Pharmacotherapy For Stimulant Use Disorders in Adults

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Pharmacotherapy for stimulant use disorders in adults
Author: Kyle Kampman, MD

Section Editor: Andrew J Saxon, MD
Deputy Editor: Richard Hermann, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2018. | This topic last updated: Jul 10, 2018.
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. Our approach to selecting treatment for
stimulant use disorder is described separately. The epidemiology, clinical manifestations, course, consequences,
assessment, 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 "Approach to treatment of stimulant use disorder in adults" and "Cocaine use disorder in adults:
Epidemiology, pharmacology, clinical manifestations, medical consequences, and diagnosis" and
"Methamphetamine use disorder: Epidemiology, clinical manifestations, course, assessment, and diagnosis" and
"Psychosocial interventions for stimulant use disorder in adults" and "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,
pharmacology, clinical manifestations, medical consequences, 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
https://www.uptodate.com/contents/pharmacotherapy-for-stimulant-use-disorders-in-adults/print?search=methamphetamine&source=search_result&s… 1/10
disorder: Epidemiology, clinical manifestations, course, assessment, 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 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 posthoc 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 "Pharmacotherapy for alcohol use disorder", 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].
Bupropion — Bupropion (300 mg/day) was not found to be efficacious compared with placebo for DSM-IV
cocaine dependence in a 12-week clinical trial of 149 patients with co-occurring cocaine and opioid dependence
receiving methadone maintenance [27]. Bupropion for methamphetamine use disorder is discussed below. (See
'Bupropion' below.)
Bupropion acts primarily as a reuptake inhibitor of dopamine and norepinephrine. It has shown to be efficacious
in treating major depression and nicotine dependence. Bupropion’s mechanism of action in the treatment of
tobacco and methamphetamine dependence may be related to its effects on dopamine reuptake. It is thought to
potentially alleviate stimulant withdrawal symptoms by facilitating dopamine neurotransmission. (See "Atypical
antidepressants: Pharmacology, administration, and side effects", section on 'Bupropion'.)
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
[28-30], while the largest and most rigorous trial of vigabatrin was negative [31].
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 [28,32,33]. GABAergic
medications also reduce the self-administration of cocaine in animal models [34,35]. 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 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
[36,37]. Topiramate also inhibits glutamate neurotransmission through a blockade of AMPA/kainate
receptors [38].
• 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 [39]. 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 [29].
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 found the topiramate-treated group to have a greater weekly proportion of cocaine
nonuse days compared with placebo (13.3 versus 5.3 percent) [30].
● Vigabatrin is an antiepileptic medication that irreversibly inhibits GABA transaminase, elevating brain GABA
concentrations. Despite promising results in earlier trials with methodologic limitations [40-42], 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 [31].
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 [43,44].
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 [45].
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 [46].
● 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 [47]. 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 [48,49].
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 [50]. The 2018 trial randomly assigned 120 subjects to additionally receive
galantamine (8 mg daily) plus computerized cognitive-behavioral therapy, galantamine, placebo, or placebo plus
computerized cognitive-behavioral therapy. 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 cognitive-behavioral
therapy 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 [51].
Other — Clinical trials of several antidepressants, including desipramine and serotonin reuptake inhibitors,
have shown inconsistent evidence of efficacy augmenting psychosocial treatment in DSM-IV cocaine
dependence. As examples:
● Fluoxetine was not found to be superior to placebo in two separate trials [52,53].
● An early clinical trial of desipramine for cocaine dependence had positive findings, but two subsequent trials
showed no difference between desipramine and placebo in primary outcomes [54-56].
● Nefazodone and selegiline were not found to be superior to placebo in separate clinical trials [57,58].
Methamphetamine use disorder — Clinical trials have tested bupropion and mirtazapine, both effective
antidepressants, in patients with methamphetamine use disorder, with findings showing greater promise for
