Behavioral, physiological, and pharmacological interaction of cocaine and disulfiram in humans.
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Adult↗
Biomedical subjects
T R Kosten
Publications and source records attributed to T R Kosten.
Serotonergic mechanisms of cocaine effects in humans.
The objective of this study was to investigate the role of serotonin (5-HT) in mediating the effects of cocaine in humans. To accomplish this, 12 subjects each participated in two randomized, double-blind test sessions separated by 1 week. In one session, subjects underwent acute depletion of the 5-HT amino acid precursor tryptophan (TRP), followed by a test dose of intranasal cocaine. In the other session, the cocaine test dose was preceded by sham depletion. Subject ratings of cocaine "high" were significantly lower following active TRP depletion than after the sham procedure. Subjects also showed an earlier but less sustained rise in self-rated nervousness during active TRP depletion. These findings are consistent with the hypothesis that 5-HT may be involved in mediating the euphorigenic and modulating the anxiogenic effects of cocaine in humans, either directly or through actions on other (e.g., dopaminergic) systems.
Adult↗
A single-blind investigation of four auricular needle puncture configurations.
In order to identify an appropriate needle puncture control for clinical trials of acupuncture we conducted a study in which ten cocaine dependent subjects rated local and systemic effects of four auricular needle puncture configurations (a) sites commonly used for addiction; (b) sites proximate to addiction specific sites; (c) sites not specific for cocaine addiction; and (d) sites in the helix. Subjects received one treatment per day on four successive days. The addiction specific sites were rated highest on local effects; proximal sites a common control were rated highest on systemic effects. A majority of patients ranked the addiction specific sites as the most preferred treatment and the helix points as the least preferred. Results suggest that needle insertion into proximate and non-specific sites may be too active for use as controls; helix regions may be more suitable.
Acupuncture Points↗
Tryptophan depletion and attenuation of cue-induced craving for cocaine.
OBJECTIVE: Although cocaine is a potent serotonin (5-HT) reuptake blocker, the role of 5-HT systems in cocaine craving and relapse in humans has been unclear. The authors evaluated whether acute reductions in central 5-HT synthesis modulated craving for cocaine in cocaine-dependent patients. METHOD: Twenty-five cocaine-dependent male inpatients were exposed to cocaine-craving cues while their 5-HT levels were lowered and during a placebo condition in a counterbalanced, double-blind design. 5-HT levels were reduced by rapidly lowering plasma levels of its precursor, tryptophan; tryptophan levels were reduced by stimulating protein synthesis with a large drink of amino acids devoid of tryptophan. During the placebo condition the patients drank an identical amino acid drink containing tryptophan. Craving was induced by exposing patients to cocaine paraphernalia and a videotape depicting drug use. Craving was assessed 7 hours after ingestion of the drink. Visual analog ratings of craving for cocaine were administered before and after cue exposure at each test session. RESULTS: Patients reported less desire for cocaine stimulated by cue exposure after drinking amino acids without tryptophan than they did after drinking placebo. The order that tryptophan depletion and placebo tests were performed influenced the impact of tryptophan depletion on cue-induced craving. CONCLUSIONS: Serotonergic systems modulate cue-induced craving for cocaine, a factor implicated in relapse to cocaine use.
Adult↗
Opiate dependence and withdrawal: preliminary assessment using single photon emission computerized tomography (SPECT).
