Novel pharmacotherapeutic treatments for cocaine addiction
© Shorter and Kosten; licensee BioMed Central Ltd. 2011
Received: 28 March 2011
Accepted: 3 November 2011
Published: 3 November 2011
Cocaine is a stimulant that leads to the rapid accumulation of catecholamines and serotonin in the brain due to prevention of their re-uptake into the neuron that released the neurotransmitter. Cocaine dependence is a public health concern and cause of significant morbidity and mortality worldwide. At present, there are no approved medications for the treatment of this devastating illness, and behavioral interventions have proven to be of limited use. However, there have been a number of recent trials testing promising agents including dopamine agonists, GABAergic medications and the cocaine vaccine. Here we discuss the most recent human clinical trials of potential medications for treatment of cocaine dependence, as well as pre-clinical studies for another promising agent, levo tetrahydropalmatine. Examination of these recent findings shows promise for GABAergic medications and the cocaine vaccine, as well as unique medications such as disulfiram, whose mechanism remains to be determined. Future work may also confirm specific subgroups of patients for treatment response based on clinical characteristics, biomarkers and pharmacogenetics. This review highlights the need for further, bigger studies in order to determine optimal clinical usage.
Cocaine is a stimulant that leads to the rapid accumulation of catecholamines and serotonin in the brain due to prevention of their re-uptake into the neuron that released the neurotransmitter. Cocaine use disorders are widely accepted as a significant cause of morbidity and mortality. Cocaine use is associated with numerous acute and chronic medical complications, ranging from coronary syndromes, myocardial infarction, and respiratory disease to neurologic and psychiatric consequences such as cerebral hemorrhage, mood disorders, and psychosis [1, 2]. Additionally, cocaine use has been associated with increased risk of HIV, hepatitis B and C, and violence [3–6].
Development of effective treatments for cocaine dependence is necessary to reduce the impact of this illness upon both the individual and society. These effective treatments need most importantly to reduce cocaine use and to have excellent compliance, which has encouraged depot and other long lasting formulations. Currently, however, there are no US Food and Drug Administration (FDA) approved medications for the treatment of this illness, and behavioral therapies alone have demonstrated limited efficacy . Our growing understanding of cocaine neurobiology has translated into numerous studies of pharmacologic agents for treatment of cocaine dependence in both animal and human models. These models include human laboratory drug administration studies using surrogate endpoints such as craving, subjective effects, and behavioral choices of money versus drug. This article reviews findings from recent cocaine pharmacotherapy clinical trials in humans that target dopamine and gamma-aminobutyric acid (GABA) neurotransmitter systems or uniquely target the cocaine itself through a vaccine preventing cocaine from getting into the brain. Additionally, preclinical studies for a novel medication, levo-tetrahydropalmatine (l-THP) are discussed.
The final common pathway for reward and reinforcement associated with substances of abuse has been extensively shown to result from dopamine release from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), prefrontal cortex (PFC), as well as other structures . The subjective effects and euphoria of cocaine use are attributed to blockade of the dopamine transporter, reuptake inhibition, and increased levels of extracellular dopamine in the mesolimbic and mesocortical pathways. Chronic use of cocaine is associated with relative dopaminergic hypofunctioning and may underlie the withdrawal symptoms and craving observed in cocaine-dependent persons who have recently established abstinence . As a result, dopamine agonists have been studied as potential pharmacotherapeutic options, since they serve to offset neuroadaptive changes associated with chronic use such as decreased dopamine D2 receptor binding  and have been used successfully for the treatment of both opiate and nicotine dependence, highlighting their potential utility for treatment of other forms of substance abuse [11, 12]. Recent trials for dopamine agonists have mainly focused on amphetamine derivatives such as dextroamphetamine (d-amphetamine) and methamphetamine, as well as modafinil and disulfiram.
D-amphetamine has shown mixed results in regards to its ability to attenuate subjective effects [13, 14]. In clinical study oral methamphetamine demonstrated an ability to reduce both craving and cocaine use, as evidenced by a statistically significant increase in the percentage of cocaine-negative urines . Concerns regarding the addictive liability of these agents in persons with a history of substance dependence remain a consideration, particularly since the dependence syndrome (characterized by development of tolerance, withdrawal, and inability to control use) has been clearly established for amphetamines . Overall, slow release formulations with strong diversion resistant formulations would be essential for use of amphetamine as a treatment agent. So far, no such formulation has been developed although a lysine conjugate of amphetamine that has been marketed for treating childhood attention deficit disorder shows some promise. However, these medications have shown some promise and merit further clinical investigation, particularly as cognitive enhancement during early abstinence becomes a more prominent focus in addictions research and these agents may also be helpful in this area.
Modafinil is a novel stimulant-like medication that promotes wakefulness and serves as a treatment for hypersomnia and narcolepsy. The mechanism of action is only partially understood at this time; however, there is evidence that this agent acts as a central alpha-1 adrenergic agonist , reduces basal cerebral GABA activity , and increases both dopamine and glutamate release in select areas of the brain [19, 20]. Chronic cocaine use results in a hypodopaminergic state as well as depletion of both extracellular glutamate levels and glutamatergic synaptic strength in the nucleus accumbens . These neurotransmitter systems serve as the principal targets of modafinil's effects and promising results in human clinical trials for treatment of cocaine dependence have been observed.
The safety of co-administration of modafinil and cocaine was established in a randomized, double blind, placebo-controlled study (N = 10) conducted by Dackis et al. . Modafinil demonstrated no significant exacerbating effects on vital sign measures or electrocardiogram (EKG) findings. As a secondary measure, pretreatment with modafinil at two oral dosages (200 mg and 400 mg, respectively) demonstrated an ability to significantly attenuate euphoria from intravenously administered cocaine in one subjective measure (P = 0.02). Importantly, this early study suggested safety as well as the possibility of a cocaine-blunting effect with modafinil.
