Effects on humans of 9 -tetrahydrocannabinol administered by smoking.

Twelve chronic marijuana users received triangle up(9)-tetrahydrocannabinol by smoking. The magnitude of their pulse increment was highly correlated with their subjective experiences. Three of the 12 subjects subsequently received triangle up(9)-tetrahydrocannabinol labeled with carbon-14; the time course of its concentration in plasma was highly correlated with the pulse increment. Subjective symptoms, however, appeared later and dissipated more slowly.

Cannabis and alcohol: effects on stimulated car driving.

The effects of cannabis and alcohol on simulated car driving were studied. Cannabis resin containing 4 percent Delta(1)-tetrahydrocannabinol was administered orally in three doses equivalent to 8, 12, and 16 milligrams of that component. Alcohol was given orally in one standard dose of 70 grams. Both cannabis and alcohol increased the time required to brake and start, whereas alcohol increased while cannabis decreased the number of gear changes. An effect of dosage on response was observed with cannabis.

Mechanism of pulsus paradoxus in clinical shock.

An inspiratory fall in systolic arterial pressure of more than 10 mm Hg (pulsus paradoxus) was noted in 30 of 61 patients with shock. Inspiratory right atrial pressures and total blood volumes were significantly lower in patients with pulsus paradoxus. Rapid infusion of dextran in 22 patients usually was effective in reversing the exaggerated inspiratory fall in systolic pressure. Total peripheral vascular resistance tended to be higher in the patients with pulsus paradoxus and administration of vasoconsrictor drugs often accentuated the respirator pressure variation. Respiratory effects on blood flow in the aorta, pulmonary artery, and venae cavae were studied in anesthetized, closed-chest dogs. In the control state, pulmonary arterial flow increased during inspiration but aortic flow remained nearly constant. After hemorrhage a sharp inspiratory fall in aortic flow was associated with decreased central blood volume and attenuation of the usual inspiratory increase in venae caval and pulmonary arterial flows. The respiratory changes in aortic flow after hemorrhage could be attributed both to depletion of the pulmonary reservoir and to alterations in pulmonary inflow related to changes in systemic venous return. These data indicate that blood volume depletion may precipitate pulsus paradoxus both in the anesthetized dog and in the critically ill patient. The occurrence of pulsus paradoxus may aid in the clinical recognition of the common syndrome of occult hypovolemia in patients with shock in the absence of signs of blood loss.

Effect of atropine on vagal release of gastrin and pancreatic polypeptide.

We studied the effect of several doses of atropine on the serum gastrin and pancreatic polypeptide responses to vagal stimulation in healthy human subjects. Vagal stimulation was induced by sham feeding. To eliminate the effect of gastric acidity on gastrin release, gastric pH was held constant (pH 5) and acid secretion was measured by intragastric titration. Although a small dose of atropine (2.3 mug/kg) significantly inhibited the acid secretory response and completely abolished the pancreatic polypeptide response to sham feeding, this dose of atropine significantly enhanced the gastrin response. Higher atropine doses (7.0 and 21.0 mug/kg) had effects on gastrin and pancreatic polypeptide release which were similar to the 2.3-mug/kg dose. Atropine (0.78 and 2.3 mug/kg) without sham feeding significantly inhibited basal acid secretion and also led to significant increases in serum gastrin above basal levels. The gastrin response to sham feeding with 2.3 mug/kg atropine was significantly greater than the sum of the gastrin responses to sham feeding alone and to 2.3 mug/kg atropine alone, indicating potentiation of vagal gastrin release by atropine. We conclude: (a) Unlike vagally mediated gastric acid secretion and pancreatic polypeptide release which can be blocked by atropine, vagal gastrin release is potentiated by atropine. This observation suggests the existence of a vagal-cholinergic pathway which normally (i.e., in the absence of atropine) inhibits gastrin release. (b) Because atropine (without sham feeding) increased basal gastrin levels, it is likely that the cholinergic pathway which inhibits gastrin release is active even when the vagus nerve is not stimulated by sham feeding.

Characterization of concentration- and use-dependent effects of quinidine from conduction delay and declining conduction velocity in canine Purkinje fibers.

