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Evaluation of a vaporizing device (Volcano®) for the pulmonary delivery of tetrahydrocannabinol

  • Hazekamp Herbal Consulting

Abstract and Figures

What is currently needed for optimal use of medicinal cannabinoids is a feasible, nonsmoked, rapid-onset delivery system. Cannabis "vaporization" is a technique aimed at suppressing irritating respiratory toxins by heating cannabis to a temperature where active cannabinoid vapors form, but below the point of combustion where smoke and associated toxins are produced. The goal of this study was to evaluate the performance of the Volcano vaporizer in terms of reproducible delivery of the bioactive cannabinoid tetrahydrocannabinol (THC) by using pure cannabinoid preparations, so that it could be used in a clinical trial. By changing parameters such as temperature setting, type of evaporation sample and balloon volume, the vaporization of THC was systematically improved to its maximum, while preventing the formation of breakdown products of THC, such as cannabinol or delta-8-THC. Inter- and intra-device variability was tested as well as relationship between loaded- and delivered dose. It was found that an average of about 54% of loaded THC was delivered into the balloon of the vaporizer, in a reproducible manner. When the vaporizer was used for clinical administration of inhaled THC, it was found that on average 35% of inhaled THC was directly exhaled again. Our results show that with the Volcano a safe and effective cannabinoid delivery system seems to be available to patients. The final pulmonal uptake of THC is comparable to the smoking of cannabis, while avoiding the respiratory disadvantages of smoking.
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Evaluation of a Vaporizing Device (Volcano
) for the
Pulmonary Administration of Tetrahydrocannabinol
Division of Pharmacognosy, Institute of Biology, Leiden University, Leiden, The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
Division of Pharmacognosy, Section Metabolomics, Institute of Biology, Leiden University, Leiden, The Netherlands
Received 1 January 2005; revised 15 April 2005; accepted 25 October 2005
Published online ? ???inWiley InterScience ( DOI 10.1002/jps.20574
xx. ß2005 Wiley-Liss, Inc. and the American Pharmacists Association J
Pharm Sci 9999:1– 10, 2005
Keywords: delta-9-tetrahydrocannabinol; cannabis; vaporizer; aerosol; pulmonary
drug delivery; formulation vehicle; controlled delivery
Cannabis (Cannabis sativa L.) has a long history
as a recreational drug and as part of traditional
medicine in many cultures of the world. Nowa-
days, cannabis is used medically by patients
suffering from diseases varying from cancer and
HIV/AIDS to multiple sclerosis, frequently
in the form of unprescribed self-medication.
, an oral form of the main psychoactive
constituent of cannabis, delta-9-tetrahydro-
cannabinol (THC), has been developed for some
indications. However, oral THC is notoriously
unreliable in its effects.
Drawbacks of Marinol
include its slow onset of action, large varia-
bility in bioavailability, and extensive first
pass metabolism. Moreover, there is the incon-
venience of taking oral medication in case of
nausea or vomiting. Therefore, for many patients
the demand for more effective cannabinoid-based
medications persists. For this group of pati-
ents cannabis smoking is a more convenient
method of administration, allowing self-titration
of the desired effects. However, inhalation of toxic
compounds during cannabis smoking poses a
serious hazard. This risk is not thought to be due
to cannabinoids, but rather to noxious pyrolytic
Consequently, the shortcomings of
smoked cannabis have been widely viewed as a
major obstacle for approval of crude cannabis as a
medicine by public health authorities.
Cannabis ‘‘vaporization’’ or ‘‘volatilization’’ is a
technique aimed at suppressing irritating respira-
tory toxins by heating cannabis to a temperature
where active cannabinoid vapors are formed, but
below the point of combustion where pyrolytic
toxic compounds are made. Vaporization offers
patients who use medicinal cannabis the advan-
tages of the pulmonary routes of administration,
that is: rapid delivery into the bloodstream, ease of
self-titration, and concomitant minimizing the
risk of over- and under-dosing, while avoiding
the respiratory disadvantages of smoking.
In a series of studies the vaporizing of can-
nabis samples was systematically tested to show
its advantage over smoking. When a variety of
smoking devices (including water pipes) were
compared, specifically examining THC and solid
smoke tars, it was found that only vaporizers were
capable of achieving reductions in tar relative to
THC when compared to direct smoking of canna-
A follow-up study tested a vaporizer that
was found to deliver THC while completely elimi-
Correspondence to: Arno Hazekamp (Telephone: 31-71-527-
4519; Fax: 31-71-527-4511;
Journal of Pharmaceutical Sciences, Vol. 9999, 1 –10 (2005)
ß2005 Wiley-Liss, Inc. and the American Pharmacists Association
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nating three specic toxins (naphthalene, benzene,
and toluene) in the solid phase of the vapor.
The study also detected a 56% reduction in tars
and a qualitative reduction in carbon monoxide,
but did not test for any other chemicals.
In a more
recent study,
GC-mass-spectrometry was used to
analyze the gas phase of vaporized cannabis for
a wide range of toxins, particularly concentrating
on the highly carcinogenic polynuclear aromatic
hydrocarbons (PAHs). The vaporizer that was
used was the Volcano
It consists of a heater,
a ventilator, a lling chamber, a valve, and a
balloon. During operation the balloon is inated
with hot air and cannabinoid vapors. Using
cannabis plant material as the sample, vapors
were found to consist overwhelmingly of cannabi-
noids, while the combusted control contained over
one hundred additional chemicals, including sev-
eral known PAHs.
Although a large variety of vaporizing devices is
available on the market, the Volcano is one of the
few devices that have been tested scientically to
some extent. It is a herbal vaporizer, intended for
the vaporization of whole cannabis plant materials
(i.e., owertops), but numerous unexplored vari-
ables could affect the efciency and output of
vaporization. These parameters are variations in
temperature; differences in specimen density,
weight, content of water and essential oils, and
consistency of material in the lling chamber;
differences in the variety and potency of cannabis
used; and use of different preparations such as
crude owertops, hashish, hash oil, etc. Because of
the paucity of data it has so far been difcult to
show that the Volcano vaporizer can be used as a
reliable tool for the reproducible administration of
THC or other cannabinoids. A solution to this
would be in the use of pure cannabinoid prepara-
tions of known concentration to guarantee an
exact and reproducible loading of cannabinoids.
