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Effect of intrapulmonary THC administration in humans

Authors:
  • Hazekamp Herbal Consulting

Abstract and Figures

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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Effect of intrapulmonary
tetrahydrocannabinol administration
in humans
L Zuurman Centre for Human Drug Research, Leiden, The Netherlands.
C Roy Sanofi-aventis, Recherche-Développement, Paris, France.
RC Schoemaker Centre for Human Drug Research, Leiden, The Netherlands.
A Hazekamp Department of Pharmacognosy, Leiden University, Leiden, The Netherlands.
J den Hartigh Hospital Pharmacy, Leiden University Medical Center, Leiden, The Netherlands.
JCME Bender Farmalyse BV, Zaandam, The Netherlands.
R Verpoorte Department of Pharmacognosy, Leiden University, Leiden, The Netherlands.
JL Pinquier Sanofi-aventis, Recherche-Développement, Paris, France.
AF Cohen Centre for Human Drug Research, Leiden, The Netherlands.
JMA van Gerven Centre for Human Drug Research, Leiden, The Netherlands.
Abstract
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.
Key words
THC; cannabis; cannabinoid; CB1 receptor; Volcano® vaporizer; healthy
volunteers; human; pharmacodynamics; pharmacokinetics
Introduction
Tetrahydrocannabinol (THC), a partial CB1/CB2 agonist, is
the most abundant and major psychoactive cannabinoid iden-
tified in the plant Cannabis sativa. Cannabinoids cause their
pharmacological effects by binding to cannabinoid receptors,
which are G-protein coupled receptors. At the moment, two
cannabis receptors (CB1 and CB2) have been identified. The
CB1 receptors are predominantly situated in the brain with
the highest densities in the hippocampus, cerebellum and the
striatum, which accounts for the well-known effects of cannabis
on motor coordination and short-term-memory processing
(Ameri, 1999; Ashton, 2001; Baker, et al., 2003), whereas they
are expressed at low levels in the brainstem (Baker, et al.,
2003). CB2 receptors are predominantly present in the spleen
and in haematopoietic cells (Ameri, 1999). CB1 receptors are
only present in these tissues in low density.
An increasing number of novel drugs in development are
targeted at cannabinoid receptors, although their exact role in
health and disease has not been fully elucidated. CB1/CB2
Original papers
Journal of Psychopharmacology
00(00) (2008) 110
©
2008 British Association
for Psychopharmacology
ISSN 0269-8811
SAGE Publications Ltd,
Los Angeles, London,
New Delhi and Singapore
10.1177/0269881108089581
Corresponding author: Lineke Zuurman, Centre for Human Drug Research, Zernikedreef 10, 2333 CL Leiden, The Netherlands. Email: linekezuurman@gmail.com
J Psychopharmacol OnlineFirst, published on May 30, 2008 as doi:10.1177/0269881108089581
Copyright 2008 by British Association for Psychopharmacology.
agonists might be of therapeutic use for muscle relaxation,
immunosuppression, sedation, improvement of mood, neuro-
protection, analgesia and reduction of intra-ocular pressure
(Grotenhermen, 2003). Dronabinol (δ-9-tetrahydrocannabinol)
and Nabilone
®
, synthetic THC analogues, are registered in dif-
ferent countries as anti-emetic and anti-anorexic agents for
patients with cancer or HIV. Recently rimonabant, a CB1
antagonist, was registered for the treatment of obesity. CB1
antagonists might also be useful for the treatment of smoking
cessation, Parkinsons disease and cognitive impairments in
Alzheimers disease and schizophrenia (Grotenhermen, 2003).
The availability of a CB1-agonist, with well-described phar-
macokinetics and pharmacodynamics could be of use as a
pharmacological tool in the clinical development of CB1 ago-
nist and antagonists. Such a well-characterized CB1 agonist
could serve as a positive control for studies with novel CB1
agonists, provide responsive biomarkers or potency bench-
marks for new drugs, or be used to show evidence of CB1-
antagonist activity in humans. THC would be the most appro-
priate candidate, but its use as a model cannabinoid is cur-
rently hampered by the lack of a reproducible and practical
mode of THC administration with a reliable pharmacokinetic
and pharmacodynamic time profile.
Intravenous administration would overcome the unfavour-
able characteristics of orally administered cannabinoids, such
as limited and variable bioavailability (Ohlsson, et al., 1980;
Hollister, et al., 1981; Wall, et al., 1983). However, adequate
injection fluids are difficult to manufacture because of the
highly lipophilic properties of THC. In man, plasma THC con-
centration profiles are similar after smoking or intravenous
administration with prompt onset and steady decrease (Noyes
Jr., et al., 1975; Husain and Khan, 1985; Mathew, et al., 2002).
Although smoking cannabis provides a reliable pharmaco-
kinetic profile (Husain and Khan, 1985; Grotenhermen, 2003),
cannabis smoke has the disadvantage that it contains a mixture
of psychoactive and partly noxious compounds, and that the
active drug is partly lost by heat. The Volcano
®
vaporizer is a
novel mode of intrapulmonary THC administration that over-
comes these issues (Hazekamp, et al., 2006). In this study, we
investigated the pharmacokinetic and pharmacodynamic
effects after inhalation of pure THC using a Volcano
®
vaporizer.
Although many studies have been performed with cannabis,
many of these have addressed the consequences of chronic can-
nabis use, and after acute administration, a wide variety of
tests was used. However, the tests that are particularly sensitive
to the acute effects of THC are not clear (Kiplinger and
Manno, 1971; Chesher, et al., 1990; Heishman, et al., 1997),
and few studies have investigated the pharmacodynamic time
profiles following THC administration. The most conspicuous
effects of cannabis are subjective and psychomimetic changes
(Zeidenberg, et al., 1973; Vachon, et al., 1974; Grotenhermen,
2003). In some studies, a reduction in smooth pursuit eye
movements was observed (Fant, et al., 1998) and changes in
pupil size have been reported by several other authors (Brown,
et al., 1977). THC increases heart rate by 20 60% (Hall and
Solowij, 1998; Sidney, 2002). The effects on blood pressure
are complex, with reports of both increases and decreases
(Hall and Solowij, 1998; Sidney, 2002; Randall, et al., 2002).
