Mechanism of Action

Methamphetamine is an indirect monoamine agonist that increases intracellular and extracellular levels of the monoamine neurotransmitters, dopamine, serotonin, and norepinephrine. Methamphetamine gains entry into neurons either as a substrate at plasmalemmal neurotransmitter transporters or via diffusion across the plasmalemmal membrane as a result of its high lipophilicity. Once inside the presynaptic nerve terminal, methamphetamine inhibits neurotransmitter uptake at the vesicular monoamine transporter-2 located on synaptic vesicles and promotes neurotransmitter release from the vesicles, the result of which is to increase cytosolic neurotransmitter levels. In addition, methamphetamine inhibits monoamine oxidase, preventing a major route of intracellular metabolism of cytosolic neurotransmitter. The increased concentrations of cytosolic monoamines are available for reverse transport by the perisynaptic plasmalemmal neurotransmitter transporter. As neurotransmitter is transported from the cytosol to the extracellular space by the plasmalemmal transporter, methamphetamine is transported from the extracellular space into the cytosol. The outcome is that neurotransmitter concentration increases in the extracellular space. Finally, methamphetamine inhibits neurotransmitter uptake by the plasmalemmal monoamine transporters, contributing to the increased extracellular neurotransmitter concentrations.

Clinical Use of Methamphetamine

Methamphetamine is available on the market as a controlled substance, manufactured under the brand name Desoxyn (Ovation Pharmaceuticals, Deerfield, IL). Methamphetamine has the same schedule II designation as other psychostimulant medications, such as amphetamine and methylphenidate, indicating both its therapeutic uses and high potential for misuse. According to the package insert and labeling, methamphetamine can be used for the treatment of attention-deficit/hyperactivity disorder in children over the age of 6, short-term weight loss in obese individuals, and narcolepsy. The parameters for US Food and Drug Administration (FDA) approval in treating exogenous obesity include only short-term (i.e., a few weeks) usage in the context of a weight reduction plan including a structured diet with exercise, and only for patients in whom obesity has been refractory to other medications. In addition, methamphetamine use in obesity is discouraged if the patient is younger than age 12. Of interest, methamphetamine is not listed as a recommended therapy for the treatment of attention-deficit/hyperactivity disorder according to the current treatment guidelines from the American Academy of Pediatrics and the American Academy of Child and Adolescent Psychiatry. Not surprisingly, it is rare for practicing physicians to prescribe methamphetamine for this indication.

The dosage recommendation by the package insert for attention-deficit/hyperactivity disorder starts with 5 mg given in the morning, and proceeds with weekly 5-mg increases until optimal clinical response has been achieved. The usual dosing for childhood attention-deficit/hyperactivity disorder is 20–25 mg given as a once- or twice-daily dose. The recommended dosage in short-term obesity treatment is 5 mg taken 30 minutes before meals. Desoxyn is available only in 5-mg tablets, and no generic manufacturer currently exists. Abbott Pharmaceuticals produced Desoxyn since its introduction in 1942 and sold its rights to Ovation Pharmaceuticals in 2002, although Abbott maintains the facilities that manufacture the product. In addition, Abbott produced a sustained-release form of methamphetamine named Desoxyn Gradumet, utilizing a plastic matrix for gradual release of the methamphetamine. This product was available in 5-, 10-, and 15-mg doses. Manufacturing of the Desoxyn Gradumet was discontinued in 1999 due to “manufacturing difficulties.”

No clinical trials are available by PubMed search for the use of methamphetamine in attention-deficit/hyperactivity disorder or obesity. However, methamphetamine and amphetamine are major metabolites of l -deprenyl (selegiline). l -Deprenyl is commonly prescribed for Parkinson disease and has been evaluated in clinical trials for the treatment of attention-deficit/hyperactivity disorder. Results suggest that selegiline may be an efficacious medication for children with this disorder, particularly children presenting with the inattentive subtype. Although methamphetamine has not received official FDA approval for use in narcolepsy, this appears to be the main use for which it is prescribed in North America. Methamphetamine is used along with other stimulants and l -deprenyl to treat the excessive sleepiness symptom of narcolepsy. The last trial evaluating methamphetamine in the treatment of narcolepsy was reported in 1993 and found that daytime sleepiness was treated successfully in adults with doses of 40–60 mg/day.

Although methamphetamine may have proven efficacy and safety in the treatment of childhood attention-deficit/hyperactivity disorder and obesity, the risks of misuse and diversion along with its current negative stigma among health care workers and the public as an abused drug make it unlikely that many physicians will endorse its clinical use for these indications.