In this study the Volcano vaporizer was eval-
uated as a novel method for the administration of
THC. Pure cannabinoid preparations were used in
order to obtain quantitative results in terms of
efciency and reproducibility of THC delivery into
the balloon of the Volcano. By changing para-
meters such as temperature setting, type of
evaporation sample, and balloon volume, the
vaporization of THC was systematically improved
to its maximum yield, while preventing the
formation of degradation products. Factors that
resulted in loss of THC by condensation, that is,
storage time of the balloon and use of the lling
chamber, were evaluated. The inter-device repro-
ducibility of THC vaporization under optimized
conditions was determined. Finally, the results of
this study were used for the clinical administra-
tion of THC by vaporizing. The amount of exhaled
THC was determined and compared to the dose,
which was inhaled through the Volcano.
Our results indicate that the Volcano is a
convenient device for the administration of THC
by inhalation.
All organic solvents were HPLC or analytical
grade, and were purchased from J.T. Baker
(Deventer, The Netherlands). Anthracene (min.
99% purity) was purchased from Aldrich (St.
Louis, MO). Deuteriated chloroform (CDCl
) was
from Eurisotop, Gif-sur-Yvette, France. Glass
ber lters (Cambridge type, borosilicate glass,
92 mm diameter) and tightly tting lter holders
for vapor extraction were obtained from Borg-
waldt Technik GmbH (Hamburg, Germany).
Cannabis plant material (female owertops)
was medical grade and obtained from Bedro-
BV (The Netherlands). It had a water
content of about 8%, a THCA content of about
12%, and virtually no free THC.
Puried THC and THCA (purity 98%) were
produced and quantied as reported earlier.
THC was of pharmaceutical grade. The cannabi-
noids were stored as ethanolic solutions at 208C
at a concentration of 50 mg/mL.
The Volcano Device
The Volcano
was obtained from Storz & Bickel
GmbH & Co. (Tuttlingen, Germany) and was
used according to the manual as provided by the
manufacturer. It is a vaporizer or evaporator
that can evaporate the active substances or
aromas from plant material by using a hot air
ow (Fig. 1). Depending on the type of lling
chamber used, whole plant material or liquid
samples (e.g., aromatic oil, extract, or pure
compounds in solution) can be used. Evaporated
compounds are collected in a detachable plastic
balloon, which can be removed and tted with
a mouthpiece for inhalation. Volume of the
balloon can be varied. Unless otherwise stated, a
balloon length of 55 cm (around 8 L) was used, as
recommended by the manufacturer. The tempera-
Author Proof
ture control ranges from setting 1 9, correspond-
ing to temperatures of 1302268C (see Tab. 1).
Before each new set of experiments the whole
device was thoroughly cleaned with ethanol.
At the start of each evaporation the Volcano
was preheated until the indicator light showed
that the target temperature was reached. The
balloon, connected to the lling chamber, was
then immediately placed onto the Volcano and the
ventilation was started. When the balloon was
completely inated, ventilation was stopped and
the content of the balloon was processed for
analysis within 5 min, unless stated otherwise.
All laboratory experiments were carried out in a
standard laboratory fume hood under constant
ventilation with an ambient room temperature of
about 228C and a humidity of 40 60%. The air was
not conditioned (e.g., by HEPA lters).
Use of the Liquid Pad
The pure cannabinoids THC or THCA were used
as ethanolic solutions. For these liquid samples an
adapted lling chamber was used, containing a
removable disc made of tightly packed stainless
steel wire mesh (liquid pad), obtained from the
manufacturer of the Volcano. For each experi-
ment the appropriate amount of the cannabinoid
was dissolved in a nal volume of 200 ml of ethanol
for application onto the liquid pad and ethanol
was allowed to evaporate for 10 min under
ambient conditions. A new liquid pad was used
for each experiment.
Extraction of THC from the Vapor and the Liquid Pad
Cannabinoids were recovered from the vapor
phase inside the balloon by condensation onto
glass ber lters, designed to capture particles
>0.1 microns. Vapor was slowly aspired through
the glass-ber lter which was then extracted
twice with 15 mL of methanol/chloroform (9:1, v/v)
under ultrasonication. After evaporating the
extraction solvent, samples were reconstituted
in 5 mL of ethanol for analysis by HPLC or NMR.
These ethanolic samples will be further referred
to as vapor extracts.
Residual THC on the liquid pad was recovered
by extracting the liquid pad twice using methanol/
chloroform (9:1, v/v) under ultrasonication. Extra-
cts were further handled as described above for the
vapor extracts. Recovery was determined by spik-
ing lters or liquid pads with THC (2 mg) and
performing the described extraction procedure.
To assess the efciency of condensation of
cannabinoids onto the glass ber lter, a wash
bottle lled with ethanol was placed after the lter.
The escaping gases were bubbled through this
liquid which was thereafter analyzed by HPLC to
measure untrapped cannabinoids.
H-Nuclear Magnetic
Resonance Spectroscopy (NMR)
Quantication of THC in the extracts was done by
H-NMR using a Bruker 300 MHz
NMR apparatus as described by Hazekamp et al.
Table 1. Temperature (8C) of the Heating Unit of the
Volcano Corresponding to the Different Temperature
Temperature Setting Temperature in 8C
1 130
3 154
5 178
7 202
9 226
Figure 1. The Volcano vaporizer.
Author Proof
In short, an exact volume of the sample was mixed
with 1.0 mg of anthracene as internal standard
for quantication. The sample was then evapo-
rated to dryness under vacuum and reconstituted
in chloroform (deuteriated) for
H-NMR analysis.
High Pressure Liquid Chromatography (HPLC)
HPLC was used for both qualitative and quanti-
tative analysis of the obtained extracts. The
HPLC proles were acquired on a Waters (Mil-
ford, MA) HPLC system consisting of a 626 pump,
a 717 plus autosampler, and a 2996 diode array
detector (DAD), controlled by Waters Millennium
3.2 software. Full spectra were recorded in the
range of 200400 nm. The analytical column was
a Vydac (Hesperia, CA) C
, type 218MS54
(4.6 250 mm, 5 mm), with a Waters Bondapak
(2 20 mm, 50 mm) guard column. The mobile
phase consisted of a mixture of methanol-water
containing 25 mM of formic acid in gradient mode;
methanol:water in ratios from 65:35 to 100:0 over
25 min, then isocratic to 28 min. The column was
reequilibrated under initial conditions for 4 min.
