro S, Fergusson DM, Horwood LJ, Harold GT | title = Tobacco smoking and cannabis use in a longitudinal birth cohort: evidence of reciprocal causal relationships | journal = Drug and Alcohol Dependence | volume = 150 | pages = 69–76 | year = 2015 | pmid = 25759089 | doi = 10.1016/j.drugalcdep.2015.02.015 | url = https://www.sussex.ac.uk/webteam/gateway/file.php?name=badiani-2015.pdf&site=358 | hdl = 10523/10359 | hdl-access = free }}{{cite journal | vauthors = Taylor M, Collin SM, Munafò MR, MacLeod J, Hickman M, Heron J | title = Patterns of cannabis use during adolescence and their association with harmful substance use behaviour: findings from a UK birth cohort | journal = Journal of Epidemiology and Community Health | volume = 71 | issue = 8 | pages = 764–770 | year = 2017 | pmid = 28592420 | pmc = 5537531 | doi = 10.1136/jech-2016-208503 }}

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.{{cite web |title=Energy drinks and risk to future substance use |url=https://www.drugabuse.gov/news-events/news-releases/2017/08/energy-drinks-risk-to-future-substance-use |website=www.drugabuse.gov |publisher=National Institute on Drug Abuse |access-date=29 March 2019 |language=en |date=8 August 2017 |archive-date=18 February 2020 |archive-url=https://web.archive.org/web/20200218230546/https://www.drugabuse.gov/news-events/news-releases/2017/08/energy-drinks-risk-to-future-substance-use |url-status=dead }}

A meta-analysis about the use of e-cigarettes of 2018 said that "Because the term 'gateway' has historically been used in colloquial, non-scientific settings and lacks a clear definition, it is not used in this report".{{cite book| author=National Academies of Sciences, Engineering, and Medicine | editor3-first=David L | editor3-last=Eaton | editor2-first=Leslie Y | editor2-last=Kwan | editor1-first=Kathleen | editor1-last=Stratton | title=Public Health Consequences of E-Cigarettes | year= 2018 |publisher=National Academies Press | pmid=29894118 | doi=10.17226/24952 | isbn=978-0-309-46834-3 |page=496}}

The role of cannabis use in regard to alcohol use and Alcohol Use Disorder (AUD) is still not fully understood. Some studies suggest better alcohol treatment completion for those who use cannabis, while other studies find the opposite.{{cite journal|last1=Subbaraman|first1=MS|title=Can cannabis be considered a substitute medication for alcohol?|journal=Alcohol and Alcoholism|date=2014|volume=49|issue=3|pages=292–8|doi=10.1093/alcalc/agt182|pmid=24402247|pmc=3992908}} A 2016 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.{{cite journal|last1=Subbaraman|first1=MS|title=Substitution and Complementarity of Alcohol and Cannabis: A Review of the Literature.|journal=Substance Use & Misuse|date=18 September 2016|volume=51|issue=11|pages=1399–414|doi=10.3109/10826084.2016.1170145|pmid=27249324|pmc=4993200}}

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 two 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.{{cite journal | doi=10.1007/s40429-017-0149-8 | volume=4 |issue = 2| year=2017 | journal=Current Addiction Reports | pages=184–193 | author=Yurasek Ali M., Aston Elizabeth R., Metrik Jane| title=Co-use of Alcohol and Cannabis: A Review | pmid=32670740 | pmc=7363401 }}{{cite journal|pmid=26875671|year=2016|last1=Weinberger|first1=A. H.|title=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|journal=Drug and Alcohol Dependence|volume=161|pages=363–7|last2=Platt|first2=J|last3=Goodwin|first3=R. D.|doi=10.1016/j.drugalcdep.2016.01.014|pmc=5028105}}

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.{{Cite journal|pages=1493–1504|pmid= 12472629|year= 2002|last1= Morral|first1= A. R.|title= Reassessing the marijuana gateway effect|journal= Addiction|volume= 97|issue= 12|last2= McCaffrey|first2= D. F.|last3= Paddock|first3= S. M.|author3-link=Susan Paddock|s2cid= 2833456|doi=10.1046/j.1360-0443.2002.00280.x}} (Review).{{Cite journal|pages=556–569|pmid=16548935|year=2006|last1=Fergusson|first1=D. M.|title=Cannabis use and other illicit drug use: Testing the cannabis gateway hypothesis|journal=Addiction|volume=101|issue=4|last2=Boden|first2=J. M.|last3=Horwood|first3=L. J.|doi=10.1111/j.1360-0443.2005.01322.x}}

