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 subjective responses.

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 smoking."(52)

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 differences."(54)

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 statistical significance."(55)

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 marijuana.

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.