Pharmacotherapy of amphetamine-type stimulant dependence: An update

Abstract

Issues

Methamphetamine or amphetamine-type stimulants are the second most frequently used illicit drug worldwide, second only to cannabis. Behavioural treatments are efficacious, but their impact is limited underscoring the need for other treatment options, notably, pharmacotherapy.

Approach

A review of randomised controlled trials of pharmacotherapies for methamphetamine or amphetamine-type stimulants was performed using PubMed and Google Scholar databases. Evidence for efficacy of medications is reported.

Key findings

Clinical trials have yielded no broadly effective pharmacotherapy. Promising signals have been observed for methylphenidate, naltrexone, bupropion and mirtazapine in subgroups of patients in reducing stimulant use (e.g. patients with less severe dependence at baseline, men who have sex with men), though none has produced an unambiguous, replicable signal of efficacy.

Implications

Problems in Phase II trials, including high drop-out rates, missing data and a lack of agreement on outcomes, complicate efforts to find a broadly effective pharmacotherapy for amphetamine-type stimulant disorders. Efforts to address these problems include calls for better validation of pharmacological target exposure, receptor binding and functional modulation. As well, there is a need for agreement in using findings from pre-clinical and early phases of the medication development process for selecting better pharmacotherapy candidates.

Conclusion

After over 20 years of efforts worldwide to develop a broadly effective medication for dependence on methamphetamine or amphetamine-type stimulants, no candidate has emerged. This highlights the need for new compounds, consistent and stringent research methods, better integration between preclinical and clinical stages of medication development, and improved collaboration between government, industry and researchers.

Between 2008–2010, about 1.2% or 1.3% of adults worldwide report use of amphetamine type stimulants (ATS) involving compounds that range from amphetamine to an array of amphetamine analogues, but exclude 3,4-methylenedioxy-N-methylamphetamine or ‘ecstasy’. This means that more individuals are estimated to use ATS than heroin or cocaine [1]. In many Asian countries, the prevalence of ATS use precipitating treatment is exceeded only by opioids. In Indonesia, ATS is the primary drug of abuse for more than one-third of people treated for substance use disorders. Indeed, the use of ATS continues to present a significant public health burden worldwide [2].

In Australia, recent (past 30 days) use of ATS (excluding ecstasy) declined among adults from a peak of 3.7% in 1998 to 2.1% in 2010, a rate that still remains one of the highest among other countries [3]. Ecstasy (a short-acting stimulant) also is used frequently by Australian adults (3.0%). In Australia and elsewhere, use of long-acting stimulants, particularly amphetamine and methamphetamine, is disproportionately popular among specific groups, including men who have sex with men [4], women [5] and criminal offenders [6]. Men aged 20–29 remain the group with the highest likelihood of amphetamine use in Australia, despite some evidence of declining rates over the past decade [3]. Methamphetamine use at levels of dependence is associated with multiple morbidities, including HIV infection, hepatitis, cardiac effects, family disruptions and prominent psychiatric consequences including psychosis [7,8]. Societal costs for methamphetamine abuse are high, estimated in 2005 at more than $23 billion in the United States and include premature death, crime, lost productivity, environmental damage, medical conditions, cognitive dysfunction, disruption of family life and infectious disease[7].

The primary interventions with evidence of efficacy are behavioural therapies, which reduce amphetamine use [9–12]. Yet the impact of these treatments is limited in that they require substantial investments in care delivery systems and trained professionals to implement the interventions with fidelity. Behavioural treatments also have moderate effect sizes in terms of abstinence and retention, underscoring the need for additional efficacious strategies, notably pharmacotherapy. This review describes the rationale and targets for pharmacotherapies for abuse or dependence on ATS, reviews the extant evidence for select agents, discusses emerging pharmacogenetic data and proposes directions for future work. A literature search was conducted by the first author using the PubMed and Google Scholar databases. An initial search for randomised placebo-controlled clinical trials treating amphetamine or methamphetamine use disorders published from 1980 through July 2012 produced 468 results. Further review identified 21 trials. The authors selectively included brief detoxification trials, human laboratory studies and pre-clinical data where appropriate.

