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A protocol for the delivery of cannabidiol (CBD) and combined CBD and Δ9-tetrahydrocannabinol (THC) by vaporisation

Authors:
  • Hazekamp Herbal Consulting

Abstract and Figures

Significant interest has emerged in the therapeutic and interactive effects of different cannabinoids. Cannabidiol (CBD) has been shown to have anxiolytic and antipsychotic effects with high doses administered orally. We report a series of studies conducted to determine the vaporisation efficiency of high doses of CBD, alone and in combination with ∆9-tetrahydrocannabinol (THC), to achieve faster onset effects in experimental and clinical trials and emulate smoked cannabis. Purified THC and CBD (40 mg/ml and 100 mg/ml respectively) were loaded onto a liquid absorbing pad in a Volcano® vaporiser, vaporised and the vapours quantitatively analysed. Preliminary studies determined 200 mg CBD to be the highest dose effectively vaporised at 230°C, yielding an availability of approximately 40% in the vapour phase. Six confirmatory studies examined the quantity of each compound delivered when 200 mg or 4 mg CBD was loaded together with 8 mg of THC. THC showed 55% availability when vaporised alone or with low dose CBD, while large variation in the availability of high dose CBD impacted upon the availability of THC when co-administered, with each compound affecting the vaporisation efficiency of the other in a dynamic and dose-dependent manner. We describe optimised protocols that enable delivery of 160 mg CBD through vaporisation. While THC administration by vaporisation is increasingly adopted in experimental studies, often with oral predosing with CBD to examine interactive effects, no studies to date have reported the administration of CBD by vaporisation. We report the detailed methodology aimed at optimising the efficiency of delivery of therapeutic doses of CBD, alone and in combination with THC, by vaporisation. These protocols provide a technical advance that may inform methodology for clinical trials in humans, especially for examining interactions between THC and CBD and for therapeutic applications of CBD. Trial registration Current Controlled Trials ISRCTN24109245
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T E C H N I C A L A D V A N C E Open Access
A protocol for the delivery of cannabidiol (CBD)
and combined CBD and Δ
9
-tetrahydrocannabinol
(THC) by vaporisation
Nadia Solowij
1*
, Samantha J Broyd
1
, Hendrika H van Hell
1
and Arno Hazekamp
2
Abstract
Background: Significant interest has emerged in the therapeutic and interactive effects of different cannabinoids.
Cannabidiol (CBD) has been shown to have anxiolytic and antipsychotic effects with high doses administered orally.
We report a series of studies conducted to determine the vaporisation efficiency of high doses of CBD, alone and in
combination with Δ
9
-tetrahydrocannabinol (THC), to achieve faster onset effects in experimental and clinical trials
and emulate smoked cannabis.
Methods: Purified THC and CBD (40 mg/ml and 100 mg/ml respectively) were loaded onto a liquid absorbing pad
in a Volcano® vaporiser, vaporised and the vapours quantitatively analysed. Preliminary studies determined 200 mg
CBD to be the highest dose effectively vaporised at 230°C, yielding an availability of approximately 40% in the
vapour phase. Six confirmatory studies examined the quantity of each compound delivered when 200 mg or 4 mg
CBD was loaded together with 8 mg of THC.
Results: THC showed 55% availability when vaporised alone or with low dose CBD, while large variation in the
availability of high dose CBD impacted upon the availability of THC when co-administered, with each compound
affecting the vaporisation efficiency of the other in a dynamic and dose-dependent manner. We describe optimised
protocols that enable delivery of 160 mg CBD through vaporisation.
Conclusions: While THC administration by vaporisation is increasingly adopted in experimental studies, often with
oral predosing with CBD to examine interactive effects, no studies to date have reported the administration of CBD
by vaporisation. We report the detailed methodology aimed at optimising the efficiency of delivery of therapeutic
doses of CBD, alone and in combination with THC, by vaporisation. These protocols provide a technical advance
that may inform methodology for clinical trials in humans, especially for examining interactions between THC and
CBD and for therapeutic applications of CBD.
