David A. Gorelick, MD, PhD
CHAPTER OUTLINE
■ COCAINE DEPENDENCE
■ CHOICE OF MEDICATION
■ AMPHETAMINE DEPENDENCE
■ SPECIAL TREATMENT SITUATIONS
■ FUTURE PROSPECTS
■ CONCLUSIONS
Stimulants such as cocaine and amphetamines are the second most widely used illegal drugs in the United States, surpassed only by cannabis. In 2011, an estimated 1.2 million Americans met psychiatric diagnostic criteria for stimulant abuse or dependence (about two-thirds on cocaine) (1), based on the DSM-IV criteria (equivalent to mild [abuse] or moderate to severe [dependence] stimulant use disorder in DSM-5) (2). In 2010, 260,000 patients reporting cocaine or amphetamines as their primary drug of abuse were admitted to publicly funded and/or licensed substance abuse treatment programs (3). Despite this clinical need, there is no well-established, broadly effective pharmacotherapy for stimulant dependence. Both clinical interest and scientific interest in pharmacologic treatment continue to be stimulated by the often disappointingly low success rates and short duration of efficacy of current psychosocial treatment approaches (4–7).
This chapter reviews the current state of pharmacologic treatment for stimulant dependence, including choice of medication and medications for use in special treatment situations, such as patients with mixed addictions or psychiatric comorbidities. Emphasis is given to the use of medications in clinical practice, rather than to laboratory studies or preclinical pharmacology. (For more information about the pharmacology of stimulant dependence, see Section 2, Chapter 10 in this text.)
More of the clinical and clinical research literature deals with cocaine than with amphetamines. These two classes of stimulants are considered separately. The extent to which findings related to cocaine can be extrapolated to other stimulants remains unclear.
COCAINE DEPENDENCE
Goals of Treatment
The goals of pharmacologic treatment of cocaine dependence are the same as for any other treatment modality, that is, to help patients abstain from cocaine use and regain control of their lives. The behavioral mechanisms by which medication achieves these goals are poorly understood and can vary across patients and medications. In theory, medication could shift the balance of reinforcement away from cocaine taking in favor of other behaviors through several mechanisms:
■ By reducing or eliminating the positive reinforcement from taking a cocaine dose (e.g., by reducing the euphoria or “high”)
■ By reducing or eliminating a subjective state (such as “craving”) that predisposes to taking cocaine
■ By reducing or eliminating negative reinforcement from cocaine withdrawal (as by reducing withdrawal-associated dysphoria)
■ By making cocaine-taking aversive
■ By increasing the positive reinforcement obtained from non–cocaine-taking behaviors
Currently available medications are considered to act by one or more of the first three mechanisms, and these mechanisms are the focus of research in medication development. No current research addresses the fourth mechanism (which would be analogous to the use of disulfiram in treating alcohol dependence). The fifth mechanism is crucial to successful treatment because it ensures that other behaviors are reinforced to replace cocaine taking as the latter is extinguished, but such medications do not exist. In current practice, this mechanism is engaged by psychosocial interventions that address issues such as vocational rehabilitation, the patient’s social network, and use of leisure time.
Because of the importance of this mechanism, as well as other factors such as medication adherence, medication almost never is used without some psychosocial treatment component. Few controlled clinical trials explicitly compare the efficacy of medication use with varying (or no) psychosocial treatments (8,9), so the relative contributions of pharmacologic and psychosocial treatments are largely unknown. The type, intensity, and duration of psychosocial treatment that should accompany pharmacologic treatment are questions with little data to guide clinical decision making. At a minimum, one would expect that addressing psychosocial factors that influence medication adherence would improve treatment outcome.
Pharmacologic Mechanisms
At least four pharmacologic approaches are potentially useful in the treatment of cocaine dependence (10). These approaches are (a) substitution treatment with a cross-tolerant stimulant (analogous to methadone maintenance treatment of opioid dependence), (b) treatment with an antagonist medication that blocks the binding of cocaine at its site of action (true pharmacologic antagonism, analogous to naltrexone treatment of opioid dependence), (c) treatment with a medication that functionally antagonizes the effects of cocaine (as by reducing the reinforcing effects of or craving for cocaine), and (d) alteration of cocaine pharmacokinetics so that less drug reaches or remains at its site(s) of action in the brain.
No medication currently is approved by the U.S. Food and Drug Administration (FDA) or any other national regulatory authority for the treatment of cocaine dependence, chiefly because no medication has met the scientifically rigorous standard of consistent, statistically significant efficacy in replicated, controlled clinical trials. Most current clinical and research attention focuses on the second and third approaches mentioned above: reducing or blocking cocaine’s actions, either directly at its neuronal binding site (true pharmacologic antagonism) or indirectly by otherwise reducing its reinforcing effects. The first approach has been evaluated in a small number of clinical trials, with mixed results. The fourth approach has shown promise in animal studies and early phase II clinical trials (11).
Cocaine has two major neuropharmacologic actions: blockade of synaptic neurotransmitter reuptake pumps, resulting in psychomotor stimulant effects, and blockade of sodium ion channels in nerve membranes, resulting in local anesthetic effects.
Cocaine’s positively reinforcing effects derive from its blockade of the dopamine reuptake pump, causing presynaptically released dopamine to remain in the synapse and enhancing dopaminergic neurotransmission (12). Cocaine’s local anesthetic effects are believed to contribute to cocaine-induced kindling, the phenomenon by which previous exposure to cocaine sensitizes the individual so that later exposure to low doses produces an enhanced response.
CHOICE OF MEDICATION
Antidepressants
Heterocyclic Antidepressants
Tricyclic and other heterocyclic antidepressants are the most widely used and best-studied class of medications for the treatment of cocaine dependence. Their use is based both on the clinical observation of frequent depressive symptoms among cocaine-dependent individuals seeking treatment (see below for Psychiatric Comorbidities: Depression) and on their pharmacologic mechanism of increasing biogenic amine neurotransmitter activity in synapses. Such an increase is achieved primarily by inhibiting presynaptic neurotransmitter reuptake pumps.
Desipramine inhibits norepinephrine reuptake, with some action on serotonin reuptake. It was the first medication found effective in an outpatient, double-blind, controlled clinical trial—a finding that received wide publicity even before the complete study was published in a peer-reviewed journal. As a result, desipramine is the best studied of the tricyclic antidepressants, with more than a half dozen controlled clinical trials in the published literature (13–15). Typical doses are 150 to 300 mg/d (about 2.5 mg/kg), similar to those used in the treatment of depression. Meta-analysis suggests a nonsignificant trend toward efficacy but with substantial heterogeneity across studies (13).
Differences in patient characteristics, concomitant treatment, and desipramine plasma concentrations may account for some of the variability in the efficacy of desipramine. For example, patients with depression (16) and without antisocial personality disorder (17) may respond best to desipramine. Patients dually dependent on cocaine and opiates may do better on desipramine if their opioid dependence is treated with buprenorphine rather than methadone or if they receive contingency management treatment along with medication (15). There is limited evidence that patients with steady-state desipramine plasma concentrations above 200 ng/mL have poorer outcomes (18), with better outcomes at concentrations around 125 ng/mL (14).
Experience with other heterocyclic antidepressants shows limited evidence for efficacy. The norepinephrine reuptake inhibitors reboxetine and maprotiline were effective in small open-label trials (19,20), while atomoxetine showed no efficacy in a small controlled clinical trial (21). Imipramine, the precursor of desipramine, which blocks serotonin reuptake much more than norepinephrine reuptake, showed no efficacy in two controlled clinical trials, except in subjects who used intranasal cocaine (22,23). Nefazodone and venlafaxine, which block both serotonin and norepinephrine reuptake, were not effective in controlled clinical trials (24–26). Mirtazapine, which increases brain serotonin and norepinephrine activity by blocking autoregulatory α2-adrenergic and 5-HT2 receptors, showed some benefit in a small open-label trial (27).
No unexpected or medically serious side effects have been reported in published clinical trials of heterocyclic antidepressants. However, patients who relapse to cocaine use while still on antidepressant medications could, in theory, be at increased risk of cardiovascular side effects. Both cocaine and the tricyclics have quinidine-like membrane effects that, when superimposed, could lead to cardiac arrhythmias. The concurrent administration of cocaine and desipramine (blood levels above 100 ng/mL) to research volunteers has produced additive increases in heart rate and blood pressure (28).
Selective Serotonin Reuptake Inhibitors
Antidepressants that selectively block the presynaptic serotonin reuptake pump have attracted interest because of the role of serotonin and its receptors in modulating dopaminergic brain reward circuits and the behavioral effects of cocaine (29,30) (see Chapter 10, Section 2). Several controlled clinical trials have not found any advantage for fluoxetine (20, 40, or 60 mg/d) (13,31), paroxetine (20 mg/d) (26), or sertraline (100 mg/d) (32) over placebo, although treatment retention was improved in two of the studies. One clinical trial found citalopram (20 mg/d) significantly better than placebo (33). That study, unlike previous studies, used contingency management in addition to cognitive– behavioral therapy, suggesting the importance influence of psychosocial treatment on medication efficacy.
Monoamine Oxidase Inhibitors
The rationale for use of monoamine oxidase (MAO) inhibitors lies in their effect of increasing brain levels of biogenic amine neurotransmitters by inhibiting a major catabolic enzyme. Limited open-label experience with phenelzine, at antidepressant doses of 30 to 90 mg/d, suggests that this medication can reduce cocaine and other stimulant use (34–36). However, its clinical usefulness may be limited by the need for dietary and concomitant medication restrictions to avoid precipitating a hypertensive crisis as well as by the theoretical possibility of potentiating cocaine-induced effects should the patient relapse to cocaine use while still taking the medication. Some researchers have argued that fear of such an aversive, potentially life-threatening reaction is what motivates abstinence while taking an MAO inhibitor (34), making the mechanism of action analogous to that of disulfiram for alcohol dependence.
Current research focuses on selective MAO inhibitors that act only on MAO type B, the predominant type in the brain, while sparing MAO type A, the predominant type in the gastrointestinal tract. It is inhibition of MAO in the gastrointestinal tract that produces a hypertensive crisis (“cheese reaction”) after ingestion of tyramine-containing foods or certain catecholaminergic medications. Selegiline, marketed for the treatment of parkinsonism and, in the transdermal form, for treatment of depression, is fairly selective for MAO type B at recommended doses (10 mg/d for parkinsonism; 12 mg/d for depression) and is being studied as a treatment for cocaine dependence. A recent multisite, controlled clinical trial using selegiline administered via a skin patch (selegiline transdermal system) found no evidence for efficacy (37).
Other Antidepressants
Bupropion has attracted interest because it is a weak inhibitor of monoamine reuptake and has some stimulant-like behavioral effects in animals. Two controlled clinical trials in methadone-maintained, cocaine-dependent patients found no significant effect on cocaine use, except in subjects also receiving contingency management treatment (38,39).
Ritanserin, a 5-HT2 receptor antagonist developed as an antidepressant, attracted interest because it reduced cocaine self-administration in some (but not all) animal studies. However, two controlled clinical trials found ritanserin no better than placebo in reducing cocaine use (40,41).
