The respiratory studies of Tashkin and the toxicological
and pharmacological studies of Perez-Reyes, Agurell, and Hollister
all indicate that it is an established research paradigm of
the scientific community that valid assertions about the effects
of marijuana can be based on studies of its constituent parts.
Additional recent research by Julian Azorlosa and his
team at Johns Hopkins University School of Medicine provides
more knowledge about the effects of THC content, puff volume,
and breathhold duration.
One objective of pharmacological research has been to
refine the measurement of the dose of marijuana delivered
by smoking as the route of administration. A 1992 study by
Azorlosa addresses this problem. Previous studies did not
provide adequate measures of the volume of smoke delivered
to the subjects, making it difficult to judge or compare dose-effect
relationships. Altering the THC content of NIDA produced marijuana
cigarettes only produces a narrow range in actual dosages.
Past studies did not measure post-smoking blood plasma levels
of THC. These factors contributed to great uncertainty about
the dosages delivered in various studies. This prevents establishing
a relationship between dose, plasma THC levels, and the pharmacological
effects of marijuana.
Azorlosa's study used a wide range of dosages, utilizing
NIDA cigarettes of 1.75% and 3.55% potency, controlled delivery
of the smoke, and measured plasma levels.
"All aspects of smoking behavior were controlled including
number of puffs, puff volume, inhalation volume, breathhold
duration and interpuff interval. Measurement of plasma THC
levels after smoking thus provided an index of systemic delivery
of a known volume and THC content of marijuana smoke. A complete
profile of dose-response and time-course data was also obtained
by measuring the effects of marijuana on physiological indices,
subjective reports and performance on several cognitive and
psychomotor tasks." (45)
The number of measured indices in the study provided
a comprehensive array of data, all establishing "orderly dose-related
increases as a function of cigarette THC content and number
of puffs." (46) The controls over delivery of smoke, number
of puffs, and other aspects of smoking behavior
"allowed an accurate assessment of how a known volume
and THC content of inhaled smoke translates into a measured
plasma THC level." (47)
The study produced four dosage conditions:
a) 4 puff, 1.75% THC=57 ng/ml;
b) 10 puff 1.75% THC or 4 puff 3.55% THC=90 to 99 ng/ml;
c) 5 puff 1.75% THC or 10 puff 3.55% THC=172 ng/ml;
d) 25 puff 3.55% THC=268 ng/ml.
Dose related effects were observed in plasma concentration,
expired air carbon monoxide, heart rate, and a majority of
Significant differences in acute doses were apparent
between the highest and lowest doses delivered.
"The results of the present study suggest that, under
acute dosing conditions, human subjects may have difficulty
discriminating between smoked marijuana doses that produce
plasma levels in the range of 90 to 170 ng/ml." (48)
At these doses, subjective measures are affected more
by marijuana than performance measures; dose-related effects
are observed in performance measures at higher doses.
"Overall, this study provided a comprehensive assessment
of the pharmacological effects of smoked marijuana over a
wider and more precisely controlled dosage range than has
been accomplished previously."(49)
A study by Azorlosa's team in 1995 addressed the effects
of puff volume and breathhold duration on plasma levels. Changes
in puff volume produced significant dose-related changes in
plasma, carbon monoxide, and subjective effects whereas changes
in breathhold duration changed plasma levels but neither carbon
monoxide nor subjective effects. (50) The increases in plasma
THC levels from breathholding are not statistically significant
except at the lowest and highest doses.
"Thus, the plasma THC data suggest that the stereotypic
behavior of marijuana smoking is useful for maximizing absorption;
however, our study suggests there are diminishing returns
with longer breathhold durations."(51)
As Tashkin determined in 1991, longer breathhold durations
increase exposure to tar and carbon monoxide. The diminishing
returns Azorlosa has established provides a basis for persuading
marijuana smokers to alter their smoking patterns to reduce
the harmfulness produced by prolonged breathhold durations.
This is additional evidence that the harmful effects of the
tars and carbon monoxide can be reduced through use of greater
filtration and change in smoking techniques.
Additional work at the Addiction Research Center at NIDA
provides more on the absorption phase of marijuana smoking.
