Factors Influencing Psychopharmacological Effect

A renewed interest in marihuana studies has been prompted by the recent clarification of the complexities of its chemistry, new techniques to quantity the amounts of active drug in natural materials, and the availability of purified tetrahydrocannabinols. These advances allow more precise scientific research on psychiopharmacological effect.

DOSE-RESPONSE RELATIONSHIP

A major advance has been a quantification of dose of THC in relation to clinically observable phenomena. This has been extensively studied over a wide dose range for marihuana (Rodin and Domino, 1970; Melges et al., 1970; Tinklenberg et al., 197O; Weil et al., 1968; Meyer et al., 1971; Clark and Nakashima, 1968; Clark et al., 1970; Jones and Stone, 1970; Mayor's Committee, 1944; Manno et al., 1970) and Delta 9 tetrahydrocannabinol (Isbell et al., 1967; Waskow et al., 1970; Hollister et al., 1968; Perez-Reyes and Lipton, 1971; Lemberger et -al., 1971; Dornbush and Freedman, 1971).

Investigations by Isbell et al. (1967), Kiplinger et al. (1971) and Renault et al. (1971) have clearly demonstrated that when reliable quantities of smoked marihuana or THC are delivered to the subject, a reproducible linear dose-dependent effect occurs on indices of physiologic, psychomotor, and mental performance as well as on mood and subjective experiences over a dose range of 12.50 to 200 micrograms of Delta 9 THC per kilogram of body weight.

In a 154 pound man this is comparable to consuming 0.88 to 17.5 milligrams of Delta 9 THC or 88 to 150 milligrams of marihuana containing one percent Delta 9 THC. It is generally assumed that good quality marihuana available in the United States contains 1% Delta 9 THC and an average marihuana cigarette consists of 500 milligrams of marihuana; thus, 5 milligrams of Delta 9 THC (Hollister, 1971).

As with most drugs, the larger the dose taken, the greater the psychopharmacologic effect. Isbell et al. (1967) noted that clinical syndromes vary from a mild euphoric feeling of relaxation at low doses (25 micrograms per kilogram) to an intensive hallucinogenic-like experience at high doses (250 micrograms per kilogram).

DOSE-TIME RELATIONSHIP

Similar time-action curves have been demonstrated for smoked Delta 9 THC and equivalent quantities of smoked marihuana (Hollister et al.,1968; Isbell et al., 1967 Renault et ai., 1971 Kiplinger et al., 1971). Symptoms began almost immediately after smoking (2-3 minutes). At lower doses, the peak effect is seen at 10 to 20 minutes and the duration of effect is 90 minutes to two hours. At higher doses, symptoms persist for three to four hours.

Therefore, as with most drugs, the larger the dose taken, the longer the action. The subjective symptoms experienced by the subject appear to parallel in time the subjective effects and some physiological indices such as pulse rate (Isbell et al., 1967; Hollister, 1968 - Renault and Schuster, 1971; Kiplinger et al., 1971; Galanter et al., 1972; Lemberger et al., 1971). Others such as reddening of the eyes have a delayed peak response and longer duration (Kiplinger et al., 1971).

ROUTE OF ADMINISTRATION

A second factor which influences the effect experienced by the user is the manner in which the substance is consumed. That is, whether it is smoked, swallowed or injected.

Isbell et al. (1967) demonstrated that smoked material is two and a half to three times as effective as orally consumed marihuana in the form of a 95% ethanolic solution in producing equivalent physiologic and subjective effects.

In addition, the oral time-action curve is extended with onset of symptoms one-half to one hour after administration. A peak effect is reached in two to three hours and the effect persists for three to five hours at low doses and six to eight hours at larger doses (Hollister et al., 1968; Isbell, et -al., 1967; Lemberger et al., 1971; Perez-Reyes, and Lipton, 1971).

In general, the effects produced by ingested THC or ingested marihuana extract are comparable to those produced by nearly one-third the amount of smoked and inhaled THC or marihuana (Hollister, 1971).

