Pharmacological approaches to methamphetamine dependence: a focused review

Abstract

Methamphetamine dependence is a serious worldwide public health problem with major medical, psychiatric, socioeconomic and legal consequences. Various neuronal mechanisms implicated in methamphetamine dependence have suggested several pharmacological approaches. A literature search from a range of electronic databases (PubMed, EMBASE, PsycInfo, the NIDA research monograph index and the reference list of clinicaltrials.gov) was conducted for the period from January 1985 to October 2009. There were no restrictions on the identification or inclusion of studies in terms of publication status, language and design type. A variety of medications have failed to show efficacy in clinical trials, including a dopamine partial agonist (aripiprazole), GABAergic agents (gabapentin) and serotonergic agents (SSRI, ondansetron, mirtazapine). Three double-blind placebo-controlled trials using modafinil, bupropion and naltrexone have shown positive results in reducing amphetamine or methamphetamine use. Two studies employing agonist replacement medications, one with d-amphetamine and the other with methylphenidate, have also shown promise. Despite the lack of success in most studies to date, increasing efforts are being made to develop medications for the treatment of methamphetamine dependence and several promising agents are targets of further research.

Introduction

Methamphetamine, already a significant drug problem in East and Southeast Asia and in North America in the past decade, has become a more prominent part of the European drug scene, especially in East European countries (Czech Republic, Slovakia). While the prevalence of methamphetamine use in the general population is low, rates in some social groups in younger age groups are significantly higher [1, 2].

Methamphetamine is available in different forms such as a pure crystalline hydrochloride salt or as formulated tablets. Routes of administration are intranasal sniffing, pulmonary inhalation, injection and oral ingestion [3]. The effects of methamphetamine use include euphoria and many of the same stimulant effects seen with cocaine, but these effects may last much longer [3].

Methamphetamine exerts multiple effects in the central nervous system and acts as a highly potent releaser of monoamines by increasing cytoplasmic concentrations of dopamine and serotonin and also norepinephrine, adrenaline and histamine [4] i) by blocking the activity of the intracellular vesicular monoamine transporter 2 (VMAT2) [5, 6], ii) by decreasing the expression of the dopamine transporter (DAT) at the cell surface [7] and iii) by inhibiting the activity of monoamine oxidase and increasing the activity and the expression of tyrosine hydroxylase [8]. Brain imaging studies of methamphetamine dependent patients have demonstrated brain structural abnormalities (severe grey-matter deficits in the cingulate, limbic and paralimbic cortices, smaller hippocampal volumes, significant white-matter hypertrophy, medial temporal lobe damage and striatal enlargement) [9, 10] and neurochemical and metabolite changes particularly prominent in the ventral striatum [11, 12]. Prolonged use leads to down-regulation of dopamine D₂-receptors and uptake sites [13]. A state of hypodopaminergic activity is reported as in other addictions [14, 15]. There is also evidence for disturbances of mood and anxiety and regional cerebral metabolic abnormalities in recently abstinent methamphetamine dependent patients [16].

Methamphetamine dependence is a serious worldwide public health problem with major medical [17–21], psychiatric [22–25], cognitive [26–29], socioeconomic and legal consequences [18].

Currently, there is no pharmacological therapy with established efficacy for the treatment of this addictive disorder, nor is there any medication approved by the regulatory authorities for such treatment [30]. The need to find effective treatments for methamphetamine dependence has been identified as a priority by the United States National Institute on Drug Abuse (NIDA) and by European investigators. Various neuronal mechanisms implicated in methamphetamine dependence have suggested several pharmacological approaches. Recent reviews on pharmacotherapy for methamphetamine dependence have been published [30–34], but this is a quickly evolving area with preclinical findings and clinical trials reported frequently. Although there is not much substantial evidence in terms of proof of concept studies and randomized clinical trials, this review will bring to light some of the newer pharmacological targets. We will focus on agents affecting the biogenic amine transporters mentioned above and other neurotransmitter systems (acetylcholine, GABA, endogenous opioids, endocannabinoids). We will also discuss pharmacological candidates in the pipeline such as immunotherapies (vaccine, anti-methamphetamine monoclonal antibodies) and other approaches based on preclinical data. We will not discuss the management of acute methamphetamine intoxication or the treatment of methamphetamine dependence in patients with comorbid psychiatric disorders.