Naloxone (0.8 mg, s.c.) effects on opiate withdrawal signs and symptoms and regional brain function were assessed in 10 methadone-maintained patients and 10 healthy subjects in a double-blind, placebo-controlled study. Regional brain function was assessed using single photon emission computerized tomography (SPECT) by evaluating the uptake of [99mTc]d,l-hexamethylpropyleneamine oxime (HMPAO) in the brain, a process related to regional cerebral perfusion. Comparisons of patients and healthy subjects after saline infusion suggested that chronic opiate dependence was associated with lower corrected activity ratios (regional count density/whole brain count density) in frontal and parietal cortices and greater activity ratios in the thalamus. Opiate-dependent patients, but not healthy subjects, developed opiate withdrawal signs and symptoms after naloxone administration. Following naloxone administration, patients undergoing opiate withdrawal exhibited lower whole brain count density than healthy subjects. They also had lower activity ratios in frontal and parietal cortices and increased thalamic activity ratios relative to healthy subjects receiving naloxone. Naloxone administration in healthy subjects, but not opiate withdrawal in patients, was associated with decreased right parietal cortex and increased right temporal cortex and left basal ganglia activity ratios. Relative to naloxone effects in healthy subjects, opiate withdrawal was associated with decreased whole brain count density and a reduced right temporal cortex activity ratio. This preliminary study reports an initial evaluation of HMPAO-SPECT imaging for assessing regional alterations in brain function during opiate dependence and withdrawal. While group differences were reported, the small magnitude of regional alterations in patients undergoing opiate withdrawal raised concern that HMPAO-SPECT methods employed were inadequate for assessing human regional brain function during phases of opiate addiction. Other emerging functional brain imaging technologies should be evaluated relative to improved HMPAO-SPECT methods for this purpose.
Adult↗
Cocaethylene: pharmacology, physiology and behavioral effects in humans.
Comorbid abuse of cocaine and alcohol is a common occurrence. Cocaethylene, the ethyl ester of benzoylecgonine, is an active metabolite formed as a result of simultaneous use of these substances. In humans, the concurrent ingestion of cocaine and alcohol, with resulting cocaethylene formation, has been associated with enhanced subjective euphoria, increased heart rate and increased plasma cocaine concentration. These findings suggest that cocaethylene may play a role in the morbidity and mortality associated with concurrent cocaine/alcohol abuse. This placebo-controlled, double-blinded study examined the behavioral and physiological effects and pharmacokinetics of intranasal cocaethylene administration in humans (n = 8), using cocaine as a comparator. Cocaethylene administration resulted in a euphoria similar to that produced by cocaine, although the effects differed significantly over time. Subjects were unable to distinguish between equimolar doses of cocaine and cocaethylene, although cocaethylene appeared to be eliminated more slowly than cocaine. Cardiovascular effects of cocaethylene and cocaine were similar. These findings are considered in light of the epidemiology and possible consequences of cocaine and alcohol abuse.
Behavior↗
Discriminative stimulus, self-reported and cardiovascular effects of orally administered cocaine in humans.
This study evaluated whether an oral dose of cocaine can serve as a discriminative stimulus in humans. Four male and one female cocaine-abusing volunteers (ages 26-41 years) were trained to discriminate between cocaine HCl (80 mg/70 kg p.o.) and placebo. Once the criterion for discrimination was met (i.e., > or = 80% correct responding for four consecutive sessions), dose-effect curves were determined for orally administered cocaine (20, 40, 80 and 120 mg/70 kg), intranasally administered cocaine (20, 40, 80 and 120 mg/70 kg) and the benzodiazepine triazolam (0.25 and 0.50 mg/70 kg p.o.). All five subjects met the criterion for the cocaine-placebo discrimination within four to seven sessions. Novel cocaine doses by either the oral or intranasal route of administration generally produced dose-related increases in cocaine-appropriate responding, whereas triazolam produced predominantly placebo-appropriate responding. Cocaine by both routes produced qualitatively similar increases in stimulant-like self-reports, blood pressure and heart rate, whereas triazolam produced increases in sedative-like ratings and no changes in cardiovascular measures. Throughout dose-effect curve determinations, the training dose of cocaine and placebo continued to be identified correctly in four of five subjects (range, 75-100% correct responding). These results suggest that orally administered cocaine (80 mg/70 kg) is discriminable from placebo, has behavioral effects that are qualitatively similar to intranasal cocaine and does not show cross-generalization to a pharmacologically dissimilar compound.
Administration, Intranasal↗
Noradrenergic dysregulation during discontinuation of cocaine use in addicts.