Trial registration: Current Controlled Trials ISRCTN24109245
Keywords: Cannabinoids, Cannabidiol (CBD), Δ
9
-Tetrahydrocannabinol (THC), Vaporisation, Intrapulmonary
Administration
* Correspondence: nadia@uow.edu.au
1
School of Psychology, Ψ-P3: Centre for Psychophysics, Psychophysiology
and Psychopharmacology and Illawarra Health and Medical Research Institute,
University of Wollongong, Wollongong, NSW 2522, Australia
Full list of author information is available at the end of the article
© 2014 Solowij et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Solowij et al. BMC Pharmacology and Toxicology 2014, 15:58
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Background
Scientific interest in understanding the effects of canna-
binoids in humans has grown in recent years with the
recognition that different compounds within cannabis
plant matter can have vastly different but also synergistic
effects. The primary psychoactive constituent of canna-
bis, Δ
9
-tetrahydrocannabinol (THC), has therapeutic
effects in humans, but has also largely been associated
with a range of adverse effects, including the induction
of psychotic-like symptoms and memory impairment [1].
Another major constituent of cannabis plant matter,
cannabidiol (CBD), has been shown to have anxiolytic
and antipsychotic properties [2,3] and to ameliorate
some of the adverse effects of THC [4,5]. THC and CBD
have been shown to have opposing effects on regional
brain activation in a range of cognitive tasks [6]. Studies
of administration of these compounds to humans have
relied on the oral administration of CBD and either
smoked, vaporised, oral or intravenous administration of
THC. Oromucosal sprays containing THC and CBD in a
1:1 ratio (nabiximols (Sativex
R
)) are increasingly being
studied for therapeutic efficacy, but these deliver low
doses, and higher doses of CBD in particular are thought
to be required for meaningful modification of clinical
outcomes [7]. Orally administered cannabinoids result in
slow and erratic absorption with limited and highly vari-
able bioavailability [8,9]. Smoking and intravenous admin-
istration produce reliable and similar pharmacokinetic
profiles [9,10], but respectively carry toxic risks and loss of
active drug by combustion, or are invasive.
Intrapulmonary administration of cannabinoids is regarded
as an effective mode of delivery since it results in fast
onset of action and high systemic bioavailability [9].
The vaporisation of cannabinoids (heating plant matter
or pure compounds to a temperature where active can-
nabinoid vapours form but below the point of combus-
tion) is a safe method of intrapulmonary administration
because it avoids risks associated with smoking and the
formation of pyrolytic toxic compounds as a result of
combustion [11]. While some studies have reported on
the effects of vaporised THC e.g. [12-14], no study has
yet reported on CBD administered via vaporiser. Oral
dosing with CBD impedes the potential to examine its
interactive effects with THC when the two compounds
are administered simultaneously, a scenario with eco-
logical validity for understanding effects in recreational
and medicinal cannabis users. Alternative routes of
administration of CBD with rapid action, such as vapor-
isation, would also benefit further investigations of its
therapeutic potential as an anxiolytic or antipsychotic,
among other applications.
The purpose of this article is to describe methodology
developed for the administration of THC alone, CBD alone
and their co-administration by means of a vaporiser for
studies of acute cannabinoid effects in humans. Since
the therapeutic (anxiolytic and antipsychotic) doses of
orally administered CBD have generally been quite high
(e.g. around 600 mg), we attempted to determine
whether it may be possible to vaporise similarly high
doses of CBD both alone, and in combination with
THC. We report optimised protocols for the delivery of
160 mg or more of CBD by vaporisation.
Methods
Purified THC (purity >98%) was produced and quantified
as reported previously [15,16]. Purified CBD (purity >98%)
was purchased from Echo Pharmaceuticals (Weesp, The
Netherlands). The cannabinoids were stored as ethanolic
solutions at 20°C at a concentration of 40 mg/ml (THC)
and 100 mg/ml (CBD). All organic solvents were HPLC
or analytical grade and were purchased from JT Baker
(Deventer, The Netherlands). Glass fibre filters (Cambridge
type, borosilicate glass, 92 mm diameter) and tightly fitting
filter holders for capturing the vapour were obtained from
Borgwaldt Technik GmbH (Hamburg, Germany).
