Heavy marijuana users show increased serum apolipoprotein C-III levels: evidence from proteomic analyses.

Marijuana (MJ) is the most commonly used illicit drug in the United States. Its abuse is associated with cognitive dysfunctions and increased resistance to blood flow in the cerebral vasculature. In addition, MJ abuse is associated with increased risks of potentially serious cardiovascular disorders. In the present study, we used the protein chip platform based on surface-enhanced laser desorption/ionization time-of-flight mass spectroscopy (SELDI-TOF-MS) to test the possibility that MJ abuse might be associated with changes in serum protein levels. Indeed, MJ users showed significant increases in three protein peaks, which were identified as three isoforms of apolipoprotein (apo) C-III. Immunoprecipitation using an apoC-III antibody also validated the identification of the proteins. Marijuana-induced increases in apoC-III levels might occur through chronic stimulation of hepatic cannabinoid receptors (CB1 and/or CB2) by its active ingredient, Delta(9)tetrahydrocannibol (THC). Thus, chronic MJ abuse might cause increased transcription and/or translation of apoC-III in the liver with corresponding changes reflected in the plasma of these patients. In any case, because apoC-III is a cardiovascular risk factor, the increased levels observed in MJ users might explain, in part, the cardiac and cerebral abnormalities reported in these patients.

Contribution of substance abuse and HIV infection to psychiatric distress in an inner-city African-American population.

We used Symptom Checklist 90-Revised (SCL90-R) to investigate psychiatric symptom severity in African-American drug-abusing individuals. Three hundred and seventeen African-American volunteers (52 control subjects; 265 drug users) were recruited, 19.2% of whom were HIV-positive. The impact of drug of choice or HIV status on mental distress was assessed. Symptomatic HIV-positive participants were excluded. The intake SCL90-R, Addiction Severity Index, and demographic data were subjected to regression analyses. Drug-abusing African Americans reported increased global distress, a finding that remained robust after we adjusted for HIV status, gender, age, and education. Drug of choice had no influence on the severity of global mental distress in our sample. Asymptomatic HIV-positive African Americans who abused drugs reported more distress than the HIV-negative drug users. Levels of global distress were similar in the HIV-negative and the HIV-positive controls. Subscales of the SCL90-R showed more symptom severity among drug-using, compared with nonusing, African Americans. Except for paranoia, anxiety, and obsessive-compulsive subscales, other symptom dimensions were significantly elevated in HIV-positive, compared with HIV-negative, drug abusers. When taken together, these findings suggest that drug abuse can exacerbate the severity of mental distress in HIV-positive patients. Treatment of these patients may be more successful if both sets of needs are addressed with matched interventions.

Antiviral medications improve cerebrovascular perfusion in HIV+ non-drug users and HIV+ cocaine abusers.

Antiviral medications have been useful in delaying the time course of HIV infection. Antiviral medications have also been reported to delay or reduce symptoms associated with AIDS related dementia and to improve cortical perfusion. The mechanism for this improvement is unclear. Thus, this report studies the effects of antiviral medications on cerebral blood flow velocity in HIV+ cocaine abusers, HIV+ control individuals and appropriate control individuals. Thirty-two unmedicated HIV+ individuals (28 cocaine abusers and 4 control individuals), 22 HIV+ individuals using antiviral medications (16 cocaine abusers and 6 HIV+ control individuals), 47 HIV- cocaine abusers, and 27 control HIV- subjects were studied. Blood flow velocities were determined for the anterior and middle cerebral arteries using transcranial Doppler sonography. HIV+ individuals on antiviral medications had lower pulsatility values, suggesting decreased resistance in the cerebral blood vessels, in comparison to HIV+ individuals not taking antiviral medications. HIV+ cocaine abusers and HIV+ control individuals using antiviral medications had pulsatility values similar to HIV- control subjects. Antiviral medications appear to reduce these cerebrovascular perfusion deficits in HIV+ individuals. The antiviral medications appear to have a direct neuroprotective effect in addition to their antiviral effects. The neuroprotective role of antiviral medications requires further investigation.

Marijuana abusers are at increased risk for stroke. Preliminary evidence from cerebrovascular perfusion data.

We have recorded blood flow velocity in the anterior and middle cerebral arteries by transcranial Doppler sonography in abstinent marijuana abusers (n = 16) and control subjects (n = 19) to assess the effects of prolonged marijuana use of the cerebrovascular system. The pulsatility index, a measure of cerebrovascular resistance, and systolic velocity were significantly (p < 0.005) increased in marijuana abusers compared to the control subjects. These findings suggest that cerebral perfusion observed in 18-30 year old marijuana abusers is comparable to that of normal 60 year-olds. Thus, chronic abuse of marijuana might be a risk factor for stroke.

Gender differences in the EEG of abstinent cocaine abusers.