Flow-rate was 1.5 mL/min and total runtime was
32 min. All determinations were carried out
at ambient temperature. The main neutral and
acidic cannabinoids were well separated with
this method.
Analyzed concentrations were
well above the limit of quantication of the used
Evaluation of Temperature Control
Temperature control was evaluated at setting 1,
3, 5, 7, and 9 (see Tab. 1). Time needed to reach
target temperature, and accuracy and stability of
target temperature were determined using an
electronic thermometer (response time; 250 ms).
Temperature was measured in the middle of the
lling chamber, on top of the liquid pad, and each
measurement was started directly after the
indicator light of the heater had switched off.
Inter-device variability for the same parameters
was tested for four different Volcano devices. All
experiments were repeated three times.
Optimization of Vaporizing Parameters
(a) Temperature: Cannabis plant material, and
pure cannabinoids THCA and THC were
vaporized at temperature settings 1, 3, 5, 7,
and 9 in order to determine the delivery
into the balloon as well as the formation of
degradation products. Vapor extracts were
qualitatively analyzed by HPLC for detec-
tion of degradation products, while quanti-
tative analysis by NMR was used for
determination of delivery.
(b) Heating time: In order to determine the
minimal time that is needed to reach
maximal evaporation of THC, the following
experiment was performed: THC (2 mg)
was applied onto the liquid pad and the
ventilation was activated for a duration
ranging from 10 to 300 s, without balloon
attached to the device so THC could
evaporate freely. Subsequently, residual
THC was extracted from the liquid pads
and extracts were quantitatively analyzed
by NMR.
Relationship Between Loaded Dose and Delivery
The relationship between quantity of THC loaded
onto the lling chamber and delivery into the
balloon was determined in the range of 28mgof
THC. Vapor extracts were analyzed by NMR and
HPLC, and each experiment was performed
Inter-Device Variability
Using the optimized parameters as determined in
this study, four Volcano devices were nally
evaluated for inter-device variability in THC
delivery. Samples of 4 mg of THC were used for
vaporizing and each Volcano was tested on ve
occasions. Vapor extracts were analyzed by NMR.
Condensation of THC onto the
Balloon and Filling Chamber
The effect of storage time of the balloons on
condensation of THC was determined by storage
of the balloon at room temperature for a duration
of up to 180 min after vaporizing (2 mg THC). The
vapor extract was then collected for analysis.
Each experiment was performed threefold.
Throughout this study balloons were always
processed within 5 min after vaporizing. There-
fore, it was determined more exactly how much
THC was lost due to condensation onto the walls
of the balloon after 5 min of storage by carefully
Author Proof
cutting the balloon (n¼5) into pieces and extract-
ing twice with ethanol under ultrasonication.
In order to determine the amount of THC that
condensated onto the lling chamber (excluding
liquid pad) and valve, after some experiments
these parts were extracted twice with ethanol
under ultrasonication. Finally, extracts were con-
centrated and THC was quantied by NMR.
Clinical Application of the Volcano
At the Centre for Human Drug Research (CHDR,
Leiden, The Netherlands) a methodology study
was performed to study the effects of THC
administration using the Volcano vaporizer. The
study was approved by the Medical Ethical
Committee of Leiden University, The Nether-
lands. Preliminary results of this study were
published recently,
and full results will be
published in the near future. In short, during
two separate occasions subjects received a rising
dose of 2, 4, 6, and 8 mg THC (loading dose in
lling chamber) or placebo (ethanol only) admi-
nistered via the Volcano, using the optimized
parameters as determined in this study. Admin-
istrations were given with 1.5 h intervals. The
balloon (8 L) had to be inhaled through the mouth
within 3 min and breath was held for 10 s after
each inhalation. Following each inhalation, sub-
jects were asked to exhale through a lter of the
same type as used for vapor extraction. Filters
were subsequently extracted as mentioned before
and the quantity of exhaled THC was determined
by NMR. Because of time restraints, no further
evaluation of lung function (e.g., FEV1) could be
Trapping and Recovery of THC for Analysis
Since no trace of THC could be found in the ethanol
fraction of the wash bottle inserted after the lter,
it was concluded that THC was completely trapped
onto the used type of lter. Recovery of THC was
found to be 99.3 (1.1)% from the lter and 83.0
(2.5)% from the liquid pad. All measurements
were corrected for these values.
Accuracy of the Temperature Setting
At all tested temperature settings it was found
that temperature reached a rst plateau after
about 30 s. After that temperatures remained
relatively stable for some time, but kept below
accepted limits (target temperature 48C, as
claimed by the manufacturer) for all tested
settings. Results can be seen in Figure 2a. How-
ever, after about 4560 s, depending on the
setting, the heating element was activated again
by the temperature sensor, and about 20 s later
temperatures increased by a few degrees bringing
the temperature within specied limits. It must
be concluded that the liquid pad and the lling
chamber need some time to heat up to the target
Reproducibility of the Vaporizer
When four different Volcano devices were eval-
uated under equal conditions to evaluate inter-
device variability (Fig. 2b), some small differences
Figure 2. (a): Temperature prole over time of the
Volcano at different settings. Dotted lines indicate
target temperatures at settings 1, 3, 5, and 7. (b):
Comparison of temperature prole of four different
Volcano devices at setting 9. Dotted lines indicate
allowed target temperature range (48C). Data is shown
as mean values of three experiments, and errorbars
indicate standard deviation.
Author Proof
in heating prole were found. Only temperature
setting 9 was evaluated here after it had been
shown to be the optimal temperature for THC
delivery. Although two devices reached target
temperature (accepted variation 48C) already
after 30 s, the two others needed 60 s or more to do
so. For two devices the temperature increased
above the maximum limit of target temperature
in the 90 s duration of our experiment. In
conclusion each individual Volcano device shows
little variability during sequential uses (intra-
device variability), although small differences do
exist between different devices (inter-device
Optimizing of Vaporizing Parameters
with Different Substrates
THCA: Under the inuence of heat THCA can be
converted into THC by decarboxylation. Indeed,
when THCA was used it was observed that this
conversion increased with temperature and max-
imum delivery of THC was about 33% at the
highest temperature setting (Fig. 3). However,
conversion was not complete and THCA was
present in the vapor extracts at a level of about
5.5 (1.3)% relative to THC.