The dynamic response of squared conduction velocity, theta 2, to repetitive stimulation in canine Purkinje fibers with quinidine was studied using a double-microelectrode technique. With stimulation, a frequency-dependent monoexponential increase in conduction delay (CD) and a decline in theta 2 were observed. The exponential rates and changes in steady-state CD and theta 2 were frequency- and concentration-dependent. The overall drug uptake rates describing blockade and the interpulse recovery interval were linearly related and steady-state values of theta 2 were linearly related to an exponential function of the stimulus intervals. Based on first-order binding, the frequency- and concentration-dependent properties of quinidine were characterized by the apparent binding and unbinding rates of 14.2 +/- 5.7 X 10(6) mol-1.s-1 and 63 +/- 12 s-1 for activated and 14.8 +/- 1.0 X 10(2) mol-1.s-1 and 0.16 +/- 0.03 s-1 for resting states. The recovery time constant extracted from the pulse train interpulse interval was 5.8 +/- 1.5 s compared with 5.1 +/- 0.6 s determined from a posttrain test pulse protocol. This study demonstrates that the kinetics of drug action can be derived from measures of impulse propagation. This provides a basis for characterizing frequency-dependent properties of antiarrhythmic agents in vivo and suggests the plausibility of a quantitative assessment of drug binding and recovery rates in man.

Effects of dibutyryl cyclic adenosine 3',5'-monophosphate and parathyroid extract on calcium and phosphorus metabolism in hypoparathyroidism and pseudohypoparathyroidism.

It has been proposed previously that the metabolic defect in pseudohypoparathyroidism which accounts for parathyroid hormone unresponsiveness is an absence or abnormal form of the adenyl cyclase system in kidney and presumably in bone. To determine whether there is an associated defect in the response mechanism to cyclic adenosine 3',5'-monophosphate (cyclic AMP), the effects of parathyroid extract (PTE), and dibutyryl cyclic AMP were compared in patients with either surgical hypoparathyroidism or pseudohypoparathyroidism. PTE and dibutyryl cyclic AMP both increased serum and urinary calcium, lowered the serum phosphorus, and increased urinary phosphorus in patients with hypoparathyroidism. PTE also increased urinary cyclic AMP in these patients. PTE increased serum and urinary calcium and urinary phosphorus but did not alter serum phosphorus or urinary cyclic AMP in the patients with pseudohypoparathyroidism. Dibutyryl cyclic AMP increased the serum and urinary calcium, lowered the serum phosphorus, and increased urinary phosphorus in all the patients with pseudohypoparathyroidism. The results indicate that (a) dibutyryl cyclic AMP can reproduce the effects of parathyroid hormone on calcium and phosphorus metabolism in man, (b) the response mechanism to cyclic AMP appears to be intact in pseudohypoparathyroidism, and (c) PTE apparently produces some of its characteristic effects on calcium and phosphorus metabolism in pseudohypoparathyroidism in the absence of an increase in urinary cyclic AMP.

Mechanisms of interleukin-2-induced hepatic toxicity.

Interleukin 2 (IL-2) mediates the regression of metastatic cancer, but its clinical use is limited by associated toxicities including hepatic dysfunction. To determine the mechanism for IL-2-induced hepatic dysfunction, we hypothesized that IL-2 activation of Kupffer cells causes leukocyte-endothelial adhesion and decreases hepatic sinusoidal blood flow. C57BL/6 mice were given injections of latex particles and prepared for intravital hepatic microscopy 2 h after i.p. IL-2 administration. Liver tissue was also prepared to quantitate hepatic tumor necrosis factor (TNF) mRNA and processed for light and electron microscopy. Phagocytosing Kupffer cells and leukocytes adherent to the endothelium were counted, and surface sinusoidal blood flow was quantitated. Kupffer cell activity was quantitated as the ratio of phagocytosing Kupffer cells to sinusoidal blood flow. IL-2 significantly increased Kupffer cell activity (0.56 +/- 0.05 for controls versus 0.84 +/- 0.05 for IL-2), significantly caused leukocyte-endothelial adhesion (26.7 +/- 7.9 for controls versus 87.0 +/- 27.6 for IL-2, WBC/mm2 endothelial surface), and significantly decreased the number of sinusoids containing blood flow per microscopic field (6.66 +/- 0.15 for controls versus 5.79 +/- 0.13 for IL-2) without causing changes in systemic hemodynamic parameters. In IL-2 treated livers, light and electron microscopy showed the constriction of sinusoids associated with swollen or ruptured mitochondria, which was consistent with hypoxic deterioration near central venules. Adherent platelets, neutrophils, and lymphocytes within sinusoids and central venules were also observed. PCR revealed that IL-2 significantly induced TNF mRNA expression in the liver. These data suggest that IL-2 activates Kupffer cells in association with the release of monokines including TNF, which causes activation of circulating leukocytes as well as hepatic sinusoidal endothelial cells. The resultant leukocyte and platelet adhesion to the endothelium may then physically impede the sinusoidal microcirculation, resulting in microscopic areas of hepatic ischemia and explaining the mechanism of IL-2-induced hepatic dysfunction.