Literature searches were conducted for the period from 1985 to October 2009, using PubMed, EMBASE, PsycInfo, the NIDA research monograph index and the reference list of clinicaltrials.gov, the main electronic sources of ongoing trials, using the following key words alone or in combination: methamphetamine, amphetamine, dependence, addiction, pharmacotherapy, immunotherapy, clinical trials.

References in empirical articles and narrative and meta-analytic reviews were used for further potential sources of articles. There were no restrictions on the identification or inclusion of studies in terms of publication status, language and design type.

Tables are included to summarize the salient details of some studies. The tables include clinical trials for those medications that appear to have shown the greatest promise at the time of this review (e.g. dopamine agonists and one antagonist, GABAergic agents and an opioid antagonist).

Human laboratory studies are not included in the tables, nor are studies involving compounds that have not yielded positive results (e.g. dopamine partial agonists, cholinesterase inhibitors, serotonergic agents).

Dopaminergic agents

Dopamine agonists

Modafinil

Modafinil is a non-amphetamine stimulant that is approved for managing symptoms of narcolepsy with or without cataplexy, obstructive sleep apnoea/hypopnoea syndrome or idiopathic hypersomnia [35–38]. The precise neurobiological mechanism of action of this medication is complex and includes dopaminergic and glutamatergic effects [39]. A recent brain imaging study showed that modafinil binds to the DAT, and thus shares some properties with methylphenidate [40].

Clinical studies suggest that modafinil may be effective in treating cocaine dependence [41–43], and might also be effective for methamphetamine dependence. Modafinil stimulant-like activity has been proposed as a potential treatment to decrease the symptoms of cocaine withdrawal [43]. No evidence of significant abuse liability has been reported [44]. Modafinil can produce cognitive benefits [45], affecting memory [46] as well as motor, attention and executive functions in healthy adults [47], in attention-deficit/hyperactivity disorder (ADHD) and schizophrenia patients [48, 49]. Modafinil may be a cognitive enhancer [50] in methamphetamine-dependent patients [51] and may therefore have the potential to improve the response to behavioural therapies. Because of its weak stimulant properties, modafinil has been cited as a putative treatment to decrease stimulant drug seeking and craving.

The findings of an open-label study of modafinil to treat methamphetamine withdrawal symptoms in an inpatient setting [53] indicated possible amelioration of these symptoms. In a small 16-week single-blind trial, modafinil was combined with cognitive behavioural therapy (CBT) for treatment of methamphetamine dependence among HIV+ gay men. Primary outcome measures were self-reported use of drugs per week plus urine toxicology assays. Sixty percent of those who completed the study reduced their methamphetamine use by over 50% [51]. More recently, 80 methamphetamine dependent patients were randomly assigned to modafinil (200 mg day⁻¹) or placebo under double-blind conditions for 10 weeks plus 12 weeks post-treatment follow-up. There were no differences in treatment retention, medication adherence, methamphetamine abstinence, craving or severity of dependence. Of possible clinical significance, there was a statistically significant reduction in systolic blood pressure in the modafinil group [54]. Modafinil therefore may have some beneficial effects in methamphetamine-dependent patients, although there is no clear evidence of its efficacy in reducing methamphetamine use.

Bupropion

Bupropion is an antidepressant that is also approved as treatment for smoking cessation [55]. It is a monoamine uptake inhibitor with stimulant-like effects in animals. It inhibits re-uptake of dopamine and norepinephrine, increases dopamine in the synaptic cleft after blocking the presynaptic DAT, and targets the norepinephrine transporter (NET) and nicotinic receptors. By restoring depleted concentrations of monoamines [56, 57], bupropion could be effective in ameliorating withdrawal symptoms and cognitive deficits in early methamphetamine abstinence, thereby reducing methamphetamine use.

A phase I clinical trial evaluating interactions between intravenous methamphetamine and sustained-release (SR) bupropion (300 mg day⁻¹) did not show any exacerbation of methamphetamine-induced cardiovascular effects [58]. Euphoria and craving were significantly reduced by bupropion in a randomized single-blind placebo-controlled trial [59]. Two recent controlled trials have been conducted [60, 61]. In a 12-week multi-site double-blind placebo-controlled study, the administration of SR bupropion 300 mg day⁻¹ combined with CBT showed promising results [60]. The intent-to-treat analysis found a trend toward less methamphetamine use in the bupropion group. Subgroup analysis indicated significantly less use in male subjects who had low to moderate baseline use (less or equal to 18 days month⁻¹). In the other randomized controlled trial, SR bupropion 300 mg day⁻¹ was compared with placebo, with both groups receiving contingency management and weekly CBT sessions for 12 weeks. Bupropion was no more effective than placebo in reducing methamphetamine use verified by urine drug screens, or in reducing the severity of depressive symptoms. However, as in the first study, bupropion was again found to reduce significantly methamphetamine use among baseline light, but not heavy, methamphetamine users in a posthoc analysis [61]. It may therefore be important to focus further evaluation of bupropion on its efficacy in light users.