Targets for Pharmacotherapies of Long-Acting Stimulants: Rationale

Pharmacotherapies evaluated for dependence on amphetamine or methamphetamine have different underlying mechanisms that may: (i) alter the neurobiology of reinforcement or reward from the drug, (ii) attenuate the negative reinforcing effects of withdrawal from and craving for the drug, or (iii) ameliorate comorbid psychiatric vulnerabilities that co-occur and that can interfere with recovery. Methamphetamine itself increases extracellular levels of monoamines both by blocking presynaptic reuptake and stimulating the release of catecholamines through the disruption of vesicular storage [13,14]. The positive or rewarding effects from methamphetamine and amphetamine use are mediated by neurotransmitter systems including dopamine, serotonin and norepinephrine [15], although dopaminergic effects appear primary in the acute euphoric effects, making this system a favoured target for pharmacotherapy. Initial positive and rewarding subjective effects of methamphetamine dull in quality with repeated use of the drug, signalling development of a series of neuroadaptations. Koob and Le Moal [16] characterise this process as the increasing recruitment of anti-reward processes, including hypoactivity in the dopaminergic system and alterations in hypothalamic-pituitary-adrenal axis functioning. Motivation to obtain non-drug rewards is attenuated [17] and early abstinence is associated with chronic irritability and dysphoria. Medications that relieve withdrawal symptoms may support continued motivation for individuals to sustain abstinence and thus present an additional rational target for a pharmacotherapy. Lastly, misusers of long-acting stimulants often show both premorbid and stimulant-related psychiatric and neurocognitive impairments [18,19]. Comorbidity between drug and other psychiatric disorders is well documented [20] and complicates treatment outcomes, with negative effects on substance abuse treatment outcomes [21]. It is plausible that treatment of comorbid psychopathology might improve outcomes.

The medications evaluated in trials for pharmacotherapies for amphetamine or methamphetamine dependence have mechanisms of action that can be categorised as antagonists or agonists. Antagonist therapy approaches use medications that block the action of the agonist to attenuate or eliminate the positive reinforcing effects of acute methamphetamine intoxication. Antagonists compete with endogenous monoamines but have no intrinsic activity at the receptor site. There is substantial support for evaluating antagonist approaches from other areas of drug dependence, including use of naltrexone for alcohol dependence and opioid dependence [22,23]. In contrast, agonist therapies are medications that bind to and trigger responses from receptors involved in the addiction process, often mimicking the action of monoamines involved in the reinforcement, withdrawal symptoms and motivational aspects of methamphetamine or amphetamine use. As such, agonist therapies promote early abstinence by providing a modest level of subjective effects, but may have their greatest impact in minimising withdrawal and negative affective symptoms. Nicotine replacement therapies are effective agonist approaches to treating nicotine dependence [24] and methadone and buprenorphine are effective agonist approaches for opioid dependence [25,26].

Clinical trials of pharmacotherapies for ATS dependence

Antagonist strategies

Naltrexone is an opioid receptor antagonist that is approved for treatment of alcohol dependence. While the primary positive reinforcing effects of methamphetamine are mediated by dopamine, opioid receptors partially modulate dopaminergic effects and may act as a relevant pharmacological target. Following an encouraging open-label trial of naltrexone for amphetamine dependence [27], 80 treatment-seeking amphetamine-dependent Swedish adults were randomised to placebo or 50 mg of naltrexone [28]. In an intention-to-treat analysis, naltrexone outperformed placebo in terms of both mean numbers of negative urine samples and continuous abstinence rates. Retention, however, was not significantly better in the medication condition. It is important to note the trial required a two-week period of abstinence prior to randomisation, which excluded 97 participants unable to meet this criterion and homogenised the sample into individuals with less severe dependence. It is possible that inclusion of methamphetamine-dependent and more severely amphetamine-dependent participants may erode these successful outcomes. Finally, adherence to oral naltrexone is suboptimal. Accordingly, a naltrexone implant has been developed to address this challenge. Tiihonen [29] assessed the naltrexone implant in a 10-week trial for individuals with comorbid opioid and amphetamine dependence. Naltrexone outperformed the placebo implant in terms of retention and proportion of drug-free urine samples. These data are encouraging, but await confirmation in several clinical trials that are currently underway.

Two relatively small open-label trials evaluated the mixed dopamine and serotonin antagonist risperidone in small samples of methamphetamine-dependent adults to show acceptability [30] and decreases in weekly methamphetamine use that correlated with plasma risperidone levels [31]. A randomised trial that did not include a placebo condition in 80 adults hospitalised with bipolar disorder and co-occurring cocaine or methamphetamine dependence reported that quetiapine and risperidone equally reduced bipolar symptoms and drug cravings, with reductions in cravings associating with reductions in stimulant use [32]. However, in non-dependent volunteers in the human laboratory, neither haloperidol nor risperidone attenuated the euphorigenic effects of methamphetamine [33], dampening rationale for further evaluation of dopamine antagonists.