The Volcano® vaporiser device (type Volcano® Digit)
was obtained from Storz & Bickel GmbH & Co. (Tuttlingen,
Germany) and was used according to the manual as
provided by the manufacturer. A standard volume bal-
loon (length of 60 cm, volume around 10 litres) was
used for all experiments unless specified otherwise. The
temperature was set to 230°C, unless specified other-
wise. All experiments were carried out in a standard
laboratory fume hood under constant ventilation with
an ambient room temperature of about 20°C and a
humidity of 4060%.
Crystalline form CBD (preliminary experiments) or
ethanolic solutions of CBD and THC (confirmatory and
replication studies) were loaded onto the vaporiser filling
chamber via a liquid pad a removable disc made of
tightly packed stainless steel wire mesh as supplied by
the manufacturer of the Volcano®. For the confirmatory
and replication studies, the desired dose of cannabinoids
(see Table 1) was applied in aliquots of maximum
400 μl, in order to prevent overloading of the liquid pad,
which may result in leaking. After each application,
Table 1 Cannabinoid doses applied and corresponding
volume of ethanolic solutions (of 40 mg/ml THC or
100 mg/ml CBD stock solutions) for each of 6 experiments
THC (mg) volume (μl) CBD (mg) volume (μl)
Experiment 1 8 200 - -
Experiment 2 - - 4 40
Experiment 3 8 200 4 40
Experiment 4 - - 200 5x400
Experiment 5 4 100 200 5x400
Experiment 6 8 200 200 5x400
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ethanol was evaporated using the Volcano® vaporiser set
at 100°C for 30 seconds. THC and CBD (with boiling
points well over 160°C) were not affected by this treat-
ment, and remained as pure compounds on the liquid
pad. Before each new experiment the filling chamber
was thoroughly cleaned with ethanol and allowed to dry
at ambient temperature. A new liquid pad was used for
each experiment.
For each experiment, the filling chamber fitted with a
loaded liquid pad was placed onto the vaporiser stabi-
lised at the desired temperature. The balloon was then
immediately attached and the ventilation was started.
When the balloon was completely inflated, ventilation
was stopped and the content of the balloon was proc-
essed for analysis within 2 min.
Extraction of cannabinoids from the vapour and the
liquid pad
Cannabinoids were recovered from the balloon by slowly
aspiring the vapour through a glass-fibre filter designed
to capture particles >0.1 microns with the use of a mem-
brane pump. Cannabinoids were then extracted from the
filter by mechanically shaking the filter for 10 minutes
with 40 ml of ethanol in 50 ml serum tubes. Supernatant
was transferred to a 100 ml volumetric flask. The pro-
cedure was repeated twice more with 25 ml of ethanol,
solutions were combined and the total volume was
brought to 100 ml with ethanol. Finally the solution was
filtered through a 0.45 μm PTFE syringe filter, and
stored at 20°C until analysis by HPLC.
A previous study showed that cannabinoids present in
the vapour are trapped >95% onto the glass fibre filter
[11]. For the present study, recovery was determined by
spiking filters in triplicate with THC (8 mg) or CBD
(200 mg) solution, allowing the filters to dry, and per-
forming the extraction procedure described above. Re-
covery from the filter was found to be 99.3 ± 1.1% for
THC and 99.1 ± 0.6% for CBD.
HPLC analysis of vapour extracts
An Agilent 1200 series HPLC was used for quantitative
analysis of the vapour extracts. The system consisted of a
G1322A degasser, G1311A quaternary pump, G1367B au-
tomated liquid sampler, and G1315D diode-array (DAD)
detector (Agilent Technologies Inc.). The software used
was Chemstation Rev. B03.02.
The analytical column was a Phenomenex C18 UHPLC
column, type Kinetex (3.0×100 mm, 2.6 μm). The mobile
phase consisted of a mixture of methanolwater (both
containing 25 mM of formic acid) in gradient mode; the
proportion of methanol was linearly increased from 75 to
100% over 10 minutes, and then kept constant for 1 minute.
