Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study

Abstract

Background Despite numerous clinical trials no efficacious medications for methamphetamine (MA) have been identified. Neuroinflammation, which has a role in MA-related reward and neurodegeneration, is a novel MA pharmacotherapy target. Ibudilast inhibits activation of microglia and pro-inflammatory cytokines and has reduced MA self-administration in preclinical research. This study examined whether ibudilast would reduce subjective effects of MA in humans. Methods Adult, non-treatment seeking, MA-dependent volunteers (N = 11) received oral placebo, moderate ibudilast (40 mg), and high-dose ibudilast (100 mg) via twice-daily dosing for 7 days each in an inpatient setting. Following infusions of saline, MA 15mg, and MA 30mg participants rated 12 subjective drug effects on a visual analog scale (VAS). Results As demonstrated by statistically-significant ibudilast×MA condition interactions (p < .05), ibudilast reduced several MA-related subjective effects including High, Effect (i.e., any drug effect), Good, Stimulated and Like. The ibudilast-related reductions were most pronounced in the MA 30mg infusions, with ibudilast 100 mg significantly reducing Effect (97.5% CI [- 12.54, -2.27]), High (97.5% CI [-12.01, -1.65]), and Good (97.5% CI [-11.20, -0.21]), compared to placebo. Conclusions Ibudilast appeared to reduce reward-related subjective effects of MA in this early-stage study, possibly due to altering the processes of neuroinflammation involved in MA reward. Given this novel mechanism of action and the absence of an efficacious medication for MA dependence, ibudilast warrants further study to evaluate its clinical efficacy.

Ibudilast attenuates expression of behavioral sensitization to cocaine in male and female rats

“…While modulation of glutamatergic neurotransmission is not a primary mechanism of ibudilast action, this effect may be significant given that the expression of cocaine sensitization is associated with increased nucleus accumbens glutamate levels following cocaine challenge during abstinence (Pierce et al, 1996). Taken together, it is not yet clear which of ibudilast's many actions are responsible for the reduction in drug-stimulated behaviors seen here and in other studies (Hutchinson et al, 2009; Beardsley et al, 2010; Snider et al, 2012; Snider et al, 2013; Bell et al, 2015; Worley et al, 2016). Thus, now that a role for ibudilast in reducing cocaine-mediated behavior has been established by the present work, further study is needed to precisely delineate the underlying mechanism(s).…”

“…Ibudilast was also found to block the development of methamphetamine sensitization in male mice (Snider et al, 2012). More recently, ibudilast was shown to reduce the reward-related subjective effects of methamphetamine (Worley et al, 2016). These data are supported by work of Becker and colleagues, which found that ibudilast reduced ethanol self-administration in non-dependent male rats as well as in dependent male mice (Bell et al, 2015).…”

“…Moreover, ibudilast reduced self-reports of methamphetamine reward-related subjective effects (Worley et al, 2016), but intriguingly, nothing is known about the ability of ibudilast to modulate cocaine-induced behaviors or sexually dimorphic effects in the context of any abused drug. Because ibudilast can modulate some neurobiological effects implicated in cocaine abuse including cAMP accumulation, glial activation, and neuroinflammation, we sought to determine if ibudilast alters the expression of behavioral sensitization to cocaine and if this response differs between male and female rats.…”

The role of neuroimmune signaling in alcoholism

“…A phase I clinical trial involving the PDE4 inhibitor ibudilast was recently completed but has not yet been reported. A recent placebo-controlled trial found that ibudilast reduced some of the subjective reward effects of methamphetamine (Worley et al, 2016). PPARγ agonists, historically used for the treatment of type II diabetes, might also be helpful in alcohol use disorders through their anti-inflammatory activities.…”

Glial and neuroinflammatory targets for treating substance use disorders

“…Ibudilast was safe and well tolerated in combination with IV methamphetamine (DeYoung et al, 2016). Worley and colleagues (2016) examined whether ibudilast would reduce subjective effects of methamphetamine among non-treatment seeking, methamphetamine-dependent volunteers (n=11). Using a within-subjects design, the subjective effects of IV methamphetamine (15 mg, 30 mg) were examined using a visual analog scale (VAS), following 7 days of maintenance on placebo, moderate-dose ibudilast (40 mg, BID), and high-dose ibudilast (100 mg, BID).…”