Adolescent rats repeatedly injected with tetrahydrocannabinol increased the self-administration of heroin (results based on 11 male rats{{Cite journal|pages=607–615|pmid=16823391|year=2007|last1=Ellgren|first1=M|title=Adolescent cannabis exposure alters opiate intake and opioid limbic neuronal populations in adult rats|journal=Neuropsychopharmacology|volume=32|issue=3|last2=Spano|first2=S. M.|last3=Hurd|first3=Y. L.|doi=10.1038/sj.npp.1301127|doi-access=free}} and >50 male rats{{cite journal| author=Tomasiewicz HC, Jacobs MM, Wilkinson MB, Wilson SP, Nestler EJ, Hurd YL| title=Proenkephalin mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability. | journal=Biol Psychiatry | year= 2012 | volume= 72 | issue= 10 | pages= 803–10 | pmid=22683090 | doi=10.1016/j.biopsych.2012.04.026 | pmc=3440551 }}), morphine (study based on 12 male rats){{Cite journal|pages=259–266|pmid=11713615|year=2001|last1=Cadoni|first1=C|title=Behavioural sensitization after repeated exposure to Delta 9-tetrahydrocannabinol and cross-sensitization with morphine|journal=Psychopharmacology|volume=158|issue=3|last2=Pisanu|first2=A|last3=Solinas|first3=M|last4=Acquas|first4=E|last5=Di Chiara|first5=G|doi=10.1007/s002130100875|s2cid=24008118}} and also nicotine (34 rats).{{Cite journal|pages=1198–1208|pmc=3656362|year=2013|last1=Panlilio|first1=L. V.|title=Prior Exposure to THC Increases the Addictive Effects of Nicotine in Rats|journal=Neuropsychopharmacology|volume=38|issue=7|last2=Zanettini|first2=C|last3=Barnes|first3=C|last4=Solinas|first4=M|last5=Goldberg|first5=S. R.|doi=10.1038/npp.2013.16|pmid=23314220}} 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,{{cite journal| author=O'Connell LA, Hofmann HA| title=The vertebrate mesolimbic reward system and social behavior network: a comparative synthesis. | journal=J Comp Neurol | year= 2011 | volume= 519 | issue= 18 | pages= 3599–639 | pmid=21800319 | doi=10.1002/cne.22735 | s2cid=34009440 | doi-access=free }}{{cite journal| author=Alcaro A, Panksepp J| title=The SEEKING mind: primal neuro-affective substrates for appetitive incentive states and their pathological dynamics in addictions and depression. | journal=Neurosci Biobehav Rev | year= 2011 | volume= 35 | issue= 9 | pages= 1805–20 | pmid=21396397 | doi=10.1016/j.neubiorev.2011.03.002 | s2cid=6613696 }}{{cite journal| author=Panksepp J| title=The basic emotional circuits of mammalian brains: do animals have affective lives? | journal=Neurosci Biobehav Rev | year= 2011 | volume= 35 | issue= 9 | pages= 1791–804 | pmid=21872619 | doi=10.1016/j.neubiorev.2011.08.003 | s2cid=207089299 | url=http://library.allanschore.com/docs/Panksepp11.pdf }} 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.{{cite journal| author=Panlilio LV, Justinova Z| title=Preclinical Studies of Cannabinoid Reward, Treatments for Cannabis Use Disorder, and Addiction-Related Effects of Cannabinoid Exposure. | journal=Neuropsychopharmacology | year= 2018 | volume= 43 | issue= 1 | pages= 116–141 | pmid=28845848 | doi=10.1038/npp.2017.193 | pmc=5719102 }}{{cite journal | vauthors = Parsons LH, Hurd YL | title = Endocannabinoid signalling in reward and addiction | journal = Nature Reviews. Neuroscience | volume = 16 | issue = 10 | pages = 579–94 | year = 2015 | pmid = 26373473 | pmc = 4652927 | doi = 10.1038/nrn4004 }} (Review).{{cite journal | vauthors = Covey DP, Wenzel JM, Cheer JF | title = Cannabinoid modulation of drug reward and the implications of marijuana legalization | journal = Brain Research | volume = 1628 | issue = Pt A | pages = 233–43 | year = 2015 | pmid = 25463025 | doi = 10.1016/j.brainres.2014.11.034 | pmc=4442758}}, [https://www.researchgate.net/profile/Dan_Covey/publication/268881748_Cannabinoid_modulation_of_drug_reward_and_the_implications_of_marijuana_legalization/links/549309f10cf22d7925d6ad09.pdf PDF] (Review).{{cite journal | vauthors = Renard J, Rushlow WJ, Laviolette SR | title = What Can Rats Tell Us about Adolescent Cannabis Exposure? Insights from Preclinical Research | journal = Canadian Journal of Psychiatry | volume = 61 | issue = 6 | pages = 328–34 | year = 2016 | pmid = 27254841 | doi = 10.1177/0706743716645288 | pmc=4872245}}, [https://www.researchgate.net/profile/Justine_Renard/publication/302593772_What_Can_Rats_Tell_Us_about_Adolescent_Cannabis_Exposure_Insights_from_Preclinical_Research/links/5772b6cf08aeef01a0b65d74.pdf?origin=publication_list PDF] (Review).