Development of the partial agonist aripiprazole brought with it enthusiasm as a putative medication for its potential to bind at the dopamine receptor but produce a response sub-maximal to a full agonist [34]. This agent was tested in amphetamine-dependent participants against placebo and methylphenidate in a three-arm randomised design but an interim analysis evidenced an iatrogenic effect of aripiprazole [35]. Comparing 19 participants randomised to aripiprazole to 17 participants in the placebo condition, an adjusted odds ratio indicated a higher proportion of amphetamine-positive urine samples for the active condition (odds ratio = 3.8, 95% confidence interval = 1.6, 9.2). In an intention-to-treat analysis, 99% of urine samples in the aripiprazole condition were positive for amphetamine. Exacerbation of drug use by atypical antipsychotics is not unprecedented [36,37]. Recently, Sulaiman randomised 37 methamphetamine-dependent adults with a history of psychosis to aripiprazole or placebo conditions [38]. Aripiprazole attenuated psychotic symptoms and was associated with twelve additional days of treatment retention, compared with the placebo group. No differences in methamphetamine use were observed.

Agonist strategies

Following the positive findings from studies of opioid and nicotine dependence, agonist replacement strategies also have been evaluated for stimulant dependence. Agonist therapies produce behavioural and neurobiological effects that are comparable or identical to the drug of addiction [39]. Dexamphetamine increases extracellular levels of dopamine through a carrier-mediated exchange at presynaptic vesicles. In a small unblinded randomised trial, Shearer [40] demonstrated initial safety and feasibility of dexamphetamine replacement therapy (60 mg/day) for injecting amphetamine-dependent individuals. The study was underpowered to detect treatment differences but no serious adverse events were observed.

Subsequently, Longo [41] randomly assigned methamphetamine-dependent participants to receive up to 110 mg/day sustained-release dexamphetamine (N = 23) or placebo (N = 26) for 12 weeks. Those in the dexamphetamine condition completed an average of 86 days compared with a significantly shorter period for the placebo condition (49 days) but no effect on methamphetamine use was observed. Although some decreases in craving for methamphetamine were observed with dexamphetamine treatment, no improvement in drug use or retention were observed in a subsequent trial [42]. The Galloway trial assessed 60 mg sustained release dexamphetamine, a dose that may be suboptimal for treating methamphetamine-dependent individuals.

Additional support for an agonist approach is provided by Tiihonen [35]. In this 20-week, randomised, double-blind, placebo-controlled trial of aripiprazole, methylphenidate or placebo among participants dependent upon injection use of amphetamine, participants assigned to the 54 mg/day slow-release methylphenidate condition (N = 17) had significantly fewer amphetamine-positive urine samples than placebo-treated patients (N = 19; odds ratio=3.77; 95% confidence interval 1.55, 9.18). As this trial was stopped by an interim analysis over concern for the aripiprazole condition, findings are considered preliminary. In confirmatory work at the University of California, Los Angeles, Ling is currently conducting a Phase II, placebo-controlled trial of methylphenidate for methamphetamine dependence.

Atypical stimulants may carry lower risks for diversion than pure agonists, thereby improving potential acceptability as therapeutics. Modafinil is a non-amphetamine type stimulant with wake-promoting properties and cognitive enhancing effects that is approved for narcolepsy and other sleep disorders. It features a pharmacological profile different from that of conventional stimulants and has a lower abuse liability [43], although preclinical data [44] and a human laboratory study [45] show modafinil increases dopamine availability in nucleus accumbens, raising concerns over its use in groups vulnerable to stimulant dependence. Indeed, at clinical doses, modafinil elevates extracellular dopamine through the inhibition of dopamine and norepinephrine transporters. These primary effects may catalyse a series of changes in serotonin, gamma-aminobutyric acid (GABA) and glutamate. The stimulating effects, paired with the cognitive enhancing effects of the medication [46] raises interest as potential pharmacotherapy for methamphetamine dependence.

Open-label trials of modafinil at doses of up to 200 mg/day [47] in HIV-positive patients with methamphetamine abuse and at 400 mg/day in a small sample of methamphetamine-dependent adults [48] found few adverse effects and no indications the medication was habit-forming or a diversion risk. In the first of three randomised, double-blind, placebo-controlled trials of modafinil for methamphetamine dependence, modafinil 200 mg/day was no more effective than placebo in pre-planned analyses of retention or of methamphetamine use in the full sample [49]. Post hoc analyses suggested that greater reductions in stimulant use were observed for the modafinil condition among participants who were compliant with their medication.

