Mario Perez-Reyes has done considerable research on the pharmacology of marijuana. The paper he and his colleagues published in 1991 on "The Pharmacologic Effects of Daily Marijuana Smoking in Humans" is instructive beyond its findings, which concern tolerance.

"Therefore, as long as marijuana is not used more than once daily, it appears that there is no need to escalate the dose to obtain the same degree of "high.

"Acceleration of the heart rate is a consistent effect of THC. In this study, a trend toward diminished cardioacceleration and a significant decrease in the heart rate acceleration time response pattern were found to occur after the period of daily marijuana smoking. Taken together, these observations suggest that tolerance to the heart rate-accelerating effects of THC develops in response to modest daily doses of the drug . . .

"That tolerance to the heart rate-accelerating effects of THC develops more readily than tolerance to its subjective effects is not understood . . .tolerance to cardio-acceleration may occur more readily as fewer neuronal circuits are involved."(34)

Like Tashkin's work, this study demonstrates that it is possible to use standardized marijuana is clinical experiments. The study used marijuana cigarettes provided by the National Institute on Drug Abuse (NIDA). The cigarettes were prepared from active and placebo material to obtain a standard 1% THC content, the average dose of THC was 8.8 mg per cigarette. (35)

This study also measured the bioavailability of marijuana by comparison with intravenously infused deuterated THC, with a calculation method that allowed for the different routes of administration. (36) The direct estimation of bioavailability of THC from marijuana smoke has not been previously available.

"Exposure to daily marijuana smoking did not alter the bioavailability of smoked THC. Wide individual variations were found, which confirms the observations of large individual variability of the manner in which marijuana cigarettes are customarily smoked."(37)

THC is studied more intensely than other cannabinoids, and the pharmacokinetics and metabolism of cannabinoids were reviewed in 1986 by Agurell, Hollister, and colleagues. (38) Hollister characterized this research during an acceptance speech for a lifetime achievement award from the College on the Problems of Drug Dependence, at which he once served as the chairman of the Drug Evaluation Committee.

"Our studies of cannabinoids over the past 22 years have touched upon virtually every aspect of their actions. They constitute the largest series of studies of the human pharmacology of marijuana on record. Some have been concerned with drug interactions, most notably with other cannabinoids; we found none."(39)

"At some point in studying drugs, it becomes desirable to measure plasma concentrations to obtain a sense of the drug's pharmacokinetics and to try to relate these to clinical effects. The Swedish group, headed by Stig Agurell, was so far ahead in techniques of measurement that I despaired of ever being able to catch them. So, following the old saying, "If you can't lick them, join them" we have collaborated with them during the past 10 years, the clinical work being done in the US and the laboratory measurements being done in Sweden. This cooperation has elucidated the patterns of drug availability from three routes of administration (smoking, ingestion and intravenous administration), has found that the kinetics of the inactive cannabinoids, CBD and CBN are similar to those of THC, has found that heavy marijuana use as compared with light use does not much change the kinetics, and has correlated clinical actions with plasma concentrations." (40)

A closer look at Agurell and Hollister's 1986 review clarifies some basic background on the toxicology of cannabinoids.

(Agurell is from Sweden, and European scientists use a different labeling system for cannabinoids than scientists in the U.S. The system used by Agurell is a monoterpene system, and refers to the active agent as delta-one THC. The U.S. uses the dibenzopyran system which refers to delta-nine THC.)

The major cannabinoids are the Tetrahydrocannabinols (THC), cannabinol (CBN) and cannabidiol (CBD).

"Of more than 60 cannabinoids . . .only D1-THC has profound psychoactive properties. CBN i.v. shows about 1/10 the potency of D1-THC in man, whereas CBD is devoid of psychotomimetic properties. D6-THC is about equipotent with D1-THC but is usually present in very small amounts compared to D1-THC, CBD, and CBN. The latter three compounds occur in marihuana-type preparations in concentrations usually around 1 to 2%." (41)

Agurell and colleagues discuss the chemical aspects of THC, the influence of various routes of administration, their relation to blood plasma levels, and other pharmacological issues. They also conclude that:

"In man it is unlikely that any active metabolite, such as 7-hydroxy- D1-THC, contributes in an important way to the effects of D1-THC after smoking or i.v. administration. After p.o. administration, however, we assume that 7-hydroxy- D1-THC contributes at least as much as D1-THC itself." (42)

"Additional findings include the following. Agurell's team also measured bioavailability, and found a difference between heavy and light users. Plasma D1-THC profiles are similar after i.v. injection and smoking.

"The pharmacokinetics and metabolism of CBD and CBN in man and animals follow the pattern similar to that of D1-THC." (43)

The authors also note that:

"Other studies suggest limited variation in pharmacokinetic parameters between heavy and light users, indicating that the development of tolerance to behavioral and pharmacological effects in THC users is most likely functional and not dispositional. D1-THC is initially metabolized in man in a way similar to that in most animals, i.e. by preferable allylic oxidation to 7-hydroxy- D1-THC." (44)

These findings, and others, support the validity of the research paradigm applied by the research community to establishing the pharmacological actions associated with marijuana use. They validate comparisons between studies involving injected THC and smoked marijuana. They validate concentration on the study of the primary psychoactive agent, THC. They provide a basis for an assertion that research does not focus on the other constituents because there is not compelling evidence that they have either harmful or dependence-producing qualities.