Crude ower tops: The use of plant material
(200 mg at 12% THCA) resulted in a maximum
THC delivery of only 29% (Fig. 3). In fresh
cannabis plant materials THC is present in the
form of its acidic precursor THCA and the use of
plant material resulted in an incomplete decar-
boxylation with about 3.8% residual THCA pre-
sent in the vapor. Besides THC, several other
cannabinoids as well as a range of other plant
components were detected. Therefore, the use of
cannabis plant material in the Volcano should not
be recommended for the administration and study
of THC alone.
Pure THC: Evaporation of THC was shown to
increase with temperature with a maximal deliv-
ery of about 53% at setting 9 (Fig. 3), while no
degradation products (delta-8-THC (D
cannabinol (CBN), or other unknown peaks in
the HPLC-chromatogram) were observed at any
setting. Therefore, using the Volcano device, it was
concluded that the highest delivery yield was
achieved with an ethanolic of pure THC. When
liquid pads were extracted after vaporizing it
showed a very low amount of residual THC,
indicating a very high yield of evaporation, at the
highest temperature setting. This strongly sug-
gests that nondelivered THC does not remain on
the liquid pad, but is probably lost by condensation
after initial evaporation.
Minimum time was determined for the maximal
evaporation of THC from the liquid pad by
measuring residual THC after vaporizing.
Figure 4 shows that the amount of residual THC
rapidly decreases between 20 and 40 s after
starting of the vaporizing. This corresponds with
the observation that in the same time-period the
(near) target temperature of the Volcano is
reached (Fig. 2a and b). After 45 s most of the
Figure 3. Amount of delta-9-tetrahydrocannabinol
(THC) delivered into the balloon after using different
sample types in the lling chamber: THC (~, 8 mg);
THCA (&, 9 mg); plant material (^, 200 mg) at different
temperature settings. Delivery is expressed as %
relative to the loaded dose of THC. For THCA and plant
material, the theoretical loaded dose of THC was
calculated based on a 100% conversion of THCA into
THC. Data is shown as mean values. Error bars indicate
standard deviation.
Figure 4. Residual THC on liquid pad after varying
vaporizing time at setting 9. Datais shown as mean values
of three experiments, and error bars indicate standard
deviation. Values were corrected for the maximum
recovery of 83% for extraction of the liquid pads.
Author Proof
THC is evaporated and just a small fraction of THC
can be found in the liquid pad extract, indicating
that vaporizing time should be at least 45 s. When
using a temperature setting of 9 with a balloon
volume of 4 L (lling time around 30 s), a low THC
delivery (only 30% for 8 mg of THC) with a high
dose variability (relative SD 22%) was observed
indicating that the maximum delivery yield was
not yet reached.
It was observed that the maximal evaporation of
THC is reached after 120 s, (Fig. 4). Since the
Volcano is blowing air at a constant rate of about 9
L per min, this corresponds to a balloon volume of
about 18 L. However, by empirical testing in our
laboratory (data not shown) it was found that a
maximum volume of about 8 L could be inhaled
within 3 min when following the protocol of the
clinical trial. Therefore, a balloon volume of 8 L
(lling time of about 55 s) was selected for further
Relationship between Loaded Dose and
Delivery under Optimal Conditions
With a Volcano operating under the aforemen-
tioned optimized conditions (temperature setting
9, balloon volume 8 L) the delivery was deter-
mined with an increasing amount of THC ranging
from 2 to 8 mg. It is shown in Figure 5 that the
delivery was proportional to the loaded dose of
THC; a linear curve was obtained with a regres-
sion coefcient (R
-value) of 0.99. From the slope
of the line, a mean delivery yield of 57.8 (6.9)%
could be calculated.
Four available devices were then tested under
conditions as mentioned above using a sample of
4 mg of THC. Differences in delivery between the
Volcano devices were relatively small. Average
delivery of all four Volcanos was 53.9 (8.1)%, and
this value was taken as the average delivery for
further considerations.
Condensation onto Balloon and Filling Chambers
Loss of THC during experiments could partially
be accounted for by incomplete evaporation and
condensation onto parts of the Volcano vaporizer.
Prolonged storage of the balloon at room tem-
perature after vaporizing led to a steadily increas-
ing loss of THC by condensation up to the point
that after 180 min almost no THC could be
detected anymore in vapor extracts (Fig. 6).
However, if the balloon was extracted within
5 min after vaporizing, less than 2% of the total
dose was recovered from the inner surface of the
balloon. Condensation of THC onto the other
parts of the Volcano setup was found to be of
signicant importance. Visual inspection of the
lling chamber shows the presence of a conden-
sate mostly on the inside of the lling chamber
just above the liquid pad. Extraction of the lling
chamber together with the valve, but excluding
the liquid pad, showed that an average of 23.6
(14.1)% of the loaded THC had condensated onto
Figure 5. Relationship between delivery of THC
under optimized setting conditions with four different
THC loading doses ranging from 2 to 8 mg. Data are
shown as mean values of three experiments and error
bars indicate standard deviation. Linearity (r
was 0.99, as determined by linear regression.
Figure 6. Relationship between storage time and
percentage of initial THC that could be recovered from
the balloon. Data are shown as mean values of three
experiments, expressed as % of initially recovered THC.
Error bars indicate standard deviation. During this
study all balloons were processed within 5 min after
evaporation, which is indicated by the dotted line.
Author Proof
these parts of the Volcano, and could therefore
account for a large part of the nondelivered THC.
Clinical Study and Loss by Exhalation
The clinical trial was nished without any serious
complaints by the test subjects. Some mild
complaints included irritation of the throat and
lungs, and coughing. However, these effects were
also observed during inhalation of placebo and
therefore could be an effect of residual ethanol.
The development of signicant physiologic chan-
ges after inhalation of vaporized THC indicates
that THC can be effectively administered by this
Interestingly, it was shown that a large propor-
tion of inhaled THC was not absorbed by the lungs.
The total amount of THC used for evaporation was
20 mg of THC for each subject (Rising dose of 2, 4, 6,
and 8 mg resulting in a total dose of 20 mg). Taking
into account the average delivery yield of 53.9% as
found in this study, only an average of 10.8 mg of
THC was totally inhaled from the balloon. The
amount of THC recovered from exhaled breath
ranged from 2.5 to 4.4 mg, which means that up to
30%40% of inhaled THC was not absorbed by the
lungs. The variability of THC in exhaled breath
(relative SD 5.4%) is comparable to the varia-
bility in delivery of THC by the Volcano. Taking
this into account it could be concluded that
absorption of THC by the lungs is probably very
similar between different subjects.