In another randomised, double-blind, placebo-controlled trial, Heinzerling [50] assessed 400 mg daily of modafinil, reasoning that the excessively high doses of methamphetamine used by dependent individuals may necessitate a higher medication dosage. Seventy-one treatment-seeking participants were randomised to placebo or modafinil for 12 weeks. Participants also received concurrent weekly cognitive behavioural therapy and contingency management. Results evidenced no significant effect for modafinil relative to placebo on methamphetamine use, retention, depressive symptoms or cravings. Anderson [51] completed a trial of 210 methamphetamine dependent individuals randomised to placebo, 200 mg, 400 mg of modafinil. There was no evidence of benefit for either medication condition in terms of percentage of participants with a week of abstinence or retention. The authors caution, however, that due to poor medication compliance, the trial does not represent a definitive test of the efficacy of modafinil. Despite these disappointing findings, some enthusiasm still exists for modafinil in its current form or one of its enantiomers, R-modafinil, as a treatment for psychostimulant dependence [52].

Some measures of efficacy are favourable for continuing to evaluate agonist medications. Yet, issues including abuse liability, diversion, tolerance and uncertain functional benefits complicate this line of research. Concerns from governmental, clinical and policy professionals over substitution-type therapies for stimulant dependence persist and dampen enthusiasm for this treatment approach.

Bupropion

Although not considered an agonist, bupropion functions as a mild stimulant and antidepressant. Bupropion is a nonselective inhibitor of the dopamine and norepinephrine transporters and also acts as an antagonist at nicotinic acetylcholine receptors [53]. Bupropion increases dopamine transmission in both the nucleus accumbens and the prefrontal cortex through inhibition of the dopamine transporter [54]. By restoring depleted levels of dopamine, bupropion may be effective in ameliorating withdrawal symptoms and cognitive deficits in patients recovering from methamphetamine dependence, thereby reducing methamphetamine use.

Elkashef [55] conducted a randomised placebo-controlled double-blind trial with 151 treatment-seeking individuals with methamphetamine dependence. On primary outcomes of retention and MA-free urine samples, bupropion sustained release did not outperform placebo. However, in pre-planned subgroup analyses, individuals who used methamphetamine 18 or fewer days in the month prior to randomisation exhibited a positive response to bupropion (urine verified). Additionally, there was some indication that the absence of depressive symptomatology and male gender were associated with superior outcomes for the study medication.

Utilising a similar design – a two-week baseline screening period followed by randomisation to 300 mg/day sustained release or to placebo for 12 weeks in the context of weekly cognitive behavioural therapy – Shoptaw [56] reached similar conclusions. Methamphetamine use, retention and cravings were not different across the two treatment conditions. Similar to Elkashef, participants with lower frequency of baseline methamphetamine use, assessed via urine drug screens during the two week baseline period, were more likely to provide methamphetamine-free urine drug screens during treatment with bupropion relative to placebo. However, participants who had three or more positive urine drug screens of the six possible during the baseline period showed no benefit from bupropion. Das and colleagues provided further confirmation with bupropion (300 mg daily) by demonstrating the acceptability of the drug in a randomised, placebo-controlled trial with 30 high-risk men who have sex with men [57]. The trial was not powered to detect differences in treatment outcome, though positive outcomes were in the direction of the active treatment arm. Recruitment and retention are feasible and bupropion was well tolerated, as indicated by the absence of adverse events and acceptable medication adherence. A larger trial (N~200) of bupropion has been completed with findings forthcoming.

In sum, dopamine-enhancing medications have demonstrated the most consistent effects on reducing methamphetamine use when evaluated in placebo-controlled randomised trials. One of the challenges to continued work using this strategy is that pure agonists have abuse liability, which elicits concerns that limit impact. Yet, as evidence continues to accrue favouring an agonist approach to treating methamphetamine and amphetamine dependence, clinicians and policymakers may find it increasingly difficult to support evidence-based treatments for other addictions while maintaining an exception in this instance.

Serotonergic medications

While methamphetamine has its greatest effects on systems involved with reward and reinforcement, it also has effects on related neurotransmitter systems, including serotonin. In early work assessing pharmacotherapies for methamphetamine dependence, imipramine [58] and fluoxetine [59] failed to impact use. Trials of other serotonergic drugs also have proven largely unsuccessful.

