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CHAPTER OUTLINE
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
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