9 -Tetrahydrocannabinol and ethyl alcohol: evidence for cross-tolerance in the rat.

Rats trained in a one-way avoidance situlation were made tolerant to the depressant effects of Delta(9)-tetrahydrocannabinol. Ethyl alcohol (3.2 grams per kilogram, intraperitoneally) did not greatly affect rats that were tolerant to delta(9)tetrahydrocannabinol but depressed the behavior of nontolerant rats. Rats made tolerant to ethyl alcohol were less affected by Delta(9)-tetrahydrocannabinol.

Phytohemagglutinin-induced lymphocyte transformation in humans receiving delta9-tetrahydrocannabinol.

Eight otherwise healthy male chronic marijuana smokers were hospitalized for a period of 30 days. Initially they received placebo, then a sustained dose of 210 milligrams of delta9-tetrahydrocannabinol (delta9-THC) per day for 18 days, followed by placebo. Lymphocyte responses to phytohemagglutinin were examined during each of these periods. Neither the daily ingestion of marijuana extract containing 210 milligrams of delta9-THC for 18 days nor the history of chronic marijuana smoking had a depressive effect on the lymphocyte responses of these subjects to phytohemagglutinin.

Tobacco smoking and MRI/MRS brain abnormalities compared to nonsmokers.

This mini review emphasizes the fact that tobacco smoking causes small but real biologic brain changes that need to be studied in depth. A crucial question is whether these anatomical/chemical changes reverse toward normal when smokers quit. This review is presented to stimulate further research to answer this question.

Composition of the aqueous phase of chromaffin granules.

Nuclear magnetic resonance spectroscopy has been used to determine the composition of the aqueous phase of bovine chromaffin granules. Relative concentrations of catecholamines (epinephrine plus norepinephrine), ATP and chromogranins have been measured from integrated intensities in the proton spectra using computer simulation techniques. Most or all of the catecholamines (97 +/- 8%) are present in the aqueous phase and contribute to the high resolution spectrum. The catecholamine:ATP molar ratio (4.41 +/- 0.45) determined by NMR is close to the value (4.45) derived from biochemical assay indicating that most or all of the ATP is present with catecholamine in the aqueous phase. Catecholamine:protein ratios show that approximately 45% of the soluble protein freed by lysis is not NMR visible. Intensity from this fraction does not appear under highly denaturing conditions (8 M urea) but reappears after hydrolysis. This behavior is similar to that of recently isolated soluble lipoprotein complexes. Variations in the NMR spectra associated with (1) different preparative procedures; (2) different suspension media, and (3) increasing osmolality are described. The fact that high concentrations of epinephrine and ATP (approximately 700 mM total) are dissolved in the aqueous phase implies that solution phase interactions at least partially ionic in nature are responsible for the low internal osmolality of chromaffin granules in vivo. Ordered phases containing a substantial fraction of the total catecholamine in an osmotically inactive form are not present.

Blood protein fraction comparisons of normal and schizophrenic patients.

Whole blood, plasma, or serum levels of various components were measured in fasting, drug-free control subjects and drug-free schizophrenic patients. Compared to normal controls, chronic schizophrenic patients showed increased alpha2-globulins and decreased plasma cholinesterase activity and ceruloplasmin activity, and acute schizophrenic patients showed decreased alpha2-globulins. Compared to chronic patients, acute schizophrenics showed decreased alpha2-globulins and IgA. Compared to normal controls of similar age, chronic schizophrenic patients weighed less, were shorter, and had smaller body surface area. The acute schizophrenic patients were significantly younger than the normal subjects or chronic schizophrenics but there was no difference in the other physical measurements. The present study indicates no gross disturbances in the blood variables studied. That some differences are statistically significant from controls is of scientific interest, but of no clinical value in the diagnosis of schizophrenia.

Accumulation of N,N-dimethyltryptamine in rat brain cortical slices.