The Volcano
vaporizer was validated for the
efcient and reproducible delivery of delta-9-THC,
and was found to be able to deliver an average
amount of about 54% of applied dose of THC into
the balloon for inhalation. THC recoveries from
smoke was found to range from 34% to 69% in a
variety of studies using different types of smoking
Because the plant material is not
burned in the Volcano, no signicant harmful
cancer causing combustion products are expected
and the noxious intake, when compared to smok-
ing, is greatly reduced.
Using the Volcano
device for pulmonary administration of THC, a
delivery is reached that is comparable to smoking,
but without the presence of degradation products
or harmful byproducts in signicant amounts.
Loading the Volcano with Cannabis plant
material or pure THCA resulted in a residual
amount of THCA in the vapor in the order of 5%
relative to THC. Not much is known about
biological effects or metabolism of THCA, and
therefore the use of THCA as sample for intended
clinical administration of pure THC should be
avoided. Older studies at least indicate that
THCA is not psychoactive in monkeys.
ugh in our study cannabis plant material was used
only for comparative reasons, it is clear that a
variety of cannabinoids and other compounds such
as terpenoids are present in the vapor.
With pure THC as the loading sample, tem-
perature setting and balloon volume were opti-
mized for a maximal, reproducible delivery of THC
without formation of detectable amounts of degra-
dation products. Using the highest temperature
setting together with a balloon volume of 8 L was
found to yield optimal results. Balloon volumes
over 8 L were not tested because of restraints in the
clinical trial protocol. The target temperature of
the Volcano was found to be not completely
accurate and stable. Possibly this is a contributing
factor to the relative variability in the delivery of
THC, which was about 15% at setting 9. However,
this is reasonable when compared to the varia-
bility that has been previously found in smoking
studies of cannabis plant material.
Accuracy of
temperature control therefore does not seem to be
of crucial importance under these conditions,
although a more accurate temperature control
might result in an even lower variability in THC
In the range of 28 mg of THC, the delivery was
found to be linear with the amount of THC used.
Prolonged storage of the balloon before inhalation
resulted in an increasing loss of THC by condensa-
tion inside the balloon and after 3 h almost no THC
could be recovered from the vapor in the balloon.
However, if the content was extracted within 5 min
after vaporization not more than 2% of THC
present was lost. Vaporized THC was visible inside
the balloon as a thin gray mist which was absent in
placebo balloons, so during the clinical trial
balloons had to be blinded with a black plastic
During the clinical administration, it was found
that about 35% of total THC was exhaled directly
after inhalation and was therefore not absorbed by
the lungs. When the efciency of delivery during
vaporizing and incomplete absorption by the lungs
is considered, the nal administered dose equaled
about 68 mg of THC of the total amount of 20 mg
loaded. The subjective effect upon the subjects
seemed to be in accordance with such a dose as
Author Proof
described in other papers.
So it seems that a
nal uptake of 3040% was reached (relative to
loaded amount of THC), which is comparable to the
efciency reached by smoking of cannabis.
It has been shown that the administration of
THC by aerosol is capable of producing the full
constellation of cannabinoid effects in mice. These
effects were CB1-receptor mediated, as shown by
the use of selective CB1 antagonists,
conrms that the pulmonary administration
of cannabinoids certainly has a clinical potential.
Several studies have been performed using an
aerosol for the administration of THC.
because cannabinoids are almost completely inso-
luble in water this requires the use of solubilizers
that are to be inhaled together with THC, which
frequently results in irritation of the lungs and
coughing. Moreover, part of an administered
aerosol can be swallowed and thereby adminis-
tered orally, complicating the effect, kinetics, and
metabolism of the administered compound. This
has already been shown for aerosol administration
of radiolabeled isoproterenol.
Using the Volcano vaporizer seems to eliminate
at least part of the problems associated with the
use of an aerosol for the delivery of THC or other
cannabinoids. It is likely that the Volcano also
produces an aerosol, that is, droplets of various
sizes in a gas phase made up of vapor and air.
However, in an articial lung model the majority of
vaporized THC could reach the deepest compart-
ment (personal communication with Volcano
manufacturer) indicating that the exhaust blown
from the Volcano consists for a large part of very
ne droplets and vapor. Nonetheless, the composi-
tion of an aerosol is partially dependent on the
ambient conditions such as humidity and presence
of nuclei for condensation. So although our results
were found to be reproducible with a relatively low
variability, these factors must be taken into
consideration for further development of the
What is currently needed for optimal use of
medicinal cannabinoids is a feasible, nonsmoked,
rapid-onset delivery system. With the Volcano a
safe and effective cannabinoid delivery system
seems to be available to patients. Although our
current study has concentrated on the delivery of
THC, it should be noted that other cannabinoids
might also have a role to play for some indications.
In several medical studies, the effect of THC or
dronabinol alone could not match the effect of a
total cannabis preparation, indicating there might
be other active cannabinoids needed for a full
range of effects.
As an example, a combination of
THC with CBD is now under clinical investigation
for the treatment of chronic pain conditions.
next step in the evaluation of the Volcano vapor-
izer should therefore include the study of mixtures
of pure cannabinoids.
The authors thank the manufacturer of the
Volcano vaporizer, Storz & Bickel GmbH & Co.,
for providing the department of Pharmacognosy
with the Volcano devices for our study. Bedrocan
BV (The Netherlands) is acknowledged for pro-
viding us with medical grade cannabis plant
materials. Farmalyse BV (Zaandam, The Nether-
lands) was involved in the development of the
procedure to produce clinical grade cannabinoid
samples of THC and THCA.
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... Vaporization is another form of cannabis administration that involves inhalation. Unlike smoking, which exposes the user to toxic combustion by-products (e.g., carbon monoxide, tar; [78]), vaporizers heat dried cannabis or cannabis extracts to temperatures high enough to produce an aerosol (i.e., vapor), but below the temperatures associated with combustion [52]. Vaporizers can generally be used more discreetly (e.g., due to less aerosol emission and less odor) compared to smoked cannabis [79,80], which further increases their appeal. ...
