The development of tolerance is another important factor that may influence the psychophysiological effects of marihuana. Although tolerance occurs with many drugs and the process has been studied for over a century, the mechanism of this complex phenomenon is not completely known. Kalant et a]., (1971) have extensively discussed tolerance to the psychotropic drugs.

Tolerance has two different connotations. The first, termed "initial tolerance," is an expression of the dose of the drug which the subject must receive at his first exposure to produce a designated degree of effect. These authors state that a variety of congenital and environmental factors contribute to the wide range of differences in "initial tolerance" observed among different individuals, sexes, species, age groups and so on.

The second meaning of tolerance is that of an "acquired change in tolerance" within the same individual as a result of repeated drug exposures so that an increased drug dose is required to produce the same specified degree of effect, or the same dose produces less effect. In this chapter, tolerance will be used synonymously with "acquired increase in tolerance." -Tolerance can only be discussed for each specific drug action and not for all the actions of a given drug on the body. That is, tolerance occurs at different rates for some of the various effects of the same drug on the body and may not occur for other effects of the same drug. The relationship between "initial tolerance" and "acquired change in tolerance" has not been clearly established.

There are two classes of tolerance based on possible mechanisms. The first, dispositional tolerance refers to changes in absorption, distribution, excretion and metabolism which produce a reduction in the intensity and duration of contact between the drug and the target tissue on which it acts.

The second, functional tolerance includes changes in the properties and functions of the target tissue making it less sensitive to the same dose of the drug. Physiological tolerance implies a, change in the target organ while psychological or "learned tolerance" implies the acquisition of new skills or functions to replace those changed in the target tissue (Kalant et al., 1971).

Considerable evidence is accumulating which demonstrates that tolerance does develop in numerous animal species (pigeons, rats, dogs, monkeys, chimpanzees, mice) to the behavioral and physiological effects of marihuana and THC in doses many times larger (from 1 mg. to 500 mg./ kg/day) than the minimal active dose (Carlini, 1968; Silva et al., 1968; McMillan et al., 1970, 1971; Frankenheim et al., 1971; Carlini et al., 1970; Thompson et al., 1971; Pirch et al., 1972; Ferraro, 1971; Elsinore, 1970; Cole et al., 1971).

Lipparini et al. (1969) were not able to demonstrate tolerance in the rabbit.

Tolerance, appears to develop rapidly to high doses even when injections are spaced up to about a week apart. Tolerance to high doses appears to be long-lasting with little loss of tolerance even after a month. But at low doses in the behavioral range, tolerance appears to completely dissipate in a few days after a single dose. The magnitude of tolerance development can be large. After repeated exposure, a dose of over one hundred times the original produces little effect (McMillan et al., 1971).

The development of tolerance to THC in animals occurs for some effects but not for others (McMillan et al., 1971; Pirch et al., 1972; Thompson et al., 1971 ). This differential development of tolerance may explain why tolerance to certain effects studied has not been demonstrated (Masur and Khazan, 1970; McMillan et al., 1971; Barry and Kubena, 1971; Kubena et al., 1971).

Lomax (1971) and Thompson et al. (1971) have noted that the development of tolerance to one effect of the drug (hypothermia or sedation) may allow the expression of the opposite effect (hyperthermia or stimulation) to which tolerance does not develop.

Cross tolerance has been demonstrated between delta-9-THC, delta-8-THC and its synthetic analogues. Cross tolerance, has not been demonstrated between THC and lysergic acid diethylamide (LSD), mescaline or morphine (McMillan et al., 1970).

Preliminary work performed by McIsaac (1971) and Harris et al., (1972) demonstrated a reduction in the duration and quality of response on a conditioned learning task by monkeys on the seeond intravenously administered dose of THC. Tolerance developed extremely rapidly so that no effect on behavior was seen after five days. After a. two-week period without THC, the animals were retested and the same degree of tolerance had persisted. The researchers believe these observations might indicate a rapid behavioral adaption or "learned" functional tolerance.

However, evidence indicates that dispositional tolerance and/or physiological type of functional tolerance also plays a role at least at higher doses. Tolerance develops to the central nervous system depressant effects, hypotherma hypopnea (Thompson et al., 1971) and the EEG effects (Pirch et al., 1971) of the drug. McMillan et al., (1971) have demonstrated that tolerance to the effects of THC on behavior can be blocked by the hepatic microsomal enzyme inhibitor, SKF-525-A which has been shown to be a potent inhibitor of THC metabolism (Dingell et al., 1971). Methodological techniques must be, developed which will allow microdistribution studies to be performed in tolerant animals with low doses of THC before the mechanism of tolerance development can be clarified.

