Official reprint from UpToDate®

www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Pharmacotherapy for stimulant use disorders in adults

Author: Kyle Kampman, MD
Section Editor: Andrew J Saxon, MD
Deputy Editor: Michael Friedman, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2020. | 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
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.

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.

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.)
 ● 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.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge David A Gorelick, MD, PhD, who contributed to an
earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Substance Abuse and Mental Health Services Administration. Results from the 2010 National Survey o
n Drug Use and Health: Summary of National Findings, NSDUH Series H-41. HHS Publication no. (SM
A) 11-4658, Substance abuse and Mental Health Services Administration, Rockville, MD 2011.

2. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics an
d Quality. Drug Abuse Warning Network, 2008: National Estimates of Drug-Related Emergency Depart
ment Visits. HHS Publication no. SMA 11-4618, Rockville, MD 2011.

3. Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol
2012; 8:33.

4. Spiller HA, Ryan ML, Weston RG, Jansen J. Clinical experience with and analytical confirmation of
"bath salts" and "legal highs" (synthetic cathinones) in the United States. Clin Toxicol (Phila) 2011;
49:499.

5. Nuijten M, Blanken P, van de Wetering B, et al. Sustained-release dexamfetamine in the treatment of

chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-
 controlled trial. Lancet 2016; 387:2226.

6. Grabowski J, Rhoades H, Schmitz J, et al. Dextroamphetamine for cocaine-dependence treatment: a

double-blind randomized clinical trial. J Clin Psychopharmacol 2001; 21:522.

7. Grabowski J, Rhoades H, Stotts A, et al. Agonist-like or antagonist-like treatment for cocaine

dependence with methadone for heroin dependence: two double-blind randomized clinical trials.
Neuropsychopharmacology 2004; 29:969.

8. Mooney ME, Herin DV, Schmitz JM, et al. Effects of oral methamphetamine on cocaine use: a
randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend 2009; 101:34.

9. Dackis CA, Kampman KM, Lynch KG, et al. A double-blind, placebo-controlled trial of modafinil for
cocaine dependence. Neuropsychopharmacology 2005; 30:205.

10. Anderson AL, Reid MS, Li SH, et al. Modafinil for the treatment of cocaine dependence. Drug Alcohol
Depend 2009; 104:133.

11. Dackis CA, Kampman KM, Lynch KG, et al. A double-blind, placebo-controlled trial of modafinil for
cocaine dependence. J Subst Abuse Treat 2012; 43:303.

12. Kampman KM, Lynch KG, Pettinati HM, et al. A double blind, placebo controlled trial of modafinil for the
treatment of cocaine dependence without co-morbid alcohol dependence. Drug Alcohol Depend 2015;
155:105.

13. Dackis C, O'Brien C. Glutamatergic agents for cocaine dependence. Ann N Y Acad Sci 2003;
1003:328.

14. Volkow ND, Fowler JS, Logan J, et al. Effects of modafinil on dopamine and dopamine transporters in
the male human brain: clinical implications. JAMA 2009; 301:1148.

15. Touret M, Sallanon-Moulin M, Fages C, et al. Effects of modafinil-induced wakefulness on glutamine

synthetase regulation in the rat brain. Brain Res Mol Brain Res 1994; 26:123.

16. Dackis CA, Lynch KG, Yu E, et al. Modafinil and cocaine: a double-blind, placebo-controlled drug
interaction study. Drug Alcohol Depend 2003; 70:29.

17. Malcolm R, Donovan C, Devane A, et al. Influence of modafinil, 400 or 800 mg/day on subjective
effects of intravenous cocaine in nontreatment seeking volunteers. Drug Alcohol Depend 2002;
66:S110.

18. Hart CL, Haney M, Vosburg SK, et al. Smoked cocaine self-administration is decreased by modafinil.
Neuropsychopharmacology 2008; 33:761.

19. McCance-Katz EF, Kosten TR, Jatlow P. Disulfiram effects on acute cocaine administration. Drug
Alcohol Depend 1998; 52:27.
20. Hameedi FA, Rosen MI, McCance-Katz EF, et al. Behavioral, physiological, and pharmacological
interaction of cocaine and disulfiram in humans. Biol Psychiatry 1995; 37:560.