Recent work has been reported which clarifies these findings. Lemberger et a]. (1971) studied absorption into the blood utilizing radioactive labeled THC by three routes of administration: smoked, ingested in 95% ethanolic solution in cherry syrup, and intravenously injected. The first appearance of the drug into the, blood was immediate intravenously; almost immediate, by inhalation; and delayed for 15 to 30 minutes when ingested.

Perez-Reyes and Lipton (1971) using labeled AO THC demonstrated that rate of absorption by the gastrointestinal tract, and the duration of action is greatly influenced by the vehicle used to ingest the drug. Speed and completeness of absorption varied when the THC was dissolved in 100% ethanol or sesame oil or emulsified with a bile salt (sodium glycocholate), and administered to a subject who had fasted 12 hours. With the bile salt vehicle, the physiologic and subjective effects were noted between 15 to 30 minutes after ingestion and lasted two to three hours. In contrast, the effects, with ethanol or sesame oil, appeared after one ,hour and lasted four to six hours.

Hollister and Gillespie (1970) hypothesized that this delayed gastrointestinal absorption of THC might be accounted for by the nonpolar vehicle required to dissolve TUC or marihuana extracts.

Furthermore, Perez-Reyes and Lipton (1971) found that the peak levels and duration of radioactivity in the plasma paralleled the physiologic and subjective effects, although the plasma levels remained high for a longer period of time than the effect. Subjects receiving the drug emulsified in sodium glycocholate or dissolved in sesame oil had three times higher plasma levels of radioactivity with much less excreted in the feces than those receiving the drug dissolved in ethanol.

These results indicate that the THC was poorly absorbed from the gastrointestinal tract when given in all alcoholic solution. The sesame oil solution and the glycocholic acid preparation allowed more complete absorption and the latter preparation was much faster. It is of interest that the degree of subjective high after ingestion of 37 milligrams Delta 9 THC also parallels the plasma radioactivity.

Thus, the subjects reported their experience, as intense and unpleasant both with the bile salt and the sesame oil, and as moderate and entirely pleasant with ethanol. (Perez-Reyes and Lipton, 1971) This correlates well with earlier findings of Hollister et a]. (1968).

QUANTIFICATION OF DOSE DELIVERED

The problem in quantifying the THC dose delivered by different routes of administration has been clarified by several studies using radioactive compounds. However, until a method for determining the THC blood concentration is developed, only estimates oil amount delivered are possible.

Radioautographic studies clearly demonstrate that intravenous injection gives the, most complete and consistent delivery (Lemberger et a]., 1971; Me Isaac et M., 1971; Ho et a]., 1971; Kennedy and Waddell, 1971; Idanpaan-Heikkila, 1971). These investigators have demonstrated that THC is poorly absorbed from the injection site after intraperitoneal or subcutaneous injection.

As discussed earlier, the completeness of absorption ocurring after oral administration of THC appears to depend upon the vehicle. Judged by radioactivity levels, almost complete absorption of the THC occurs with an oil or bile acid vehicle, but absorption is incomplete with an alcohol vehicle. (Perez-Reyes et al., 1971)

Recent animal studies performed for NIMH indicated that the oral dose necessary to produce comparable gross behavioral changes in lab animals is about three times higher than the intravenous dose (Marihuana and Health. 1971: 171). Ferraro (1971) demonstrated the comparability of effective oral doses of THC in chimpanzees and humans. Furthermore, preliminary work performed in the laboratories of M. Isaac (1971) and Harris (1971) and Mechoulam (1971) appear to indicate that the intravenously administered dose of Delta 9 THC necessary to produce detectable behavioral changes in monkeys (20 to 50 microgram/ kg) on conditioned learning tasks is comparable to that in man. (Kiplinger et a]., 1971; Lemberger et al., 1971).

The dose of THC absorbed from natural marihuana extracts ingested orally is uncertain. THC is present as an acid in variable quantities in natural marihuana. THC acid has not presently been proven to be active. Claussen and Korte (1968) reported that the THC carboxylic acid is converted to free THC during the smoking process. Whether these, acids are active themselves; are absorbed from the gastrointestinal tract or converted there into THC; or are decarboxylated in the, body is unknown presently.

