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Siminialayi Iyeopu Minakiri - One of the best experts on this subject based on the ideXlab platform.

  • Disulfiram and copper gluconate in cancer chemotherapy a review of the literature
    Cancer Research, 2014
    Co-Authors: Georgewill Udeme Owunari, Siminialayi Iyeopu Minakiri
    Abstract:

    Repurposing non- cancer related drugs with possible antitumoral activities is a promising strategy for identifying prospective new anticancer drugs in a cost efficient and time saving way. Repurposing Disulfiram has recently become of interest because of its pre-clinically described anticancer effects against various human cancers, which include breast, cervical, colorectal, lung, melanoma, prostate as well as myeloma and leukaemia. Epidemiological studies reveal a trend to reduced cancer risks in cancer patients using Disulfiram for chronic alcoholism treatment while already reported literature point to the efficacy of Disulfiram on cancer cell lines. Disulfiram has been shown to be effective either as a stand alone or in combination with other drugs against metastatic liver cancer, lung cancer, prostate cancer, glioblastoma and melanoma. Preclinical studies indicate that Disulfiram when combined with copper ions acts as a proteasome inhibitor, to induce oxidative stress, reduce NFƙB (Nuclear factor ƙappa Binding) activity and enhance the sensitivity of cancer cells to chemotherapeutic agents. This study analyzed existing literature and found that Disulfiram in combination with copper gluconate is a promising therapeutic agent for use in cancer chemotherapy.

  • Disulfiram and copper gluconate in cancer chemotherapy a review of the literature
    Cancer Research, 2014
    Co-Authors: Georgewill Udeme Owunari, Siminialayi Iyeopu Minakiri
    Abstract:

    Repurposing non- cancer related drugs with possible antitumoral activities is a promising strategy for identifying prospective new anticancer drugs in a cost efficient and time saving way. Repurposing Disulfiram has recently become of interest because of its pre-clinically described anticancer effects against various human cancers, which include breast, cervical, colorectal, lung, melanoma, prostate as well as myeloma and leukaemia. Epidemiological studies reveal a trend to reduced cancer risks in cancer patients using Disulfiram for chronic alcoholism treatment while already reported literature point to the efficacy of Disulfiram on cancer cell lines. Disulfiram has been shown to be effective either as a stand alone or in combination with other drugs against metastatic liver cancer, lung cancer, prostate cancer, glioblastoma and melanoma. Preclinical studies indicate that Disulfiram when combined with copper ions acts as a proteasome inhibitor, to induce oxidative stress, reduce NFƙB (Nuclear factor ƙappa Binding) activity and enhance the sensitivity of cancer cells to chemotherapeutic agents. This study analyzed existing literature and found that Disulfiram in combination with copper gluconate is a promising therapeutic agent for use in cancer chemotherapy.

Michel Treilhou - One of the best experts on this subject based on the ideXlab platform.

  • Comparative study of the effects of ziram and Disulfiram on human monocyte-derived macrophage functions and polarization: involvement of zinc
    Cell Biology and Toxicology, 2020
    Co-Authors: Melissa Parny, José Bernad, Mélissa Prat, Marie Salon, Agnès Aubouy, Elsa Bonnafé, Agnès Coste, Bernard Pipy, Michel Treilhou
    Abstract:

    Ziram, a zinc dithiocarbamate is widely used worldwide as a fungicide in agriculture. In order to investigate ziram-induced changes in macrophage functions and polarization, human monocytes-derived macrophages in culture were treated with ziram at 0.01–10 μmol.L^−1 for 4–24 h. To characterize zinc involvement in these changes, we also determined the effects of Disulfiram alone (dithiocarbamate without zinc) or in co-incubation with ZnSO_4. We have shown that ziram and Disulfiram at 0.01 μmol.L^−1 increased zymosan phagocytosis. In contrast, ziram at 10 μmol.L^−1 completely inhibited this phagocytic process, the oxidative burst triggered by zymosan and the production of TNF-α, IL-1β, IL-6, and CCL2 triggered by LPS. Disulfiram had the same effects on these macrophages functions only when combined with zinc (10 μmol.L^−1). In contrast, at 10 μmol.L^−1 ziram and zinc associated-Disulfiram induced expression of several antioxidants genes HMOX1, SOD2, and catalase, which could suggest the induction of oxidative stress. This oxidative stress could be involved in the increase in late apoptosis induced by ziram (10 μmol.L^−1) and zinc associated-Disulfiram. Concerning gene expression profiles of membrane markers of macrophage polarization, ziram at 10 μmol.L^−1 had two opposite effects. It inhibited the gene expression of M2 markers (CD36, CD163) in the same way as the Disulfiram-zinc co-treatment. Conversely, ziram induced gene expression of other M2 markers CD209, CD11b, and CD16 in the same way as treatment with zinc alone. Disulfiram-zinc association had no significant effects on these markers. These results taken together show that ziram via zinc modulates macrophages to M2-like anti-inflammatory phenotype which is often associated with various diseases.

