Cognitive enhancement in combination with 'brain repair' may be optimal for the treatment of stimulant addiction.

The recent review by Sofuoglu [1] highlights a number of key points regarding treatment considerations for stimulant dependence, including: (i) the lack of available and effective pharmacotherapies, (ii) the persistence of cognitive impairments accompanying stimulant dependence and (iii) the adverse effects of neuropsychiatric symptoms on addiction recovery outcomes. Overall, Sofuoglu [1] provides a compelling rationale for cognitive enhancers as a potential treatment for stimulant addiction; however, additional strategies are also worth investigation. To date, pharmacotherapeutic development for stimulant addiction has focused primarily on: (i) dopamine re-uptake inhibitors (e.g. bupropion) and other dopaminergic agents to chemically block the reward associated with drug taking, (ii) antidepressants, anxiolitics or antipsychotics to reduce psychiatric symptoms such as depression or anxiety during withdrawal and early remission from addiction and (iii) medications [e.g. ondansetron, a serotonin receptor antagonist (5-HT3)] to reduce cravings and withdrawal symptoms. In their comprehensive review, Sofuoglu adds to this list by summarizing the literature on cognitive enhancers that target primarily the cholinergic and noradrenergic systems. In short, approaches to stimulant treatment have centered on neurotransmitters and agents that directly impact neurotransmitter systems. Unfortunately, the results from clinical trials continue to be disappointing, with only marginally improved outcomes and unacceptable relapse rates [2–4]. Further, long-term use of many of these medications may not be optimal, given their high abuse potential (e.g. methylphenidate, modafinil [5]). New strategies are therefore needed desperately. Because stimulants act through multiple neural mechanisms, alternatives to neurotransmitter agonist or antagonist receptor-based therapies warrant exploration. One key limitation of neurotransmitter-based therapies is that, alone, they do not offer a mechanism for repairing stimulant-induced neuronal injury—which might be vital for successful recovery. For example, it is known that methamphetamine causes long-term structural damage to regions of the brain that control cognitive and psychiatric function [6–8]. Similarly, methamphetamine-dependent adults evidence high rates of neuropsychiatric impairments, including persistent cognitive, mood, anxiety and other psychiatric disorders up to 3 years or longer following abstinence [9–13]. Agents designed specifically to repair neuronal damage may have increased potential to help adults regain lost function, re-engage in meaningful work and relationships and avoid relapse. A growing literature demonstrates that methamphetamine alters peripheral and central immune functions [9,14–17] and that immune factors such as cytokines, chemokines and adhesion molecules probably play a role in the development of methamphetamine-induced neuronal injury and neuropsychiatric impairment [9,18]. At the cellular level, activated microglia contribute to neurodegeneration through proinflammatory processes, including the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 or through oxidative mechanisms [18], and a global pattern of microglial activation and microgliosis has been observed in the brains of methamphetamine abusers at least 2 years into abstinence [19]. Significant potential for intervention may therefore lie within immunotherapies that can optimally regulate the delicate balance of immune factors, promote brain repair, minimize neuroinflammatory damage and attenuate neuropsychiatric symptoms following addiction. Such a discovery would represent a major scientific breakthrough that could broadly impact addiction treatment and outcomes.