Provocation of postural hypotension by insulin in diabetic autonomic neuropathy.

The effect of insulin administration on blood pressure has been investigated in eight diabetes with autonomic neuropathy. Systolic and diastolic pressures fell considerably after insulin in all of them. This effect was aggravated by tilting to the vertical position. Five patients fainted when upright with systolic blood pressures less than 50 mm. Hg. This hypotensive effect of insulin occurs whether it is administered intravenously, intramuscularly, or subcutaneously. The onset of the effect is almost immediate after intravenous insulin, is progressive, and may last for several hours. It coincides with a falling blood glucose level and occurs before hypoglycemic levels are reached, and it may be present when the blood glucose level is still elevated. Diurnal variations of postural hypotension have been recorded in some patients, the standing blood pressure falling with the onset of insulin action and rising again as the latter declines. Some of our patients were unable to differentiate between symptoms of hypoglycemia and hypotension. Postural hypotension may account for some episodes of sudden loss of consciousness without warning, usually attributed to hypoglycemia.

Phosphorylation of C-protein in intact amphibian cardiac muscle. Correlation between 32P incorporation and twitch relaxation.

The molecular mechanisms by which neurotransmitters modulate the force of contraction of cardiac muscle are incompletely understood. Hartzell and Titus (1982. J. Biol. Chem. 257:2111-2120) have recently reported that C-protein, an integral component of the thick filament, is reversibly phosphorylated in response to ionotropic agents. In this communication, C-protein phosphorylation (as measured by isotopic labeling with 32P) is correlated with changes in the rate of relaxation of twitch tension. On the average, isoproterenol simultaneously increases peak systolic tension twofold, decreases twitch relaxation time from a control value of approximately 450 to approximately 300 ms, and increases C-protein phosphorylation two- to threefold, with a maximum effect occurring less than 60 s after addition of 1 microM isoproterenol. Carbamylcholine, in contrast, decreases peak systolic tension more rapidly than it affects relaxation or C-protein phosphorylation. The maximum decrease in peak tension (60%) occurs within 1 min of addition of 0.5 microM carbamylcholine, but relaxation time increases slowly to 800 ms over approximately 6 min. The increase in relaxation time correlates well with the decrease in 32P incorporation into C-protein (r = 0.94). Changing beat frequency between 0.2 and 1/s has no effect on C-protein phosphorylation but does alter relaxation time (relaxation time decreases approximately 100 ms when beat frequency is changed from 0.5 to 1/s) and thus alters the quantitative relationship between C-protein phosphorylation and relaxation rate. These results suggest that two separate processes affect relaxation. It is proposed that the level of C-protein phosphorylation sets the boundaries over which relaxation is regulated by a second process that is dependent upon beat frequency and probably involves changes in intracellular Ca.

Marijuana consumption and tolerance to physiological and subjective effects.

The relation between marijuana consumption and the development of tolerance was investigated during a 31-day study. Volunteers with a history of moderate or heavy marijuana use were given access to one-gram (2.1% delta9 tetrahydrocannabinol [THC]) marijuana cigarettes during a 21-day smoking period. Both groups tended to increase consumption during this time. Heavy users averaged 5.7 cigarettes per day and indicated a progressive decline in ratings of intoxication and duration of pulse rate effect. Moderate users averaged 3.2 cigarettes per day but showed no changes in either of these reactions during this time. Results suggested that tolerance does not develop to the two most reliable indexes of marijuana intoxication unless heavy doses of delta9 THC are self-administered repeatedly. Also, the tendency to increase consumption during this time is not necessarily associated with the development of tolerance.

Naloxone-induced behavioral and physiological effects in normal and manic subjects.

