Marihuana: standardized smoke administration and dose effect curves on heart rate in humans.

A spirometer was used to deliver marihuana and placebo smoke to human subjects. This procedure produced linear dose-effect curves on heart rate and replicable dose effects in individual subjects. No differences were observed between experienced and inexperienced smokers in responsiveness to heart rate increases produced by marihuana.

Delta-9-tetrahydrocannabinol: metabolism and disposition in long-term marihuana smokers.

Radioactively labeled delta-9-tetrahydrocannabinol (delta(9)THC) administered intravenously to chronic marihuana smokers disappeared from the blood plasma with a half-life of 28 hours as compared to 57 hours for nonusers of marihuana. Apparent volumes of distribution did not significantly differ between the two groups. Within 10 minutes after administration of delta(9)THC, 11-hydroxy-delta(9)THC is present in the plasma of nonusers and chronic users. This metabolite was also present in urine and feces of nonusers and long-term marihuana smokers. In addition, polar metabolites were excreted in urine and feces of both groups for more than 1 week.

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.

Intravenous injection in man of 9 -tetrahydrocannabinol and 11-OH- 9 -tetrahydrocannabinol.

A microsuspension of Delta(9)-tetrahydrocannabinol and of its metabolic derivative 11-OH-Delta(9)-tetrahydrocannabinol has been prepared with 25 percent human serum albumin as the vehicle. Intravenous infusion of this preparation to humans indicates that both tetrahydrocannabinols are equally potent in producing the typical marihuana-like pschological and physiological effects.

Marijuana and driving in real-life situations.

It is evident that the smoking of marijuana by human subjects does have a detrimental effect on their driving skills and performance in a restricted driving area, and that this effect is even greater under normal conditions of driving on city streets. The effect of marijuana on driving is not uniform for all subjects, however, but is in fact bidirectional; whether or not a significant decline occurs in driving ability is dependent both on the subject's capacity to compensate and on the dose of marijuana. For those subjects who improved their performance, the explanation may lie in overcompensation and possibly the sedative effect of the drug. Whereas the street portion of this study approximated normal driving conditions, it should be emphasized that the context of the driving experience een on city streets was experimental. the design of this study maximal safeguards in terms of a dual control vehicle and a driver observr; in addition, the subjects were proffessionally screened and, with rare exception, they were emotionally stable. Given the experimental setting and set, the safeguards, and the nature of the study sample, idiosyncratic behaviour that might occure under normal driving condition would be less likely to occur in a study such as this. Other identified factors might lead to more stringent conclussions regarding the effects of marijuana on driving.The first is night driving, which may be more stressful. But an even more important unanswered question is the cumulative effect of alcohol and marijuana on driving (64 percent of the study sample reported alcohol in combination with marihjuana before driving). Third, the doses of marijuana used in this study were within the range of social marijuana usage(1); more heroic doses might be taken before driving. Fourth, the effect of marijuana on reactions and decision during high speed is still another unknown. What are the recommendations that emarge from this study? Driving under the influence of marijuana should be avoided as much as should driving under the influence of alcohol. More investigation is urgently required-and high priority should be given to studies that approximate normal conditions of driving and in which alcohol and marijuana are administered to the same subjects.

Marihuana in man: three years later.

The past 3 years of renewed research on the effects of marihuana in man has added little not previously known about the clinical syndromes produced by the drug. The major advance has been a quantification of dose in relation to clinical phenomena, and a beginning of an understanding of the drug's metabolism. The crucial clinical experiments in regard to the social questions about marihuana, such as the possible deleterious effects from chronic use, cannot be answered by laboratory experiments. These must be settled by close observations made on those who experiment on themselves. It should be possible, within a relatively short time, to determine whether marihuana has any medical utility, but the future would appear to be no more promising than the past in this regard. The mechanisms by which marihuana alters mental functions are not likely to be answered in man, nor even answered soon by animal studies. As marihuana may be unique among drugs in that more experimentation has been accomplished in man than in animals, it may be necessary to look to additional animal studies to provide leads for pertinent future studies in man.

Antineoplastic activity of cannabinoids.