The column was re-equilibrated under initial conditions
for 4 min. Flow-rate was 0.5 ml/min and injection volume
was 2 μl. Eluted compounds were detected at a wavelength
of 228 nm. All determinations were carried out at a col-
umn temperature of 40°C. The HPLC method used was
previously described ([11]; adapted in [17]) and validated
again here.
The method was validated for linearity, accuracy, pre-
cision, and limit of quantification (LOQ). To establish
the linearity of the method, 6-point calibration curves
were prepared for THC and for CBD in the range of
0.01 to 1.0 mg/ml, with each analyte concentration ana-
lysed in 3-fold. Repeatability was determined by analys-
ing six replicates of the same sample (THC 1 mg/ml).
Intraday precision was calculated by analysing all analyte
samples three different times in a day. The same proced-
ure was followed for four different days to determine
interday precision. Recovery was determined by spiking
glass-fiber filters in triplicate with THC (8 mg) or CBD
(200 mg) solution, allowing the filters to dry, and per-
forming the extraction procedure described above.
The method showed excellent validation results, with an
average linearity of 0.9996 and 0.9994 for THC and CBD,
respectively. Intraday precision was 2.0% (THC) and 1.8%
(CBD), while interday precision was 4.1% (THC) and 4.9%
(CBD). Limit of quantification (THC and CBD) was set
equal to the lowest analyte concentration analysed, which
was 0.01 mg/ml. Recovery from the filter was found to be
99.3 ± 1.1% for THC and 99.1 ± 0.6% for CBD.
Preliminary experiments
A series of preliminary experiments was conducted first to
determine optimum forms of CBD for vaporisation (crys-
talline versus ethanolic solution), maximum volumes of
ethanolic solution that could be held by the liquid pad,
and hence maximum doses that could be achieved. The
quantity of cannabinoids delivered into each balloon and
the residue remaining on the liquid pad were quantified
by HPLC. Solubility concerns for CBD in ethanolic solu-
tion and anticipated inability of the liquid pad to hold the
large quantities of liquid, led to preliminary testing using
CBD in crystalline form. 100 mg CBD was directly loaded
onto the liquid pad and vaporised at two different temper-
atures, 210°C and 230°C, into three subsequent balloons
(to capture as much CBD vapour as possible) [Pilot
study 1; see Additional file 1]. Next, higher doses of
crystalline CBD 200 mg and 300 mg were attempted
to be vaporised into a single standard balloon at 230°C
[Pilot study 2; see Additional file 1]. In Pilot study 3
[see Additional file 1], 200 mg of crystalline CBD was
vaporised at 230°C into standard size and extra large
(XL; 90 cm) size balloons to determine whether the
amount delivered could be increased by allowing a lon-
ger time for compounds to vaporise. Finally, we pro-
ceeded to establish whether CBD in ethanolic solution
of similar concentration would vaporise similarly to
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what we had established for crystalline CBD [Pilot
study 4; see Additional file 1]. This was deemed to be
particularly pertinent since pure THC is generally
vaporised dissolved in ethanol and it would be desirable
for randomised administration studies of both com-
pounds to humans to deliver each compound similarly,
and enable ethanol to be used in a placebo condition.
Duetotheresinous,stickynatureofCBD,westarted
with 100 mg CBD dissolved in a 10% ethanolic solution
loaded onto the liquid pad of the vaporiser by pipetting
1 ml of solution, in several separate aliquots at a time
in order to prevent overloading of the liquid pad and
vaporising ethanol each time at 100°C for 30 sec. A fur-
ther aim for Pilot study 4 was to assess the potential for
co-administration of THC and CBD through the vapor-
iser. 10 mg THC (0.4 ml from a 4% ethanolic solution)
was vaporised alone and in combination with the
100 mg CBD, into a normal size balloon at 230°C. This
series of preliminary studies was used to determine the
optimum dose delivery and vaporisation protocols for
planned use in a randomised controlled trial (RCT) of
cannabinoid (THC and CBD) administration to humans
[18]. Final confirmatory and replication studies were
undertaken using doses described in Table 1 as 6 separ-
ate experiments repeated in triplicate, with results
described below.