14C-DMT accumulates in rat brain cortical slices incubated at 37 C. This process has many of the properties of an active uptake mechanism. It is temperature-sensitive, sodium-dependent, saturable, and is inhibited by metabolic inhibitors. Tryptamine derivatives were more effective than the catecholamines in competing for 14C-DMT accumulation. A number of psychotropic drugs were inhibitors of 14C-DMT accumulation. In general, irrespective of pharmacologic class, the tertiary amines were more potent than the secondary or primary amines, although there were some exceptions. Most of the accumulated 14C-DMT was associated with the cytoplasmic fraction. Of the portion associated with the crude mitochondrial fraction, 54.4% was associated with nerve-ending fraction.

Lithium-induced increases in red blood cell choline and memory performance in Alzheimer-type dementia.

To investigate the relationship between RBC choline and memory in Alzheimer-type senile dementia (SDAT), lithium carbonate was administered to 14 SDAT patients in doses of 400-600 mg/day for 5 weeks. A battery of memory tests was administered at baseline and at weekly intervals. Five patients with serum concentrations below 0.6 meq/liter developed neurotoxicity and were dropped from further analysis. For the remaining patients, Li+ with mean serum concentrations up to 0.6 meq/liter did not alter memory scores significantly. The dramatic increases in RBC choline during the study, however, suggest that RBC choline is not correlated with memory functioning in SDAT.

Lack of clinically significant improvement of patients with tardive dyskinesia following phosphatidylcholine therapy.

A double-blind controlled study was undertaken to examine the value of phosphatidylcholine as a treatment for tardive dyskinesia (TD) in 19 psychiatric patients. All patients were maintained on their usual psychotropic medication throughout the entire study. In addition, they were given either phosphatidylcholine (30 g/day) or placebo for 6 weeks. Thirteen of the patients received the crossover treatment for 6 weeks, after which 10 of the 13 were continued on the crossover medication for an additional 6 weeks. At the end of the study, 5 patients had received phosphatidylcholine for 12 weeks and another 12 patients had received the drug for only 6 weeks. Plasma and red blood cell choline levels were monitored every 3 weeks as a measure of compliance. Although some patients showed clinical improvement of their TD, the results did not differ significantly between active drug and placebo. This was in spite of a marked elevation of plasma and red blood cell choline (up to 300% for the Lafayette Clinic patients and up to 400% for the patients from the Ypsilanti Regional Psychiatric Hospital) during treatment with phosphatidylcholine. Side effects of the drug included occasional gastrointestinal upsets and diarrhea but, in general, the medication was tolerated very well. The results indicate that large doses of phosphatidylcholine of soya origin are of no clinical value in treating symptoms of TD in spite of very large increases in blood choline.

NMR chemistry analysis of red blood cell constituents in normal subjects and lithium-treated psychiatric patients.

Red blood cells from 18 lithium carbonate-treated patients with bipolar affective disorder and 12 normal volunteers were analyzed using 1H-nuclear magnetic resonance (NMR) spectroscopy. The spectra were analyzed for alanine, adenosine triphosphate (ATP), choline, 2,3-diphosphoglycerol, glucose, glutathione, glycine, and lactate. Significant elevations of choline and lactate were found in the lithium-treated patients compared with normal, unmedicated subjects. The elevation of lactate due to anaerobic metabolism in the red blood cells was further investigated via fluorometric analysis and appears to be caused by blood standing at room temperature. The observed increases in red blood cell choline are sufficiently high and statistically significant to warrant additional studies on the dramatic effects of lithium on this red cell metabolite, which might be important for an understanding of its mechanism of action in psychiatric disorders.

Regional cerebral blood flow effects of nicotine in overnight abstinent smokers.