Methylphenidate

Methylphenidate is the most commonly prescribed medication for childhood ADHD worldwide. It has binding affinity for both the dopamine and norepinephrine transporter but not to the serotonin transporter. The functional effect is to block catecholamine re-uptake from and increase catecholamine release into the synapse. It has pharmacological effects similar to cocaine and amphetamine, but may produce less neuroadaptation and have less abuse liability (for review, see [62]). Reports suggest that immediate-release oral methylphenidate has more potential for abuse [63, 64] than SR methylphenidate [65, 66]. A 20 week randomized study of SR methylphenidate (54 mg day⁻¹), aripiprazole (15 mg day⁻¹), and placebo for intravenous amphetamine dependence revealed promising results. Interim analysis showed that methylphenidate was an effective treatment reducing intravenous stimulant use in patients with severe dependence, in contrast to aripiprazole and to placebo. The primary outcome measure was the proportion of amphetamine-positive urine samples [67]. Further studies with methylphenidate are planned by the NIDA.

Dextroamphetamine (d-amphetamine)

Dextroamphetamine promotes release of dopamine, norepinephrine and serotonin. Despite the fact that this compound has a high potential for abuse, maintenance programs using d-amphetamine have reported positive outcomes, such as decrease in amphetamine use and injecting [68]. A double-blind, controlled clinical trial indicated that d-amphetamine may be effective for the treatment of cocaine dependence [69] and a small pilot open trial suggested that d-amphetamine may increase treatment engagement in patients with methamphetamine dependence [70]. Preliminary results of an Australian double-blind placebo-controlled trial with sustained release (SR) d-amphetamine (from 20 to 110 mg day⁻¹) demonstrated increased retention and a lower level of dependence in the SR d-amphetamine group. This study provides preliminary evidence that SR d-amphetamine may be an efficacious treatment option for methamphetamine dependence [71].

Dopamine D₂ partial agonists

Dopamine D₂-receptor partial agonists have also been proposed as possible treatments for stimulant dependence [72]. Aripiprazole, a second generation antipsychotic, acts as a partial agonist at both the dopamine D₂ and 5-HT_1A receptors [73]. Two human laboratory studies showed that aripiprazole (10 or 20 mg) significantly attenuated the discriminative stimulus and subjective rated effects of orally administrated d-amphetamine [74, 75]. However, in a more recent study [76], aripiprazole treatment increased some of the rewarding and stimulatory effects produced by acute methamphetamine, suggesting that 15 mg aripiprazole is unlikely to be efficacious for the treatment of methamphetamine dependence. Supporting these findings, a recent controlled trial comparing aripiprazole, methylphenidate and placebo had to be terminated prematurely. An interim analysis showed that aripiprazole-treated subjects had significantly more amphetamine-positive urines than those treated with placebo [67].

Dopamine antagonists

Conventional (first generation) antipsychotics act chiefly as dopamine D₂-receptor antagonists. Newer second generation antipsychotics also act on serotonin receptors. These medications have also been proposed as potential treatments for stimulant dependence.

Risperidone (3, 6 mg day⁻¹) was evaluated in a 4 week open-label study in veterans seeking methamphetamine dependence treatment. Outcome measures were self-reports of substance use, urine drug tests and adverse effects. Methamphetamine use decreased in association with risperidone treatment and the medication was well tolerated [77]. An open trial evaluating long-acting injectable risperidone in methamphetamine dependence has recently been completed (see http://clinicaltrials.gov, identifier NCT00284206) but no results are yet available (Table 1).

Table 1.

