Substance abuse in PLWHA has been associated with multiple indicators of HIV disease progression, including immunosuppression, neurotoxicity, increased viral replication and apoptosis [789]. However, inconsistencies across studies have been reported, likely owing in part to measurement and sampling issues (e.g. different measures or definitions of substance abuse, types of outcomes examined and participant-specific factors such as age and socio-economic status) [10]. In particular, the class of substance may have an important impact on outcomes. Different substance classes interact differently with prescribed antiretroviral (ARV) medication regimens. For example, amphetamine use can increase the risk of toxicity, whilst methadone use can reduce absorption of ARVs in the gastrointestinal tract [8]. There is still much to be learned about if and how each class of substance may uniquely affect HIV-related outcomes amongst PLWHA. Further complicating this research is the fact that polysubstance use is common, and individuals may alternate between intermittent periods of abstinence and relapse. The most commonly studied substances include alcohol, cocaine, methamphetamine and heroin. As noted by Wainberg et al., enhancing our understanding of the mechanisms through which different types and combinations of substance impact HIV disease progression is critical for developing interventions to improve outcomes and quality of life amongst PLWHA who have co-occurring substance use disorders.

Substance abuse is also associated with risk behaviours that impact clinical outcomes, including poorer medication adherence and treatment utilization [11, 12]. In fact, substance use itself may present a barrier to effective care, including hesitancy to disclose substance use or even to seek treatment due to fear of discrimination or stigma [13]. This may be particularly true in regions of the world where substance use is prosecuted, or where HIV treatment is withheld from people who report substance use. Recent research indicates that access to needle and syringe programs is limited in many countries where drug use is stigmatized and that access to HIV services may be limited as well [14]. In addition, many HIV programs may not have adequate resources to provide addiction-related services and treatment. Substance use amongst PLWHA is associated with sexual risk behaviours that increase both the risk of HIV transmission to others and the risk of acquiring other sexually transmitted infections [1516171819]. Developing interventions to target and reduce these risk behaviours amongst PLWHA who use substances is an important component of effective prevention efforts.

Research thus far has demonstrated that substance use can have profound neurocognitive effects in PLWHA. There are independent effects of HIV and substance use on neurocognitive functioning, but when substance use and HIV co-occur, substance use can exacerbate HIV-associated neurocognitive impairment [202122232425]. Each substance class may produce unique effects on neurocognitive functioning. These neurocognitive impairments can have deleterious effects on quality of life and day-to-day functioning, including driving and employment [26], which may in turn affect other variables such as engagement in risk behaviours and treatment adherence.

Compared to other classes of drugs, relatively few studies have examined the impact of marijuana use on PLWHA. Marijuana is the most commonly used drug amongst PLWHA. In the United States, studies have found that over one-third of PLWHA report using marijuana in the past year, and of those who use marijuana, many report using marijuana daily [272829]. Marijuana is unique from other drug classes (such as cocaine, methamphetamine and alcohol) in that several medicinal uses for marijuana have been identified, including the relief of symptoms associated with HIV, such as pain, nausea, anxious or depressed mood and loss of appetite [29–33]. Therefore, marijuana use amongst PLWHA may be recreational, medicinal or both, and it is unclear whether these motivations for use have any differential impact on clinical outcomes. Whilst some recent research has shown that heavy and chronic marijuana use is associated with poorer treatment adherence [34, 35], other studies report that marijuana use may facilitate adherence or have no impact at all [36–39]. The effects of marijuana intoxication likely impact medication adherence directly, which in turn leads to poorer clinical outcomes, but there are also several other indirect mechanisms that may impact outcomes, including changes in neuropsychological functioning, impairment in psychosocial functioning and potentially worsening of psychiatric symptoms [40, 41].

Research on the impact of marijuana on neurocognitive functioning in the general population has shown mixed results, with some studies reporting only short-term effects that resolve quickly after cessation of marijuana use and others finding that deficits in functioning persist over time [42–45]. In particular, chronic marijuana use has been associated with long-term deficits in executive function, such as decision making and impulsivity [43, 44, 46–48]. However, marijuana-related deficits may be more pronounced in HIV-infected individuals, given their vulnerability to neurocognitive impairment.

Initial studies in examining marijuana use in PLWHA have attempted to examine how marijuana use and HIV infection may interact to impact neurocognitive functioning. Cristiani et al. [40] examined neuropsychological performance amongst healthy controls and HIV-infected individuals, and found that HIV-infected individuals who were symptomatic and used marijuana more frequently performed more poorly on assessment measures than HIV-infected individuals who reported little to no marijuana use. Chang et al