Confirmatory/replication studies
Having identified a range of properties pertinent to opti-
mising vaporisation of CBD, we then selected specific
doses for confirmation and replication toward the planned
RCT. A dose of 8 mg THC was selected as the desired
dose to administer based on previous studies of THC ad-
ministration to humans through a vaporiser e.g. [12-14].
This was designed to achieve clinically relevant intoxica-
tion without significant adverse effects. For CBD, the goal
of the planned RCT was to deliver a dose close to, or
equivalent to, the 600 mg CBD doses that have been dem-
onstrated to have psychoactive (regional brain activation)
or therapeutic effects in humans, when administered orally
e.g. [3,6]. Since our preliminary experiments indicated that
more than 200 mg CBD could not be vaporised efficiently
into a single balloon, we decided to administer two bal-
loons with a 200 mg loaded dose of CBD for vaporisation
into each to achieve a higher administered dose. A further
goal of the RCT was to administer THC and CBD in com-
bination, at high and low doses of CBD (keeping the dose
of THC constant). The low dose of CBD was set at 4 mg,
to emulate a 2:1 THC:CBD ratio that had been more com-
mon in street level cannabis products (although highly
variable) [19,20]. Thus, a series of 6 experiments tested the
quantity of THC and/or CBD delivered into each balloon
when THC and CBD were each vaporised alone, and in
combination.
The temperature setting of the Volcano® vaporiser for
each experiment was kept constant at 230°C. The liquid
pad was loaded with CBD and/or THC, each in ethano-
lic solution according to the doses for each experiment
as outlined in Table 1. All experiments used a normal
size balloon and each experiment was performed in trip-
licate (i.e. 6 experiments repeated three times) using a
fresh dose, a new liquid pad and a new balloon each
time, and a single vaporisation to fill the balloon.
Results
Preliminary experiments
Results from the series of pilot studies [see Additional
file 1] determined that vaporisation of CBD at 230°C
was superior to 210°C, in terms of the quantity of CBD
delivered into the balloon (Pilot study 1). A saturation
effect appeared to occur at 200 mg CBD, with greater
quantities resulting only in excessive resinous residue
remaining on the liquid pad (Pilot study 2). A greater
amount of CBD vapour was delivered into the XL bal-
loon than into the standard size balloon (Pilot study 3);
the amount delivered into the standard balloon was
similar to that of the previous pilot study, thus replicat-
ing the delivered dose of approximately 25% following
the loading and vaporising of 200 mg CBD. A decision
was made to continue experiments with the normal size
balloon for its greater ease (shorter duration) of inhal-
ation (for the participants in the planned RCT [18]).
100 mg of CBD dissolved in ethanol (Pilot study 4) de-
livered a similar amount of vapour as was observed in
the prior work using 100 mg solid form CBD, about 25%
of the loaded dose, thus replicating this finding and es-
tablishing the viability of loading CBD dissolved in etha-
nolic solution. The amount of vaporised CBD delivered
into the balloon was approximately half that observed
with 200 mg CBD loaded (the proportion being deliv-
ered as vapour remaining the same approximately
25%). Finally, this study also determined that the pres-
ence of CBD (100 mg) decreased the amount of THC
vaporised into the standard balloon after loading 10 mg
THC, by about half, with a small reduction also to the
delivered dose of CBD [see Additional file 1 for depic-
tion of data from each Pilot study].
Confirmatory/replication studies
Results from the series of 6 experiments are depicted in
Figure 1. Each column shows the average amount of
THC or CBD (mg, SEM), HPLC quantified from the
vapour delivered into the balloon from three repetitions.
Experiment 1 indicated that 8 mg THC when vaporised
alone delivered approximately 6.3 (SD 0.53) mg THC into
the balloon for inhalation. Experiment 2 indicated that
4 mg CBD when vaporised delivered approximately 3.9
(SD 0.13) mg CBD into the balloon. When 4 mg CBD was
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combined with 8 mg THC (Experiment 3), there was
no significant change to the amount of each compound
delivered from when each was delivered alone (THC:
p>0.96;CBD:p>0.65).Experiment4determinedthat
when 200 mg CBD was vaporised, almost 82 mg CBD
(41%) was delivered into the balloon on average, but
there was significant variability (large standard errors).