Dopamine Agonists (Antiparkinson Agents)
A variety of direct and indirect dopamine agonist medications have been evaluated, based on the dopamine depletion hypothesis of cocaine dependence (42), although the data supporting the hypothesis in humans are equivocal (43). Dopamine agonists, by stimulating synaptic dopamine activity, would ameliorate the effects of decreased dopamine activity caused by cessation of cocaine use; these include anhedonia, anergia, depression, and cocaine craving. In rats, dopamine receptor agonists such as bromocriptine and lisuride reduce cocaine self-administration and reverse the reduced metabolic rate and elevated intracranial self-stimulation threshold produced in dopaminergic mesocorticolimbic brain regions after cessation of chronic cocaine administration (44). Bromocriptine, pergolide, and amantadine, all marketed for the treatment of parkinsonism (another dopamine deficiency condition), are the most commonly studied dopamine agonist medications (45).
Findings with direct dopamine receptor agonists (primarily at the D2 subtype) are inconsistent. A controlled clinical trial found that bromocriptine (started during inpatient treatment) did not significantly reduce relapse to cocaine use during subsequent outpatient treatment (46). Three controlled clinical trials of pergolide (a mixed D1/D2 agonist) found it no different than placebo (47–49). A controlled clinical trial of pramipexole found it no better than placebo (26). In contrast, a controlled clinical trial of cabergoline (50) and an open-label trial of ropinirole (51) found them effective.
Amantadine is an indirect dopamine agonist that acts by releasing dopamine presynaptically. It also is a weak antagonist at the N-methyl-D-aspartate (NMDA) glutamate receptor. Only one of more than half a dozen controlled clinical trials found amantadine (200 to 400 mg/d) better than placebo (45,52,53). An initial finding of benefit among outpatients with more severe cocaine withdrawal symptoms was not replicated in a larger trial (53).
The amino acid L-dopa, a precursor for the synthesis of catecholamines that is used in the treatment of parkinsonism, has been used to increase brain dopamine levels in the treatment of cocaine dependence, both alone and in combination with carbidopa, a peripheral amino acid decarboxylase inhibitor that prevents systemic side effects by blocking the conversion of L-dopa to dopamine outside the brain. Three controlled clinical trials found no advantage of L-dopa/carbidopa over placebo (50,54). A fourth controlled clinical trial found a medication advantage over placebo only in subjects also receiving contingency management treatment (8).
L-Tyrosine, the amino acid precursor of L-dopa, reduced cocaine craving in a small (12 patients) double-blind study of inpatients (55), but was not effective in reducing cocaine use in two outpatient clinical trials at 2 g every 8 hours (open label) or 800 or 1,600 mg twice a day (double blind) (56,57).
Disulfiram
Disulfiram can be considered a functional dopamine agonist because it blocks the conversion of dopamine to norepinephrine by the enzyme dopamine-β-hydroxylase, thereby increasing dopamine concentrations (58). Five small controlled clinical trials in cocaine-dependent patients without alcohol dependence (but with, in four studies, concurrent opioid dependence treated with methadone or buprenorphine) found disulfiram (250 mg/d) significantly better than placebo in promoting cocaine abstinence (59,60). However, two recent, larger controlled clinical trials (both in methadone-maintained patients) found no efficacy for disulfiram (61,62). Some of the heterogeneity in treatment response may be due to genetic factors. One of the recent positive clinical trials found no significant efficacy for disulfiram in the subgroup of patients with the dopamine-β-hydroxylase gene allele that results in low enzyme activity (60). Two other recent small controlled clinical trials in methadone-maintained patients that found no disulfiram efficacy overall did find significant efficacy in subgroups with functional variants in the ankyrin repeat and kinase domain-containing 1 (ANKK1) and dopamine D2 receptor (DRD2) genes (63) and α1A-adrenoreceptor (ADRA1A) gene (64).
Although disulfiram is well tolerated in clinical trials, where subjects are screened for medical and psychiatric comorbidity, questions have been raised about its safety in routine clinical practice (65). Several human laboratory studies give conflicting results on the safety of the cocaine– disulfiram interaction (66), although the most recent study found no clinically significant adverse effects from even the triple interaction of cocaine–alcohol–disulfiram (67). These findings suggest that disulfiram may be a promising treatment for cocaine dependence in some subgroups of patients, although raising a caution about potential adverse drug interactions should patients use cocaine while on the medication.
Stimulants
By analogy with methadone maintenance treatment of opioid dependence or nicotine replacement treatment of tobacco dependence, maintenance treatment of cocaine-dependent patients with stimulant medication might be clinically beneficial in reducing cocaine craving and use (68). As with methadone, advantages might include use of the less medically risky oral route of administration (vs. injected or smoked cocaine), use of pure medication of known potency (thus avoiding adulterant effects or inadvertent overdose), and use of a medication with slower onset and longer duration of action (thus avoiding “rush”/“crash” cycling) (69).
Several orally active psychomotor stimulants marketed for the treatment of attention deficit hyperactivity disorder (ADHD) or as appetite suppressants have been used to test the substitution approach (45,70). Two small controlled clinical trials with sustained-release D-amphetamine found significant reductions in cocaine use at 30 to 60 mg daily, with no difference from placebo at lower doses (15 to 30 mg). A trial using immediate-release D-amphetamine (20 to 60 mg daily) found no effect. A controlled clinical trial of the combination of sustained-release D-amphetamine with modafinil found poorer efficacy than with amphetamine alone or placebo (71). Two clinical trials of methylphenidate also found no benefit (70). None of these studies reported significant adverse effects, suggesting that stimulant substitution treatment might be safe in cocaine-using patients.
Mazindol, a stimulant originally marketed for appetite suppression, has less abuse potential than amphetamines (classified as a Schedule IV controlled substance) and was ineffective in three controlled clinical trials (70,72).
Modafinil, used for the treatment of excessive sleepiness in narcolepsy, obstructive sleep apnea, and shift work sleep disorder, can be considered a weak stimulant (Schedule IV). Its mechanisms of action are unclear, but include some blockade of presynaptic dopamine transporters as well as increases in brain glutamate release and decreases in gamma aminobutyric acid (GABA) release (73). A small phase II clinical trial found that 400 mg daily significantly reduced cocaine use (74). A later multisite clinical trial found no significant reduction in cocaine use in the study sample as a whole (75). However, in the subgroup of subjects without alcohol dependence, both 200 and 400 mg daily of modafinil significantly increased the percentage of abstinent days. Modafinil was safe and well tolerated. It does not appear to evoke cocaine craving or itself produce euphoria (73,76). In phase I human laboratory studies, modafinil does not potentiate the effects of cocaine (77), nor does it alter cocaine pharmacokinetics, except for a decrease in the area under the cocaine plasma concentration–time curve over the first 3 hours after intravenous cocaine administration (78). These findings suggest that modafinil could be safely used in selected subgroups of cocaine-using patients.
In principle, cocaine itself, in a slow-onset formulation or route of administration, might be used for agonist maintenance treatment (79,80), in the same way that slow-onset transdermal or transbuccal nicotine is used to treat dependence on rapid-onset smoked nicotine (cigarettes). Oral cocaine salt capsules (100 mg four times a day) significantly attenuated the response to an intravenous cocaine challenge (25 mg) (80) and reduced coca paste smoking in an open-label series of 18 patients in Lima, Peru (where oral cocaine products are legal) (81). A larger series of 200 patients treated with coca tea, also in Lima, reported that almost 80% reduced their cocaine smoking (81). A case series of 50 coca paste smokers in La Paz, Bolivia, reported that chewing 100 to 200 g of coca leaf per week for a mean of 2 years substantially improved the mental health of one-third of the patients and improved the socioeconomic functioning of almost half (data on cocaine smoking were not reported) (82).
Antipsychotics
The older (so-called first-generation) antipsychotics, which are potent dopamine receptor antagonists (chiefly D2 [post-synaptic] subtype), do not significantly alter cocaine craving or use, as evidenced by clinical experience with patients with schizophrenia who abuse cocaine while receiving chronic antipsychotic treatment (83–85). Greater efficacy was expected from the newer “second-generation” anti-psychotics, in part because of their broader spectrum of receptor binding (including dopamine D1 and serotonin receptors). However, this promise has not been confirmed in clinical trials of cocaine users without comorbid psychiatric disorders (86). A small open-label trial of olanzapine in 21 patients dually dependent on cocaine and opioids (being treated with methadone) reported a decrease in cocaine use in 53.2% of patients (87). However, three more recent controlled clinical trials reported no significant advantage for olanzapine over placebo (88,89). Two controlled clinical trials using oral risperidone (90,91) and one using long-acting injectable risperidone (92) also found no advantage over placebo.
Caution should be exercised when prescribing any anti-psychotic to cocaine users because of their potential vulnerability to the neuroleptic malignant syndrome, based on their presumed cocaine-induced dopamine depletion (93). Cocaine or amphetamine users may also be at elevated risk of antipsychotic-induced movement disorders (94–97).
Anticonvulsants
Anticonvulsants might be effective in the treatment of cocaine dependence because they increase inhibitory GABA activity and/or decrease excitatory glutamate activity in the brain, both actions that would decrease the response to cocaine in the dopaminergic corticomesolimbic brain reward circuit (10,98–100).
Carbamazepine is the most studied anticonvulsant, but the promise of early open-label studies has not been confirmed in controlled trials. Four of five double-blind outpatient trials found no significant effect on cocaine use (101). Gabapentin was ineffective in three controlled clinical trials (102–104), as were lamotrigine (102) and valproic acid (89) in single trials.
Several other anticonvulsants have shown more promising results. Tiagabine, which increases GABA activity by blocking its presynaptic reuptake, significantly reduced cocaine use in two controlled clinical trials at doses of 12 or 24 mg daily (104,105) but had no effect in a third trial at 20 mg daily (106). All three trials used concomitant cognitive–behavioral therapy. Topiramate, which decreases glutamate activity by blocking AMPA-type glutamate receptors and increases GABA activity (by an unknown mechanism), significantly reduced cocaine use in a controlled clinical trial at up to 200 mg daily, in conjunction with cognitive–behavioral therapy (107). Vigabatrin (γ-vinyl-GABA), which increases GABA activity by inhibiting the breakdown of GABA by GABA transaminase, reduced cocaine use in three small open-label studies and a controlled clinical trial (108), but not in a larger controlled clinical trial (109). Phenytoin (300 mg daily) significantly reduced cocaine use in one controlled clinical trial, especially at serum concentrations above 6.0 μg/mL (110).
Baclofen, an antispasmodic rather than anticonvulsant, increases GABA activity by acting as an agonist at GABAB receptors. One controlled clinical trial found that baclofen (60 mg daily) did not significantly reduce cocaine use, except in the subgroup of subjects with heavier cocaine use (111).
Nutritional Supplements and Herbal Products
Nutritional Supplements
The use of amino acid mixtures, either alone or with other nutritional supplements (vitamins and minerals), has been widely publicized in the drug abuse treatment field, encouraged by their freedom from the regulations imposed on prescription medications and their perceived safety and absence of side effects. Proprietary mixtures, including tyrosine (the amino acid precursor of L-dopa) and L-tryptophan (the amino acid precursor of serotonin), have been marketed with claims of efficacy (112), but a double-blind, 28-day cross-over study found no significant effect of tyrosine and tryptophan (1 g of each daily) on cocaine craving or withdrawal symptoms (113). A more recent controlled clinical trial found L-tryptophan, even when coupled with contingency management treatment, no better than placebo in reducing cocaine use (114). L-Carnitine (500 mg/d) plus coenzyme Q10 (200 mg/d) was no better than placebo in an 8-week controlled clinical trial (89). A small controlled clinical trial found magnesium L-aspartate (732 mg daily), an easily absorbed form of magnesium, no better than placebo (115).
