Pharmacotherapy for stimulant use disorders in adults

INTRODUCTION — Cocaine, methamphetamine, and other stimulant use disorders are significant public health problems. In the United States, for example, there are 1.5 million regular cocaine users and approximately 353,000 regular methamphetamine users [1]. Cocaine and methamphetamine users have significantly elevated rates of medical morbidity and utilization of health care resources [2].

No medications have been shown in randomized trials to be consistently efficacious for stimulant use disorders. Only psychosocial interventions have proven efficacy in reducing stimulant use in patients with stimulant use disorder, but these treatments alone are insufficient for many patients, prompting research into the neurobiology of stimulant use disorder and trials of several augmenting medications.

Pharmacotherapy for stimulant use disorders is discussed here. The epidemiology, clinical manifestations, course, consequences, assessment, and diagnosis of cocaine use disorder and methamphetamine use disorder are described separately. Psychosocial interventions for stimulant use disorders and prescription drug misuse are also described separately.

●(See "Cocaine use disorder in adults: Epidemiology, clinical features, and diagnosis".)

●(See "Methamphetamine use disorder: Epidemiology, clinical features, and diagnosis".)

●(See "Psychosocial interventions for stimulant use disorder in adults".)

●(See "Prescription drug misuse: Epidemiology, prevention, identification, and management".)

APPROACH TO TREATMENT — Our approach to selecting treatment for stimulant use disorder, including psychosocial interventions and medication, is described separately. (See "Approach to treatment of stimulant use disorder in adults".)

STIMULANTS — Most trials of stimulant use disorder have studied patients using cocaine. Cocaine, amphetamine, and methamphetamine have similar mechanisms of action. This suggests that medications that show some evidence of efficacy for cocaine use may also be efficacious for amphetamine and methamphetamine, and vice versa. Clinical trials have begun testing this hypothesis, but few results have been published to date. Differences in stimulants’ mechanisms of action are summarized below.

Cocaine — The reinforcing properties of cocaine are mediated by its ability to block the dopamine transporter and increase dopaminergic activity in critical brain regions. (See "Cocaine use disorder in adults: Epidemiology, clinical features, and diagnosis" and "Cocaine: Acute intoxication".)

Methamphetamine — The reinforcing effects of methamphetamine are mediated both by blockade of the dopamine transporter and by stimulating the presynaptic release of dopamine. (See "Methamphetamine use disorder: Epidemiology, clinical features, and diagnosis" and "Methamphetamine: Acute intoxication".)

Amphetamines — Amphetamines and other diverted pharmaceutical stimulants have a mechanism of action similar to methamphetamine with both blockade of the dopamine transporter as well as stimulate release of dopamine. Methylphenidate has a mechanism of action more similar to that of cocaine with simple blockade of the dopamine transporter. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Stimulants'.)

Synthetic cathinones — Cathinones are beta-ketone amphetamine analogs. Abuse of synthetic cathinones (bath salts) emerged in Europe in 2009 and spread to the United States in 2010 [3,4]. These drugs were initially marketed in the United States as “bath salts” or “plant food” to avoid controlled-substance restrictions. The mechanism of action of cathinones is similar to that of methamphetamine. Cathinones block the reuptake of dopamine, norepinephrine, and serotonin, as well as stimulate the release of dopamine. (See "Acute amphetamine and synthetic cathinone ("bath salt") intoxication".)

PHARMACOTHERAPY — No medications have shown consistent evidence of efficacy for stimulant use disorder in clinical trials. Several medications have shown promise in trials of patients with the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) disorders, cocaine dependence and methamphetamine dependence, but more robust clinical trials are needed before their use can be recommended.

Cocaine use disorder

Dopamine agonists — Analogous to methadone’s use in the treatment of opioid use disorder, dopamine agonists, long-acting amphetamine and methamphetamine, have been tested in patients with stimulant use disorder. The drugs bind to the same receptor as cocaine, but are less abusable than cocaine because of their relatively slower uptake and longer duration of action [1].