Because inhalation is the most widely used route of administration of marihuana, several laboratories have investigated the effect of combustion and smoking oil marihuana. Because techniques and conditions varied between laboratories, precise quantification of the delivery to the smoker's lungs is uncertain.

Manno, et al. (1970) calculated that about 50% of the THC contained in a marihuana cigarette would be delivered to the smoker's lungs for absorption if the entire cigarette were smoked in 10 minutes and each inhalation was retained for 30 seconds with no sidestream loss. Truitt (1971) and co-workers (Foltz et al., 1971) found that 50%c of THC was pyrolyzed and 6% was lost in the side stream while noting that almost 21% of the THC remained in the butt when three-fourths of the cigarette is consumed.

Agurell and Leander (1971) studied the transfer of THC using actual smoking subjects where only the main stream smoke was collected. They found that 14-29%% of the THC was transferred in the mainstream smoke for a cigarette and 45% for a pipe. However, they stated that this amount transferred would be comparable if no butt was left.

Agurell and Leander found that the amount transferred was not effected by depth of inhalation but that smokers using deep inhalation retained 80% of the transferred THC while those using superficial inhalation tended to exhale more than 20% of the transferred THC. Mikes and Waser (1971) also found about 22% in the mainstream smoke.

These divergent data appear to be comparable when corrected for loss to sidestream and retention in the unsmoked portion. Thus, the efficiency of delivery of THC by smoking and inhalation using good techniques, and smoking the entire cigarette approximates 40-50% of the original THC contained. A small fraction is lost in the uninhaled sidestream smoke, about 50% is destroyed during pyrolysis and a variable amount is exhaled from the respiratory dead space.

In apparent confirmation, Lemberger et al. (1971, 1972), using radiolabeled THC added to a marihuana cigarette, found that the initial plasma level of radioactivity after smoking was about onehalf the level after intravenous injection. Oral administration of the same dose of THC in an alcohol vehicle produced about one-half the peak level as smoking. However, Galanter et al. (1972) noted marked variability in the amount of THC absorbed using a standardized routine of inhaling, breath-holding and finishing the cigarette within a set time period.

EFFECT OF PYROLYSIS ON THE CANNABINOIDS

Several investigators have studied the effect of pyrolysis on the cannabinoids. Most have concluded that only negligible changes occur in the original cannabinoid fraction of marihuana except for decarboxylation of the acids to the cannabinoids. No evidence was found for isomerization of Delta 9 THC or Delta 8 THC nor the formation of any new pyrolysis products (Manno et al., 1970; Coutselinis & Miras, 1970; Claussen and Korte, 1968; Foltz et al., 1971; Agurell and Leander, 1971). Mikes and Waser (1971) suggested that a small percentage of cannabidiol was converted to Delta 9 THC, but this observation was not confirmed by the other groups.

Coutselinis and Miras (1970) noted that less THC was destroyed during smoking when Delta 9 THC was the only cannabinoid present rather than when a resin or a mixture of cannabinoids were present. This was believed to be at least partially accounted for by the distribution of THC in the cigarette. More destruction occurred when the THC was evenly distributed in the cigarette than when it was present in a well-defined lump.

SET AND SETTING

A most important variable encountered when evaluating the effect of marihuana is the interaction of the drug with the non-drug factors, set and setting. Set refers to the drug-taker's biological make-up including personality, past drug experiences, personal expectations of drug effect, and mood at the time of the drug experience. Setting refers to the external surroundings and social context in which the individual takes the drug. Set and setting exert their largest effect on psychoactive drugs, like marihuana, with subtle subjective mental effect and minimal physiological effect. Set and setting exert a variable but often marked influence on the potential drug effects (Waskow et al., 1970; Wickler, 1970).

The results of a series of experiments by Jones (1971) suggests the subjective state produced by "a socially relevant dose of smoked marihuana.... 9mg THC" is determined more by set and setting than by the THC content of the marihuana.