In the current study, the pharmacodynamic effects of pure
THC were measured using a battery of central nervous system
(CNS) assessments that have been shown to be sensitive to a
wide range of CNS-active agents (Steveninck, et al., 1999; Vis-
ser, et al., 2002). In addition, heart rate and blood pressure
were measured frequently.
Methods
Design
This was a double-blind, randomized, two-way balanced
placebo-controlled, cross-over study of inhaled rising doses of
THC (Table 1). Informed consent was obtained in writing
before any study-specific procedure was carried out. After a
general health screen, eligible subjects were enrolled in the
study. Subjects were acquainted with the experimental methods
and conditions, and with the inhalation procedure using
alcohol-vehicle in a training session within 1 week before the
first study day. Pharmacodynamic and pharmacokinetic mea-
surements were performed frequently on both study days. A
follow-up visit (medical screening) was scheduled within
2 weeks after the second study day. The study protocol was
approved by the Medical Ethics Review Board of Leiden Uni-
versity Medical Center and performed according to the princi-
ples of ICH-GCP, the Helsinki declaration and Dutch
regulations.
Subjects
Twelve healthy men (2127 years) with a history of mild can-
nabis use for at least 1 year were included in the study. Subjects
were not allowed to use cannabis more than once a week (the
average was calculated over the last 6 months), and had to be
able to refrain from using cannabinoids during the study. Use
of other drugs or any medication was not allowed. Subjects
with a positive THC test at screening were tested again, and
Table 1 Study design
8.0010.00 10.00 11.30 13.00 14.30
Study day 1 Arrival at unit
and study preparations
2mgTHC 4mgTHC 6mgTHC 8mgTHC
Study day 2 Placebo Placebo Placebo placebo
2 Intrapulmonary THC administration in humans
were required to be negative before the first study day. Subjects
with a positive drug test on a study day were excluded. Subjects
had to refrain from smoking and use of coffee and tea on study
days. The subject had to maintain a normal daynight rhythm
in the week before each study day. Severe physical exercise
shortly before the study days had to be avoided. Subjects
were financially compensated for their participation.
Treatments
THC was purified according to GMP-compliant procedures
(Farmalyse BV, Zaandam, The Netherlands) from the flowers
of C. sativa grown under Good Agricultural Practice (Bedro-
can BV Medicinal Cannabis, Veendam, The Netherlands)
(Choi, et al., 2004; Hazekamp, et al., 2004; Hazekamp, et al.,
2005). Each dose (2, 4, 6 or 8 mg) of THC (>98% purity by
HPLC/GC) was dissolved in 200 µL of 100 vol% alcohol.
THC was stored in the dark at 20 °C in 1 mL amber glass
vials containing a teflon screw-cap secured with Para film to
minimize evaporation. The solvent was used as placebo.
On each study day, rising doses of THC (2, 4, 6 and 8 mg)
or placebo were administered by inhalation at 90-min intervals
using a Volcano
®
vaporizer (Storz-Bickel GmbH, Tüttlingen,
Germany). Before the start of the study, the efficiency and
reproducibility of THC delivery into the balloon of the Vol-
cano was evaluated (Hazekamp, et al., 2006). Five to ten min-
utes before administration THC was vaporized at a tempera-
ture of about 225 °C and the vapour was stored in a
transparent polythene bag equipped with a valved mouthpiece,
preventing the loss of THC in between inhalations. The trans-
parent bag was covered with a black plastic bag to prevent
unblinding. Subjects were not allowed to speak, and were
instructed to inhale deeply and hold their breath for 10 s after
each inhalation. Within 23 min, the bag was to be fully emp-
tied. The inhalation procedure was practiced at screening using
the solvent as a placebo.
The inhalation schedule was predicted to cause incremental
THC plasma concentrations and effects, with cumulative peak
plasma levels corresponding to a single dose of approximately
11 mg, which roughly corresponds to the THC-contents in one
or two marijuana cigarettes. The decision to proceed to the
next highest THC dose was made by a physician, based on
adverse events (AEs) and physical signs. Because of the long
half-life of THC, study days were separated by a washout
period of at least 2 weeks.
Pharmacokinetic measurements
Blood sampling and THC-laboratory analyses For determina-
tion of the concentration of plasma THC and its two most
important metabolites (11-OH-THC and 11-nor-9-carboxy-
THC), venous blood was collected in aluminium-foiled
EDTA tubes of 4.5 mL. Blood samples were taken at baseline
and at 10, 20 and 80 min after each THC administration. Addi-
tional samples were taken at 5, 35 and 55 min after administra-
tion of 6 mg THC and at 375, 425, 495, 545 and 1440 min after
the first THC administration. After blood collection, the tubes
were placed in ice water (04 °C) and centrifuged within 1 h for
10 min at 2000 × g at 4 °C. The THC samples were handled
sheltered from light. Plasma samples were stored at a tempera-
ture of 20 °C for less than 3 months before laboratory analy-
sis. Concentrations of THC and the metabolites were shown to
be stable over this period.
Pharmacodynamic measurements
Pharmacodynamic assessment was performed in a quiet and
temperature-controlled room with standardized illumination
with only one subject per session in the same room. All tests
were measured twice pre-dose and obtained frequently at fixed
timepoints after each consecutive THC dose.
Plasma peak concentration was followed by a short distri-
bution phase (approximately 25 min) and a longer elimination
phase (roughly 250 min). Average plasma THC concentrations,
10 min after the fourth dose (50.3 ± 14.4 ng/mL), exceeded the
11-OH-THC concentrations (6.8 ± 2.8 ng/mL) by 7.4-fold, and
the 11-nor-9-carboxy-THC concentrations (21.8 ± 4.8 ng/mL)
by 2.3-fold. There was a very small between-subject variability
in THC plasma concentrations as illustrated by the low stan-
dard deviations.
Heart rate and blood pressure
Blood pressure and heart rate were measured in supine position
after a rest of approximately 5 min, twice pre-dose and repeat-
edly post-dose on each of the two study days. All measure-
ments were carried out with an automated sphygmomanometer
(Nihon Kohden, Life Scope EC, Tokyo, Japan).