Dopamine agonists and antagonists

Pharmacological agents	Study design Sample characteristics	Outcomes	Results	Main limitations	References
Modafinil (400 mg day−1)	10-day open-label study 14 methamphetamine dependent patients seeking treatment Amphetamine use for at least 3 days a week over the previous month Amphetamine use within the previous 96 h	Primary outcomesWithdrawal syndrome Sleep disturbance Secondary outcomesTolerance Adverse effects or events	Milder withdrawal syndrome Less sleep disturbance Safe and well tolerated	Patients and clinicians aware of study group allocation Small sample size Study outcomes were assessed against a historical comparison group enrolled in a separate study	[53]
Modafinil (50 to 200 mg day−1) and HIV medications Modafinil (100 to 400 mg day−1) (not on HIV medications)	16-week pilot study: 12-week single blind trial + 4-week placebo phase 13 patients seeking to reduce or stop methamphetamine use Seven of 13 met DSM-IV criteria for stimulant abuse and 6 for dependence Mean duration for abuse or dependence: 43 months Mean reported days of use/week: 4 Primary route of use: smoking (9 patients) HIV+ (11/13 men)	Primary outcomesSelf-reported use of days per week (urine toxicology assays) Secondary outcomesCraving (Methamphetamine Craving Scale; Obsessive/Compulsive Methamphetamine Use Scale) Depression (Beck Depression Inventory II) Side effects or adverse events	Decrease of methamphetamine use by >50% Decreased craving No side effects except in 2 patients	Difficulty in recruitment Low number of responders High attrition rates	[51]
Modafinil (200 mg day−1)	10-week randomized, double-blind, placebo-controlled clinical trial + 12-week post-treatment follow-up 80 methamphetamine-dependent subjects seeking treatment 2–3 days of methamphetamine use per week or more Most subjects injected methamphetamine on a daily basis, with a third who preferred to smoke it	Primary outcomeSelf-reported use of days per week (urine toxicology assays) Secondary outcomesTreatment retention Medication adherence Craving Severity of dependence Other substance dependence Adverse events	No differences in treatment retention, medication adherence, methamphetamine abstinence, craving or severity of dependence. More methamphetamine-negative urine samples in the modafinil group Significant reductions in systolic blood pressure and weight gain No medication-related serious adverse events	Absence of an objective quantitative measure, reliance on self-reported outcomes A sample size too small to detect reliably the small differences between modafinil and placebo	[54]
SR bupropion (300 mg day−1)	12-week double-blind placebo-controlled study and a 30-day follow-up 151 methamphetamine dependent patients seeking treatment Primary route of administration: smoking Days of methamphetamine use in last 30 days (less or equal to 18 days or superior to 18 days)	Primary outcomeChange in proportion of participants having a methamphetamine -free week. Secondary outcomesUrine for quantitative methamphetamine Self-report of methamphetamine use Subgroup analyses of balancing factors and comorbid conditions Addiction severity, craving Risk behaviours for HIV Use of other substances	Decrease of methamphetamine use (intent-to-treat analysis) Decreased use in male subjects who had low to moderate baseline use (less or equal to 18 days per month) (Subgroup analysis)	Poor therapeutic response in female patients Imbalance between groupson the presence of ADHD (15% of participants) Lack of training for inter-rater reliability between raters using DSM-IV checklist	[60]
SR bupropion (300 mg day−1)	12-week randomized, double-blind, placebo-controlled clinical trial 73 methamphetamine dependent patients	Primary outcomeMethamphetamine use (as assessed via urine drug screens) Secondary outcomesTreatment retention Severity of depressive symptoms Methamphetamine craving Adverse effects Cigarette smoking among methamphetamine dependent patients	Significant decrease of methamphetamine use among light users (post hoc analysis) Decrease of self-reported cigarette use	Small sample size Lowered power of the study Attrition of the participants	[61]
SR methylphenidate (54 mg day−1)	20-week randomized placebo controlled trial With 3 arms including aripirazole and placebo as well as methylphenidate 17 amphetamine or methamphetamine dependent patients 5 women, HIV infection (n= 4), hepatitis B or C infection (n= 13) Duration of use: 15 years	Primary outcomeProportion of amphetamine-positive urine samples Secondary outcomesAdverse effects	Decrease of amphetamine intravenous use in the SR methylphenidate group reaching significance after 18 weeks (intention-to-treat analysis) No adverse effects	Small sample size Long period of time to achieve full benefit from this treatment	[67]
d-amphetamine (from 20 to 60 mg day−1)	12-week open, two-group pre-post randomized controlled trial 41 amphetamine dependent patients seeking treatment d-amphetamine group (n= 20) and control group (counselling (n= 21))	Primary outcomeAmphetamine and methamphetamine use (urine toxicology assays). Secondary outcomesAdverse events Psychotic symptoms	Reduced amphetamine use and severity of dependence in both group d-amphetamine group significantly more likely to attend counselling and receiving twice as many sessions as the control group. No adverse events or psychotic symptoms	Small sample size Study group restricted to subjects who were able to attend an inner-city clinic on a daily basis Possible selective attrition bias	[70]
SR d-amphetamine (from 20 to 110 mg day−1)	16-week randomized double blind, placebo-controlled clinical trial 49 methamphetamine dependent patients Positive urine sample and use of methamphetamine on 3 or more days per week over the previous 12 months Sufficient hair length for hair analysis	Primary outcomesMethamphetamine use and degree of dependence over time, and treatment retention. Secondary outcomesAdverse effects	Better retention in treatment in the SR d-amphetamine group Lower degree of methamphetamine dependence Trend to a greater reduction in self-reported methamphetamine use No serious adverse events	High attrition rates in the placebo group Number of subjects in each group	[71]
Risperidone (3.6 mg day−1)	4-week open-label study 11 veteran methamphetamine dependent patients seeking treatment	Primary outcomeSelf-reports of substance use (urine drug tests) Secondary outcomesAdverse effects	Decrease of methamphetamine use	Small sample size No placebo group	[77]