In one experiment, a greater variety and more intense pleasurable symptoms occurred in a fourman group allowing unstructured interpersonal interaction than in unstructured solitary test situations. Contrasting behavioral patterns were observed by the investigator and reported subjectively by the individuals. Subjects tested individually demonstrated a relaxed, slightly drowsy, undramatic state as they read, listened to the radio, or sit doing nothing. In the group setting there was elation, euphoria, uncontrolled laughter, a marked lack of sedation and much conversation. (Jones, 1971)

This strongly emphasizes the importance of setting in the marihuana experience. The reason is apparent why marihuana is usually used with other people. However, most investigators studying its effects evaluate their subjects alone, in well-controlled, sterile, scientific laboratories.

The importance of the placebo effect (the subject experiences a drug effect from an inert material) to the "social high" obtained from marihuana was studied in another experiment (Jones and stone, 1970; Jones, 1971). Misjudgments of the pharmacologic potency of both the smoked placebo (marihuana without THC) and active marihuana were commonly made by the subjects although physiologic and performance indices routinely matched the distinction correctly. The smoking of a material that smells and tastes like marihuana by individuals with marihuana experience appeared to produce a mental state that is interpreted as being high if combined with the expectation of becoming high.

The importance of learning to get high was demonstrated when individuals who smoked marihuana less than twice a month were compared with those who used marihuana at least seven times a week. Although both groups rated the active marihuana equally potent, the frequent users rated the placebo equally to the active drug, while the infrequent users experienced significantly less high from the placebo.

The infrequent users' experiences appears to reflect mainly pharmacologic factors with moderate set-setting influence. However, the frequent users' response to the placebo appears to reflect mainly learned set-setting influence and minimal pharmacologic factors. (Jones, 1971)

Smith and Mehl (1970) call learning to get high " reverse tolerance." During the early exposures to marihuana the individual learns to appreciate the subtle drug effect with repeated experience with the drug. Consequently, less drug may be required to experience the desired high in the early stages of marihuana use.

Further evidence for this is seen when the familiar smoking route and smell and taste cues are made ineffective by giving the active and inactive material by the oral route (Jones and Stone, 1970). Both groups of users can significantly distinguish the intoxication produced by 25mg of active material. But the frequent user rates this high significantly poorer than his smoking high while the infrequent user rates them correctly.

TOLERANCE

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.

REVERSE TOLERANCE

Smith and Mehl's (1970) clinical observations of many marihuana smokers suggest a J-shaped time curve of tolerance to marihuana. A novice marihuana smoker often reports feeling no high or requiring considerably more drug to get high on his first few trials with the drug than after he obtains more experience with the drug. This phenomenon has been called "reverse tolerance." These clinicians believed this represented "learning to get high" or acquiring the ability to appreciate or become sensitive to the subtle aspects of the intoxication.

Goode (1971) found that more frequent and term marihuana smokers tend to require fewer "joints" to get high but differences were not statistically significant.

Weil et al. (1968) reported that experienced users of marihuana achieved a "high" after being given the same dose as naive (non-users) persons who did not experience a high but did demonstrate objective physiologic and psychomotor drug effects.

Meyer et al. (1971) found that heavy marihuana, users (daily for three years) were most sensitive to the "high" and required less marihuana to achieve a social high than infrequent intermittent users (use one to four times per month for less than two years).

Phillips et al. (1971) reported an increase in severity of symptoms after repeated administration of THC to rats. This "sensitization" may be a correlate of reverse tolerance.

Lemberger et al. (1971) supplied additional evidence for reverse tolerance based on the intravenous administration of 0.5 mg of THC to experimental subjects. Naive subjects experienced no effect from this small dose. However, daily marihuana users, who were told they were receiving a non-pharmacologically active dose of THC, reported a "marihuana high," which lasted up to 90 minutes.

Lemberger et al. (1971, 1972) and Mechoulam (1970) suggested the possibility that enzymes necessary to convert THC to a more active compound require prior use of marihuana.

Reverse tolerance appears to be a complex phenomenon. Jones (1971) presented evidence which stressed the importance of expectation, setting and prior drug experience on learning to get "high." As the user gains more experience with marihuana, the more the individual's mind is able to respond to the expectation of the "high" by actually becoming high when given an inert material which smells and looks like marihuana.

Weil (1971) believes that the capacity to get "high" is an inherent characteristic of each individual's mind. He, believes that marihuana facilitates the user's abilitv to achieve this altered state of consciousness, that is, learn how to get high.