M. Marselos - One of the best experts on this subject based on the ideXlab platform.

  • Pharmaceutical Agents Known to Produce Disulfiram-Like Reaction: Effects on Hepatic Ethanol Metabolism and Brain
    2016
    Co-Authors: Petros Nikolaos Karamanakos, Vassiliki A Boumba, Christoforos Thomas, Michalis Malamas, Theodore Vougiouklakis, M. Marselos
    Abstract:

    Several pharmaceutical agents produce ethanol intolerance, which is often depicted as Disulfiram-like reaction. As in the case with Disulfiram, the underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the hepatic aldehyde dehydrogenases. In the present study, chloram-phenicol, furazolidone, metronidazole, and quinacrine, which are reported to produce a Disulfiram-like reaction, as well as disul-firam, were administered to Wistar rats and the hepatic activ-ities of alcohol and aldehyde dehydrogenases (1A1 and 2) were determined. The expression of aldehyde dehydrogenase 2 was fur-ther assessed by Western blot analysis, while the levels of brain monoamines were also analyzed. Finally, blood acetaldehyde was evaluated after ethanol administration in rats pretreated with Disulfiram, chloramphenicol, or quinacrine. The activity of alde-hyde dehydrogenase 2 was inhibited by Disulfiram, chlorampheni

  • the mechanism of alcohol intolerance produced by various therapeutic agents
    Pharmacology & Toxicology, 2009
    Co-Authors: Vasilis Vasiliou, Michalis Malamas, M. Marselos
    Abstract:

    : According to clinical reports, several therapeutic agents produce ethanol intolerance, which is often referred as Disulfiram reaction. The mechanism of this manifestation was investigated in the Wistar rat, by measuring the alcohol and aldehyde dehydrogenases (ADH, ALDH) of the liver and the brain after subacute administration of chloramphenicol (100 mg/kg × 4, intraperitoneally), chlorpropamide (80 mg/kg × 4, intrateritoneally), Disulfiram (150 mg/kg × 4, intraperitoneally), griseofulvin (100 mg/kg × 4, intraperitoneally), isoniazid (200 mg/kg × 4, intraperitoneally), metronidazole (200 mg/kg × 4, intraperitoneally), and procarbazine (100 mg/kg × 4, intraperitoneally). All substances tested decrease the activity of the low-Km ALDH in the brain, with the exception of griseofulvin. The hepatic low-Km enzyme is also inhibited, with the exception of griseofulvin and metronidazole. The high-Km ALDH responds in an inconsistent way, while ADH is not affected at all. The results suggest that the so-called “Disulfiram-reaction” is mediated mainly, but not exclusively, by inhibition of the low-Km ALDH.

  • Inhibition of rat hepatic CYP2E1 by quinacrine: molecular modeling investigation and effects on 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mutagenicity
    Archives of Toxicology, 2008
    Co-Authors: Petros Nikolaos Karamanakos, D. T. P. Trafalis, G. D. Geromichalos, P. Pappas, P. Harkitis, M. Konstandi, M. Marselos
    Abstract:

    Increased activity of CYP2E1 has been associated with increased risk of chemically-mediated cancers, through enhanced activation of a variety of procarcinogens. In this context, inhibition of CYP2E1 is potentially of significance in xenobiotic toxicity. The aim of the present study was to test the hypothesis that quinacrine inhibits hepatic CYP2E1. For this purpose, Disulfiram (75 mg/kg i.p) as an inhibitor and isoniazid (100 mg/kg i.p) as an inducer of CYP2E1, as well as quinacrine (50 mg/kg i.p) were administered to Wistar rats and the hepatic activity of CYP2E1 was measured. The expression of CYP2E1 was further assessed by Western blot analysis. As expected, Disulfiram inhibited, while isoniazid induced the activity and expression of the enzyme. Interestingly, treatment with quinacrine resulted in a significant decrease of CYP2E1 activity and expression. To investigate any similarities in the inhibition of CYP2E1 by quinacrine and Disulfiram, molecular modeling techniques were adopted and revealed that quinacrine molecule anchors inside the same binding pocket of the protein where Disulfiram is also attached. Finally, as assessed by the sister chromatid exchanges (SCE) assay, quinacrine was demonstrated to reduce the mutagenic effects of the tobacco-specific N -nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is known to be converted to active mutagen in the liver principally through CYP2E1. We suggest that these antimutagenic effects of quinacrine could be possibly attributed, at least in part, to its ability to block the bioactivation of NNK, mainly by the inhibition of CYP2E1. Our results, even preliminary, indicate that quinacrine as an inhibitor of CYP2E1 might be protective against chemically-induced toxicities such as NNK-induced mutagenicity.

  • pharmaceutical agents known to produce Disulfiram like reaction effects on hepatic ethanol metabolism and brain monoamines
    International Journal of Toxicology, 2007
    Co-Authors: Petros Nikolaos Karamanakos, Periklis Pappas, Vassiliki A Boumba, Christoforos Thomas, Michalis Malamas, Theodore Vougiouklakis, M. Marselos
    Abstract:

    Several pharmaceutical agents produce ethanol intolerance, which is often depicted as Disulfiram-like reaction. As in the case with Disulfiram, the underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the hepatic aldehyde dehydrogenases. In the present study, chloramphenicol, furazolidone, metronidazole, and quinacrine, which are reported to produce a Disulfiram-like reaction, as well as Disulfiram, were administered to Wistar rats and the hepatic activities of alcohol and aldehyde dehydrogenases (1A1 and 2) were determined. The expression of aldehyde dehydrogenase 2 was further assessed by Western blot analysis, while the levels of brain monoamines were also analyzed. Finally, blood acetaldehyde was evaluated after ethanol administration in rats pretreated with Disulfiram, chloramphenicol, or quinacrine. The activity of aldehyde dehydrogenase 2 was inhibited by Disulfiram, chloramphenicol, and furazolidone, but not by metronidazole or quinacrine. In addition, although well known for metronidazole, quinacrine also did not increase blood acetaldehyde after ethanol administration. The protein expression of aldehyde dehydrogenase 2 was not affected at all. Interestingly, all substances used, except Disulfiram, increased the levels of brain serotonin. According to our findings, metronidazole and quinacrine do not produce a typical Disulfiram-like reaction, because they do not inhibit hepatic aldehyde dehydrogenase nor increase blood acetaldehyde. Moreover, all tested agents share the common property to enhance brain serotonin, whereas a respective effect of ethanol is well established. Therefore, the ethanol intolerance produced by these agents, either aldehyde dehydrogenase is inhibited or not, could be the result of a "toxic serotonin syndrome," as in the case of the concomitant use of serotonin-active medications.

  • differentiation of Disulfiram effects on central catecholamines and hepatic ethanol metabolism
    Pharmacology & Toxicology, 2001
    Co-Authors: Petros Nikolaos Karamanakos, Periklis Pappas, P Stephanou, M. Marselos
    Abstract:

    Disulfiram is used in the treatment of chronic alcoholism, because of the unpleasant symptoms it provokes after ethanol intake. The underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhi­ bition of the liver aldehyde dehydrogenases. In addition, it is known that Disulfiram also has some neurotoxic properties. The aim of our study was to investigate the relationship between the pharmacological and neurotoxicological properties of Disulfiram with respect to the doses applied. Increasing doses of Disulfiram (25, 50, 75, 100 and 150 mg/kg) were administered intraperitoneally to Wistar rats and the hepatic enzyme activities of alcohol and aldehyde dehydrogenases were measured, Also, in two brain subregions (midbrain and hypothalamus) the levels of noradrenaline, dopamine, 3,4­ dihydroxyphenylacetic acid and homovanillic acid were determined. The higher dose of Disulfiram (150 mg/kg) produced lethal effects in all treated animals. Aldehyde dehydrogenase activities were inhibited by Disulfiram in a dose-dependent way, while alcohol dehydrogenase was not affected at all. Concerning the levels of brain biogenic amines, Disulfiram produced a significant reduction in noradrenaline and an increase in dopamine levels in both structures of the brain, in a dose-dependent way. However, the lowest dose applied (25 mg/kg) had no effects on brain catecholamines. It is known that high doses of Disulfiram may cause severe encephalopathy and peripheral neuropathy in humans, which could be attributed to the impairment of the metabolism of brain biogenic amines, due to inhibition of dopamine-~-hydroxylase. Our experimental data show that Disulfiram affects the level of brain biogenic amines at dose levels higher than those inhibiting the activity of aldehyde dehydrogenase. Therefore, in clinical practice 'Disulfiram reaction' could still be achieved with a low dosage regimen not producing neurotoxicity.

Georgewill Udeme Owunari - One of the best experts on this subject based on the ideXlab platform.

  • Disulfiram and copper gluconate in cancer chemotherapy a review of the literature
    Cancer Research, 2014
    Co-Authors: Georgewill Udeme Owunari, Siminialayi Iyeopu Minakiri
    Abstract:

    Repurposing non- cancer related drugs with possible antitumoral activities is a promising strategy for identifying prospective new anticancer drugs in a cost efficient and time saving way. Repurposing Disulfiram has recently become of interest because of its pre-clinically described anticancer effects against various human cancers, which include breast, cervical, colorectal, lung, melanoma, prostate as well as myeloma and leukaemia. Epidemiological studies reveal a trend to reduced cancer risks in cancer patients using Disulfiram for chronic alcoholism treatment while already reported literature point to the efficacy of Disulfiram on cancer cell lines. Disulfiram has been shown to be effective either as a stand alone or in combination with other drugs against metastatic liver cancer, lung cancer, prostate cancer, glioblastoma and melanoma. Preclinical studies indicate that Disulfiram when combined with copper ions acts as a proteasome inhibitor, to induce oxidative stress, reduce NFƙB (Nuclear factor ƙappa Binding) activity and enhance the sensitivity of cancer cells to chemotherapeutic agents. This study analyzed existing literature and found that Disulfiram in combination with copper gluconate is a promising therapeutic agent for use in cancer chemotherapy.

  • Disulfiram and copper gluconate in cancer chemotherapy a review of the literature
    Cancer Research, 2014
    Co-Authors: Georgewill Udeme Owunari, Siminialayi Iyeopu Minakiri
    Abstract:

    Repurposing non- cancer related drugs with possible antitumoral activities is a promising strategy for identifying prospective new anticancer drugs in a cost efficient and time saving way. Repurposing Disulfiram has recently become of interest because of its pre-clinically described anticancer effects against various human cancers, which include breast, cervical, colorectal, lung, melanoma, prostate as well as myeloma and leukaemia. Epidemiological studies reveal a trend to reduced cancer risks in cancer patients using Disulfiram for chronic alcoholism treatment while already reported literature point to the efficacy of Disulfiram on cancer cell lines. Disulfiram has been shown to be effective either as a stand alone or in combination with other drugs against metastatic liver cancer, lung cancer, prostate cancer, glioblastoma and melanoma. Preclinical studies indicate that Disulfiram when combined with copper ions acts as a proteasome inhibitor, to induce oxidative stress, reduce NFƙB (Nuclear factor ƙappa Binding) activity and enhance the sensitivity of cancer cells to chemotherapeutic agents. This study analyzed existing literature and found that Disulfiram in combination with copper gluconate is a promising therapeutic agent for use in cancer chemotherapy.

Thomas R Kosten - One of the best experts on this subject based on the ideXlab platform.

