This study discovered a prominent association of polytoxicomania with early accumulation of environmental risk factors, comprising urbanicity, migration, sexual abuse, physical abuse and, as secondary risks, alcohol, and cannabis. In particular, preadult polytoxicomania is >220 times more likely to develop in subjects exposed to ≥3 risks. In addition, polytoxicomania in later life occurs with higher probability after adolescent accumulation of negative environmental impact. Thus, our data show that multiple drug use has obviously remarkable roots in preadult risk factor buildup. In perfect agreement with previous reports (e.g., [39–41]), we find clear escalation in percentage of violent behavior with increasing numbers of drugs consumed. Strikingly, the number of accumulated risk factors appears to be more informative than the type of environmental risk factor. Nonetheless, our data strongly underline the well-known significance of cannabis and alcohol as gateway/starter drugs [29, 42–46].

In fact, all individuals with preadult polytoxicomania reported using cannabis. This confirms a tremendous association between cannabis and preadult polytoxicomania, even though not ultimately proving causality. A more causal perspective is perhaps offered by our data on polytoxicomania arising in adulthood. In adult polytoxicomanic individuals, the preadult risk factors temporally clearly precede the occurrence of polytoxicomania. Also in this group, cannabis is the by far most frequent preadult risk factor (occurring in 70–92% of individuals). Considering this extraordinary impact of cannabis, legalization and commercialization of its use will certainly increase not only incidence and prevalence of psychosis [47–53], but also of polytoxicomania.

Importantly, smoking as the sole risk factor did not increase the chance of developing polytoxicomania and did not influence our accumulation model further. Along these lines, heavy increase in tobacco consumption is highly frequently observed in alcoholics upon alcohol abstinence. This phenomenon is called ‘“Suchtverlagerung” or shift in addictive behaviors and is not associated with generation of polytoxicomania (but causes other severe problems [54]), again emphasizing the “non-specificity” of nicotine consumption in this regard. Nevertheless, it cannot be entirely excluded that tobacco has a minor role as “co-gateway” drug together with cannabis (as cannabis use is tightly associated with smoking status).

Cannabis and alcohol are sometimes seen as potential consequences of early-life stress, like physical and/or sexual abuse, considered as some sort of self-treatment [55]. However, the VIF for all variables in our model was low (all VIF < 1.2), indicating that there was no considerable multicollinearity between the risk factor variables. This suggests an independent input of each variable to the model including independent contributions of cannabis/alcohol and stress-related variables such as physical or sexual abuse.

We show that suicidality, as a severe form of autoaggression, follows a similar stair-pattern, but only in individuals exhibiting heteroaggression as well. Based on all these results, one could speculate that any kind of behavioral traits might be shaped by preadult environmental risk exposure; nevertheless, we did not see any respective influence of the here determined risks on the severity of autistic phenotypes in adulthood. It seems that autistic features are predominantly genetically induced [56, 57]. However, impact of intrauterine damage, e.g., viral infections, on development of autism is well established [58] and, like other potential postnatal risk factors, not recorded here.

The present findings are derived from a large, deeply phenotyped sample of schizophrenic subjects with uniquely comprehensive information on multiple drug consumption, but their translation to the general population has still to ensue with some caution. Nevertheless, preadult polytoxicomania in our sample occurs way before onset of the disease, and may thus reflect general mechanisms of damage to the juvenile brain that predispose to multiple drug consumption rather than any direct association with mental illness. The view of essential generalizability receives support by our studies on violent aggression, where we had the chance to include two general population samples that revealed the same stair-pattern of aggression development with risk accumulation as the 4 independent schizophrenia cohorts [16]. The earlier onset of mental illness in polytoxicomanic individuals shown here emphasizes another devastating role of multiple drug use on brain functions and on outcome in mental disease. Mechanistically, this phenomenon as well as the observed behavioral alterations are likely mediated by epigenetic changes that occur relatively non-specifically in response to accumulated risk factor exposure in early life. These epigenetic changes apparently increase, as others and we have reported previously, the propensity for later substance abuse, depression, violent aggression, and a range of other negative health outcomes [16, 59–61].

On top of the remarkable environmental impact on polytoxicomania, we provide first evidence of a genetic predisposition to this behavioral abnormality as extracted from our novel GWAS–PGAS approach. This novel approach was only possible based on the comprehensive and precise information on drug consumption in our sample, which allowed the accurate classification of just mildly varying phenotypes for respective GWAS. We defined strict criteria for this GWAS–PGAS approach, which is potentially applicable to other genetic association studies as well. Our procedure is grounded on the working hypotheses that true genetic signals remain stable despite mild modifications in phenotype definition and are likely not isolated but in linkage disequilibrium with related signals, and that genetic associations with the target phenotype (here: polytoxicomania) are independent of any other disease diagnosis (here: schizophrenia). Diagnoses-overlapping, i.e., pleiotropic genes [38] were purposely excluded here. The mild variation of phenotype definitions allowed us to identify genetic associations that are more specific for polytoxicomania and not “contaminated” by associations stemming solely from single substance abuse.

We ultimately extracted an interesting set of markers as potential “bouquet of common genetic denominators” for juvenile polytoxicomania, many of them strongly expressed in brain and kidney. Unfortunately, no comparable sample of deeply phenotyped polytoxicomanic individuals is presently available for replication studies—despite intensive worldwide search—but would be crucial to have. Nevertheless, the nature of the obtained first genetic results seems encouraging.