Huber, Shoptaw and colleagues [60] assessed the selective serotonin reuptake inhibitor sertraline (50 mg twice daily) in a four-arm randomised design. Two hundred and twenty-nine participants were assigned to sertraline only, sertraline and contingency management, placebo and contingency management, or placebo only. Individuals in all conditions received thrice-weekly relapse-prevention groups. Contingency management significantly improved methamphetamine use outcomes, while participants assigned to the sertraline-only condition resulted in poorer retention and lower likelihood of sustained abstinence than the other treatment conditions.

Ondansetron, a 5-HT₃ antagonist, has antiemetic properties and has previously shown some promise for the treatment of alcoholism [61,62]. Although ondansetron does not act directly on the dopaminergic system, activation of the 5-HT₃ receptor modulates central dopamine function [63], highlighting this as a potential target for pharmacotherapy. Based on some encouraging preclinical data, Johnson and colleagues [64] assessed three doses of ondansetron in a double-blind placebo-controlled trial with 150 methamphetamine-dependent participants. No significant differences were observed for the medication at any of the doses in reducing methamphetamine use or any reports of withdrawal, craving or severity of dependence. A previous study with cocaine identified a non-linear dose-response function whereby 1 mg exerted iatrogenic effects but therapeutic effects were observed for 4 mg [65]. However, none of the doses evaluated (0.50 mg, 2 mg, 8 mg) evidenced any benefit beyond placebo in terms of methamphetamine-free urine samples or treatment retention. In sum, from the negative fluoxetine findings in the trial conducted by Batki [59], discouraging preliminary paroxetine findings from Piasecki [66], and the apparent worsening of outcomes with sertraline, Shoptaw [60] concluded that marketed serotonin-specific reuptake inhibitors may be ineffective for treating methamphetamine dependence. It remains that compounds in development that have selective activity at specific serotonergic receptors may be efficacious approaches. Indeed, one such medication, mirtazapine, has demonstrated some promise.

Mirtazapine is a pharmacologically distinctive antidepressant with sedative and anxiolytic properties that enhances both noradrenergic and serotonergic activity. Its actions on the serotonergic system are different from those of selective serotonin reuptake inhibitors, including enhanced transmission of 5-HT_1A receptors and blockade of 5-HT₂ and 5-HT₃ [67]. Colfax [68] reported outcomes of a trial of mirtazapine (15 mg twice daily) in 60 men who have sex with men showing men assigned to receive mirtazapine showed fewer methamphetamine-positive urine samples compared to those assigned to placebo. Interestingly, men who have sex with men who were assigned to receive mirtazapine also showed significant reductions in sexual risk behaviours compared to those assigned to receive placebo. While the primary outcome in this study was not end-of-treatment abstinence, which remains the most relevant consideration for developing an indication for methamphetamine dependence, it is encouraging that a prospectively defined significant finding was reported. A replication of this early finding is planned.

Mirtazapine also has been evaluated as a withdrawal agent. Cruickshank and colleagues [69] assessed mirtazapine in a randomised double-blind trial of 31 methamphetamine-dependent adults. No differences were detected in retention or in self-reported withdrawal symptoms. Substantially limiting the interpretability of the data, the medication was administered for only two weeks and attrition was substantial (48%).

GABAergic mechanisms

The GABA system interacts with dopaminergic processes, and its activation exerts an inhibitory effect on the reward system. This feature suggests that GABA agents may have some efficacy in attenuating the reinforcing effects of stimulants. Some preclinical evidence suggested modest efficacy for cocaine dependence of the selective GABA_B agonist baclofen, and a clinical trial found some support as a treatment for cocaine dependence [70]. Gabapentin was originally developed as an anticonvulsant but its utility in treating neuropathic pain has been well documented. It does not appear to block GABA uptake or metabolism [71] but has global effects on GABA in the brain [72].

Heinzerling [73] randomised 88 participants to one of three clinical trial arms: baclofen (20 mg thrice daily), gabapentin (800 mg thrice daily) or placebo. Treatment was administered for 16 weeks. Neither medication was distinguishable from placebo in terms of the primary outcomes, although there was evidence of a signal for baclofen in reducing methamphetamine use among the subgroup of participants who demonstrated better medication adherence. In a randomised, placebo controlled trial of a proprietary concoction of flumazenil injections (a benzodiazepine antagonist), gabapentin and hydroxyzine in 120 methamphetamine-dependent adults [74], no effects were seen on methamphetamine use, treatment retention or drug craving. Elkashef [75] assessed topiramate with a target dose of 200 mg/day in 140 methamphetamine dependent adults. There was no clear evidence of efficacy for the medication; however, among individuals who were abstinent at the beginning of treatment, topiramate appeared to facilitate abstinence during the second half of the trial. As the research expands, it is conceivable that a particular medication may not help to instil abstinence but may be efficacious for prevention of relapse (or the reverse). Table 1 summarises the most promising medications and those demonstrating iatrogenic effects.