Pupil size
For pupil size (pupil/iris ratio) measurements, a picture of both
eyes was taken using a Digital camera (Minolta DiMAGE,
Tokyo, Japan) using a flashlight after at least 5 min adaptation
in subdued lighting. For each eye, the diameters of the pupil
and the iris in millimetres were determined. The pupil/iris
ratio was subsequently calculated as a measure of pupil size.
Smooth pursuit and saccadic eye movement
Recording and analysis of saccadic and smooth pursuit eye
movements were conducted with a personal computer using a
validated Spike2 script (Cambridge Electronic Design Limited,
Cambridge, UK). Disposable silversilver chloride electrodes
(Mediscore, VDP Medical, Nieuwegein, The Netherlands)
were applied on the forehead and beside the lateral canthi of
both eyes of the subject for the registration of the electro-
oculographic signals. Skin resistance was reduced to less than
5kΩ before application of the electrodes. Head movements
were restrained using a fixed head support. The equipment
used for stimulus display was manufactured by Nihon Kohden
Intrapulmonary THC administration in humans 3
Corporation (Tokyo, Japan). For signal collection and amplifi-
cation, a CED 1401 Power AD-converter (Cambridge Elec-
tronics Design, Cambridge, UK), a Grass telefector
(F-15EB/B1) and a 15LT series Amplifier Systems (Grass-
Telefactor, Braintree, RI, USA) was used.
For recording and analysis of smooth pursuit eye move-
ments, the target moved sinusoidally at frequencies ranging
from 0.3 to 1.1 Hz, increased by eight steps of 0.1 Hz. The
amplitude of target displacement corresponded to 22.5 degrees
eyeball rotations to both sides. Four cycles were recorded for
each stimulus frequency. The average time during which the
eyes were in smooth pursuit of the target, expressed as a per-
centage of stimulus duration, was used as the measurement
parameter.
The target for the saccadic eye movements consisted of an
array of light emitting diodes on a bar, fixed at 50 cm in front
of the head support. Saccadic eye movements were recorded
for stimulus amplitudes of approximately 15° to either side.
Fifteen saccades were recorded with interstimulus intervals
varying randomly between 3 and 6 s. Average values of latency
(reaction time), saccadic peak velocity and inaccuracy of all
artefact-free saccades were used as parameters. Saccadic inac-
curacy was calculated as the absolute value of the difference
between the stimulus angle and the corresponding saccade,
expressed as a percentage of the stimulus angle.
Pharmaco-EEG
EEG recordings were made using silver chloride electrodes,
fixed with collodion at Fz, Cz, Pz and Oz positions, with the
same common ground electrode as for the eye movement regis-
tration (international 10/20 system). The electrode resistances
were kept below 5 kΩ. EEG signals were obtained from leads
Fz-Cz and Pz-Oz and a separate channel to record eye move-
ments (for artefacts). The signals were amplified by use of a
Grass telefector (F-15EB/B1) and a 15LT series Amplifier Sys-
tems (Grass-Telefactor) with a time constant of 0.3 s and a low
pass filter at 100 Hz. Data collection and analysis were per-
formed using a validated Spike2 script. Per session eight conse-
cutive blocks of 8 s were recorded. The signal was
AD-converted using a CED 1401 Power AD-converter and
stored on hard disk for subsequent analysis. Data blocks con-
taining artefacts were identified by visual inspection and these
were excluded from analysis. For each lead, fast Fourier trans-
form analysis was performed to obtain the sum of amplitudes
in the δ- (0.53.5 Hz), θ- (3.57.5 Hz), α- (7.511.5 Hz) and
β- (11.530 Hz) frequency ranges. Outcome parameters were
the square root of the total power in each band for each lead.
Body sway
The body sway meter allows measurement of body movements
in a single plane, providing a measure of postural stability.
Body sway was measured with an apparatus similar to the
Wright ataxia meter (Wright, 1971). With a string attached to
the waist, all body movements in the anteroposterior direction
over a period of 2 min were integrated and expressed as milli-
metre sway on a digital display. The contribution of vision to
postural control was eliminated by asking subjects to close
their eyes. Subjects were not allowed to talk during the mea-
surement, and were asked to wear the same comfortable low-
heeled shoes at all measurements.
Adaptive tracking
The adaptive tracking test was performed as originally
described by Borland and Nicholson (1984), using customized
equipment and software (Hobbs, 2000, Hertfordshire, UK).
Adaptive tracking is a pursuit-tracking task. A circle moved
randomly about a screen. The subject had to try to keep a
dot inside the moving circle by operating a joystick. If this
effort was successful, the speed of the moving circle increased.
Conversely, the velocity was reduced if the test subject could
not maintain the dot inside the circle. Average performance
was scored after a 3-min period. Each test was preceded by a
run-in period. After four to six practice sessions, learning
effects are limited. The adaptive tracking test is more sensitive
to the impairment of eyehand coordination by drugs than
compensatory pursuit tasks or other pursuit tracking tasks,
such as the pursuit rotor. The adaptive tracking test has proved
to be useful for measurement of CNS effects of alcohol, various
psychoactive drugs and sleep deprivation (Steveninck, et al.,
1993; Steveninck, et al., 1999).
Visual analogue scales
From the visual analogue scales (VAS), as originally described
by Norris (1971) (16 items), three factors can be derived, as
described by Bond and Lader (1974), corresponding to alert-
ness, contendness and calmness. Increased scores of these scales
indicate enhanced subjective feelings of alertness, contendness
(in general) and calmness. Psychedelic effects were monitored
by an adapted version of the VAS (13 items), originally
described by Bowdle et al. (1998).
Analysis
Pharmacokinetic assay Plasma samples for determination of
THC, 11-OH-THC and 11-nor-9-carboxy-THC were stored at
a temperature of 20 °C before bioanalysis. Analysis was per-
formed using a validated high-performance liquid chromatog-
raphy with tandem mass spectrometric detection. Calibration
range was 1.00500 ng/mL for all compounds. Over this
range, the intra-assay coefficient of variation was between
4.0% and 6.5%. The inter-assay coefficient of variation was
between 1.4% and 9.4%.