GABA agents

By decreasing transmission in the mesolimbic dopamine system, the gamma-aminobutyric acid (GABA) agonists may reduce the reinforcing effects of stimulants [78, 79]. For this reason, GABA agonists have been proposed as potential therapeutic agents for treating methamphetamine dependence.

Clinical trials with baclofen (GABA_B receptor agonist) [80], gabapentin (nonselective GABA agonist) [80, 81] and gamma-vinyl-GABA (Vigabatrin) (GABA transaminase inhibitor) [82, 83] in methamphetamine dependent patients are summarized in Table 2.

Table 2.

GABA agents

Pharmacological agents	Study design Sample characteristics	Outcomes	Results	Main limitations	References
Baclofen (60 mg day−1)	16-week, randomized, placebo-controlled, double-blind trial with 3 arms including gabapentin and placebo as well as baclofen 25 methamphetamine dependent patients Primary route of use: smoking	Primary outcomeMethamphetamine use (urine drug tests) Secondary outcomesTreatment retention, depressive symptoms, methamphetamine cravings, adverse events	Not effective in reducing methamphetamine use Small treatment effect relative to placebo among participants who reported taking a higher percentage of study medication (post hoc analyses)	Small sample size Increasing attrition of the participants biological measures of medication adherence not performed	[80]
Gabapentin (2400 mg day−1)	16-week, randomized, placebo-controlled, double-blind trial with 3 arms including baclofen and placebo as well as gabapentin 26 methamphetamine dependent patients Primary route of use: smoking	Primary outcomeMethamphetamine use (urine drug tests) Secondary outcomesTreatment retention, depressive symptoms, methamphetamine cravings, adverse events	Not effective in reducing methamphetamine use	Small sample size Increasing attrition of the participants biological measures of medication adherence not performed	[80]
Vigabatrin (from 1 to 3 g day−1)	9-week open-label safety study 28 methamphetamine and/or cocaine dependent patients	Primary outcomesChange of visual fields, visual acuity, ocular adverse effects Secondary outcomesMethamphetamine use	No ophthalmologic adverse effects Decrease of methamphetamine use	Small sample size Open label design No control group High drop-out rate (approximately 50%)	[83]
Vigabatrin (from 1.5 to 3 g day−1)	9-week open-label safety study 30 methamphetamine and/or cocaine dependent patients	Primary outcomesChange of visual fields, visual acuity, ocular adverse effects Secondary outcomesMethamphetamine use	No ophthalmologic adverse effects Decrease of methamphetamine use	Small sample size Open label design No control group High drop-out rate (approximately 50%)	[83]

Urschel and colleagues reported favourable results for an open trial of a proprietary mixture of flumazenil, gabapentin and hydroxyzine in reducing methamphetamine use [81]. A subsequent controlled trial, however, failed to find any significant advantage for the medication combination over placebo [84].A recent human laboratory study indicated that gamma-vinyl-GABA treatment was well tolerated but not efficacious in attenuating the positive subjective effects of methamphetamine [85]. As yet, there have been no reports of randomized controlled trials to determine whether gamma-vinyl-GABA is effective as a treatment for methamphetamine dependence.