In addition to examining the impact of modafinil on the euphorigenic effects of cocaine, early research focused on the similarity of modafinil to stimulant medications in order to assess the extent of its potential abuse liability in both humans and animals [23, 24]. Overall, the perceived risk of abuse associated with this medication has been found to be limited, since modafinil possesses, at most, a weakly reinforcing effect . More recently, a double-blind, randomized, outpatient study (N = 12) conducted in cocaine addicted subjects found that modafinil at three different doses (200 mg, 400 mg, and 600 mg/day, respectively) failed to elicit a reinforcing effect, as the medication was chosen at the same frequency as placebo and was not associated with positive subjective effects .
Recent clinical trials of modafinil in human subjects have highlighted either (1) the medication's impact upon actual cocaine use or (2) its ability to mitigate symptoms associated with cocaine abstinence. The rationale for using this medication relates to its stimulant like properties and potential efficacy as a substitution agent that can reduce craving for cocaine. With regard to its effect upon cocaine use, modafinil was examined in a randomized, double-blind, placebo-controlled study (N = 210) at two doses (200 mg and 400 mg); however, no significant differences were observed between the modafinil and placebo groups in their change in the average weekly percentage of cocaine non-use days . Of note, modafinil 200 mg demonstrated a significant reduction in craving as a secondary outcome. Interestingly, post-hoc analysis also found an increase in cocaine non-use days among those with co-morbid alcohol dependence who were treated with modafinil, suggesting a possible target subgroup among cocaine-addicted persons.
The impact of modafinil on sleep in chronic cocaine users was examined in a randomized, placebo-controlled, inpatient study (N = 20) by Morgan et al. The researchers found that modafanil 400 mg decreased nighttime sleep latency and increased slow-wave sleep time . Additionally, by the third week of abstinence from cocaine, the modafinil group experienced longer total sleep time and shorter rapid eye movement (REM) latency. Ultimately, modafanil demonstrated a normalizing effect on sleep, which could be particularly important during early phases of abstinence since sleep disturbance has been associated with relapse into substance abuse and there are currently no proven pharmacologic treatment options for this form of insomnia . Modafinil continues to represent an area of exciting promise in the pharmacologic management of cocaine dependence, since it appears to have limited reinforcing effects, reduces cocaine craving, decreases cocaine use among sub-populations of cocaine users (that is, those with co-morbid alcohol dependence), and treats symptoms characteristic of the abstinence syndrome.
Disulfiram, an aldehyde dehydrogenase inhibitor as well as a dopamine-beta-hydroxylase (DBH) inhibitor, is approved for treatment of alcohol dependence. Because the DBH enzyme converts dopamine to norepinephrine, its inhibition leads to a decrease in neuronal and synaptic norepinephrine levels relative to dopamine . This neurobiochemical mechanism has been proposed as a potential therapy for cocaine dependence, extensively studied in human clinical trials, and found to result in modulation of the reinforcing properties of cocaine and reduction of cocaine use [30–32]. Most recently, a double-blind, placebo-controlled randomized clinical trial (RCT) of disulfiram for treatment of cocaine dependence in methadone-stabilized individuals showed that in the group receiving 250 mg/day, there was a significant decrease in cocaine-positive urines over time when compared to lower doses of the medication or placebo . Interestingly, lower dosages of the medication (62.5 mg and 125 mg, respectively) were associated with increased self-report of cocaine use as well as cocaine-positive urines. Future study of disulfiram should focus on dosing strategy as well as identification of subpopulations in which the drug is maximally effective.
Nepicastat, a selective DBH-inhibitor that has yet to come to market, is currently under investigation for treatment of cocaine dependence. In preclinical trials, nepicastat has demonstrated an ability to (1) increase synaptic levels of dopamine, (2) decrease brain norepinephrine levels, and (3) block cocaine-induced reinstatement of cocaine seeking in rats without affecting food-primed reinstatement of food seeking . These results suggest similarity between disulfiram and nepicastat in terms of their ability to attenuate responses to drug-related cues and represent an exciting prospect in the pharmacotherapy of cocaine dependence.
In addition to its action at the dopamine transporter, cocaine binds to the norepinephrine transporter (NET) and serotonin transporter (SERT), causing inhibition of presynaptic uptake of these monoamines as well . During acute cocaine intoxication, enhanced dopamine transmission in the nucleus accumbens is accompanied by increased release of serotonin , and there is evidence supporting the contributing role of serotonin to cocaine reward and reinforcement . In the dorsal raphe nucleus, increased extracellular levels of serotonin result in activation of 5-hydroxytryptamine-1a (5HT-1a) autoreceptors and reduce firing of these neurons . Cocaine withdrawal is characterized by serotonin depletion throughout the brain and decreased levels of 5HT in the nucleus accumbens . Interestingly, in rat studies, enhancement of serotonergic transmission in the nucleus accumbens through administration of exogenous 5HT served to offset the dopamine deficit caused by cocaine withdrawal .
Given these interactions, preclinical studies have examined the impact of pharmacologic manipulation of the serotonin system on cocaine effects. Early studies in rats demonstrated that serotonin-enhancing medications were associated with decreased self-administration of cocaine [41, 42]. However, human clinical trials examining the efficacy of serotonergic medications (that is, selective serotonin reuptake inhibitors (SSRI)) in the treatment of cocaine dependence have yielded mixed results [43–46].
The discrepancy between findings from animal and human trials regarding the effect of serotonergic medications might be due to differences in the circumstances leading to reinstatement of cocaine use. In a review by Filip et al., the authors stress that activity at different subtypes of serotonin receptors can have different effects on cocaine use. For example, cocaine-seeking behavior induced by environmental cues (conditioned stimuli) can be modified by serotonergic medications that counteract the 5HT deficit of withdrawal or suppress cocaine-induced changes in this neurotransmitter system .
Moeller et al. tested this particular hypothesis in a recent double-blind, placebo-controlled RCT (N = 76) examining citalopram (20 mg/day) combined with cognitive behavioral therapy (CBT) and contingency management (CM) over 12 weeks in the treatment of cocaine dependence . The subjects in the citalopram group demonstrated a substantial decrease in the number and probability of cocaine positive urine drug screens. As a future direction, the use of behavioral therapy platforms to address response to drug-related cues in conjunction with serotonergic agents may be the necessary adjunct to treatment to improve the efficacy of these medications.