The most recent results from trials of dopamine agonists have been promising, but replication is needed in stimulant-dependent patients in routine treatment settings. Three earlier trials (the latter three below) achieved mixed results with high dropout rates, while the more recent trial had high rates of study completion and found dexamphetamine sustained-release (SR) to reduce days of cocaine use:

●A clinical trial in the Netherlands randomly assigned 73 patients with treatment-refractory heroin and cocaine dependence to receive either 12 weeks of oral dexamphetamine-SR, 60 mg/day, or placebo; both groups received methadone and diacetylmorphine (heroin-assisted treatment) [5]. Eighty-nine percent of participants completed the trial, in which dexamphetamine-SR treatment resulted in fewer days of cocaine use compared with placebo (mean 44.9 versus 60.6 days); similar results were seen for secondary cocaine use outcomes. No serious adverse events occurred in dexamphetamine-treated patients.

●A 12-week clinical trial in 128 patients with DSM-IV cocaine dependence compared dextroamphetamine with placebo [6]. Patients were randomized to placebo, low-dose dextroamphetamine (30 mg daily) or high-dose dextroamphetamine (60 mg daily). Treatment retention was better in the low-dose amphetamine group. Cocaine use was lower in the high-dose amphetamine group, but not to a statistically significant extent. Dropout rates for all groups were high.

●In a subsequent trial by the same group in 120 patients with combined DSM-IV cocaine and opioid-dependence stabilized on methadone, reductions in cocaine use were seen in patients treated with 60 mg of dextroamphetamine compared with placebo or 30 mg of dextroamphetamine [7]. Treatment retention was poor, with less than 50 percent of subjects completing the trial.

●An eight-week trial in 82 patients with DSM-IV cocaine dependence compared treatment with sustained methamphetamine, immediate release methamphetamine, or placebo [8]. Patients in the sustained release methamphetamine group submitted fewer cocaine-positive urine drug screens during the trial compared with the immediate release and placebo groups (29 versus 66 and 60 percent). Only 32 percent of patients completed the trial.

Modafinil — Modafinil, a mild stimulant used to treat narcolepsy and shift-work sleep disorder, showed initial promise for DSM-IV cocaine dependence that was not borne out in larger trials [9-12]. Modafinil has been tested for its ability to increase abstinence in cocaine-dependent patients and to reduce cocaine withdrawal symptoms [13].

Modafinil has been shown to increase dopaminergic neurotransmission by blocking the dopamine transporter [14]. Modafinil also enhances glutamate-neurotransmission [15]. It may be efficacious for cocaine use disorder by ameliorating glutamate depletion seen in chronic cocaine users [13]. Modafinil was found to block the euphoric effects of cocaine in three human laboratory studies [16-18].

Results of modafinil clinical trials have been mixed:

●In a clinical trial in 62 patients with DSM-IV cocaine dependence treated for eight weeks, modafinil-treated patients (400 mg daily) submitted significantly more cocaine metabolite-free urine samples compared with placebo-treated patients (42 versus 22 percent), and were rated as more improved compared with placebo-treated patients [9].

●A 12-week multicenter trial randomly assigned 210 patients with DSM-IV cocaine dependence to receive modafinil or placebo. No difference was found between the two groups in cocaine use outcomes [10]. In a post hoc analysis among patients who were not concurrently alcohol-dependent, modafinil increased abstinence from cocaine compared with placebo.

●An eight-week clinical trial comparing modafinil (200 or 400 mg/day) with placebo in 210 patients with DSM-IV cocaine dependence found no difference between groups cocaine use or cocaine craving [11].

●An eight-week trial with 94 cocaine-dependent patients, but without concomitant alcohol dependence, found that patients treated with modafinil were more likely to be abstinent from cocaine during the last three weeks of the trial compared with patients receiving placebo (23 versus 9 percent) [12].

Disulfiram — Disulfiram, a medication with some evidence of efficacy in alcohol use disorder, has shown promise for cocaine use disorder. (See "Alcohol use disorder: Pharmacologic management", section on 'Disulfiram'.)