BACKGROUND: Most people agree that dependence to tobacco is mediated by the effects of nicotine on the central nervous system, albeit the neural pathways involved are not clearly delineated. We investigated the effect of nasal nicotine spray on regional cerebral blood flow (rCBF) in a sample of habitual smokers, with H2 15O and positron emission tomography (PET). METHODS: Eighteen volunteer smokers were studied after 12 hours of smoking deprivation. Regional cerebral blood flow measures were obtained with PET and 50 mCi H2 15O in six consecutive scans. Nicotine spray and a placebo spray were administered in a single-blind design, preceded and followed by baseline studies. Images were coregistered and anatomically standardized. Square (9-mm side) regions of interest were placed in 10 preselected brain regions, bilaterally. The effects of the experimental condition and gender were tested with two-way repeated-measures analysis of variance in each of the regions studied. RESULTS: Nicotine reduced rCBF in the left anterior temporal cortex and in the right amygdala. Increases were noted in the right anterior thalamus. CONCLUSIONS: In habitual smokers after overnight abstinence, nicotine induced differing effects on regional blood flow relative to whole brain blood flow. Increases were observed in the thalamus, a region rich in nicotinic receptors, and reductions in limbic and paralimbic (amygdala, anterior temporal cortex) regions.

Effects of urine acidification on plasma and urine phencyclidine levels in overdosage.

A gas chromatography--mass fragmentography--electron impact (GC-MS-EI) assay of phencyclidine (PCP) was adapted for human plasma and urine. This assay is specific for PCP and very sensitive (approximately 1 ng/ml). Patients with the putative diagnosis of PCP overdosage were studied to correlate plasma and urinary levels with clinical state. Urinary PCP levels were enhanced in an acid urine, which suggests that acidification of the urine is an adjunct in the therapy of PCP overdosage.

Effects of tobacco smoking and abstinence on middle latency auditory evoked potentials.

OBJECTIVE: To evaluate the effects of tobacco cigarette smoking and overnight abstinence on middle latency auditory evoked potentials among smokers and nonsmokers. METHODS: Groups of 9 to 10 adult male and female nonsmokers and smokers participated in the study. Each person volunteered for two laboratory sessions conducted in the early afternoon on 2 separate days. Smokers abstained from tobacco products 6 to 15 hours before the abstinent session and maintained their usual smoking behavior before the smoking session. The nonsmokers had a similar laboratory experience but sham smoked by means of inhaling air. Middle latency auditory evoked potentials were recorded from Cz to both ears as reference. RESULT: The latencies of the Na and Pa potentials during the smoking session were significantly (p < 0.01) shorter than those in abstinent smokers and nonsmokers. After smoking, peak-to-trough amplitudes for the V-Na, Na-Pa, and Pa-Nb potentials were larger than those after abstinence and significantly larger than those among nonsmokers. CONCLUSIONS: The shorter latencies of the middle latency brain wave components in the smoking session suggest faster processing of sensory information after cigarette smoking. Larger Pa amplitudes after cigarette smoking suggest a higher arousal level than that among partially abstinent smokers and nonsmokers.

Effects of repeated doses of scopolamine on the electroencephalographic stages of sleep in normal volunteers.

Single doses of scopolamine markedly alter sleep patterns in man. This study intended to evaluate the persistence of these changes during continued administration. The design consisted of a sequence of habituation, no-medication, saline (control), scopolamine (0.006 mg/kg intramuscularly 3 consecutive nights), and saline. The first dose of scopolamine markedly retarded the onset of stage rapid eye movement (REM) sleep (p less than 0.005) and diminished the total amount of REM sleep during the night (p less than 0.025). A decrease in total number of eye movements (p less than 0.05) and an increase in body movements (p less than 0.025) were also observed. Changes after the second dose of scopolamine were less marked but still significant. The third dose of scopolamine produced less marked changes than the preceding two. When compared with the first scopolamine night, the onset of stage REM was retarded to a lesser extent (p less than 0.05) and the total amount of REM sleep was increased (p less than 0.05). An increase in the duration of the first REM period was also observed. Rebound effects on the appearance of the first REM period (p less than 0.01), number of eye movements (p less than 0.001), total amount of REM sleep (p less than 0.01), and body movements were observed in the last saline night.