Full-text available
Purpose of Review With cannabis legalization expanding throughout the world, an unprecedented number of people now have access to legal cannabis. This expanded legalization has also created an extensive retail market that includes a litany of cannabis products, which vary on factors such as chemical profile (i.e., chemotype), formulation, and intended route of administration. Despite increases in cannabis access and product variety, research on the effects of product and user characteristics on drug effect profiles is limited. Recent Findings Controlled laboratory studies are important because they can reveal what factors influence the pharmacokinetic (PK) and pharmacodynamic (PD; e.g., subjective, cognitive, psychological) effects of cannabis and its principal constituents D-9-tetrahydrocannbinol (D-9-THC) and cannabidiol (CBD). In this review, we describe the various product (e.g., chemotype, route of administration) and user factors (e.g., frequency of use, sex, and age) that influence the PK and PD effects of cannabis. Summary Understanding the factors that impact the PK/PD profile of cannabis could be used to promote more consistency in drug effects, as well as cannabinoid delivery for medical purposes. Furthermore, such knowledge is key to informing eventual regulatory actions and dosing guidelines for cannabis products.
... The consumption of e-liquids containing tetrahydrocannabinol (THC, the principal psychoactive ingredient of marijuana) using ENDS devices is referred to as marijuana vaping and is recognized as a new public health challenge (Krishnasamy et al., 2020). Unlike the traditional marijuana vaporizers that heat the plant matter without burning it (Hazekamp et al., 2006), recent devices with more novel forms use a processed marijuana concentrate (e.g., wax, oil, or liquid) that can be used in ENDS devices (Daniulaityte et al., 2017), making them more appealing to young people. Young adults (YA) are considered as the most vulnerable group who are at risk for marijuana vaping (Navon et al., 2019;Pokhrel et al., 2020). ...
Introduction This study attempted to identify risk profiles of marijuana vaping by state-level recreational marijuana legalization (RML) status among U.S. young adults (YA). Methods Data were drawn from the most recent two waves of restricted use files of the Population Assessment of Tobacco and Health Study with state identifiers. We analyzed 6,155 young adult (18-24 years) respondents who were naïve to marijuana vaping at Wave 4 and had matched data at Wave 5. We employed a two-stage machine learning approach to predict marijuana vaping initiation at Wave 5 with predictors measured at Wave 4. Results Among YA who had never vaped marijuana at Wave 4, 19% of those who lived in the states with RML and 15% of those who lived in the states without RML reported marijuana vaping at Wave 5. Substance-use-related predictors were rarely found as leading predictors in the states with RML. In the states without RML, substance use behaviors, including electronic nicotine delivery systems and smokeless tobacco use, and the presence of externalizing symptoms emerged as predictors for marijuana vaping. Results also revealed that nonlinear interactions between the predictors of marijuana vaping. Conclusions Our results highlight the importance of accounting for the RML status in developing risk profiles of marijuana vaping. Externalizing symptoms may be a behavioral endophenotype of marijuana vaping in the states without RML. Machine learning appears to be a promising analytical approach to identify complex interactions between factors in predicting an emerging risk behavior such as marijuana vaping.
... GH001 (GH Research, Dublin, Ireland) is an investigational drug product based on a proprietary formulation of highly pure, GMP pharmaceutical grade 5-MeO-DMT for administration via inhalation. Liquid GH001 was administered after a standardized vaporization procedure using the Volcano Medic Vaporization System (Storz and Bickel, Germany), approved in Europe, Australia, and Canada for medical use with cannabinoids (Gieringer et al., 2004;Hazekamp et al., 2006;Abrams et al., 2007). The device consists of a hot air generator, which allows formation of an aerosol from GH001, and a detachable valve balloon (3 L) from which the aerosol is inhaled by the participant with a single breath. ...
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5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) is a tryptamine with ultra-rapid onset and short duration of psychedelic effects. Prospective studies for other tryptamines have suggested beneficial effects on mental health outcomes. In preparation for a study in patients with depression, the present study GH001-HV-101 aimed to assess the impact of four different dose levels of a novel vaporized 5-MeO-DMT formulation (GH001) administered via inhalation as single doses of 2 ( N = 4), 6 ( N = 6), 12 ( N = 4) and 18 mg ( N = 4), and in an individualized dose escalation regimen ( N = 4) on the safety, tolerability, and the dose-related psychoactive effects in healthy volunteers ( N = 22). The psychedelic experience was assessed with a novel Peak Experience Scale (PES), the Mystical Experience Questionnaire (MEQ), the Ego Dissolution Inventory (EDI), the Challenging Experience Questionnaire (CEQ), and the 5-Dimensional Altered States of Consciousness Questionnaire (5D-ASC). Further aims were to assess the impact of 5-MeO-DMT on cognitive functioning, mood, and well-being. Higher doses of 5-MeO-DMT produced significant increments in the intensity of the psychedelic experience ratings as compared to the lowest 2 mg dose on all questionnaires, except the CEQ. Prominent effects were observed following single doses of 6, 12, and 18 mg on PES and MEQ ratings, while maximal effects on PES, MEQ, EDI, and 5D-ASC ratings were observed following individualized dose escalation of 5-MeO-DMT. Measures of cognition, mood, and well-being were not affected by 5-MeO-DMT. Vital signs at 1 and 3 h after administration were not affected and adverse events were generally mild and resolved spontaneously. Individualized dose escalation of 5-MeO-DMT may be preferable over single dose administration for clinical applications that aim to maximize the experience to elicit a strong therapeutic response.
... 20 Cannabis flower vaporizers are hand-held or tabletop devices that pass hot air over milled cannabis to produce an aerosol. 21,22 A total of 2.9% of U.S. 16−19 year olds reported past 30 day flower vaping. 23 Dabbing, another popular method for cannabis consumption first reported in 2014, 24 consists of flash vaporization of cannabis wax/shatter/oil on a heated surface connected to a water pipe ( Figure 1b). ...
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The outbreak of e-cigarette or vaping product use-associated lung injury (EVALI) has been cause for concern to the medical community, particularly given that this novel illness has coincided with the COVID-19 pandemic, another cause of severe pulmonary illness. Though cannabis e-cigarettes tainted with vitamin E acetate were primarily associated with EVALI, acute lung injuries stemming from cannabis inhalation were reported in the literature prior to 2019, and it has been suggested that cannabis components or additives other than vitamin E acetate may be responsible. Despite these concerning issues, novel cannabis vaporizer ingredients continue to arise, such as Δ8-tetrahydrocannabinol, Δ10-tetrahydrocannabinol, hexahydrocannabinol, and cannabichromene. In order to address cannabis e-cigarette safety and vaping in an effective manner, we provide a comprehensive knowledge of the latest products, delivery modes, and ingredients. This perspective highlights the types of cannabis vaping modalities common to the United States cannabis market, with special attention to cartridge-type cannabis e-cigarette toxicology and their involvement in the EVALI outbreak, in particular, acute lung injurious responses. Novel ingredient chemistry, origins, and legal statuses are reviewed, as well as the toxicology of known cannabis e-cigarette aerosol components.