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.{{cite journal|author1=E. R. Kandel|author2-link= Denise Kandel|title= A Molecular Basis for Nicotine as a Gateway Drug|journal= New England Journal of Medicine|volume= 371|issue= 10|author2= D. B. Kandel|pages=932–943|pmc=4353486|year= 2014|doi= 10.1056/NEJMsa1405092|pmid= 25184865|author1-link= Eric Kandel}} 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,{{Cite journal|pmid= 27077359|pmc= 4880234|year= 2016|last1= Keyes|first1= K. M.|title= Birth Cohorts Analysis of Adolescent Cigarette Smoking and Subsequent Marijuana and Cocaine Use|journal= American Journal of Public Health|volume= 106|issue= 6|pages= 1143–9|last2= Hamilton|first2= A|last3= Kandel|first3= D. B.|doi= 10.2105/AJPH.2016.303128}} as well as other drugs.{{cite journal| author=Ren M, Lotfipour S| title=Nicotine Gateway Effects on Adolescent Substance Use. | journal=West J Emerg Med | year= 2019 | volume= 20 | issue= 5 | pages= 696–709 | pmid=31539325 | doi=10.5811/westjem.2019.7.41661 | pmc=6754186 }}

In rats, alcohol increased the probability of later addiction to cocaine and again relevant alterations in the reward system were identified.{{cite journal| author=Griffin EA, Melas PA, Zhou R, Li Y, Mercado P, Kempadoo KA | title=Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5. | journal=Sci Adv | year= 2017 | volume= 3 | issue= 11 | pages= e1701682 | pmid=29109977 | doi=10.1126/sciadv.1701682 | pmc=5665598 | bibcode=2017SciA....3E1682G }}{{cite journal| author=Anderson EM, Penrod RD, Barry SM, Hughes BW, Taniguchi M, Cowan CW| title=It is a complex issue: emerging connections between epigenetic regulators in drug addiction. | journal=Eur J Neurosci | year= 2019 | volume= 50 | issue= 3 | pages= 2477–2491 | pmid=30251397 | doi=10.1111/ejn.14170 | s2cid=52816486 | url=https://pubmed.ncbi.nlm.nih.gov/30251397 }} 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.{{cite journal| author=Lopez-Quintero C, Pérez de los Cobos J, Hasin DS, Okuda M, Wang S, Grant BF | title=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). | journal=Drug Alcohol Depend | year= 2011 | volume= 115 | issue= 1–2 | pages= 120–30 | pmid=21145178 | doi=10.1016/j.drugalcdep.2010.11.004 | pmc=3069146 }}{{cite journal| author=Bickel WK, Snider SE, Quisenberry AJ, Stein JS, Hanlon CA| title=Competing neurobehavioral decision systems theory of cocaine addiction: From mechanisms to therapeutic opportunities. | journal=Prog Brain Res | year= 2016 | volume= 223 | pages= 269–93 | pmid=26806781 | doi=10.1016/bs.pbr.2015.07.009 | pmc=5495192 }}

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.{{cite journal| author=Curran CP, Marczinski CA| title=Taurine, caffeine, and energy drinks: Reviewing the risks to the adolescent brain. | journal=Birth Defects Res | year= 2017 | volume= 109 | issue= 20 | pages= 1640–1648 | pmid=29251842 | doi=10.1002/bdr2.1177 | pmc=5737830 }} These findings correspond to epidemiological data that people who consume energy drinks generally showed an increased tendency to take alcohol and other substances.{{cite journal| author=Arria AM, Caldeira KM, Kasperski SJ, O'Grady KE, Vincent KB, Griffiths RR | title=Increased alcohol consumption, nonmedical prescription drug use, and illicit drug use are associated with energy drink consumption among college students. | journal=J Addict Med | year= 2010 | volume= 4 | issue= 2 | pages= 74–80 | pmid=20729975 | doi=10.1097/ADM.0b013e3181aa8dd4 | pmc=2923814 }}

