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 people who consume energy drinks generally showed an increased tendency to take alcohol and other substances. Personal, social and genetic factors 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 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. 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.
Gateway drug effect
Late effect
Bowditch effect
Acute toxicity
Fixed drug reaction
Abscopal effect
Side Effect
Haldane effect