Statistics All pharmacodynamic endpoints were summarized
by treatment and time, and were presented graphically as mean
over time with standard deviation as error bars. The pharma-
codynamic endpoints were analysed separately by mixed model
analyses of variance (using SAS PROC MIXED, SAS for Win-
4 Intrapulmonary THC administration in humans
dows, V9.1.2; SAS Institute, Inc., Cary, North Carolina, USA)
with treatment, period, time and treatment by time as fixed
effects, with subject, subject by time and subject by treatment
as random effect and with the (average) baseline value as
covariate. Treatment effect was reported as the contrast
between the placebo and THC treatment where the average
of the measurements up to (and including) 10 h was calculated
within the statistical model. Additionally, the average response
of the values obtained in the 90 min after the final administra-
tion of THC (identified as the fourth dose effect) was com-
pared between treatments within the statistical model. Con-
trasts were reported along with 95% confidence intervals.
EEG and body sway data were analysed after log-
transformation and all other parameters were analysed without
transformation except for VAS Bowdle (see below). Log-
transformed contrasts were back-transformed resulting in geo-
metric mean ratios with associated confidence intervals. These
were re-expressed as percentage change from placebo.
Examination of average graphs (and summary measures
over time) indicated that the VAS measuring psychedelic
effects showed a very skewed frequency distribution. As zeroes
can naturally occur for these data (response from 0 to 100), a
10
log transformation was applied after first adding 2 to all
values. The rationale for log(x + 2) instead of the more com-
mon log( x + 1) transformation was that, after examining scat-
ter plots of the psychedelic variables, a clear gap was observed
between the log(1) values and the remaining values. After
implementing the log(x + 2) transformation, the gap decreased
and a more homogenous distribution was obtained.
To reduce the number of VAS Bowdle scales and facilitate
the interpretation of the results, cluster analysis and factor
analysis was performed on the transformed psychedelic VAS
scales. Two distinct clusters were found. VAS feeling drowsy
was removed from the first cluster because this was not really
considered a psychedelic effect, and drowsiness is more prop-
erly assessed using Bond and Lader VAS alertness. The two
resulting clusters can be interpreted as two modalities of psy-
chedelic effects roughly corresponding to external perception
and internal perception. Changes in external perception
reflect a misperception of an external stimulus or a change in
the awareness of the subjects surroundings. Internal perception
reflects inner feelings that do not correspond with reality.
Table 2 gives an overview of the parameters included in exter-
nal and internal perception.
A subsequent factor analysis indicated that the factor load-
ings were more or less the same for factors in the two clusters.
This means that the two new composite factors can be derived
by simply averaging the (transformed) psychedelic VAS Bowdle
scales (Table 2). Because the log + 2 transformation makes
back-transformation problematic and the resulting scales have
favourable statistical properties, it was decided not to back-
transform the results. To avoid confusion, the unit U was
used instead of average (log + 2 mm) in reporting the results.
PK/PD modelling
PD parameters showing a significant treatment effect
and clear concentration-dependency were analysed using phar-
macokineticpharmacodynamic (PK/PD) modelling. Nonlin-
ear mixed effect modelling as implemented in the NONMEM
program (Version 5, Globomax LLC, Ellicot City, Maryland,
Table 2 Fourth dose treatment effect (8 mg THC) of the different parameters of the Visual Analogue Scales (VAS) of psychedelic effects, which are
also presented as two composite scales: external perception and internal perception
Estimate of
difference (U)
95% Cl
External perception
a
0.616 (0.371, 0.860)
VAS 1: my body parts seemed to change their shape or position 0.223 (0.005, 0.451
VAS 2: my surroundings seemed to change in size, depth, or shape 0.408 (0.144, 0.671)
VAS 3: the passing of time was altered 0.808 (0.479, 1.137)
VAS 5: it was difficult to control my thoughts 1.047 (0.705, 1.388)
VAS 6: the intensity of colours change 0.448 (0.180, 0.716)
VAS 7: the intensity of sound changes 0.761 (0.487, 1.034)
Internal perception
b
0.212 (0.066, 0.357)
VAS 4: I had feelings of unreality 0.502 (0.249, 0.754)
VAS 8: I heard voices and sounds that were not real 0.144 (0.021, 0.266)
VAS 9: I had the idea that events, objects, or other people had particular meaning that was specific for me 0.149 (0.017, 0.281)
VAS 10: I had suspicious ideas or the belief that others were against me 0.127 (0.019, 0.274)
VAS 13: I felt anxious 0.144 (0.062, 0.349)
Data are population average, 95% confidence interval (CI) and P value.
THC, tetrahydrocannabinol.
a
External perception = [
10
log(VAS1 + 2) +
10
log(VAS2 + 2) +
10
log(VAS3 + 2) +
10
log(VAS5 + 2) +
10
log(VAS6 + 2) +
10
log(VAS7 + 2)]/6.
b
Internal perception = [
10
log(VAS4 + 2) +
10
log(VAS8 + 2) +
10
log(VAS9 + 2) +
10
log(VAS10 + 2) +
10
log(VAS13 + 2)]/5.
Intrapulmonary THC administration in humans 5
USA) was used. The PK/PD modelling is described in detail by
Strougo et al. (2007).
Results
Subjects
Twelve healthy men were included in the study. Their ages
were in the range 2127 years with a mean of 23 ± 2 years.
The mean height and weight were respectively 185 ± 6 cm
(range 174194 cm) and 83 ± 8 kg (range 73100 kg). All sub-
jects were familiar with the effects of cannabis. Two subjects
used cannabis four times a month, six subjects used it two to
three times a month, three subjects used cannabis just once a
month and two subjects used cannabis less than once a month.
All subjects completed the study.
Clinical effects
Most AEs were mild, transient and did not require medical
intervention, except for occasional use of paracetamol. The
most frequently observed events were well-known THC effects
such as drowsiness, sleepiness, attention deficit and feeling
high. In addition, also minor AEs such as headache and eye
irritation were reported. During THC inhalation, five subjects
had to cough, whereas other subjects were required to hold
their breath for 10 s. This was not reported after inhalation of
the alcohol-vehicle during placebo occasions. Two of 12 sub-
jects experienced side effects severe enough to decide not to
administer the last dose of 8 mg THC. One of these subjects
was too sleepy to perform any test, and the other subject vom-
ited just after administration of the third dose.