mirtazapine. Clinical trials of medications this disorder started later compared with those for cocaine use disorder
and have evaluated fewer medications.
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. Bupropion is
discussed in greater detail above. (See 'Bupropion' above.)
The 12-week clinical trial compared bupropion (300 mg/day) with placebo in 151 patients with DSM-IV
methamphetamine dependence [59]. 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 [60].
Mirtazapine — A clinical trial suggested that mirtazapine may be efficacious in the treatment of
methamphetamine use disorder. 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.
The 12-week trial, conducted with 60 methamphetamine-dependent men who have sex with men, found that
patients receiving mirtazapine submitted fewer methamphetamine-positive urine drug screens during the trial
compared with patients receiving placebo [61].
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".)
SUMMARY
● 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".)
● No medications have shown consistent evidence of efficacy in the treatment of stimulant use disorder in
clinical trials. 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. Some medications
have shown promise in trials of patients using cocaine or methamphetamine, but more robust clinical trials
are needed before their use can be recommended. (See 'Pharmacotherapy' above and "Approach to
treatment of stimulant use disorder in adults", section on 'Approach to treatment'.)
● The dopamine agonists, long-acting amphetamine and methamphetamine, bind to the same receptor as
cocaine, but are less abusable than cocaine because of their relatively slower uptake and longer duration of
action. Earlier clinical trials of these medications in patients with cocaine use disorder have found mixed
results compared with placebo and high dropout rates, but a more recent trial with a high completion rate
found reduced cocaine use across primary and secondary outcomes in patients also receiving heroin
maintenance treatment for heroin dependence. Further trials are needed to replicate these results in
stimulant dependent patients in more routine treatment settings. (See 'Dopamine agonists' above.)
● Modafinil, a mild stimulant used to treat narcolepsy and shift-work sleep disorder, has shown mixed results
in several clinical trials of patients with DSM-IV cocaine dependence. Modafinil was found to block the
euphoric effects of cocaine in three human laboratory studies. (See 'Modafinil' above.)
● Disulfiram, a medication with some evidence of efficacy in alcohol use disorder, has shown promise for
cocaine use disorder. Some, but not all, clinical trials of disulfiram in cocaine dependent patients found that
patients receiving the medication had decreased cocaine use compared with placebo-treated patients. (See
'Disulfiram' above and "Pharmacotherapy for alcohol use disorder", section on 'Disulfiram'.)
● Several antidepressants have been tested in clinical trials of cocaine-dependent patients with mixed results
including serotonin reuptake inhibitors and tricyclic antidepressants. Mirtazapine was found to reduce
positive urine drug screens in a trial of methamphetamine-dependent men compared with placebo. Trials of
bupropion have been negative in samples of patients with cocaine use disorder and with methamphetamine
use disorder compared with placebo. (See 'Other' above and 'Mirtazapine' above and 'Bupropion' above.)
● GABAergic medications, topiramate and vigabatrin, have been tested in patients with DSM-IV cocaine
dependence; clinical trials have found mixed results for topiramate, while the largest and most rigorous trial
of vigabatrin was negative. (See 'GABAergic medications' above.)
● A vaccine, TA-CD, has shown mixed results in the treatment of DSM-IV cocaine dependence, with the larger
of two trials showing no difference in cocaine use compared with placebo injection, and similarly negative
results in a subgroup of subjects with high immunoglobin G levels. TA-CD stimulates the production of
cocaine-specific antibodies that bind to cocaine molecules, prevent them from crossing the blood-brain
barrier. (See 'TA-CD vaccine' above.)
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Topic 106878 Version 11.0
Contributor Disclosures
Kyle Kampman, MD Grant/Research/Clinical Trial Support: Braeburn [Opioid use disorder]. Andrew J Saxon,
MD Grant/Research/Clinical Trial Support: Medicasafe [Medication dispensing]. Consultant/Advisory Boards:
Neurocrine Biosciences [Tardive dyskinesia (Valbenazine)]. Richard Hermann, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
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1/8/2019 Pharmacotherapy for stimulant use disorders in adults - UpToDate

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Author: Kyle Kampman, MD

Cocaine use disorder

Results of modafinil clinical trials have been mixed:

Clinical trials have shown mixed results for the vaccine:

Cholinergic medications — Galantamine, a reversible and competitive inhibitor of acetylcholinesterase, has

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