Gender differences in the EEG were explored in cocaine-abusing individuals not seeking treatment. Twenty currently abstinent cocaine-abusing females aged 21-41 were studied. Their cocaine use history was matched to 20 currently abstinent cocaine-abusing males. Twelve female and 20 male non-drug-abusing individuals served as a control group. Resting eyes closed EEG was recorded from 8 leads. The males who used cocaine had elevated EEG beta (p<0.0125) and reduced alpha (p<0.0125) when compared to the cocaine-abusing females and control subjects. These findings suggest that the EEG of cocaine-abusing women may be more normal than that of cocaine-abusing men. Such gender-specific differences for cocaine-abusing populations may require gender-specific treatment to improve outcome.

Caffeine withdrawal increases cerebral blood flow velocity and alters quantitative electroencephalography (EEG) activity.

RATIONALE: Cessation of daily caffeine consumption produces a withdrawal syndrome comprised of subjective symptoms and functional impairment. Few controlled studies have examined the physiological effects of caffeine withdrawal. OBJECTIVE: The present study examined the effect of caffeine withdrawal on cerebral blood flow velocity and quantitative EEG. METHODS: Ten volunteers reporting moderate caffeine intake (mean 333 mg/day) participated in this double-blind study. Subjects completed several tests when maintaining their normal diet (baseline period) and during two 1-day periods during which they consumed caffeine-free diets and received capsules containing placebo (placebo test session) or caffeine (caffeine test session) in amounts equal to their baseline daily caffeine consumption. Blood flow velocity was determined for four arteries: right and left middle (MCA), and right and left anterior (ACA) cerebral arteries using pulsed transcranial Doppler sonography. EEG was recorded for 3 min from eight scalp sites while subjects sat, with eyes closed, in a sound-attenuated electronically shielded chamber. Subjective effects were assessed with questionnaires. RESULTS: Results showed an effect of the placebo (21-h withdrawal) condition compared to the caffeine condition. Placebo significantly increased the mean velocity, systolic velocity and diastolic velocity (cm/s) in all four cerebral arteries. In the MCA, the pulsatility index was significantly decreased following placebo. Placebo significantly increased EEG theta power. Placebo also produces subjective effect changes, including increases in heavy feelings in arms and legs and decreases in ability to concentrate. The caffeine and baseline conditions produced similar results on both the physiological and subjective measures. CONCLUSION: Cessation of daily caffeine consumption produced changes in cerebral blood flow velocity and quantitative EEG. These changes may be related to classic caffeine withdrawal symptoms of headache, drowsiness and decreased alertness.

Neurovascular deficits in cocaine abusers.

The nature of the neurological and cerebrovascular deficits in cocaine abusers and whether they persist in abstinence is unclear. Blood flow velocity of the anterior and middle cerebral arteries was measured by transcranial Doppler sonography in cocaine abusers (n = 50) and control subjects (n = 25). Blood flow velocity was measured within 3 days and again after about 28 days after being admitted to an inpatient research ward to determine whether blood flow velocity improved during monitored abstinence conditions. The mean, systolic, and diastolic velocities as well as the pulsatility index in middle and anterior cerebral arteries significantly differed between controls and cocaine abusers (p < .05). Cerebrovascular resistance is increased in cocaine abusers and the increase persists for over a month of abstinence. Further research is needed to determine whether cerebrovascular resistance can be improved by pharmacological manipulations and whether improved blood flow relates to improved treatment outcome.

The regulation of cerebral blood flow during intravenous cocaine administration in cocaine abusers.

Cocaine abuse is associated with heightened risk of life-threatening neurological complications such as strokes, seizures, and transient ischemic attacks. We used transcranial Doppler (TCD) sonography, a continuous measure of cerebral blood flow velocity, to better understand the changes in cerebral hemodynamics produced by cocaine administration, which may lead to an increased risk for stroke in cocaine abusers. Heart rate and blood pressure were also measured. Blood flow velocity of seven cocaine abusers was studied during placebo, 10-, 25-, and 50-mg intravenous (i.v.) injections of cocaine. A significant increase in mean and systolic velocity which lasted for about two minutes was observed with all doses of cocaine, with no change in the placebo condition. This increase in systolic velocity indicates that cocaine produces an immediate and brief period of vasoconstriction in large arteries of the brain. The present results elucidate the time course of cocaine's acute cerebrovascular effects and provide a better understanding of etiology of cocaine-related stroke and transient ischemic attacks.

Cocaine dependence. A clinical syndrome requiring neuroprotection.