Herbal Products
Various herbal and plant-derived products have been touted as treatments for drug abuse, but few have undergone controlled clinical evaluation. One that received substantial publicity, but not yet clinical evaluation, is ibogaine, an indole alkaloid found in the root bark of the West African shrub Tabernanthe iboga. This compound is claimed to suppress cocaine (and opioid and alcohol) withdrawal and craving for several months after a single oral dose (116). Ginkgo biloba (120 mg/d for 8 weeks) was no better than placebo in a controlled clinical trial (117).
Calcium Channel Blockers
Calcium channel blockers have been suggested as treatment for cocaine dependence because of their effects on neurotransmitter release and inhibition of cocaine’s psychological effects in some, but not all, studies of human research volunteers (118). However, amlodipine showed no efficacy in a controlled clinical trial (118).
Other Medications
A wide variety of other medications have been evaluated for the treatment of cocaine dependence, often on the basis of promising case reports or animal studies suggesting that they influenced the reinforcing effects of cocaine.
Ondansetron, a 5-HT3 receptor antagonist approved for the treatment of nausea and vomiting, significantly reduced cocaine use in a small controlled clinical trial (119). The effect was significant only at the highest dose (4 mg twice daily).
Varenicline, a partial agonist at α4β2 nicotinic acetylcholine receptors approved for smoking cessation, significantly reduced cocaine use in a small controlled clinical trial (120).
Naltrexone, a mu opioid receptor antagonist marketed for the treatment of alcohol dependence and opioid dependence, showed some efficacy at 50 mg/d in cocaine-dependent outpatients without alcohol or opioid dependence, but only when combined with relapse prevention therapy (121).
Doxazosin, an α1-adrenergic receptor antagonist approved for treatment of hypertension, when rapidly titrated over 4 weeks to a daily dosage of 8 mg, significantly reduced cocaine use in a recent small, controlled clinical trial (122).
Numerous medications have been found no better than placebo in (usually small-scale) controlled clinical trials. These include mecamylamine, a nicotinic cholinergic receptor antagonist (123); the acetylcholinesterase inhibitors donepezil (32) and galantamine (124); propranolol, a beta-adrenergic receptor antagonist (53); reserpine, a depleter of presynaptic monoamine neurotransmitters (125); hydergine, an agonist at dopamine and serotonin receptors and antagonist at alpha-adrenergic receptors that stimulates blood flow (50); pentoxifylline, a phosphodiesterase inhibitor (26); riluzole, an inhibitor of glutamate release (26); memantine, an NMDA glutamate receptor antagonist (126); N-acetylcysteine, which increases brain glutamate levels (127); celecoxib, a nonsteroidal anti-inflammatory drug (128); lithium (129); citicoline, which is neuroprotective and increases phospholipid turnover and monoaminergic neurotransmission (130); and dehydroepiandrosterone (DHEA), an endogenous steroid precursor of androstenedione, itself a precursor of androgenic and estrogenic hormones (131). DHEA is also a sigma-1 receptor agonist.
Medication Combinations
Concurrent use of two different medications is studied in the hope that such combinations will enhance efficacy while minimizing side effects, either by acting on a single neurotransmitter system by two different mechanisms or by acting on two different neurotransmitter systems. Concurrent open-label use of the dopaminergic agents bupropion and bromocriptine in cocaine-dependent outpatients is safe, albeit with little efficacy (132). Concurrent use of pergolide (a dopamine D1/D2 receptor agonist) and haloperidol (a dopamine D2 receptor antagonist), designed to produce relatively pure D1 agonist action, also showed efficacy (133), as did combined use of amantadine and propranolol (53). The combination of extended-release mixed amphetamine salts and topiramate was significantly better than placebo in achieving 3 consecutive weeks of abstinence (134), but there were no individual drug groups to allow evaluation of the origin of the therapeutic effect. The combination of metyrapone, a cortisol synthesis inhibitor, and the benzo-diazepine oxazepam tended to reduce cocaine craving and use in a small controlled clinical trial (135), but the 50% dropout rate limits the internal validity of the study.
The combined use of the dopamine releaser phentermine and the serotonin releaser fenfluramine, each marketed as an appetite suppressant, received substantial publicity during the 1990s as the so-called “phen–fen” treatment for obesity and addictive disorders. This medication combination had mixed results in the outpatient treatment of cocaine dependence (136). The combination no longer is available since the withdrawal of fenfluramine because of its association with primary pulmonary hypertension and valvular heart disease (137). Combinations that replace fenfluramine with a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine have not been systematically evaluated.
Other Physical Treatments
Acupuncture is an ancient Chinese treatment that involves mechanical (with needles), thermal (moxibustion), or electrical (electroacupuncture) stimulation of specific points on the body surface (138). The mechanism of action is unknown; speculation has included stimulation of endogenous opioid systems. Acupuncture of the outer ear (auricular) gained popularity as a treatment for drug withdrawal, especially using five standard locations recommended by the National Acupuncture Detoxification Association (NADA): kidney, liver, lung, shen men, and sympathetic. Meta-analyses of nine published studies (six using the NADA locations) did not find a significant benefit of active acupuncture over sham treatment (139,140).
Transcranial magnetic stimulation (TMS) involves activation of brain cells by magnetic fields generated by electromagnetic coils placed on the scalp. Repetitive TMS (rTMS) is approved as a treatment for depression and is under study as a treatment for addiction (141). Single and multiple sessions of rTMS of the prefrontal cortex (either right or left) reduce cocaine craving (142,143).
AMPHETAMINE DEPENDENCE
Many of the medications evaluated for the treatment of cocaine dependence have also been studied for the treatment of dependence on amphetamines (amphetamine or methamphetamine), often for the same pharmacologic rationale (144,145). As with cocaine dependence, most controlled clinical trials do not show efficacy.
The most promising approaches to date appear to be agonist substitution with stimulants and blockade of μ opioid receptors. Three of five controlled clinical trials with D-amphetamine (one using a sustained-release formulation) found a significant reduction in amphetamine or methamphetamine use compared with placebo (68,146,147). There were no significant adverse events in any study. Slow-release methylphenidate (54 mg daily) reduced amphetamine use significantly more than did placebo in one controlled clinical trial (148). However, modafinil (200 or 400 mg daily) had no significant effect on methamphetamine use in three controlled clinical trials (149–151). Naltrexone, both orally and as a subcutaneous implant, significantly reduced amphetamine use in controlled clinical trials (152,153), although oral naltrexone combined with N-acetylcysteine was not effective in reducing methamphetamine use (154).
Baclofen, an antispasmodic that increases GABA activity by acting as an agonist at GABAB receptors, had no overall effect on methamphetamine use in a controlled clinical trial, but did significantly reduce use in a subgroup of highly medication-adherent subjects (155). Gabapentin, an anticonvulsant with an unknown mechanism of action, was no different from placebo, even in the adherent subgroup.
Heterocyclic antidepressants show inconsistent efficacy. Mirtazapine significantly reduced methamphetamine use in a small controlled clinical trial (156), and bupropion showed no overall efficacy in three small controlled clinical trials (157,158), but did significantly reduce methamphetamine use in the subgroup of subjects with lower levels of methamphetamine use (157). The antipsychotic risperidone, either oral or long-acting injectable, reduced methamphetamine use in two open-label trials (159,160). Another second-generation antipsychotic, aripiprazole (15 mg daily), showed no efficacy in a small controlled clinical trial (148).
Medications not showing efficacy in the treatment of amphetamine or methamphetamine dependence include tricyclic antidepressants (e.g., imipramine, desipramine), selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine) (161), ondansetron (a 5-HT3 receptor antagonist) (162), topiramate (236), and the calcium channel blocker amlodipine (144,145).
SPECIAL TREATMENT SITUATIONS
Mixed Dependence
Opioid Dependence
Concurrent opioid use, including dependence, is a common clinical problem among cocaine-dependent individuals. Some individuals use cocaine and opioids simultaneously (as in the so-called speedball) to enhance the drugs’ subjective effects. Up to 20% or more of opioid-dependent patients in methadone maintenance treatment also use cocaine for a variety of reasons, including continuation of prior polydrug abuse, replacement for the “high” no longer obtained from opioids, self-medication for the sedative effects of high methadone doses, or attenuation of opioid withdrawal symptoms (163,164). Three different pharmacologic approaches have been used for the treatment of dual cocaine and opioid dependence: adjustment of methadone dose, maintenance with another opioid medication, and addition of medication targeting the cocaine dependence.
Higher methadone doses (usually 60 mg or more daily) generally are associated with less opioid use by patients in methadone maintenance. This relationship also holds in general for cocaine use among patients in methadone maintenance (165,166), although exceptions have been reported (167). Increasing the methadone dose as a contingency in response to cocaine use can be effective in reducing such use (and more so than decreasing the methadone dose in response to a cocaine-positive urine sample) (165,168).
Buprenorphine is a partial opioid agonist (μ recept or agonist/κ receptor antagonist) used for the agonist substitution treatment of opioid dependence (169). Advantages over methadone (a pure μ receptor agonist) include a milder withdrawal syndrome and higher therapeutic index (i.e., safety in overdose). Some (but not all) studies in patients concurrently dependent on both opioids and cocaine suggest that cocaine use (as well as opioid use) is reduced at higher buprenorphine doses (16 to 32 mg daily) (170–172). Making buprenorphine dosing partially dependent on cocaine-free urine samples can also reduce cocaine use in opioid-dependent patients (173).
Nonopioid medications for the treatment of cocaine dependence frequently are evaluated in methadone- or buprenorphine-maintained, opioid-dependent outpatients because the opioid agonist maintenance component substantially enhances treatment retention and adherence, improving the internal validity of the trial. A variety of the medications discussed earlier, including desipramine, fluoxetine, amantadine, bromocriptine, disulfiram, and bupropion, have been studied in opioid-maintained, cocaine-dependent patients. There is no evidence that such maintenance treatment significantly influences medication efficacy, but no studies have directly addressed this issue.
Alcohol Dependence
Alcohol dependence is a common problem among cocaine-dependent individuals, both in the community and in treatment settings, with rates of comorbidity as high as 90% (174). Alcohol use by cocaine-dependent patients is associated with poorer treatment outcome (174,175) that can be related to a variety of factors, including production of the toxic psychoactive metabolite cocaethylene (176), stimulation of cocaine craving by alcohol (174), or alteration of medication metabolism by the hepatic effects of alcohol.
Two medications used in the treatment of alcohol dependence have been studied in the treatment of outpatients concurrently dependent on cocaine and alcohol. Disulfiram substantially decreased both cocaine and alcohol use in two clinical trials (177,178) and a small case series (179), but not in a third clinical trial (180). Naltrexone, a μ opioid receptor antagonist marketed for the treatment of alcohol dependence and opioid dependence, also substantially decreased both cocaine and alcohol use at 150 mg daily (181,182), but not at 50 mg daily (183–185) or 100 mg daily (180,186), the doses more typically used in treatment of alcohol or opioid dependence. Combined treatment with both disulfiram (250 mg daily) and naltrexone (100 mg daily) significantly improved abstinence from cocaine and alcohol (180).