Pharmacokinetic and pharmacodynamic data analysis
All data were used for the pharmacodynamic and pharmacoki-
netic analysis. However, for the average figures shown in this
article, two subjects were excluded. These subjects did not
receive the highest THC dose and consequently had deviating
concentration and effecttime profiles that would have dis-
torted the average graphs.
Pharmacokinetics
THC plasma peak levels were reached within few minutes
(Figure 1).
Heart rate and blood pressure
Heart rate increased in a dose-related manner compared with
placebo (Figure 2). The average increase after the fourth dose
of 8 mg was 19 bpm (95% CI 13.2, 25.5 bpm). After the initial
increase, heart rate decreased rapidly after each dose, and
hardly any accumulation was seen with repeated dosing (Fig-
ure 2). Blood pressure did not change after THC administra-
tion (fourth dose effect: systolic blood pressure: 1 mmHg:
95% CI 8, 6; diastolic blood pressure: 0.5 mmHg: 95%
CI 8, 7).
Pupil size
Compared with placebo, slight increases were seen in pupil/iris
ratio that were only significant after the fourth dose of 8 mg
THC (0.025: 95% CI 0.003, 0.047).
Smooth pursuit and saccadic eye movement
No changes in smooth pursuit eye movements occurred (fourth
dose effect: 3%: 95% CI 9, 3). Compared with placebo, sac-
Figure 1 Mean (SD) observed profile of plasma THC: closed circles,
common measurement points for all four doses; open circles, extra
assessments for third dose. THC administration: 2 mg at T = 0; 4 mg at
T = 90; 6 mg at T = 180, 8 mg at T = 270.
Figure 2 Mean (SD) time profile of heart rate. THC administration: 2 mg
at T = 0; 4 mg at T = 90; 6 mg at T = 180, 8 mg at T = 270.
6 Intrapulmonary THC administration in humans
cadic latency (20 ms: 95% CI 10, 30) and saccadic inaccuracy
(3.1%: 95% CI 1, 5) increased only after the fourth dose of
8 mg THC. No changes were found in saccadic peak velocity
(fourth dose effect: 14 deg/s: 95% CI 4, 32).
Electro-enchephalography (EEG)
After the highest dose of THC, there were decreases in the
power of Pz-Oz δ-(16%: 95% CI 24, 7), Pz-Oz θ-(15%:
95% CI 24, 5) and Pz-Oz β-activity (12%: 95% CI 18,
4). No changes were found in α-activity (6%: 95% CI
17%, 5%). In the Fz-Cz region, changes in β-activity were
predominant. No changes in δ- and θ-activity were seen in
Fz-Cz region. Although EEG was affected significantly by
active treatment, the average time profiles did not indicate a
clear dose and concentration dependency.
Body sway
After THC administration, dose-related increases were seen in
body sway, which decreased slowly after each dose and did not
return to baseline between doses (Figure 3). Consequently, the
effect accumulated with repeated dosing to a 109% increase
over placebo: (95% CI 72, 152) after the highest dose.
Adaptive tracking
Compared with placebo, no changes were observed in adaptive
tracking performance (fourth dose effect: 1%: 95% CI 3, 1).
Visual analogue scales
VAS Bond and Lader The VAS alertness was affected by
THC in a dose-related manner. The decrease accumulated to
34 mm: 95% CI 42, 26 after the fourth dose. A decrease
was seen in VAS contendness after the fourth dose (7mm
95% CI 13, 1) but no change was seen in VAS calmness
(3 mm: 95% CI 10, 4).
VAS Bowdle internal and external perception Many of the
individual VAS measuring psychedelic effects showed treat-
ment effects (Table 2), with VAS feeling high as one of the
most responsive scales (1.1 U: 95% CI 0.9, 1.3). The composite
score of external perception showed a dose response effect of
THC (Figure 4) and an increase of 0.6 U after the fourth dose
(95% CI 0.4, 0.7). Although a significant treatment effect was
also reported for the internal perception composite scale
Figure 3 Mean (SD) time profile of body sway. THC administration: 2 mg
at T = 0; 4 mg at T = 90; 6 mg at T = 180, 8 mg at T = 270.
Figure 4 Mean (SD) time profile VAS external perception . THC
administration: 2 mg at T = 0; 4 mg at T = 90; 6 mg at T = 180, 8 mg at
T = 270.
Figure 5 Mean (SD) time profile VAS internal perception. THC
administration: 2 mg at T = 0; 4 mg at T = 90; 6 mg at T = 180, 8 mg at
T = 270.
Intrapulmonary THC administration in humans 7
(0.2 U: 95% CI 0.1, 0.4 after the fourth dose), concentration
and dose dependency were much less pronounced than the
effect for external perception and seemed to be associated
with an on/off effect or at least a very steep doseresponse
curve (no response after 2 mg, maximum response at doses of
4 mg and higher) (Figure 5).
PK/PD modelling
The effects of THC lagged behind the THC plasma concentra-
tion, showing hysteresis. Equilibration half-lives that quantify
hysteresis varied from 7.68 min for heart rate and from 39.2 to
84.8 min for the effects on the CNS. The PK/PD modelling is
described in detail by Strougo et al. (2007).
Discussion
This study was designed to investigate the acceptability and
usefulness of a novel mode of intrapulmonary THC adminis-
tration using a Volcano
®
vaporizer and pure THC instead of
cannabis. A recent study showed that the vapour contains 98%
THC and that about 54% (SD ±8%) of this was delivered to
the vapour collection balloon of the administration system by
the Volcano
®
vaporizer (Hazekamp, et al., 2006). Therefore, in
our study an estimated average cumulative dose of 11 mg of
THC was inhaled from the balloon. This is comparable with
the doses used in the literature because most studies report
effects of 12 marijuana cigarettes containing between
2.530 mg THC, of which roughly half is lost by heat. In this
study, the average plasma THC profiles indicate very limited
inter-individual variability, characterizing the Volcano
®
vapor-
izer as a suitable method for the administration of pure THC.