Disulfiram is postulated to affect cocaine use by decreasing the reinforcing properties of cocaine or by making cocaine use aversive [19,20]. Disulfiram blocks the degradation of cocaine by plasma esterases and blocks the conversion of dopamine to norepinephrine by the enzyme dopamine beta-hydroxylase. The effect of disulfiram on plasma esterases leads to extremely high cocaine levels and disulfiram's effect on dopamine beta-hydroxylase may alter dopamine/norepinephrine balance in neurons so as to enhance the likelihood of cocaine abstinence [19,21].

In three of four clinical trials comparing disulfiram (250 mg daily) with placebo, the disulfiram-treated group reduced cocaine use in patients with DSM-IV cocaine dependence [22-25]. As an example, a trial in 208 patients with co-occurring DSM-IV alcohol and cocaine dependence found the combination of disulfiram (250 mg daily) and naltrexone (100 mg daily) led to greater sustained abstinence from both cocaine and alcohol compared with placebo [26].

GABAergic medications — Vigabatrin and topiramate are GABAergic medications that have been tested in cocaine use disorder; clinical trials have found mixed results on the efficacy of topiramate in preventing relapse [27-29], while the largest and most rigorous trial of vigabatrin was negative [30].

Mesocortical dopaminergic neurons receive modulatory inputs from both GABAergic and glutamatergic neurons. GABA is primarily an inhibitory neurotransmitter in the central nervous system, and activation of GABAergic neurons tends to decrease activation in the dopaminergic reward system. Preclinical trials of medications that foster GABAergic neurotransmission have suggested that these compounds reduce the dopamine response to both cocaine administration and to conditioned reminders of prior cocaine use [27,31,32]. GABAergic medications also reduce the self-administration of cocaine in animal models [33,34]. GABAergic medications could potentially prevent relapse either by blocking cocaine-induced euphoria, or by reducing craving caused by exposure to conditioned reminders of prior cocaine use.

●Topiramate – Topiramate has been found to have mixed results on cocaine use in dependent patients in clinical trials, described below. Topiramate increases cerebral levels of GABA, and facilitates GABA neurotransmission [35,36]. Topiramate also inhibits glutamate neurotransmission through a blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate receptors [37].

•A 13-week clinical trial in 40 patients with DSM-IV cocaine dependence compared topiramate (200 mg daily) with placebo, finding that patients assigned to receive topiramate were more likely to be abstinent during the last five weeks of the trial [38]. In a secondary analysis among patients who returned for at least one visit after receiving medications, patients in the topiramate group were more likely to achieve at least three weeks of continuous abstinence from cocaine compared with patients in the placebo group (59 versus 26 percent). Topiramate patients were more likely than placebo patients to be rated “very much improved” at their last visit (71 versus 32 percent).

•A 13-week trial randomly assigned 170 patients with DSM-IV cocaine and alcohol dependence treated with weekly individual psychotherapy to additionally receive topiramate (300 mg daily) or placebo [28]. No difference was seen in weekly abstinence from cocaine or alcohol use between patients receiving topiramate versus placebo. In a secondary analysis, patients receiving topiramate were more likely to achieve three weeks of continuous abstinence from cocaine during the trial compared with the placebo group (20 versus 6 percent).

•A 12-week clinical trial in 142 patients with DSM-IV cocaine dependence treated with cognitive-behavioral therapy (CBT) found the topiramate-treated group to have a greater weekly proportion of cocaine nonuse days compared with placebo (13.3 versus 5.3 percent) [29].

●Vigabatrin – Vigabatrin is an antiseizure medication that irreversibly inhibits GABA transaminase, elevating brain GABA concentrations. Despite promising results in earlier trials with methodologic limitations [39-41], a clinical trial comparing vigabatrin (3 mg daily) with placebo in 186 subjects with DSM-IV cocaine dependence found no difference in cocaine use between groups [30].

An association between the use of vigabatrin and visual field defects has limited its usefulness as an anticonvulsant. Data suggest that visual field defects associated with vigabatrin occur after relatively long-term exposure and are less commonly associated with brief treatments [42,43].

TA-CD vaccine — A vaccine, TA-CD, has shown mixed results in the treatment of DSM-IV cocaine dependence. TA-CD stimulates the production of cocaine-specific antibodies that bind to cocaine molecules, preventing them from crossing the blood-brain barrier. Since cocaine is inhibited from entering the brain, its euphoric and reinforcing effects would be reduced. Animal trials of TA-CD have shown that the vaccine produces cocaine-specific antibodies and decreases self-administration of cocaine in rodents [44].