Ibogaine, the primary indole alkaloid found in the root bark of the African shrub, Tabernanthe iboga, has shown promise not only in the treatment of cocaine dependence, but in alcohol, opiate, and methamphetamine dependence as well, representing the first agent that could be beneficial in multiple substance use disorders (SUDs) . The pharmacologic properties of ibogaine have been extensively studied and ibogaine has demonstrated an affinity for a number of receptor sites including opioid (kappa, mu, and delta), N-methyl-d-aspartate (NMDA), sigma (1 and 2), dopamine transporter (DAT), SERT, and nicotinic . The action of this medication at multiple receptor sites in combination has been identified as the predominant factor underlying the putative anti-addictive properties of ibogaine. However, despite general agreement on the sites of activity of this medication, there remain some contradictory findings in regards to the action of ibogaine within the brain. For example, Baumann et al found that ibogaine and noribogaine had little effect on extracellular levels of dopamine in the rat nucleus accumbens, while Glick et al. showed that these agents caused a significant decrease in dopamine levels [51, 52]. These differences may be due to differences in study design, method of administration of ibogaine and/or the gender of the animals. In regards to serotonergic transmission, both ibogaine and noribogaine have been shown to increase extracellular 5HT in the brain .
Regarding its impact on cocaine use, both ibogaine and its active metabolite, noribogaine, have been shown to significantly decrease cocaine self-administration, an effect that persisted in some animals for several days following only a single dose . Although ibogaine is associated with potentially intolerable side effects, such as tremor and impaired coordination, noribogaine does not appear to cause these problems, suggesting this agent may be easier to tolerate .
One focus in clinical trials has been to isolate specific iboga alkaloids, such as 18-methoxycoronaridine (18-MC), in order to test their efficacy in treating chemical dependency with minimal adverse reactions . Importantly, 18-MC has demonstrated an ability to reduce cocaine self administration without apparent toxicity . Of note, 18-MC has also shown an ability to reduce self administration of other drugs of abuse, including morphine, methamphetamine, nicotine, and alcohol . To date, there have been no human clinical trials for treatment of cocaine dependence with iboga alkaloids; however, this class of medications, with enhanced safety profiles, could represent an exciting intervention in the treatment of not only cocaine dependence, but other drug use disorders as well.
There is significant evidence for the involvement of brain GABA systems in perpetuation of the addictive process and the enhancement of GABA activity in addicted individuals is associated with decrease in drug craving and relapse . More specifically, GABA has demonstrated the ability to suppress dopamine release in the striatum, also blunting cocaine-induced release of dopamine in animals. The translation of our understanding of this neurobiology into successful human clinical trials has been somewhat difficult. An additional complicating factor with this class of medications is that given the widespread distribution of the GABAergic system within the central nervous system (CNS), these medications may be associated with various side effects. Recent studies of vigabatrin, baclofen, valproate, and topiramate yield mixed results in their ability to improve outcomes in cocaine-addicted persons.
Vigabatrin, also known as gamma-vinyl-GABA (GVG), is an irreversible inhibitor of GABA transaminase that reduces the breakdown of GABA, thereby increasing its activity within the synapse . In preclinical studies GVG has been shown to reduce cocaine-induced dopamine release by 25% or more in laboratory animals; however, there has also been an association with visual field defects in 1/3 of persons exposed to the medication for extended periods . In a recently published RCT (N = 103), GVG, when compared to placebo, resulted in a higher percentage of subjects achieving and maintaining abstinence from cocaine by the end of the trial (20% of GVG group (n = 50) versus 7.5% of placebo (n = 53)) . Interestingly, participants in the GVG group were also more likely to report abstinence from alcohol by the end of study (43.5% versus 6.3%). Study retention was significantly higher in the GVG group and the medication was well tolerated. Ongoing study of GVG is necessary, particularly given its potential implications for the subpopulation of patients with cocaine dependence and comorbid alcohol abuse/dependence.
Baclofen, a GABA(B) receptor agonist, is used widely as a treatment of spasticity and has demonstrated efficacy in preclinical trials for treatment of cocaine dependence. In various rat studies, baclofen demonstrated the ability to reduce cocaine self-administration [59, 60] and cocaine-induced reinstatement , cocaine-seeking behaviors , and cocaine-induced release of dopamine (DA) in the shell of the nucleus accumbens .
In an earlier double blind, placebo-controlled RCT (N = 70), Shoptaw et al. found that administration of baclofen (20 mg three times a day) resulted in statistically significant reductions in cocaine use when compared to placebo . Although baclofen did not demonstrate a statistically significant impact on cocaine craving, participants were more likely to submit cocaine-negative urine samples between weeks three to eight of treatment. This finding may suggest the possible utility of this medication in those needing assistance with relapse prevention, rather than abstinence initiation. Of note, the authors also examined the impact of the level of cocaine use at baseline on treatment outcome, finding that those with a more severe form of cocaine dependence were more likely to respond to baclofen treatment. A more recent multisite, double-blind RCT assessed the safety and efficacy of 60 mg baclofen treatment for in 160 subjects diagnosed with severe cocaine dependence . The groups (treatment versus placebo) did not differ in terms of treatment retention rates or change in mean weekly percentage of cocaine non-use days. The limited success of baclofen may be due to its use in a population identified as severely cocaine dependent or because it was used to assist with abstinence initiation, rather than relapse prevention. Examination of baclofen in subjects with mild to moderate cocaine dependence or in those who have already established abstinence may yield more promising results.
Valproate, which enhances GABA levels by increasing glutamic acid decarboxylase (GAD) activity and inhibiting GABA transaminase activity, was examined in a RCT, within-subjects, crossover study design meant to assess its effect on cue-induced cocaine craving . Subjects identified as crack cocaine dependent (N = 20) were titrated to 1, 500 mg/day of valproate and subsequently exposed to a series of neutral and cocaine-related cues. Interestingly, under treatment conditions with valproate, participants reported higher craving (that is, 'desire to use now') in response to cue exposure when compared to placebo condition. Due to limited sample size, however, further study of this medication may still be warranted.