Intravenous naloxone hydrochloride (20 mg) was administered to eight normal control subjects and 12 affective disorder patients manifesting manic or hypomanic symptoms. On two consecutive days, in a counterbalanced order, naloxone and placebo were given in a double-blind crossover design. The overall effect of naloxone was to decrease pulse rate and to promote lethargy and inactivation. The normal controls manifested reduced feelings of well-being, and the manic patients noted a subjective sense of slowing. There was a variable response pattern to naloxone in the manic patients in which four of the 12 patients manifested an observable reduction in their manic symptoms and behavior after the naloxone administration. Naloxone seems to have had a nonspecific subduing effect in both normal subjects and patients and may also have had a selectively greater effect in a small subsample of the manics.

Noradrenergic function in schizophrenia.

Yohimbine, an alpha 2-adrenergic receptor antagonist that increases noradrenergic function, was administered to 16 healthy subjects and 18 drug-free schizophrenic patients with (n = 10) and without (n = 8) tardive dyskinesia (TD). Outcome measures of this double-blind, placebo-controlled study included changes in behavior, plasma 3-methoxy-4-hydroxy-phenylglycol (MHPG) level, blood pressure, and heart rate. A subgroup of six patients experienced a notable dysphoric arousal reaction that occurred 60 to 90 minutes following administration of 20 mg of yohimbine, this reaction was not observed in healthy subjects. The schizophrenic group as a whole (not the subgroup) showed a statistical trend toward a greater yohimbine-induced increase in plasma MHPG level and systolic sitting blood pressure. The patients with TD did not differ from those without TD or from healthy controls in their response to yohimbine. These results do not support the hypothesis that noradrenergic dysfunction plays a strong central role in the pathogenesis of schizophrenia or TD. However, further studies of noradrenergic dysfunction in sub-groups of patients with schizophrenia are indicated.

Neuroendocrine response to 5-hydroxytryptophan in seasonal affective disorder.

A double-blind random-ordered comparison of the effects of placebo and 5-hydroxytryptophan (200 mg, orally) in ten depressed patients with seasonal affective disorder (SAD) and ten controls disclosed slightly but significantly higher basal levels of serum prolactin and a trend toward higher basal levels of serum cortisol in the patients with SAD compared with controls. After administration of 5-HTP, the cortisol level significantly increased and the prolactin level significantly decreased in both patients and controls. No differences in the melatonin level, growth hormone level, blood pressure, or pulse rate and no side effects were noted between patients and controls in the two study conditions; the timing of basal and 5-hydroxytryptophan-stimulated hormonal secretions was similar for both groups. These results are discussed with reference to current hypotheses of the cause of SAD.

L-deprenyl in Alzheimer's disease. Preliminary evidence for behavioral change with monoamine oxidase B inhibition.

Since monoamine neurotransmitter disturbances exist in some cases of dementia of the Alzheimer's type (DAT), monoamine-enhancing drugs may ameliorate some symptoms of DAT. L-Deprenyl is a monoamine oxidase (MAO) inhibitor that is generally free of undesired effects. At low doses (10 mg/d) it selectively inhibits MAO-B, an enzyme whose level is elevated in the brains of patients with DAT who are studied post mortem. At higher doses it has more complex effects, including inhibition of MAO-A plus MAO-B. We administered 10 mg/d and 40 mg/d of L-deprenyl to 17 patients with DAT in a double-blind, placebo-controlled, serial treatment. Total Brief Psychiatric Rating Scale scores decreased significantly during 10-mg/d treatment, with decreases in measures of anxiety/depression, tension, and excitement. Approximately one half of the patients' conditions were judged to be improved clinically, with evidence of increased activity and social interaction along with reduced tension and retardation. Similar but smaller changes were observed during 40-mg/d treatment. The behavioral changes were associated with improvement in performance on a complex cognitive task requiring sustained effort. There were minimal physiologic and side effects. The greater effect of low-dose L-deprenyl therapy suggests that it is the inhibition of MAO-B, and not MAO-A, that may be important in the behavioral effects of L-deprenyl administration to patients with DAT.

Abrupt withdrawal from therapeutically administered diazepam. Report of a case.

Subjective, behavioral, and physiologic changes followed abrupt withdrawal of diazepam (Valium) in a patient who had been treated with 30 to 45 mg of diazepam daily for 20 months. Precipitous weight loss and orthostatic pulse rate increase were a part of the abstinence syndrome, which occurred between the fifth and ninth days of withdrawal. Accompanying these changes in physiologic measures were discomforting symptoms and dysphoria that were aversive and reinforcing to drug taking since the patient sought diazepam administration. These observations suggest that changes in mood, feeling states, and behavior may be the most prominent characteristics of the abstinence syndrome associated with physical dependence on this dose level of diazepam.