Clinical trials have shown mixed results for the vaccine:

●In a clinical trial in 115 patients with DSM-IV cocaine and opiate-dependence maintained on methadone, patients treated with TA-CD who achieved high IgG antibody levels were more likely to achieve abstinence from cocaine than patients treated with a placebo injection [45].

●A clinical trial in 300 cocaine-dependent patients randomly assigned to receive active vaccine or placebo found no difference in cocaine use (measured by urine drug screens) between groups [46]. Subjects with anti-cocaine immunoglobulin G (IgG) levels of ≥42 mcg/mL (high IgG) did not have lower rates of cocaine use than either low IgG subjects or placebo-treated subjects.

Two earlier trials found that the vaccine was well tolerated and stimulated high antibody titers; one methodologically limited trial found an association with reduced euphoric effects of cocaine in 16 patients [47,48].

Cholinergic medications — Galantamine, a reversible and competitive inhibitor of acetylcholinesterase, has shown some promise in a clinical trial of patients with co-occurring cocaine use disorder and opioid use disorder on methadone maintenance [49]. The 2018 trial randomly assigned 120 subjects to additionally receive galantamine (8 mg daily) plus computerized CBT, galantamine, placebo, or placebo plus computerized CBT. At the trial’s end, no difference was seen by treatment group in primary cocaine outcomes (change in percent days of abstinence) or secondary cocaine outcomes (negative urine screens and cognitive function). Patients assigned to receive galantamine only and CBT only used cocaine less frequently compared with patients assigned to receive placebo. In a small pilot trial, galantamine was well tolerated and associated with reductions in cocaine use in subjects with cocaine use disorder [50].

Other treatments with limited data to support their use — Clinical trials have shown mixed results regarding the effect of antidepressants [51-55] and other medication combinations for the treatment of cocaine use disorder.

●Antidepressants – Bupropion, a dopamine and norepinephrine reuptake inhibitor, has been shown to be efficacious in treating major depression and nicotine dependence. It has been proposed to alleviate stimulant withdrawal symptoms by facilitating dopamine neurotransmission. However, in a 12-week clinical trial including 149 patients with co-occurring cocaine and opioid dependence receiving methadone maintenance, bupropion was not found to be efficacious compared with placebo for cocaine dependence [56]. Bupropion for methamphetamine use disorder is discussed below. (See 'Methamphetamine use disorder' below and "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Bupropion'.)

Citalopram 40 mg but not citalopram 20 mg appeared to improve duration of abstinence and likelihood of cocaine negative urine drug screen [57]. However, in two separate trials, fluoxetine was found to have similar effect to placebo in outcomes of cocaine use or craving [51,52].

●Others – Varenicline, a selective nicotinic acetylcholine receptor agonist used for smoking cessation has shown mixed results in the treatment of cocaine use disorder [58,59]. Most recently, varenicline was evaluated in a 12-week trial, involving 156 subjects with cocaine use disorder (DSM-IV cocaine dependence). Subjects were randomly assigned to 2 mg of varenicline versus placebo [60]. Each group received relapse prevention psychotherapy as well. Cocaine abstinence, as measured by urine drug screen was similar between the treated and placebo groups (8 versus 9 percent, respectively). Additionally, symptoms of cocaine withdrawal and craving were similar between groups.

The combination of topiramate with extended-release mixed amphetamine salts showed promise in promoting abstinence from cocaine in two separate clinical trials [61,62]. The combination of topiramate and phentermine decreased cocaine self-administration in a human laboratory trial [63]. Trials investigating the use of ondansetron (a serotonin receptor blocking agent with associated dopamine inhibition) [64], cannabidiol [65], and selegiline [66] have shown no benefits over placebo in the treatment of cocaine use disorder.

