2. Cannabis and Its Effects

ADMINISTRATION, ABSORPTION, DISTRIBUTION AND PHYSIOLOGICAL FATE

Administration and Absorption

In North America, marijuana is usually smoked in hand-rolled cigarettes known as 'joints', 'J's', 'sticks', 'muggles', 'numbers' or 'reefers', the butt of which is often called a 'roach'. Marijuana cigarettes may vary in size from a few hundred milligrams up to several grams. Commission research indicates that a typical 'joint' in Canada might contain about one-third of a gram of marijuana. [h] (Regular tobacco cigarettes usually weigh about one gram.) Depending on the potency of the material and various characteristics of the user, anything from a fraction of a 'joint' up to one or even two cigarettes might be considered a typical acute dose. Hashish is also sometimes smoked in cigarette form, perhaps mixed with tobacco or marijuana for easier burning, but is more often smoked in a pipe, or burned on the tip of a pin or tobacco cigarette. A variety of conventional and special pipes, including water pipes (hookahs) and custom-made instruments are commonly employed in the smoking of hashish and marijuana. Cannabis is routinely mixed with tobacco and, less often, with other active drugs in the East and South America, but these practices are not as common in North America.

Although the literature is inconsistent, it would appear that approximately one-half of the THC and THC acids present in a cannabis cigarette are available as THC in the smoke after combustion. 179,399,618 Commission research has confirmed this estimate in natural plant material, with slightly lower figures for alfalfa impregnated with synthetic Delta 9 THC.180 With the exception of the change of cannabinoid acids to neutral forms, there seems to be little consistent alteration in the proportion of cannabinoids which survive burning. Under some conditions, a significant proportion of the THC may escape in the side stream of smoke between inhalations, or remain in the butt of the cigarette. Consequently, users generally smoke all of the available material, including the 'roach', and minimize 'dead' burning time by passing around and sharing the cigarette. The proportion of THC delivered when cannabis is smoked in a pipe or a water pipe may not be the same as that in cigarette form,180 but possible differences have not yet been clarified. Neither has the pyrolysis of hashish been adequately studied and compared with other cannabis forms.8,180 Major problems with the quantitative analysis of cannabis call into question much of the past and present work in this area.

Cannabis smoke is usually inhaled deep into the lungs and held there for an extended time, in order to maximize absorption of the active compounds. While cannabis users in North America often retain the smoke in their lungs for up to a minute or longer, preliminary laboratory data suggest that the retention of almost all of the cannabinoids in the inhaled smoke may occur after a considerably shorter interval (less than half a minute may be sufficient).399,487 By contrast. prolonged retention of inhaled smoke is not common among cannabis users in either India or Jamaica, although deep inhalation techniques are typically used.412,534 On the basis of the present data, then, it would appear that under optimal conditions, a smoker may absorb up to one-half of the THC available in the cannabis material. Under most conditions however, both social and experimental, considerably less of the THC actually enters the physiological system[n] The lack of standard administration techniques generally renders detailed or quantitative comparisons quite tenuous, both among experiments and between laboratory and social situations.

The onset of psychological effects is almost immediate when smoking the more potent forms of cannabis, and the peak effects usually occur within minutes of administration. Depending on dose, major effects usually last several hours while milder ones may endure for half a day or longer.

Absorption of THC by the gastrointestinal tract is quite effective, but relatively slow and erratic.359 The food content of the stomach may affect the rate of absorption. Even though cannabis resin is poorly soluble in water, effective emulsions or suspensions of cannabinoids in water can be achieved for oral consumption, and in the East cannabis is often used in making tea or other beverages. Mild bhang drinks, served cold, are common in parts of India. In some countries, hashish is incorporated into buttered candies, called majoon, or into other foods. Prior cooking may increase the potency of eaten cannabis by changing inactive THCA to THC. The effects of cannabis taken orally usually begin after about an hour and gradually reach a peak within several hours, then slowly decline. Several investigators have reported a surprising abrupt (but delayed) onset of potent symptoms after ingestion.16,243,402 Very high doses may produce acute effects lasting more than a day, although the drug is not ordinarily used in such large quantities in North America. Cannabis is also effective when administered rectally.

The subjective effects of eating cannabis are sometimes said to be noticeably different, qualitatively, from those of smoking. It is uncertain whether this alleged difference might be due to chemical changes resulting from the heat in smoked material, the effects of the digestive juices or other metabolic processes after ingestion, or differences in rapidity and efficiency of absorption and distribution with the two methods. In spite of the THC loss due to burning, on a weight basis, inhalation is the more effective mode of administration; THC in material smoked reportedly produces effects comparable in intensity to approximately three times the same quantity taken orally Since, at most, only half of the original THC in smoked cannabis is actually delivered and absorbed, inhalation may be five to ten times as effective a mode of administration. This general formula may not apply to crude cannabis preparations if a substantial proportion of the THC present is in acid forms (THCA), since these compounds are apparently inactive when taken orally, but are converted to active THC when smoked. Furthermore, if THC is given by oral ingestion, the vehicle in which it is administered (for example, alcohol, sesame oil or glycocholic acid solution) can significantly affect the rate of absorption and the intensity and duration of the drug effects.495 Clearly, further work is needed in this area employing up-to-date analytic techniques.

Since Delta 9 THC is poorly soluble in water, adequate injection procedures are difficult to achieve. A variety of solvents and other agents have been employed as injection vehicles in animal experiments with varying degrees of success. Interperitoneal injections are inefficient and often cause serious complications, 270,272,580 and intravenous administration of pure materials is difficult. Water soluble THC derivatives have recently been developed, but their similarity to natural THC has not yet been established. 287,516 There have been a few reports of individuals self-injecting crude concoctions of cannabis extract intravenously. Such injections can produce serious adverse effects which may not be attributable solely to the pharmacological properties of the cannabinoids, but may occur in reaction to other insoluble foreign particles in the prepared concentrate.