Diagnosis of Methamphetamine Use Disorder

With the transition to fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the term “use disorder” replaced “abuse” and “dependence” to describe what had been referred to as addiction. The basis of a substance use disorder is a cluster of symptoms, which indicate that an “individual continues using the substance despite significant substance-related problems.” The diagnosis is restricted to cases in which two or more symptoms have been present in the past 12 months. The symptoms incorporate four general categories including impaired control, social impairment, risky use, and pharmacological criteria (e.g., tolerance, withdrawal). Methamphetamine use disorder is classified under the broader category of stimulant use disorders. The severity of the disorder is specified based on the number of symptoms present: mild (2–3), moderate (4–5), and severe (6+). In addition to presenting as a primary disorder, methamphetamine use disorder also can be associated secondarily with the induction of psychotic disorders, intoxication delirium, mood disorders, anxiety disorders, sleep disorders, and/or sexual dysfunction. Further notable changes to the symptom checklist between editions of the Diagnostic and Statistical Manual of Mental Disorders were the removal of legal problems and the addition of craving.

Escalation of Methamphetamine Use

As is the case with other drugs of abuse, methamphetamine is often used in binge-like patterns that are characterized by periods of high intake, followed by “crashes” after the drug supply is depleted. Individuals often exhibit a developmental trajectory from experimentation with low doses, followed by escalation to higher binge intake, although the various patterns of intake that capture methamphetamine use across different individuals are difficult to characterize fully due to the clandestine nature of use within the population. Interviews with chronic methamphetamine abusers suggest that most individuals initiate methamphetamine use by self-administering the drug at long intervals, a so-called recreational pattern. Many individuals subsequently progress into dose escalation, with shorter intervals between successive self-administrations, thus manifesting as a binge-and-crash pattern. The escalation into higher dose intake may reflect, at least in part, tolerance to many of the peripheral and central effects of methamphetamine.

Animal models have characterized the nature of escalation in methamphetamine use with repeated administration. Escalation of methamphetamine use occurs when rats are given extended access to intravenous methamphetamine in an operant conditioning chamber. With this procedure, rats are first trained to press a lever to intravenously self-infuse methamphetamine during daily 1-hour sessions. When subsequently shifted to 6-hour daily sessions, rats will escalate their intake pattern across sessions. This escalation is typically noted when comparing the intake of methamphetamine within rats across 6-hour sessions, as well as when comparing the intake of methamphetamine during the first hour of the 6-hour session with the intake of rats maintained on daily 1-hour sessions. Escalation of methamphetamine use enhances the ability of methamphetamine to prime reinstatement of extinguished lever-pressing, suggesting that the development of an escalating pattern of intake may exacerbate the rate of relapse in abstinent humans.

Emerging research on age and sex differences in escalation has revealed that adolescents and females self-administer more methamphetamine during extended access conditions, compared to adults and males, respectively. In an attempt to more closely model human binge patterns of intake, a recent study provided male and female rats with 96-hour access to intravenous methamphetamine over a 5-week period. A crash was defined as no lever pressing for ≥6 hours and binges constituted all lever pressing in the 24+ hours prior to the crash. Using this model, duration of binge episodes increased from ∼20 hours during week 1 to more than 50 hours by week 5. Furthermore, self-administration during normal sleep cycles and short interinfusions intervals (<1 minute) increased from week 1 to week 5. As such, this model of methamphetamine self-administration appears to closely parallel human patterns of binge exposure and may yield new mechanistic insights into the consequences of such exposure.

Attempts to attenuate escalation of methamphetamine self-administration using animal models of extended access have revealed promising effects of pharmacological and behavioral interventions. The group II metabotropic glutamate receptor agonist, LY379268, selectively and dose-dependently decreased methamphetamine self-administration under progressive ratio schedules of reinforcement both before and after extended access conditions. Acute administration of the selective kappa opioid receptor antagonist, norbinaltorphimine (30 mg/kg, i.p.), blocked escalation of methamphetamine self-administration assessed for 11 days, as well as decreased responding on a progressive ratio schedule of reinforcement. Attenuation of methamphetamine seeking was observed also following a single infusion of norbinaltorphimine (4 μg/0.5 μL) administered bilaterally and directly into nucleus accumbens shell. Assessments of behavioral interventions have supported a role for physical exercise in reducing methamphetamine seeking. Specifically, access to wheel running in the home cage attenuated escalation of methamphetamine self-administration relative to sedentary rats and rats with prior access to wheel running. In another study, 30 days of wheel running during withdrawal from 22 days of extended access to methamphetamine reduced extinction responding as well as context- and cue-induced reinstatement.

Escalation of methamphetamine use has a number of deleterious neurobehavioral effects. Compared with nonescalating use, escalating use of methamphetamine impairs performance on the novel object recognition test in rats, which parallels neurocognitive impairments observed in abstinent methamphetamine abusers. Furthermore, extended access to methamphetamine increases thresholds for intracranial self-stimulation of the medial forebrain bundle and other depressive-like behaviors. In the prefrontal cortex, microRNAs associated with apoptosis and synaptic plasticity are increased following 14 days of extended access methamphetamine self-administration. Escalation of methamphetamine use in rats also promotes cell death and decreases the genesis of neurons and glia (astrocytes and oligodendrocytes) in the medial prefrontal cortex. The medial prefrontal cortex is a component of a complex frontal neurocircuitry involved in response inhibition and self-control. Damage to the medial prefrontal cortex and related frontal structures may disinhibit behavior, thereby yielding a compulsive escalation of methamphetamine intake. In addition, because the medial prefrontal cortex is involved in the processing of stimulant reward, it may be that damage to this region reduces the rewarding effect of methamphetamine, leading to a compensatory escalation of intake.