Effects of tobacco smoking on human ocular smooth pursuit.

OBJECTIVE: Test the hypothesis that nicotine-induced nystagmus results in reduced ocular smooth performance and pupil diameter in tobacco smokers. METHODS: Twenty nonsmokers (age range, 20 to 45 years; mean age +/- SE, 31.5 +/- 1.7 years) and 14 smokers (age range, 17 to 50 years; mean age +/- SE, 30.6 +/- 2.6 years) were studied after a minimum of 2 hours of tobacco abstinence. Subjects were studied before and immediately after they inhaled air through a sham cigarette or after they smoked one of their preferred brand of cigarettes, respectively. RESULTS: A very small, consistent, and statistically significant increase in smooth pursuit was found with both eyes to a 15 degrees per second moving target after one tobacco cigarette was smoked. This was due to improvement in left and not right eye smooth pursuit. The nonsmokers had no significant change in 15 degrees per second pursuit after sham smoking. Nonsmokers and smokers did not differ in left eye 6 degrees per second smooth pursuit before or after sham or tobacco smoking. The changes in right eye 6 degrees per second smooth pursuit were inconsistent and differed at various times between the two groups. During the smooth pursuit task the pupil diameter of the nonsmokers increased, but there was no change in the tobacco smokers. Black subjects had smaller baseline pupils than white subjects, unrelated to smoking status. CONCLUSIONS: Contrary to the hypothesis, tobacco smokers had a very small but significant improvement in left eye pursuit but no change in pupil diameter. Race-related differences in baseline pupil diameter were similar in both nonsmokers and smokers.

Relationship of electroencephalographic and cardiovascular changes to plasma nicotine levels in tobacco smokers.

OBJECTIVE: The effects of smoking one tobacco or placebo cigarette on the mean change in voltage of the electroencephalogram (EEG), arterial blood pressure, heart, and eye blink rates were correlated with the increase in plasma nicotine, exhaled carbon monoxide, and carboxyhemoglobin levels. METHODS: Twenty nonsmokers (age range, 19 to 42 years; mean age +/- SE, 27.0 +/- 1.9 years) and 65 regular tobacco smokers (age range, 20 to 48 years; mean age +/- SE, 27.7 +/- 0.8 years) were studied about 10 to 12 hours after overnight tobacco deprivation and immediately after inhaling air through a straw or after smoking one of their own brands of cigarettes, respectively. RESULTS: An increase of at least 10 ng/ml plasma nicotine was needed to obtain a statistically significant decrease in alpha 1 and an increase in beta EEG activity. An increase of at least 15 ng/ml plasma nicotine was needed to obtain a statistically significant decrease in delta EEG activity. The mean dominant alpha frequency, heart rate, systolic and diastolic blood pressure, exhaled carbon monoxide, and carboxyhemoglobin levels increased significantly with increasing plasma nicotine concentrations. CONCLUSIONS: Measurement of plasma nicotine levels is especially important to quantify the relationship between tobacco smoking, mean EEG activity, and cardiovascular changes. Nicotine plasma concentrations greater than 10 micrograms/ml produce consistent and statistically significant changes in brain wave activity. Smaller increments in plasma nicotine produce less consistent EEG changes.

Free and bound choline blood levels after phosphatidylcholine.

In six normal subjects we investigated the effects of oral phosphatidylcholine (lecithin) on the concentrations of plasma choline, erythrocyte choline, and choline-containing lipids. Plasma choline levels rose 1 hr after treatment and remained elevated for 8 hr, with peaks at 3 and 4 hr after phosphatidylcholine. Erythrocyte choline levels also rose, although the rise was slightly delayed relative to plasma choline. There was no change in the plasma choline-containing lipid concentration. These results demonstrate that, in normal subjects, oral phosphatidylcholine indices prolonged rises in plasma and erythrocyte choline concentrations and is therefore useful when such effects are desired.

