The Report of the National Commission on Marihuana and Drug Abuse

Effects of Short-Term or Subacute Use

ANIMAL STUDIES (PRECLINICAL)

Studies have only begun in this area in the last 10 years. Subacute toxicity studies in rats involving 30 daily intraperitoneal injections of up to 30 mg/kg THC were recently reported by Phillips et al. (1971). No fatalities were observed. Total body and organ weight (rains were significantly retarded over the period. However, no significant differences in organ histology were detected although in a few animals there were suggestions of change in liver and testicular cells. An interesting phenomena also observed was a suggestion of increased sensitivity to effects of Delta 9 THC occurring after two weeks of daily treatment.

Thompson et al. (1971) under contract to NIMH studied the toxicity in rats treated daily for seven, 28, 91 and then 119 days with oral Delta 9 THC, A" THC and crude marihuana extract at doses from 50 to 500 mg/kg. The findings were generally similar for all three preparations although A" effect was greater than All THC which in turn was greater than CME.

A bimodal pattern of behavorial toxicity was exhibited by the cannabinoids for all time periods of dosing ranging from five to 119 days. Initially, a dose-related generalized central nervous system depression was noted. This was characterized by huddled posture, inactivity, drowsiness, slow movements, unkempt appearance, loss of appetite, wide stance, constipation, weight loss, depressed respiration and heart rate and fall in body temperature. Tolerance gradually developed to the initial depressant effects starting after two to five doses and continued at different rates for different parameters.

Concomitant to the development of tolerance, rats exhibited progressively more hyperactivity, manifesting increased exploratory behavior, grooming and motor activity. The daily duration of the altered behavior progressively shortened. Tolerance to the hyperactivity was not seen in the rats. Later, in the experimental period, the rats became hyper-irritable and exhibited fighting behavior, especially at lower doses. Additionally, tremors and later chronic convulsions occurred in significant numbers of rats.

The onset and frequency of chronic convulsions were dose-related and the severity increased as the duration of dosage was extended. Cumulative toxicity, as evidenced by increased mortality, was observed in the rats but most deaths and maximal toxicity (central depression) occurred 36 to 72 hours following first treatment. Drug dose-related histopathological changes in all treated rats (in addition to decreased body and organ weight gains) were hypocellularity of the spleen and bone marrow, vacuolization of the adrenal gland and degeneration of the testes (seminiferous tubules) or ovarian stronia. Extended doses from five to119 days were not significantly more toxic except to the adrenals. No evidence of abstinence syndromes were noted upon abrupt cessation of these doses.

Similar behavorial and clinical findings were observed in monkeys given 50-500 mg oral Delta 9 THC, All THC and equivalent CME for up to 91 days. Cumulative toxicity was less severe and all monkeys survived the initial moderately severe central nervous system depression. Tolerance to the depression occurred and the monkeys returned to their undrugged behavior. Mild hyperactivity was noted only in several of the median dosed animals.

Three of 28 monkeys studied became moribund on days 10, 14 and 16 respectively. These were sacrificed and the only histopathology seen was severe hemorrhagic and probably drug-related enterocolitis. The bone marrow and kidney changes seen probably were due to severe electrolyte imbalance resulting from the intestinal lesion. The thymus lesion is consistent with stress due to this electrolyte imbalance. Pancreatic atrophy was due to weight changes. Eight additional monkeys were sacrificed at 28 days in fair-to-good condition and no histopathology was demonstrable. Several other monkeys had bloody diarrhea, but recovered spontaneously without demonstrable histopathology.

The remaining 17 monkeys were all in fair-to good condition at 28 days and hyperactivity was no longer observed. They were treated at the same dose for an additional 63 days. Tolerance to the central depression continued to develop so that the effects lasted only one to two hours at 91 days. No additional monkey fatalities were recorded -and the remaining 17 monkeys were normal histopathological at autopsy. Urine and ophthalmological examinations were all within normal limits. Hematological and blood chemical changes after 28 and 91 days were minor and little affected in the surviving monkeys.

Thus, a. minimal toxicity in monkeys, either physical or behavorial, is evident after 91 daily doses orally of enormous amounts of Delta 9 THC. However, significant cumulative toxicity, primarily a generalized central nervous system depression, is evident in the first few days but tolerance rapidly develops to these effects. A dose-related hemorrhagic enterocolitis occurred which may lead to electrolyte imbalance and death in a few monkeys. This probably is a direct irritative phenomena.

Again, the enormous daily doses of THC that were administered to these animals cannot, be compared to the daily doses used in man even by the heaviest users.

The effects were observed of 28 daily administrations to monkeys of intravenous Delta 9 THC in sesame oil-Tween 80-saline vehicle at doses of 5, 15 and 45 mg/kg. Behavioral, clinical, hematological and hemochemical changes were similar for monkeys given single or repeated injections. However, the duration was extended in the 28-day groups and tolerance gradually developed. Delayed death indicative of cumulative toxicity occured on days eight and 19 in two of four animals given the largest dose.

Histopathological changes, noted in the two animals which succumbed and in one of the highdose monkeys, were acute hemorrhagic pneumonia resembling the finding in the single-intravenous studies at doses of 128 mg/kg or greater. Additionally in the repeated dose study, edema, ulceration and fibrosis at the injection sites probably contributed to minor hematological and hemachemical alterations.

In summary, the 1972 Marihuana and Health Report to the Congress from the Secretary of HEW noted that these doses were employed in rodents and mammals to test the limits of toxicity. The doses are much higher than those used by man and the routes of administration substantially dif ferent. These studies have shown that the margin of safety between the lethal dose and the pharmacologically active doses of Delta 8 and All THC and crude marihuana extract is large. Consequently, it has been determined that these compounds could be safely administered to man for Phase I and early Phase II clinical studies (Secretary of HEW, Feb. 11, 1972, p. 158-160).