Cocaine use has increased the frequency of medical complications among younger individuals. Neurological and neurovascular complications include strokes, seizures, transient ischemic attacks, and headaches. Subclinical deficits in cerebral perfusion and EEG have been noted in this population. Although these subclinical deficits may be an indication of increased risk of medical complications, the prophalactic treatment of cocaine abusers with neuroprotective agents has not yet been advocated. Blood flow of the anterior and medial cerebral arteries was measured by transcranial Doppler sonography in cocaine abusers (n = 70) and control subjects (n = 20) to determine whether cocaine abusers might have reduced cerebral blood flow in large cerebral arteries. Blood flow was measured within three days of and again about 28 days after admission of subjects to an inpatient research ward to determine whether blood flow improved with monitored abstinence. The mean, systolic, and diastolic velocities as well as the Pulsatility Index (PI) in both arteries differed between the control and cocaine abusers (p < 0.05). After about a month of abstinence, blood flow for the cocaine-dependent subjects increased. These preliminary findings suggest that blood flow is reduced in cocaine abusers and that there is a slight improvement with abstinence. Further research is needed to determine whether blood flow in abstinent cocaine abusers can be increased by pharmacological manipulations.

Subclinical neurological and neurovascular deficits in cocaine dependence. Gender and psychosocial considerations.

Neurological and neurovascular deficits were reported in cocaine abusers. In order to examine the contribution of cocaine use severity as well as other psychosocial factors to these deficits, we examined the following measures in a sample of cocaine abusers (n = 70): blood flow (transcranial Doppler sonography), and psychosocial measures (the Norbeck Social Support Questionnaire, the Symptom Check List 90R, the Beck Hopelessness Scale, and the Ellison Wellness Scale). Blood flow in the anterior and medial cerebral arteries was lower in the cocaine abusers than in the control subjects. Both cocaine use and psychosocial measures significantly predicted decreases in blood flow.

Neurophysiological signs of cocaine dependence: increased electroencephalogram beta during withdrawal.

To determine whether a central nervous system marker of cocaine dependence might exist, the resting electroencephalogram (EEG) of 33 drug-free, cocaine-dependent men (DSM-III-R criteria) was compared with two control groups [nondrug group (n = 10) and drug group who abused drugs, but were not cocaine dependent (n = 20)]. The EEG was recorded from eight sites after about 10 days of monitored abstinence (range 4-15 days) on a closed research ward for the drug-using individuals. The EEG was recorded for the nondrug control group as outpatients. The drug history was determined by the drug history questionnaire and a medical screening interview. The percent of EEG beta activity for the cocaine-dependent subjects was greater than that of both control groups (p < .05) as well as a normative database (HZI: Tarrytown, NY). The percent of EEG beta in frontal and central areas of the cocaine-dependent individuals was correlated with the frequency of cocaine use during the last 30 days. High levels of EEG beta may be a neurophysiological withdrawal sign in cocaine-dependent men.

The effects of nimodipine on the EEG of substance abusers.

Cocaine abusers have increased EEG beta and areas of reduced cortical blood flow. Since, nimodipine has neuroprotective effects and increases blood flow, we investigated the efficacy of single and multiple doses of the nimodipine in normalizing the EEG of substance abusers. Fourteen subjects received single (0, 30, 60 mg) and eleven received multiple daily (up to 150 mg in 12 hours) doses of nimodipine to determine whether this drug would increase EEG alpha and decrease beta in substance abusers. The EEG was recorded from eight scalp locations (F3, C3, P3, O1, F4, C4, P4 and O2) for three minutes during eyes closed, and eyes open conditions. Single and multiple doses of nimodipine produced significant increases in EEG alpha and decreases in EEG beta in the eyes open condition. Thus, nimodipine may have potential therapeutic implications in the treatment of cocaine dependence. Chronic nimodipine dosing in cocaine-dependent individuals is now needed to confirm its efficacy in the treatment of cocaine dependence.

Nimodipine improves information processing in substance abusers.

We examined whether nimodipine can improve information processing in healthy drug abusers using cognitive event-related potential (ERP) methodology. Placebo and 30- and 60-mg doses of nimodipine were administered on separate days in a random double-blind design to twelve male subjects, who used cocaine and/or opiates as well as alcohol and marijuana. The subjects performed the auditory rare event monitoring (AREM) task and the paired letter version of the visual continuous performance task (CPT) before oral drug administration as well as one and two hours after drug ingestion. The EEG was recorded from 7 scalp locations. The P3 component of the ERPs to the target stimulus was reduced with repeated testing on the placebo day. The 30-mg dose of nimodipine blocked the decrease in P3, which reflects stimulus evaluation in both tasks. Chronic administration of nimodipine may alleviate the cognitive deficits observed in substance abusers during abstinence and prevent treatment relapse.

Event-related potentials and alpha synchronization in preadolescent boys at risk for psychoactive substance use.