Catecholamine metabolism in anorexia nervosa.

Urinary catecholamine levels were measured in 25 anorexia nervosa patients at the time when they were acutely ill with secondary depressive symptoms and again after treatment and weight gain to see whether changes in weight, activity levels, and symptoms of depression occurring during treatment might be associated with changes in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations. The latter was significantly lower in the acutely ill anorectics than in the control group. An increase in urinary MHPG concentration after treatment was significantly correlated with a decrease in depressive symptomatology. The increase in urinary MHPG level during treatment did not correlate significantly with change in patient's activity level. There seems to be a relationship between MHPG and the symptom of depression in a group of patients who do not carry a primary diagnosis of depression.

Plasma norepinephrine and dopamine-beta-hydroxylase activity in schizophrenia.

Plasma norepinephrine (NE) and dopamine-beta-hydroxylase (DBH) activity may be altered by changes in posture, pulse rate, and BP. Twenty-three drug-free schizophrenic, ten schizoaffective, and 24 normal control subjects, and a separate group of eight schizophrenic patients treated with chlorpromazine hydrochloride and haloperidol comprised the sample. Drug-free schizophrenic patients showed higher plasma NE levels while standing and higher pulse rates when supine and standing than normal subjects. Following chlorpromazine therapy, but not following haloperidol treatment, plasma NE level increased with patients supine and standing, pulse rate increased with patients standing, and systolic BP decreased with patients standing. These findings suggest (1) a decreased peripheral alpha-adrenergic postsynaptic receptor sensitivity in schizophrenia and (2) a peripheral alpha-adrenergic blocking mechanism in chlorpromazine-induced hypotension.

Effects of tolerance on the anxiety-reducing function of alcohol.

Thirty-two male social drinkers were arranged into two tolerance groups, based on changes in standing stability after ingestion of alcohol. Subjects consumed either a large (1.0 g/kg) or small (0.5 g/kg) dose of alcohol. On finishing their drinks, subjects were requested to interact with a female confederate whose continued silence induced anxiety. Heart rate, skin conductance, overt behavior, and self-report measures were taken. Heart rate increased more at the small than the large dose, consistent with the tension-reduction hypothesis. Further, heart rate of high-tolerance subjects increased significantly more than that of low-tolerance subjects, which suggests that alcohol was less effective at tension reduction for the high-tolerance group. Finally, measures of both skin conductance and heart rate showed significant dose-by-tolerance interactions. High-tolerance subjects were more aroused than were low-tolerance subjects at the small but not at the large dose, suggesting that high-tolerance subjects must consume more alcohol to achieve the same autonomic effect experienced by the low-tolerance subjects.

Marihuana and setting.

Marihuana or placebo cigarettes were smoked by 12 subjects in two environments, one "favorable" and one "neutral". The object was to determine the contribution of setting to the effects reported from the drug. Two quantifiable self-report measurements, the linear euphoriant scale and the card-sort version of the Addiction Research Center Inventory (marihuana and hallucinogen scales), were the major reporting criteria. Analyses of variance consistently demonstrated strong effects for subjects and drug but not for the environmental conditions. Reports of marihuana effects may be assumed to be highly colored by psychological differences in the mental set of subjects, or biological variations in their responses to the drug. The actual environment in which the drug is taken seems to play little, if any, role.

Biochemical changes during clomipramine treatment of childhood obsessive-compulsive disorder.

Peripheral measures of serotonergic and noradrenergic function were obtained in 29 obsessive-compulsive adolescents and 31 age- and sex-matched controls, as well as in a subsample of 22 patients after five weeks of treatment with clomipramine hydrochloride (134 +/- 33 mg/d) (mean +/- SD) given in a double-blind placebo-controlled trial. Drug-free obsessive-compulsive subjects did not differ from controls on measures of platelet serotonin and monoamine oxidase (MAO) activity, nor on plasma epinephrine or norepinephrine concentrations at rest and after a standard orthostatic challenge procedure. Compared with placebo, treatment with clomipramine was clinically effective and produced a marked decrease in platelet serotonin concentration, a trend toward a reduction in platelet MAO activity, and a rise in standing plasma norepinephrine. Clinical improvement during drug therapy was closely correlated with pretreatment platelet serotonin concentration and MAO activity, as well as with the decrease in both measures during clomipramine administration. This suggests that the effects of clomipramine on serotonin uptake may be essential to the antiobsessional action observed.