21. Karamanakos PN, Pappas P, Stephanou P, Marselos M. Differentiation of disulfiram effects on central
catecholamines and hepatic ethanol metabolism. Pharmacol Toxicol 2001; 88:106.

22. Carroll KM, Fenton LR, Ball SA, et al. Efficacy of disulfiram and cognitive behavior therapy in cocaine-
dependent outpatients: a randomized placebo-controlled trial. Arch Gen Psychiatry 2004; 61:264.

23. Carroll KM, Nich C, Ball SA, et al. Treatment of cocaine and alcohol dependence with psychotherapy
and disulfiram. Addiction 1998; 93:713.

24. George TP, Chawarski MC, Pakes J, et al. Disulfiram versus placebo for cocaine dependence in
buprenorphine-maintained subjects: a preliminary trial. Biol Psychiatry 2000; 47:1080.

25. Petrakis IL, Carroll KM, Nich C, et al. Disulfiram treatment for cocaine dependence in methadone-
maintained opioid addicts. Addiction 2000; 95:219.

26. Pettinati HM, Kampman KM, Lynch KG, et al. A double blind, placebo-controlled trial that combines
disulfiram and naltrexone for treating co-occurring cocaine and alcohol dependence. Addict Behav
2008; 33:651.

27. Margolin A, Kosten TR, Avants SK, et al. A multicenter trial of bupropion for cocaine dependence in
methadone-maintained patients. Drug Alcohol Depend 1995; 40:125.

28. Gerasimov MR, Ashby CR Jr, Gardner EL, et al. Gamma-vinyl GABA inhibits methamphetamine,
heroin, or ethanol-induced increases in nucleus accumbens dopamine. Synapse 1999; 34:11.

29. Kampman KM, Pettinati HM, Lynch KG, et al. A double-blind, placebo-controlled trial of topiramate for
the treatment of comorbid cocaine and alcohol dependence. Drug Alcohol Depend 2013; 133:94.

30. Johnson BA, Ait-Daoud N, Wang XQ, et al. Topiramate for the treatment of cocaine addiction: a
randomized clinical trial. JAMA Psychiatry 2013; 70:1338.

31. Somoza EC, Winship D, Gorodetzky CW, et al. A multisite, double-blind, placebo-controlled clinical trial
to evaluate the safety and efficacy of vigabatrin for treating cocaine dependence. JAMA Psychiatry
2013; 70:630.

32. Dewey SL, Smith GS, Logan J, et al. GABAergic inhibition of endogenous dopamine release measured
in vivo with 11C-raclopride and positron emission tomography. J Neurosci 1992; 12:3773.

33. Dewey SL, Chaurasia CS, Chen CE, et al. GABAergic attenuation of cocaine-induced dopamine
release and locomotor activity. Synapse 1997; 25:393.

34. Kushner SA, Dewey SL, Kornetsky C. The irreversible gamma-aminobutyric acid (GABA) transaminase
inhibitor gamma-vinyl-GABA blocks cocaine self-administration in rats. J Pharmacol Exp Ther 1999;
290:797.
35. Roberts DC, Andrews MM, Vickers GJ. Baclofen attenuates the reinforcing effects of cocaine in rats.
Neuropsychopharmacology 1996; 15:417.

36. Kuzniecky R, Hetherington H, Ho S, et al. Topiramate increases cerebral GABA in healthy humans.
Neurology 1998; 51:627.

37. Petroff OA, Hyder F, Mattson RH, Rothman DL. Topiramate increases brain GABA, homocarnosine,
and pyrrolidinone in patients with epilepsy. Neurology 1999; 52:473.

38. Gibbs JW 3rd, Sombati S, DeLorenzo RJ, Coulter DA. Cellular actions of topiramate: blockade of
kainate-evoked inward currents in cultured hippocampal neurons. Epilepsia 2000; 41 Suppl 1:S10.

39. Kampman KM, Pettinati H, Lynch KG, et al. A pilot trial of topiramate for the treatment of cocaine
dependence. Drug Alcohol Depend 2004; 75:233.

40. Brodie JD, Figueroa E, Dewey SL. Treating cocaine addiction: from preclinical to clinical trial
experience with gamma-vinyl GABA. Synapse 2003; 50:261.

41. Brodie JD, Figueroa E, Laska EM, Dewey SL. Safety and efficacy of gamma-vinyl GABA (GVG) for the
treatment of methamphetamine and/or cocaine addiction. Synapse 2005; 55:122.