Distribution, Biotransformation and Excretion

Although THC in pure form has high fat solubility, recent animal studies indicate that the drug does not seem to show any specific affinity for neural tissue, nor does it appear to concentrate initially in the body's fat stores. Initial distribution of the drug seems to be determined primarily by the vascularity of (or the blood flow through) the tissues. THC and its metabolites accumulate quite rapidly in the liver, kidneys, spleen and lungs --  the primary organs of absorption, metabolism and excretion. A significant amount may also be found in the testes.8,83,271,338' No significant blood-brain barrier exists in mice.222 The relative concentration of metabolites in bile, gastrointestinal tract and bladder increases until excretion. In rodents, THC has been shown to cross the placental barrier and enter the foetus in pregnant females.294 Sex differences in sensitivity to cannabinoids have been demonstrated in some animals, which may be a function of differences in drug metabolism, and in body water and fat. Females of some species seem to be more responsive to cannabis effects than males.80,137,471 No comparable human studies have been reported to date. (In both animal and human studies, males have been predominantly used as subjects.)

THC is extensively metabolized in humans, primarily in the liver, but also in other tissues, including the lungs, and the various metabolites are excreted in the feces and urine. Little or no free or unaltered THC is eliminated from the body. Although much of the administered THC is almost immediately bound to lipoproteins in the blood plasma, 338,643,669 metabolism apparently begins nearly as soon as the drug enters the body, and metabolites have been identified in plasma within minutes after administration. The major THC metabolites are mono- and clihydroxy compounds. Deriving from these primary metabolites are a large number of secondary Metabolites. THC is progressively metabolized. primarily by non-specific oxidases in the microsomal enzyme system in the liver. This may be a significant factor for drug interaction considerations, since many other drugs are metabolized by the same system.

In man, studies of radio-labeled materials suggest that about one-half of the THC metabolites are excreted within a few days, and most are eliminated within a week, although small amounts may be retained for longer periods.359,361 (In this respect, cannabis is more similar to some of the major tranquilizers, sedatives and anti-depressants than to alcohol, which is more quickly metabolized and excreted.) Some investigators have cautioned that cannabinoid metabolites may persist in the body for extended periods (especially with chronic heavy use), perhaps producing cumulative effects of possible adverse consequence.80,489 There is little experimental evidence of this in humans to date, but the possibility must be thoroughly explored. Excretion might be slowed by an apparent entero-hepatic circulation (seen in animals) in which some of the metabolites which are excreted via the gall bladder and bile duct into the intestine, are subsequently reabsorbed and recycled.339' Increased toxicity, with time, of massive doses of cannabinoids, repeated daily, has been noted in rodents,225,502 but relevance of these conditions to humans has not been demonstrated.

Metabolism and excretion of cannabinoids is apparently more rapid in chronic daily cannabis users than in inexperienced subjects.361' Regular use of cannabis may increase the body's production of THC metabolizing enzymes in a fashion similar to that occurring with barbiturates. This suggests a mechanism for tolerance, and perhaps cross-tolerance to other drugs using the same metabolic enzyme system for biotransformation. 80,491

A major metabolite, 11-hydroxy THC, appears rapidly in the blood of humans after cannabis has been administered,358,361 and has been shown to have pharmacological activities similar to, and perhaps more potent than, THC in animals. 128,223,618 This finding supports earlier speculation that the primary effects of cannabis may be due, at least in part, to THC metabolites, rather than to the original molecule alone.420 Such a phenomenon might offer a partial explanation for the "reverse-tolerance" or "sensitization" to cannabis effects often reported in users. Other hypotheses bearing on this phenomenon will be discussed later in the section on Tolerance and Dependence.

The Detection of Cannabinoids in the Body

The identification of cannabinoids and their metabolites, and their distribution in body fluids and tissues. as discussed above, has primarily been based on research involving small quantities of radio-active materials. To date, no simple and efficient method has been developed for the detection and quantification of unlabelled cannabinoids in the body. Consequently. it has been impossible to directly relate cannabis effects to plasma or tissue drug (THC or metabolite) levels. Some gross relationship between subjective effects and general plasma radio-activity has been seen, however. Greatly improved research techniques for both quantitative and qualitative analysis of cannabinoids and their metabolites in body tissue, blood and urine are currently being developed. The fluorescent assay of biological fluids pioneered by King and Forney336. is being extended by Bullock91 into a very sensitive method for detecting metabolites. Improved extraction and detection triethods for cannabinoid metabolites in urine have been reported, including a simple and relatively fast thin layer chromatographic method based on conversion of the metabolites to cannabinol.17,129,317,520,677  Radioimmunoassay techniques 94,96,182,203,552 and spin-label immunoassay techniques 289,365 are currently being developed.[o] The latter method could be applied routinely to large numbers of cases as it takes very little time (5 minutes) but requires expensive equipment and a supply of THC antibody. However, even these techniques being developed may have limited practical applicability outside of the research laboratory.

It is sometimes possible to detect the use of, or general contact with, cannabis from saliva samples or from chloroform skin swabs after intervals of hours or even days.524,589 In addition, it may be possible to detect the odour of cannabis smoke on users or on their breath. However, these techniques would not provide quantitative information regarding the magnitude of dose used or absorbed, or the intensity of intoxication, and therefore cannot be of much use in determining concurrent cognitive or psychomotor impairment.