With extremely high doses of methamphetamine, profound hyperthermia and neurotoxicity are observed. In rats, neurotoxic effects can be observed following 1 day of high-dose methamphetamine treatment (10 mg/kg; 4 injections at 2-h intervals), an effect characterized by marked depletion of monoamine levels across various cortical and subcortical structures. This neurotoxicity parallels the reductions in dopamine markers measured with positron emission tomography or with postmortem sampling in human methamphetamine abusers. However, interpretation of results from studies using rats and the 1-day binge treatment protocol is limited, since human methamphetamine abusers do not typically reach high doses until long-term use leads to escalation of intake. In particular, a recent study by O’Neil et al. demonstrated that the neurotoxic effects of a methamphetamine 1-day binge noted earlier in rats was blunted substantially when an escalating dose procedure was used. This decrease in neurotoxicity is not related to altered pharmacokinetics, as no changes in brain or plasma methamphetamine concentrations were observed following a methamphetamine binge in rats treated previously with escalating doses of methamphetamine.

Pharmacokinetics of Methamphetamine

Although methamphetamine is used clinically as an oral formulation, illicit use of methamphetamine more typically involves self-administration via the inhalation, intranasal, or intravenous routes. Unfortunately, information about the precise pharmacokinetics of methamphetamine use via these latter routes is sparse. Bioavailability via the intravenous route is 100%, whereas bioavailability via the intranasal route is 79% and via the inhalation route is 67%. Although there is little opportunity to obtain blood samples from methamphetamine users during a binge, one study reported on blood concentrations taken from individuals arrested for suspicious behavior. Among individuals in which methamphetamine was detected, the blood levels were found to range between ∼0.5 and 10 μM. In controlled laboratory studies, the plasma half-life of methamphetamine was found to be approximately 10 hours in humans, which is considerably longer than the plasma half-life of 70 minutes found in rats. In rats, the plasma concentration of methamphetamine reaches a maximum level faster following intraperitoneal administration (5–10 minutes) than following subcutaneous administration (20–30 minutes); however, ∼42% of methamphetamine administered via intraperitoneal injection is subject to significant first-pass metabolism, which reduces bioavailability to ∼52%.

The major inactive metabolite of methamphetamine is p-hydroxymethamphetamine, which can be detected readily in the urine of methamphetamine abusers. Methamphetamine is p -hydroxylated to p -hydroxymethamphetamine in liver microsomes. Of interest, in both rats and humans, a significant portion of methamphetamine is N -demethylated into amphetamine . Amphetamine is also a potent psychostimulant that is p -hydroxylated to the inactive metabolite p -hydroxyamphetamine. Because the conversion of methamphetamine to amphetamine is faster than the elimination of amphetamine from the blood, the concentration of amphetamine can actually exceed the level of methamphetamine when sampled at a long interval following a single bolus injection of intravenous methamphetamine. In humans, the plasma half-life is slightly longer for l -methamphetamine than for d -methamphetamine (∼14 hours vs. 10 hours).

Mechanisms of Methamphetamine Reward

In addition to clear evidence of abuse, methamphetamine is a potent reinforcer in humans tested under highly controlled laboratory conditions. Methamphetamine reward is manifest both as a subjective report of liking and as a behavioral choice of methamphetamine self-administration over placebo. (We use the term “reward” to refer to both subjective and behavioral effects, whereas “reinforcement” is a more specific term that refers to operant behavior.) The response to oral methamphetamine (5 or 10 mg) or placebo was evaluated in healthy research participants in a residential laboratory facility. Over an 8-day choice procedure, participants had the opportunity to self-administer the dose of methamphetamine that they most recently sampled or to receive a $1 voucher. As expected, methamphetamine was chosen more than placebo, and methamphetamine (10 mg) increased subjective ratings indicative of drug liking, demonstrating that oral methamphetamine is rewarding in humans. In another residential laboratory study, effects of repeated oral methamphetamine or placebo administration in humans were evaluated. Relative to placebo, tolerance developed to the positive subjective effects of methamphetamine across repeated administration, which may be a factor leading to escalating use among at-risk individuals. Another study assessed the impact of an alternate reinforcer (money) on oral methamphetamine self-administration and employed individuals with a past-year history of methamphetamine use. Choice of oral methamphetamine (8 or 16 mg) versus money ($0.25, up to $2) differed as a function of the response cost associated with the alternate reinforcer, such that methamphetamine was chosen more frequently when the response requirement for money was high. In any case, the majority of choices were for methamphetamine regardless of the response cost for money, demonstrating that the choice of methamphetamine was relatively resistant to changes in the cost for the alternate reinforcer.