A recent controlled clinical trial found no significant effect of topiramate compared to placebo in reducing cocaine or alcohol use in outpatients with comorbid dependence, although topiramate-treated participants had better treatment retention and were more likely to be cocaine abstinent during the final 3 weeks of the 13-week trial (187).
Psychiatric Comorbidities
Treatment-seeking, cocaine-dependent individuals have high rates of psychiatric comorbidity (i.e., psychiatric diagnoses other than another substance use disorder), with rates as high as 65% for lifetime disorders and 50% for current disorders (188,237). The most common comorbid disorders tend to be major depression, bipolar spectrum, phobias, and posttraumatic stress disorder (189). Personality disorders are common among treatment-seeking, cocaine-dependent individuals, with rates as high as 69% (190). The most common of these is antisocial personality disorder (191).
Depression
Antidepressants vary in their efficacy for reducing cocaine use among patients with comorbid major depression, although there are few direct comparisons or controlled clinical trials (192,193). Desipramine, imipramine, and bupropion have usually, but not always (194,195), been found effective, whereas SSRIs (e.g., fluoxetine) and mirtazapine (196) are usually not effective. Venlafaxine (150 to 300 mg daily) and nefazodone (200 mg twice daily) show some efficacy in small clinical trials (197,198).
Bipolar Disorder
Both anticonvulsant “mood stabilizers” and antipsychotics have been used to treat comorbid bipolar disorder and cocaine dependence. Case series and open-label trials suggest that anti-convulsants such as valproate, divalproex, lamotrigine, and carbamazepine have some efficacy in reducing cocaine use in dually diagnosed patients (199,238–241) and are more effective than lithium (129). Combining lithium with an anticonvulsant may be helpful in treatment-resistant patients (199).
The second-generation antipsychotics show mixed results in cocaine-dependent patients with comorbid bipolar disorder. Quetiapine reduced cocaine use in one of the two clinical trials (200,201); risperidone reduced cocaine use in one trial (201). Switching treated patients to aripiprazole did not reduce their cocaine use (202).
One controlled clinical trial found that adding citicoline, a precursor in the biosynthesis of cell membranes, to existing medication was better than adding placebo in reducing cocaine use by dually diagnosed patients (203).
Attention Deficit Hyperactivity Disorder
Up to one-fourth of cocaine-dependent adults have either adult ADHD or a history of childhood ADHD (204,205). Stimulant and dopaminergic medications are the mainstay of treatment for ADHD, suggesting that some of these patients may be self-medicating their ADHD with cocaine. Case series and clinical trials generally find that such medications successfully treat ADHD symptoms and reduce cocaine use in adults: dextroamphetamine (up to 60 mg/d), methamphetamine (15 mg/d), and bupropion (up to 100 mg three times a day) (206–208). However, one of two recent controlled clinical trials with sustained-release methylphenidate found no significant reduction in cocaine use (209,210), nor did a controlled clinical trial with immediate-release methylphenidate (211). A controlled clinical trial with sustained-release bupropion (209) and an open-label trial with atomoxetine (212) also found no significant decrease in cocaine use.
Schizophrenia
Although schizophrenia is not a common comorbid psychiatric disorder among cocaine-dependent individuals, cocaine use and abuse are common among treatment-seeking patients with schizophrenia (213). Clinical experience indicates that first-generation antipsychotics, at doses that are effective in the treatment of schizophrenia, do not significantly alter cocaine craving or use (214,215). One exception may be flupenthixol, a mixed dopamine D1/D2 receptor and 5-HT2A receptor antagonist that is not marketed in the United States (216). Depot flupenthixol (40 mg of decanoate intramuscularly every 2 weeks) reduced cocaine use and improved psychopathology in a small case series of cocaine-using patients with schizophrenia (242).
Several case series and open-label trials suggest that the second-generation antipsychotics, including clozapine, olanzapine, quetiapine, risperidone, and aripiprazole, may be more effective than older (first-generation) antipsychotics in reducing cocaine and other drug use among patients with schizophrenia (214,215). However, two head-to-head controlled clinical trials found no difference between olan-zapine and haloperidol in reducing cocaine use, with each medication reducing cocaine craving in one of the trials (217,218). A controlled clinical trial comparing olanzapine and risperidone found a trend favoring greater reduction in cocaine use by olanzapine (219).
Use of cocaine or amphetamines can exacerbate or provoke antipsychotic-induced movement disorders (94,95) and increase vulnerability to the neuroleptic malignant syndrome (93).
Medical Comorbidities
Few data are available to guide the pharmacotherapy of cocaine dependence in medically ill patients, making this an important issue for future clinical research. Prudent clinical practice requires a careful medical evaluation of any patient before starting medication, with special attention to medical conditions common in cocaine-dependent individuals. Such conditions would include viral hepatitis and alcoholic liver disease, which might alter the metabolism of prescribed medications, and HIV infection. The presence of the latter necessitates caution in prescribing medications with a known potential for inhibiting immune function. Clinical experience suggests that buprenorphine (220,221) and bupropion can be used safely in HIV-positive patients (222), although antiretroviral medications may decrease bupropion plasma concentrations (223).
Gender-Specific Issues
Women tend to be excluded from or underrepresented in many clinical trials of cocaine dependence pharmacotherapy (224), in part because of concern, embodied in former FDA regulations, over risk to the fetus and neonate should a female subject become pregnant. Thus, there is a substantial lack of information about gender-specific issues of pharmacotherapy in general and the pharmacotherapy of cocaine dependence in particular (225,243). This situation should improve in the future because current FDA and National Institutes of Health regulations require appropriate representation of women in clinical trials. Meanwhile, clinicians must deal on an ad hoc basis with the treatment implications of possible gender differences in medication pharmacokinetics (such as those resulting from differences in body mass and composition) and in pharmacodynamics (such as those related to the menstrual cycle or exogenous hormones such as oral contraceptives).
In the absence of directly relevant and systematically collected data, caution should be used when prescribing medications to pregnant women with stimulant dependence and to those with pregnancy potential, keeping in mind both the risks of medication and the risks of continued stimulant use. Some medications proposed for the treatment of cocaine dependence (such as tricyclic antidepressants, bupropion, and buprenorphine) have little potential for morphologic teratogenicity or disruption of pregnancy, although there are few or no data on behavioral teratogenicity. Some medications do pose at least slight risk, such as amantadine (associated with pregnancy complications), lithium (associated with cardiac malformations and neonatal toxicity), anti-convulsants (associated with increased risk of congenital malformations), and antipsychotics (associated with nonspecific congenital anomalies and neonatal withdrawal).
Some medications (e.g., disulfiram, naltrexone) may generate different treatment responses in men versus women (62,182). The reasons for such gender differences are poorly understood, but may include differences in medication pharmacokinetics, hormonal interactions, or subjects’ psychological or socioeconomic status.
Age
Although adolescents make up a substantial minority of heavy cocaine users, they have been largely excluded from clinical trials of cocaine pharmacotherapies because of legal and informed consent considerations. On the basis of the scarcity of published case reports, it appears that medication is not often used in the treatment of adolescent cocaine dependence.
FUTURE PROSPECTS
Future progress in pharmacologic treatment for cocaine dependence is likely to come from development of new medications with novel or more selective mechanisms of action. New medications should evolve from an improved understanding of the neuropharmacology of cocaine dependence and animal studies of the interactions of cocaine with novel compounds (10,99,100).
Preclinical studies with compounds that bind to the same presynaptic dopamine transporter site as does cocaine (thereby keeping cocaine from acting), but which do not themselves produce robust reinforcing effects (because of slow onset of effect and tight, long-lasting binding), suggest that such compounds may be useful as functional cocaine “antagonists” (226). Manipulation of brain dopamine activity with selective dopamine receptor ligands, especially for the D3 type, attenuated the rewarding effects of cocaine in several animal studies (227) and awaits the development of compounds suitable for clinical trials. Medications that presynaptically release both dopamine and serotonin also show promise in animal studies (228).
Cocaine administration, like stress, activates the hypo-thalamic–pituitary–adrenal (HPA) axis, and stress may play a role in relapse to cocaine use after abstinence (100). These observations stimulated interest in corticotrophin-releasing factor receptor antagonists, some of which reduce cocaine self-administration in animals (229).
The endogenous cannabinoid (endocannabinoid) brain neurotransmitter system modulates the dopaminergic reward system (100,230). Blockade of cannabinoid CB1 receptors inhibits relapse to cocaine self-administration after abstinence in animals (231). Therefore, CB1 receptor antagonists (or inverse agonists) have promising therapeutic potential if they become available for clinical research, although this will require compounds without the psychiatric side effects seen with previously available agents (232).
The failure of existing medications to show consistent efficacy in the treatment of cocaine dependence has prompted growing interest in pharmacokinetic approaches, that is, preventing ingested cocaine from entering the brain and/or enhancing its elimination from the body (11). The former approach could be implemented by active or passive immunization to produce binding antibodies that keep cocaine from crossing the blood–brain barrier. The latter approach could be implemented by administration of an enzyme (e.g., butyrylcholinesterase) that catalyzes cocaine hydrolysis or by immunization with a catalytic antibody. These pharmacokinetic approaches already show promise in attenuating cocaine’s behavioral effects in animals. An anticocaine vaccine (i.e., active immunization against cocaine) showed promise in significantly reducing cocaine use in a phase II controlled clinical trial (233). Further work is needed to increase the consistency of the antibody response and lengthen the duration that antibody concentrations remain high enough to block cocaine use.
CONCLUSIONS
The absence of any medication that meets FDA standards for efficacy and safety leaves physicians with little clear-cut guidance for pharmacologic treatment of stimulant dependence. Among existing medications marketed for other indications, none has yet been proved broadly effective in replicated controlled clinical trials. Disulfiram appears the most promising, especially for patients with comorbid alcohol abuse. Tricyclic antidepressants such as desipramine and imipramine (but not SSRIs such as fluoxetine) may be of use in patients with milder dependence or with comorbid depression. Anticonvulsants such as topiramate, tiagabine, and phenytoin (but not carbamazepine or gabapentin) show promise in controlled clinical trials and warrant further evaluation. The stimulant maintenance approach also warrants further evaluation using medications with low abuse potential (e.g., modafinil or sustained-release methylphenidate or amphetamine) or perhaps even a slow-onset (e.g., oral or transdermal) form of cocaine itself.
More sophisticated patient–treatment matching could enhance the efficacy of current medications by taking into account both patient characteristics that can influence treatment response (e.g., severity of dependence, withdrawal status, psychiatric comorbidity, or concomitant medications) and characteristics of the psychosocial treatment accompanying the medication (234). For example, a few studies suggest that some medications (e.g., bupropion, L-dopa, SSRIs) that are not effective when used with drug abuse counseling or cognitive–behavioral therapy may be effective when combined with contingency management treatment (8,33,39).