Tiagabine, a GABA reuptake inhibitor, has been examined in two recent human clinical trials. In an earlier RCT (N = 141), the group receiving tiagabine (20 mg/day) did not differ significantly from placebo in terms of cocaine craving and global function . Additionally, there was no significant change in cocaine use in either the study or placebo groups. A later study compared the impact of tiagabine versus lorazepam, a benzodiazepine and GABA-enhancing medication, and placebo. The authors found that tiagabine increased slow-wave sleep by three times in those recently establishing abstinence from cocaine use . Importantly, tiagabine did not differ from placebo in regards to impact on cognitive function (that is, vigilance task, measures of impulsivity), while lorazepam was found to cause next-day impairment. There may be a possible indication for tiagabine in the period of early abstinence, since this medication might improve the sleep disturbance characteristic of withdrawal; however, additional study is warranted to determine the extent of its effect upon establishment of abstinence, cocaine craving, and relapse.
The final GABAergic medication to have been recently tested in human clinical study is topiramate which, in addition to potentiation of GABA(A) receptor mediated input, antagonizes glutamatergic afferents to the mesocorticolimbic dopaminergic system . Kampman et al. demonstrated the efficacy of topiramate in the treatment of cocaine dependence in a randomized, double-blind, placebo-controlled RCT (N = 40) . Over the first eight weeks of the study, topiramate was titrated by 25 mg/week to a target dose of 200 mg/day. During that period, topiramate did not demonstrate a statistically significant ability to reduce cocaine use. After week eight, topiramate-treated subjects were more likely to be abstinent from cocaine when compared to placebo, as measured by twice-weekly urine benzoylecgonine test (UBT).
In an open label, outpatient study of cocaine dependent men (N = 28), participants received topiramate, ranging in dose from 25 to 300 mg/day . Interestingly, the only statistically significant finding of the study was a decrease in craving intensity, although this effect was seen in only 25% of participants. Further study of topiramate in a larger, placebo-controlled RCT is necessary in order to determine the extent of this medication's impact upon craving. Also, the addition of genetic analysis into future trials might help to determine underlying differences in subgroups of patients and provide clues regarding differential response patterns.
Levo-tetrahydropalmatine (l-THP), a tetrahydroprotoberberine alkaloid, is one of the primary active agents found in the plant genera Corydalis and Stephania . Two species in particular, Corydalis ambiguo and Stephania tetranda, are included among the 50 fundamental herbs in Chinese traditional medicine and are used for various purposes including treatment of anxious insomnia and chronic pain due to their sedative/hypnotic and analgesic properties, respectively [72, 73]. The mechanism of action of l-THP, elucidated by studies in rats, centers around antagonism of dopamine D1 and D2 receptors  and was further evidenced by its ability to reverse the effects of apomorphine, a known dopamine receptor agonist . Additionally, there is evidence to suggest antagonist activity at D3 receptor sites . In addition to activity in the dopaminergic system, l-THP has shown an ability to act as both an alpha-1 adrenergic receptor antagonist (Mantsch, 2007) and an allosteric modulator of gamma-aminobutyric acid (GABA)A receptors . Interestingly, this agent has a similar effect to modafinil, but acts through a different mechanism.
Taken altogether, the unique neurobiochemical profile of l-THP may translate into an exciting area of promise in the study of pharmacotherapy for cocaine dependence. In rats, l-THP has demonstrated an ability to dose-dependently reduce cocaine self-administration and attenuate cocaine-induced reinstatement under both fixed-ratio  and progressive-ratio scheduling . Further, oral administration of l-THP was found to attenuate cocaine-seeking behavior within various reinstatement paradigms (that is, cocaine, stress, and environmental associated cues) . These findings in animal studies suggest that l-THP may represent an effective future pharmacotherapeutic option in the treatment of cocaine dependence.
Substance abuse vaccines represent an exciting area of promise in the treatment of chemical dependency. The introduction of these agents into our pharmacologic armamentarium represents an important shift in our conceptualization of drug use, since its foundation rests upon the idea of substances of abuse as agents 'foreign' to the body and susceptible to immunologic mechanisms. Currently, clinical trials for vaccines treating both cocaine and nicotine dependence are ongoing, with vaccines for methamphetamine and heroin in preclinical development stages.
The cocaine vaccine, TA-CD, is composed of a cocaine hapten conjugated to inactivated cholera toxin B, resulting in the creation of a molecule capable of stimulating an antibody response . These antibodies are cocaine specific; ingestion of the substance by any means (intranasal, inhalational, intravenous) results in its binding and the creation of immune complexes unable to cross the blood-brain-barrier due to their relatively larger size. These molecules are then broken down by cholinesterases in the circulation, converting the cocaine into inactive metabolites that are then excreted .
In phase I clinical study (N = 34), participants receiving TA-CD were able to mount an immunologic response resulting in the creation of cocaine-specific antibodies . Subjects reported a reduction in the subjective effects and euphoria from smoked cocaine [82, 83].
Similarly positive findings were found during a phase II clinical study of two dose levels (100 ug × 4 injections, or 400 ug × 5 injections). Subjects receiving the higher dose were found to have higher mean antibody levels and were also more likely to remain abstinent at six-month follow-up (relapse in 89% in the low-dose group compared to 43% in the high-dose group) [82, 80].
In the initial phase IIb trial (N = 115), TA-CD was administered to methadone-maintained cocaine-dependent individuals at a single dose (360 ug × 5 injections) in comparison to placebo. Those subjects with high antibody production were found to have a greater percentage of cocaine-free urines . In all phases of testing, the safety profile of the vaccine was favorable, with any serious adverse effects being deemed unrelated to the vaccine. Currently, TA-CD is undergoing large-scale, multisite, phase IIb clinical testing, although there are limitations in these studies including only 40% of the patients attaining fully blocking levels of antibodies. Better adjuvants are clearly needed.