Unlike 11-OH-THC, 11-nor-9-carboxy-THC is a non-
psychotropic metabolite of THC (Grotenhermen, 2003).
Although 11-OH-THC is equipotent or twice as potent as THC
(Perez-Reyes, et al., 1972; Howlett, et al., 2004), the observed
plasma THC concentrations are roughly 25 times higher than
the observed plasma concentrations of 11-OH-THC. This indi-
cates that the observed effects are due to THC itself.
The effect of THC on different CNS and non-CNS tests was
investigated. Many of the THC-effects were dose-dependent
after administration of repeated doses of 2, 4, 6 and 8 mg.
High densities of CB1-receptors are found in the basal ganglia,
cerebellum amygdala and forebrain (Ashton, 2001; Mackie,
2005). This may explain why THC had clear dose-dependent
effects on postural stability and a number of subjective para-
meters after administration of rising doses of THC (2, 4, 6
and 8 mg). Body sway clearly increased with dose, which
agrees with previous reports of the marijuana effects (Liguori,
et al., 2003).
The sensitive subjective parameters included in particular
alertness of the VAS of Bond and Lader; the newly derived
external perception scale, which is a composite subscale of
VAS Bowdles for psychedelic effects, and the VAS-scale for
feeling high. Alertness is closely related to the ability to pay
attention, to concentrate on a specific issue, and attention defi-
cit is a well-known effect of cannabis. The Bond and Lader
VAS scales for contendness and calmness are rarely affected by
CNS-active drugs (Steveninck, et al., 1999; Visser, et al., 2002)
and they do not seem to be prominently affected by THC. The
changes in the external perception reflect a misperception of
an external stimulus or a change in the awareness of the sub-
jects surroundings. This is a well-know effect of THC and has
been observed after oral administration of 15 mg THC (Zei-
denberg, et al., 1973), making the composite scale of external
perception a useful tool for assessing the effects of THC. Lim-
ited changes were seen on internal perception, which reflects
inner feelings not corresponding with reality. Feelings of unre-
ality, hallucinations, paranoia and anxiety have been observed
after use of high doses of cannabis and in cannabis naive sub-
jects (Dittrich and Woggon, 1974; DSouza, et al., 2004). In
this study, subjects familiar with the effects of cannabis were
included and possibly the doses in our study were not high
enough to elicit such effects. Interestingly, all observed CNS
effects showed accumulation of the effects because the effect
of the previous dose had not faded before the next dose was
administered.
In the current study, limited decreases in EEG δ, θ and
β-activity were reported. One of the earliest signs of drowsiness
is the disappearance of the occipital dominant α-activity (Vis-
ser, et al., 2002). Although subjects reported being drowsy, no
changes in α-rhythm were seen in this study. In the literature,
the EEG results obtained after cannabis use are often contra-
dictory. Acute reactions to the drug have sometimes been com-
patible with a waking type activation of the EEG pattern, but
increased slow wave EEG characteristics of a resting or sleep
state have also been seen, and there seem to be no obvious
localizations of the EEG changes to any particular brain region
(Iversen, 2000).
The literature reports conflicting results on tracking tests,
which is probably because of differences in tasks (Roth, et al.,
1973). The critical tracker task used by Stoller et al. resembles
the tracker test used in this study. They reported a statistically
significant effect on the critical tracking test after the oral
administration of 22.5 mg THC (Stoller, et al., 1976). Because
the pulmonary administration of THC is on average approxi-
mately 2.63 times more potent than oral administration
(Isbell, et al., 1967), this result should resemble the cumulative
effect after the fourth dose in this study. However, we did not
observe significant changes.
The presence of CB1 receptors in the sphincter pupillae
muscle provides a possible site of action by cannabinoids on
pupil dilation or contraction (Straiker, et al., 1999). This
study showed a slight increase in pupil/iris ratio after the fourth
dose of 8 mg THC. Conflicting results have been published
after administration of THC, which do not seem to be clearly
related to differences in dosing (Weil, et al., 1968; Zeidenberg,
et al., 1973; Brown, et al., 1977).
CB1 receptors are sparsely found in the brainstem (Herken-
ham, et al., 1990; Mackie, 2005), which may explain why few
changes in smooth pursuit and saccadic eye movements were
8 Intrapulmonary THC administration in humans
seen. Smooth pursuit eye movements are primarily steered by
the paramedian pontine reticular formation and saccadic eye
movements by the superior colliculus (Leigh and Zee, 1991).
The lower brain stem areas also control cardiovascular func-
tion. Orthostatic hypotension has been reported in literature
(Hall and Solowij, 1998; Sidney, 2002). In this study, no
changes in blood pressure have been seen, which may be due
to the supine blood pressure measurements. In this respect, the
sharp dose-dependent increase in heart rate could be consid-
ered as a compensatory mechanism for a loss of vascular tone.
The increase in heart rate was clearly dose-dependent and
closely associated with THC plasma concentrations. Tachycar-
dia was significant with an average increase of 19 bpm after the
fourth dose, without any indications for blood pressure reduc-
tions. On the contrary, with different CNS parameters hardly
any accumulation was seen in heart rate after rising doses of
THC. These results correspond to data found in literature
(Zuardi, et al., 1982; Heishman, et al., 1997; Hall and Solowij,
1998; Sidney, 2002). The faster response in heart rate before the
onset of subjective effects has also been observed after oral
administration of 15 mg THC (Zeidenberg, et al., 1973). Liter-
ature also reported that THC plasma concentration already
dropped significantly before maximum psychotropic effects
were achieved (Ohlsson, et al., 1980; Chiang and Barnett,
1984). These observations make it likely that a peripheral
mechanism is involved in the increase in heart rate. This is sup-
ported by PK/PD modelling of the current study, which
showed a relatively short equilibration half-life for heart rate of
7.68 min (Strougo, et al., 2007). This is much shorter than the
equilibration half-lives found on CNS effects, which varied
from 39.2 to 84.8 min. In addition, CB1 receptors are present
in human atrial muscle (Bonz, et al., 2003) but they are sparse
in the lower brainstem areas controlling cardiovascular func-
tion (Herkenham, et al., 1990). In combination, these results
suggest that the increase in heart rate seen after THC adminis-
tration is not mediated by brain stem centres, but is established
by a direct effect of THC on the heart.