  • randomized clinical trial of Disulfiram for cocaine dependence or abuse during buprenorphine treatment
    Drug and Alcohol Dependence, 2014
    Co-Authors: Richard S Schottenfeld, Joseph F. Cubells, Marek C Chawarski, Tony P George, Jaakko Lappalainen, Thomas R Kosten
    Abstract:

    Abstract Background Disulfiram may be efficacious for treating cocaine dependence or abuse, possibly through inhibiting dopamine β-hydroxylase (DβH). Consequently, this randomized, placebo-controlled clinical trial of Disulfiram during buprenorphine maintenance treatment evaluated the study hypothesis that Disulfiram is superior to placebo and explored whether Disulfiram response is greatest for participants with a single nucleotide polymorphism coding for genetically low DβH (T-allele carriers). Methods We randomized 177 buprenorphine-treated opioid dependent participants with cocaine dependence or abuse to 12 weeks of double-blind treatment with Disulfiram 250 mg daily ( n  = 91) or placebo ( n  = 86). Of 155 participants genotyped, 84 were CC-homozygous, and 71 CT or TT genotypes. Primary outcomes included days per week cocaine use, number of cocaine-negative urine tests, and maximum consecutive weeks of cocaine abstinence. We analyzed an intention-to-treat comparison between Disulfiram and placebo. We also explored potential pharmacogenetic interactions and examined treatment responses of four participant groups based on medication (Disulfiram or placebo) by genotype (CC-homozygous or T-allele carrier) classification. Results Disulfiram participants reported significantly less frequent cocaine use; the differences in cocaine-negative urine tests or consecutive weeks abstinence were not significant. Frequency of cocaine use was lowest in Disulfiram-treated T-allele carriers; differences in cocaine-negative urine tests or consecutive weeks abstinence were not significant among the four medication-genotype groups. Conclusions The findings provide limited support for the efficacy of Disulfiram for reducing cocaine use and suggest that its mechanism of action may involve inhibition of DβH. Further studies of its efficacy, mechanism of action, and pharmacogenetics of response are warranted.

  • ankk1 and drd2 pharmacogenetics of Disulfiram treatment for cocaine abuse
    Pharmacogenetics and Genomics, 2013
    Co-Authors: Catherine J Spellicy, Sara C Hamon, Mark J Harding, Thomas R Kosten, David A. Nielsen
    Abstract:

    Objective Disulfiram is a potential cocaine addiction pharmacotherapy. Since dopamine deficiency has been found with cocaine addiction, our objective was to examine whether functional variants in the ankyrin repeat and kinase domain-containing 1 (ANKK1) and/or the dopamine receptor D2 (DRD2) genes interact with response to treatment with Disulfiram. Materials and methods Cocaine and opioid codependent (DSM-IV) patients were stabilized on methadone and subsequently randomized into treatment groups - Disulfiram (250 mg/day, N=31) or placebo (N=37). They were genotyped for ANKK1 (rs1800497) and DRD2 (rs2283265) polymorphisms, and the data were evaluated for an association between a cocaine-free state, as assessed by cocaine-free urine samples, and Disulfiram treatment. Data were analyzed using repeated measures analysis of variance corrected for population structure. Results Patients with CT or TT ANKK1 genotypes dropped from 80 to 52% cocaine-positive urines on Disulfiram (N=13; P≤0.0001), whereas those on placebo (N=20) showed no treatment effect. Patients carrying the CC ANKK1 genotype showed no effect on treatment with Disulfiram (N=18) or placebo (N=17). The GT/TT DRD2 genotype group showed a significant decrease in the number of cocaine-positive urine samples on Disulfiram (N=9; 67-48%; P ≤ 0.0001), whereas the GG DRD2 genotype group showed only a marginal decrease (N=23; 84-63%; P=0.04). Genotype pattern analysis revealed that individuals carrying at least one minor allele in either gene responded better to Disulfiram treatment (N=13; P ≤ 0.0001) compared with individuals carrying only the major alleles (N=17). Conclusion A patient's genotype for ANKK1, DRD2, or both, may be used to identify individuals for whom Disulfiram may be an effective pharmacotherapy for cocaine dependence.