In Experiment 6, the combination of 8 mg THC with
200 mg CBD when vaporised, resulted in reduced de-
livery of each compound into the balloon relative to
when each was vaporised alone: 4.4 (SD 0.22) mg THC
was delivered (55%) (significantly different from Ex-
periment 1, p < 0.05; and Experiment 3, p < 0.015), and
74.3 (SD 18.17) mg CBD was delivered (37.2%) (but this
did not differ statistically from Experiment 4, p > 0.79);
again there was large variation for CBD. Experiment 5 was
subsequently conducted to establish what would happen if
half the quantity of THC (4 mg) were combined with
200 mg CBD. This was performed in order to determine
whether a second balloon could be administered to partic-
ipants with additional THC to equalise the quantity of
THC delivered when in combination with high dose CBD,
to that when administered alone. Again the quantity of
THC delivered into the balloon was approximately
halved: 2.2 (SD 0.28) mg (55%), and slightly more CBD
was delivered: 77.6 (SD 12.06) mg (38.9%). Experiments
5 and 6 indicated that a saturation effect in the vapour
mayoccurwhenthetwocompoundsarevaporisedto-
gether at high CBD doses (but not at low CBD doses as
in Experiment 3). Despite the trend evident in Figure 1,
the quantity of CBD delivered across experiments 4, 5
and 6 did not differ statistically (p > 0.94).
Discussion
To our knowledge, this is the first reported methodo-
logical study toward intrapulmonary administration of
CBD alone and in combination with THC in the litera-
ture. We provide here a systematically optimised proto-
col for the delivery of CBD, and CBD together with
THC, by means of vaporisation. Vaporisation provides a
safe and efficient delivery system for cannabis and can-
nabinoid compounds, avoiding the respiratory toxins in-
herent in smoking, making it useful for clinical trials.
The rapid delivery into the bloodstream producing im-
mediate effects made possible by this method of admin-
istration may benefit in particular human research
studies that have to date relied on oral administration of
CBD, with its delayed onset of effects and inherent
problems regarding bioavailability and liver metabolism.
Benefits may also extend to research toward further de-
velopment of CBD for therapeutic use for a range of
indications and disorders including amongst others,
schizophrenia [3] and anxiety disorders [21]. Adminis-
tration of THC and CBD together mimics the natural
constituency of cannabis plant matter, prior to the
more recent selective breeding that has resulted in the
reduction or even elimination of CBD while maximis-
ing THC content [20], and the methods described here
Figure 1 HPLC quantification of THC and CBD in vapour delivered into a 60 cm (approximately 10 litre) balloon after vaporisation of
8 mg THC, and 4 mg CBD or 200 mg CBD, loaded alone and in combination onto the liquid pad of a Volcano® vaporiser and vaporised
at 230°C. Data represent averages across three repetitions; error bars are SEM.
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can assist with enabling researchers to examine the ef-
fects of the two compounds delivered simultaneously.
The ability to do this by vaporisation overrides the ne-
cessity to pre-dose with oral CBD hours prior to the
administration of inhaled THC, which in itself results
in altered pharmacokinetics and pharmacodynamics
[22] (but see also [23,24]), and provides for the develop-
ment of a better understanding of the interaction between
the two compounds, enabling well-designed experiments
of dose-dependent effects.