Methamphetamine use disorder — Trials investigating bupropion, mirtazapine, and a combination of bupropion and naltrexone for methamphetamine use disorder have shown mixed results. For example:

●Bupropion and naltrexone – In a clinical trial, 403 subjects with methamphetamine use disorder were assigned to receive either a combination of injectable extended-release naltrexone with oral extended-release bupropion or placebo [67]. At 12 weeks, overall weighted response rates (three out of four methamphetamine negative urine samples) were low in both groups but higher in the treatment group than in the placebo group (14 versus 3 percent). Secondary outcomes such as percentage of participants with negative urine samples and methamphetamine craving scores favored the treatment group.

●Bupropion – Bupropion was not efficacious in reducing methamphetamine use in a clinical trial, though a secondary analysis suggested that it may be useful for less severe methamphetamine use disorder.

The 12-week clinical trial compared bupropion (300 mg/day) with placebo in 151 patients with DSM-IV methamphetamine dependence [68]. Both groups received behavioral therapy. No difference was seen between groups in the primary outcome of methamphetamine use; there was a nonsignificant trend favoring bupropion. A subgroup analysis found that bupropion use was associated with a greater proportion of patients with a methamphetamine-free week compared with placebo among male patients with light methamphetamine use [69].

●Mirtazapine – Two clinical trials and a subsequent meta-analysis suggest that mirtazapine may be efficacious in the treatment of methamphetamine use disorder [70-72]. Mirtazapine blocks alpha 2-autoreceptors and alpha 2-heteroreceptors, as well as 5-HT2 and 5-HT3 receptors. It is thought to raise synaptic levels of serotonin norepinephrine and dopamine [70,71]. In one trial including 120 individuals with methamphetamine use disorder, individuals receiving mirtazapine had fewer positive urine tests at 24 weeks (relative risk 0.75, 95% CI 0.56-1.00) and 36 weeks (relative risk 0.73, 95% CI 0.57-0.96) than those in placebo group [71].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stimulant use disorder and withdrawal" and "Society guideline links: Cocaine use and cocaine use disorder".)

SUMMARY AND RECOMMENDATIONS

●Stimulant use disorder – In clinical trials, medications have not shown consistent evidence of efficacy for stimulant use disorder. Psychosocial interventions have proven efficacy in reducing stimulant use in patients with stimulant use disorder. However, psychosocial treatments alone are insufficient for many patients. (See 'Introduction' above.)

●Stimulants – Cocaine, amphetamine, and methamphetamine have similar mechanisms of action. This suggests that medications showing evidence of efficacy for one type of stimulant use disorder may be effective in the treatment of others. (See 'Stimulants' above.)

●Cocaine use disorder – The following have shown some promise in the treatment of cocaine use disorder. However, more robust trials are needed before their use can be recommended.

•Dopamine agonists – Dopamine agonists bind to the same receptor as cocaine, but are less likely to be subject to abuse than cocaine because of their relatively slower uptake and longer duration of action. (See 'Dopamine agonists' above.)

•Modafinil – Modafinil, a mild stimulant used to treat narcolepsy and shift-work sleep disorder, showed initial promise that has not been borne out in larger trials (See 'Modafinil' above.)

•Disulfiram – Disulfiram, a medication with some evidence of efficacy in alcohol use disorder may decrease the reinforcing properties of cocaine by making it aversive. (See 'Disulfiram' above.)

•GABAergic medications – GABAergic medication may decreased activation in the dopaminergic reward system, diminishing acute euphoric effects and leading to reduced craving. Clinical trials have shown mixed efficacy for topiramate in preventing relapse from cocaine use disorder while trials of vigabatrin have not supported it use. (See 'GABAergic medications' above.)

•Others with limited supporting data – TA-CD vaccine, galantamine, bupropion, varenicline, and combinations of topiramate with amphetamine salts have limited to no data supporting their use in the treatment of cocaine use disorder. (See 'TA-CD vaccine' above and 'Cholinergic medications' above and 'Other treatments with limited data to support their use' above.)

●Methamphetamine use disorder – Trials investigating bupropion, mirtazapine, and a combination of bupropion and naltrexone have shown mixed results for treatment of methamphetamine use disorder. (See 'Methamphetamine use disorder' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David A Gorelick, MD, PhD, who contributed to an earlier version of this topic review.