  • pharmacogenetic randomized trial for cocaine abuse Disulfiram and dopamine β hydroxylase
    Biological Psychiatry, 2013
    Co-Authors: Thomas R Kosten, Mark J Harding, Sara C Hamon, Wen Huang, Jaakko Lappalainen, Guiying Wu, David A. Nielsen
    Abstract:

    Background Disulfiram has been an effective cocaine addiction pharmacotherapy, and one of its possible mechanisms of efficacy is through copper chelation and inhibition of an enzyme involved in catecholamine metabolism, dopamine β-hydroxylase (DβH), which converts dopamine to norepinephrine. A variant in the gene encoding DβH leads to reduced DβH activity, and as such, Disulfiram might not be an effective treatment of cocaine dependence for individuals with this variant. This study explored that potential matching. Methods Seventy-four cocaine- and opioid-codependent (DSM-V) subjects were stabilized on methadone for 2 weeks and subsequently randomized into Disulfiram (250 mg/day, n = 34) and placebo groups ( n = 40) for 10 weeks. We genotyped the DBH gene polymorphism, −1021C/T (rs1611115), that reduces DβH enzyme levels and evaluated its role for increasing cocaine free urines with Disulfiram. Results With repeated measures analysis of variance, corrected for population structure, Disulfiram pharmacotherapy reduced cocaine-positive urines from 80% to 62% ( p = .0001), and this Disulfiram efficacy differed by DBH genotype group. Patients with the normal DβH level genotype dropped from 84% to 56% on Disulfiram ( p = .0001), whereas those with the low DBH level genotype showed no Disulfiram effect. Conclusions This study indicates that the DBH genotype of a patient could be used to identify a subset of individuals for which Disulfiram treatment might be an effective pharmacotherapy for cocaine dependence.

  • modifying the role of serotonergic 5 httlpr and tph2 variants on Disulfiram treatment of cocaine addiction a preliminary study
    Genes Brain and Behavior, 2012
    Co-Authors: David A. Nielsen, Mark J Harding, Sara C Hamon, Wen Huang, Thomas R Kosten
    Abstract:

    Disulfiram is a cocaine pharmacotherapy that may act through increasing serotonin, benefiting patients with genetically low serotonin transporter levels (5-HTTLPR, S′ allele carriers) and low serotonin synthesis (TPH2, A allele carriers). We stabilized 71 cocaine and opioid co-dependent patients on methadone for 2 weeks and randomized them into Disulfiram and placebo groups for 10 weeks. We genotyped the SLC6A4 5-HTTLPR (rs4795541, rs25531) and TPH2 1125A>T (rs4290270) variants and evaluated their role in moderating Disulfiram treatment for cocaine dependence. Cocaine-positive urines dropped from 78% to 54% for the Disulfiram group and from 77% to 76% for the placebo group among the 5-HTTLPR S′ allele carriers (F = 16.2; df = 1,301; P < 0.0001). TPH2 A allele carriers responded better to Disulfiram than placebo (F = 16.0; df = 1,223; P < 0.0001). Patients with both an S′ allele and a TPH2 A allele reduced cocaine urines from 71% to 53% on Disulfiram and had no change on placebo (F = 21.6; df = 1,185; P < 0.00001).

  • Disulfiram enhances subjective effects of dextroamphetamine in humans
    Pharmacology Biochemistry and Behavior, 2008
    Co-Authors: Mehmet Sofuoglu, Thomas R Kosten, James Poling, Andrew J Waters, Andrew Sewell, Kevin P Hill
    Abstract:

    Disulfiram has shown promise in several clinical trials for cocaine addiction, but its potential utility in the treatment of amphetamine addiction has not been examined. The goal of this study was to determine the effects of Disulfiram on acute physiological and subjective responses to dextroamphetamine in healthy volunteers. Five male and 5 female subjects participated in an outpatient double-blind, placebo-controlled, crossover study. Subjects were randomly assigned to a sequence of Disulfiram (250 mg/day) or placebo treatments each lasting for 4 days. Day four of each treatment period was the experimental session, in which subjects orally ingested a single dose of dextroamphetamine (20 mg/70 kg). Outcome measures included heart rate, blood pressure, plasma cortisol and prolactin, subjective and performance on the Sustained Attention to Response Test (SART). Disulfiram did not affect dextroamphetamine-induced increases in heart rate, blood pressure, cortisol, or prolactin. Disulfiram did enhance some of the subjective effects of dextroamphetamine including ratings of “high,” “anxious,” “bad drug effects,” “want more drug” and “drug liking” and was also associated with decreased performance in the SART test. How these enhanced subjective amphetamine responses affect cocaine use behavior remains to be determined in future clinical trials.