Lipophilic compounds such as THC that cross the blood
brain barrier tend to accumulate in the brain, which explains
the prolongation of the CNS effects, in contrast to the much
faster response of heart rate. The equilibration half-lives that
quantify hysteresis varied from 39.2 to 84.8 min for the effects
on the CNS. This range may reflect various mechanisms of
action, in which receptor density and receptor distribution
between different brain regions, activation of secondary neuro-
transmitters systems or perhaps yet unidentified CB-receptors
may play a role.
Only limited and transient side effects were seen. We, there-
fore, consider administration of rising doses up to 6 or 8 mg
pure THC using the Volcano
®
vaporizer, a safe method of
THC administration. Two of 12 subjects experienced side
effects severe enough to decide not to administer the last dose
of 8 mg THC. Therefore, a study design with rising doses up to
6 mg is preferable, as it seems to allow CNS testing on all
doses, at least for all subjects with previous experience with
THC.
In conclusion, this study showed a range of pharmacody-
namic effects of THC, using a novel mode of intrapulmonary
THC administration. Some of these effects were clearly dose-
and concentration-related, and started with the lowest dose of
2 mg. These dose-related effects include impairments of subjec-
tive alertness and postural stability, feeling high and psyche-
delic effects and an increase in heart rate. The most sensitive
effects seem to correspond to brain regions that have the high-
est densities of cannabinoid receptor localization. These results
can be useful in the development of therapeutically beneficial
cannabinoid agonists and antagonists, and in studies of the
pharmacology and physiology of cannabinoid systems in
humans.
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10 Intrapulmonary THC administration in humans
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... The medical vaporizer was kindly donated by Storz & Bickel GmbH & Co. Volcano Medic vaporizers have been approved for scientific research and medical use of cannabis and have been used in several scientific studies. [29][30][31][32][33] The CSC staff used the Volcano aluminum capsules with a liquid pad to prepare and classify the extracts. Capsules were stored in plastic bags in a −20°C freezer. ...
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Background: Although δ-9-tetrahydrocannabinol (THC), the main cannabinoid from the cannabis plant, is responsible for the psychotomimetic effects of cannabis, cannabidiol (CBD), the second most abundant cannabinoid in the cannabis plant, does not show any psychotomimetic effect. Cannabidiol has even been proposed to be antipsychotic and to counteract some of the psychotomimetic effects of THC. The aim of this study was to test the potential antipsychotomimetic effects of CBD. Method: Eighteen members from a cannabis social club were tested for subjective and psychotomimetic effects under the effects of different full-spectrum cannabis extracts containing either THC, CBD, THC + CBD, or placebo in a naturalistic, randomized, double-blind, crossover, placebo-controlled study. Results: Results showed that participants under the effects of THC + CBD showed lower psychotomimetic scores in subjective scales when compared with THC alone. Subjective scores were lower under the effects of CBD and placebo when compared with THC + CBD. Cannabidiol and placebo did not show any psychotomimetic effect. Conclusions: This study provides evidence for both the psychotomimetic effects of THC and the antipsychotomimetic effects of CBD when it is coadministered with THC in real-world situations, which can be very relevant for the clinical practice of medical cannabis. Ultimately, this study substantiates the link between the endocannabinoid system and psychotic-like symptoms and has important implications for the understanding of schizophrenia and the therapeutic potential of CBD as an antipsychotic. Lastly, we demonstrate how reliable methodologies can be implemented in real situations to collect valid ecological evidence outside classic laboratory settings.
... In particular, acute cannabis exposure may increase intrusion errors and the likelihood of forming false memories of events that never occurred [24][25][26][27] . The psychotomimetic effects that can develop during acute cannabis exposure [28][29][30][31][32][33][34] include perceptual distortions, cognitive disorganization and mania 35 . In the majority of cannabis users these symptoms are mild 36 , but in a small subset of users these can develop into a full-blown cannabis-induced psychosis characterized by depersonalization, paranoid feelings, derealization 37 and hallucinations 38 . ...
Article
Acute cannabis intoxication may induce neurocognitive impairment and is a possible cause of human error, injury and psychological distress. One of the major concerns raised about increasing cannabis legalization and the therapeutic use of cannabis is that it will increase cannabis‐related harm. However, the impairing effect of cannabis during intoxication varies among individuals and may not occur in all users. There is evidence that the neurocognitive response to acute cannabis exposure is driven by changes in the activity of the mesocorticolimbic and salience networks, can be exacerbated or mitigated by biological and pharmacological factors, varies with product formulations and frequency of use and can differ between recreational and therapeutic use. It is argued that these determinants of the cannabis-induced neurocognitive state should be taken into account when defining and evaluating levels of cannabis impairment in the legal arena, when prescribing cannabis in therapeutic settings and when informing society about the safe and responsible use of cannabis. Acute cannabis exposure modulates numerous aspects of neurocognitive function; however, the effects experienced by individuals are highly variable. Ramaekers and colleagues here review the neural basis of cannabis-induced neurocognitive changes and response variability, and consider the legal, therapeutic and societal implications.
... In healthy individuals, SPEM appears less sensitive to chronic cannabis use than AS. Cannabis or delta-9-tetrahydrocannabinol (THC) has been shown to decrease performance in smooth pursuit acutely in some 33,34 but not all studies [35][36][37] ; however, these effects do not persist beyond acute intoxication 33 . Substance misuse is not associated with deterioration in smooth pursuit performance as seen in patients with schizophrenia 38 . ...
