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
"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.
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
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
"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
"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."
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."
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.