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.{{cite journal|pages=84–97|pmc=2835832|year=2010|last1=Degenhardt|first1=L|title=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|journal=Drug and Alcohol Dependence|volume=108|issue=1–2|last2=Dierker|first2=L|last3=Chiu|first3=W. T.|last4=Medina-Mora|first4=M. E.|last5=Neumark|first5=Y|last6=Sampson|first6=N|last7=Alonso|first7=J|last8=Angermeyer|first8=M|last9=Anthony|first9=J. C.|last10=Bruffaerts|first10=R|last11=De Girolamo|first11=G|last12=De Graaf|first12=R|last13=Gureje|first13=O|last14=Karam|first14=A. N.|last15=Kostyuchenko|first15=S|last16=Lee|first16=S|last17=Lépine|first17=J. P.|last18=Levinson|first18=D|last19=Nakamura|first19=Y|last20=Posada-Villa|first20=J|last21=Stein|first21=D|last22=Wells|first22=J. E.|last23=Kessler|first23=R. C.|doi=10.1016/j.drugalcdep.2009.12.001|pmid=20060657}} 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 people who used illicit substances 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.{{Cite journal|pmid=27023175|pmc=4872459|year=2016|last1=Stringer|first1=S|title=Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium|journal=Translational Psychiatry|volume=6|issue=3|pages=e769|last2=Minică|first2=C. C.|last3=Verweij|first3=K. J.|last4=Mbarek|first4=H|last5=Bernard|first5=M|last6=Derringer|first6=J|last7=Van Eijk|first7=K. R.|last8=Isen|first8=J. D.|last9=Loukola|first9=A|last10=MacIejewski|first10=D. F.|last11=Mihailov|first11=E|last12=Van Der Most|first12=P. J.|last13=Sánchez-Mora|first13=C|last14=Roos|first14=L|last15=Sherva|first15=R|last16=Walters|first16=R|last17=Ware|first17=J. J.|last18=Abdellaoui|first18=A|last19=Bigdeli|first19=T. B.|last20=Branje|first20=S. J.|last21=Brown|first21=S. A.|last22=Bruinenberg|first22=M|last23=Casas|first23=M|last24=Esko|first24=T|last25=Garcia-Martinez|first25=I|last26=Gordon|first26=S. D.|last27=Harris|first27=J. M.|last28=Hartman|first28=C. A.|last29=Henders|first29=A. K.|last30=Heath|first30=A. C.|display-authors=29|doi=10.1038/tp.2016.36}}

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.{{Cite journal|pages=195–200|pmid= 16402286|year= 2006|last1= Lynskey|first1= M. T.|title= Early onset cannabis use and progression to other drug use in a sample of Dutch twins|journal= Behavior Genetics|volume= 36|issue= 2|last2= Vink|first2= J. M.|last3= Boomsma|first3= D. I.|doi= 10.1007/s10519-005-9023-x|citeseerx= 10.1.1.79.4510|s2cid= 8263454}}, [http://www.tweelingenregister.org/nederlands/verslaggeving/NTR_publicaties_2006/Lynskey_BG_2006.pdf PDF] {{Webarchive|url=https://web.archive.org/web/20190524104403/http://www.tweelingenregister.org/nederlands/verslaggeving/NTR_publicaties_2006/Lynskey_BG_2006.pdf |date=2019-05-24 }}{{cite journal | vauthors = Agrawal A, Lynskey MT | title = Cannabis controversies: how genetics can inform the study of comorbidity | journal = Addiction | volume = 109 | issue = 3 | pages = 360–70 | year = 2014 | pmid = 24438181 | pmc = 3943474 | doi = 10.1111/add.12436 }} (Review).

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.{{cite journal|last1=Cleveland|first1=HH|last2=Wiebe|first2=RP|title=Understanding the association between adolescent marijuana use and later serious drug use: gateway effect or developmental trajectory?|journal=Development and Psychopathology|date=2008|volume=20|issue=2|pages=615–32|doi=10.1017/S0954579408000308|pmid=18423097|s2cid=19232946|url=https://www.researchgate.net/publication/5429788}}

• Drug policy
• Substance abuse prevention
• Substance use disorder
• Tobacco and other drugs

{{Reflist|30em}}

• 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.

• 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.

• {{cite book|first=Erich|last= Goode|chapter=Marijuana use and the progression to dangarous drugs | editor-last=Miller | editor-first=Loren |title=Marijuana Effects on Human Behavior | publisher=Elsevier Science | location=Burlington | year=1974 | isbn=978-1-4832-5811-9 | pages=303–338}}

• [https://www.drugabuse.gov/publications/research-reports/marijuana/marijuana-gateway-drug Is marijuana a gateway drug?], website of the National Institute on Drug Abuse at the National Institutes of Health.
• Virginia Gewin: [http://www.nature.com/news/2011/111102/full/news.2011.627.html Smoking stokes cocaine cravings: Molecular mechanism found for controversial 'gateway drug' hypothesis], Nature News, November 2, 2011.
• Video: Eric Kandel and Denise Kandel: [https://www.youtube.com/watch?v=9uKKC8FjjGI E-Cigarettes May Promote Illicit Drug Use and Addiction], Columbia University, January 16, 2015.

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