Table 1.

Pharmacological Agent (Reference)	Study Design	Findings	Comment
Agents demonstrating some promise
methylphenidate 54 mg/day (35)	Three-arm randomized double-blind design (methylphenidate, aripiprazole, placebo); N=53, 20 weeks of treatment, injection use history for all participants; urine samples twice weekly	Patients in methyphenidate condition were less likely to provide amphetamine-positive samples during course of treatment (odds ratio=.46; p=.008)	Study was terminated prematurely due to iatrogenic effect of aripiprazole. A trial of methylphenidate for MA depenedence is ongoing
bupropion 150 mg twice daily (55)	Randomized double-blind placebo-controlled design; N=151, 12 weeks of treatment; urine samples thrice weekly	No group difference for primary outcome of probability of MA-free week; subgroup of modest users (fewer than 19 days use in past month) benefitted from bupropion in terms of probability of MA-free week (p=.03)	Some suggestion that men may benefit from bupropion while women receive no benefit
bupropion 150 mg twice daily (56)	Randomized double-blind placebo-controlled design; N=73, 12 weeks of treatment; urine samples thrice weekly	No group difference for primary outcome of probability of MA-free week; subgroup of light users during 2-week baseline period benefitted from bupropion in terms of probability of MA-free week (odds ratio=2.81; p<.001)	Very similar pattern of results to Elkashef et al. (55) suggesting that among light users, bupropion may be efficacious
mirtazapine 30 mg/day (68)	Randomized double-blind placebo-controlled design; N=60, sample composed exclusively of men who have sex with men, 12 weeks of treatment; urine samples once weekly	Patients in mirtazapine condition were less likely to provide methamphetamine-positive samples during course of treatment (relative risk=.57; p=.02)	Unusually high retention in this study. A replication of these findings is underway. An underpowered randomized trial assessed the efficacy of mirtazapine for managining MA-withdrawal reported null findings (69)
naltrexone capsules 50 mg/day (28)	Randomized double-blind placebo-controlled design; N=80, 12 weeks of treatment; urine samples twice weekly	Patients in naltrexone group featured more amphetamine-free urine samples (p<.05)	Medication adherence was 63% and adherence was strongly related to treatment outcomes
naltrexone implant (Prodetoxon)	Randomized double-blind placebo-controlled design; N=100, sample composed patients with concurrent amphetamine and opioid dependence; 10 weeks of treatment, urine samples collected once weekly	The proportion of drug-free urine samples was 38% in the naltrexone group and 16% in the placebo group (p=0.01). Retention was 52% in naltexone condition and 28% in placebo condition (p=.01)	Relevance for primary users of amphetamine are unclear as naltrexone did not produce more amphetamine-negative urine samples specifically, when compared with placebo
Medications with possible iatrogenic effects
aripiprazole 15 mg/day	Three-arm randomized design (methylphenidate, aripiprazole, placebo); N=53, 20 weeks of treatment, injection use history for all participants; urine samples collected twice weekly	Patients in aripiprazole condition were more likely to provide amphetamine-positive samples during course of treatment (odds ratio=3.77; p=.003)	Study was terminated prematurely due to iatrogenic effect of aripiprazole. Subsequent findings with aripiprazole have been discouraging
sertaline 50 mg twice daily	Four-arm randomized double-blind (with respect to medication condition) placebo controlled trial. 2×2, sertraline vs. placebo, contingency management vs. no contingency management); 12 weeks of treatment, urine samples collected thrice weekly	No main effect was observed for sertraline on MA use; however, the sertraline-only condition featured more MA-positive samples (p<.05) and poorer retention (p<.05)	Taken together with other negative findings for fluoxetine and paroxetine, SSRIs appear to be poor candidates for MA pharmacotherapy

Explaining variability of treatment outcomes

Moderating variables and pharmacogenetics

Clinicians and researchers have long noted variation in responses to pharmacotherapies and the expectation that a single medication will meet the needs of all amphetamine dependent patients is unreasonable [39]. Previous research identified lower educational attainment, more extensive treatment exposure and greater baseline methamphetamine use as characteristics portending negative outcomes [76–78]. Using data from a randomised controlled trial of bupropion, Dean [79] assessed the relative value of neurocognitive function, psychiatric function, demographics, and pre-treatment substance use variables in predicting abstinence and retention. Using a statistical methodology that inductively prioritises variables on the basis of their predictive validity – classification and regression trees – a multivariate model was determined. Although the predictors of poor outcomes included impaired neurocognition and nicotine dependence, level of baseline use of methamphetamine overwhelmed the predictive power of these other variables. These findings encourage careful accounting of baseline drug-use patterns in planning clinical trials.