Evidence for the development of marked tolerance by man has been suggested by studies of heavy daily very long term users of hashish, charas or ganja in foreign countries. Reports from the, Eastern literature (Chopra and Chopra, 1939; Dhunjibhoy, 1930; Ewans, 1904) and more recently from Greece (Miras, 1965; Fink et al., 1971) and Afghanistan (Weiss, 1971) relate daily consumption of enormous quantities of potent cannabis preparation estimated to contain up to about one gram of THC per day.

Weiss (1971) has noted that daily charas smokers start with small doses and then in order to achieve the same effect gradually increase their daily dose about 5-6 times over a 20 to 30 year period. Generally, most reach their maximum dose by age 40 and then gradually decrease their daily dose by 50% usually ceasing use by their 60's. Some smokers have been noted to raise their original daily dose up to a maximum of 10 times within the first two years.

Others have noted that moderate use for many years does not necessitate increased doses (Sigg, 1963).

At least part of the increase in daily amount of drug used is accounted for by the finding that the duration -of the intoxication becomes shorter over the years so that the very heavy smoker must consume the drug more frequently to remain intoxicated. Additionally, smokers report that they have on occasion discontinued use for days or months after which they experienced similar effects at smaller doses (Weiss, 1971).

Fink et al. (1971) noted that as hashish users total daily dose was decreased by more than half over the years, the frequency of use per day declined correspondingly.

Rubin and Comitas (1972) noted that very long term Jamaican ganja smokers generally consumed an average of seven spliffs daily (a ganja cigarette several times the size of an American marihuana cigarette) with a maximum of 24.

Further evidence for the development of tolerance, at least to certain of the depressant effects, is that these very long term smokers apparently tolerate the extremely high doses well without dysphoria or decreased ability to perform their usual activities (Weiss, 1971; Fink et al., 1971; Rubin and Comitas, 1972).

Smith and Mehl (1970) noted the, accumulating American anecdotal evidence of mild tolerance development after heavy daily use for a number of years. Jones (1971) and Meyer et a]. (1971) have suggested diminished effect on physiologic and psyochomotor performance, that is, little or no impairment of function in daily users compared with infrequent, intermittent users of marihuana. Additionally, several investigators have noted that frequent users had little or no impairment on psychomotor performance tasks while marihuananaive individuals given the same dose had impaired function. (Clark et al., 1968, 1970; Jones and Stone, 1970; Mayor's Committee, 1944; Weil et al., 1968).

Subsequently (Mendelson et al., 1972) repetitive daily (free access) use over a 21-day period by groups of long-term intermittent (average 7.7 sessions per month) and moderate, marihuana users (daily average, 33 smoking sessions per month) was studied. The development, of tolerance was strongly suggested to the physiological pulse rate and general depressant effect on activity as well as psychological effects which impair recent memory, time estimation and psychomotor coordination.

No tolerance development occurred to the subjective effects of marihuana for experienced users over the 21-day period (global "highness", somatic, perceptual, awareness, feeling, control, friendliness, ambivalence and altered thinking). Furthermore, with the exception of a higher ambivalence rating for the daily riser group, there were no differences in the subjective reports of the daily users or intermittent users. (Mendelson et al., 1972). The ambivalence score is believed (Katz et al., 1968) to be the best measure of "psychedelic ef fects" of hallucinogenic drugs.

In a prior study (Meyer et al., 1971) found that while the heavy smokers experienced more profound subjective effects soon after smoking, they were less intoxicated than the intermittent users one hour later.

These findings suggest to the investigators that the quality of the "high" may be different for heavy and intermittent users and may change with heavy use. Tolerance, to the subjective effects of marihuana may occur predominantly to the depressant effects so that the stimulatory effects (or hallucinatory-like) would be predominant in the heavy users. The intermittent users who smoked marihuana several times daily in the, current study showed no increase in the ambivalence, rating.

The increased daily frequency of marihuana use by both groups over time by shortening the interval between smoking sessions appears consistent with earlier observations (Meyer et al., 1971) that the duration of the desired "high" is shorter in heavy users than in intermittent users.

Fink et al. (1971) confirmed several of these findings in a study in which intermittent users smoked a fixed dose (14 mg. of THC) of marihuana. They noted a suggestion of development of tolerance to pulse rate, short-term memory, digit symbol substitution but not to the subjective high or EEG changes. However, the subjects did feel that the duration of the intoxication shortened progressively during the second half of the experiment.

Schuster and Renault (1971) administered twice daily fixed doses of marihuana (smoke from 430 mg. of marihuana with 1.5% THC content) to intermittent users over a 10-day period. A peak tachycardia, of 20 to 30 beats per minute and a usual social high were produced. Preliminary observations revealed the development of tolerance to time estimation in a few days, but no evidence for tolerance to the tachycardia, orthostatic blood pressure, or rating of the high.

Hollister (1971), in preliminary studies found no significant evidence of tolerance after five daily oral doses of 20 mg. of THC. Clinical responses measured were subjective judgment of the high, mood, pulse rate, reading comprehension or excretion of urinary metabolites.