Lewis lung adenocarcinoma growth was retarded by the oral administration of delta9-tetrahydrocannabinol (delta9-THC), delta8-tetrahydrocannabinol (delta8-THC), and cannabinol (CBN), but not cannabidiol (CBD). Animals treated for 10 consecutive days with delta9-THC, beginning the day after tumor implantation, demonstrated a dose-dependent action of retarded tumor growth. Mice treated for 20 consecutive days with delta8-THC and CBN had reduced primary tumor size. CBD showed no inhibitory effect on tumor growth at 14, 21, or 28 days. Delta9-THC, delta8-THC, and CBN increased the mean survival time (36% at 100 mg/kg, 25% at 200 mg/kg, and 27% at 50 mg/kg, respectively), whereas CBD did not. Delta9-THC administered orally daily until death in doses of 50, 100, or 200 mg/kg did not increase the life-spans of (C57BL/6 times DBA/2)F1 (BDF1) mice hosting the L1210 murine leukemia. However, delta9-THC administered daily for 10 days significantly inhibited Friend leukemia virus-induced splenomegaly by 71% at 200 mg/kg as compared to 90.2% for actinomycin D. Experiments with bone marrow and isolated Lewis lung cells incubated in vitro with delta9-THC and delta8-THC showed a dose-dependent (10(-4)-10(-7)) inhibition (80-20%, respectively) of tritiated thymidine and 14C-uridine uptake into these cells. CBD was active only in high concentrations (10(-4)).

Effects of marijuana extract and tetrahydrocannabinol on electroencephalographic sleep patterns.

Marijuana extract, given in daily doses containing 70 to 210 mg delta-9-tetrahydrocannabinol (THC), induced effects on sleep that were virtually identical to those produced by the same doses of relatively pure (96%) THC. Both drugs reduced eye movements density with some tolerance developing to this effect. Stage 4 tendend to increase with drug administration. Abrupt withdrawal led to extremely high densities of eye movement, increased rapid eye movement (REM) durations, and a sharp but transient fall in stage 4 to baseline levels. These effects may be useful in the elucidation of the pharmacology of sleep. The effects on sleep of THC administration (but not withdrawal) closely resemble those induced by lithium. For this reason, we suggest further studies of THC in affective disorders. Evidence available thus far suggests that THC produces dysphoric symptoms in unipolar but not in bipolar depressed patients; these differences in response may prove of diagnostic value. An adequate therapeutic trial of THC in bipolar depressed patients has not yet been carried out.

Interactions in man of delta-9-tetrahydrocannabinol. II. Cannabinol and cannabidiol.

Oral doses of delta-9-tetrahydrocannabinol (THC) 20 mg, combined with placebo or with 40 mg dses of cannabinol (CBN) and cannabidiol (CBD), were given to volunteers. The combination of THC with CBN produced no detectable changes in the quality, intensity, or duration of the effects of THC alone. The THC-CBD combination tended to delay onset and prolong effects of THC, while making them somewhat more intense. Even this interactive effect was slight, providing no reason to abandon the current practice of basing doses of marihuana for clinical studies solely on THC content.

Chronic hashish use and mental disorder.

The authors compared 47 long-term users of hashish with a control group of 40 subjects matched for age, ethnic origin, education, etc., in order to determine whether they differed significantly on psychiatric, physical health, and demographic variables. There was a significantly higher incidence of personality disorders, unemployment, and prison sentences in the group of chronic users. However, in contrast to the findings of other researchers, the hashish users did not have organic psychoses, nor did they differ from control subjects in neurologic signs or EEG and echo encephalogram patterns.

Distribution of tritium labelled delta 1-tetrahydrocannabinol in the rat brain following intraperitoneal administration.

Tritiated Delta(1)-tetrahydrocannabinol was injected intraperitoneally into rats and its distribution measured in the brain for up to 30 days after administration. The results showed that there was no selective distribution in any one area of the brain. The maximum levels of radioactivity occurred 1 h after the injection of the tetrahydrocannabinol, thereafter the levels fell very slowly, with demonstrable activity still present at the end of 30 days.

The ring test: a quantitative method for assessing the 'cataleptic' effect of cannabis in mice.

1. A bioassay for cannabis, called the ring test, has been developed in which the percentage of the total time spent on a horizontal wire ring during which a mouse remains completely immobile is recorded.2. The effect of cannabis on mobility is a dose-related, graded response.3. Threshold doses of cannabis extract are 12.5 mg/kg when injected intravenously, and 100 mg/kg when injected intraperitoneally or subcutaneously.4. The method provides a measure of the ;cataleptic' effect of cannabis. Chlorpromazine in doses of 1 mg/kg upwards also produces the effect but barbitone does not.5. It is concluded that Delta(1)-tetrahydrocannabinol (Delta(1)-THC) is largely responsible for the effect of cannabis extract on mobility; the potency ratio of Delta(1)-THC to cannabis extract is between 10 and 20. Delta(1)-Tetrahydrocannabidivarol (Delta(1)-THD) also affects mobility but is less active than Delta(1)-THC. Cannabidiol has no effect when injected intraperitoneally in doses up to 100 mg/kg.

