The effect of an enormous daily oral dose of the drug (up to about one hundred thousand times the minimal behaviorally effective human dose) was recently studied in rats and monkeys for three months. A severe, generalized nervous system depression was evident the first few days. Evidence of cumulative toxicity was observed at these doses. Severe central -nervous system depression produced fatalities in some rats in the first few days until tolerance developed. Later, extreme hyperactivity developed.

The monkeys experienced severe central nervous system depression and one group showed mild hyperactivity, but all rapidly returned to normal behavior after the development of tolerance to these effects. Minimal dose-related toxic effects on bodily organs were noted at autopsy at the conclusion of the experiment. These non-specific findings of unknown meaning included bypocellularity of the bone marrow and spleen and hypertrophy of the adrenal cortex.

A 28-day study employing intravenous administration of from one to ten thousand times the minimal effective human dose to monkeys produced -similar findings clinically. In the high dose groups delayed deaths from acute hemorrhagic pneumonia were possibly caused by accumulation of clumps of THC in the lung producing irritation similar to that seen at the injection sites. No other organ pathology was noted. These animal studies illustrated that the margin of safety between active dose and toxic dose was enormous.

A few studies have recently been carried out to observe the effect of a few weeks of daily marihuana smoking in man. The amount smoked was a relatively large American dose. Frequency of use was once to several times daily.

During the 21-day Boston free-access study, no harmful effects were observed on general bodily functions, motor functions, mental functions, personal or social behavior or work performance. Total sleep time and periods of sleep were increased. Weight gain was uniformly noted.

No evidence of physical dependence or signs of withdrawal were noted. In the heaviest smokers, -moderate psychological dependence was suggested by an increased negative mood after cessation of smoking.

Tolerance appeared to develop to the immediate effects of the drug on general bodily functions (pulse rate) and psychomotor-cognitive performance (time estimation, short-term memory, and shootinggallery skill) but not to the "high." Marihuana intoxication did not significantly inhibit the ability of the subjects to improve with practice through time on these psychological-motor tasks.

Neither immediate nor short-term (21 day) high-dose marihuana intoxication decreased motivation to engage in a variety of social and goal-directed behaviors. No consistent alteration that could be related to marihuana smoking over this period of time was observed in work performance of a simple task, participation in aspects of the research study, or interest and participation in a variety of personal activities, such as writing, reading, interest and knowledge of current world events, or participation in athletic or aesthetic activities.

Marihuana smoking appeared to affect patterns of social interactions. Although use of the drug was found to be a group social activity around which conversation and other types of social behavior were centered, it was not uncommon for some or all of the smokers to withdraw from the social interaction and concentrate on the subjective drug experience.

During the first part of the smoking period, both intermittent and daily users demonstrated a marked decrement in total interaction. Total interaction continued to diminish among intermittent users but increased above presmoking levels among the daily users during the later parts of the smoking period. The quality of the interaction was more convivial and less task-oriented when marihuana was available to the group.

Additionally, an assessment of the effect of marihuana on risktaking behavior revealed that daily users tended to become more conservative when engaging in decision-making under conditions of risk.