The experiments performed in triplicate here deter-
mined the doses that could be achieved in our own RCT
as follows (to demonstrate the application of the proto-
cols we report here) [18]. Five conditions were deemed
to be achievable and to ensure blinding to drug condi-
tion and enable comparability of conditions, by adminis-
tering two normal size balloons to each participant on
each occasion, using ethanolic solutions of 4% THC and
10% CBD: 1) 8 mg THC alone (200 μl in first balloon
plus 200 μl pure ethanol in second balloon); 2) 400 mg
CBD alone (2 ml in each balloon); 3) 8 mg THC + 4 mg
CBD (200 μl and 40 μl respectively in first balloon,
200 μl pure ethanol in second balloon); 4) 12 mg THC
+ 400 mg CBD (200 μl and 2 ml respectively in first bal-
loon, 100 μl and 2 ml respectively in second balloon); 5)
pure ethanol as placebo (200 μl in each balloon). Where
only ethanol was administered, the ethanol vapours were
blown off as described above, such that only mildly etha-
nol vapour flavoured air was delivered. Condition 3
aimed to examine the effects of a low dose of CBD when
combined with THC, emulating the effects of street
levelcannabis (as it once was), and for comparative pur-
poses with the high dose CBD with THC condition
(Condition 4), the latter emulating the previously deter-
mined therapeutic effects of high doses of oral CBD
(described above, here with maximum feasible dose
achievable through vaporisation). The results of the ex-
periments reported here determined that the quantities
of cannabinoids actually delivered via vaporisation
would be comparable across the primary conditions of
interest: the two balloon and adjusted THC dose method
delivered approximately 6.2-6.6 mg THC across each of
the conditions with THC (conditions 1, 3 and 4), whilst
acknowledging the variability for CBD in delivering ap-
proximately 150160 mg CBD across the two balloons in
the two high dose CBD conditions (2 and 4). The results
also established the almost 100% dose delivered for the
low (4 mg) CBD dose when administered in combination
with THC (Condition 3).
A limitation of this methodological report is that it has
focused entirely on the technical aspects of feasibility of
vaporisation of CBD (alone and in combination with
THC). While these experiments have determined the
amount of drug that can be loaded on the liquid pad of
the Volcano® vaporiser and the proportion actually deliv-
ered into the balloon as vapour, further research is
required to take this to the next step of determining the
amount actually taken up by human inhalers of the va-
pours, how much is exhaled following controlled breath
holding protocols, and the bioavailability of these com-
pounds when administered through a vaporiser, as has
thus far been determined for THC only [11,12]. The
work reported here is the necessary first step for any
further studies of this type with human subjects. Further
limitations to consider with the vaporisation route of
administration are that despite attempts to adhere to
controlled breath holding, there may be variability in
absorption related to the depth of respiration, individ-
ual patterns of breathing and coughing, as well as the
variable size of particles in the vapour adhering at dif-
fering points within the respiratory system (e.g. in the
throat) versus reaching the alveoli where absorption is
most rapid and efficient.
The results from the series of studies conducted indi-
cate that with small doses of CBD, such as the 4 mg we
applied, 97.5% may be delivered into the balloon follow-
ing vaporisation. With THC (8 mg) up to 80% of the
dose loaded was delivered into the balloon, substantially
greater than the 54% previously reported [11], possibly
due to improvements in the heating efficiency of the
vaporiser. With high dose CBD, only about 40% of the
dose was delivered, indicating that evaporation does not
increase linearly with the loaded dose. An optimal dose of
200 mg CBD can be effectively and efficiently vaporised to
deliver approximately 80 mg of CBD. Human research
participants may be asked to inhale two normal size bal-
loons (standard with the Volcano® vaporiser) to achieve a
combined dose of approximately 160 mg. A larger dose
may be delivered if the CBD is vaporised into larger (XL)
balloons, but these are 1.5 times larger than the normal
size balloons, requiring significantly more inhalations,
while the resultant dose delivered is not 1.5 times greater.
The presence of both compounds reduces the delivery of
each when the dose of CBD is high, likely due to satur-
ation effects in the vapour. Further adjustments could po-
tentially be made to vaporisation protocols and the doses
loaded to try to better achieve the desired dose delivered.