Mendelson et al. (1972) did not find evidence for reverse tolerance. In fact, the daily users were more likely than the intermittent users to smoke two cigarettes per occasion. Both groups had had an average of five years of marihuana use. Several other investigators did not obtain any evidence of reverse tolerance after repetitive daily use in experienced subjects (Hollister, 1971; Schuster and Renault, 1971; Fink et al., 1971).

METABOLISM

Metabolism of the drug by the body exerts an important influence on the psychopharmacologic effect of marihuana. Many laboratories in many countries have been examining the metabolism, of the cannabinoids using in vitro liver microsomal enzyme preparations.

With the recent availability of radiolabeled Delta 9 and Delta l THC, cannabinol and cannabidiol much activity has occurred in vivo in animals. A comprehensive review of these areas including studies of absorption, disposition, excretion, metabolism and stimulation-inhibition of metabolism is beyond the scope of this report. Readers interested in further details in this area are referred to an excellent comprehensive review by Lemberger (1972).

From animal and in vitro studies it appears that the liver rapidly changes Delta 9 and Delta 11 THC in a similar manner by hydroxylation to 11-OH THC. This compound appears to be as potent or possibly more potent pharmacologically than the parent compounds This metabolite appears to be, rapidly hydroxylated to 8-11 dihydroxy Delta 9 THC (7-11 dihydroxy All THC) which is inactive. The 8-OH Delta THC appears to be a minor active metabolite (Christensen et al., 1971; Burstein et 1970; Ben-Zvi et al., 1970; Foltz et al., 1970; Wall et al., 1970,71; Nilsson et al., 1970).

These metabolites are excreted primarily into the bile and then to the feces. Some evidence exists for an enterohepatic circulation returning the drug to the blood. (Miras and Coutselinis, 1970; Klausner and Dingell, 1971)

Another metabolic pathway appears to be present resulting in a series of acidic metabolites excreted primarily in the urine (Agurell et al, I., 1970). Recently, Burstein and Rosenfeld (1971) isolated and identified a majo r rabbit urinary metabolite, 11-carboxy-2'-hydroxy-Delta 9 THC. They postulate that other acidic metabolites might be esters or amides of this compound (Figure 7).

Recently, Nakazawa and Costa (1971) demonstrated that A' THC was metabolized by lung microsomes forming two unidentified products not found in liver homogenates.

Lemberger et al. (1970, 1971, 1972) and Galanter et al. (1972) have performed metabolic studies in mail using intravenous, oral and smoked Delta 9 THC. These studies indicate that the THC disappears from the plasma in two phases.

The initial rapid phase has two components and represents metabolism by the liver and redistribution from the blood to the tissues. The slower second phase represents tissue retention and slow release and subsequent metabolism.

The plasma 1/2 life of THC was significantly shorter in daily users than nonusers at both the first component of phase one (10 minutes versus 13 minutes) and phase two (27 hours versus 56 hours). Tissue distribution was similar in daily and nonuser (1/2 life 2 hours).

Therefore, immediate metabolism of THC and subsequent metabolism is more rapid for daily user than the non-user implying specific enzyme induction. THC persists in the plasma for a considerable period of time, at least three days, with a half life of 57 hours for nonusers and 28 hours for daily users.

The presence of 11-hydroxy THC and more polar metabolites in the plasma of both users and nonusers within 10 minutes indicates that the metabolite probably accounts for the pharmacological activity of marihuana, not THC.

Further metabolism of the 11-hydroxy THC to more polar inactive 8-11 dihydroxy A' THC metabolite occurs more rapidly in users than nonusers. During the first few hours after injection, unchanged THC, its polar metabolites and nonpolar metabolites in the plasma, decline rapidly and then level off as they are distributed to the tissues. THC persists in the plasma, for at least three days, and both users and non-users excrete metabolites in the urine and feces for more than a week.