Topiramate has also been evaluated in methamphetamine dependence. It has several neuro-pharmacological actions: blockade of voltage-dependent sodium channels, enhancement of GABA neurotransmission at GABA_A receptors, blockade of glutamate receptors (AMPA/kainate subtype), and inhibition of carbonic anhydrase.

In a double-blind study of topiramate (100 or 200 mg) compared with placebo, in subjects receiving low or high dose (15 or 30 mg) intravenous methamphetamine, acute dosing of topiramate appeared to enhance the positive effects of methamphetamine and to act as an anticraving agent [86]. The effects of topiramate on cognitive performance were also evaluated in both the presence and absence of low and high dose intravenous methamphetamine. Cognitive effects were mixed, with a trend for improvement in attention while there was worsening psychomotor retardation [87]. One possible explanation may be that topiramate could increase plasma methamphetamine concentrations [88]. As of yet, there have been no reports of clinical trials to determine whether topiramate is effective as a treatment for methamphetamine dependence.

Cholinesterase inhibitors

Acetylcholine has been implicated in the reinforcing and locomotor activating effects produced by methamphetamine. Acetylcholinesterase inhibitors may play a role in reducing methamphetamine seeking behaviour in animals. For example, donepezil attenuated the reinstatement of methamphetamine-seeking behaviour induced by exposure to cues and self administration in rats. This effect could possibly be due to activation of nicotinic, but not of muscarinic, cholinergic receptors in the nucleus accumbens core, prelimbic cortex, amygdala and hippocampus [89].

Rivastigmine equally inhibits both butyrylcholinesterase and acetylcholinesterase and has selectivity for central nervous system activity [90]. It has no affinity for dopaminergic, adrenergic, muscarinic or opioid receptors [91]. In a 2 week double-blind placebo-controlled human laboratory study, cardiovascular and subjective effects of rivastigmine (1.5 or 3 mg) in combination with intravenous methamphetamine (30 mg) were evaluated in dependent patients. The 3 mg dosage significantly reduced methamphetamine-induced increases in diastolic blood pressure and self-reports of craving and anxiety [92]. Another controlled study found that the same dosage may reduce positive subjective effects in an experimental model of intravenous self-administration in human volunteers [93]. At this time, there are no reports of clinical trials of rivastigmine in methamphetamine dependence.

Serotonergic agents

Selective serotonin re-uptake inhibitors (SSRI)

Methamphetamine affects neural networks associated with depression [94]. Inhibited serotonergic signals lead to increased amphetamine self-administration in animals [95], while serotonin transporter inhibition decreases the rewarding effects of psychostimulants [96]. For example, pre-treatment with fluoxetine had inhibitory effects on methamphetamine-induced locomotor sensitization in mice [97]. Evidence exists for a modulatory role of the serotonin system in the discriminative stimulus effects of methamphetamine [98]. However, controlled clinical trials of fluoxetine [99, 100] and paroxetine [101] have shown no efficacy for reducing methamphetamine use. Moreover, in a large randomized, placebo-controlled trial using a counselling platform of Matrix Model relapse prevention groups [102], sertraline (100 mg day⁻¹) failed to improve methamphetamine use outcomes and actually worsened retention. Taken together, these results suggest that sertraline and possibly the entire class of SSRIs are ineffective and may be contra-indicated for methamphetamine dependence [103].

Ondansetron

Ondansetron, an anti-emetic agent, is a serotonin 5-HT₃ receptor antagonist. 5-HT₃ receptor activation increases dopamine activity in the nucleus accumbens [104], making blockade of these receptors a potential treatment approach. In a preliminary, multi-site, randomized, double-blind, 8 week controlled trial, ondansetron (0.25, 1 or 4 mg twice daily) combined with CBT was not superior to placebo at decreasing methamphetamine use, craving, withdrawal and clinical severity of dependence [105].