42. Brodie JD, Case BG, Figueroa E, et al. Randomized, double-blind, placebo-controlled trial of vigabatrin
for the treatment of cocaine dependence in Mexican parolees. Am J Psychiatry 2009; 166:1269.

43. Schmitz B, Schmidt T, Jokiel B, et al. Visual field constriction in epilepsy patients treated with vigabatrin
and other antiepileptic drugs: a prospective study. J Neurol 2002; 249:469.

44. Manuchehri K, Goodman S, Siviter L, Nightingale S. A controlled study of vigabatrin and visual
abnormalities. Br J Ophthalmol 2000; 84:499.

45. Kantak KM, Collins SL, Lipman EG, et al. Evaluation of anti-cocaine antibodies and a cocaine vaccine
in a rat self-administration model. Psychopharmacology (Berl) 2000; 148:251.

46. Martell BA, Orson FM, Poling J, et al. Cocaine vaccine for the treatment of cocaine dependence in
methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial. Arch Gen
Psychiatry 2009; 66:1116.

47. Kosten TR, Domingo CB, Shorter D, et al. Vaccine for cocaine dependence: a randomized double-blind
placebo-controlled efficacy trial. Drug Alcohol Depend 2014; 140:42.

48. Kosten TR, Rosen M, Bond J, et al. Human therapeutic cocaine vaccine: safety and immunogenicity.
Vaccine 2002; 20:1196.

49. Martell BA, Mitchell E, Poling J, et al. Vaccine pharmacotherapy for the treatment of cocaine
dependence. Biol Psychiatry 2005; 58:158.

50. Carroll KM, Nich C, DeVito EE, et al. Galantamine and Computerized Cognitive Behavioral Therapy for
Cocaine Dependence: A Randomized Clinical Trial. J Clin Psychiatry 2018; 79.
 51. Sofuoglu M, Carroll KM. Effects of galantamine on cocaine use in chronic cocaine users. Am J Addict
2011; 20:302.

52. Batki SL, Washburn AM, Delucchi K, Jones RT. A controlled trial of fluoxetine in crack cocaine
dependence. Drug Alcohol Depend 1996; 41:137.

53. Grabowski J, Rhoades H, Elk R, et al. Fluoxetine is ineffective for treatment of cocaine dependence or
concurrent opiate and cocaine dependence: two placebo-controlled double-blind trials. J Clin
Psychopharmacol 1995; 15:163.

54. Gawin FH, Kleber HD, Byck R, et al. Desipramine facilitation of initial cocaine abstinence. Arch Gen
Psychiatry 1989; 46:117.

55. Kosten TR, Morgan CM, Falcione J, Schottenfeld RS. Pharmacotherapy for cocaine-abusing
methadone-maintained patients using amantadine or desipramine. Arch Gen Psychiatry 1992; 49:894.

56. Campbell J, Nickel EJ, Penick EC, et al. Comparison of desipramine or carbamazepine to placebo for
crack cocaine-dependent patients. Am J Addict 2003; 12:122.

57. Ciraulo DA, Knapp C, Rotrosen J, et al. Nefazodone treatment of cocaine dependence with comorbid
depressive symptoms. Addiction 2005; 100 Suppl 1:23.

58. Elkashef A, Fudala PJ, Gorgon L, et al. Double-blind, placebo-controlled trial of selegiline transdermal
system (STS) for the treatment of cocaine dependence. Drug Alcohol Depend 2006; 85:191.

59. Elkashef AM, Rawson RA, Anderson AL, et al. Bupropion for the treatment of methamphetamine
dependence. Neuropsychopharmacology 2008; 33:1162.

60. Shoptaw S, Heinzerling KG, Rotheram-Fuller E, et al. Randomized, placebo-controlled trial of

bupropion for the treatment of methamphetamine dependence. Drug Alcohol Depend 2008; 96:222.

61. Colfax GN, Santos GM, Das M, et al. Mirtazapine to reduce methamphetamine use: a randomized
controlled trial. Arch Gen Psychiatry 2011; 68:1168.

Topic 106878 Version 16.0

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]; Alkermes Inc [Opioid use disorder]; Indivior [Opioid use disorder]. Other
Financial Interest: Alkermes, Inc [Opioid use disorder]. Michael Friedman, 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.

Conflict of interest policy