Opiate self-administration as seen with addiction can have different CNS consequences than “steady-state” (e.g., continuous via a pump or time-release drug implant) exposure to the same drug (Kreek 1987, 2001; Kreek et al. 2002), and we predict the pharmacokinetic differences in opiate exposure will markedly impact neuroHIV progression. Differential effects based on “on-off” and “steady-state” drug administration schedules have been reported for the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis, the endogenous opioid system, and the dopamine system (Kreek 1973; Kreek et al. 2002; George et al. 2012). Acute opiate exposure typically activates the HPA axis, corticotropin releasing factor, and peripheral steroidogenesis in a species-dependent manner (Koob and Kreek 2007; Cleck and Blendy 2008). Alternatively, chronic self-administration of short-acting opiates suppresses diurnal cortisol rhythmicity (Facchinetti et al. 1984; Vuong et al. 2010), while opiate withdrawal typically evokes HPA activation (Culpepper-Morgan and Kreek 1997; Kreek 2007; Paris et al. 2020). The daily, repeated bouts of relative withdrawal seen with opiate addiction cause sustained HPA activation, stress (Koob and Kreek 2007; Koob 2020), and immune suppression (Eisenstein 2019). Importantly, maintenance therapy with the long-acting drug methadone achieves steady-dose opiate levels and normalization of the HPA axis (Kreek 1973). Further, it is known that HIV infection significantly alters the HPA axis, due to CNS toxicity and cytokine production (Costa et al. 2000; George and Bhangoo 2013; Chrousos and Zapanti 2014).