Professor Darke, in his scholarly and thoughtful critique, appreciates, as do I, the coexistence of painful psychiatric conditions such as post-traumatic stress disorder (PTSD) and borderline personality disorders (BPD) in the development of addiction, which precedes, and subsequently becomes associated with, the development of heroin dependence [1]. He cites the preponderance of childhood histories of deprivation, traumatic abuse and neglect, conditions that precipitate and cause life-long suffering, and, as one scholar of PTSD has eloquently offered, it is a condition in which there is a failure of time to heal all wounds [2]. Major trauma is a condition that disrupts essential aspects of life, involving regulation of emotions, sense of self, relationship and self-care [3,4]. Professor Darke concludes that the association between these conditions is not by chance, and that the evidence supports the self-medication hypothesis (SMH) and its fundamental premise. Namely, drug-dependent individuals resort to, and become dependent on, these agents because they relieve human psychological suffering and not because they are seeking pleasure from the drugs.In what follows, I will focus primarily on issues that Professor Darke raises which do not appear as much to support the SMH or might seem inconsistent with it. Namely, he offers that (i) there is less of a basis to conclude that drug preference postulated by the SMH is tenable or necessary and, (ii) given that the SMH at its roots is an attempt at self-correction, it does not align so well with the extraordinary pain, danger, self-harm and damage associated with, and a consequence of, addiction.Notwithstanding the absence of empirical evidence, clinical observations (practice-based evidence) suggest that there is a considerable degree of preference/ specificity for an individual's drug-of-choice. I would emphasize that it is a range of painful, unbearable or confusing feeling states that individuals self-medicate that might or might not be associated with psychiatric disorders. Few would argue that intense feelings of rage, aggression and violence predominate with PTSD and BPD. In my experience, it is these intense emotions that heroin-dependent individuals self-medicate. Based on the evaluations of many heroin-dependent individuals, they repeatedly indicate that their main drug preference remains heroin, albeit they use many other substances.It is why in many of my recent publications [5][6][7] I have adopted an overarching understanding of addictive conditions as a self-regulation disorder and, in my experience, other drugs are then employed to self-medicate all the other psychological and behavioral dysregulation induced by the heroin dependency.It is worth mentioning here that my thinking was influenced by the fact that in the mid-1960s, in the middle of my psychiatric training, our nomenclature for the then psychotropic medications changed from referring to them as 'minor tranquilizers' (e.g. Librium) or 'major tranquilizer' (e.g. Thorazine) to designating the ...