In addition to the variables highlighted above, genetic features are likely to function as moderators of therapeutic responsiveness. The substantial between-individual variability in medication response, paired with generally small intra-patient variability, suggests the role of heritable factors in medication response [80]. These observations have generated great interest among addiction researchers in pharmacogenetics – the study of genetic factors that account for the variability in treatment responsiveness. Through a variety of mechanisms – drug metabolism, absorption, distribution and excretion – genetic factors may interact with pharmacotherapies to impact treatment outcomes. Medication treatments tailored for specific genetic profiles may promote positive therapeutic responses, mitigate problems associated with toxicity, and improve compliance.

Several single nucleotide polymorphisms (SNP) have been linked to dopaminergic signalling [81], a clear target for pharmacological approaches to methamphetamine dependence. Initial studies have identified associations between SNPs and susceptibility for methamphetamine dependence [82] and methamphetamine-induced psychosis [83], and a study of neurocognition found that the neurotoxic effects of methamphetamine use varied as a function of a gene regulating the metabolism of the drug [84], but have yet to be replicated. Haile and colleagues [85] reviewed this evidence and suggested promise of pharmacogenetics for stimulant dependence, although they lamented the absence of studies explicitly examining treatment responsiveness. Preliminary pharmacogenetic studies from our group found an interaction between the well characterised Val158Met SNP in catechol-O-methyltransferase, the enzyme that metabolises catecholamines, and treatment with modafinil for methamphetamine dependence in Hispanics with modafinil outperforming placebo in Val/Val homozygotes but not Met carriers [86]. Results from the same sample show an interaction between the Val66Met SNP and BDNF and gender on baseline frequency of methamphetamine use, an important predictor of treatment outcomes, with higher baseline frequency of methamphetamine use concentrated among females with Val/Val genotype [87].

While preliminary, the study highlights the potential of biomarkers, including pharmacogenetic markers, to guide medication development for methamphetamine dependence. Numerous polymorphisms likely have a role in treatment response, partially explaining the lack of a broadly effective medication. Polymorphisms related to the metabolism of the pharmacological agent, of methamphetamine (or amphetamine) or of associated neurotransmitter systems, may be relevant in optimising treatment outcomes.

Conclusions and future directions

Dependence on amphetamine and methamphetamine represent a substantial public health burden. While methamphetamine use appears to have levelled off in the past decade in Australia and the United States, other trends are more troublesome, including the overrepresentation of methamphetamine abuse in hospital admissions and troubling public health burdens such as infectious disease transmission. Behavioural interventions demonstrate efficacy and currently represent the best treatment option. However, the rates of relapse associated with behavioural treatment are unacceptably high. Numerous pharmacotherapies have been assessed in randomised, placebo-controlled trials but most have failed to demonstrate efficacy.

Unsuccessful clinical trials require substantial resources, expose participants to ineffective treatments and divert scientific attention away from other avenues of research. Yet Phase II failures for medications for stimulant dependence are representative of broader trends. The Centre for Medicines Research recently analysed Phase II failure rates from 16 pharmaceutical companies, finding an increase from 72% in 2006–2007 to 82% in 2008–2009 – attrition rates considered to be unsustainably high [88]. The failure rates for central nervous system disorders appear even higher than for drugs being developed for other indications [89]. A general consensus exists that current models of medication development must be revised to make process of drug discovery more predictable and less costly [90]. Some researchers have highlighted the need for better validation of pharmacological target exposure, receptor binding, and functional modulation [91] while others underscore problems even earlier in drug development, namely target identification [92,93]. Dependence on long-acting stimulants represent a complex disease of staged neuroplasticity involving multiple brain systems [16,17]. Introducing additional complications, emerging preclinical evidence suggests that the dopaminergic system –the principle focus in addiction medication research – is dependent on competent functioning of the GABA system [94] and cholinergic interneurons [95]. Determining optimal pharmacological targets is difficult. Novel research methodologies that effectively evaluate the promise of a putative addiction pharmacotherapy are needed to make research more efficient [96]. Work is now being directed towards assessing and optimising the predictive validity of research methodologies – preclinical and human laboratory designs – that advance or remove agents from medication discovery programs [97].