Topographic electroencephalogram of propofol-induced conscious sedation.

OBJECTIVES: To determine the effects of increasing doses of propofol that induce conscious sedation on the topographic electroencephalogram (EEG) of human volunteers and to test the hypothesis that more frontal brain areas are affected by low doses of propofol. METHODS: The scalp EEG was recorded monopolarly from 16 different sites based on the 10-20 International System. Microcomputer-based hardware and RHYTHM 7.1 software were used to obtain quantitative power frequency topographic EEG data. A total of 10 normal adult volunteers were given incremental doses of propofol targeted to plasma concentrations of 0 to 1200 ng/ml. RESULTS: Sedative concentrations of propofol produced a dramatic increase in beta 1, an increase in alpha 2 and beta 2, and an increase in delta activity at the largest concentration, with almost no change in theta activity. The increase in beta 1 activity had a linear correlation with plasma propofol levels (r = 0.9). Topographic mapping indicated that beta 1 activation was primarily in the frontal and central regions, with focal changes more in the left hemisphere. CONCLUSIONS: Topographic brain EEG mapping techniques indicate that frontal brain beta 1 EEG activity may be useful as an objective brain index of propofol conscious sedation.

Ketamine kinetics in unmedicated and diazepam-premedicated subjects.

Plasma ketamine concentrations after diazepam and placebo pretreatment were examined in a double-blind, randomized, cross-over study. Eight healthy male subjects received either diazepam or a 0.9% NaCl placebo before ketamine and received the alternate combination 5 to 24 days later. Ten minutes before ketamine dosing, diazepam, 0.3 mg/kg, or placebo in equal volume was injected intravenously at a rate not exceeding 5 mg/min. Ketamine, 2.2 mg/kg iv, was injected over 1 min. For the clinically relevant period for anesthesia (1 to 30 min), diazepam-ketamine treatment resulted in higher plasma levels at most time points, but diazepam pretreatment did not alter plasma levels of metabolite KI and pseudometabolite KII nor the 24-hr urinary excretion of ketamine, KI, and KII. Ketamine kinetics followed a three-term exponential decline under both treatment conditions. After placebo-ketamine dosing, plasma t 1/2s were as follows: distribution (pi t 1/2) = 24.1 sec, redistribution (alpha t 1/2) = 4.68 min, and elimination (beta t 1/2) = 2.17 hr. After diazepam-ketamine dosing, t 1/2s were: pi t 1/2 = 25.0 sec, alpha t 1/2 6.37 min, and beta t 1/2 = 2.32 hr.

Short-term effects of smoking marijuana on balance in patients with multiple sclerosis and normal volunteers.

A double-blind randomized placebo-controlled study of inhaled marijuana smoke on postural responses was performed in 10 adult patients with spastic multiple sclerosis (MS) and 10 normal volunteers matched as closely as possible for age, sex, and weight. A computer-controlled dynamic posturographic platform with a video line scan camera measured shoulder displacement in response to pseudorandom platform movements. Premarijuana smoking patient tracking was inferior to that of the normal volunteers as indicated by the higher noise variance of the former. Smoking one marijuana cigarette containing 1.54% delta 9-tetrahydrocannabinol increased postural tracking error in both the patients and normal control subjects with both eyes open and closed; this untoward effect was greatest for the patients. The tracking error was also accompanied by a decrease in response speed for the patients with their eyes closed. Marijuana smoking further impairs posture and balance in patients with spastic MS.

Decreased blood platelet MAO activity in unmedicated chronic schizophrenic patients.

The authors found lower platelet monoamine oxidase (MAO) activity in 13 unmedicated chronic schizophrenic male patients in comparison to 13 mentally normal control male subjects--a finding that agrees with previous studies showing MAO activity to be low in the platelets of chronic schizophrenic patients. The authors urge that studies exploring endocrine factors and the role of hospitalization be undertaken to attempt to explain this finding.