Improved understanding of the neurobiology of dependence should lead to new and more effective medications in the future, possibly by manipulation of the glutamate or endocannabinoid systems or HPA axis or by a pharmacokinetic mechanism. Regardless of which medications show promise in the future, their adoption into clinical practice should be guided by acceptable scientific proof of efficacy and safety, based on data from replicated, well-designed, adequately powered controlled clinical trials. Clinicians should also keep in mind the distinctions between efficacy (treatment works in a research setting in a selected research population getting close attention) and effectiveness (treatment works in a heterogeneous population in a realistic clinical environment) and between a statistically significant and clinically meaningful treatment effect (235).
ACKNOWLEDGMENT
Dr. Gorelick is supported by the Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse.
REFERENCES
1.Substance Abuse and Mental Health Services Administration. Results from the 2011 national survey on drug use and health: summary of national findings, (NSDUH Series H-44, DHHS Publication No. SMA 12-4713). Rockville, MD: Substance Abuse and Mental Health Services Administration, 2012.
2.Compton WM, Dawson DA, Goldstein RB, et al. Crosswalk between DSM-IV dependence and DSM-5 substance use disorders for opioids, cannabis, cocaine and alcohol. Drug Alcohol Depend2013;132:387–390.
3.Substance Abuse and Mental Health Services Administration. Treatment episode data set (TEDS): 2000–2010. state admissions to substance abuse treatment services, DASIS Series: S-63, DHHS Publication No. (SMA) 12-4729. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2012.
4.Knapp WP, Soares BG, Farrel M, et al. Psychosocial interventions for cocaine and psychostimulant amphetamines related disorders. Cochrane Database Syst Rev 2007;(3):CD003023.
5.Lee NK, Rawson RA. A systematic review of cognitive and behavioural therapies for methamphetamine dependence. Drug Alcohol Rev 2008;27:309–317.
6.Dutra L, Stathopoulou G, Basden SL, et al. A meta-analytic review of psychosocial interventions for substance use disorders. Am J Psychiatry 2008;165:179–187.
7.Penberthy J, Ait-Daoud N, Vaughan M, et al. Review of treatment for cocaine dependence. Curr Drug Abuse Rev 2010;3:49–62.
8.Schmitz JM, Mooney ME, Moeller FG, et al. Levodopa pharmacotherapy for cocaine dependence: choosing the optimal behavioral therapy platform. Drug Alcohol Depend 2008;94:142–150.
9.Carroll KM, Kosten TR, Rounsaville BJ. Choosing a behavioral therapy platform for pharmacotherapy of substance users. Drug Alcohol Depend 2004;75:123–134.
10.Gorelick DA, Gardner EL, Xi ZX. Agents in development for the management of cocaine abuse. Drugs 2004;64:1547–1573.
11.Gorelick, DA. Pharmacokinetic strategies for treatment of drug overdose and addiction. Future Med Chem 2012;4:227–243.
12.Howell LL, Kimmel HL. Monoamine transporters and psychostimulant addiction. Biochem Pharmacol 2008;75:196–217.
13.Pani PP, Trogu E, Vecchi S, et al. Antidepressants for cocaine dependence and problematic cocaine use. Cochrane Database Syst Rev 2011;(12):CD002950.
14.Kosten T, Oliveto A, Feingold A, et al. Desipramine and contingency management for cocaine and opioid dependence in buprenorphine maintained patients. Drug Alcohol Depend2003;70:315–325.
15.Kosten T, Sofuoglu M, Poling J, et al. Desipramine treatment for cocaine dependence in buprenorphine- or methadone-treated patients: baseline urine results as predictor of response. Am J Addict2005;14:8–17.
16.Ziedonis DM, Kosten TR. Pharmacotherapy improves treatment outcome in depressed cocaine addicts. J Psychoactive Drugs 1991;23(4):417–425.
17.Arndt IO, McLellan AT, Dorozynsky L, et al. Desipramine treatment for cocaine dependence. J Nerv Ment Dis 1994;182(3):151–156.
18.Khalsa ME, Gawin FH, Rawson R, et al. A desipramine ceiling in cocaine abusers. Problems of Drug Dependence, 1992 (NIDA Research Monograph 132). Rockville, MD: National Institute on Drug Abuse, 1993:18.
19.Brotman AW, Witkie SM, Gelenberg AJ, et al. An open trial of maprotiline for the treatment of cocaine abuse. J Clin Psychopharmacol 1988;8:125–127.
20.Szerman N, Peris L, Mesias B, et al. Reboxetine for the treatment of patients with cocaine dependence disorder. Hum Psychopharmacol 2005;20:189–192.
21.Walsh SL, Middleton LS, Wong CJ, et al. Atomoxetine does not alter cocaine use in cocaine dependent individuals: a double blind randomized trial. Drug Alcohol Depend 2013;130:150–157.
22.Nunes EV, McGrath PJ, Quitkin FM, et al. Imipramine treatment of cocaine abuse: possible boundaries of efficacy. Drug Alcohol Depend 1995;39:185–195.
23.Galloway GP, Newmeyer J, Knapp T, et al. Imipramine for the treatment of cocaine and methamphetamine dependence. J Addict Dis 1994;13:201–216.
24.Specker S, Crosby R, Borden J, et al. Nefazodone in the treatment of females with cocaine abuse. Drug Alcohol Depend 2000;60 (Suppl 1):S179.
25.Passos SR, Camacho LA, Lopes CS, et al. Nefazodone in out-patient treatment of inhaled cocaine dependence: a randomized double-blind placebo-controlled trial. Addiction2005;100:489–494.
26.Ciraulo DA, Sarid-Segal O, Knapp CM, et al. Efficacy screening trials of paroxetine, pentoxifylline, riluzole, pramipexole and venlafaxine in cocaine dependence. Addiction2005;100(Suppl 1):12–22.
27.Zueco Perez PL. Mirtazapine in the treatment of cocaine-dependence in patients with methadone. Actas Esp Psiquiatr 2002;30:337–342.
28.Fischman MW, Foltin RW, Nestadt G, et al. Effects of desipramine maintenance on cocaine self-administration by humans. J Pharmacol Exp Ther 1990;253(2):760–770.
29.Filip M, Frankowska M, Zaniewska M, et al. The serotonergic system and its role in cocaine addiction. Pharmacol Rep 2005;57:685–700.
30.Muller CP, Huston JP. Determining the region-specific contributions of 5-HT receptors to the psychostimulant effects of cocaine. Trends Pharmacol Sci 2006;27:105–112.
31.Winstanley EL, et al. A randomized controlled trial of fluoxetine in the treatment of cocaine dependence among methadone-maintained patients. J Subst Abuse Treat 2011;40: 255–264.
32.Winhusen TM, Somoza EC, Harrer JM, et al. A placebo-controlled screening trial of tiagabine, sertraline and donepezil as cocaine dependence treatments. Addiction 2005;100(Suppl 1):68–77.
33.Moeller FG, Schmitz JM, Steinberg JL, et al. Citalopram combined with behavioral therapy reduces cocaine use: a double-blind, placebo-controlled trial. Am J Drug Alcohol Abuse2007;33:367–378.
34.Brewer C. Treatment of cocaine abuse with monoamine oxidase inhibitors. Br J Psychiatry 1993;163:815–816.
35.Maletzky BM. Phenelzine as a stimulant drug antagonist. Int J Addict 1977;12(5):661–665.
36.Golwyn DH. Cocaine abuse treated with phenelzine. Int J Addict 1988;23:897–905.
37.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 Depend2006;85:191–197.
38.Margolin A, Kosten TR, Avants SK, et al. A multicenter trial of bupropion for cocaine dependence in methadone maintained patients. Drug Alcohol Depend 1995;40:125–131.
39.Poling J, Oliveto A, Petry N, et al. Six-month trial of bupropion with contingency management for cocaine dependence in a methadone-maintained population. Arch Gen Psychiatry2006;63:219–228.
40.Cornish JW, Maany I, Fudala PJ, et al. A randomized, double-blind, placebo-controlled study of ritanserin pharmacotherapy for cocaine dependence. Drug Alcohol Depend 2001;61:183–189.
41.Johnson BA, Chen YR, Swann AC, et al. Ritanserin in the treatment of cocaine dependence. Biol Psychiatry 1997;42:932–940.
42.Dackis CA, Gold MS. Pharmacological approaches to cocaine addiction. J Subst Abuse Treat 1985;2:139–145.
43.Gorelick DA. Pharmacological treatment of cocaine addiction. Einstein QJ Biol Med 1999;16:61–69.
44.Pulvirenti L, Koob GF. Lisuride reduces intravenous cocaine self-administration in rats. Pharmacol Biochem Behav 1994;47(4):819–822.
45.Amato L, Minozzi S, Pani PP, et al. Dopamine agonists for the treatment of cocaine dependence. Cochrane Database Syst Rev 2011;(12):CD003352.
46.Gorelick DA, Wilkins JN. Bromocriptine treatment for cocaine addiction: association with plasma prolactin levels. Drug Alcohol Depend 2006;81:189–195.
47.Levin FR, McDowell D, Evans SM, et al. Pergolide mesylate for cocaine abuse: a controlled preliminary trial. Am J Addict 1999;8:120–127.
48.Malcolm R, Herron J, Sutherland SE, et al. Adverse outcomes in a controlled trial of pergolide for cocaine dependence. J Addict Dis 2001;20:81–92.
49.Focchi GR, Leite MC, Andrade AG, et al. Use of dopamine agonist pergolide in outpatient treatment of cocaine dependence. Subst Use Misuse 2005;40:1169–1177.
50.Shoptaw S, Watson DW, Reiber C, et al. Randomized controlled pilot trial of cabergoline, hydergine and levodopa/carbidopa: Los Angeles Cocaine Rapid Efficacy Screening Trial (CREST). Addiction2005;100(Suppl 1):78–90.
51.Meini M, Capovani B, Sbrana A, et al. A pilot open-label trial of ropinirole for cocaine dependence. Am J Addict 2008;17:165–166.
52.Shoptaw S, Kintaudi PC, Charuvastra C, et al. A screening trial of amantadine as a medication for cocaine dependence. Drug Alcohol Depend 2002;66:217–224.
53.Kampman KM, Dackis C, Lynch KG, et al. A double-blind, placebo-controlled trial of amantadine, propranolol, and their combination for the treatment of cocaine dependence in patients with severe cocaine withdrawal symptoms. Drug Alcohol Depend 2006;85:129–137.
54.Mooney ME, Schmitz JM, Moeller FG, et al. Safety, tolerability and efficacy of levodopa-carbidopa treatment for cocaine dependence: two double-blind, randomized, clinical trials. Drug Alcohol Depend2007;88:214–223.
55.Cold JA. NeuRecover-DA in the treatment of cocaine withdrawal and craving, a pilot study. Clin Drug Investig 1996;12:1–7.
56.Galloway GP, Frederick SL, Thomas S, et al. A historically controlled trial of tyrosine for cocaine dependence. J Psychoactive Drugs 1996;28:305–309.
57.Thomas HM, Campbell J, Laster L, et al. Efficacy of two doses of tyrosine in retaining crack cocaine abusers in outpatient treatment. Prob Drug Depend 1995 (NIDA Research Monograph 162) Rockville, MD: National Institute on Drug Abuse, 1996:148.
58.Gaval-Cruz M and Weinshenker D. Mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse. Mol Interv 2009;9:175–187.