Delta-9-THC is extensively metabolized to more polar compounds which were excreted in the urine and feces. Urinary excretion and biliary excretion (reflected a day later in the feces) was greatest during the initial 24 hours, then gradually tapered off. All THC is metabolized since no unchanged THC was excreted in the feces or urine. No difference in total cumulative excretion was observed but a significantly larger percentage of the metabolites were excreted in the urine of users than nonusers. About 40-45% of the metabolites were collected in the feces in both groups in one week. Urinary excretion in this period accounted for 30% in daily users and 22% in nonusers. (Lemberger et al., 1970, 1971, 1972)

Perez-Reyes et al. (1971) found a similar pattern of excretion of metabolites after oral administration.

Urine contained no Delta 9 THC, only a small quantity (3%) of 11-hydroxy THC and 90% more polar acidic compounds as yet unidentified. (Lemberger, 1971). Preliminary studies by Burstein and Rosenfeld ('1971) suggest that these human acidic urinary metabolites are identical to the 11-carboxy-2' hydroxy THC found in rabbits.

In man, Lemberger et al. (1971, 1972) found that 11-OH THC and 8-11-OH THC were primarily excreted in the feces. Twenty-two percent of the metabolites in the feces were unchanged 11-hydroxy THC and slightly less were 8-11-dihyd-roxy THC. The remainder were unidentified more polar compounds, perhaps conjugates of these metabolites.

All user subjects (Lemberger et al., 1970, 1971, 1972) but no non-user noted a high after intravenous injection of the 0.5 mg dose of Delta 9 THC. This would be a dose range of 5 to 7 micrograms/kg. Highs have been noted by Kiplinger et al. (1971) with smoking THC to deliver a dose of 6.25 micrograms/kg. The high for some lasted up to 90 minutes. Thus, the plasma levels of Delta 9 THC and its metabolites seen after intravenous injection suggest that psychopharmacologic effects are seen in the first component of the rapid phase and terminated by redistribution and metabolism after the initial phase. The 11-hydroxy Delta 9 THC would be present at this early phase and is probably responsible for the activity of Delta 9 THC in marihuana.

Further evidence that the 11-OH Delta 9 THC is responsible for marihuana's effect was seen in oral and inhalation studies. By the oral route, blood levels of unchanged THC were relatively low compared to the radioactivity levels of the metabolic products at the time of peak subjective effect. While the blood level of unchanged THC at the peak oral effect was identical to that after intravenous injection of the 0.5 mg. dose, the psychologic, effect was much more pronounced after oral administration of the larger 20 mg. dose of THC. Again after inhalation, the plasma levels of the metabolites correlate temporally with the subjective effects but the plasma levels of unchanged Delta 9 THC do not. (Lemberger, 1970, 1971, 1972; Galanter, 1972)

PATTERN OF USE

The drug effect of marihuana can only be realistically discussed within the context of who the user is, how long he has used, how much and how frequently he uses and what is the social context of the use. In general, for virtually any drug the heavier the use pattern, that is the longer the duration, the more frequently the use and the larger the quantity used on each occasion, the greater the risk for either direct or indirect damage.

Tolerance development is only one of a variety of occurrences which are related to the repetitive use of marihuana. Any discussion of drug effect must take into account the time period over which the drug is used (duration of use). This is necessary in order to detect cumulative effects or more subtle gradually-occurring changes. Of course, the issue of causality is quite complex because of the multitude of factors other than marihuana use that have a direct or indirect effect on the individual over a period of years.

For the purposes of this report, immediate or acute effects will refer to those drug effects which occur during the drug intoxication or shortly following it. Short-term or sub-acute will arbitrarily refer to periods of less than two years; long-term, from two to 10 years; and very long term (or chronic), greater than 10 years.

Frequency of use, will arbitrarily be designated in the following manner: experimental use refers to use of marihuana at least one time but not more than once a month; intermittent use refers to use more than once a month but not more than 10 times a month (several times a week) ; moderate use refers to use of the drug more than 10 times a month but not more than once a day; heavy use designates use more than once, daily and very heart use refers to use many times a day, usually with potent preparations (high THC content), producing almost continual intoxication so that the smoker's brain is rarely drug free.

AMOUNT OF DRUG CONSUMED

Relatively little actual data are available on the amount of marihuana, smoked per occasion or per day by current users in the United States. (McGlothlin, 1971, 1972). Estimates of the quantity of THC consumed are difficult because of the variability of potency as well as weight and size of the marihuana cigarette ("joint") and the degree of cleaning of stems and seeds from the dried leaves manicuring").