BACKGROUND: The primary objective of the study was to prospectively determine possible noradrenergic dysregulation in cocaine addicts by assessing biochemical, behavioral, and cardiovascular responses to intravenous yohimbine hydrochloride during early and late discontinuation of cocaine use. METHODS: Twelve male and two female hospitalized cocaine-dependent subjects (mean +/- SD age, 30.9 +/- 7.3 years) who were not seeking primary treatment for addiction participated voluntarily for monetary remuneration. Following an initial test dose of intranasal cocaine, 2 mg/kg, cocaine addicts received single-blind, monitored cocaine insufflation, 2 mg/kg three times each day, for 3 consecutive days. One to two days (early discontinuation) and 15 to 16 days (late discontinuation) after the last dose of cocaine, subjects received double-blind, randomized intravenous infusions of yohimbine hydrochloride, 0.4 mg/kg, or placebo. Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and plasma cortisol levels, anxiety-related symptoms on clinician- and subject-rated scales, blood pressure, and heart rate were measured throughout each test day. Ten of 14 subjects completed the entire study. RESULTS: Subjects had a significantly greater placebo-corrected MHPG response to yohimbine during early compared with late discontinuation. Subjects rated themselves significantly more nervous following yohimbine administration during early compared with late discontinuation. Seventy-one percent of subjects experienced a yohimbine-induced panic attack during early discontinuation compared with none during late discontinuation. CONCLUSIONS: The results of this study provide evidence of an underlying dysregulation in noradrenergic function and a vulnerability to panic anxiety during early discontinuation of cocaine use in addicts. Additional investigations of noradrenergic function appear warranted to further clarify derangements associated with cocaine addiction.
Administration, Intranasal↗
HIV infection and cocaine use in methadone maintained and untreated intravenous drug users.
In a survey of 424 intravenous drug users (IVDUs) of whom 107 were currently enrolled in a methadone maintenance program (MMP), we assessed risk behaviors for Human Immunodeficiency Virus (HIV) transmission and conducted HIV testing. We found that African Americans were over-represented in the HIV infected group and under-represented in the methadone maintenance treatment group. Furthermore, subjects in current methadone maintenance treatment reported fewer drug injections in the last 30 days, a reduced speedball (a heroin/cocaine mixture) injection frequency and reduced total cocaine and injected cocaine use. HIV infected subjects reported 20% more cocaine use and injected cocaine use than HIV negatives. However, this difference was due to African Americans reporting more cocaine use and at the same time being over-represented in the HIV infected group. Stratified analysis by ethnicity found significant MMP effects for all ethnic groups, but only one significant HIV status effect, and this was limited to African Americans. Cocaine injection frequency in African Americans was significantly higher for the HIV infected versus non-infected subjects. We conclude that i.v. cocaine use is a risk factor associated with HIV infection and that methadone maintenance treatment is associated with reducing this risk factor. Furthermore, African American cocaine users are at great risk for HIV infection, and increased efforts for engagement in treatment are necessary.
Adolescent↗
Buprenorphine: duration of blockade of effects of intramuscular hydromorphone.
Six opioid-dependent in-patients were maintained on daily sublingual doses of buprenorphine at 2, 6, and 12 mg/day for five days at each dose in a randomized, balanced sequence. Placebo buprenorphine was substituted for the next three days, and challenge doses of the mu agonist hydromorphone were administered on the three days. Planned comparisons in a 3-factor ANOVA showed dose-dependent hydromorphone effects, significant blockade of 'high' by the 12 mg buprenorphine dose, and no differences on hydromorphone-induced 'high' across 72 h of active buprenorphine. The data suggest that the blockade by buprenorphine of 'high' persists for at least 72 h after the last dose of buprenorphine.
Administration, Sublingual↗
Stimulant withdrawal.