Summary/Future directions of research
These prospects in the pharmacologic management of cocaine dependence have demonstrated in human clinical trials an ability to reduce subjective reward, craving, and withdrawal symptoms associated with cocaine use, however, there is still much progress to be made, before they are viable widespread treatments Of the dopamine agonist medications, although they have been demonstrated to decrease the euphoric, as well as, in some cases, the withdrawal symptoms, concerns regarding the addictive liability of amphetamine-type medications continue to limit the widespread acceptance and use of this treatment. Further, findings in clinical trials of GABAergic medications have been less clear in their demonstration of significant efficacy in treating cocaine dependence. They have shown some ability to reduce cocaine craving or to improve sleep duration and quality in those recently abstaining from cocaine, and cocaine abusers with comorbid alcohol dependence may represent a subpopulation particularly responsive to the effects of GVG. The cocaine vaccine, TA-CD, has demonstrated the ability to elicit an immunologic response capable of reducing the subjective reward of cocaine use in both animals and humans. These results make immunologic treatment of substance use disorders an exciting direction for treatment of not only cocaine dependence, but other substances as well. Finally, findings from preclinical trials for l-THP suggest this medication, already used for centuries as an herbal medication for other disorders, may be helpful in reducing cocaine use.
Examination of these recent findings shows promise for GABAergic medications and the cocaine vaccine, as well as for unique medications such as disulfiram, whose mechanism remains to be determined. Further studies with all of these agents are likely to be worthwhile, although the focus for disulfiram needs to be on its potential mechanism of action such as its inhibition of dopamine beta hydroxylase using more specific agents like nepicastat. Alternatively, the copper chelation caused by disulfiram is being examined using more specific copper chelating compounds that have been developed for Wilson's disease. Alternative agents with fewer side effects are being examined for vigabitrin. Finally, more effective vaccines have been developed in animals using better adjuvants than alum such as squalene or MPL60 as alternatives. Clearly progress has been made in developing new and unique agents and mechanisms of action for reducing cocaine dependence. Specific barriers to developing better treatments are clearly related to the overall challenges of getting industry support and FDA approval when no previous medication has been approved for cocaine dependence. Small companies are working well with the US National Institute on Drug Abuse (NIDA) to develop these therapies, but the larger pharmaceutical industry will be essential partners for the FDA process in bringing any of these treatments to market. Some aspects of cocaine addiction need to be better understood in order to make further progress. In particular, the mechanisms of action relevant to disulfiram's efficacy for cocaine need to be identified in order to develop better, safer, and more specific agents. Furthermore, it is likely that treatment will need to be more tailored for specific subsets of patients. These subsets may be identified through clinical characteristics (severity of dependence based on number of days of month of using cocaine), biomarkers (urine levels of the cocaine metabolite benzoylecognine or having immunoglobulin M (IgM) antibodies to cocaine before first vaccine dose) and pharmacogenetic markers
(functional polymorphisms associated with the gene coding for dopamine beta hydroxylase),
List of abbreviations
cognitive behavioral therapy
central nervous system
US Food and Drug Administration
randomized clinical trial
rapid eye movement
selective serotonin reuptake inhibitors
substance use disorders
urine benzoylecgonine test
ventral tegmental area
Funding was provided by VA SUD-QUERI, DOD, NIH grants K05-DA0454, P50-DA18197
- Devlin RJ, Henry JA: Clinical review: Major consequences of illicit drug consumption. Crit Care. 2008, 12: 202.View ArticlePubMedPubMed CentralGoogle Scholar
- Kaye S, Darke S: Injecting and non-injecting cocaine use in Sydney, Australia: physical and psychological morbidity. Drug Alcohol Rev. 2004, 23: 391-398.View ArticlePubMedGoogle Scholar
- Chaisson RE, Bacchetti P, Osmond D, Brodie B, Sande MA, Moss AR: Cocaine use and HIV infection in intravenous drug users in San Francisco. JAMA. 1989, 261: 561-565.View ArticlePubMedGoogle Scholar
- Chaisson MA, Stoneburner RL, Hildebrandt DS, Ewing WE, Telzak EE, Jaffe HW: Heterosexual transmission of HIV-1 associated with the use of smokeable freebase cocaine (crack). AIDS. 1991, 5: 1121-1126.View ArticleGoogle Scholar
- Estrada AL: Epidemiology of HIV/AIDS, hepatitis B, hepatitis C, and tuberculosis among minority injection drug users. Public Health Rep. 2002, 117 (Suppl 1): S126-134.PubMedPubMed CentralGoogle Scholar
- Carvalho HB, Seibel SD: Crack cocaine use and its relationship with violence and HIV. Clinics (Sao Paulo). 2009, 64: 857-866.Google Scholar
- Simpson DD, Joe GW, Fletcher BW, Hubbard RL, Anglin MD: A national evaluation of treatment outcomes for cocaine dependence. Arch Gen Psych. 1999, 56: 507-514.View ArticleGoogle Scholar