59.Pani PP, Trogu E, Vacca R, et al. Disulfiram for the treatment of cocaine dependence. Cochrane Database Syst Rev 2010;CD007024.
60.Kosten TR, Wu G, Huang W, et al. Pharmacogenetic randomized trial for cocaine abuse: disulfiram and dopamine-β-hydroxylase. Biol Psychiatry 2013;73:219–224.
61.Oliveto A, Poling J, Mancino MJ, et al. Randomized, double blind, placebo-controlled trials of disulfiram for the treatment of cocaine dependence in methadone-stabilized patients. Drug Alcohol Depend2011;113:184–191.
62.Carroll KM, Nich C, Shi JM, et al. Efficacy of disulfiram and Twelve Step Facilitation in cocaine-dependent individuals maintained on methadone: a randomized placebo-controlled trial. Drug Alcohol Depend2012;126:224–231.
63.Spellicy CJ, Kosten TR, Hamon SC, et al. ANKK1 and DRD2 pharmacogenetics of disulfiram treatment for cocaine abuse. Pharmacogenet Genomics 2013;23:333–340.
64.Shorter D, Nielsen DA, Huang W, et al. Pharmacogenetic randomized trial for cocaine abuse: disulfiram and α1A-adrenoreceptor gene variation. Eur Neuropsychopharmacol2013;23:1401–1407.
65.Malcolm R, Olive MF, Lechner W. The safety of disulfiram for the treatment of alcohol and cocaine dependence in randomized clinical trials: guidance for clinical practice. Expert Opin Drug Saf 2008;7:459–472.
66.Baker J, Jatlow P, Pade P, et al. Acute cocaine responses following cocaethylene infusion. Am J Drug Alcohol Abuse 2007;33:619–625.
67.Roache JD, Kahn R, Newton TF, et al. A double-blind, placebo-controlled assessment of the safety of potential interactions between intravenous cocaine, ethanol, and oral disulfiram. Drug Alcohol Depend2011;119:37–45.
68.Shearer J. The principles of agonist pharmacotherapy for psychostimulant dependence. Drug Alcohol Rev 2008;27:301–308.
69.Lile JA. Pharmacological determinants of the reinforcing effects of psychostimulants: relation to agonist substitution treatment. Exp Clin Psychopharmacol 2006;14:20–33.
70.Mariani JJ, Levin FR. Psychostimulant treatment of cocaine dependence. Psychiatr Clin North Am 2012;35:425–439.
71.Schmitz JM, Rathnayaka N, Green CE, et al. Combination of modafinil and d-amphetamine for the treatment of cocaine dependence: a preliminary investigation. Front Psychiatry2012;3:77.
72.Kosten TR, Steinberg M, Diakogiannis IA. Crossover trial of mazindol for cocaine dependence. Am J Addict 1993;2:161.
73.Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry 2006;67:554–566.
74.Dackis CA, Kampman KM, Lynch KG, et al. A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology 2005;30:205–211.
75.Anderson AL, Reid MS, Li SH, et al. Modafinil for the treatment of cocaine dependence. Drug Alcohol Depend 2009;104:133–139.
76.O’Brien CP, Dackis CA, Kampman K. Does modafinil produce euphoria? Am J Psychiatry 2006;163:1109.
77.Malcolm R, Swayngim K, Donovan J, et al. Modafinil and cocaine interactions. Am J Drug Alcohol Abuse 2006;32:577–587.
78.Donovan JL, DeVane CL, Malcolm RJ, et al. Modafinil influences the pharmacokinetics of intravenous cocaine in healthy cocaine-dependent volunteers. Clin Pharmacokinet2005;44:753–765.
79.Gorelick DA. The rate hypothesis and agonist substitution approaches to cocaine abuse treatment. Adv Pharmacol 1998;42:995–997.
80.Walsh SL, Haberny KA, Bigelow GE. Modulation of intravenous cocaine effects by chronic oral cocaine in humans. Psychopharmacology (Berl) 2000;150:361–373.
81.Llosa T, Llosa L. Oral cocaine as agonist therapy in cocaine dependence. Presented at College on Problems of Drug Dependence Annual Meeting, Orlando, FL June 2005.
82.Hurtado-Gumucio J. Coca leaf chewing as therapy for cocaine maintenance. Ann Med Interne (Paris) 2000;151(Suppl B):B44–B48.
83.Brady K, Anton R, Ballenger JC, et al. Cocaine abuse among schizophrenic patients. Am J Psychiatry 1990;147:1164–1167.
84.Farren CK, Hameedi FA, Rosen MA, et al. Significant interaction between clozapine and cocaine self-administration by humans. Drug Alcohol Depend 2000;59:153–163.
85.Ohuoha DC, Maxwell JA, Thomson LE 3rd, et al. Effect of dopamine receptor antagonists on cocaine subjective effects: a naturalistic case study. J Subst Abuse Treat 1997;14:249–258.
86.Amato L, Minozzi S, Pani PP, et al. Antipsychotic medications for cocaine dependence. Cochrane Database Syst Rev 2007;(3):CD006306.
87.Bano MD, Mico JA, Agujetas M, et al. Olanzapine efficacy in the treatment of cocaine abuse in methadone maintenance patients. Interaction with plasma levels. Actas Esp Psiquiatr2001;29:215–220.
88.Hamilton JD, Nguyen QX, Gerber RM, et al. Olanzapine in cocaine dependence: a double-blind, placebo-controlled trial. Am J Addict 2009;18:48–52.
89.Reid MS, Casadonte P, Baker S, et al. A placebo-controlled screening trial of olanzapine, valproate, and coenzyme Q10/L-carnitine for the treatment of cocaine dependence. Addiction2005;100(Suppl 1):43–57.
90.Grabowski J, Rhoades H, Silverman P, et al. Risperidone for the treatment of cocaine dependence: randomized, double-blind trial. J Clin Psychopharmacol 2000;20:305–310.
91.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;29:969–981.
92.Loebl T, Angarita GA, Pachas GN, et al. A randomized, double-blind, placebo-controlled trial of long-acting risperidone in cocaine-dependent men. J Clin Psychiatry 2008;69:480–486.
93.Akpaffiong MJ, Ruiz P. Neuroleptic malignant syndrome: a complication of neuroleptics and cocaine abuse. Psychiatr Q 1991;62:299–309.
94.Decker KP, Ries RK. Differential diagnosis and psychopharmacology of dual disorders. Psychiatr Clin North Am 1993;16(4):703–718.
95.van Harten PN, van Trier JC, Horwitz EH, et al. Cocaine as a risk factor for neuroleptic-induced acute dystonia. J Clin Psychiatry 1998;59:128–130.
96.Henderson JB, Labbate L, Worley M. A case of acute dystonia after single dose of aripiprazole in a man with cocaine dependence. Am J Addict 2007;16:244.
97.Duggal HS. Cocaine use as a risk factor for ziprasidone-induced acute dystonia. Gen Hosp Psychiatry 2007;29:278–279.
98.Kalivas PW. Neurobiology of cocaine addiction: implications for new pharmacotherapy. Am J Addict 2007;16:71–78.
99.Brown RM, Kupchik YM, Kalivas PW. The story of glutamate in drug addiction and of N-acetylcysteine as a potential pharmacotherapy. JAMA Psychiatry 2013;70:895–897.
100.Karila L, Gorelick D, Weinstein A, et al. New treatments for cocaine dependence: a focused review. Int J Neuropsychopharmacol 2008;11:425–438.
101.Minozzi S, Amato L, Davoli M, et al. Anticonvulsants for cocaine dependence. Cochrane Database Syst Rev 2008;(2):CD006754.
102.Berger SP, Winhusen TM, Somoza EC, et al. A medication screening trial evaluation of reserpine, gabapentin and lamotrigine pharmacotherapy of cocaine dependence. Addiction2005;100(Suppl 1): 58–67.
103.Bisaga A, Aharonovich E, Garawi F, et al. A randomized placebo-controlled trial of gabapentin for cocaine dependence. Drug Alcohol Depend 2006;81:267–274.
104.Gonzalez G, Desai R, Sofuoglu M, et al. Clinical efficacy of gabapentin versus tiagabine for reducing cocaine use among cocaine dependent methadone-treated patients. Drug Alcohol Depend 2007;87:1–9.
105.Gonzalez G, Sevarino K, Sofuoglu M, et al. Tiagabine increases cocaine-free urines in cocaine-dependent methadone-treated patients: results of a randomized pilot study. Addiction2003;98:1625–1632.
106.Winhusen T, Somoza E, Ciraulo DA, et al. A double-blind, placebo-controlled trial of tiagabine for the treatment of cocaine dependence. Drug Alcohol Depend 2007;91:141–148.
107.Kampman KM, Pettinati H, Lynch KG, et al. A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Depend 2004;75:233–240.
108.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 Psychiatry2009;166:1269–1277.
109.Somoza EC, Winship D, Gorodetsky CW, et al. A multi-site, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of vigabatrin for treating cocaine dependence. JAMA Psychiatry2013;70(6):630–637.
110.Crosby RD, Pearson VL, Eller C, et al. Phenytoin in the treatment of cocaine abuse: a double-blind study. Clin Pharmacol Ther 1996;59:458–468.
111.Shoptaw S, Yang X, Rotheram-Fuller EJ, et al. Randomized placebo-controlled trial of baclofen for cocaine dependence: preliminary effects for individuals with chronic patterns of cocaine use. J Clin Psychiatry 2003;64:1440–1448.
112.Blum K, Allison D, Trachtenberg MC, et al. Reduction of both drug hunger and withdrawal against advice rate of cocaine abusers in a 30-day inpatient treatment program by the neuronutrient tropamine. Curr Ther Res 1988;43:1204–1214.
113.Chadwick MJ, Gregory DL. A double-blind amino acids, L-tryptophan and L-tyrosine, and placebo study with cocaine-dependent subjects in an inpatient chemical dependency treatment center. Am J Drug Alcohol Abuse 1990;16:275–286.
114.Jones HE, Johnson RE, Bigelow GE, et al. Safety and efficacy of L-tryptophan and behavioral incentives for treatment of cocaine dependence: a randomized clinical trial. Am J Addict2004;13:421–437.
115.Margolin A, Kantak K, Copenhaver M, et al. A preliminary, controlled investigation of magnesium L-aspartate hydrochloride for illicit cocaine and opiate use in methadone-maintained patients. J Addict Dis2003;22:49–61.
116.Szumlinski KK, Maisonneuve IM, Glick SD. Iboga interactions with psychomotor stimulants: panacea in the paradox? Toxicon 2001;39:75–86.
117.Kampman K, Majewska MD, Tourian K, et al. A pilot trial of piracetam and ginkgo biloba for the treatment of cocaine dependence. Addict Behav 2003;28:437–448.
118.Malcolm R, LaRowe S, Cochran K, et al. A controlled trial of amlodipine for cocaine dependence: a negative report. J Subst Abuse Treat 2005;28:197–204.
119.Johnson BA, Roache JD, Daoud N, et al. A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of cocaine dependence. Drug Alcohol Depend 2006;84:256–263.
120.Plebani JG, Lynch KG, Yu Q, et al. Results of an initial clinical trial of varenicline for the treatment of cocaine dependence. Drug Alcohol Depend 2012;121:163-166.