The current paper is a review of the literature on abstinence symptomatology after stimulant use. The studies performed indicate biological and physical changes during abstinence. One outpatient study suggests a phasic model of stimulant abstinence which is characterized by a 'crash', 'withdrawal', and 'extinction' phase. However, two inpatient studies do not confirm these findings. In contrast, these latter two studies did not find a crash phase and reported a gradual improvement of mood during these 21-day and 28-day inpatient stays. Biological measures suggest changes in receptor, endocrinological and neurochemical activity. One study found hyperprolactinemia throughout the 4-week period, while another study using PET and FDG ([18F]-Fluorodeoxyglucose) found increased brain glucose metabolism in the dopamine-rich areas of the basal ganglia and orbitofrontal cortex. Another study using PET and F18-Methylspiroperidol found decreased dopamine D2 receptor binding during cocaine withdrawal and also a separate study using PET and F-18-Dopa discovered low dopaminergic brain activity. To date, few studies have been performed, and the lack of clear-cut physical withdrawal symptoms as seen in alcohol, sedative, and opiate withdrawal makes it difficult to demonstrate definitively the presence of withdrawal during stimulant abstinence. Amphetamine withdrawal has been less studied, but empirical data suggest that the symptoms are similar to cocaine withdrawal. Further studies are needed to better delineate the presence of acute versus chronic post-use symptoms.
Affect↗
Platelet alpha-granule release in cocaine users.
BACKGROUND: Cocaine use has been associated with arterial occlusion resulting from platelet-rich thrombi and with an accelerated, often atypical atherosclerotic lesion that could be ascribed to platelet activation and platelet alpha-granule release. METHODS AND RESULTS: Using a flow cytometric method to quantitate the percent of circulating activated platelets in whole blood (those that express the alpha-granule membrane protein P-selectin), we found that 5 of 25 samples from 12 long-term cocaine users had a baseline level of circulating activated platelets > 3 SD (range, 19% to 60%) above the mean (4.4 +/- 3.7%, mean +/- 1 SD) for 85 nonusers (sample n = 130). This subset resulted in a significantly higher mean baseline level of circulating activated platelets (11.8 +/- 14.4%) for all cocaine users (P = .01). By contrast, cocaine and its metabolites, at concentrations documented as obtainable during in vivo cocaine use (10(-7) to 10(-5) mol/L), had no effect on in vitro platelet activation or aggregation, either directly or in concert with platelet agonists. However, in experiments in which cocaine users received blinded infusions of placebo or cocaine, the mean percent of circulating activated platelets rose significantly (P < .05) after infusion of either placebo (peak 77 +/- 31%) or cocaine (peak 65 +/- 28%), the latter at doses resulting in peak plasma cocaine levels averaging < 10(-6) mol/L. CONCLUSIONS: Long-term cocaine use in some subjects is intermittently associated with high basal levels of circulating platelets that have undergone alpha-granule release. The inability of cocaine and its metabolites at concentrations of 10(-7) to 10(-5) mol/L to cause platelet P-selectin expression in vitro in this study, coupled with the acute increase in circulating activated platelets observed in vivo after either cocaine or placebo infusion, suggests that in vivo platelet alpha-granule release associated with cocaine use may occur through indirect rather than direct effects of the drug.
Blood Platelets↗
Nicotine dependence and schizophrenia.
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Adult↗
Reduction of opiate withdrawal-like symptoms by cocaine abuse during methadone and buprenorphine maintenance.
In a 6-month randomized trial comparing 125 opiate-dependent patients who were assigned to four treatment groups (2 or 6 mg of buprenorphine and 35 or 65 mg of methadone), we examined the effects of cocaine use on opiate withdrawal symptoms measured on a 25-item scale on which the scores range from 0 to 75. For the methadone-maintained patients receiving the relatively low dose (35 mg), weekly withdrawal symptoms were highest when the urine toxicology for that week indicated no cocaine use. Similar associations were found for buprenorphine. Thus, when using cocaine at a low maintenance opiate dose, persistent opiate withdrawal symptoms were reduced, which is consistent with previous naloxone-precipitated withdrawal studies. Interestingly, with a higher dose of buprenorphine (6 mg), cocaine may have increased opiate withdrawal symptoms, suggesting a possible mechanism for the reduction of illicit cocaine abuse also recently observed in another study in patients treated with high dose (120 mg) methadone maintenance. This has led to a two-component model for the relationship between cocaine and opiate withdrawal-like symptoms at high versus low opiate maintenance dose. This two-component model also reconciles the contradictory findings of prior studies.
