Genetic factors are known major determinants of addiction, while dopamine is known to be involved in reward and motivation.^13,26 Changes in dopaminergic signaling may therefore be expected to influence individual tendencies to addiction. We have, in this study, examined the relationships between a known polymorphism of the DAT1 gene coding for a key protein in the dopaminergic signaling pathway, cannabis use, and cannabis dependence among patients receiving treatment for cannabis use disorders at a tertiary treatment facility within Lagos in Nigeria.

The modal age of the smokers in this study was relatively higher than what was reported by most authors. This age difference was probably more due to the population sampled. It would be expected that where youth populations were targeted, such as secondary or tertiary institutions, the modal age could be lower, as expected.²⁷ However, in a study conducted at a tertiary treatment facility for drug abusers, the mean age reported was closer to our finding.²⁸ The same study by Effiong et al. also reported the mean age at the onset of smoking, which fell within the modal class for the age at smoking onset found in our study.

Most of the smokers in this study were single. Marital status has been associated with cannabis smoking, and having a marriage partner could influence smoking status as this could reduce the effect of boredom, peer pressure, and exposure to the lifestyle that could predispose to smoking.²⁹ We found that most of the participants were either private employees or private business owners; this was contrary to what was expected in our environment, where cannabis smoking and other drug use are often most prevalent among road transport workers.³⁰ Nevertheless, this could also be because people in this occupation, due to their lifestyle, are less likely to be brought to a drug treatment facility where we recruited our participants. Furthermore, in agreement with the findings of Adejoh et al.,³¹ peer pressure was the commonest reason for the initiation of cannabis smoking. The quantities of cannabis smoked by the participants we sampled were higher than those reported previously in a study conducted among male university students in Nigeria.³² These differences could be why our study participants were at the treatment facility.

We first estimated the allele and genotype frequencies of the DAT1 3′ UTR VNTR polymorphisms across the populations of non-smokers and smokers. There were very few other alleles like the 3R, 7R, and 8R found among the participants. However, because all of them existed in heterozygous form with the 10R, they were all classified with 10R. The allele and genotype frequencies we found in this study are comparable to those found in some African, European, and other populations, with the 10R being the major allele.^{33bibr34-11782218231163696-35}

In addition, after testing the genotype frequencies for conformation to the Hardy-Weinberg equilibrium (HWE) test, the genotype frequencies in the smokers’ population conformed to HWE, showing that the genotype frequencies have remained constant over time. This is similar to the finding by Bhaskar et al³⁶ in a population with alcohol dependence. Contrary to the study by Bhaskar et al., who also reported that the genotype distribution within the control population conformed to the HWE, we found that the genotype frequencies within the non-smokers’ population deviated from HWE. Given the ethnic diversity of the Nigerian population, this deviation from the HWE might be due to interbreeding, while forces like population stratification and natural selection could also be responsible.³⁷ We noted that the 10R allele was more associated with cannabis smoking. The odds ratio shows that the likelihood of smoking was almost twice with the 10R compared to the 9R. A study by Guo et al³⁸ reported that the 10R allele was more associated with risky behavior, including problematic use of cannabis, alcohol, tobacco, cocaine, heroin, and other illegal drugs. Another study by Stolf et al³⁹ also found that the 10R/10R genotype was significantly associated with crack cocaine use.

Drug addiction or dependence can be described as nonmedical self-administration of drugs with characteristics of intoxication or withdrawal symptoms. Addiction usually manifests with 3 main symptom categories: exaggerated substance use, social or lifestyle impairment, and risky substance use.²⁶ Although the 10R was associated with cannabis smoking in this study, we found that among the smokers, there was almost no relationship between the allele distributions and cannabis dependence. Both 9R and 10R were distributed almost equally among those that were cannabis dependent and those that were not. To the best of our knowledge, no study has linked this DAT1 polymorphism to cannabis dependence. Nevertheless, some authors have reported that the 9R allele was associated with alcohol dependence,³⁶ and alcohol-withdrawal symptoms, such as seizures and delirium tremens.⁴⁰ Other reports have shown the contrary among tobacco smokers.^41,42 While the mechanism of action of alcohol is mainly through GABA signaling,⁴³ nicotine acts mainly by binding specific nicotinic acetylcholine receptors.⁴⁴ Addiction to substances often involves dopamine signaling directly or indirectly. Although the THC in the cannabis through the cannabinoid receptor indirectly activates the dopaminergic system,⁴⁵ the effect of the 9R allele might also be modulated by other genetic factors.

The DAT1 VNTR is located in the 3′ untranslated region of the transporter protein, and it does not affect the amino acid sequence. However, it is a functional polymorphism that affects the transporter protein density.⁴⁶ Striatal dopamine is important for positive symptoms of substance use disorders like increased drug intake and craving; it also leads to impaired decision-making that underlies compulsive behavior, reduced sociality, and risk-taking.²⁶ The 9R allele was associated with increased DAT activity in the studies on human adults using positron emission tomography (PET) or single-photon emission computed tomography (SPECT).⁴⁶ The increase in the density of the DAT will expectedly lead to increased mopping up of dopamine back into the presynaptic neuron and thus the termination of dopamine action.⁴⁷

In our results, the 9R allele was slightly more associated with lower severity than the 10R allele, although this was not statistically significant. A study reported that the 9R/9R genotype was protective against a spectrum of risky behaviors, such as substance abuse, compared to the 9R/10R and 10R/10R genotypes in young adulthood.³⁸ Similarly, as noted above,^41,42 the 9R has been described as protective against a high level of dependence among alcoholics and cigarette smokers. Besides, we did not observe any difference between the carriers of the 2 alleles and CUDIT scores, showing that the DAT 3′ VNTR polymorphisms were not associated with cannabis use disorder among the participants. It must be noted that the smokers were recruited from the psychiatric facility where they were being treated for substance use disorder. It is, therefore, not surprising that most of them met the criteria for cannabis dependence and cannabis use disorder.

We found that most participants in this study had family members who used cannabis, and they also started using cannabis at an early age. Smokers with the 10R allele were more likely to have a family member using cannabis than the carriers of the 9R allele, although this difference was also insignificant. Likewise, no pattern in our results suggested any of the alleles could predict the age at the onset of cannabis use, although most participants with the 10R alleles tended to start smoking below the age of 20. Besides, the results did not also show that any of the 2 major alleles were predictive of the quantity of cannabis used by the participants. All these may be because drug use often has complex etiology involving many genes interacting with one another and social and environmental factors.