... from 15 to 31 mg [19]. The use of the Volcano ® vaporizer was validated for intrapulmonary THC administration and found to efficiently and reproducibly deliver about 54% of loaded THC into the balloon of the vaporizer [32]. Approx. ...
Cannabis has become legal in much of the United States similarly to many other countries, for either recreational or medical use. The use of cannabis products is rapidly increasing while the body of knowledge of its myriad of effects still lags. In vitro and clinical data show that cannabis’ main constituents, delta-9-tetrahydrocannabinol and cannabidiol, can affect the pharmacokinetics (PK), safety and pharmacodynamics (PD) of other drugs. Within the context of clinical drug development, the widespread and frequent use of cannabis products has essentially created another special population; that is, the cannabis user. We propose that all clinical drug development programs include a Phase 1 study to assess the drug-drug interaction potential of cannabis as a precipitant on the PK, safety and if applicable, the PD of all new molecular entities (NMEs) in a combination of healthy adult subjects as well as frequent and infrequent cannabis users. This data should be required to inform drug labeling and aid health care providers in treating any patient, as cannabis has quickly become another common concomitant medication and cannabis users, a new special population.
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Introduction: The purpose of this article is to describe the chemical and pharmacological characteristics of THC and its metabolites, the methods used for detection for clinical and forensic purposes and their stability in reference biological matrices. Psychoactive aspects or aspects relating to the problem of abuse or addiction will not be explained. Methodology: The article was written by integrating the authors' individual knowledge of pharmacology with printed material and online articles extracted from Google Scholar and PubMed. We used articles dealing with the chemical and toxicological analytical aspects of cannabis, selected from those published from 1990 to today. Discussion and Conclusions: THC has interesting chemical-biological properties from high lipophilicity to mainly hepatic metabolization, CYP-mediated with the genesis of various metabolites, one of which is particularly active. Their long half-life and the prevalent distribution in the adipose tissue prolongs the effects in the chronic user, making the detection window up to over a month from the last intake. Blood, urine and hair are the reference matrices but saliva is also becoming increasingly used for this purpose
Past research on cannabis has been limited in scope to THC potencies lower than legally available and efforts to integrate the effects into models of driving performance have not been attempted to date. The purpose of this systematic review is to understand the implications for modeling driving performance and describe future research needs. The risk of motor vehicle crashes increases 2-fold after smoking marijuana. Driving during acute cannabis intoxication impairs concentration, reaction time, along with a variety of other necessary driving-related skills. Changes to legislation in North America and abroad have led to an increase in cannabis’ popularity. This has given rise to more potent strains, with higher THC concentrations than ever before. There is also rising usage of novel ingestion methods other than smoking, such as oral cannabis products (e.g., brownies, infused drinks, candies), vaping, and topicals. The PRISMA guidelines were followed to perform a systematic search of the PubMed database for peer-reviewed literature. Search terms were combined with keywords for driving performance: driving, performance, impairment. Grey literature was also reviewed, including congressional reports, committee reports, and roadside surveys. There is a large discrepancy between the types of cannabis products sold and what is researched. Almost all studies that used inhalation as the mode of ingestion with cannabis that is around 6% THC. This pales in comparison to the more potent strains being sold today which are closer to 20%. Which is to say nothing of extracts, which contain around 60% or more THC. Experimental protocol is another gap in research that needs to be filled. Methodologies that involve naturalistic (real world) driving environments, smoked rather than vaporized cannabis, and non-lab certified products introduce uncontrollable variables. When considering the available literature and the implications of modeling the impacts of cannabis on driving performance, two critical areas emerge that require additional research: The first is the role of cannabis potency. Second is the route of administration. Does the lower peak THC level result in smaller impacts on performance? How long does potential impairment last along the longer time-course associated with different pharmacokinetic profiles. It is critical for modeling efforts to understand the answers to these questions, accurately model the effects on driver performance, and by extension understand the risk to the public.
Despite therapeutic use dating back thousands of years, there are still significant gaps among healthcare professionals, patients, and the public regarding the understanding of cannabis, its components, and their pharmacological and potential therapeutic benefits. Cannabis continues to gain popularity, especially in the last 10 years such that demands for policy evolution, needs for additional research, and requests for medical training cannot be ignored. Medical professionals are increasingly exposed to patients who request advice regarding medical cannabis treatments. Consequently, there is an important opportunity to learn from other countries’ experiences and acknowledge that limited academic training might affect proper and informed recommendations for medical cannabis applications. Starting from the general aspects of the cannabis plant, this chapter described its main characteristics and the terminology used to describe various elements. Such fundamental understanding is essential to support future learning of the clinical application of cannabinoid-based medicines.
Over the past few years, considerable attention has focused on cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), the two major constituents of Cannabis sativa, mainly due to the promising potential medical uses they have shown. However, more information on the fate of these cannabinoids in human subjects is still needed and there is limited research on the pharmacokinetic drug-drug interactions that can occur in the clinical setting and their prevalence. As the use of cannabinoids is substantially increasing for many indications and they are not the first-line therapy in any treatment, health care professionals must be aware of drug-drug interactions during their use as serious adverse events can happen related with toxic or ineffective outcomes. The present chapter overview summarizes our current knowledge on the pharmacokinetics and metabolic fate of CBD and THC in humans and discusses relevant drug-drug interactions, giving a plausible explanation to facilitate further research in the area.