Adult↗
Concurrent cocaine-ethanol ingestion in humans: pharmacology, physiology, behavior, and the role of cocaethylene.
Simultaneous abuse of cocaine and ethanol is a common occurrence. Cocaethylene, the ethyl ester of benzoylecgonine, has been detected in the urine of patients reporting concurrent use of cocaine and ethanol, and high levels have been found in the blood of victims of fatal drug overdose. This placebo-controlled, double-blind study examined the pharmacokinetic, physiologic, and behavioral effects of dual cocaine and ethanol administration in humans (n = 6). Cocaethylene was found in the plasma only after administration of both cocaine and ethanol, and appeared to be eliminated more slowly than cocaine. Plasma cocaine concentrations were significantly higher during cocaine/ethanol administration. Euphorigenic effects were both enhanced and prolonged, and heart rate was significantly increased, following cocaine/ethanol administration as compared to administration of cocaine or ethanol alone.
Adult↗
Effects of sham and real auricular needling: implications for trials of acupuncture for cocaine addiction.
We conducted a single-blind study (n = 48) comparing subjective evaluations of needles inserted into sham and real auricular acupuncture points. Both ears were needled concurrently, one in sham sites and the other in active points used in the treatment of cocaine addiction. Subjects then completed a questionnaire rating the intensity of five sensations in each ear, and also attempted to identify which ear received sham and which ear received real acupuncture. Results showed that real points were more painful than sham; there were no other overall differences. Subjects' ability to identify which ear received sham and which ear received real acupuncture did not rise above the level of chance.
Acupuncture Points↗
Should protracted withdrawal from drugs be included in DSM-IV?
OBJECTIVE: The authors reviewed both clinical data and selected laboratory research related to withdrawal from alcohol, opiates, and stimulants in order to draw a conclusion about whether the phenomenon of protracted withdrawal exists and should be included in DSM-IV. METHOD: Studies were located through computerized searches and reference sections of published articles. RESULTS: Symptoms extending beyond the period of acute withdrawal in alcohol and opiate dependence have been fairly consistently described; this is not the case with cocaine. Nevertheless, protracted alcohol and opiate withdrawal has not been conclusively demonstrated because of the failure of studies to do multiple time point sampling, to use standardized instruments and control groups, and to re-administer the substance in an attempt to suppress withdrawal symptoms. Further, the concept of protracted withdrawal itself is ambiguously defined. This confounds interpretation of the literature and precludes derivation of a unified concept of the term, which would be necessary for adding the diagnosis to DSM-IV. CONCLUSIONS: There is insufficient documentation to justify inclusion of protracted withdrawal in DSM-IV because of methodologic limitations of the studies and lack of consensus definition of the term itself. An outline for conceptualizing protracted withdrawal is offered in which the symptoms can be seen as: 1) a global post-use syndrome, 2) attenuated physiologic rebound, 3) toxic residuals, 4) expression of preexisting symptoms unmasked by cessation of use. Future efforts to identify signs and symptoms of protracted withdrawal should carefully define the parameters of the syndrome.
Central Nervous System Stimulants↗
Effects of acute buprenorphine on responses to intranasal cocaine: a pilot study.
Five inpatients dependent on both intravenous cocaine and heroin were detoxified from opiates. They were then given 5 days of double-blind treatment with active or placebo buprenorphine 2 mg/d sublingually, followed by a crossover to the converse for 5 days (buprenorphine or placebo). Intranasal cocaine challenges (2 mg/kg) were performed on Days 3 and 5 of each treatment. Buprenorphine significantly enhanced patients' ratings of cocaine-induced pleasurable effects, and augmented cocaine-induced pulse increases. The buprenorphine enhancement of subjective cocaine effects appeared to be more prominent on Day 3 than on Day 5. This reduction from Day 3 to Day 5 suggests that cocaine may interact differently with buprenorphine as treatment is more prolonged.
Adult↗