Numerous studies have evaluated event-related potentials (ERPs) as biological indicators of the liability for alcoholism. This study extends that approach by investigating ERPs in boys at risk for other substance use disorders. Prepubertal (10-12 years) sons of fathers diagnosed with psychoactive substance dependence (n = 28) were compared to matched sons of nonaffected fathers (n = 26) on an auditory ERP oddball task. Multivariate analyses of variance applied to peak amplitude and latency measures indicated small to moderate between-groups differences at midline or parietal sites: N2 and P3 amplitude; P2, N2, P3, and Nc latency. This replicated P3 amplitude findings in alcoholism-risk studies, though the effect size was moderate. Analysis of event-related alpha power indicated significantly longer latency of alpha synchronization and oscillations of desynchronization in boys at risk. The alpha power findings were statistically the more robust of the measures applied. The role of neurocognitive factors in determining liability for substance use disorders is discussed.

Lack of evidence for context-dependent cocaine-induced sensitization in humans: preliminary studies.

Cocaine-induced behavioral sensitization is the well-documented phenomenon where repeated doses of cocaine elicit increasingly greater effects on motoric activity in rats. Some observations suggest that behavioral sensitization may provide a model for understanding the mechanisms of drug-craving elicited by environmental triggers or cues. The process of fully validating such an animal model for its ability to detect effective anticraving medicines is a difficult and long-term undertaking. As a first step in that direction, we decided to determine if cocaine can produce conditioned behavioral sensitization in humans using a paradigm fairly similar to that used for rodents. Because humans do not react to cocaine with the pronounced motor activation observed in rodents, we measured a variety of end points, including blood pressure (BP), heart rate (HR), respiratory rate, pupil diameter, hormones (prolactin and cortisol), and subjective responses using the questionnaire for drug-related feelings (QDRF) and the EEG. To mimic the home and test cages used in rodent studies, two rooms were used: a small test chamber and a regular room with a window and furnishings. On day 1 each subject received a drug infusion (either saline or 40 mg cocaine IV) in both locations. On day 2, all subjects received an infusion (saline or 25 mg cocaine IV) in the test chamber. All drug infusions were conducted double blind. The paired group received cocaine on both days in the test chamber. The unpaired group received cocaine in regular room on day 1, and cocaine in the test chamber on day 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Cocaine-induced increases in EEG alpha and beta activity: evidence for reduced cortical processing.

To understand the effects of cocaine on the cerebral cortex, 14 male polydrug abusers were enrolled in a study on the effects of cocaine on the electroencephalogram (EEG). The experimental treatments were placebo, 20 mg cocaine or 40 mg cocaine i.v. administered in a double-blind, pseudorandom design. The EEG was recorded from 13 electrode positions over the left hemisphere during a 3-minute baseline recording and for 30 minutes after initiation of the i.v. injection. The spectral power for delta, theta, alpha and beta EEG bands was calculated from data collected in each 3-minute interval. Cocaine significantly increased beta in frontal and central areas and enhanced alpha in frontal and temporal regions. Cocaine-induced increases in EEG beta power had a cortical distribution similar to those produced by barbiturates and benzodiazepines. As all of these drugs reduce cortical glucose metabolism, the increases in beta power may reflect a reduction in cortical neural activity.

Cognitive brain potential alterations in boys exposed to opiates: in utero and lifestyle comparisons.

Several studies have observed that intrauterine exposure to opiates results in emotional and cognitive complications for the child, but genetic and postnatal social-environmental factors may also affect the CNS development of these children. To assess the relative contribution of the in utero and social-environmental (lifestyle) effects of opiate exposure, event-related potentials (ERPs) and performance were studied in three groups of 7- to 12-year-old boys: (1) the in utero/lifestyle group (IU/LS) contained 16 boys who were exposed to opiates (in utero and lived with opiate-abusing mothers, (2) the lifestyle group (LS) included 14 boys who lived with opiate-abusing mothers, and (3) the control group (CON) composed of 13 boys. The cognitive ERP components and task performance were recorded in the Auditory Rare Event Monitoring (AREM) task and the Sternberg Memory task (Sternberg, 1975). On the AREM and Sternberg Memory tasks, P200 component was significantly decreased for the IU/LS and LS groups. On the Sternberg Memory task, percent correct was also significantly impaired in IU/LS and LS groups. The ERP alterations in the boys living with opiate-abusing mothers with and without intrauterine opiate exposure were similar. A dysfunctional social environment may contribute to the cognitive deficits seen in the sons of opiate-abusing mothers.

Effects of cocaine on P3B in cocaine abusers.

Little is known about the effects of cocaine on cognitive tasks. Event-related potentials (ERP) were recorded in 7 cocaine abusers during the performance of the auditory oddball task before and after the intravenous injections of saline and cocaine (60-80 mg). The P3B and slow wave components of the ERP were significantly larger 60-210 min after the cocaine than after the placebo injection. The results suggest that cocaine abusers have difficulty in maintaining optimal stimulus processing during extended testing. Cocaine blocks this decrement in stimulus processing.