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This randomised, double-blind, placebo-controlled, cross-over study was designed to identify which pharmacodynamic parameters most accurately quantify the effects of delta-9-Tetrahydrocannabinol (THC), the predominantly psychoactive component of cannabis. In addition, we investigated the acceptability and usefulness of a novel mode of intrapulmonary THC administration using a Volcano® vaporizer and pure THC instead of cannabis. Rising doses of THC (2, 4, 6 and 8 mg) or vehicle were administered with 90 minutes intervals to twelve healthy males using a Volcano® vaporizer. Very low between-subject variability was observed in THC plasma concentrations, characterising the Volcano® vaporizer as a suitable method for the administration of THC. Heart rate showed a sharp increase and rapid decline after each THC administration (8 mg: 19.4 bpm: 95% CI 13.2, 25.5). By contrast, dose dependent effects of body sway (8 mg: 108.5%: 95% CI 72.2%, 152.4%) and different subjective parameters did not return to baseline between doses (Visual Analogue Scales of 'alertness' (8 mg:-33.6 mm: 95% CI-41.6,-25.7), 'feeling high' (8 mg: 1.09 U: 95% CI 0.85, 1.33), 'external perception' (8 mg: 0.62 U: 95% CI 0.37, 0.86)). PK/PD-modeling of heart rate displayed a relatively short equilibration half-life of 7.68 min. CNS parameters showed equilibration half-lives ranging between 39.4-84.2 min. Some EEG-frequency bands, and pupil size showed small changes following the highest dose of THC. No changes were seen in saccadic eye movements, smooth pursuit and adaptive tracking performance. These results may be applicable in the development of novel cannabinoid agonists and antagonists, and in studies of the pharmacology and physiology of cannabinoid systems in humans.
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Cannabis vaporization is a technology designed to deliver inhaled cannabinoids while avoiding the respiratory hazards of smoking by heating cannabis to a temperature where therapeutically active cannabinoid vapors are produced, but below the point of combustion where noxious pyrolytic byproducts are formed.This study was designed to evaluate the efficacy of an herbal vaporizer known as the Volcano®, produced by Storz & Bickel GmbH&Co. KG, Tuttlingen, Germany ( Three 200 mg samples of standard NIDA cannabis were vaporized at temperatures of 155°–218°C. For comparison, smoke from combusted samples was also tested.The study consisted of two phases: (1) a quantitative analysis of the solid phase of the vapor using HPLC-DAD-MS (High Performance Liquid Chromatograph-Diode Array-Mass Spectrometry) to determine the amount of cannabinoids delivered; (2) a GC/MS (Gas Chromatograph/ Mass Spectrometer) analysis of the gas phase to analyze the vapor for a wide range of toxins, focusing on pyrene and other polynuculear aromatic hydrocarbons (PAHs).The HPLC analysis of the vapor found that the Volcano delivered 36%–61% of the THC in the sample, a delivery efficiency that compares favorably to that of marijuana cigarettes.The GC/MS analysis showed that the gas phase of the vapor consisted overwhelmingly of cannabinoids, with trace amounts of three other compounds. In contrast, over 111 compounds were identified in the combusted smoke, including several known PAHs.The results indicate that vaporization can deliver therapeutic doses of cannabinoids with a drastic reduction in pyrolytic smoke compounds. Vaporization therefore appears to be an attractive alternative to smoked marijuana for future medical cannabis studies.
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Chromatographic and spectroscopic data was determined for 16 different major cannabinoids from Cannabis sativa plant material as well as 2 human metabolites of Δ‐tetrahydrocannabinol. Spectroscopic analysis included UV absorbance, infrared‐spectral analysis, (GC‐) mass spectrometry, and spectrophotometric analysis. Also, the fluorescent properties of the cannabinoids are presented. Most of this data is available from literature but scattered over a large amount of scientific papers. In this case, analyses were carried out under standardised conditions for each tested cannabinoid so spectroscopic data can be directly compared. Different methods for the analysis of cannabis preparations were used and are discussed for their usefulness in the identification and determination of separate cannabinoids. Data on the retention of the cannabinoids in HPLC, GC, and TLC are presented.
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A simple method is presented for the preparative isolation of seven major cannabinoids from Cannabis sativa plant material. Separation was performed by centrifugal partition chromatography (CPC), a technique that permits large‐scale preparative isolations. Using only two different solvent systems, it was possible to obtain pure samples of the cannabinoids; (−)‐Δ‐(trans)‐tetrahydrocannabinol (Δ‐THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), (−)‐Δ‐(trans)‐tetrahydrocannabinolic acid‐A (THCA), cannabigerolic acid (CBGA), and cannabidiolic acid (CBDA). A drug‐type and a fiber‐type cannabis cultivar were used for the isolation. All isolates were shown to be more than 90% pure by gas chromatography. This method makes acidic cannabinoids available on a large scale for biological testing. The method described in this report can also be used to isolate additional cannabinoids from cannabis plant material.
Particle size and mass concentration are important determinants of site and quantity of respiratory tract deposition of aerosols. Particle concentrations and size distributions of smoke from marijuana cigarettes with different concentrations (as measured in the marijuana leaf) of Δ9-tetrahydrocannabinol (Δ9-THC) were measured using a single particle aerodynamic relaxation time (SPART) analyzer. The SPART analyzer measures aerodynamic diameter of single suspended particles at a rate of 3000/min. Cigarettes were smoked using a 35-cc, 2-sec puffing device attached to a diluter; dilution and analysis were completed within 4 sec of puff generation. The size distribution of smoke from all marijuana cigarettes was similar to that for tobacco cigarettes, ranging from 0.35 to 0.43 μm (count median aerodynamic diameter). The particle number and mass concentration increased as Δ9-THC concentration increased, being, respectively, 2.2- and 3.8-fold higher in the marijuana cigarette leaf with highest Δ9-THC concentration compared to the placebo marijuana cigarette. These data indicate the need for quantitative comparisons of other potentially toxic constituents in marijuana cigarettes of different Δ9-THC concentrations.
Particle size and mass concentration are important determinants of site and quantity of respiratory tract deposition of aerosols. Particle concentrations and size distributions of smoke from marijuana cigarettes with different concentrations (as measured in the marijuana leaf) of Δ9-tetrahydrocannabinol (Δ9-THC) were measured using a single particle aerodynamic relaxation time (SPART) analyzer. The SPART analyzer measures aerodynamic diameter of single suspended particles at a rate of 3000/min. Cigarettes were smoked using a 35-cc, 2-sec puffing device attached to a diluter; dilution and analysis were completed within 4 sec of puff generation. The size distribution of smoke from all marijuana cigarettes was similar to that for tobacco cigarettes, ranging from 0.35 to 0.43 μm (count median aerodynamic diameter). The particle number and mass concentration increased as Δ9-THC concentration increased, being, respectively, 2.2- and 3.8-fold higher in the marijuana cigarette leaf with highest Δ9-THC concentration compared to the placebo marijuana cigarette. These data indicate the need for quantitative comparisons of other potentially toxic constituents in marijuana cigarettes of different Δ9-THC concentrations.