Methamphetamine reward may be dependent to some extent on the pharmacokinetics of the drug. Drug reward is enhanced when there is a rapid onset of effect, which may explain why methamphetamine abusers tend to prefer the inhalation and intravenous routes of delivery over the oral route. In addition, the rate of self-administration may be determined by the offset (elimination half-life) of the drug effect, with longer offset durations leading to less frequent self-administrations. These general principles may be important points to consider in attempts to develop effective pharmacotherapies for methamphetamine abuse. In particular, therapeutic agents designed to substitute for or block the rewarding effect of methamphetamine should ideally have a slow onset of action and a prolonged duration of action in order to minimize their potential for abuse. Nonetheless, it may be desirable for pharmacotherapeutic agents to have some rewarding effect because this will enhance patient compliance.

To better understand the neurobiological basis of methamphetamine reward and to develop new potential pharmacotherapies, a number of laboratory animal models have been developed. One widely used model is drug self-administration, which is based on fundamental principles of operant conditioning. In this model, rodents or nonhuman primates are trained to make an operant response (e.g., lever press) to receive a drug infusion. Responding is reinforced typically on a fixed ratio schedule in which a fixed number of responses lead to an infusion. Alternatively, a progressive ratio schedule can be used in which the number of responses required to earn an infusion increases incrementally after each infusion until a break point (cessation of responding) is achieved; the progressive ratio schedule is thought to estimate the relative effectiveness of the drug to serve as a reinforcer. A modification to the classic drug self-administration paradigm involves applying principles from behavioral economics. A demand curve can be generated by increasing the fixed ratio requirement (i.e., up to fixed ratio 240) over several days and plotting the number of reinforcements earned (consumption) as a function of response requirement (price). Unit price defined as the response requirement per unit of reinforcer is useful for comparing reinforcers and minimizing the impact of a drug’s pharmacological effects on drug seeking. As expected based on human literature, both rats and nonhuman primates self-administer methamphetamine avidly and in a dose-dependent manner.

Relapse is modeled in laboratory animals using a variety of reinstatement procedures that can be primed by exposure to the drug, drug-associated cues, or stress. For these assessments, rats are trained to self-administer the drug as described earlier and then undergo several days of extinction, during which the drug is no longer available and operant responding is extinguished. Thereafter, rats are primed to reinitiate drug-seeking through exposure to the drug, reintroduction of cues previously associated with delivery of the drug, or exposure to a stressor. It is important to note that tests of reinstatement are performed under extinction conditions. Increases in operant responding relative to extinction levels are interpreted as evidence of reinstatement of drug seeking.

Another model for measuring methamphetamine reward in rodents is the conditioned place preference preparation. This is a Pavlovian procedure in which the drug is paired with one distinct context and placebo is paired with a different context. When allowed to choose between the two different contexts in a drug-free state, rats show a preference for the drug-paired context. This preference is thought to reflect a secondary rewarding effect of the context due to its association with the drug, and it is a model of contextual control of drug seeking rather than a direct measure of the primary reinforcing effect of the drug per se. Similar to self-administration, methamphetamine-conditioned place preference has been demonstrated in both rats and mice.

Another animal model for evaluating methamphetamine reward is the brain stimulation reward preparation. In this model, a bipolar stimulating electrode is implanted chronically into the lateral hypothalamus, a region through which courses the medial forebrain bundle. The medial forebrain bundle connects dopaminergic cell bodies in the ventral tegmental area to the limbic terminal fields of the nucleus accumbens and prefrontal cortex, and stimulation of this pathway is highly reinforcing. Rats are first evaluated for brain stimulation reward threshold by adjusting the frequency of stimulation pulses in a series of ascending and descending increments. When a drug of abuse is subsequently administered, the brain stimulation threshold is lowered, thus providing an index of rewarding strength. Corroborating the findings with self-administration and conditioned place preference, methamphetamine has been shown to decrease the threshold for brain stimulation reward.

Animal models, coupled with neuroimaging technologies in humans, have uncovered some of the basic neural mechanisms that underlie methamphetamine reward. Although the reward circuitry is complex, involving multiple circuits and neurochemical systems, dopaminergic neurotransmission in the mesocorticolimbic dopamine pathway undoubtedly plays a critical role in the psychostimulant effects of methamphetamine. Methamphetamine reward results from increased dopamine release in limbic terminal fields, which is regulated by the vesicular monoamine transporter. Methamphetamine increases extracellular dopamine concentrations by inhibiting the action of the vesicular monoamine transporter, which sequesters dopamine into vesicular stores, as well as by inhibiting monoamine oxidase, which diminishes dopamine metabolism, thereby making cytosolic dopamine more available for methamphetamine-induced reversal of the plasmalemmal dopamine transporter. In addition to these dopamine-regulating cellular targets in the dopaminergic terminal fields, a number of other systems impinge on reward-relevant dopamine neurons, including γ-aminobutyric acid (GABA), glutamatergic, and nicotinic acetylcholine receptors localized within the midbrain ventral tegmental area region. In addition, prefrontal cortical regions provide descending input into both the dopaminergic cell body and terminal regions. Functional magnetic resonance imaging analyses in humans demonstrate that, in addition to increasing neural activity in the nucleus accumbens, methamphetamine increases activity in the orbitofrontal and anterior cingulate cortices. Furthermore, using functional magnetic resonance and positron emission tomography imaging, abnormalities in brain structure and chemistry are observed in individuals using methamphetamine, including reductions in the density of dopamine transporters, dopamine D2 receptors, serotonin transporters, and vesicular monoamine transporters, particularly in striatum.