Mirtazapine

Mirtazapine is a serotonin (5HT_2A and 5HT₃ receptors), histamine H₁ and adrenergic α₂ antagonist [106]. A pre-clinical study demonstrated that mirtazapine reversed methamphetamine-induced behavioural sensitization, condition preference place and motor sensitization [107]. As an antidepressant with anxiolytic and sedative properties, mirtazapine has been evaluated in the treatment of methamphetamine withdrawal in an outpatient setting. An open trial of mirtazapine compared with modafinil in inpatients showed inferiority to modafinil in countering methamphetamine withdrawal symptoms [53]. A small double-blind placebo-controlled trial of mirtazapine (15 mg for 2 days and 30 mg for 12 days) with drug counselling also failed to find a significant treatment effect [108].

Opioid antagonist: naltrexone

There is evidence that the endogenous opioid system plays a role in the reinstatement of methamphetamine seeking behaviour and behavioural sensitization [109] in methamphetamine self-administering animals. Naltrexone, an opioid antagonist, attenuated cue- but not drug-induced methamphetamine in animals [110]. In humans, naltrexone may reduce the reinforcing effects of amphetamine via modulation of the opioid system [111]. Naltrexone 50 mg along with CBT was evaluated in a 12 week open clinical trial for amphetamine dependence. This medication was well tolerated with moderate rates of compliance [112]. In a double-blind placebo-controlled design, naltrexone 50 mg significantly attenuated the subjective effects produced by dexamphetamine in dependent patients. Craving was also significantly blocked [113]. Moreover, it also was effective in reducing amphetamine use in a recent double-blind, placebo-controlled outpatient clinical trial [114]. Naltrexone therefore appears to be a highly promising medication for amphetamine dependence (Table 3).

Table 3.

Opioid antagonist

Pharmacological agents	Study design Sample characteristics	Outcomes	Results	Main limitations	References
Naltrexone (50 mg day−1)	12-week open clinical trial 20 amphetamine-dependent patients	Primary outcomesAdverse events Compliance to medication (assessed by by the presence of naltrexone's metabolite, 6-beta-naltrexol in urine) Tolerability: patient's self-report and observed adverse effects along with plasma markers of hepatotoxicity.	No serious adverse events Moderate rates of compliance Decrease of amphetamine use	Small sample size Open label design High attrition rate	[112]
Naltrexone (50 mg day−1)	Randomized double-blind placebo-controlled design. 20 abstinent amphetamine-dependent patients DSM-IV criteria for ADHD Drug-free from amphetamine for a minimum of 30 days Residence in Stockholm county.	Primary outcomeDifference in subjective measures of amphetamine effects (use of a Visual Analog Scale). Secondary outcomesEffects of naltrexone on physiological and biochemical responses to amphetamine, as measured by changes in blood pressure, heart rate, skin conductance and cortisol.	Significant decrease of the subjective effects produced by dexamphetamine Reduction in dexamphetamine craving No difference between the groups on the physiological measures.	Study was conducted in a small homogenous population of male amphetamine-dependent individuals. Small dexamphetamine dose	[113]
Naltrexone (50 mg day−1)	12-week double-blind, placebo-controlled clinical trial 80 treatment-seeking amphetamine-dependent individuals Amphetamine use on at least 12 days in the past 12 weeks.	Primary outcomeNumber of negative amphetamine urine samples during 12 weeks of treatment (of a total of 24 samples) Secondary outcomesTreatment retention Medication adherence Craving Pill count Adverse events	Decrease in amphetamine use High treatment retention and medication adherence Significant reduction in craving No serious adverse events	Sample selected for the study did not achieve an equal representation of the genders. Treatment outcomes assessed for 3 months Long-term effects in this population are unknown.	[114]

Calcium channel blockers

Calcium-channel blockers (CCBs) have been proposed as a treatment for methamphetamine dependence because of their modulating effects on dopaminergic tone [115]. Human laboratory studies with selective dihydropyridine CCBs isradipine [115] and amlodipine [116] found reduced subjective and physiological responses to methamphetamine. However, a controlled outpatient clinical trial of amlodipine failed to show any efficacy in reducing methamphetamine use [117].

Pharmacological candidates in the pipeline

Immunotherapies

Immunotherapies, either active immunization (vaccines) or passive administration of anti-methamphetamine monoclonal antibodies (AMMA), are an innovative treatment strategy for drug addiction. Vaccines may be effective in blocking the effects of drugs of abuse [118] and have advantages over conventional medications in that they would have no direct psychoactive effects and no abuse liability. Their effects may persist for months, improving patient adherence to treatment [119]. Nicotine and cocaine vaccines have advanced to the level of clinical trials [120, 121], whereas a new generation of active immunization therapies for methamphetamine is at an advanced stage of preclinical development [122]. A methamphetamine vaccine has been shown to produce antibodies in rats but did not attenuate their locomotor activity in response to the drug [123].