Effects of delta9-tetrahydrocannabinol on social behaviour in mice: comparison between two vehicles.

Two vehicles for the intraperitoneal administration of delta9-tetrahydrocannabinol (delta9-THC) were compared, using aspects of social behaviour in mice and 5 doses of delta9- THC, with vehicle alone and saline control groups. 10% propane-1,2-diol-1% Tween 80-saline (vehicle B) seemed to be more effective than 1% Tween 80-saline (vehicle A) since depressant effects of --1 delta9-THC on behaviour tended to occur at lower doses with this vehicle. Few differences in behaviour could be detected among the three control groups. In general the overall number of behavioural acts decreased with increasing doses of delta9-THC, but with vehicle B low doses selectively decreased the number of 'social' (including aggressive) as distinct from 'individual' acts. Low doses of the drug in vehicle A sometimes stimulated behaviour, whereas with vehicle B such doses mostly produced depression; however, 2.5 mg/kg delta9-THC, in either vehicle, markedly increased the percentage of animals which showed both aggression and flight acts--a rare combination among controls. Our findings are consistent with other evidence that propylene glycol is an effective vehicle for the i.p. administration of delta9-THC.

Antitussive activity of some naturally occurring cannabinoids in anesthetized cats.

Experimental cough was elicited in pentobarbital-anesthetized cats by either electrical stimulation of the superior laryngeal nerve or by mechanical stimulation of the tracheal mucosa. Intravenous administration of delta9-tetrahydrocannabinol (THC) effectively reduced the amplitude of the cough response in both these models of experimentally induced cough with ED50 values (AtD50) of 1.84 and 0.78 mg/kg, respectively. This cough suppressant activity of THC was more similar to codeine-PO4 than dextromethorphan-HBr. On the other hand, both cannabinol (CBN) and cannabidiol (CBD) were devoid of antitussive activity at doses as high as 10.0 mg/kg.

Marijuana influenced changes in GSR activation peaking during paired-associate learning.

Activation Peaking (AP) refers to a patterned physiological response occurring during learning. Marijuana has been found to interfere with both paired-associate learning and phasic GSR activity. Therefore, a study was performed to assess the effects of marijuana intoxication on paired-associate learning and concomitant GSR AP. Two marijuana usage categories were employed--light and heavy usage Ss. Within each category four groups were run in a design to test state-dependent effects. Each S was seen twice with a seven-day inter-session interval. The groups were P-P, P-M, M-M and P-M with P equals placebo and M equals 14 mg delta-9 THC. At each sessions S learned a nine-word paired-associate list to a criterion of one correct recitation, and then received 100 percent overlearning. No usage or group differences were found in level of basal conductance, except lights showed habituation over sessions and heavies did not. Magnitude of phasic GSR activation, aligned for AP, was significantly reduced for both heavy usage and marijuana intoxicated Ss. Also, only on placebo days was an AP effect evident. The results were discussed in terms of marijuana's effects on learning and physiology with emphasis on possible mechanisms of action.

Spontaneous behavior and sleep-wakefulness cycle in isolated and paired REM sleep deprived-marihuana treated rats.

The correlation between marihuana-induced aggressive behavior and changes in the sleep-wakefulness cycle was studied in chronically implanted rats. Marihuana injection in non-REM deprived rats did not induce aggressiveness irrespective of the animals being caged in isolation or paired. During this procedure quantization of the sleep-awake cycle revealed that wakefulness was increased while slow wave and REM sleep were decreased, mainly in the paired animals. REM deprived-marihuana injected animals recorded in isolation behaved like the control solution-injected rats. They showed a large rebound of REM and were not aggressive at the end of the 8 hr sessions. Conversely, when these animals were paired during the recording periods, they remained continuously awake and showed numerous episodes of aggressiveness. These results suggest that the aggressiveness inducing properties of marihuana are related to the REM deprivation and to the increased environmental stimulation achieved by pairing the animals.

Cannabis intoxication: effects of monetary incentive on performance, a controlled investigation of behavioural tolerance in moderate users of cannabis.

The study examined the effect of monetary incentive on the performance of five tasks after two heterogeneous groups of experienced users of cannabis and previously naive subjects had smoked placebo material and two dose levels of cannabis. The performance of the motivated subjects was compared with that of two non-motivated matched groups. Dose-related impairment was found on four of the five tasks, supporting previous findings of cannabis-induced impairment of short-term memory, goal-directed behavior and choice reaction times. Results for three of the tasks suggested that the performance of the motivated subjects was less affected by the drug than was the performance of the non-motivated subjects. There was no difference between the performance of subjects naive and experienced with respect to drug use.