- Koob GF: Neurobiology of addiction. Toward the development of new therapies. Ann N Y Acad Sci. 2000, 909: 170-185.View ArticlePubMedGoogle Scholar
- Kosten TR, George TP, Kosten TA: The potential of dopamine agonists in drug addiction. Expert Opin Investig Drugs. 2002, 11: 491-499.View ArticlePubMedGoogle Scholar
- Volkow ND, Ding YS, Fowler JS, Wang GJ: Cocaine addiction: hypothesis derived from imaging studies with PET. J Addict Dis. 1996, 15: 55-71.View ArticlePubMedGoogle Scholar
- Donny EC, Brasser SM, Bigelow GE, Stitzer ML, Walsh SL: Methadone doses of 100 mg or greater are more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteers. Addiction. 2005, 100: 1496-509.View ArticlePubMedGoogle Scholar
- Silagy C, Lancaster T, Stead L, Mant D, Fowler G: Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2004, CD000146-3
- Rush CR, Stoops WW, Hays LR: Cocaine effects during D-amphetamine maintenance: a human laboratory analysis of safety, tolerability and efficacY. Drug Alcohol Depend. 2009, 99: 261-271.View ArticlePubMedGoogle Scholar
- Rush CR, Stoops WW, Sevak RJ, Hays LR: Cocaine choice in humans during D-amphetamine maintenance. J Clin Psychopharmacol. 2010, 30: 152-159.View ArticlePubMedGoogle Scholar
- Mooney ME, Herin DV, Schmitz JM, Moukaddam N, Green CE, Grabowski J: Effects of oral methamphetamine on cocaine use: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 2009, 101: 34-41.View ArticlePubMedGoogle Scholar
- Darke S, Kaye S, McKetin R, Duflou J: Major physical and psychological harms of methamphetamine use. Drug Alcohol Rev. 2008, 27: 253-262.View ArticlePubMedGoogle Scholar
- Dutell J, Rambert FA, Pessonnier J, Hermant JF, Gombert R, Assous E: Central alpha 1-adrenergic stimulation in relation the behavior stimulating effects of modafinil; studies with experimental animals. Eur J Pharmacol. 1990, 180: 49-58.View ArticleGoogle Scholar
- Tanganelli S, Ferraro L, Bianchi C, Fuxe K: 6-hydroxy-dopamine treatment counteracts the reduction of cortical GABA release produced by the vigilance promoting drug modafinil in the awake freely moving guinea-pig. Neurosci Lett. 1994, 171: 201-204.View ArticlePubMedGoogle Scholar
- Ferraro L, Tanganelli S, O'Connor WT, Antonelli T, Rambert F, Fuxe K: The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism. Eur J Pharmacol. 1996, 306: 33-39.View ArticlePubMedGoogle Scholar
- Ferraro L, Antonelli T, O'Connor WT, Tanganelli S, Rambert F, Fuxe K: The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus. Neuroreport. 1997, 8: 2883-2887.View ArticlePubMedGoogle Scholar
- Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP: A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology. 2005, 30: 205-211.View ArticlePubMedGoogle Scholar
- Dackis CA, Lynch KG, Yu E, Samaha FF, Kampman KM, Cornish JW, Rowan A, Poole S, White L, O'Brien CP: Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study. Drug Alcohol Depend. 2003, 70: 29-37.View ArticlePubMedGoogle Scholar
- Deroche-Gamonet V, Darnaudery M, Bruins-Slot L, Piat F, Le Moal M, Piazza PV: Study of the addictive potential of modafinil in naïve and cocaine-experienced rats. Psychopharmology (Berl). 2002, 161: 387-395.View ArticleGoogle Scholar
- Jasinksi DR: An evaluation of the abuse potential of modafinil using methylphenidate as a reference. J Psychopharmacol. 2000, 14: 53-60.View ArticleGoogle Scholar
- Vosburg SK, Hart CL, Haney M, Rubin E, Foltin RW: Modafinil does not serve as a reinforcer in cocaine abusers. Drug Alcohol Depend. 2010, 106: 233-236.View ArticlePubMedGoogle Scholar
- Anderson AL, Reid MS, Li SH, Holmes T, Shemanski L, Slee A, Smith EV, Kahn R, Chiang N, Vocci F, Ciraulo D, Dackis C, Roache JD, Salloum IM, Somoza E, Urschel HC, Elkashef AM: Modafinil for the treatment of cocaine dependence. Drug Alcohol Depend. 2009, 104: 133-139.View ArticlePubMedPubMed CentralGoogle Scholar
- Morgan PT, Pace-Schott E, Pittman B, Stickgold R, Malison RT: Normalizing effects of modafinil on sleep in chronic cocaine users. Am J Psychiatry. 2010, 167: 331-340.View ArticlePubMedGoogle Scholar
- Roth T, Workshop Participants: Does effective management of sleep disorders reduce substance dependence?. Drugs. 2009, 69 (Suppl 2): 65-75.View ArticlePubMedGoogle Scholar
- Bourdelat-Parks BN, Anderson GM, Donaldson ZR, Weiss JM, Bonsall RW, Emery MS, Liles LC, Weinshenker D: Effects of dopamine beta-hydroxylase genotype and disulfiram on inhibition of catecholamine homeostasis in mice. Psychopharmacology (Berl). 2005, 183: 72-80.View ArticleGoogle Scholar
- Carroll KM, Nich C, Ball SA, McCance E, Rounsaville BJ: Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction. 1998, 93: 713-727.View ArticlePubMedGoogle Scholar
- McCance-Katz EF, Kosten TR, Jatlow P: Disulfiram effects on acute cocaine administration. Drug Alcohol Depend. 1998, 52: 27-39.View ArticlePubMedGoogle Scholar
- Petrakis IL, Carroll KM, Nich C, Gordon LT, McCance-Katz EF, Frankforter T, Rounsaville BJ: Disulfiram treatment for cocaine dependence in methadone-maintained opioid addicts. Addiction. 2000, 95: 219-228.View ArticlePubMedGoogle Scholar
- Oliveto A, Poling J, Mancino MJ, Feldman Z, Cubells JF, Pruzinsky R, Gonsai K, Cargile C, Sofuoglu M, Chopra MP, Gonzalez-Haddad G, Carroll KM, Kosten TR: Randomized, double-blind, placebo-controlled trial of disulfiram for the treatment of cocaine dependence in methadone-stabilized patients. Drug Alcohol Depend. 2011, 113: 184-191.View ArticlePubMedGoogle Scholar