A greater understanding of the neurocircuitry involved in methamphetamine reward has provided new targets for the development of medications to treat methamphetamine use disorder. As mentioned previously, the dopamine transport inhibitor bupropion was found to be effective in a double-blind, placebo-controlled clinical trial. However, because bupropion is also a nicotinic acetylcholine receptor antagonist, it is not clear whether its efficacy is due to blockade of the dopamine transporter, blockade of nicotinic receptors, or blockade of both mechanisms concomitantly. Preclinical studies also have provided evidence that blockade of the vesicular monoamine transporter with lobeline or related synthetic analogs may be a beneficial approach. ^a Moreover, although direct blockade of dopamine D2 receptors is not a likely approach to treat methamphetamine abuse due to the induction of extrapyramidal side effects, effort has focused on atypical antipsychotics, such as sertindole or SB-277011A, which act at either serotonin-2 receptors or dopamine D3 receptors, respectively.

a References 2, 13, 41, 56, 103, 146.

In addition to the direct effects of medications on the vesicular dopamine transporters, plasmalemmal transporters, and dopamine receptors, an alternative approach is to target systems that modulate mesocorticolimbic dopamine neurons. For example, preclinical work has indicated that medications that enhance GABA transmission by blocking the metabolic enzyme GABA transaminase may be useful for treating methamphetamine use disorders. At least one study has shown that the GABA acid transaminase inhibitor, γ-vinyl GABA, is safe in human abusers, even among those who continue to use methamphetamine. GABA receptor selective agonists are also under investigation, as are glutamate receptor antagonists.

Several other novel approaches for treating methamphetamine use disorder are in the pipeline. For example, novel congeners of the iboga plant alkaloid, ibogaine, may be useful, although the potential utility of these alkaloids awaits characterization of their neuropharmacological mechanisms of action. In addition, a recent study indicates that medications that suppress the endogenous opioid peptide, nociceptin, may attenuate methamphetamine reward. There is also accumulating preclinical evidence that oxytocin, the endogenous neuropeptide that is classically implicated in pair-bonding, decreases methamphetamine seeking and may have therapeutic potential. Additional therapeutics gaining attention as potential treatments for methamphetamine use disorder are sigma receptor ligands and N -acetylcysteine, the precursor to cysteine, with antioxidant properties. Regardless of the mechanism, however, any pharmacotherapeutic approach for treating methamphetamine use disorder should be considered an adjunct to behavioral therapies. As mentioned earlier, the utility of contingency management and cognitive behavioral therapy to maintain abstinence rates among methamphetamine abusers has been demonstrated, and further work is needed to determine whether the combination of pharmacotherapy and psychosocial interventions has a synergistic effect.

Human Studies in the Treatment of Methamphetamine Use Disorder

In response to a sharp increase in illicit use of methamphetamine in the mid- to late 1990s, the US government implemented supply-side interventions, including the Combat Methamphetamine Epidemic Act, to curtail illicit synthesis of methamphetamine by regulating the sale of its precursors (e.g., pseudoephedrine). These interventions resulted in short-term reductions in methamphetamine use. As a consequence, methamphetamine has been supplied to users in the United States through its southern border. Illicit methamphetamine sales are estimated at $13 billion per year in the United States. Methamphetamine smuggled into the United States is of high purity and low cost, leading to increased rates of methamphetamine overdose deaths, which more than doubled between 2010 and 2014. Globally, methamphetamine is the most commonly seized amphetamine-type stimulant. In 2014, 108 tons of methamphetamine were seized worldwide, which was an increase of more than 300% since 2009. Despite efforts to disrupt the supply, misuse of methamphetamine remains a global health problem. Although many scientists and practitioners seem to assume that the more extensive experience and literature on the treatment of cocaine misuse can be extrapolated to methamphetamine, the mechanisms of action between cocaine and methamphetamine are sufficiently different, along with differences in the surrounding drug culture, to warrant independent trials and the unique treatment of people who misuse methamphetamine and wish to quit.