The analytic data available indicates most of the marihuana used in the United States is of Mexican origin and averages about I % THC per dry cleaned weight of marihuana (Lerner and Zeffert, 1968; Jones, 1971). Subjective ratings by experienced marihuana users appear to substantiate the data that marihuana containing 1% THC is of average quality (Jones and Stone, 1970; Weil et al., 1968).

Marihuana cigarettes are estimated (McGlothlin, 1971, 1972) to average about 0.5 g in weight and, therefore, contain about 5 mg of THC. Cigarettes used in the eastern states are generally smaller than those, rolled in the west (McGlothlin, 1971; New York Police Department, 1969, 1970)

Most data indicates that for the large majority of users one-half to one cigarette (2.5 to 5 mg THC) is sufficient to "get high" in intermittent moderate users, although often two or more cigarettes were smoked to achieve additional effect (Nisbet and Vakil, 1972; Shean and Fechtmann, 1971; McGlothlin et al., 1970- McGlothlin, 1972; Jones, 1971; Goode, 1970).

Current American daily users appear to consume one to two cigarettes per occasion (Jones, 1971) although some users estimate they smoke three to five cigarettes per occasion (McGlothlin et al., 1970). Goode (1971), however, found practically no relationship between amount required to get high and frequency of use (daily to less than monthly) or duration of use (less than two years to six or more years). In fact, the heavy and longer term users were less likely to require more "joints."

Thus, the estimated 15 mg THC for current daily users is about one-half that estimated for confirmed regular users 30 years ago in the United States (Mayor's Committee, 1944; Charen and Perelman, 1946) and one-third to one-fourth the median daily consumption of daily users in North Africa and India.

The maximum daily consumption of 10 cigarettes (50 mg THC) for current heavy U.S. marihuana smokers (Jones, 1971; McGlothlin, 1972) is about the same as the average amount consumed by daily chronic users in other countries, and about one-fourth or less of the maximum in these countries (Soueif, 1967; Sigg, 1963; Indian Hemp Drug Commission's Report, 1893-1894; Chopra, 1940; Chopra and Chopra, 1939).

Studies of American military in Vietnam (U.S. Congress, 1971; Colbach and Crowe, 1970; Forrest, 1970), and Germany (Tennant et al., 1971) described the daily use of quantities of hashish or potent marihuana comparable to amounts consumed by regular chronic users in other countries.

Experimental data appear to confirm these estimates of quantity of THC consumed. Isbell et al. (1967) and Jones (1971) found that most subjects reported a normal "high" after smoking 5-10 mg of THC. Meyer et al. (1971) found that a "very high" state was attained by ad libitum smoking of 3.12 mg THC by daily users and 3.78 mg THC by intermittent users.

In experiments by Johnson and Domino (1971), subjects were urged to smoke until they were as high as they had ever been on marihuana and felt they could not smoke any more. These subjects smoked from one to four cigarettes containing 8.7 mg of THC to reach this level of intoxication. The range was from 8.7 to 30 mg of THC with a mean of about 20 mg THC.

Intermittent and daily users were allowed to smoke marihuana on a free choice basis over a 21day period in studies by Mendelson et al. (1972). Each cigarette contained one gram of marihuana of approximately 2% THC content, or about 20 mg of THC.

Subjects were asked to rate their high on a 10 point scale with 10 corresponding to highest ever; five as moderately high and zero, no effect. Ratings for the daily user group ranged from zero to nine with an average of about six for all cigarettes rated. Individual means ranged f rom three to about seven. On almost all occasions, subjects in both groups smoked the entire cigarette.

Kiplinger et al. (1971) and Lemberger, et al. (1971) noted that daily long-term users were able to detect effects of the "high" at doses calculated to deliver as low as 5-7 micrograms/kg THC (equivalent to smoking about 100 mgs. of marihuana containing 1 % THC). Perhaps this explains the finding that many users are able to "get high" smoking US wild-growing marihuana containing front near zero to 0.5% THC (Lerner, 1969; Phillips et al., 1970; Fetterman et al., 1971).