- Schroeder J, Cooper DA, Schank JR, Lyle MA, Gaval-Cruz M, Ogbonmwan YE, Pozdeyev N, Freeman KG, Iuvone PM, Edwards GL, Holmes PV, Weinshenker D: Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine: -hydroxylase. Neuropsychopharmacology. 2010, 35: 2440-2449.View ArticlePubMedPubMed CentralGoogle Scholar
- Rothmann RB, Baumann MH: Monoamine transporters and psychostimulant drugs. Eur J Pharmacol. 2003, 479: 23-40.View ArticleGoogle Scholar
- Parsons LH, Justice JB: Serotonin and dopamine sensitization in the nucleus accumbens, ventral tegmental area and dorsal raphe nucleus following repeated cocaine administration. J Neurochem. 1993, 61: 1611-1619.View ArticlePubMedGoogle Scholar
- Pentkowski NS, Acosta JI, Browning JR, Hamilton ED, Neisewander JL: Stimulation of 5-HT(1B) receptors enhances cocaine reinforcement yet reduces cocaine-seeking behavior. Addict Biol. 2009, 14: 419-430.View ArticlePubMedPubMed CentralGoogle Scholar
- Aronson SC, Black JE, McDougle CJ, Scanley BE, Jatlow P, Kosten TR, Heninger GR, Price LH: Serotonergic mechanisms of cocaine effects in humans. Psychopharmacology. 1995, 119: 179-185.View ArticlePubMedGoogle Scholar
- Parsons LH, Koob GF, Weiss F: Extracellular serotonin is decreased in the nucleus accumbens during withdrawal from cocaine self-administration. Behav Brain Res. 1996, 73: 225-228.View ArticlePubMedGoogle Scholar
- Parsons LH, Koob GF, Weiss F: Serotonin dysfunction in the nucleus accumbens of rats during withdrawal after unlimited access to intravenous cocaine. J Pharmacol Exp Ther. 1995, 274: 1182-1191.PubMedGoogle Scholar
- Carroll ME, Lac ST, Ascencio M, Kragh R: Fluoxetine reduces intravenous cocaine self-administration in rats. Pharmacol Biochem Behav. 1990, 35: 237-244.View ArticlePubMedGoogle Scholar
- Peltier R, Schenk S: Effects of serotonergic manipulations on cocaine self-administration in rats. Psychopharmacology. 1993, 110: 390-394.View ArticlePubMedGoogle Scholar
- Batki SL, Washburn AM, Delucchi K, Jones RT: A controlled trial of fluoxetine in crack cocaine dependence. Drug Alcohol Depend. 1996, 41: 137-142.View ArticlePubMedGoogle Scholar
- Grabowski SL, Washburn AM, Delucchi K, Jones RT: A controlled trial of fluoxetine in crack cocaine dependence. Drug Alcohol Depend. 1996, 41: 137-142.View ArticleGoogle Scholar
- Covi L, Hess JM, Kreiter NA, Haertzen CA: Effects of combined fluoxetine and counseling in the outpatient treatment of cocaine abusers. Am J Drug Alcohol Abuse. 1995, 21: 327-344.View ArticlePubMedGoogle Scholar
- Walsh SL, Preston KL, Sullivan JT, Fromme R, Bigelow GE: Fluoxetine alters the effects of intravenous cocaine in humans. J Clin Psychopharmacol. 1994, 14: 396-407.PubMedGoogle Scholar
- Filip M, Frankowska M, Zaniewska M, Golda A, Przegalinski E: The serotonergic system and its role in cocaine addiction. Pharmacol Rep. 2005, 57: 685-700.PubMedGoogle Scholar
- Moeller FG, Schmitz JM, Steinberg JL, Green CM, Reist C, Lai LY, Swann AC, Grabowski J: Citalopram combined with behavioral therapy reduces cocaine use: a double-blind, placebo-controlled trial. Am J Drug Alcohol Abuse. 2007, 33: 367-378.View ArticlePubMedGoogle Scholar
- Glick SD, Maisonneuve IM: Development of novel medications for drug addiction: The legacy of an African shrub. Ann N Y Acad Sci. 2000, 909: 88-103.View ArticlePubMedGoogle Scholar
- Glick SD, Maisonneuve IM: Mechanisms of antiaddictive actions of ibogaine. Ann N Y Acad Sci. 1998, 844: 252-264.View ArticleGoogle Scholar
- Baumann MH, Rothman RB, Pablo JP, Mash DC: In vivo neurobiological effects of ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine) in rats. J Pharmacol Exp Ther. 2001, 297: 531-539.PubMedGoogle Scholar
- Glick SD, Pearl SM, Cai J, Maisonneuve IM: Ibogaine-like effects of noribogaine in rats. Brain Res. 1996, 713: 294-297.View ArticlePubMedGoogle Scholar
- Glick SD, Kuehne ME, Raucci J, Wilson TE, Larson TD, Keller RW, Carlson JN: Effects of iboga alkaloids on morphine and cocaine self-administration in rats: Relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Brain Res. 1994, 657: 14-22.View ArticlePubMedGoogle Scholar
- Maisonneuve IM, Glick SD: Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment. Pharmacol Biochem Behav. 2003, 75: 607-618.View ArticlePubMedGoogle Scholar
- Glick SD, Kuehne ME, Maisonneuve IM, Bandarage UK, Molinari HH: 18-Methoxycoronaridine, a non-toxic iboga alkaloid congener: effects on morphine and cocaine self-administration and on mesolimbic dopamine in rats. Brain Res. 1996, 719: 29-35.View ArticlePubMedGoogle Scholar
- Kalivas PW: Neurobiology of cocaine addiction: implications for new pharmacotherapy. Am J Addict. 2007, 16: 71-78.View ArticlePubMedGoogle Scholar
- Morgan AE, Dewey SL: Effects of pharmacologic increases in brain GABA levels on cocaine-induced changes in extracellular dopamine. Synapse. 1998, 30: 119-129.View ArticlePubMedGoogle Scholar
- Brodie JD, Case BG, Figueroa E, Dewey SL, Robinson JA, Wanderling JA, Laska EM: Randomized, double-blind, placebo-controlled trial of vigabatrin for the treatment of cocaine dependence in Mexican parolees. Am J Psychiatry. 2009, 166: 1269-1277.View ArticlePubMedGoogle Scholar
- Roberts DC, Andrews MM, Vickers GJ: Baclofen attenuates the reinforcing effects of cocaine in rats. Neuropsychopharmacology. 1996, 15: 417-423.View ArticlePubMedGoogle Scholar
- Brebner K, Phelan R, Roberts DC: Effect of baclofen on self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules. Psychopharmacology (Berl). 2000, 148: 314-321.View ArticleGoogle Scholar