A wide range of neuropharmacological strategies are being pursued in the search for an efficacious pharmacotherapy for methamphetamine use disorder. Recent evidence can be found through a search of registered clinical trials ( clinicaltrials.gov ), which is now required for all institutional review board–approved clinical trials. A search of “methamphetamine” to capture both new and older terminologies (i.e., use disorder, dependence, abuse) yielded 271 listed studies, which is a sixfold increase in the number of clinical trials since the first edition of this chapter was published in 2011. Previously, few double-blind, randomized, placebo-controlled trials of pharmacotherapy for methamphetamine were available in the literature, but the National Institute on Drug Abuse Methamphetamine Clinical Trials Group clearly has contributed to the substantial increase in trials during the past 6 years. These human and laboratory studies generally use one of two approaches for the treatment of methamphetamine use disorder. The more common approach has been medication repurposing, whereby medications with an existing approved indication (e.g., antidepressants) are evaluated for efficacy in treating methamphetamine use disorder. The second approach is to determine the safety and efficacy of novel candidate compounds as therapeutics for methamphetamine use disorder (e.g., Nickell et al. ).

For some users, the initial stage of treatment of methamphetamine use disorder is the medical management of withdrawal, particularly if the user is a binge or heavy user. This phase is characterized by increased sleep, eating, depressive symptoms, anxiety, poor concentration, and craving-related symptoms. The other common scenario for withdrawal is when the user is incarcerated and unable to obtain methamphetamine. A randomized, double-blind, placebo-controlled trial of the antidepressant mirtazapine in 31 outpatients undergoing treatment for methamphetamine withdrawal showed no benefit in terms of withdrawal symptoms or retention. Mirtazapine, which acts as an antagonist or inverse agonist at 5-HT ₂ receptors, improved time of sleep in the 2-week period during which it was evaluated. Mirtazapine was then assessed in conjunction with modafinil, a dopamine reuptake inhibitor used to treat narcolepsy and sleep apnea. An open-label comparison of modafinil (400 mg/day; n = 14) and mirtazapine (60 mg/day; n = 13) with treatment as usual with periciazine (2.5–10 mg/day) demonstrated less withdrawal severity with modafinil and mirtazapine ; however, these results must be interpreted with caution because this study lacked a placebo-controlled, double-blind design. A subsequent randomized, double-blind, placebo-controlled study revealed that mirtazapine (15 mg initial dose up to 30 mg/day at bedtime) administered to methamphetamine-using men who have sex with men, decreased methamphetamine use and decreased risky sexual behavior, suggesting that mirtazapine may be efficacious in a subset of methamphetamine users.

Early clinical studies have identified the potential pharmacotherapeutic benefit of bupropion, a norepinephrine and dopamine reuptake inhibitor used as an antidepressant as well as for smoking cessation, in treating aspects of methamphetamine use disorder including memory function. Initial safety studies indicated that methamphetamine administration during bupropion treatment was safe and that bupropion reduced acute methamphetamine subjective effects and cue-induced craving for methamphetamine, supporting the evaluation of bupropion as a therapeutic. Subsequently, a relatively large placebo-controlled trial evaluated the use of bupropion for the treatment of methamphetamine use disorder. Twelve weeks of treatment with sustained-release bupropion (150 mg twice daily) versus placebo followed by a 30-day follow-up in five outpatient treatment facilities ( n = 152 participants) showed some benefit when combined with behavioral interventions. In this study, bupropion treatment increased the number of weeks abstinent, although only the male subgroup that was ranked as low-to-moderate for methamphetamine usage showed significant improvement over placebo. Subsequent studies have confirmed findings from this original study suggesting that bupropion is not efficacious for maintaining abstinence, except in a subset of individuals who adhered tightly to the medication regimen. However, in a study including adolescents, bupropion was found in contrast to decrease the number of methamphetamine-free urine samples. Taken together, bupropion may not be an effective candidate to treat methamphetamine use disorder, and in some populations, it appears to worsen outcomes.

An open-label study evaluated a sequential dosing algorithm consisting of hydroxyzine, flumazenil, and gabapentin to treat methamphetamine use disorder. Hydroxyzine is a sedating antihistamine acting as an inverse agonist at histamine receptors that can be used to treat anxiety or allergies. Flumazenil is a benzodiazepine antagonist that is used to treat drowsiness. Gabapentin is an anticonvulsant that increases GABA neurotransmission and is used in the treatment of seizure disorders. In that study, 50 adults using methamphetamine were administered hydroxyzine (50 mg), followed 1 hour later by flumazenil (0.1–0.3 mg intravenously over 30 minutes) and gabapentin (initial dose 300 mg/day up to 1500 mg/day) for 4 weeks, and were followed for 8 weeks. A 47% reduction in methamphetamine use for the entire treatment group was found, with a 65% reduction specifically for the 36 participants who completed the 8-week evaluation, suggesting efficacy of the sequential medication regimen. Caution is needed with respect to interpretation, however, due to the open-label design and lack of inclusion of a placebo comparison in the study design. In contrast, a randomized double-blind, placebo-controlled study evaluating 16 weeks of treatment with either gabapentin (800 mg twice daily; n = 26), baclofen (a muscle relaxant acting as a GABA _B receptor agonist; 20 mg 3 times daily; n = 25), or placebo ( n = 37) showed that neither medication was superior to placebo, revealing a lack of efficacy for methamphetamine use disorder. A more recent study assessing hydroxyzine (50 mg), flumazenil (2 mg), and gabapentin (initial dose 300 mg up to 1200 mg/day) confirmed that the medication combination, termed PROMETA was no better than placebo in treating methamphetamine use disorder.