Preclinical studies have also shown the therapeutic potential of the AMMA approach [124–126]. Reduction of methamphetamine self-administration, locomotor activity and inhibition of discriminative stimulus effects of methamphetamine was shown in rats and pigeons [127–129]. The two primary indications for the use of AMMA in the treatment of human methamphetamine dependence would be overdose and relapse prevention [33, 122].

Endocannabinoid system

Cannabinoid CB₁ receptors modulate the dopamine-releasing effects of drugs of abuse and are involved in relapse to drug seeking for many addictive drugs [130]. The endocannabinoid system may serve as a modulator of the reinstating effects of methamphetamine-priming and cues [131]. In a recent study, pre-treatment with methanandamide, a CB₁ agonist, elicited cross-sensitization to methamphetamine effects in mice, whereas pre-treatment with JWH 015, a CB₂ agonist, did not. Combined pre-treatment with methamphetamine and the cannabinoid antagonist AM 251 suppressed sensitization to methamphetamine [132]. No human studies are available as of yet.

Nicotinic agents

Lobeline, an alkaloid constituent of Lobelia, is used as a respiratory stimulant for tobacco smoking cessation. As a partial agonist at nicotinic receptors, it interacts with the DAT and VMAT2 proteins involved in dopamine storage and release [133, 134]. It alters dopamine function by inhibition of dopamine uptake and promotion of dopamine release from storage vesicles within the pre-synaptic terminal on the VMAT2 [135]. Lobeline or its analogues act as a methamphetamine antagonist, in that they decrease self-administration [136], attenuate stereotypy and antagonize discrimination of the subjective effects (for review, see [137]). Two ongoing double-blind placebo-controlled studies are underway at the time of writing: one assessing intravenous methamphetamine and sublingual lobeline interactions and the other tolerability, safety and pharmacokinetics of multiple dosages of lobeline (see http://clinicaltrials.govidentifiers NCT00100074 and NCT00519259).

Benzoquinolizine derivatives

Evidence exists that VMAT2 plays a crucial role in psychostimulant pharmacology. Benzoquinolizine derivatives, such as tetrabenazine, have high affinity for VMAT2. Tetrabenazine is approved, in some countries, with license applications pending in several European countries and the United States, for the treatment of hyperkinetic movement disorders. This pharmacological agent decreases locomotor activity and aggressiveness in monkeys and decreases methamphetamine-induced hyperactivity in rodent animal models [138, 139]. The NIDA is currently conducting an animal study.

Conclusion

Methamphetamine dependence is a growing problem in various areas of the world. The development of effective treatments for methamphetamine dependence has become a pressing concern. Recent improvements in the understanding of the underlying neurobiology of methamphetamine dependence have led to a number of potentially useful pharmacological agents. The general research strategy adopted has to a large extent resembled the approach to research on cocaine dependence pharmacotherapy, and has aimed at similar pharmacological targets and employed similar preclinical and clinical methods.

The development of methamphetamine pharmacotherapies is at an early stage. No substantial evidence for efficacious treatment has yet emerged. Clinical trials using aripiprazole, GABA agents (gabapentin, baclofen, vigabatrin), SSRIs, ondansetron and mirtazapine have failed to show efficacy.

Only three double-blind placebo-controlled trials have shown positive results in reducing methamphetamine or amphetamine use. One clinical trial of naltrexone has shown evidence of efficacy for treatment for amphetamine dependence, and trials involving bupropion and modafinil have demonstrated possible benefit in treating methamphetamine use in selected methamphetamine-dependent patients. The use of agonist replacement medications such as d-amphetnaine and modafinil may also hold promise in the treatment of methamphetamine dependence. Despite the lack of clear and robust success to date, increasing efforts are being made to develop medications for the treatment of methamphetamine dependence.

Competing interests

Dr Batki: Alkermes, Inc. (research grant). Dr Aubin has received sponsorship to attend scientific meetings, speaker honorariums and consultancy fees from Pfizer, McNeil, GlaxoSmithKline, Pierre-Fabre Sante, Sanofi-Aventis and Merck-Lipha. Dr Laurent Karila, Dr Amine Benyamina and Professor Michel Reynaud have no competing interests.