For example, we opted to have participants inhale two
standard size balloons to maximise the dose of CBD deliv-
ered, judging it to be impracticable to have participants in-
hale two XL size balloons (because of their large volume
and the time restraints and other demands on participants
in our RCT); for other experiments researchers may opt
to use one or two XL size balloons and achieve greater
dosing by this means, with less wastage of the CBD dose
loaded. Further, using our data reported above, in order to
compare the effects of loaded doses of 8 mg THC and
400 mg CBD in combination, with the effects of each
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compound separately, we opted to load the vaporiser with
8 mg THC and 200 mg CBD for delivery into the first bal-
loon (vaporised to deliver approximately 4.4 mg THC and
74 mg CBD), and we loaded 4 mg THC and 200 mg CBD
for delivery into the second balloon (vaporised to deliver
2.2 mg THC and 78 mg CBD). The total doses delivered
from these two balloons equal 6.6 mg THC and 152 mg
CBD; this achieved equivalence broadly with the 6.2 mg
THC and 163 mg CBD delivered when each compound
was delivered separately. Alternatively, THC and CBD
could be loaded and vaporised separately into two bal-
loons that the participant inhales sequentially, but this
could result in quite different pharmacokinetic and pharma-
codynamic effects compared to simultaneous administra-
tion of the two compounds and the methodology depends
upon the questions to be addressed in the research.
Conclusions
Many questions arise regarding additive, synergistic and
interactive effects of THC and CBD and the field is ripe
for the further investigation of these intriguing com-
pounds. The methods, protocols and preliminary data pre-
sented here established the optimal efficiency of delivery
of both low and high doses of CBD, alone and in combin-
ation with THC, by vaporisation. While intrapulmonary
administration generally results in high systemic bioavail-
ability, the extent of absorption of the high doses of CBD
that we were able to achieve, relative to oral doses of
600 mg, remains to be determined, as do their potential
therapeutic effects. The studies informed the development
of methods for a randomised controlled trial of simultan-
eous acute administration of these cannabinoids by vapor-
isation to human research participants in our laboratory
[18], and may assist researchers with designing their own
future clinical trials and experimental human studies
a
.
Endnote
a
A note of caution to future researchers. CBD when
vaporised produces dense vapour that is irritating to the
throat for some participants and generates sometimes sig-
nificant coughing. We have facilitated the comfort of partic-
ipants inhaling CBD vapours by offering small sips of water
or juice, ice or sweets to suck and soothe the irritation, or
sometimes unmedicated cough lozenges. Further, the dense
vapours produced by CBD are visibly different to the less
dense vapours produced by THC. It is recommended for
blinding purposes to mask these differences by covering the
balloon (e.g. with an opaque plastic bag or fabric cover).
Additional file
Additional file 1: Results of preliminary experiments (Pilot studies
14). Brief description of methodology and graphical depiction of results.
Competing interests
All authors declare that they have no competing interests. AH is Head of
Research and Development at Bedrocan BV, The Netherlands, who had no
further role in this study.
Authorscontributions
NS conceived of the study, designed the series of experiments and drafted the
manuscript. SJB contributed significantly to the study design and planning of
the series of experiments. HHvH provided critical intellectual input and
interpretation. AH conducted the experiments and drafted portions of the
manuscript. All authors contributed to critical revision toward and approved the
final manuscript.
Acknowledgements
This research was supported by the National Health and Medical Research
Council of Australia (NHMRC) [Project Grant APP1007593] and the Australian
Research Council (ARC) [Future Fellowship FT110100752]. The funding sources
had no role in these studies other than financial support. The Volcano®
Vaporiser was provided by Storz & Bickel GMBH & Co. KG, Tuttlingen, Stuttgart,
Germany, who also had no further role in the study. We thank the reviewers for
their helpful comments in improving the manuscript.
Author details
1
School of Psychology, Ψ-P3: Centre for Psychophysics, Psychophysiology
and Psychopharmacology and Illawarra Health and Medical Research Institute,
University of Wollongong, Wollongong, NSW 2522, Australia.
2
Department of
Plant Metabolomics, Faculty of Science, Leiden University, Einsteinweg 55, 2333
CC Leiden, The Netherlands.
Received: 19 May 2014 Accepted: 30 September 2014
Published: 16 October 2014
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doi:10.1186/2050-6511-15-58
Cite this article as: Solowij et al.:A protocol for the delivery of
cannabidiol (CBD) and combined CBD and Δ
9
-tetrahydrocannabinol
(THC) by vaporisation. BMC Pharmacology and Toxicology 2014 15:58.
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