Until this point we have discussed therapeutic strategies that affect directly either access of methamphetamine to the brain or its intracellular and membrane dopaminergic substrates. A different approach is to employ therapeutic drugs that mimic, antagonize or otherwise affect other chemically coded brain neurotransmitter systems that modulate the mesolimbic dopamine system and hence possibly alter the rewarding effects of stimulants. Examples include drugs whose actions affect GABA and glutamate, renin–angiotensin, serotonin, endogenous opioid and endocannabinoid pathways.

GABA and glutamate

GABAergic drugs modulate dopamine release in the ventral pallidum [86]. Gamma vinyl‐GABA is a GABA transaminase inhibitor [87-89]. It is approved in Europe and Canada as an anticonvulsant medication (Vigabatrin, Sabril, Ovation, Deerfield, IL, USA), but not in the United States. In pre‐clinical proof‐of‐concept studies investigators demonstrated that gamma vinyl‐GABA could antagonize increases in nucleus accumbens dopamine in response to the stimulants cocaine and methamphetamine, as well as ethanol and heroin. In other words, they demonstrated therapeutic potential for gamma vinyl‐GABA by affecting a common reward pathway [90, 91]. In a preliminary open‐label clinical trial on volunteers with a history of cocaine abuse a cohort of the participants were able to remain drug free for 28 days [92]. The investigators subsequently conducted another open‐label clinical trial that included methamphetamine as well as cocaine abusers [93]. Eighteen of 30 participants completed the trial and tested negative for methamphetamine and cocaine at study completion. There have been reports that gamma vinyl‐GABA causes visual field defects [94, 95]. No adverse effects on visual field were noted in the human studies cited [92, 93]. Neither study included controls, thus while the data are encouraging, one cannot conclude that the treatment itself accounted for the positive outcome.

Modafinil is a non‐amphetamine {2‐[(diphenylmethyl)sulfinyl]acetamide} weak psychostimulant that is effective for treating narcolepsy [96, 97]. It was approved by the FDA in 1998 as Provigil (Cephalon, Fraser, PA, USA) with the indications ‘to improve wakefulness in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder’. It has been suggested that modafinil may act via GABAergic or glutamatergic mechanisms, but definitive evidence is still lacking [98-100]. Modafinil binds to the dopamine transporter, but with very low affinity [101, 102]. It is not self‐administered, nor is it reinforcing in rats [103]. In rhesus monkeys trained to self‐administer cocaine, it was reported to serve as a reinforcer at high doses [104]. While it did not substitute for the subjective effects of cocaine in a human drug discrimination study, questions have been raised concerning euphorigenic properties in patients [105, 106]. Modafinil is scheduled as class IV by the US Drug Enforcement Agency. Dackis et al. [107] conducted a randomized, double‐blind, placebo‐controlled trial to determine whether modafinil might improve clinical outcome in cocaine‐dependent patients receiving standardized psychosocial treatment. They observed that modafinil‐treated patients had more ‘clean’ urine samples compared to placebo‐treated controls and were more likely to maintain protracted abstinence. None of the patients failed to complete the study as a result of adverse events.

Modafinil may also have potential as a methamphetamine pharmacotherapy. Modafinil does not increase anxiety in an animal (mouse) model and appears to augment the efficacy of antidepressants in depressed patients [108, 109]. The antidepressant effect of modafinil may make it useful in reducing feelings of the dysphoria of early methamphetamine abstinence and thereby promote both sustenance of abstinence and greater engagement in behavioral therapy. In addition, as it is a weak stimulant, modafinil may decrease craving and methamphetamine‐seeking. Modafinil may also be useful for treating methamphetamine dependence in an indirect way; that is, by improving concentration, daytime alertness and cognitive functions of methamphetamine‐dependent subjects and thus allowing them to benefit from cognitive–behavioral therapy and other treatment compliance‐enhancing forms of psychosocial therapy.

Topiramate is a sulphamate‐substituted fructose derivative that was designed originally as an oral hypoglycemic [110]. It is approved by the FDA as Topamax (Ortho‐McNeil, Titusville, NJ, USA) and indicated as an anticonvulsant and for migraine prophylaxis. Its use as a therapeutic has extended far beyond its label indications [111, 112]. The precise mechanism(s) of action by which topiramate causes its salutary effects on seizure and migraine is unknown, because it has a broad range of pharmacological effects. Most notably, topiramate affects both GABA and glutamatergic systems [113]. It increases brain GABA as well as antagonizing α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA)/kainate but not N‐methyl‐ d‐aspartate (NMDA) receptor‐mediated currents [114-116]. This aspect of its pharmacology would conceivably facilitate its modulating the cortico‐mesolimbic dopamine system thought to underlie the reinforcing properties of alcohol, nicotine and psychomotor stimulants such as cocaine and amphetamines [20, 112, 117]. Using this theoretical construct topiramate has been tested in clinical trials for efficacy in decreasing consumption of a number of abused substances. Topiramate has been demonstrated to be effective in reducing alcohol consumption and craving and prolonging abstinence in alcohol‐dependent subjects as well as supporting abstinence from cigarette smoking [118, 119]. Moreover, Kampman et al. [120] have demonstrated that topiramate can help achieve and maintain abstinence in cocaine‐dependent individuals. Johnson et al. [121] recently completed a Phase I safety interaction trial on the effects of acute topiramate on the positive subjective effects of acute methamphetamine in non‐treatment‐seeking methamphetamine addicts. They observed that the combination was well tolerated, but acute administration of topiramate appeared to slightly enhance rather than attenuate the positive subjective effects of intravenous methamphetamine at the doses tested. Topiramate did not increase methamphetamine craving.