A placebo-controlled, cross-over study investigating topiramate, an anticonvulsant used for seizures and migraines, showed that acute administration (up to 200 mg) enhanced, rather than attenuating, the positive subjective effects of methamphetamine. A phase II double-blind, placebo-controlled, proof-of-concept study determined the safety and efficacy of chronic topiramate for the treatment of methamphetamine use disorder. Participants ( n = 140) meeting the DSM-IV criteria for methamphetamine dependence were randomized to receive topiramate at 25 mg escalating to 200 mg or placebo daily during weeks 1–5, and then topiramate 200 mg daily during weeks 6–12. The primary outcome measure was abstinence from methamphetamine during weeks 6–12. Generally, topiramate was well-tolerated and safe; however, no significant topiramate treatment effect was found. Exploratory data analyses indicated that participants ( n = 35) whose baseline methamphetamine use was less than 18 days out of the previous 30, or who had negative urine prior to randomization ( n = 26), experienced a topiramate treatment effect ( p = 0.03 and 0.02, respectively). Thus despite the failure of the primary outcome variable, a subset of light methamphetamine users was identified as positive responders to treatment. In a subsequent study of 57 participants with methamphetamine use disorder, topiramate (50 mg initial dose up to 200 mg daily) significantly reduced positive urine screens at 6 weeks relative to placebo; however, no group differences were found at any other time point, including at the conclusion of the 10-week study. In addition, there were no differences between topiramate and placebo in retention or percent completion of the trial. Collectively, topiramate does not appear to be promising as a therapeutic for methamphetamine use disorder.

A small open-label study of 11 methamphetamine-dependent veterans showed decreased use with the atypical antipsychotic risperidone (average dose, 3.6 mg/day) over a 4-week treatment period. A randomized, double-blind trial evaluating 80 participants with concurrent DSM-IV-defined bipolar I or II and methamphetamine or cocaine dependence showed that both quetiapine and risperidone, both serotonin-2 and dopamine D2 receptor antagonists used to treat psychiatric disorders including schizophrenia and bipolar disorder, reduced drug craving and improved manic, mixed, and depressive symptoms; however, limitations in interpretation are noted due to the lack of a placebo control group.

Ondansetron (0.25, 1, or 4 mg twice daily) versus placebo was evaluated along with cognitive behavioral therapy in a small, randomized, double-blind, placebo-controlled trial in individuals seeking treatment for methamphetamine dependence. Ondansetron is a serotonin-3 receptor antagonist used to treat nausea and vomiting. This 8-week trial found no benefit of ondansetron on any measured markers of methamphetamine use, withdrawal, or craving. Another trial evaluating sertraline (50 mg twice daily), a serotonin transporter inhibitor, which is used for the treatment of depression, anxiety, posttraumatic stress disorder, and obsessive-compulsive disorder, was found to worsen some outcome measures of methamphetamine use compared to placebo.

Aripiprazole, a partial agonist at dopamine D2 receptors and approved by the FDA for the treatment of schizophrenia, was evaluated in human laboratory studies in which participants discriminated the interoceptive effects of 15 mg of d -amphetamine from placebo. Aripiprazole (20 mg, but not at 10 mg) attenuated the discriminative stimulus effects of d -amphetamine; however, the high dose of aripiprazole alone produced performance decrements. The low dose of aripiprazole attenuated some of the subject-rated effects of d -amphetamine and did not impair performance, suggesting that aripiprazole may have therapeutic benefit. In a subsequent double-blind inpatient study employing 16 methamphetamine-dependent participants, treatment with aripiprazole (15 mg orally) resulted in higher ratings on the Addiction Research Center Inventory subscales, reflecting euphoria and amphetamine-like effects following administration of methamphetamine (15 and 30 mg intravenously). Furthermore, aripiprazole had no effect on abstinence-induced and cue-induced craving over the time course of treatment. In a study of seven non–treatment-seeking methamphetamine users, aripiprazole (15 mg) acutely decreased oral methamphetamine self-administration on a progressive ratio schedule of reinforcement and reduced some of the positive subjective effects of oral methamphetamine (4 and 8 mg) administration. However, at the highest dose of methamphetamine (16 mg), aripiprazole augmented some of the positive subjective effects. Subsequent double-blind, placebo-controlled clinical trials found no differences between aripiprazole and placebo on methamphetamine abstinence, although aripiprazole increased retention in one study. Thus this dopamine D2 receptor partial agonist does not appear to be an effective treatment for methamphetamine use disorder.