121.Schmitz JM, Stotts AL, Rhoades HM, et al. Naltrexone and relapse prevention treatment for cocaine-dependent patients. Addict Behav 2001;26:167–180.
122.Shorter D, Lindsay JA, Kosten TR. The alpha-1 adrenergic antagonist doxazosin for treatment of cocaine dependence: a pilot study. Drug Alcohol Depend 2013;131:66–70.
123.Reid MS, Angrist B, Baker SA, et al. A placebo controlled, double-blind study of mecamylamine treatment for cocaine dependence in patients enrolled in an opiate replacement program. J Subst Abuse2005;26:5–14.
124.Sofuoglu M, Carroll KM. Effects of galantamine on cocaine use in chronic cocaine users. Am J Addict 2011;20:302–303.
125.Winhusen T, Somoza E, Sarid-Segal O, et al. A double-blind, placebo-controlled trial of reserpine for the treatment of cocaine dependence. Drug Alcohol Depend 2007;91:205–212.
126.Bisaga A, Aharonovich E, Cheng WY, et al. A placebo-controlled trial of memantine for cocaine dependence with high-value voucher incentives during a pre-randomization lead-in period. Drug Alcohol Depend 2010;111:97–104.
127.LaRowe SD, Kalivas PW, Nicholas JS, et al. A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence. Am J Addict 2013;22(5):443–452.
128.Reid MS, Angrist B, Baker S, et al. A placebo-controlled screening trial of celecoxib for the treatment of cocaine dependence. Addiction 2005;100(Suppl 1):32–42.
129.Nunes EV, McGrath PJ, Wager S, et al. Lithium treatment for cocaine abusers with bipolar spectrum disorders. Am J Psychiatry 1990;147(5):655–657.
130.Licata SC, Penetar DM, Ravichandran C, et al. Effects of daily treatment with citicoline: a double-blind, placebo-controlled study in cocaine-dependent volunteers. J Addict Med2011;5:57–64.
131.Shoptaw S, Majewska MD, Wilkins J, et al. Participants receiving dehydroepiandrosterone during treatment for cocaine dependence show high rates of cocaine use in a placebo-controlled pilot study. Exp Clin Psychopharmacol 2004;12:126–135.
132.Montoya ID, Preston K, Rothman R, et al. Open-label pilot study of bupropion plus bromocriptine for treatment of cocaine dependence. Am J Drug Alcohol Abuse 2002;28:1–8.
133.Malcolm R, Moore JA, Brady KT, et al. Pergolide/haloperidol for the treatment of cocaine dependence. Problems of Drug Dependence, 1999 (NIDA Research Monograph 180). Rockville, MD: National Institute on Drug Abuse, 1999:165.
134.Mariani J, Pavlicova M, Bisaga A, et al. Extended-release mixed amphetamine salts and topiramate for cocaine dependence: a randomized controlled trial. Biol Psychiatry 2012;72:950–956.
135.Kablinger AS, Lindner MA, Casso S, et al. Effects of the combination of metyrapone and oxazepam on cocaine craving and taking: a double-blind, randomized, placebo-controlled study. J Psychopharmacol2012;26:973–981.
136.Kampman KM, Rukstalis M, Pettinati H, et al. The combination of phentermine and fenfluramine reduced cocaine withdrawal symptoms in an open trial. J Subst Abuse Treat2000;19:77–79.
137.Connolly HM, McGoon MD. Obesity drugs and the heart. Curr Probl Cardiol 1999;24:745–792.
138.Margolin A. Acupuncture for substance abuse. Curr Psychiatry Rep 2003;5:333–339.
139.Gates S, Smith LA, Foxcroft DR. Auricular acupuncture for cocaine dependence. Cochrane Database Syst Rev 2006;(1):CD005192.
140.Mills EJ, Wu P, Gagnier J, et al. Efficacy of acupuncture for cocaine dependence: a systematic review and meta-analysis. Harm Reduction J 2005;2:4.
141.Bellamoli E, Manganotti P, Schwartz RP, et al. rTMS in the treatment of drug addiction: an update about human studies. Behav Neurol 2013;in press.
142.Camprodon JA, Martinez-Raga J, Alonso M, et al. One session of high frequency repetitive transcranial magnetic stimulation (rTMS) to the right prefrontal cortex transiently reduces cocaine craving. Drug Alcohol Depend 2007;86:91–94.
143.Politi E, Fauci E, Santoro A, et al. Daily sessions of transcranial magnetic stimulation to the left prefrontal cortex gradually reduce cocaine craving. Am J Addict 2008;17:345–346.
144.Ciketic S, Hayatbakhsh MR, Doran CM, et al. A review of psychological and pharmacological treatment options for methamphetamine dependence. J Subst Abuse 2012;17:363–383.
145.Hill KP, Sofuoglu M. Biological treatments for amphetamine dependence: recent progress. CNS Drugs 2007;21:851–869.
146.Longo M, Wickes W, Smout M, et al. Randomized controlled trial of dexamphetamine maintenance for the treatment of methamphetamine dependence. Addiction 2009;105:146–154.
147.Galloway GP, Buscemi R, Coyle JR, et al. A randomized, placebo-controlled trial of sustained-release dextroamphetamine for treatment of methamphetamine addiction. Clin Pharmacol Ther 2011:89:276–282.
148.Tiihonen J, Kuoppasalmi K, Fohr J, et al. A comparison of aripiprazole, methylphenidate, and placebo for amphetamine dependence. Am J Psychiatry 2007;164:160–162.
149.Shearer J, Darke S, Rodgers C, et al. A double-blind, placebo-controlled trial of modafinil (200 mg/day) for methamphetamine dependence. Addiction 2009;104:224–233.
150.Heinzerling KG, Swanson A-N, Kim S, et al. Randomized, double-blind, placebo-controlled trial of modafinil for the treatment of methamphetamine dependence. Drug Alcohol Depend2010;109:20–29.
151.Anderson AL, Li SH, Biswas K, et al. Modafinil for the treatment of methamphetamine dependence. Drug Alcohol Depend 2012;120:135–141.
152.Tiihonen J, Krupitsky E, Verbitskaya E, et al. Naltrexone implant for the treatment of polydrug dependence: a randomized controlled trial. Am J Psychiatry 2012;169:531–536.
153.Jayaram-Lindstrom N, Hammarberg A, Beck O, et al. Naltrexone for the treatment of amphetamine dependence: A randomized placebo-controlled trial. Am J Psychiatry 2008;165:11: 1442–1448.
154.Grant JE, Odlaug BL, Kim SW. A double-blind, placebo-controlled study of N-acetylcysteine plus naltrexone for methamphetamine dependence. Eur Neuropsychopharmacol2010;20:823–828.
155.Heinzerling KG, Shoptaw S, Peck JA, et al. Randomized, placebo-controlled trial of baclofen and gabapentin for the treatment of methamphetamine dependence. Drug Alcohol Depend2006;85:177–184.
156.Colfax GN, Santos G-M, Das M, et al. Mirtazapine to reduce methamphetamine use: a randomized controlled trial. Arch Gen Psychiatry 2011;68:1168–1175.
157.Brensilver M, Heinzerling KG, Swanson A-N, et al. A retrospective analysis of two randomized trials of bupropion for methamphetamine dependence: suggested guidelines for treatment discontinuation/ augmentation. Drug Alcohol Depend 2012;125:169–172.
158.Das M, Santos D, Matheson T, et al. Feasibility and acceptability of a phase II randomized pharmacologic intervention for methamphetamine dependence in high-risk men who have sex with men. AIDS2010;24:991–1000.
159.Meredith CW, Jaffe C, Yanasak E, et al. An open-label pilot study of risperidone in the treatment of methamphetamine dependence. J Psychoactive Drugs 2007;39:167–172.
160.Meredith CW, Jaffe C, Cherrier M, et al. Open trial of injectable risperidone for methamphetamine dependence. J Addict Med 2009;3:55–65.
161.Zorick T, Sugar CA, Hellemann G, et al. Poor response to sertraline in methamphetamine dependence is associated with sustained craving for methamphetamine. Drug Alcohol Depend2011;118:500–503.
162.Johnson BA, Ait-Daoud N, Elkashef AM, et al. A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of methamphetamine dependence. Int J Neuropsychopharmacol 2008;11:1–14.
163.Leri F, Bruneau J, Stewart J. Understanding polydrug use: review of heroin and cocaine co-use. Addiction 2003;98:7–22.
164.Dobler-Mikola A, Hattenschwiler J, Meili D, et al. Patterns of heroin, cocaine, and alcohol abuse during long-term methadone maintenance treatment. J Subst Abuse Treat 2005;29:259–265.
165.Tennant F, Shannon J. Cocaine abuse in methadone maintenance patients is associated with low serum methadone concentrations. J Addict Dis 1995;14:67–74.
166.Peles E, Kreek MJ, Kellogg S, et al. High methadone dose significantly reduces cocaine use in methadone maintenance treatment (MMT) patients. J Addict Dis 2006;25:43–50.
167.Grabowski J, Rhoades H, Elk R, et al. Methadone dosage, cocaine, and opiate abuse. Am J Psychiatry 1993;150(4):675.
168.Stine SM, Freeman M, Burns B. Effect of methadone dose on cocaine abuse in a methadone program. Am J Addict 1992;1(4): 294–303.
169.Mattick RP, Kimber J, Breen C, et al. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2008:(2);CD002207.
170.Schottenfeld R, Pakes J, Ziedonis D, et al. Buprenorphine: dose-related effects on cocaine and opioid use in cocaine-abusing opioid-dependent humans. Biol Psychiatry 1993;34:66–74.
171.Montoya ID, Gorelick DA, Preston KL, et al. Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence. Clin Pharmacol Ther 2004;75:34–48.
172.Schottenfeld RS, Chawarski MC, Pakes JR, et al. Methadone versus buprenorphine with contingency management or performance feedback for cocaine and opioid dependence. Am J Psychiatry2005;162:340–349.
173.Gross A, Marsch LA, Badger GJ, et al. A comparison between low-magnitude voucher and buprenorphine medication contingencies in promoting abstinence from opioids and cocaine. Exp Clin Psychopharmacol 2006;14:148–156.
174.Gorelick DA. Alcohol and cocaine: clinical and pharmacological interactions. Recent Dev Alcohol 1992;11:37–56.
175.Carroll KM, Nich C, Ball SA, et al. Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction 1998;93:713–728.
176.Pennings EJ, Leccese AP, Wolff FA. Effects of concurrent use of alcohol and cocaine. Addiction 2002;97:773–783.
177.Carroll KM, Nich C, Ball SA, et al. One-year follow-up of disulfiram and psychotherapy for cocaine-alcohol users: sustained effects of treatment. Addiction 2000;95:1335–1349.
178.Higgins ST, Budney AJ, Bickel WK, et al. Disulfiram therapy in patients abusing cocaine and alcohol. Am J Psychiatry 1993;150(4):675–676.
179.Grassi MC, Cioce AM, Giudici FD, et al. Short-term efficacy of disulfiram or naltrexone in reducing positive urinalysis for both cocaine and cocaethylene in cocaine abusers: a pilot study. Pharmacol Res2007;55:117–121.
180.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 Behav2008;33:651–667.