Stronger collaborations between industry and academic researchers are also being pursued. In the United States, the National Center for Advancing Translational Sciences was recently established with relevant priority areas including de-risking the therapeutic pipeline, predictive toxicity and target validation. In Europe, the Innovative Medicines Initiative was created to foster stronger collaboration between industry and academic researchers. In 2011 industry, government and academic representatives convened a meeting devoted to the topic of repurposing medications [98]. Recently, dozens of compounds – many targeting the CNS – have been made available by pharmaceutical companies to academic researchers. These drug candidates are not being actively pursued by industry due to concerns regarding efficacy, safety or market considerations. Although the compounds have failed to demonstrate clear efficacy, safety or marketability for their initial indication, many of the drugs feature mechanisms relevant to addiction and may yet demonstrate clinical benefit or elucidate the pathophysiological mechanisms of addiction. Despite the need for collaborations across various basic and clinical research disciplines and various legal, economic and regulatory complexities, repurposing efforts hold substantial promise [99].

Medication adherence continues to be a vexing challenge undermining the internal validity of clinical trials. A recent trial of modafinil is representative of this [51]. It is plausible that one or more efficacious medications have been dismissed due to poor medication adherence. Various strategies have been deployed to assess and encourage adherence including quantifying urinary riboflavin that can be formulated with the study medications, pill counts, and electronic assessment of pill-bottle opening and closing (“MEMS” caps). Yet, all of these methods feature drawbacks. The U.S. National Institute on Drug Abuse (NIDA) program staff has recently highlighted the importance of extended delivery formulations for medication candidates in the pipeline [100].

Although the preponderance of findings from clinical trials have been negative, not all results have been disappointing. Agonist replacement therapies show some promise. Concerns, however, have been raised regarding public health implications of widespread implementation of this strategy. Additionally, agonist therapies will likely require significant behavioural support and oversight in order to deliver robust public health benefits.

Of encouragement is the consistent observation from randomised controlled trials that bupropion has a signal in subjects who are able to establish some periods of abstinence from methamphetamine during the weeks preceding treatment initiation. NIDA has completed a second, confirmatory trial of bupropion and if results are similar to existing studies, support would exist for use of the medication as a pharmacotherapy.

Pharmacotherapies with novel mechanisms are also being evaluated. Shoptaw and Heinzerling are assessing ibudilast, a phosphodiesterase inhibitor that may attenuate the cascade of methamphetamine-induced glial activation and release of cytokines upon initial abstinence. A Phase I trial is being completed and a Phase II trial of the compound will open enrolment in 2013. Mirtazapine, an antidepressant with notable anxiolytic effects, demonstrated promise in a preliminary study and is being assessed in a larger trial.

Varenicline, a partial agonist at alpha-4, beta-2 nicotinic acetylcholine receptors [101], is being examined as a pharmacotherapy following promising pilot data and encouraging results with both cocaine [102] and alcohol [103]. Although few studies have assessed medications with cholinergic mechanisms for methamphetamine dependence, evidence suggests involvement of the cholinergic system in the neurochemical effects of methamphetamine use [104], the reinstatement of methamphetamine MA-seeking in animal models [105], and reduced subjective effects of methamphetamine in a human laboratory study [106]. As the role of glutamatergic mechanisms become more prominent in models of addiction [107], attention has also been directed to compounds that restore glutamate homeostasis. N-acetylcysteine, an amino acid cystine precursor, restores glutamate levels reduced by chronic cocaine exposure and this effect endures long after the cessation of active treatment [108]. Promising preclinical and human laboratory studies [109] with cocaine have stimulated interest in N-acetylcysteine as a pharmacotherapy for methamphetamine dependence, though a Phase II trial is years away. NIDA has recently signalled an interest in a dopamine D3 receptor for cocaine dependence [110]. Two randomised controlled trials will evaluate buspirone as a relapse prevention treatment among cocaine dependent patients being discharged from inpatient treatment facilities [111].

After over 20 years of concerted effort to develop a broadly effective medication for MA dependence, no candidate has emerged. This highlights the need for new research methodologies, better integration between basic and clinical sciences, and improved collaboration between government, industry and academic researchers.