Marilyn Huestis and her colleagues applied rapid blood
collection, a paced smoking protocol and the timely collection
of physiologic and behavioral measures for their 1995 paper
on the "Characterization of the absorption phase of marijuana
The rapid blood collection was assisted by use of a continuous
withdrawal pump, and this allowed the team to produce sophisticated
time lines for a variety of physical and behavioral indices.
"This study was designed to characterize the absorption
of D9-tetrahydrocannabinol during marijuana smoking and to
define the onset, peak, and duration of the pharmacodynamic
effects of marijuana."(53)
The study utilized six subjects who smoked placebo, 1.75%
THC and 3.55% THC cigarettes obtained from NIDA. THC is found
in plasma after the first puff, and plasma levels peaked at
9 minutes, before the last puff sequence began at 9.8 minutes.
Plasma levels dropped by about one-third from their peak after
15 minutes, and levels at thirty minutes had dropped by about
three-fourths. After 2 hours plasma levels flattened out at
5 ng/ml, and remained detectable for about 12 hours. The difference
in the plasma drug concentrations varied significantly, and
were characterized by the authors as "wide interindividual
Heart rate increases of 46 and 56 beats/min. peaked at
17.4 minutes and 13.8 minutes for the low and high THC cigarettes
respectively. The subject with the lowest THC levels had the
greatest increase in pulse. Hear rate remains elevated for
3 hours after the highest dose, but the affects of the low
dose disappear by this time.
"Mean arterial pressure and systolic blood pressure also
increased after marijuana smoking, but effects did not reach
Other physiological tests included skin temperature (decreased),
and tests on the eyes measuring critical flicker fusion and
pupil dilation (no changes.)
The study used visual analog scales to measure "feel
drug" and "like drug". Large variations were present in the
responses to "feel drug," but mean peak differences were reached
after 16 and 10 minutes (for low and high dose, respectively).
The subject with the lowest concentration (and highest heart
rate change) also had the highest score on this index. The
scoring of "like drug" was more consistent, and mean peak
differences were observed at 8.4 and 10.2 minutes respectively.
Effects were noticeable for 6 - 12 hours.
"The visual analog scale "How much to you dislike the
drug?" was not sensitive to the effects of smoked marijuana;
there was no distinction in responses of the subjects between
the placebo and active drug conditions."(56)
The study used the Walter Reed performance battery to
provide performance indices.
"Three different parameters were assessed in each performance
task; percentage of correct responses, throughput, and speed.
None of the five tasks showed significant effects on throughput
and speed after marijuana smoking. After smoking one 1.75%
or 3.55% D-9-tetrahydrocannabinol cigarette, the percentage
of correct scores on the logical reasoning task were significantly
lower than after placebo. The mean peak decrease in accuracy
for the logical reasoning task was observed at the time of
first measurement at 22 minutes . . . The performance accuracy
on the logical reasoning task had returned to baseline levels
within 3 hours for all subjects. No significant differences
in accuracy after marijuana smoking were noted in the matrix,
serial addition and subtraction, manikin, and time wall performance
tasks. In the time wall task, subjects had to estimate the
completion of a 10-second time span. . .no significant differences
in estimated time were observed after marijuana smoking. Response
speed also was evaluated for all tasks and was not affected
by marijuana administration."(57)
Only a few studies had previously attempted to collect
blood during the smoking process, two of the three papers
Huestis cites are by Perez-Reyes. While this paper hypothesizes
that peak THC plasma levels are reached before smoking cessation
as a function of puff volume, its real importance lies in
the team's application of rapid blood collecting to the characterization
of the absorption phase of marijuana smoking.
"Studies that combine rapid blood collection, paced smoking
protocols, and timely collection of physiologic and behavioral
measures are essential for the complete characterization of
the absorption phase of marijuana smoking."(58)
This study also found similarity between time-to-peak
drug levels and effects for some measurements. It has previously
been believed that time-delays existed between peak physiologic
and behavioral effects.
An additional significance of the studies discussed above
is that they demonstrate a tremendous degree of scientific
specificity has been achieved in the study of the pharmacology
and toxicology of marijuana smoke, and that extremely sophisticated
technological innovations (such as allow measurement of puff
volume and rapid blood collection) provide extremely accurate
tools for controlled evaluation studies of the effects of
Discussion will now turn from marijuana smoke, its harm
to the lungs, and its delivery of a dose of cannabinoids to
the body to the pharmacological profile of the cannabinoids.