181.Oslin DW, Pettinati HM, Volpicelli JR, et al. The effects of naltrexone on alcohol and cocaine use in dually addicted patients. J Subst Abuse Treat 1999;16:163–167.
182.Pettinati HM, Kampman KM, Lynch KG, et al. Gender differences with high-dose naltrexone in patients with co-occurring cocaine and alcohol dependence. J Subst Abuse Treat2008;34:378–390.
183.Carroll KM, Ziedonis D, O’Malley S, et al. Pharmacologic interventions for alcohol- and cocaine-abusing individuals. Am J Addict 1993;2(1):77–79.
184.Hersh D, Van Kirk JR, Kranzler HR. Naltrexone treatment of comorbid alcohol and cocaine use disorders. Psychopharmacology (Berl) 1998;139:44–52.
185.Schmitz JM, Stotts AL, Sayre SL, et al. Treatment of cocaine-alcohol dependence with naltrexone and relapse prevention therapy. Am J Addict 2004;13:333–341.
186.Schmitz JM, Lindsay JA, Green CE, et al. High-dose naltrexone therapy for cocaine-alcohol dependence. Am J Addict 2009;18:356–362.
187.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 Depend2013;133(1):94–99.
188.Rounsaville BJ, Anton SF, Carroll K, et al. Psychiatric diagnoses of treatment-seeking cocaine abusers. Arch Gen Psychiatry 1991;48:43–51.
189.Conway KP, Compton W, Stinson FS, et al. Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 2006;67:247–257.
190.Weiss RD, Mirin SM, Griffin ML, et al. Personality disorders in cocaine dependence. Compr Psychiatry 1993;34:145–149.
191.Compton WM, Conway KP, Stinson FS, et al. Prevalence, correlates, and comorbidity of DSM-IV antisocial personality syndromes and alcohol and specific drug use disorders in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 2005;66:677–685.
192.Rounsaville BJ. Treatment of cocaine dependence and depression. BiolPsychiatry 2004;56:803–809.
193.Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA 2004;291:1887–1896.
194.Gonzalez G, Feingold A, Oliveto A, et al. Comorbid major depressive disorder as a prognostic factor in cocaine-abusing buprenorphine-maintained patients treated with desipramine and contingency management. Am J Drug Alcohol Abuse 2003;29:497–514.
195.McDowell D, Nunes EV, Seracini AM, et al. Desipramine treatment of cocaine-dependent patients with depression: a placebo-controlled trial. Drug Alcohol Depend 2005;80:209–221.
196.Afshar M, Knapp CM, Sarid-Segal O, et al. The efficacy of mirtazapine in the treatment of cocaine dependence with comorbid depression. Am J Drug Alcohol Abuse 2012;38:181–186.
197.Raby WN, Rubin EA, Garawi F, et al. A randomized, double-blind, placebo-controlled trial of venlafaxine for the treatment of depressed cocaine-dependent patients. Am J Addict2013;108(6):1084–1094.
198.Ciraulo DA, Knapp C, Rotrosen J, et al. Nefazodone treatment of cocaine dependence with comorbid depressive symptoms. Addiction 2005;100(Suppl 1):23–31.
199.Goldberg JF, Garno JL, Leon AC, et al. A history of substance abuse complicates remission from acute mania in bipolar disorder. J Clin Psychiatry 1999;60:733–740.
200.Brown ES, Nejtek VA, Perantie DC, et al. Quetiapine in bipolar disorder and cocaine dependence. Bipolar Disord 2002;4:406–411.
201.Nejtek VA, Avila M, Chen LA, et al. Do atypical antipsychotics effectively treat co-occurring bipolar disorder and stimulant dependence? A randomized, double-blind trial. J Clin Psychiatry 2008;69(8):e1–e10.
202.Brown ES, Jeffress J, Liggin JD, et al. Switching outpatients with bipolar or schizoaffective disorders and substance abuse from their current antipsychotic to aripiprazole. J Clin Psychiatry 2005;66:756–760.
203.Brown ES. A randomized, placebo-controlled trial of citicoline add-on therapy in outpatients with bipolar disorder and cocaine dependence. Biol Psychiatry 2007;61:565.
204.Schubiner H. Substance abuse in patients with attention-deficit hyperactivity disorder: therapeutic implications. CNS Drugs 2005;19:643–655.
205.Kollins SH. A qualitative review of issues arising in the use of psychostimulant medications in patients with ADHD and co-morbid substance use disorders. Curr Med Res Opin2008;24:1345–1357.
206.Castaneda R, Levy R, Hardy M, et al. Long-acting stimulants for the treatment of attention-deficit disorder in cocaine-dependent adults. Psychiatr Serv 2000;51:169–171.
207.Downey KK, Schubiner H, Schuster CR. Double-blind placebo controlled stimulant trial for cocaine-dependent ADHD adults. Prob Drug Depend, 1999 (NIDA Research Monograph 180). Rockville, MD: National Institute on Drug Abuse, 1999:116.
208.Levin FR, Evans SM, McDowell DM, et al. Methylphenidate treatment for cocaine abusers with adult attention-deficit/ hyperactivity disorder: a pilot study. J Clin Psychiatry 1998; 59:300–305.
209.Levin FR, Evans SM, Brooks DJ, et al. Treatment of methadone-maintained patients with adult ADHD: double-blind comparison of methylphenidate, bupropion and placebo. Drug Alcohol Depend2006;81:137–148.
210.Levin FR, Evans SM, Brooks DJ, et al. Treatment of cocaine dependent treatment seekers with adult ADHD: double-blind comparison of methylphenidate and placebo. Drug Alcohol Depend 2007;87:20–29.
211.Schubiner H, Saules KK, Arfken CL, et al. Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp Clin Psychopharmacol2002;10:286–294.
212.Levin FR, Mariani JJ, Secora A, et al. Atomoxetine treatment for cocaine abuse and adult attention-deficit hyperactivity disorder (ADHD): a preliminary open trial. J Dual Diagn2009;5:41–56.
213.Buckley PF. Prevalence and consequences of the dual diagnosis of substance abuse and severe mental illness. J Clin Psychiatry 2006;67(Suppl 7):5–9.
214.Green AI. Treatment of schizophrenia and comorbid substance abuse: pharmacologic approaches. J Clin Psychiatry 2006;67(Suppl 7):31–35.
215.San L, Arranz B, Martinez-Raga J. Antipsychotic drug treatment of schizophrenic patients with substance abuse disorders. Eur Addict Res 2007;13:230–243.
216.Soyka M & De Vry J. Flupenthixol as a potential pharmacotreatment of alcohol and cocaine abuse/dependence. Eur Neuropsychopharmacol 2000;10:325–332.
217.Sayers SL, Campbell EC, Kondrich J, et al. Cocaine abuse in schizophrenic patients treated with olanzapine versus haloperidol. J Nerv Ment Dis 2005;193:379–386.
218.Smelson DA, Ziedonis D, Williams J, et al. The efficacy of olanzapine for decreasing cue-elicited craving in individuals with schizophrenia and cocaine dependence: a preliminary report. J Clin Psychopharmacol 2006;26:9–12.
219.Akerele E, Levin FR. Comparison of olanzapine to risperidone in substance-abusing individuals with schizophrenia. Am J Addict 2007;16:260–268.
220.Sullivan LE, Bruce RD, Haltiwanger D, et al. Initial strategies for integrating buprenorphine into HIV care settings in the United States. Clin Infect Dis 2006;43(Suppl 4):S191–S196.
221.Carrieri MP, Vlahov D, Dellamonica P, et al. Use of buprenorphine in HIV-infected injection drug users: negligible impact on virologic response to HAART. The Manif-2000 Study Group. Drug Alcohol Depend 2000;60:51–54.
222.Avants SK, Margolin A, DePhilippis D, et al. A comprehensive pharmacologic-psychosocial treatment program for HIV-seropositive cocaine- and opioid-dependent patients. J Subst Abuse Treat1998;15:261–265.
223.Hogeland GW, Swindells S, McNabb JC, et al. Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects. Clin Pharmacol Ther 2007;81:69–75.
224.Gorelick DA, Montoya ID, Johnson EO. Sociodemographic representation in published studies of cocaine abuse pharmacotherapy. Drug Alcohol Depend 1998;49:89–93.
225.Rayburn WF, Bogenschutz MP. Pharmacotherapy for pregnant women with addictions. Am J Obstet Gynecol 2004;191:1885–1897.
226.Rothman RB, Baumann MH, Prisinzano TE, et al. Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction. Biochem Pharmacol 2008;75:2–16.
227.Heidbreder CA, Newman AH. Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapies for addictions and related disorders. Ann N Y Acad Sci2010;1187:4–34.
228.Rothman RB, Blough BE, Baumann MH. Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions. AAPS J 2007;9:E1–E10.
229.Specio SE, Wee S, O’Dell LE, et al. CRF(1) receptor antagonists attenuate escalated cocaine self-administration in rats. Psychopharmacology (Berl) 2008;196:473–482.
230.Parolaro D, Rubino T. The role of the endogenous cannabinoid system in drug addiction. Drug News Perspect 2008;21:149–157.
231.Wiskerke J, Pattij T, Schoffelmeer ANM, et al. The role of CB1 receptors in psychostimulant addiction. Addict Biol 2008;13:225–238.
232.Le Foll B, Gorelick DA, Goldberg SR. The future of endocannabinoid-oriented clinical research after CB1 antagonists. Psychopharmacology (Berl) 2009;205:171–174.
233.Martell BA, Orson FM, Poling J, et al. Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients. Arch Gen Psychiatry 2009;66:1116–1123.
234.Carroll KM, Rounsaville BJ, Gordon LT, et al. Psychotherapy and pharmacotherapy for ambulatory cocaine abusers. Arch Gen Psychiatry 1994;51:177–187.
235.Miller WR, Manuel JK. How large must a treatment effect be before it matters to practitioners? An estimation method and demonstration. Drug Alcohol Rev 2008:1–5.
236.Elkashef A, Kahn R, Yu E, et al. Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial. Addiction 2012;107:1297–1306.
237.Thevos AK, Brady KT, Grice D, et al. A comparison of psychopathy in cocaine and alcohol dependence. Am J Addict 1993;2:279–286.
238.Brown ES, Suppes T, Adinoff B, et al. Drug abuse and bipolar disorder: comorbidity or misdiagnosis? J Affect Disord 2001;65:105–115.
239.Sattar SP, Petty F. Valproate in the treatment of bipolar disorder and co-morbid substance abuse: a 24-week open label trial. Am J Addict 2008;17:329.
240.Salloum IM, Douaihy A, Cornelius JR, et al. Divalproex utility in bipolar disorder with co-occurring cocaine dependence: a pilot study. Addict Behav 2007;32:410–415.
241.Brown ES, Sunderajan P, Lu LT, et al. A randomized, double-blind, placebo-controlled trial of lamotrigine therapy in bipolar disorder, depressed or mixed phase and cocaine dependence. Neuropsychopharmacology 2012;37:2347–2354.
242.Levin FR, Evans SM, Coomaraswammy S, et al. Flupenthixol treatment for cocaine abusers with schizophrenia: a pilot study. Am J Drug Alcohol Abuse 1998;24:343–360.
243.Helmbrecht GD, Thiagarajah S. Management of addiction disorders in pregnancy. J Addict Med 2008;2(1):1–16.