A double-blind, placebo-controlled, between-group human laboratory study evaluated rivastigmine as a treatment for methamphetamine use disorder. Rivastigmine is an acetylcholinesterase inhibitor used for the treatment of dementia. Initially, methamphetamine (30 mg) or placebo was self-administered intravenously in the controlled laboratory setting. Subsequently, participants chose either to self-administer a 3 mg dose of methamphetamine or placebo or to receive a monetary alternative ($0.05–$16). The number of choices for methamphetamine infusion was greater than for placebo, and the number of money choices was greater when placebo was available than when methamphetamine was available. Rivastigmine (1.5 or 3 mg; n = 6–9) did not alter the total number of methamphetamine infusions compared with placebo; however, the higher dose of rivastigmine reduced the positive subjective effects of self-administered methamphetamine. These findings were confirmed in a follow-up study, in which rivastigmine (6 mg) failed to reduce methamphetamine self-administration in participants with methamphetamine use disorder, but decreased “likely to use methamphetamine” at the lowest methamphetamine dose (15 mg, but not 30 mg) relative to placebo. Thus a reduction in methamphetamine-induced subjective effects does not predict a decrease in self-administration.

Substitution therapies have proven beneficial in the treatment of nicotine and opioid use disorders, and recently, a similar approach has been evaluated for treatment of methamphetamine use disorder. d -Amphetamine is an indirect monoamine agonist used in the treatment of attention-deficit/hyperactivity disorder and narcolepsy. In a human laboratory setting, d -amphetamine (40 mg) was found to attenuate physiological and some subjective effects of intranasal methamphetamine, but failed to reduce intranasal methamphetamine (10, 20, 30 mg) self-administration. A randomized, double-blind, placebo-controlled clinical trial found that d -amphetamine (60 mg/day) was no different from placebo on measures of methamphetamine use, but reduced symptoms of withdrawal and craving. A study using a higher dose of d -amphetamine (110 mg/day), found that compared to placebo, d -amphetamine increased retention and modestly decreased psychometric measures of dependence, but there were no differences in self-report or physiological measures of methamphetamine use.

Methylphenidate is an inhibitor at norepinephrine and dopamine transporters that is used also to treat attention-deficit/hyperactivity disorder and narcolepsy. Methylphenidate has been assessed in clinical trials for methamphetamine use disorder. In one randomized, double-blind, placebo-controlled, 22-week study, methylphenidate (up to 54 mg daily) increased participant retention in the study, but was no different from placebo on the number of methamphetamine positive urine screens. In contrast, two subsequent randomized, double-blind, placebo-controlled studies found that treatment with methylphenidate (up to 54 mg daily) decreased methamphetamine use relative to placebo. A consideration regarding the use of substitution therapies is the risk for misuse or diversion of the medications that are intended to treat the drug use disorder. Coupled with the indeterminate nature of the clinical findings, substitution therapies for treating methamphetamine use disorder may not be the best approach.

Immunotherapies are emerging as potential treatments for methamphetamine use disorder. An anti-methamphetamine monoclonal antibody, ch-mAb7F9, has been developed to reduce methamphetamine distribution to brain. The antibody binds the methamphetamine in the peripheral compartment, and the antibody bound complex is too large to cross the blood-brain barrier, thereby preventing its pharmacological action in brain. Recently, a phase I clinical trial followed 47 healthy volunteers for 147 days and determined that ch-mAb7F9 was safe and well-tolerated. Pharmacokinetic analyses revealed that pharmacologically relevant concentrations of ch-mAb7F9 were maintained for ∼5 weeks following the highest dose (20 mg/kg) of antibody administered. An advantage of this approach is the long-time interval between administration of the therapy, which theoretically, could improve medication compliance. Some notable limitations of this approach include that active immunization is not tenable in immunocompromised individuals (e.g., HIV) and that beneficial effects can require several weeks needed for the appropriate immunological response to be realized, although passive immunization can circumvent some of these issues. Ultimately, this approach may be most appropriate for highly motivated individuals as a prevention of relapse and likely will be most efficacious when paired with other pharmacotherapies and/or psychosocial interventions.

Medication nonadherence and enrollment of professional subjects recently have been identified as factors that may contribute to high rates of negative findings in clinical trials. Medication nonadherence refers to participants not taking their study medication as instructed. Professional subjects refer to participants that feign or exaggerate symptoms of the disorder under study to enroll in the clinical trial for financial gain. Unwitting enrollment of professional subjects may artificially inflate the efficacy of placebo. Medication nonadherence has been reported to be as high as 39% in a recent review of eight clinical trials, and may obfuscate the therapeutic benefits of study medications. Thus medication nonadherence and enrollment of professional subjects may culminate in a misrepresentation or underestimation of the efficacy of the pharmacotherapies being evaluated. One approach to address this unanticipated problem may be to reevaluate potential therapeutics for methamphetamine use disorder that showed efficacy in human laboratory studies but not in clinical trials.

Finally, it is important to draw attention to the general consensus that any medication for methamphetamine abuse will be most effective in the context of concomitantly delivered behavioral therapies, much like other drugs of abuse. Behavioral therapies have included cognitive behavioral therapy, contingency management, or both. Outcome-based studies on cognitive behavioral therapy have shown reductions in methamphetamine abuse and relapse of abuse. Contingency management procedures, although effective when individuals are actively in drug treatment, have not been shown to have long-term benefit once the individuals are on their own.