Several ad libitum experiments were performed with marihuana of unknown composition (Williams et al., 1946; Siler et al., 1933) using "confirmed regular marihuana users" confined over a 39 and six-day period. The users, who generally consumed three cigarettes per day, under these rather artificial conditions of the, experiment consumed means of 17 (range nine to 26) and five (range one to 20) cigarettes per day respectively.

Miras and Coutsilinis (1970) reported recent experimental data on chronic Greek hashish users who routinely use, single smoked doses of hashish containing 100 mg of THC. Under ad libitum conditions, these users averaged 150-350 mg of THC per day over a 30-day period.

The subjects studied during a 21-day period of free choice Marihuana consumption by Mendelson et al. (1972) generally consumed all of one cigarette containing 20 mg of THC per smoking session. 'The subjects who were previously daily users were more likely during the experiment to consumer more, than one, cigarette per session than the, previously intermittent users.

Individual consumption by the intermittent users ranged from an average of about one-half to
six cigarettes per day (group mean three) while the daily users consumed an average of three-anda-half to nine cigarettes per day (group mean six-and-a-half). Reasons given by the subjects for the dramatic shift in the frequency of marihuana use included boredom, testing the limits of their endurance, demonstrating its harmlessness to the research staff, and subtle social pressure.

DURATION OF USE

Very little American data exists on the duration of marihuana use. Practically no data exists which demonstrates the extent that persons who initiated marihuana use some 20-40 years ago have continued its use. Robins and Murphy (1967) in a follow-up study of St. Louis black males noted that 20% of those who had tried marihuana by age 24 were still using it to some degree 15 years later. McGlothlin et a]. (1970, 1971) reported on a sample of predominantly white adults who began using, marihuana in adolescence and had continued infrequent use for more than 20 years.

In the case of Western and particularly middle class American use of marihuana, the rapid climb to prominence of the phenomenon since the midsixties raises the question of whether the entire drug movement is transient or permanent. Certainly, the majority of the youthful users and many of the adults have used the drug less than 10 years and probably less than five years.

One 1970 survey (Lipp, 1970) revealed that 77% of those students who initiated marihuana use four to five years earlier were still using it to some degree. A recent study (Walters et a]., 1972) indicates that students who first used marihuana before entering college in September 1965 and had continued use of marihuana in February 1969 ("old user") differed from the, vast majority of users who began their drug use in college ("new user").

The old user is more likely to experiment with a wide variety of drugs, to be extremely active in radical political organizations, to be alienated from American society, to be less definite about career plans, and to have more heterosexual activities.

The Commission-sponsored National Survey indicated that marihuana use by both youth (12-17 years of age) and adults (18 and over) is experimental in approximately 75% of those who have ever used marihuana. These individuals have, either stopped using it (66% of adults and 57% of youth) or are, using, it once, a month or less. In contrast, 13% of the ever used subsample (12% adults, 16% youth) use marihuana once a week or more.

In other non-Western countries, cannabis use frequently persists for long periods. Especially in the East, persons using it for 20-40 years or more are not uncommon. In other cultures, initiation is most common in adolescence. Once the habit is established it is likely to continue on a daily basis for many years and frequently continues as a lifetime practice (Weiss, 1971; Sigg, 1963; Soueif, 1967; Watt, 1936; Chopra and Chopra, 1939; Bouquet, 1951; VN, 1957).

Probably the duration of use will vary considerably depending on cultural acceptance or rejection (McGlothlin, 1972).

INTERACTION WITH OTHER DRUGS

Little experimental work has been done on the interaction between marihuana and other drugs used socially or medically although this will become an important area as usage increases.

Marihuana is often used with sweet wines to enhance its effect. Some evidence for an additive effect of marihuana and alcohol on motor and mental performance and subjective effect has been seen experimentally (Manno et al., 1971; Jones and Stone, 1970). Some degree of additive effects would be expected with barbiturates based on their similarity to alcohol. A more complex, mixed pattern of effect might be expected with amphetamines and hallucinogens. These latter combinations are rarely used socially (Hollister, 1971).

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Marihuana, A Signal of Misunderstanding