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It is unclear whether early psychosis in the context of cannabis use is different from psychosis without cannabis. We investigated this issue by examining whether abnormalities in oculomotor control differ between patients with psychosis with and without a history of cannabis use. We studied four groups: patients in the early phase of psychosis with a history of cannabis use (EPC; n = 28); patients in the early phase of psychosis without (EPNC; n = 25); controls with a history of cannabis use (HCC; n = 16); and controls without (HCNC; n = 22). We studied smooth pursuit eye movements using a stimulus with sinusoidal waveform at three target frequencies (0.2, 0.4 and 0.6 Hz). Participants also performed 40 antisaccade trials. There were no differences between the EPC and EPNC groups in diagnosis, symptom severity or level of functioning. We found evidence for a cannabis effect ( χ ² = 23.14, p < 0.001), patient effect ( χ ² = 4.84, p = 0.028) and patient × cannabis effect ( χ ² = 4.20, p = 0.04) for smooth pursuit velocity gain. There was a large difference between EPC and EPNC ( g = 0.76–0.86) with impairment in the non cannabis using group. We found no significant effect for antisaccade error whereas patients had fewer valid trials compared to controls. These data indicate that impairment of smooth pursuit in psychosis is more severe in patients without a history of cannabis use. This is consistent with the notion that the severity of neurobiological alterations in psychosis is lower in patients whose illness developed in the context of cannabis use.
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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.
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The use of cannabis preparations has steadily increased. Although cannabis was traditionally assumed to only have mild vegetative side effects, it has become evident in recent years that severe cardiovascular complications can occur. Cannabis use has recently even been added to the risk factors for myocardial infarction. This review is dedicated to pathogenetic factors contributing to cannabis-related myocardial infarction. Tachycardia is highly important in this respect, and we provide evidence that activation of CB1 receptors in brain regions important for cardiovascular regulation and of presynaptic CB1 receptors on sympathetic and/or parasympathetic nerve fibers are involved. The prototypical factors for myocardial infarction, i.e., thrombus formation and coronary constriction, have also been considered, but there is little evidence that they play a decisive role. On the other hand, an increase in the formation of carboxyhemoglobin, impaired mitochondrial respiration, cardiotoxic reactions and tachyarrhythmias associated with the increased sympathetic tone are factors possibly intensifying myocardial infarction. A particularly important factor is that cannabis use is frequently accompanied by tobacco smoking. In conclusion, additional research is warranted to decipher the mechanisms involved, since cannabis use is being legalized increasingly and Δ9-tetrahydrocannabinol and its synthetic analogue nabilone are indicated for the treatment of various disease states.
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Recent advances in cannabidiol (CBD) use in canines and felines for anxiety management, pain management, and anti-inflammatory effects were reviewed using a literature search conducted with the following keywords: CBD, anxiety, inflammation, pain, dogs, cats, and companion animals. For decades, research on CBD has been hindered due to the status of cannabis (C. sativa L.) as an illicit drug. Limited safety data show that CBD is well-tolerated in dogs, with insufficient information on the safety profile of CBD in cats. Upon oral supplementation of CBD, elevation in liver enzymes was observed for both dogs and cats, and pharmacokinetics of CBD are different in the two species. There is a significant gap in the literature on the therapeutic use of CBD in cats, with no feline data on anxiety, pain, and inflammation management. There is evidence that chronic osteoarthritic pain in dogs can be reduced by supplementation with CBD. Furthermore, experiments are required to better understand whether CBD has an influence on noise-induced fear and anxiolytic response. Preliminary evidence exists to support the analgesic properties of CBD in treating chronic canine osteoarthritis; however, there are inter- and intra-species differences in pharmacokinetics, tolerance, dosage, and safety of CBD. Therefore, to validate the anxiety management, pain management, and anti-inflammatory efficacy of CBD, it is essential to conduct systematic, randomized, and controlled trials. Further, the safety and efficacious dose of CBD in companion animals warrants investigation.
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Cannabis use is widespread among adolescents and has been associated with long-term negative outcomes on neurocognitive functions. However, the factors that contribute to the long-term detrimental effects of cannabis use remain poorly understood. Here, we studied how Reelin deficiency influences the behavior of mice exposed to cannabis during adolescence. Reelin is a gene implicated in the development of the brain and of psychiatric disorders. To this aim, heterozygous Reeler (HR) mice, that express reduced level of Reelin, were chronically injected during adolescence with high doses (10mg/kg) of Δ9-tetrahydrocannabinol (THC), a major psychoactive component of cannabis. Two weeks after the last injection of THC, mice were tested with multiple behavioral assays, including working memory, social interaction, locomotor activity, anxiety-like responses, stress reactivity, and pre-pulse inhibition. Compared to wild-type (WT), HR mice treated with THC showed impaired social behaviors, elevated disinhibitory phenotypes and increased reactivity to aversive situations, in a sex-specific manner. Overall, these findings show that Reelin deficiency influences behavioral abnormalities caused by heavy consumption of THC during adolescence and suggest that elucidating Reelin signaling will improve our understanding of neurobiological mechanisms underlying behavioral traits relevant to the development of psychiatric conditions.
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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.
Article
The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by ?9-TCH in normal volunteers, and whether this effect occurs by a general block of the action of ?9-TCH or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg ?9-TCH, 1 mg/kg CBD, a mixture containing 0.5 mg/kg ?9-TCH and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by ?9-TCH, however this effect also extended to marihuanalike effects and to other subjective alterations induced by ?9-TCH. This antagonism does not appear to be caused by a general block of ?9-TCH effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of ?9-TCH.
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A dose-response study of the effect of orally administered Δ9-tetrahydrocannabinol (THC) on human mood and skills performance was conducted. Using five dose levels of THC (0, 5, 10, 15, 20 mg) with 16 volunteers per dosage group, mood and performance measures were recorded at five testing occasions, one before and four after drug administration. The slope of the linear regression of performance on the test battery was significant for up to 200 minutes after dosage. That is to say, oral THC, at the doses used, produced significant dose-dependent impairment of performance for a period in excess of three hours. A similar time course for the effect of THC on the subjective assessment of intoxication (‘stone’) suggested a correlation between drug-induced impairment skills and the effects on mood.
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A microsuspension of Δ9-tetrahydrocannabinol and of its metabolic derivative 11-OH-Δ9-tetrahydrocannabinol has been prepared with 25 percent human serum albumin as the vehicle. Intravenous infusion of this preparation to humans indicates that both tetrahydrocannabinols are equally potent in producing the typical marihuana-like pschological and physiological effects.