- Campbell UC, Lac ST, Carroll ME: Effects of baclofen on maintenance and reinstatement of intravenous cocaine self-administration in rats. Psychopharmacology (Berl). 1999, 143: 209-214.View ArticleGoogle Scholar
- Di Ciano P, Everitt BJ: The GABA(B) receptor agonist baclofen attenuates cocaine- and heroin-seeking behavior by rats. Neuropsychopharmacology. 2003, 28: 510-518.View ArticlePubMedGoogle Scholar
- Fadda P, Scherma M, Fresu A, Collu M, Fratta W: Baclofen antagonizes nicotine-, cocaine-, and morphine-induced dopamine release in the nucleus accumbens of rat. Synapse. 2003, 50: 1-6.View ArticlePubMedGoogle Scholar
- Shoptaw S, Yang X, Rotheram-Fuller EJ, Hsieh YC, Kintaudi PC, Charuvastra VC, Ling W: 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.View ArticlePubMedGoogle Scholar
- Kahn R, Biswas K, Childress AR, Shoptaw S, Fudala PJ, Gorgon L, Montoya I, Collins J, McSherry F, Li SH, Chiang N, Alathari H, Watson D, Liberto J, Beresford T, Stock C, Wallace C, Gruber V, Elkashef A: Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals. Drug Alcohol Depend. 2009, 103: 59-64.View ArticlePubMedPubMed CentralGoogle Scholar
- Reid MS, Thakkar V: Valproate treatment and cocaine cue reactivity in cocaine dependent individuals. Drug Alcohol Depend. 2009, 102: 144-150.View ArticlePubMedPubMed CentralGoogle Scholar
- Winhusen T, Somoza E, Ciraulo DA, Harrer JM, Goldsmith RJ, Grabowski J, Coleman FS, Mindrum G, Kahn R, Osman S, Mezinskis J, Li SH, Lewis D, Horn P, Montgomery MA, Elkashef A: A double-blind, placebo-controlled trial of tiagabine for the treatment of cocaine dependence. Drug Alcohol Depend. 2007, 91: 141-148.View ArticlePubMedGoogle Scholar
- Morgan PT, Malison RT: Pilot study of lorazepam and tiagabine effects on sleep, motor learning, and impulsivity in cocaine abstinence. Am I Drug Alcohol Abuse. 2008, 34: 692-702.View ArticleGoogle Scholar
- Johnson BA: Recent advances in the development of treatments for alcohol and cocaine dependence: focus on topiramate and other modulators of GABA or glutamate function. CNS Drugs. 2005, 19: 873-896.View ArticlePubMedGoogle Scholar
- Kampman KM, Pettinati H, Lynch KG, Dackis C, Sparkman T, Weigley C, O'Brien CP: A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Depend. 2004, 75: 233-240.View ArticlePubMedGoogle Scholar
- Reis AD, Castro LA, Faria R, Laranjeira R: Craving decrease with topiramate in outpatient treatment for cocaine dependence: an open label trial. Rev Bras Psiquiatr. 2008, 30: 132-135.View ArticlePubMedGoogle Scholar
- Mantsch JR, Li SJ, Risinger R, Awad S, Katz E, Baker DA, Yang Z: Levo-tetrahydropalmatine attenuates cocaine self-administration and cocaine-induced reinstatement in rats. Psychopharmacology (Berl). 2007, 192: 581-591.View ArticleGoogle Scholar
- Xi ZX, Yang Z, Li S, Li X, Dillon C, Peng XQ, Spiller K, Gardner EL: Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: Experiments with self-administration and brain stimulation in rats. Neuropharmacology. 2007, 53: 771-782.View ArticlePubMedPubMed CentralGoogle Scholar
- Jin GZ, Wang XL, Shi WX: Tetrahydroprotoberberine - a new chemical type of antagonist of dopamine receptors. Sci Sin B. 1986, 29: 527-534.PubMedGoogle Scholar
- Marcenac F, Jin GZ, Gonon F: Effect of l-tetrahydropalmatine on dopamine release and metabolism in the rat striatum. Psychopharmacology (Berl). 1986, 89: 89-93.View ArticleGoogle Scholar
- Halbsguth C, Meissner O, Haberlein H: Positive cooperation of protoberberine type 2 alkaloids from Corydalis cava on the GABA (A) binding site. Planta Med. 2003, 69: 305-309.View ArticlePubMedGoogle Scholar
- Mantsch JR, Wisniewski S, Vranjkovic O, Peters C, Becker A, Valentine A, Li SJ, Baker DA, Yang Z: Levo-tetrahydropalmatine attenuates cocaine self-administration under a progressive-ratio schedule and cocaine discrimination in rats. Pharmacol Biochem Behav. 2010, 97: 310-316.View ArticlePubMedPubMed CentralGoogle Scholar
- Figueroa-Guzman Y, Mueller C, Vranjkovic O, Wisniewski S, Yang Z, Li SJ, Bohr C, Graf EN, Baker DA, Mantsch JR: Oral administration of levo-tetrahydropalmatine attenuates reinstatement of extinguished cocaine seeking by cocaine, stress or drug-associated cues in rats. Drug Alcohol Depend. 2011, 116: 72-79.View ArticlePubMedGoogle Scholar
- Fox BS, Kantak KM, Edwards MA, Black KM, Bollinger BK, Botka AJ, French TL, Thompson TL, Schad VC, Greenstein JL, Gefter ML, Exley MA, Swain PA, Briner TJ: Efficacy of a therapeutic cocaine vaccine in rodent models. Nature Med. 1996, 2: 1129-1132.View ArticlePubMedGoogle Scholar
- Orson FM, Kinsey BM, Singh RA, Wu Y, Kosten TR: Vaccines for cocaine abuse. Hum Vaccin. 2009, 5: 194-199.View ArticlePubMedPubMed CentralGoogle Scholar
- Kosten TR, Rosen M, Bond J, Settles M, St Clair Roberts J, Shields J, Jack L, Fox B: Human therapeutic cocaine vaccine: safety and immunogenicity. Vaccine. 2002, 20: 1196-1204.View ArticlePubMedGoogle Scholar
- Martell BA, Mitchell E, Poling J, Gonsai K, Kosten TR: Vaccine pharmacotherapy for the treatment of cocaine dependence. Biol Psych. 2005, 58: 158-164.View ArticleGoogle Scholar
- Haney M, Kosten TR: Therapeutic vaccines for substance dependence. Expert Rev Vaccines. 2004, 3: 11-18.View ArticlePubMedGoogle Scholar
- Martell BA, Orson FM, Poling J, Mitchell E, Rossen RD, Gardner T, Kosten TR: Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double blind, placebo-controlled efficacy trial. Arch Gen Psych. 2009, 66: 1116-1123.View ArticleGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/9/119/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.